tag:blogger.com,1999:blog-3027702206083738342024-03-18T01:08:38.857-07:00Medicinal Chemistry InternationalMEDICINAL CHEMISTRY AT ITS BEST, Tracks information on drugs on worldwide basis by Dr Anthony Melvin Crasto, worlddrugtracker, helping millions with websites, 6 million hits on google, one lakh connections worldwide, email amcrasto@gmail.com, call +91 9323115463 IndiaDRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.comBlogger168125tag:blogger.com,1999:blog-302770220608373834.post-80244511698298879482020-10-23T19:23:00.002-07:002020-10-23T19:23:23.049-07:00MILVEXIAN<p> </p><figure class="wp-block-image" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin-bottom: 1em;"><img alt="2D chemical structure of 1802425-99-5" scale="0" src="https://chem.nlm.nih.gov/chemidplus/structure/1802425-99-5" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></figure><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">MILVEXIAN</p><p><br /></p><p><a href="https://newdrugapprovals.org/2020/10/24/milvexian/">https://newdrugapprovals.org/2020/10/24/milvexian/</a></p><p><br /></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com17tag:blogger.com,1999:blog-302770220608373834.post-15888497965480094412020-10-11T19:20:00.001-07:002020-10-11T19:22:21.333-07:00Cetuximab sarotalocan sodium<p> <span face=""Open Sans", Tahoma, Verdana, Segoe, sans-serif" style="color: #222222; font-size: 16px;">Cetuximab Sarotalocan Sodium (Genetical Recombination)</span></p><p style="color: #222222; font-family: "Open Sans", Tahoma, Verdana, Segoe, sans-serif; font-size: 16px; padding: 0px 0px 1em;"><br /><a data-mce-href="https://jpdb.nihs.go.jp/jan/chemdraw5_eng/Cetuximab_Sarotalocan_Sodium_(Genetical_Recombination).cdx" href="https://jpdb.nihs.go.jp/jan/chemdraw5_eng/Cetuximab_Sarotalocan_Sodium_(Genetical_Recombination).cdx" style="color: #222222;"><img data-mce-src="https://jpdb.nihs.go.jp/jan/gif_eng/Cetuximab_Sarotalocan_Sodium_(Genetical_Recombination).png" src="https://jpdb.nihs.go.jp/jan/gif_eng/Cetuximab_Sarotalocan_Sodium_(Genetical_Recombination).png" style="height: auto; margin-bottom: 10px; margin-top: 8px; max-width: 100%;" /></a><br /><br /><span class="chemicalname">Cetuximab Sarotalocan Sodium is an antibody-drug-conjugate (molecular weight: 156,000-158,000) consisting of tetrasodium salt of Sarotalocan (6-({[3-({(<i>OC</i>-6-13)-bis({3-[bis(3-sulfopropyl)(3-sulfonatopropyl)azaniumyl]propyl}dimethylsilanolato-κ<i>O</i>,κ<i>O</i>')[(phtalocyaninato(2-)κ<i>N</i><span style="bottom: 1ex; font-size: 12px; height: 0px; line-height: 0; position: relative; vertical-align: baseline;">29</span>,κ<i>N</i><span style="bottom: 1ex; font-size: 12px; height: 0px; line-height: 0; position: relative; vertical-align: baseline;">30</span>,κ<i>N</i><span style="bottom: 1ex; font-size: 12px; height: 0px; line-height: 0; position: relative; vertical-align: baseline;">31</span>,κ<i>N</i><span style="bottom: 1ex; font-size: 12px; height: 0px; line-height: 0; position: relative; vertical-align: baseline;">32</span>)-1-yl]silicon}oxy)propoxy]carbonyl}amino)hexanoyl (C<span style="font-size: 12px; height: 0px; line-height: 0; position: relative; top: 0.5ex; vertical-align: baseline;">70</span>H<span style="font-size: 12px; height: 0px; line-height: 0; position: relative; top: 0.5ex; vertical-align: baseline;">96</span>N<span style="font-size: 12px; height: 0px; line-height: 0; position: relative; top: 0.5ex; vertical-align: baseline;">11</span>O<span style="font-size: 12px; height: 0px; line-height: 0; position: relative; top: 0.5ex; vertical-align: baseline;">24</span>S<span style="font-size: 12px; height: 0px; line-height: 0; position: relative; top: 0.5ex; vertical-align: baseline;">6</span>Si<span style="font-size: 12px; height: 0px; line-height: 0; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>; molecular weight: 1,752.22)) attached to an average of 2-3 Lys residues of Cetuximab.</span><br /><br />[2166339-33-7 , Cetuximab sarotalocan]</p><p style="color: #222222; font-family: "Open Sans", Tahoma, Verdana, Segoe, sans-serif; font-size: 16px; padding: 0px 0px 1em;"><a href="https://newdrugapprovals.org/2020/10/12/cetuximab-sarotalocan-sodium/">https://newdrugapprovals.org/2020/10/12/cetuximab-sarotalocan-sodium/</a></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-302770220608373834.post-23837717137590734362020-09-25T19:26:00.006-07:002020-09-25T19:26:55.186-07:00Bulevirtide acetate<p> <img height="269" src="http://drugapprovalsint.com/wp-content/uploads/2020/09/str1-2.jpg" width="587" /></p><p>Bulevirtide acetate</p><p>SEE</p><p><a href="https://newdrugapprovals.org/2020/09/26/bulevirtide-acetate/">https://newdrugapprovals.org/2020/09/26/bulevirtide-acetate/</a></p><p><br /></p><p>////////////<a href="https://newdrugapprovals.org/tag/2020-approvals/" rel="tag" style="background-color: white; color: #f99734; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 10px; outline-offset: -2px; outline: 0px; text-transform: uppercase;">2020 APPROVALS</a><span style="background-color: white; color: #999999; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 10px; text-transform: uppercase;">, </span><a href="https://newdrugapprovals.org/tag/%e3%83%96%e3%83%ac%e3%83%93%e3%83%ab%e3%83%81%e3%83%89%e9%85%a2%e9%85%b8%e5%a1%a9/" rel="tag" style="background-color: white; color: #f99734; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 10px; text-decoration-line: none; text-transform: uppercase;">ブレビルチド酢酸塩</a><span style="background-color: white; color: #999999; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 10px; text-transform: uppercase;">, </span><a href="https://newdrugapprovals.org/tag/bulevirtide-acetate/" rel="tag" style="background-color: white; color: #f99734; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 10px; text-decoration-line: none; 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font-family: "Open Sans", Tahoma, Verdana, Segoe, sans-serif; font-size: 16px; padding: 0px 0px 1em;">KDDLLCGAAT AGNMLHWWFD QNKDQIKRYL EEHPEKQKIN FNGEQMFDVK EAIDTKNHQL<br />DSKLFEYFKE KAFPYLSTKH LGVFPDHVID MFINGYRLSL TNHGPTPVKE GSKDPRGGIF<br />DAVFTRGDQS KLLTSRHDFK EKNLKEISDL IKKELTEGKA LGLSHTYANV RINHVINLWG<br />ADFDSNGNLK AIYVTDSDSN ASIGMKKYFV GVNSAGKVAI SAKEIKEDNI GAQVLGLFTL<br />STGQDSWNQT N</p><p style="color: #222222; font-family: "Open Sans", Tahoma, Verdana, Segoe, sans-serif; font-size: 16px; padding: 0px 0px 1em;">Imlifidase</p><p style="color: #222222; font-family: "Open Sans", Tahoma, Verdana, Segoe, sans-serif; font-size: 16px; padding: 0px 0px 1em;">イムリフィダーゼ;</p><p>READ AT</p><p><a href="https://newdrugapprovals.org/2020/09/22/imlifidase/">https://newdrugapprovals.org/2020/09/22/imlifidase/</a></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com3tag:blogger.com,1999:blog-302770220608373834.post-29746257411920369672020-09-17T19:24:00.005-07:002020-09-21T19:28:24.347-07:00Clascoterone<p> </p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;"><img alt="Cortexolone 17α-propionate.svg" scale="0" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/e9/Cortexolone_17%CE%B1-propionate.svg/250px-Cortexolone_17%CE%B1-propionate.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">Clascoterone</p><p><a href="https://newdrugapprovals.org/2020/09/18/clascoterone/">https://newdrugapprovals.org/2020/09/18/clascoterone/</a></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com19tag:blogger.com,1999:blog-302770220608373834.post-48481125956316061862020-09-12T20:37:00.003-07:002020-09-12T20:37:59.884-07:00Copper Cu 64 dotatate, 銅(Cu64)ドータテート;<p> <img alt="Copper dotatate Cu-64.png" scale="0" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=124220636&t=l" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; height: auto; max-width: 100%; vertical-align: middle;" /></p><p data-adtags-visited="true" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;"><img alt="2D chemical structure of 1426155-87-4" scale="0" src="https://chem.nlm.nih.gov/chemidplus/structure/1426155-87-4" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></p><p data-adtags-visited="true" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;"><img alt="Figure imgf000004_0001" scale="0" src="https://patentimages.storage.googleapis.com/3a/15/c5/300f352058af3b/imgf000004_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></p><p class="inline-ad-slot" data-adtags-visited="true" data-adtags-width="500" id="inline-ad-0" style="background-color: white; color: #333333; float: left; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; height: 0px; margin: 0px auto; overflow: hidden; width: 500px;"></p><p data-adtags-visited="true" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">Copper Cu 64 dotatate</p><p data-adtags-visited="true" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">銅(Cu64)ドータテート;</p><p>READ AT</p><p><span style="font-family: "Calibri","sans-serif"; font-size: 11.0pt; line-height: 115%; mso-ansi-language: EN-US; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: "Times New Roman"; mso-bidi-language: AR-SA; mso-bidi-theme-font: minor-bidi; mso-fareast-font-family: Calibri; mso-fareast-language: EN-US; mso-fareast-theme-font: minor-latin; mso-hansi-theme-font: minor-latin;"><a href="http://medcheminternational.blogspot.com/">http://medcheminternational.blogspot.com/</a></span></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com7tag:blogger.com,1999:blog-302770220608373834.post-71751585338536750812019-01-30T06:43:00.001-08:002019-01-30T06:43:26.648-08:00Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Graphical abstract: Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones" data-mce-src="https://pubs.rsc.org/en/Image/Get?imageInfo.ImageType=GA&imageInfo.ImageIdentifier.ManuscriptID=C8GC03570A" src="https://pubs.rsc.org/en/Image/Get?imageInfo.ImageType=GA&imageInfo.ImageIdentifier.ManuscriptID=C8GC03570A" style="height: auto; max-width: 100%;" title="Graphical abstract" /></div>
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Abstract</h3>
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An environmentally benign decarboxylative cyclization in water has been developed to synthesize 4-quinolones from readily available isatoic anhydrides and 1,3-dicarbonyl compounds. Isatins are also compatible for the reaction to generate 4-quinolones in the presence of TBHP in DMSO. This protocol provides excellent yields under mild conditions for a broad scope of 4-quinolones, and has good functional group tolerance. Only un-harmful carbon dioxide and water are released in this procedure. Moreover, the newly synthesized products have also been selected for anti-malarial examination against the chloroquine drug-sensitive <em>Plasmodium falciparum</em> 3D7 strain. <strong>3u</strong> is found to display excellent anti-malarial activity with an IC<small><sub>50</sub></small> value of 33 nM.<br />
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Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones</h2>
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<span class="article__author-link"><a data-mce-href="https://pubs.rsc.org/en/results?searchtext=Author%3AYue%20Ma" href="https://pubs.rsc.org/en/results?searchtext=Author%3AYue%20Ma">Yue Ma</a>,<sup>a</sup> </span><span class="article__author-link"><a data-mce-href="https://pubs.rsc.org/en/results?searchtext=Author%3AYongping%20Zhu" href="https://pubs.rsc.org/en/results?searchtext=Author%3AYongping%20Zhu">Yongping Zhu</a>,<sup>a</sup> </span><span class="article__author-link"><a data-mce-href="https://pubs.rsc.org/en/results?searchtext=Author%3ADong%20Zhang" href="https://pubs.rsc.org/en/results?searchtext=Author%3ADong%20Zhang">Dong Zhang</a>,<sup>a</sup> </span><span class="article__author-link"><a data-mce-href="https://pubs.rsc.org/en/results?searchtext=Author%3AYuqing%20Meng" href="https://pubs.rsc.org/en/results?searchtext=Author%3AYuqing%20Meng">Yuqing Meng</a>,<sup>a</sup> </span><span class="article__author-link"><a data-mce-href="https://pubs.rsc.org/en/results?searchtext=Author%3ATian%20Tang" href="https://pubs.rsc.org/en/results?searchtext=Author%3ATian%20Tang">Tian Tang</a>,<sup>a</sup> </span><span class="article__author-link"><a data-mce-href="https://pubs.rsc.org/en/results?searchtext=Author%3AKun%20Wang" href="https://pubs.rsc.org/en/results?searchtext=Author%3AKun%20Wang">Kun Wang</a>,<sup>a</sup> </span><span class="article__author-link"><a data-mce-href="https://pubs.rsc.org/en/results?searchtext=Author%3AJi%20Ma" href="https://pubs.rsc.org/en/results?searchtext=Author%3AJi%20Ma">Ji Ma</a>,<sup>a</sup> </span><span class="article__author-link"><a data-mce-href="https://pubs.rsc.org/en/results?searchtext=Author%3AJigang%20Wang" href="https://pubs.rsc.org/en/results?searchtext=Author%3AJigang%20Wang">Jigang Wang</a><sup>a</sup> and </span><span class="article__author-link"><a data-mce-href="https://pubs.rsc.org/en/results?searchtext=Author%3APeng%20Sun" href="https://pubs.rsc.org/en/results?searchtext=Author%3APeng%20Sun">Peng Sun</a>*<sup>a</sup> </span></div>
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*Corresponding authors</div>
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<sup>a</sup>Artermisinin Research Center and Institute of Chinese Meteria Medica, Academy of Chinese Medical Sciences, Beijing, P. R. China<br /><b>E-mail:</b><a data-mce-href="mailto:psun@icmm.ac.cn" href="mailto:psun@icmm.ac.cn" title="psun@icmm.ac.cn">psun@icmm.ac.cn</a></div>
<a data-mce-href="https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C8GC03570A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract" href="https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C8GC03570A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract">https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C8GC03570A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract</a><br />
ethyl 2-(4-(benzyloxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (3u) White solid, m.p. 288-289 oC;<br />
1H NMR (600 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.72 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.52 (td, J = 8.5, 1.7 Hz, 1H), 7.43 – 7.35 (m, 4H), 7.29 – 7.21 (m, 4H), 7.10 (td, J = 7.5, 0.5 Hz, 1H), 5.17 (s, 2H), 3.91 (q, J = 7.1 Hz, 2H), 2.00 (s, 1H), 0.83 (t, J = 7.1 Hz, 3H) ppm;<br />
13C NMR (150 MHz, DMSO-d6) δ 174.1, 166.2, 156.2, 148.0, 139.8, 137.2, 132.8, 132.0, 130.5, 129.4, 128.7, 128.2, 127.6, 125.5, 125.2, 124.3, 123.6, 120.9, 118.9, 116.4, 115.8, 113.5, 70.2, 60.2, 14.0 ppm;<br />
HRMS (ESI) calcd for [C25H21NO4+H]+ 400.1471, found 400.1463.<br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2019/01/STR1-1.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2019/01/STR1-1.jpg" rel="attachment wp-att-10998"><img alt="STR1" class="alignnone size-full wp-image-10998" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2019/01/STR1-1.jpg" height="426" src="http://www.allfordrugs.com/wp-content/uploads/2019/01/STR1-1.jpg" style="height: auto; max-width: 100%;" width="637" /></a> <a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2019/01/STR2.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2019/01/STR2.jpg" rel="attachment wp-att-10999"><img alt="STR2" class="alignnone size-full wp-image-10999" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2019/01/STR2.jpg" height="436" src="http://www.allfordrugs.com/wp-content/uploads/2019/01/STR2.jpg" style="height: auto; max-width: 100%;" width="665" /></a></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com140tag:blogger.com,1999:blog-302770220608373834.post-89415448083384521712016-06-21T20:41:00.003-07:002016-06-21T20:41:34.178-07:00Roxadustat, ASP 1517, FG 4592<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="" data-mce-src="http://upload.wikimedia.org/wikipedia/commons/thumb/d/dc/Roxadustat.svg/512px-Roxadustat.svg.png" src="http://upload.wikimedia.org/wikipedia/commons/thumb/d/dc/Roxadustat.svg/512px-Roxadustat.svg.png" style="height: auto; max-width: 100%;" /></div>
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ROXADUSTAT</div>
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ASP1517; ASP 1517; ASP-1517; FG-4592; FG 4592; FG4592; Roxadustat.</div>
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CAS 808118-40-3<br />Chemical Formula: C19H16N2O5<br />Exact Mass: 352.10592</div>
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<a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Fibrogen,+Inc.%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Fibrogen,+Inc.%22">Fibrogen, Inc.</a></div>
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THERAPEUTIC CLAIM, Treatment of anemia</div>
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<a data-mce-href="https://www.google.co.in/url?sa=t&rct=j&q=&esrc=s&source=web&cd=9&cad=rja&ved=0CHEQFjAI&url=http%3A%2F%2Fwww.ama-assn.org%2Fresources%2Fdoc%2Fusan%2Froxadustat.pdf&ei=v-S_UotBycCsB5jpgIAI&usg=AFQjCNHf83xKn0k1-4unBotjmcECRAJPSg&sig2=mGqu1Jb9KQN3eHJxjUUuPw&bvm=bv.58187178,d.bmk" href="https://www.google.co.in/url?sa=t&rct=j&q=&esrc=s&source=web&cd=9&cad=rja&ved=0CHEQFjAI&url=http%3A%2F%2Fwww.ama-assn.org%2Fresources%2Fdoc%2Fusan%2Froxadustat.pdf&ei=v-S_UotBycCsB5jpgIAI&usg=AFQjCNHf83xKn0k1-4unBotjmcECRAJPSg&sig2=mGqu1Jb9KQN3eHJxjUUuPw&bvm=bv.58187178,d.bmk">Roxadustat nonproprietary drug name</a></h3>
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CHEMICAL NAMES</div>
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(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycine</div>
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1. Glycine, N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl)carbonyl]-</div>
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2. N-[(4-hydroxy-1-methyl-7-phenoxyisoquinolin-3-yl)carbonyl]glycine</div>
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MF C19H16N2O5<br />MW 352.3<br />SPONSOR FibroGen<br />CODE FG-4592; ASP1517<br />CAS 808118-40-3<br />WHO NUMBER 9717</div>
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Roxadustat, also known as ASP1517 and FG-4592, is an HIF α prolyl hydroxylase inhibitor in a cell-free assay. It stabilizes HIF-2 and induces EPO production and stimulates erythropoiesis. Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin</div>
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FG-4592 (also known as ASP1517), 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid,</div>
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is a potent small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH),<br />an enzyme up-regulating the expression of endogenous human erythropoietin (Epo).<br />It is currently being investigated as an oral treatment for anemia associated with chronic kidney disease (CKD).</div>
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Unlike other anemia treating agents, erythropoiesis-stimulating agents (ESAs),</div>
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FG-4592 inhibits HIF, through a distinctive mechanism, by stabilization of HIF. According to previous studies,</div>
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FG-4592 is capable of correcting and maintaining hemoglobin levels in CKD patients not<br />receiving dialysis and in patients of end-stage renal disease</div>
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who receives dialysis but do not need intravenous iron supplement.</div>
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<i>Reference</i></div>
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<i>1. Luis Borges. Different modalities of erythropoiesis stimulating agents.</i><br /><i> Port J Nephrol Hypert 2010; 24(2): 137-145</i><br /><i>2. “FibroGen and Astellas announce initiation of phase 3 trial of FG-4592/ASP1517 for treatment </i></div>
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<i>of anemia of chronic kidney disease” Fibrogen Press Release. Dec 11 2012</i><br /><i>3. “FibroGen announces initiation of phase 2b studies of FG-4592, </i></div>
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<i>an oral HIF prolyl hydroxylase inhibitor, for treatment of anemia”</i></div>
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<li class="data-list__property" id="at-a-glance_origniator"><strong class="data-list__property-key">Originator </strong><span class="data-list__property-value">FibroGen</span></li>
<li class="data-list__property" id="at-a-glance_developer"><strong class="data-list__property-key">Developer </strong><span class="data-list__property-value">Astellas Pharma; AstraZeneca; FibroGen</span></li>
<li class="data-list__property" id="at-a-glance_class"><strong class="data-list__property-key">Class </strong><span class="data-list__property-value">Amides; Antianaemics; Carboxylic acids; Isoquinolines; Small molecules</span></li>
<li class="data-list__property" id="at-a-glance_mechanismOfAction"><strong class="data-list__property-key">Mechanism of Action </strong><span class="data-list__property-value">Basic helix loop helix transcription factor modulators; Hypoxia-inducible factor-proline dioxygenase inhibitors</span></li>
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<li class="data-list__property"><strong class="data-list__property-key">Phase III </strong><span class="data-list__property-value">Anaemia</span></li>
<li class="data-list__property"><strong class="data-list__property-key">Discontinued </strong><span class="data-list__property-value">Sickle cell anaemia</span></li>
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Most Recent Events</h3>
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<li class="data-list__property"><strong class="data-list__property-key">09 Jun 2016</strong> <span class="data-list__property-value property-value--event-details">Phase-III clinical trials in Anaemia in Japan (PO)</span></li>
<li class="data-list__property"><strong class="data-list__property-key">20 May 2016</strong> <span class="data-list__property-value property-value--event-details">In collaboration with FibroGen, Astellas Pharma plans a phase III trial for Anaemia (In chronic kidney disease patients undergoing peritoneal dialysis) in Japan (PO) (NCT02780726)</span></li>
<li class="data-list__property"><strong class="data-list__property-key">19 May 2016</strong> <span class="data-list__property-value property-value--event-details">In collaboration with FibroGen, Astellas Pharma plans a phase III trial for Anaemia (In erythropoiesis stimulating agent-naive, chronic kidney disease patients undergoing haemodialysis) in Japan (PO) (NCT02780141)</span></li>
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Roxadustat (FG-4592) is a novel new-generation oral hypoxia-induciblefactor (HIF) prolyl hydroxylase inhibitor (PHI) for the treatment of ane-mia in patients with chronic kidney disease (CKD). HIF is a cytosolic tran-scription factor that induces the natural physiological response to lowoxygen conditions, by stimulating erythropoiesis and other protectivepathways. Roxadustat has been shown to stabilize HIF and induce ery-thropoiesis. Consequently, it corrects anemia and maintains hemoglo-bin levels without the need for intravenous iron supplementation in CKDpatients not yet receiving dialysis and in end-stage renal disease pa-tients receiving dialysis. There are many concerns about the use of ery-thropoiesis-stimulating agents (ESA) to treat anemia as they causesupra-physiologic circulating erythropoietin (EPO) levels and are asso-ciated with adverse cardiovascular effects and mortality. Available clin-ical data show that modest and transient increases of endogenous EPOinduced by HIF-PHI (10- to 40-fold lower than ESA levels) are sufficientto mediate erythropoiesis in CKD patients. Evidence suggests that rox-adustat is well tolerated and, to date, no increased risk of cardiovascu-lar events has been found. This suggests that roxadustat provides adistinct pharmacological and clinical profile that may provide a saferand more convenient treatment of CKD anemia</div>
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FG-4592 is a new-generation hypoxia-inducible factor prolyl hydroxylase inhibitor in early clinical trials at FibroGen for the oral treatment of iron deficiency anemia and renal failure anemia. Preclinical studies are ongoing for the treatment of sickle cell anemia.</div>
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The investigational therapy is designed to restore balance to the body's natural process of erythropoiesis through mechanisms including: natural EPO production, suppression of the effects of inflammation, downregulation of the iron sequestration hormone hepcidin, and an upregulation of other iron genes, ensuring efficient mobilization and utilization of the body's own iron stores. In April 2006, FG-4592 was licensed to Astellas Pharma by originator FibroGen in Asia, Europe and South Africa for the treatment of anemia. FibroGen retains rights in the rest of the world. In 2007, the FDA put the trial on clinical hold due to one case of death by fulminant hepatitis during a phase II clinical trial for patients with anemia associated with chronic kidney disease and not requiring dialysis. However, in 2008, the FDA informed the company that clinical trials could be resumed. Phase II/III clinical trials for this indication resumed in 2012. In 2013, the compound was licensed to AstraZeneca by FibroGen for development and marketing in US, CN and all major markets excluding JP, Europe, the Commonwealth of Independent States, the Middle East and South Africa, for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD).<br />PATENTS<br />WO 2004108681<br />WO 2008042800<br />WO 2009058403<br />WO 2009075822<br />WO 2009075824<br />WO 2012037212<br />WO 2013013609<br />WO 2013070908</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-29.png" href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-29.png" rel="attachment wp-att-7060"><img alt="STR1" class="alignnone size-full wp-image-7060" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-29.png" height="510" src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-29.png" style="height: auto; max-width: 100%;" width="640" /></a></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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CN 104892509</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">MACHINE TRANSLATED</span></div>
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<span class="notranslate">Connaught orlistat (Roxadustat) by the US company Phibro root (FibroGen) R & D, Astellas AstraZeneca and licensed by a hypoxia-inducible factor (HIF) prolyl hydroxylase small molecule inhibitors, codenamed FG-4592.</span><span class="notranslate">As a first new oral drug, FG-4592 is currently in Phase III clinical testing stage, for the treatment of chronic kidney disease and end-stage renal disease related anemia.</span> <span class="notranslate">Because the drug does not have a standard Chinese translation, so the applicant where it is transliterated as "Connaught Secretary him."</span></div>
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<span class="notranslate">Connaught orlistat (Roxadustat, I) the chemical name: N_ [(4- hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl) carbonyl] glycine, its structural formula is:</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00031.png" href="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00031.png"><img alt="Figure CN104892509AD00031" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00031.png" id="idf0002" src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00031.png" style="height: auto; max-width: 100%;" /></a></div>
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<span class="notranslate">The original research company's international patent W02004108681 Division provides a promise he was prepared from the intermediate and intermediate Connaught Secretary for his synthetic route:</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00032.png" href="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00032.png"><img alt="Figure CN104892509AD00032" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00032.png" height="255" id="idf0003" src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00032.png" style="height: auto; max-width: 100%;" width="640" /></a></div>
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<span class="notranslate"> Zhejiang Beida company's international patent W02013013609 preparation and acylation of core intermediate was further optimized synthesis route is:</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00041.png" href="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00041.png"><img alt="Figure CN104892509AD00041" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00041.png" id="idf0004" src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00041.png" style="height: auto; max-width: 100%;" /></a></div>
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<span class="notranslate">n PhO. eight XOOH</span></div>
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<span class="notranslate"> original research company's international patent W02014014834 and W02014014835 also provides another synthetic route he Connaught Secretary prepared:</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00042.png" href="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00042.png"><img alt="Figure CN104892509AD00042" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00042.png" height="331" id="idf0005" src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00042.png" style="height: auto; max-width: 100%;" width="640" /></a></div>
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<span class="notranslate">Analysis of the above synthetic route, although he continued to Connaught Division to improve and optimize the synthesis, but its essence rings manner that different form quinoline ring is basically the same mother.</span> <span class="notranslate">Especially methyl isoquinoline replaced either by way of introducing the Suzuki reaction catalyzed by a noble metal element, either through amine reduction achieved.</span> <span class="notranslate">Moreover, the above reaction scheme revelation raw materials are readily available, many times during the reaction need to be protected and then deprotected.</span> <span class="notranslate">Clearly, the preparation process is relatively complicated, high cost, industrial production has brought some difficulties.</span></div>
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<img alt="Figure CN104892509AD00052" data-mce-src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00052.png" src="https://patentimages.storage.googleapis.com/CN104892509A/CN104892509AD00052.png" style="height: auto; max-width: 100%;" /></h1>
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<span class="notranslate">Example One:</span></div>
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<span class="notranslate">tyrosine was added to the reaction flask and dried (18. lg, 0.1 mmol) and methanol 250mL, cooling to ice bath 0_5 ° C, was added dropwise over 1 hour a percentage by weight of 98% concentrated sulfuric acid 10g.</span> <span class="notranslate">Drops Albert, heating to reflux.</span> <span class="notranslate">The reaction was stirred for 16-20 hours, TLC the reaction was complete.</span> <span class="notranslate">Concentrated under atmosphere pressure, the residue was added water 100mL, using 10% by weight sodium hydroxide to adjust the pH to 6. 5-7.0, precipitated solid was filtered, washed with methanol and water chloro cake (I: 1) and dried in vacuo tyrosine methyl ester as a white solid (11) 15.38, yield 78.5% out 1--] \ ^ 111/2: 196 [] \ 1 + 1] +!.</span></div>
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<span class="notranslate">Example Two:</span></div>
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<span class="notranslate">[0041] a nitrogen atmosphere and ice bath, was added to the reaction flask tyrosine methyl ester (II) (9. 8g, 50mmol), potassium methoxide (3. 5g, 50mmol) and methanol 50mL, until no gas generation after, was heated to reflux, the reaction was stirred for 2 hours.</span> <span class="notranslate">Concentrated under atmosphere pressure to remove the solvent, the residue was added dimethylsulfoxide 25mL, freshly prepared copper powder (0.2g, 3. Lmmol), was slowly warmed to 150-155 ° C, for about half an hour later, a solution of bromobenzene ( 7. 9g, 50mmol), continue to heat up to 170-175 ° C, the reaction was stirred for 3 hours, TLC detection of the end of the reaction.</span> <span class="notranslate">Was cooled to 60 ° C, and methanol was added to keep micro-boiling, filtered while hot, the filter cake washed three times with hot ethanol, and the combined organic phases, was cooled to square ° C, filtered, and dried in vacuo to give a white solid of 2-amino-3- ( 4-phenoxyphenyl) propanoate (111) 8 11.5, yield 84.9% as 1 -] \ ^ 111/2:! 272 [] \ 1 + 1] +.</span></div>
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<span class="notranslate"> Example Three:</span></div>
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<span class="notranslate"> in the reaction flask was added 2-amino-3- (4-phenoxyphenyl) propionic acid methyl ester (III) (10. 8g, 40mmol), 40% by weight acetaldehyde (20g, 0. 2mol ) and the percentage by weight of 35% concentrated hydrochloric acid 50mL, refluxed for 1 hour.</span> <span class="notranslate">Continue 40% by weight was added acetaldehyde (10g, 0.1mol), and the percentage by weight of 35% concentrated hydrochloric acid 25mL, and then the reaction was refluxed for 3-5 hours.</span> <span class="notranslate">Was cooled to 4-7 ° C, ethyl acetate was added, and extracted layers were separated.</span> <span class="notranslate">The aqueous layer was adjusted with sodium hydroxide solution to pH 11-12, extracted three times with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid of 1-methyl-3-carboxylate -7- phenoxy-1,2,3,4-tetrahydroisoquinoline (IV) 8 4g, 70.7% yield; Mass spectrum (EI): EI-MS m / z: 298 [M + H] + .</span></div>
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<span class="notranslate"> Example Four:</span></div>
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<span class="notranslate">Under ice bath, the reaction flask was added methyl 3-carboxylate I- -7- phenoxy-1,2, 3,4-tetrahydro-isoquinoline (IV) (5. 9g, 20mmol) and dichloromethane 100mL, 0 ° C and under stirring added potassium carbonate (13. 8g, 0. lmol), p-toluenesulfonyl chloride (11. 4g, 60mmol), the addition was completed, the ice bath was removed and stirred at room temperature 3 hour.</span> <span class="notranslate">Water was added 30mL, after stirring standing layer, the organic phase was washed with dilute hydrochloric acid, water and saturated brine, and concentrated, the resulting product was added a 30% by weight sodium hydroxide solution (8. 0g, 60mmol) and dimethyl sulfoxide 60mL, gradually warming to 120-130 ° C, the reaction was stirred for 2-4 hours to complete the reaction by TLC.</span> <span class="notranslate">Cooled to room temperature, water was added lOOmL, extracted three times with ethyl acetate, the combined organic phase was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated, the resulting oil was treated with ethyl acetate and n-hexane (1: 3) recrystallization, vacuum dried to give an off-white solid 1-methyl-3-carboxylate 7-phenoxyheptanoic isoquinoline (V) 5. 25g, yield 89. 6%; EI-MS m / z: 294 [M + H] VH NMR (DMS0-d6) δ 2. 85 (s, 3H), 3 · 97 (s, 3H), 7 · 16-7. 24 (m, 3H), 7 · 49-7. 60 (m, 4Η), 8 · 35 (d, J = 9 · 0,1Η), 8 · 94 (s, 1Η).</span></div>
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<span class="notranslate">Example five:</span></div>
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<span class="notranslate">[0047] added 1-methyl-3-carboxylic acid methyl ester 7-phenoxyheptanoic isoquinoline (V) (2. 93g, IOmmol) and glacial acetic acid 50mL reaction flask, stirring solution of 30% by weight hydrogen peroxide 5mL, warmed to 60-70 ° C, was slowly added dropwise within 10 hours the percentage by weight of a mixture of 30% hydrogen peroxide 2mL and 12mL of glacial acetic acid, a dropping was completed, the reaction was continued for 20-24 hours.</span> <span class="notranslate">Concentrated under reduced pressure, ethanol was added, distillation is continued to be divisible remaining glacial acetic acid.</span> <span class="notranslate">The residue was dissolved with dichloromethane, washed with 5% by weight of sodium bicarbonate, the organic phase was separated, dried over anhydrous sodium sulfate.</span> <span class="notranslate">Filtered and the resulting solution was added p-toluenesulfonyl chloride (3. 8g, 20mmol), was heated to reflux, the reaction was stirred for 3-4 hours, TLC detection completion of the reaction.</span> <span class="notranslate">The solvent was distilled off under reduced pressure, cooled to room temperature, methanol was added, the precipitated solid, cooled to square ° C, allowed to stand overnight.</span> <span class="notranslate">Filtered, the filter cake washed twice with cold methanol and vacuum dried to give an off-white solid 1- methyl-3-methyl-4-hydroxy-phenoxy-isoquinoline -7- (VI) I. 86g, yield 60.2 %; EI-MS m / z:.. 310 [M + H] +, 1H NMR (DMS0-d6) δ 2.90 (s, 3H), 4.05 (s, 3H), 7 17-7 26 (m, 3H ), 7. 49-7. 61 (m, 4H), 8. 38 (d, J = 9. 0,1H), 11. 7 (s, 1H) 〇</span></div>
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<span class="notranslate"> Example VI:</span></div>
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<span class="notranslate"> in the reaction flask with magnetic stirring and pressure to join I- methyl-3-methyl-4-hydroxy-7-phenoxyheptanoate isoquinoline (VI) (1.55g, 5mmol), glycine (I. 13g, 15mmol) and sodium methoxide (3. 25g, 6mmol) in methanol (30mL).</span><span class="notranslate">Sealed, slowly heated to 120 ° C, the reaction was stirred for 8-10 hours to complete the reaction by TLC.</span> <span class="notranslate">Cooled to room temperature, solid precipitated.</span> <span class="notranslate">Filtration, and the resulting solid was recrystallized from methanol, acetone and then beating the resulting solid was dried under vacuum to give a white solid Connaught orlistat 1.40g, yield 79.5%;</span></div>
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<span class="notranslate">EI-MS m / z: 353 [M + H] +,</span></div>
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<span class="notranslate">1H NMR (DMS0-d6) S2.72 (s, 3H), 3 · 99 (d, J = 6 · 0, 2H), 7 · 18-7. 28 (m, 3H), 7 · 49-7. 63 (m, 4H), 8 · 31 (d, J = 8 · 8,1H), 9 · 08 (s, lH), 13.41 (brs, lH).</span></div>
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PATENT</div>
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<a data-mce-href="https://www.google.com/patents/WO2014014835A2?cl=en" href="https://www.google.com/patents/WO2014014835A2?cl=en">WO 2014014835</a></div>
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<img alt="" data-mce-src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000059_0001.png" src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000059_0001.png" style="height: auto; max-width: 100%;" /></div>
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Example 10. Preparation of Compound A</div>
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a) 5-Phenoxyphthalide</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000056_0001.png" href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000056_0001.png"><img alt="Figure imgf000056_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000056_0001.png" height="76" id="imgf000056_0001" src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000056_0001.png" style="height: auto; max-width: 100%;" width="364" /></a></div>
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[0200] A reactor was charged with DMF (68 Kg), and stirring was initiated. The reactor was then charged with phenol (51 Kg), acetylacetone (8 Kg), 5-bromophthalide (85 Kg), copper bromide (9 Kg), and potassium carbonate (77 Kg). The mixture was heated above 85 °C and maintained until reaction completion and then cooled. Water was added. Solid was filtered and washed with water. Solid was dissolved in dichloromethane, and washed with aqueous HCl and then with water. Solvent was removed under pressure and methanol was added. The mixture was stirred and filtered. Solid was washed with methanol and dried in an oven giving 5- phenoxyphthalide (Yield: 72%, HPLC: 99.6%). b) 2-Chloromethyl-4-phenoxybenzoic acid methyl ester</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000056_0002.png" href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000056_0002.png"><img alt="Figure imgf000056_0002" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000056_0002.png" height="92" id="imgf000056_0002" src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000056_0002.png" style="height: auto; max-width: 100%;" width="664" /></a></div>
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[0201] A reactor was charged with toluene (24 Kg), and stirring was initiated. The reactor was then charged with 5-phenoxyphthalide (56 Kg), thionyl chloride (41 Kg), trimethyl borate (1</div>
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Kg), dichlorotriphenylphosphorane (2.5 Kg), and potassium carbonate (77 Kg). The mixture was heated to reflux until reaction completion and solvent was removed leaving 2-chloromethyl-4- phenoxybenzoyl chloride. Methanol was charged and the mixture was heated above 50 °C until reaction completion. Solvent was removed and replaced with DMF. This solution of the product methyl 2-chloromethyl-4-phenoxybenzoic acid methyl ester in DMF was used directly in the next step (HPLC: 85%). c) 4-Hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (la)</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000057_0001.png" href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000057_0001.png"><img alt="Figure imgf000057_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000057_0001.png" height="132" id="imgf000057_0001" src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000057_0001.png" style="height: auto; max-width: 100%;" width="656" /></a></div>
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[0202] A reactor was charged with a solution of 2-chloromethyl-4-phenoxybenzoic acid methyl ester (~68 Kg) in DMF, and stirring was initiated. The reactor was then charged with p- toluenesulfonylglycine methyl ester (66 Kg), potassium carbonate (60 Kg), and sodium iodide (4 Kg). The mixture was heated to at least 50 °C until reaction completion. The mixture was cooled. Sodium methoxide in methanol was charged and the mixture was stirred until reaction completion. Acetic acid and water were added, and the mixture was stirred, filtered and washed with water. Solid was purified by acetone trituration and dried in an oven giving la (Yield from step b): 58%; HPLC: 99.4%). 1H NMR (200 MHz, DMSO-d6) δ 11.60 (s, 1 H), 8.74 (s, 1H),</div>
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8.32 (d, J = 9.0 Hz, 1 H), 7.60 (dd, J = 2.3 & 9.0 Hz, 1H), 7.49 (m, 3 H), 7.24 (m, 3 H), 3.96 (s, 3 H); MS-(+)-ion M+l = 296.09 d) Methyl l-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate</div>
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(lb)</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000057_0002.png" href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000057_0002.png"><img alt="Figure imgf000057_0002" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000057_0002.png" height="104" id="imgf000057_0002" src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000057_0002.png" style="height: auto; max-width: 100%;" width="660" /></a></div>
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[0203] A flask was charged with la (29.5 g) and acetic acid (44.3 g ± 5%), and then stirred. Bis-dimethylaminomethane (12.8 g ± 2%) was slowly added. The mixture was heated to 55 ± 5 °C and maintained until reaction completion. The reaction product was evaluated by MS, HPLC and 1H NMR. 1H NMR (200 MHz, DMSO-d6) δ 11.7 (s, 1 H), 8.38 (d, J = 9.0 Hz, 1 H), 7.61 (dd, J = 9.0, 2.7 Hz, 1 H), 7.49 (m, 3 H), 7.21 (m, 3 H), 5.34 (s, 2 H), 3.97 (s, 3 H), 1.98 (s, 3 H); MS-(+)-ion M+l = 368.12. e) Methyl l-((acetoxy)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (lc)</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000058_0001.png" href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000058_0001.png"><img alt="Figure imgf000058_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000058_0001.png" height="144" id="imgf000058_0001" src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000058_0001.png" style="height: auto; max-width: 100%;" width="608" /></a></div>
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[0204] The solution of lb from a) above was cooled below 25 °C, at which time acetic anhydride (28.6 g ± 3.5 %) was added to maintain temperature below 50 °C. The resulting mixture was heated to 100 ± 5 °C until reaction completion.</div>
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[0205] The solution of lc and Id from above was cooled to less than 65 ± 5 °C. Water (250 mL) was slowly added. The mixture was then cooled to below 20 ± 5 °C and filtered. The wet cake was washed with water (3 x 50 mL) and added to a new flask. Dichloromethane (90 mL) and water (30 mL) were added, and the resulting mixture was stirred. The dichloromethane layer was separated and evaluated by HPLC.</div>
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[0206] The organic layer was added to a flask and cooled 5 ± 5 °C. Morpholine was added and the mixture was stirred until reaction completion. Solvent was replaced with acetone/methanol mixture. After cooling, compound lc precipitated and was filtered, washed and dried in an oven (Yield: 81%, HPLC: >99.7%). 1H NMR (200 MHz, DMSO-d6) δ 11.6 (S, 1 H), 8.31 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 2.3 Hz, 1 H), 7.49 (m, 3 H), 7.24 (m, 3 H), 3.95 (s, 3 H), 3.68 (s, 2H), 2.08 (s, 6 H); MS-(+)-ion M+l = 357.17. f) Methyl 4-hydroxy-l-methyl-7-phenoxyisoquinoline-3-carboxylate (le)</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000058_0002.png" href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000058_0002.png"><img alt="Figure imgf000058_0002" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000058_0002.png" height="92" id="imgf000058_0002" src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000058_0002.png" style="height: auto; max-width: 100%;" width="472" /></a></div>
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[0207] A reactor was charged with lc (16.0 g), Pd/C (2.08 g), anhydrous Na<sub>2</sub>C0<sub>3</sub> (2.56 g) and ethyl acetate (120 mL). The flask was vacuum-purged with nitrogen (3X) and vacuum-purged with hydrogen (3X). The flask was then pressurized with hydrogen and stirred at about 60 °C until completion of reaction. The flask was cooled to 20-25 °C, the pressure released to ambient, the head space purged with nitrogen three times and mixture was filtered. The filtrate was concentrated. Methanol was added. The mixture was stirred and then cooled. Product precipitated and was filtered and dried in an oven (Yield: 90%, HPLC: 99.7%). g) [(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid</div>
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(Compound A)</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000059_0001.png" href="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000059_0001.png"><img alt="Figure imgf000059_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000059_0001.png" height="88" id="imgf000059_0001" src="https://patentimages.storage.googleapis.com/WO2014014835A2/imgf000059_0001.png" style="height: auto; max-width: 100%;" width="556" /></a></div>
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[0208] A pressure flask was charged with le (30.92 g), glycine (22.52 g), methanol (155 mL), sodium methoxide solution (64.81 g) and sealed (as an alternative, sodium glycinate was used in place of glycine and sodium methoxide). The reaction was heated to about 110 °C until reaction was complete. The mixture was cooled, filtered, washed with methanol, dried under vacuum, dissolved in water and washed with ethyl acetate. The ethyl acetate was removed and to the resulting aqueous layer an acetic acid (18.0 g) solution was added. The suspension was stirred at room temperature, filtered, and the solid washed with water (3 x 30 mL), cold acetone (5-10 °C, 2 x 20 mL), and dried under vacuum to obtain Compound A (Yield: 86.1%, HPLC: 99.8%). Example 11. Biological Testing</div>
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[0209] The solid forms provided herein can be used for inhibiting HIF hydroxylase activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF), and can be used to treat and prevent HIF-associated conditions and disorders (see, e.g., U.S. Patent No. 7,323,475, U.S. Patent Application Publication No. 2007/0004627, U.S. Patent Application Publication No. 2006/0276477, and U.S. Patent Application Publication No. 2007/0259960, incorporated by reference herein).</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">SYNTHESIS</span>.......<a data-mce-href="http://zliming2004.lofter.com/post/1cc9dc55_79ad5d8" href="http://zliming2004.lofter.com/post/1cc9dc55_79ad5d8">.</a></h1>
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<a data-mce-href="http://zliming2004.lofter.com/post/1cc9dc55_79ad5d8" href="http://zliming2004.lofter.com/post/1cc9dc55_79ad5d8">http://zliming2004.lofter.com/post/1cc9dc55_79ad5d8</a></h1>
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Condensation of 5-bromophthalide (I) with phenol (II) in the presence of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (III), which upon lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene yields 2-chloromethyl-4-phenoxybenzoyl chloride (IV). Esterification of acid chloride (IV) with MeOH at 50 °C furnishes the methyl ester (V), which is then condensed with methyl N-tosylglycinate (VI) in the presence of K2CO3 and NaI in DMF at 50 °C to afford N-substituted aminoester (VII). Cyclization of the intermediate diester (VII) using NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (VIII), which is submitted to Mannich reaction with bis-dimethylaminomethane (IX) in the presence of AcOH at 57 °C to provide the dimethylaminomethyl compound (X). Treatment of amine (X) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-acetoxymethyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XI). Hydrogenolysis of the benzylic acetate (XII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XII), which finally couples with glycine (XIII) in the presence of NaOMe in MeOH at 110 °C to afford the target roxadustat (1-3).</div>
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<img alt="FG-4592 - zliming2004 - zliming2004的博客" data-mce-src="http://img2.ph.126.net/nJfGEbZ_ODr6Gu1mNHl96g==/6631343743117255718.jpg" height="640" src="http://img2.ph.126.net/nJfGEbZ_ODr6Gu1mNHl96g==/6631343743117255718.jpg" style="height: auto; max-width: 100%;" title="FG-4592 - zliming2004 - zliming2004的博客" width="539" /></div>
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Cyclization of 4-phenoxyphthalic acid (I) with glycine (II) at 215 °C gives the phthalimide (III), which upon esterification with MeOH and H2SO4 at reflux yields methyl ester (IV). Subsequent rearrangement of phthalimidoacetate (IV) by means of Na in BuOH at 97 °C, followed by flash chromatography provides the isoquinoline-2-carboxylate (V). Bromination of intermediate (V) using POBr3 and NaHCO3 in acetonitrile leads to butyl 8-bromo-3-hydroxy-6-phenoxy-isoquinoline-2-carboxylate (VI), which upon hydrolysis with NaOH in refluxing H2O/EtOH furnishes carboxylic acid (VII). Substitution of bromine in intermediate (VII) using MeI and BuLi in THF at -78 °C, followed by alkylation with PhCH2Br in the presence of K2CO3 in refluxing acetone affords the 2-methyl isoquinoline (VIII). Ester hydrolysis in intermediate (VIII) using KOH in MeOH gives the corresponding carboxylic acid (IX), which is then activated with i-BuOCOCl and Et3N in CH2Cl2, followed by coupling with benzyl glycinate hydrochloride (X) to yield benzylated roxadustat (XI). Finally, debenzylation of intermediate (XI) with H2 over Pd/C in EtOAc/MeOH provides the title compound (1).</div>
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<img alt="FG-4592 - zliming2004 - zliming2004的博客" class="" data-mce-src="http://img2.ph.126.net/WsWUqx-rs7fEKdKLvG77AA==/2482046344652781425.jpg" height="640" src="http://img2.ph.126.net/WsWUqx-rs7fEKdKLvG77AA==/2482046344652781425.jpg" style="height: auto; max-width: 100%;" title="FG-4592 - zliming2004 - zliming2004的博客" width="569" /></div>
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Condensation of 4-nitro-ortho-phthalonitrile (I) with phenol (II) in the presence of K2CO3 in DMSO gives 4-phenoxy-ortho-phthalonitrile (III) (1), which upon hydrolysis with NaOH (1) or KOH (2) in refluxing MeOH yields 4-phenoxyphthalic acid (IV) (1,2). Dehydration of dicarboxylic acid (IV) using Ac2O and AcOH at reflux furnishes the phthalic anhydride (V), which is then condensed with methyl 2-isocyanoacetate (VI) using DBU in THF to provide oxazole derivative (VII). Rearrangement of intermediate (VII) with HCl in MeOH at 60 °C leads to isoquinoline derivative (VIII), which is partially chlorinated by means of POCl3 at 70 °C to afford 1-chloro-isoquinoline derivative (IX). Substitution of chlorine in intermediate (IX) using Me3B, Pd(PPh3)4 and K2CO3 in refluxing dioxane gives methyl 4-hydroxy-1-methyl-7-phenoxy-3-carboxylate (X), which is then hydrolyzed with aqueous NaOH in refluxing EtOH to yield the carboxylic acid (XI). Coupling of carboxylic acid (XI) with methyl glycinate hydrochloride (XII) by means of PyBOP, (i-Pr)2NH and Et3N in CH2Cl2 yields roxadustat methyl ester (XII), which is finally hydrolyzed with aqueous NaOH in THF to afford the target roxadustat (1).</div>
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CLIPS</div>
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SAN FRANCISCO, Nov 12, 2013 (BUSINESS WIRE) -- FibroGen, Inc. (FibroGen), today announced that data from a China-based Phase 2 study of roxadustat (FG-4592), a first-in-class oral compound in late stage development for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD), were presented in an oral session at the 2013 American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia.</div>
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Roxadustat is an orally administered, small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. HIF is a protein that responds to oxygen changes in the cellular environment and meets the body's demands for oxygen by inducing erythropoiesis, the process by which red blood cells are produced and iron is incorporated into hemoglobin (Hb).</div>
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The randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy, safety, and tolerability of roxadustat in the correction of anemia in patients (N=91) with chronic kidney disease who had not received dialysis treatment, were not receiving erythropoiesis-stimulating agents (ESAs), and had Hb levels less than 10 g/dL. The correction study randomized patients 2:1 between roxadustat and placebo for 8 weeks of dosing, and included a low-dose cohort (n=30) and high-dose cohort (n=31). Intravenous (IV) iron was not allowed. The study also evaluated iron utilization, changes in serum lipids, and other biomarkers during treatment with roxadustat.</div>
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Data from this study suggest that roxadustat effectively corrected hemoglobin levels in anemic CKD patients in a dose-dependent manner as compared to placebo, and did so in the absence of IV iron supplementation regardless of degree of iron repletion at baseline. At the end of the 8-week treatment period, subjects showed mean maximum Hb increases from baseline of 2.6 g/dL in the high dose cohort and 1.8 g/dL in the low dose cohort, as compared to 0.7 g/dL in the placebo group (p < 0.0001) from mean baseline Hb of 8.8 g/dL, 8.8 g/dL, and 8.9 g/dL in the high dose, low dose, and placebo groups, respectively. 87% of patients in the high-dose cohort, 80% of patients in the low-dose cohort, and 23% of patients in the placebo group experienced a hemoglobin increase of 1 g/dL or greater from baseline (p < 0.0001). Similarly, 71% of patients in the high-dose cohort, 50% of patients in the low-dose cohort, and 3% of patients in the placebo group achieved target hemoglobin of 11 g/dL or greater (p < 0.0001). Serum iron levels remained stable in subjects randomized to roxadustat while the subjects underwent brisk erythropoiesis.</div>
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Study data also suggest that roxadustat may lower cholesterol. Dyslipidemia is highly prevalent in chronic kidney disease patients and a major cardiovascular risk factor in this population. Patients treated with roxadustat experienced a statistically significant reduction in total cholesterol (p <0.0001) and low-density lipoprotein (LDL) cholesterol (p <0.0001) at the end of the treatment period. The relative proportion of high density lipoprotein (HDL) cholesterol to LDL cholesterol increased significantly (p <0.02). Overall LDL cholesterol levels declined by a mean of 26% and median of 23% from a mean baseline value of 103 mg/dL.</div>
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Roxadustat was well tolerated by patients in the study with incidence of adverse events similar across all groups. In contrast to the exacerbation of hypertension observed in studies in which patients received currently available ESA therapies, subjects who received roxadustat in the present study showed small decreases in blood pressure that were similar to blood pressure changes in the placebo group. No cardiovascular serious adverse events were reported in patients treated with roxadustat.</div>
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The efficacy and safety of roxadustat are currently being investigated in a global pivotal Phase 3 development program.</div>
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"There is a global need for effective, safe, and accessible anemia therapies," said Thomas B. Neff, Chief Executive Officer of FibroGen. "Side effects associated with current treatments include exposure to supra-physiological levels of erythropoietin and depletion of iron stores. Preliminary clinical findings show that oral administration of roxadustat (FG-4592) is able to correct anemia and maintain hemoglobin levels in patients with chronic kidney disease, to do so with peak erythropoietin levels within physiological range, and to achieve these effects without the administration of intravenous iron. These results suggest roxadustat, as an oral agent, has the potential to overcome the treatment barriers and inconveniences of current ESA therapies, including administration by injection and IV iron supplementation, in treating anemia in CKD patients."</div>
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About Chronic Kidney Disease (CKD) and Anemia</div>
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Diabetes, high blood pressure, and other conditions can cause significant damage to the kidneys. If left untreated, those can result in chronic kidney disease and progress to kidney failure. Such deterioration can lead to patients needing a kidney transplant or being placed on dialysis to remove excess fluid and toxins that build up in the body. The progression of CKD also increases the prevalence of anemia, a condition associated with having fewer of the red blood cells that carry oxygen through the body, and/or lower levels of hemoglobin, the protein that enables red blood cells to carry oxygen. As hemoglobin falls, the lower oxygen-carrying capacity of an anemic patients' blood results in various symptoms including fatigue, loss of energy, breathlessness, and angina. Anemia in CKD patients has been associated with increased hospitalization rates, increased mortality, and reduced quality of life.</div>
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Chronic kidney disease is a worldwide critical healthcare problem that affects millions of people and drives significant healthcare cost. In the US, prevalence of CKD has increased dramatically in the past 20 years, from 10 percent of the adult population (or approximately 20 million U.S. adults) as stated in the National Health and Nutrition Evaluation Survey (NHANES) 1988-1994, to 15 percent (or approximately 30 million U.S. adults) in NHANES 2003-2006. In 2009, total Medicare costs for CKD patients were $34 billion. China has an estimated 145 million CKD patients, or approximately five times the number of CKD patients in the U.S. (Lancet April 2012).</div>
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About Roxadustat / FG-4592</div>
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Roxadustat (FG-4592) is an orally administered small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity, in development for the treatment of anemia in patients with chronic kidney disease (CKD). HIF is a protein transcription factor that induces the natural physiological response to conditions of low oxygen, "turning on" erythropoiesis (the process by which red blood cells are produced) and other protective pathways. Roxadustat has been shown to correct anemia and maintain hemoglobin levels without the need for supplementation with intravenous iron in CKD patients not yet receiving dialysis and in end-stage renal disease patients receiving dialysis. An Independent Data Monitoring Committee has found no signals or trends to date to suggest that treatment with roxadustat is associated with increased risk of cardiovascular events, thrombosis, or increases in blood pressure requiring initiation or intensification of antihypertensive medications.</div>
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About FibroGen</div>
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FibroGen is a privately-held biotechnology company focused on the discovery, development, and commercialization of therapeutic agents for treatment of fibrosis, anemia, cancer, and other serious unmet medical needs. FibroGen's FG-3019 monoclonal antibody is in clinical development for treatment of idiopathic pulmonary fibrosis and other proliferative diseases, including pancreatic cancer and liver fibrosis. Roxadustat (FG-4592), FibroGen's small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, is currently in clinical development for the treatment of anemia. FibroGen is also currently pursuing the use of proprietary recombinant human type III collagens in synthetic corneas for treatment of corneal blindness. For more information please visit: <a data-mce-href="http://www.fibrogen.com/" href="http://www.fibrogen.com/">www.fibrogen.com</a> .</div>
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<img alt="" class="irc_mi iULWYoeBgm4w-pQOPx8XEepE" data-mce-src="http://jpdb.nihs.go.jp/jan/gif/Roxadustat.png" height="232" src="http://jpdb.nihs.go.jp/jan/gif/Roxadustat.png" style="height: auto; max-width: 100%;" width="712" /></div>
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<h3 class="block-title-5 text-center alert-info">
References</h3>
1: Besarab A, Provenzano R, Hertel J, Zabaneh R, Klaus SJ, Lee T, Leong R, Hemmerich S, Yu KH, Neff TB. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant. 2015 Oct;30(10):1665-73. doi: 10.1093/ndt/gfv302. Epub 2015 Aug 3. PubMed PMID: 26238121; PubMed Central PMCID: PMC4569392.<br />
2: Forristal CE, Levesque JP. Targeting the hypoxia-sensing pathway in clinical hematology. Stem Cells Transl Med. 2014 Feb;3(2):135-40. doi: 10.5966/sctm.2013-0134. Epub 2013 Dec 26. PubMed PMID: 24371328; PubMed Central PMCID: PMC3925058.<br />
3: Bouchie A. First-in-class anemia drug takes aim at Amgen's dominion. Nat Biotechnol. 2013 Nov;31(11):948-9. doi: 10.1038/nbt1113-948b. PubMed PMID: 24213751.<br />
4: Flight MH. Deal watch: AstraZeneca bets on FibroGen's anaemia drug. Nat Rev Drug Discov. 2013 Oct;12(10):730. doi: 10.1038/nrd4135. PubMed PMID: 24080688.<br />
5: Beuck S, Schänzer W, Thevis M. Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis. Drug Test Anal. 2012 Nov;4(11):830-45. doi: 10.1002/dta.390. Epub 2012 Feb 24. Review. PubMed PMID: 22362605.<br />
6: Cases A. The latest advances in kidney diseases and related disorders. Drug News Perspect. 2007 Dec;20(10):647-54. PubMed PMID: 18301799.</div>
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//////////ASP1517, ASP 1517, ASP-1517, FG-4592, FG 4592, FG4592, Roxadustat, PHASE 3, ASTELLAS, <i>FibroGen, 808118-40-3</i></div>
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O=C(O)CNC(C1=C(O)C2=C(C(C)=N1)C=C(OC3=CC=CC=C3)C=C2)=O</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com5tag:blogger.com,1999:blog-302770220608373834.post-64355308407622845682016-05-01T05:30:00.000-07:002016-05-01T05:30:01.006-07:00SQ 109, Pyrrole Hybrid Derivatives, Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria<div dir="ltr" style="text-align: left;" trbidi="on">
<img alt="Abstract Image" class="" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2016/jmcmar.2016.59.issue-6/acs.jmedchem.6b00031/20160318/images/medium/jm-2016-00031m_0003.gif" height="404" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2016/jmcmar.2016.59.issue-6/acs.jmedchem.6b00031/20160318/images/medium/jm-2016-00031m_0003.gif" width="789" /><br />
<br />
Novel
pyrroles have been designed, synthesized, and evaluated against
mycobacterial strains. The pyrroles have originally been designed as
hybrids of the antitubercular drugs BM212 (<b>1</b>) and SQ109 (<b>2</b>),
which showed common chemical features with very similar topological
distribution. A perfect superposition of the structures of <b>1</b> and <b>2</b>
revealed by computational studies suggested the introduction of bulky
substituents at the terminal portion of the pyrrole C3 side chain and
the removal of the C5 aryl moiety. Five compounds showed high activity
toward<i>Mycobacterium tuberculosis</i>, while <b>9b</b> and <b>9c</b> were highly active also against multidrug-resistant clinical isolates. Compound <b>9c</b>
showed low eukaryotic cell toxicity, turning out to be an excellent
lead candidate for preclinical trials. In addition, four compounds
showed potent inhibition (comparable to that of verapamil) toward the
whole-cell drug efflux pump activity of mycobacteria, thus turning out
to be promising multidrug-resistance-reversing agents.<br />
<h1 class="articleTitle">
<span class="hlFld-Title">Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1<i>H</i>-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and <i>N</i>-Adamantan-2-yl-<i>N</i>′-((<i>E</i>)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine
(SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular
Agents Effective against Multidrug-Resistant Mycobacteria</span></h1>
<div id="articleMeta">
<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Bhakta%2C+Sanjib" href="http://pubs.acs.org/author/Bhakta%2C+Sanjib" id="authors">Sanjib Bhakta</a></span><span class="NLM_xref-aff"><sup>†</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Scalacci%2C+Nicol%C3%B2" href="http://pubs.acs.org/author/Scalacci%2C+Nicol%C3%B2" id="authors">Nicolò Scalacci</a></span><span class="NLM_xref-aff"><sup>‡</sup></span><span class="NLM_xref-aff"><sup>⊥</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Maitra%2C+Arundhati" href="http://pubs.acs.org/author/Maitra%2C+Arundhati" id="authors">Arundhati Maitra</a></span><span class="NLM_xref-aff"><sup>†</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Brown%2C+Alistair+K" href="http://pubs.acs.org/author/Brown%2C+Alistair+K" id="authors">Alistair K. Brown</a></span><span class="NLM_xref-aff"><sup>#</sup></span><span class="NLM_xref-aff"><sup>‡</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Dasugari%2C+Saiprasad" href="http://pubs.acs.org/author/Dasugari%2C+Saiprasad" id="authors">Saiprasad Dasugari</a></span><span class="NLM_xref-aff"><sup>‡</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Evangelopoulos%2C+Dimitrios" href="http://pubs.acs.org/author/Evangelopoulos%2C+Dimitrios" id="authors">Dimitrios Evangelopoulos</a></span><span class="NLM_xref-aff"><sup>§</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/McHugh%2C+Timothy+D" href="http://pubs.acs.org/author/McHugh%2C+Timothy+D" id="authors">Timothy D. McHugh</a></span><span class="NLM_xref-aff"><sup>§</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Mortazavi%2C+Parisa+N" href="http://pubs.acs.org/author/Mortazavi%2C+Parisa+N" id="authors">Parisa N. Mortazavi</a></span><span class="NLM_xref-aff"><sup>†</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Twist%2C+Alexander" href="http://pubs.acs.org/author/Twist%2C+Alexander" id="authors">Alexander Twist</a></span><span class="NLM_xref-aff"><sup>‡</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Petricci%2C+Elena" href="http://pubs.acs.org/author/Petricci%2C+Elena" id="authors">Elena Petricci</a></span><span class="NLM_xref-aff"><sup>∥</sup></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Manetti%2C+Fabrizio" href="http://pubs.acs.org/author/Manetti%2C+Fabrizio" id="authors">Fabrizio Manetti</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00031#cor1" href="http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00031#cor1"><sup>*</sup></a><span class="NLM_xref-aff"><sup>∥</sup></span><span class="NLM_x">, and </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Castagnolo%2C+Daniele" href="http://pubs.acs.org/author/Castagnolo%2C+Daniele" id="authors">Daniele Castagnolo</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00031#cor2" href="http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00031#cor2"><sup>*</sup></a><span class="NLM_xref-aff"><sup>⊥</sup></span><span class="NLM_xref-aff"><sup>‡</sup></span></span></div>
<div class="affiliations">
<div id="aff1">
<sup>†</sup> Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, <span class="institution">University of London</span>, Malet Street, London WC1E 7HX, <span class="country">U.K.</span></div>
<div id="aff2">
<sup>‡</sup> Department of Applied Sciences, <span class="institution">Northumbria University Newcastle</span>, Ellison Place, NE1 8ST, Newcastle upon Tyne,<span class="country">U.K.</span></div>
<div id="aff3">
<sup>§</sup> Centre for Clinical Microbiology, <span class="institution">University College London</span>, London, NW3 2PF <span class="country">U.K.</span></div>
<div id="aff4">
<sup>∥</sup> Dipartimento di Biotecnologie, Chimica e Farmacia, <span class="institution">Università di Siena</span>, Via Aldo Moro 2, I-53100 Siena, <span class="country">Italy</span></div>
<div id="aff5">
<sup>⊥</sup> Institute of Pharmaceutical Science, <span class="institution">King’s College London</span>, 150 Stamford Street, London SE1 9NH, <span class="country">U.K.</span></div>
<div id="aff6">
<sup>#</sup> School of Medicine, Pharmacy and Health, <span class="institution">Durham University</span>, Queen’s Campus, Stockton-on-Tees, TS17 6BH, <span class="country">U.K.</span></div>
</div>
<div id="citation">
<cite>J. Med. Chem.</cite>, <span class="citation_year">2016</span>, <span class="citation_volume">59</span> (6), pp 2780–2793</div>
<div id="doi">
<strong>DOI: </strong>10.1021/acs.jmedchem.6b00031</div>
<div id="pubDate">
Publication Date (Web): February 23, 2016</div>
<div id="artCopyright">
Copyright © 2016 American Chemical Society</div>
<div id="correspondence">
*FB: e-mail, <a data-mce-href="mailto:fabrizio.manetti@unisi.it" href="mailto:fabrizio.manetti@unisi.it">fabrizio.manetti@unisi.it</a>; tel, <span class="phone">+390577234256</span>., *D.C.: e-mail, <a data-mce-href="mailto:daniele.castagnolo@kcl.ac.uk" href="mailto:daniele.castagnolo@kcl.ac.uk">daniele.castagnolo@kcl.ac.uk</a>; tel, <span class="phone">+44(0)2078484506</span>.</div>
</div>
<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00031" href="http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00031">http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00031</a><br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/05/str1.png" href="http://www.allfordrugs.com/wp-content/uploads/2016/05/str1.png" rel="attachment wp-att-6008"><img alt="str1" class="alignnone size-full wp-image-6008" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/05/str1.png" height="397" src="http://www.allfordrugs.com/wp-content/uploads/2016/05/str1.png" width="673" /></a><br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/05/str1-1.png" href="http://www.allfordrugs.com/wp-content/uploads/2016/05/str1-1.png" rel="attachment wp-att-6009"><img alt="str1" class="alignnone size-full wp-image-6009" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/05/str1-1.png" height="468" src="http://www.allfordrugs.com/wp-content/uploads/2016/05/str1-1.png" width="679" /></a><br />
<b>SQ109</b> is a drug undergoing development for treatment of <a data-mce-href="https://en.wikipedia.org/wiki/Tuberculosis" href="https://en.wikipedia.org/wiki/Tuberculosis" title="Tuberculosis">tuberculosis</a>.<sup class="reference" id="cite_ref-1"><a data-mce-href="https://en.wikipedia.org/wiki/SQ109#cite_note-1" href="https://en.wikipedia.org/wiki/SQ109#cite_note-1">[1]</a></sup><sup class="reference" id="cite_ref-2"><a data-mce-href="https://en.wikipedia.org/wiki/SQ109#cite_note-2" href="https://en.wikipedia.org/wiki/SQ109#cite_note-2">[2]</a></sup><br />
<h2>
<span class="mw-headline" id="Background">Background</span></h2>
On October 16, 2007, it was given the status of <a data-mce-href="https://en.wikipedia.org/wiki/Orphan_drug" href="https://en.wikipedia.org/wiki/Orphan_drug" title="Orphan drug">Orphan drug</a> by the U.S. <a data-mce-href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a> (FDA) for use against drug-susceptible and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Drug-resistant" href="https://en.wikipedia.org/wiki/Drug-resistant" title="Drug-resistant">drug-resistant</a> TB bacteria.<sup class="reference" id="cite_ref-3"><a data-mce-href="https://en.wikipedia.org/wiki/SQ109#cite_note-3" href="https://en.wikipedia.org/wiki/SQ109#cite_note-3">[3]</a></sup><br />
SQ109
completed three phase I studies in the U.S. and one Phase II efficacy
studies in tuberculosis patients in Africa. SQ109 showed activity
against both drug susceptible and <a data-mce-href="https://en.wikipedia.org/wiki/Multi-drug-resistant_tuberculosis" href="https://en.wikipedia.org/wiki/Multi-drug-resistant_tuberculosis" title="Multi-drug-resistant tuberculosis">Multi-drug-resistant tuberculosis</a> bacteria, including <a data-mce-href="https://en.wikipedia.org/wiki/Extensively_drug-resistant_tuberculosis" href="https://en.wikipedia.org/wiki/Extensively_drug-resistant_tuberculosis" title="Extensively drug-resistant tuberculosis">Extensively drug-resistant tuberculosis</a> strains. In preclinical studies SQ109 enhanced the activity of anti-tubercular drugs <a data-mce-href="https://en.wikipedia.org/wiki/Isoniazid" href="https://en.wikipedia.org/wiki/Isoniazid" title="Isoniazid">isoniazid</a> and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Rifampin" href="https://en.wikipedia.org/wiki/Rifampin" title="Rifampin">rifampin</a> and reduced by >30% the time required to cure mice of experimental TB.<br />
SQ109 is being developed by OOO Infectex in <a data-mce-href="https://en.wikipedia.org/wiki/Russia" href="https://en.wikipedia.org/wiki/Russia" title="Russia">Russia</a>
and by Sequella Inc internationally. In July 2012, Infectex received
notification from the Russian Ministry of Health for approval to begin
the pivotal clinical trial associated with a drug registration
submission, and can proceed with the clinical development of SQ109 for
treatment of tuberculosis in the Russian Federation.<sup class="reference" id="cite_ref-4"><a data-mce-href="https://en.wikipedia.org/wiki/SQ109#cite_note-4" href="https://en.wikipedia.org/wiki/SQ109#cite_note-4">[4]</a></sup><br />
<br />
<h2>
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist">
</div>
<br />
<ul>
<li id="cite_note-1"><span class="reference-text"><cite class="citation journal">Jia, L.; Tomaszewski, J. E.; Hanrahan, C.; Coward, L.; Noker, P.; Gorman, G.; Nikonenko, B.; Protopopova, M. (2009). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575972" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575972" rel="nofollow">"Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug"</a>. <i>British Journal of Pharmacology</i> <b>144</b> (1): 80–87. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1038%2Fsj.bjp.0705984" href="https://dx.doi.org/10.1038%2Fsj.bjp.0705984" rel="nofollow">10.1038/sj.bjp.0705984</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575972" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575972" rel="nofollow">1575972</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/15644871" href="https://www.ncbi.nlm.nih.gov/pubmed/15644871" rel="nofollow">15644871</a>.</cite></span></li>
<li id="cite_note-2"><br /></li>
<li id="cite_note-2"><span class="reference-text"><cite class="citation journal">Meng,
Q.; Luo, H.; Liu, Y.; Li, W.; Zhang, W.; Yao, Q. (2009). "Synthesis and
evaluation of carbamate prodrugs of SQ109 as antituberculosis agents". <i>Bioorganic & Medicinal Chemistry Letters</i> <b>19</b> (10): 2808–10. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1016%2Fj.bmcl.2009.03.091" href="https://dx.doi.org/10.1016%2Fj.bmcl.2009.03.091" rel="nofollow">10.1016/j.bmcl.2009.03.091</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/19362471" href="https://www.ncbi.nlm.nih.gov/pubmed/19362471" rel="nofollow">19362471</a>.</cite></span></li>
<li id="cite_note-3"><br /></li>
<li id="cite_note-3"><span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.medscape.com/viewarticle/565674?src=mp" href="http://www.medscape.com/viewarticle/565674?src=mp" rel="nofollow">"New FDA Orphan Drugs: AVI-4658, SQ109, ATIR"</a>. <i>Medscape Medical News</i>. 11 November 2007.</cite></span></li>
<li id="cite_note-4"><br /></li>
</ul>
<span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.reuters.com/article/2012/07/26/idUS37877+26-Jul-2012+BW20120726" href="http://www.reuters.com/article/2012/07/26/idUS37877+26-Jul-2012+BW20120726" rel="nofollow">"PRESS
RELEASE Maxwell Biotech Venture Fund`s Portfolio Company, Infectex,
Receives Russian Regulator`s Approval to Conduct Pivotal Clinical Trial
for Sequella's Antibiotic, SQ109, for Tuberculosis"</a>. Reuters. 26 July 2012.</cite></span><br />
<br />
<table class="infobox bordered mce-item-table"><caption>SQ109</caption><tbody>
<tr><td colspan="2"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:AntitubercularSQ109.svg" href="https://en.wikipedia.org/wiki/File:AntitubercularSQ109.svg"><img alt="AntitubercularSQ109.svg" data-file-height="152" data-file-width="512" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/db/AntitubercularSQ109.svg/275px-AntitubercularSQ109.svg.png" height="82" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/db/AntitubercularSQ109.svg/275px-AntitubercularSQ109.svg.png" width="275" /></a></td></tr>
<tr><th colspan="2">Names</th></tr>
<tr><td colspan="2"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_nomenclature" href="https://en.wikipedia.org/wiki/Chemical_nomenclature" title="Chemical nomenclature">IUPAC name</a><br />
<div>
<i>N</i>-Adamantan-2-yl-<i>N'</i>-((<i>E</i>)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine</div>
</td></tr>
<tr><th colspan="2">Identifiers</th></tr>
<tr><td><div>
<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/IUPHAR/BPS" href="https://en.wikipedia.org/wiki/IUPHAR/BPS" title="IUPHAR/BPS">IUPHAR/BPS</a></div>
</td><td><span title="www.guidetopharmacology.org"><a class="external text" data-mce-href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=summary&ligandId=7997" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=summary&ligandId=7997" rel="nofollow">7997</a></span></td></tr>
<tr><td><a data-mce-href="https://en.wikipedia.org/wiki/Jmol" href="https://en.wikipedia.org/wiki/Jmol" title="Jmol">Jmol</a> 3D model</td><td><span title="chemapps.stolaf.edu (3D interactive model)"><a class="external text" data-mce-href="http://chemapps.stolaf.edu/jmol/jmol.php?model=CC%28%3DCCC%2FC%28%3DC%2FCNCCN%5BC%40%40H%5D1C2CC3CC%28C2%29CC1C3%29%2FC%29C" href="http://chemapps.stolaf.edu/jmol/jmol.php?model=CC%28%3DCCC%2FC%28%3DC%2FCNCCN%5BC%40%40H%5D1C2CC3CC%28C2%29CC1C3%29%2FC%29C" rel="nofollow">Interactive image</a></span></td></tr>
<tr><td><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></td><td><span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/5274428" href="https://pubchem.ncbi.nlm.nih.gov/compound/5274428" rel="nofollow">5274428</a></span></td></tr>
<tr><td colspan="2"><div class="NavFrame collapsed" id="NavFrame1">
<div class="NavHead">
<a data-mce-href="https://en.wikipedia.org/wiki/Simplified_molecular-input_line-entry_system" href="https://en.wikipedia.org/wiki/Simplified_molecular-input_line-entry_system" title="Simplified molecular-input line-entry system">SMILES</a><a class="NavToggle" data-mce-href="https://en.wikipedia.org/wiki/SQ109#" href="https://en.wikipedia.org/wiki/SQ109#" id="NavToggle1">[show]</a></div>
</div>
</td></tr>
<tr><th colspan="2">Properties</th></tr>
<tr><td><div>
<a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Chemical formula</a></div>
</td><td><span title="Carbon">C</span><sub>22</sub><span title="Hydrogen">H</span><sub>38</sub><span title="Nitrogen">N</span><sub>2</sub></td></tr>
<tr><td><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></td><td>330.56 g·mol<sup>−1</sup></td></tr>
</tbody></table>
<table class="top-summary-items mce-item-table"><tbody>
<tr><td class="breakword">SQ109;
SQ-109; SQ 109; UNII-9AU7XUV31A; CHEMBL561057;
N'-(2-adamantyl)-N-[(2E)-3,7-dimethylocta-2,6-dienyl]ethane-1,2-diamine; <a class="section-toc-link link-btn important-btn" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/5274428#section=Names-and-Identifiers" data-section="Names-and-Identifiers" href="https://pubchem.ncbi.nlm.nih.gov/compound/5274428#section=Names-and-Identifiers">More...</a></td></tr>
<tr><th>Molecular Formula:</th><td><a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C22H38N2&sort=mw&sort_dir=asc" href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C22H38N2&sort=mw&sort_dir=asc" title="Find all compounds with formula C22H38N2">C<sub>2</sub><sub>2</sub>H<sub>3</sub><sub>8</sub>N<sub>2</sub></a></td></tr>
<tr><th>Molecular Weight:</th><td>330.55052 g/mol</td></tr>
</tbody></table>
SQ109
is an orally active, small molecule antibiotic for treatment of
pulmonary TB. Currently in Phase I clinical trials, SQ109 could replace
one or more drugs in the current first-line TB drug regimen, simplify
therapy, and shorten the TB treatment regimen.<br />
<table class="mce-item-table"><thead>
<tr><th>Patent ID</th><th>Date</th><th>Patent Title</th></tr>
</thead><tbody>
<tr><td><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140045791.PGNR.&OS=DN/20140045791&RS=DN/20140045791" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140045791.PGNR.&OS=DN/20140045791&RS=DN/20140045791">US2014045791</a></td><td class="nowrap">2014-02-13</td><td>COMBINATION THERAPY TO TREAT MYCOBACTERIUM DISEASES</td></tr>
<tr><td><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8202910.PN.&OS=PN/8202910&RS=PN/8202910" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8202910.PN.&OS=PN/8202910&RS=PN/8202910">US8202910</a></td><td class="nowrap">2012-06-19</td><td>Compositions and methods for treatment of infectious disease</td></tr>
<tr><td><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20110118307.PN.&OS=PN/20110118307&RS=PN/20110118307" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20110118307.PN.&OS=PN/20110118307&RS=PN/20110118307">US2011118307</a></td><td class="nowrap">2011-05-19</td><td>Compositions and methods for the treatment of infectious diseases</td></tr>
<tr><td><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7842729.PN.&OS=PN/7842729&RS=PN/7842729" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7842729.PN.&OS=PN/7842729&RS=PN/7842729">US7842729</a></td><td class="nowrap">2010-11-30</td><td>Anti tubercular drug: compositions and methods</td></tr>
<tr><td><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090281054.PN.&OS=PN/20090281054&RS=PN/20090281054" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090281054.PN.&OS=PN/20090281054&RS=PN/20090281054">US2009281054</a></td><td class="nowrap">2009-11-12</td><td>COMPOSITIONS AND METHODS COMPRISING CAPURAMYCIN ANALOGUES</td></tr>
<tr><td><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7456222.PN.&OS=PN/7456222&RS=PN/7456222" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7456222.PN.&OS=PN/7456222&RS=PN/7456222">US7456222</a></td><td class="nowrap">2008-11-25</td><td>Anti tubercular drug: compositions and methods</td></tr>
<tr><td><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6951961.PN.&OS=PN/6951961&RS=PN/6951961" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6951961.PN.&OS=PN/6951961&RS=PN/6951961">US6951961</a></td><td class="nowrap">2005-10-04</td><td>Methods of use and compositions for the diagnosis and treatment of infectious disease</td></tr>
<tr><td><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20040033986.PN.&OS=PN/20040033986&RS=PN/20040033986" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20040033986.PN.&OS=PN/20040033986&RS=PN/20040033986">US2004033986</a></td><td class="nowrap">2004-02-19</td><td>Anti tubercular drug: compositions and methods</td></tr>
<tr><td><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20040019117.PN.&OS=PN/20040019117&RS=PN/20040019117" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20040019117.PN.&OS=PN/20040019117&RS=PN/20040019117">US2004019117</a></td><td class="nowrap">2004-01-29</td><td>Anti tubercular drug: compostions and methods</td></tr>
</tbody></table>
<a data-mce-href="file:///C:/Users/Inspiron/Downloads/jm6b00031_si_001.pdf" href="https://www.blogger.com/null">/////</a>//<span class="hlFld-Title">SQ109, bm 212</span></div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com4tag:blogger.com,1999:blog-302770220608373834.post-79443089241334118792016-04-26T20:44:00.006-07:002016-04-26T20:44:49.537-07:00Albutrepenonacog alfa<div dir="ltr" style="text-align: left;" trbidi="on">
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
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<div class="alt" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
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<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
101NSADNKVVCS CTEGYRLAEN QKSCEPAVPF PCGRVSVSQT SKLTRAETVF</div>
<div class="alt" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
151PDVDYVNSTE AETILDNITQ STQSFNDFTR VVGGEDAKPG QFPWQVVLNG</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
201KVDAFCGGSI VNEKWIVTAA HCVETGVKIT VVAGEHNIEE TEHTEQKRNV</div>
<div class="alt" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
251IRIIPHHNYN AAINKYNHDI ALLELDEPLV LNSYVTPICI ADKEYTNIFL</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
301KFGSGYVSGW GRVFHKGRSA LVLQYLRVPL VDRATCLRST KFTIYNNMFC</div>
<div class="alt" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
351AGFHEGGRDS CQGDSGGPHV TEVEGTSFLT GIISWGEECA MKGKYGIYTK</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
401VSRYVNWIKE KTKLTPVSQT SKLTRAETVF PDVDAHKSEV AHRFKDLGEE</div>
<div class="alt" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
451NFKALVLIAF AQYLQQCPFE DHVKLVNEVT EFAKTCVADE SAENCDKSLH</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
501TLFGDKLCTV ATLRETYGEM ADCCAKQEPE RNECFLQHKD DNPNLPRLVR</div>
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601CCQAADKAAC LLPKLDELRD EGKASSAKQR LKCASLQKFG ERAFKAWAVA</div>
<div class="alt" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
651RLSQRFPKAE FAEVSKLVTD LTKVHTECCH GDLLECADDR ADLAKYICEN</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
701QDSISSKLKE CCEKPLLEKS HCIAEVENDE MPADLPSLAA DFVESKDVCK</div>
<div class="alt" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
751NYAEAKDVFL GMFLYEYARR HPDYSVVLLL RLAKTYETTL EKCCAAADPH</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
801ECYAKVFDEF KPLVEEPQNL IKQNCELFEQ LGEYKFQNAL LVRYTKKVPQ</div>
<div class="alt" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
851VSTPTLVEVS RNLGKVGSKC CKHPEAKRMP CAEDYLSVVL NQLCVLHEKT</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
901PVSDRVTKCC TESLVNRRPC FSALEVDETY VPKEFNAETF TFHADICTLS</div>
<div class="alt" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
951EKERQIKKQT ALVELVKHKP KATKEQLKAV MDDFAAFVEK CCKADDKETC</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
1001FAEEGKKLVA ASQAALGL</div>
<div class="row" style="font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<div class="col-xs-4">
<div class="good-title" style="color: #333333;">
<br /></div>
<div class="good-title">
<span style="color: red;">Albutrepenonacog alfa</span></div>
<div class="good-title" style="color: #333333;">
recombinant factor IX</div>
<div class="clearfix" style="color: #333333;">
<span class="pull-left good-bq">(Idelvion<sup>®</sup>)</span><i class="pull-left icon-bq icon-blackRed">Approved, 2016-03-04 USFDA</i></div>
<div style="color: #333333;">
A recombinant albumin-human coagulation factor IX (FIX) fusion protein indicated for the treatment and prevention of bleeding in patients with hemophilia B.</div>
<div class="pic-logo" style="color: #333333;">
<img alt="" data-mce-src="http://182.92.230.50:82/drug/images/PB0298-LOGO-01.png" height="57" src="http://182.92.230.50:82/drug/images/PB0298-LOGO-01.png" style="height: auto; max-width: 100%;" width="400" /></div>
</div>
<div class="col-xs-4" style="color: #333333;">
<div class="addr yfdm">
<span class="offset-r10 f-red">Research Code</span> <span class="f-red f_n">CSL-654</span></div>
<div class="detailTitle">
CAS 1357448-54-4</div>
<div class="detailHeader">
<div class="indexName">
Blood-coagulation factor IX (synthetic human) fusion protein with peptide (synthetic linker) fusion protein with serum albumin (synthetic human)</div>
<div class="classIdentifiers">
<table class="table table-bordered mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Type</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Recombinant coagulation factor</td><td rowspan="6" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="380"><a class="fancybox-buttons" data-fancybox-group="biology" data-mce-href="http://182.92.230.50:82/drug/biology/PB0298-Albutrepenonacogalfa-structure-01.png" href="http://182.92.230.50:82/drug/biology/PB0298-Albutrepenonacogalfa-structure-01.png"><img alt="" class="" data-mce-src="http://182.92.230.50:82/drug/biology/PB0298-Albutrepenonacogalfa-structure-01.png" height="312" src="http://182.92.230.50:82/drug/biology/PB0298-Albutrepenonacogalfa-structure-01.png" style="height: auto; max-width: 100%;" width="312" /></a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Source</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Human</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Formula</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">C5077H7846N1367O1588S67</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Weight</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">~125000</td></tr>
</tbody></table>
</div>
<div class="otherNames">
<h3>
Other Names</h3>
<ul>
<li>Albutrepenonacog alfa</li>
</ul>
</div>
<div class="sequenceData">
<h3 class="delegateToggle sequenceLabel" data-toggle-ids="SEQUENCE_DETAILS_1357448-54-4_content" data-toggle-to="on">
Protein Sequence</h3>
Sequence Length: 1018modified (modifications unspecified)</div>
</div>
</div>
<div class="col-xs-2 thumbnail-b offset-t15" style="color: #333333;">
<ul class="data-list__content">
<li class="data-list__property" id="at-a-glance_origniator"><strong class="data-list__property-key">Originator </strong><span class="data-list__property-value">CSL Behring</span></li>
<li class="data-list__property" id="at-a-glance_class"><strong class="data-list__property-key">Class </strong><span class="data-list__property-value">Albumins; Antihaemorrhagics; Blood coagulation factors; Recombinant fusion proteins</span></li>
<li class="data-list__property" id="at-a-glance_mechanismOfAction"><strong class="data-list__property-key">Mechanism of Action </strong><span class="data-list__property-value">Blood coagulation factor replacements; Factor X stimulants</span></li>
</ul>
<ul class="data-list__content" id="at-a-glance_orphanStatus">
<li class="data-list__property"><strong class="data-list__property-key show-tooltip">Orphan Drug Status </strong><span class="data-list__property-value">Yes - Haemophilia B</span></li>
</ul>
</div>
</div>
<div class="col-xs-2 thumbnail-b offset-t15" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<ul class="data-list__content data-list__content--highest-dev-phases">
<li class="data-list__property"><strong class="data-list__property-key">Marketed </strong><span class="data-list__property-value">Haemophilia B</span></li>
</ul>
<h3 class="data-list__heading" id="at-a-glance_mostRecentEvents">
Most Recent Events</h3>
<ul class="data-list__content data-list__content--most-recent-events">
<li class="data-list__property"><strong class="data-list__property-key">21 Mar 2016 </strong><span class="data-list__property-value property-value--event-details">Launched for Haemophilia B (In adolescents, In children, In adults) in USA (IV) - First global launch</span></li>
<li class="data-list__property"><strong class="data-list__property-key">07 Mar 2016 </strong><span class="data-list__property-value property-value--event-details">Preregistration for Haemophilia B in Australia (IV) before March 2016</span></li>
<li class="data-list__property"><strong class="data-list__property-key">04 Mar 2016 </strong><span class="data-list__property-value property-value--event-details">Registered for Haemophilia B (In children, In adolescents, In adults) in USA (IV)</span></li>
</ul>
<div>
<table border="1" cellpadding="10" cellspacing="0" class="generalInfo gvTables" id="MainContent_PublicProductProfileControl_dvGeneralInformationMain" rules="all"><tbody>
<tr><td style="font-family: inherit; font-size: inherit;">Company</td><td style="font-family: inherit; font-size: inherit;">CSL Ltd.</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Description</td><td style="font-family: inherit; font-size: inherit;">Fusion protein linking recombinant coagulation Factor IX with recombinant albumin</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Molecular Target</td><td style="font-family: inherit; font-size: inherit;">Factor IX <a class="company_link mce-item-anchor" href="https://www.blogger.com/null" id="MainContent_PublicProductProfileControl_dvGeneralInformationMain_hlMolecularTarget2" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url(http://www.allfordrugs.com/wp-includes/js/tinymce/skins/lightgray/img/anchor.gif) 50% 50% no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;"></a></td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Mechanism of Action</td><td style="font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Therapeutic Modality</td><td style="font-family: inherit; font-size: inherit;">Biologic: Fusion protein</td></tr>
</tbody></table>
</div>
<div>
<table border="1" cellspacing="0" class="generalInfo gvTables" id="MainContent_PublicProductProfileControl_dvGeneralInformationMainSingleIndication" rules="all"><tbody>
<tr><td style="font-family: inherit; font-size: inherit;">Latest Stage of Development</td><td style="font-family: inherit; font-size: inherit;">Approved</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Standard Indication</td><td style="font-family: inherit; font-size: inherit;">Hemophilia</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Indication Details</td><td style="font-family: inherit; font-size: inherit;">Treat and prevent bleeding episodes in hemophilia B patients; Treat hemophilia B</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Regulatory Designation</td><td style="font-family: inherit; font-size: inherit;">U.S. - Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients);<br />EU - Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients);<br />Switzerland - Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients)</td></tr>
</tbody></table>
</div>
<ul class="data-list__content data-list__content--most-recent-events">
<li class="data-list__property"><table border="0" cellpadding="3" cellspacing="0" class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187); width: 100%px;"><tbody>
<tr><td align="left" height="20" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top" width="25%"><div align="left">
BNF Category:</div>
</td><td align="left" bgcolor="#FFFFFF" class="tableBottomRows" height="20" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top" width="75%"><div align="left">
Antifibrinolytic drugs and haemostatics (02.11)</div>
</td></tr>
<tr><td align="left" height="20" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top" width="25%">Pharmacology:</td><td align="left" bgcolor="#FFFFFF" class="tableBottomRows" height="20" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top" width="75%">Albutrepenonacog alfa is a recombinant factor IX (rIX-FP) albumin fusion protein, designed to exhibit an extended half-life. Factor IX has a short half-life which necessitates multiple injections.</td></tr>
<tr><td align="left" height="20" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top" width="25%">Epidemiology:</td><td align="left" bgcolor="#FFFFFF" class="tableBottomRows" height="20" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top" width="75%">Haemophilia B is a genetic disorder caused by missing or defective factor IX, a clotting protein. It has a prevalence of around 1 in 50,000 live births in the UK and is more common in males. In 2012-13, there were 476 hospital admissions in England due to haemophilia B, accounting for 508 finished consultant episodes and 125 bed days.</td></tr>
<tr><td align="left" height="20" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top" width="25%">Indication:</td><td align="left" bgcolor="#FFFFFF" class="tableBottomRows" height="20" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top" width="75%">Haemophilia B</td></tr>
</tbody></table>
</li>
</ul>
</div>
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<img alt="" data-mce-src="http://182.92.230.50:82/drug/biology/PB0298-Albutrepenonacogalfa-structure-01.png" src="http://182.92.230.50:82/drug/biology/PB0298-Albutrepenonacogalfa-structure-01.png" style="height: auto; max-width: 100%;" /></div>
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Albutrepenonacog alfa was approved by the U.S. Food and Drug Administration (FDA) on March 4, 2016. It was developed and marketed as Idelvion<sup>®</sup> by CSL Behring.<br />
Albutrepenonacog alfa is a recombinant albumin-human coagulation factor IX (FIX) fusion protein, which replaces the missing FIX needed for effective hemostasis. It is indicated for the treatment and prevention of bleeding in children and adults with hemophilia B.<br />
Idelvion<sup>®</sup> is available as injection (lyophilized powder) for intravenous use, containing 250 IU, 500 IU, 1000 IU or 2000 IU of albutrepenonacog alfa in single-use vials. In control and prevention of bleeding episodes and perioperative management, the required dosage is determined using the following formulas: Required Dose (IU) = Body Weight (kg) x Desired Factor IX rise (% of normal or IU/dL) x (reciprocal of recovery (IU/kg per IU/dL)). In routine prophylaxis, the recommended dose is 25-40 IU/kg (for patients ≥12 years of age) or 40-55 IU/kg (for patients <12 years of age) every 7 days.</div>
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On 25 February 2016, the <span class="glossary-term">Committee for Medicinal Products for Human Use</span> (<span class="glossary-term">CHMP</span>) adopted a positive opinion, recommending the granting of a <span class="glossary-term">marketing authorisation</span> for the <span class="glossary-term">medicinal product</span> IDELVION, intended for treatment and prophylaxis of bleeding in patients with Haemophilia B. IDELVION was designated as an orphan <span class="glossary-term">medicinal product</span>on 04 February 2010. The applicant for this <span class="glossary-term">medicinal product</span> is CSL Behring GmbH.<br />
IDELVION will be available as 250 IU, 500 IU, 1000 IU and 2000 IU Powder and solvent for solution for injection. The <span class="glossary-term">active substance</span> of IDELVION is albutrepenonacog alfa, an antihaemorrhagic, blood coagulation factor IX, (<span class="glossary-term">ATC code</span>: B02BD04). It works as replacement therapy and temporarily increases plasma levels of factor IX, helping to prevent and control bleeding.<br />
The benefits with IDELVION are its ability to stop the bleeding when given on demand and prevent bleeding when used as routine prophylaxis or for surgical procedures. The most common side effects are injection site reaction and headache.<br />
The full <span class="glossary-term">indication</span> is: "the treatment and prophylaxis of bleeding in patients with Haemophilia B (congenital factor IX deficiency)". Idelvion can be used in all age groups. It is proposed that IDELVION be prescribed by physicians experienced in the treatment of haemophilia B.<br />
Detailed recommendations for the use of this product will be described in the <span class="glossary-term">summary of product characteristics</span> (SmPC), which will be published in the <span class="glossary-term">European public assessment report</span> (EPAR) and made available in all official European Union languages after the <span class="glossary-term">marketing authorisation</span> has been granted by the European Commission.</div>
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<table border="1" cellpadding="0" cellspacing="0" class="summary" summary="Detailed product information for Idelvion"><tbody>
<tr class="alt"><th scope="row" style="font-family: inherit; font-size: inherit;">Name</th><td style="font-family: inherit; font-size: inherit;">Idelvion</td></tr>
<tr><th scope="row" style="font-family: inherit; font-size: inherit;">INN or common name</th><td style="font-family: inherit; font-size: inherit;">albutrepenonacog alfa</td></tr>
<tr class="alt"><th scope="row" style="font-family: inherit; font-size: inherit;">Therapeutic area</th><td style="font-family: inherit; font-size: inherit;"><span class="category">Hemophilia B</span></td></tr>
<tr><th scope="row" style="font-family: inherit; font-size: inherit;"><span class="glossary-term">Active substance</span></th><td style="font-family: inherit; font-size: inherit;">albutrepenonacog alfa</td></tr>
<tr class="alt"><th scope="row" style="font-family: inherit; font-size: inherit;">Date opinion adopted</th><td style="font-family: inherit; font-size: inherit;">25/02/2016</td></tr>
<tr><th scope="row" style="font-family: inherit; font-size: inherit;">Company name</th><td style="font-family: inherit; font-size: inherit;">CSL Behring GmbH</td></tr>
<tr class="alt"><th scope="row" style="font-family: inherit; font-size: inherit;">Status</th><td style="font-family: inherit; font-size: inherit;">Positive</td></tr>
<tr><th scope="row" style="font-family: inherit; font-size: inherit;">Application type</th><td style="font-family: inherit; font-size: inherit;">Initial authorisation</td></tr>
</tbody></table>
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//////Albutrepenonacog alfa, CSL-654, Idelvion; Recombinant factor IX - CSL Behring, Recombinant factor IX fusion protein linked with human albumin, rFIX-FP - CSL Behring; rIX-FP, <strong class="data-list__property-key show-tooltip">Orphan Drug Status, </strong><span class="data-list__property-value"> Haemophilia B, recombinant factor IX , FDA 2016</span></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-302770220608373834.post-77680278624378464122015-12-27T18:43:00.000-08:002015-12-27T18:45:15.520-08:00New Drug Approvals blog by Dr Anthony Crasto hits ten lakh views in 211 countries<div dir="ltr" style="text-align: left;" trbidi="on">
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New Drug Approvals hits ten lakh views in 211 countries<br />
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THANKS AND REGARD'S<br />
DR ANTHONY MELVIN CRASTO Ph.D<br />
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<b>Dr. Anthony Melvin Crasto</b><br />
Principal Scientist, Glenmark Pharma</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-302770220608373834.post-20684289069590669072015-11-17T04:23:00.002-08:002018-04-02T02:07:21.571-07:00LIK 066, Licogliflozin diprolinate<div dir="ltr" style="text-align: left;" trbidi="on">
<br />
<a href="https://newdrugapprovals.files.wordpress.com/2015/11/imgf000135_00011.png"><img alt="imgf000135_0001" class="alignnone size-medium wp-image-15779" height="263" src="https://newdrugapprovals.files.wordpress.com/2015/11/imgf000135_00011.png?w=300&h=263" width="300" /></a><br />
<br />
Licogliflozin diprolinate<br />
<a href="https://newdrugapprovals.files.wordpress.com/2015/11/lik-066.png"><img alt="lik 066" class="alignnone wp-image-15789" height="405" src="https://newdrugapprovals.files.wordpress.com/2015/11/lik-066.png?w=630&h=405" width="630" /></a><br />
LIK-066, a new flozin on the horizon<br />
C23 H28 O7 . 2 C6 H11 N O, 642.7795, <span class="searchhit">1 :2 co-crystal of Example 62 : L-proline. A melting point 176°C…<a href="https://www.google.com/patents/WO2011048112A1?cl=en">WO2011048112</a></span><br />
CAS 1291095-45-8, (1<em>S</em>)-1,5-anhydro-1-<em>C</em>-[3-
[(2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-4-ethylphenyl]-
D-glucitol (1:1) WITH L-Proline, compd., 1:1 Proline Co-crvstal ,
1:1 Proline Co-crvstal …..<span class="searchhit">…<a href="https://www.google.com/patents/WO2011048112A1?cl=en">WO2011048112</a></span><br />
CAS BASE 1291094-73-9, 416.46, C<sub>23</sub> H<sub>28</sub> O<sub>7</sub><br />
(1S)-1,5-Anhydro-1-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-ethylphenyl]-D-glucitol bis[1-[(2S)-pyrrolidin-2-yl]ethanone]<br />
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol<br />
Sodium glucose transporter-2 inhibitor<br />
SGLT 1/2 inhibitor<br />
<a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Novartis+Ag%22">Novartis Ag</a> innovator<br />
Clinical trial……..<a href="https://clinicaltrials.gov/ct2/show/NCT01915849">https://clinicaltrials.gov/ct2/show/NCT01915849</a><br />
<a href="https://clinicaltrials.gov/ct2/show/NCT02470403">https://clinicaltrials.gov/ct2/show/NCT02470403</a><br />
<ul class="data-list__content data-list__content--most-recent-events">
<li class="data-list__property"><strong class="data-list__property-key">10 Jun 2015</strong> <span class="data-list__property-value property-value--event-details"> Novartis initiates enrolment in a phase II trial for Type 2 diabetes mellitus in USA (NCT02470403) </span></li>
<li class="data-list__property"><strong class="data-list__property-key">02 Apr 2014</strong> <span class="data-list__property-value property-value--event-details">
Novartis terminates a phase II trial in Type-2 diabetes mellitus in
USA, Poland, Argentina, Hungary, Puerto Rico and South Africa
(NCT01824264) </span></li>
<li class="data-list__property"><strong class="data-list__property-key">01 Jan 2014</strong> <span class="data-list__property-value property-value--event-details"> Novartis completes a phase II trial in Type 2 diabetes mellitus in USA (NCT01915849) </span></li>
</ul>
<div>
<span style="color: red;"><strong>Licogliflozin, a SGLT-1/2 inhibitor, is in phase II clinical development at Novartis for the treatment of metabolic disorders, for the treatment of heart failure in patients with type 2 diabetes, for the treatment of obesity and for the treatment of polycystic ovary syndrome (PCOS) in overweight and obese women. Phase II trials for the treatment of type 2 diabetes had been discontinued.</strong></span></div>
SEE ALSO<br />
<a href="https://newdrugapprovals.files.wordpress.com/2015/11/imgf000135_00011.png"><img alt="imgf000135_0001" class="alignnone size-medium wp-image-15779" height="263" src="https://newdrugapprovals.files.wordpress.com/2015/11/imgf000135_00011.png?w=300&h=263" width="300" /></a><br />
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000061_0002.png"> <img alt="Figure imgf000061_0002" class="patent-full-image" src="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000061_0002.png" height="224" id="imgf000061_0002" width="310" /><img alt="Figure imgf000059_0002" class="patent-full-image" src="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000059_0002.png" height="148" id="imgf000059_0002" width="456" /> </a></div>
<a href="http://www.google.co.in/patents/WO2012140597A1?cl=en#">WO2012140597</a><br />
<br />
<strong><img alt="" height="113" src="https://upload.wikimedia.org/wikipedia/en/thumb/7/76/Novartis.svg/1024px-Novartis.svg.png" width="640" /></strong><br />
LIK-066 is in phase II clinical studies at Novartis for the treatment of type 2 diabetes.<br />
In June 2014, the EMA’s PDCO adopted a positive opinion on a pediatric investigation plan (PIP) for LIK-066 for type 2 diabetes<br />
Diabetes mellitus is a metabolic disorder characterized by recurrent
or persistent hyperglycemia (high blood glucose) and other signs, as
distinct from a single disease or condition. Glucose level abnormalities
can result in serious long-term complications, which include
cardiovascular disease, chronic renal failure, retinal damage, nerve
damage (of several kinds), microvascular damage and obesity.<br />
<img alt="" src="https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcREp9Yf7pREgiMwtMM001emzC7ItENdxwOHc_3504dbArkhbaJZ" /><br />
Type 1 diabetes, also known as Insulin Dependent Diabetes Mellitus
(IDDM), is characterized by loss of the insulin-producing β-cells of the
islets of Langerhans of the pancreas leading to a deficiency of
insulin. Type-2 diabetes previously known as adult- onset diabetes,
maturity-onset diabetes, or Non-Insulin Dependent Diabetes Mellitus
(NIDDM) – is due to a combination of increased hepatic glucose output,
defective insulin secretion, and insulin resistance or reduced insulin
sensitivity (defective responsiveness of tissues to insulin). Chronic
hyperglycemia can also lead to onset or progression of glucose toxicity
characterized by decrease in insulin secretion from β-cell, insulin
sensitivity; as a result diabetes mellitus is self-exacerbated [Diabetes
Care, 1990, 13, 610].<br />
Chronic elevation of blood glucose level also leads to damage of
blood vessels. In diabetes, the resultant problems are grouped under
“microvascular disease” (due to damage of small blood vessels) and
“macro vascular disease” (due to damage of the arteries). Examples of
microvascular disease include diabetic retinopathy, neuropathy and
nephropathy, while examples of macrovascular disease include coronary
artery disease, stroke, peripheral vascular disease, and diabetic
myonecrosis.<br />
Diabetic retinopathy, characterized by the growth of weakened blood
vessels in the retina as well as macular edema (swelling of the macula),
can lead to severe vision loss or blindness. Retinal damage (from
microangiopathy) makes it the most common cause of blindness among
non-elderly adults in the US. Diabetic neuropathy is characterized by
compromised nerve function in the lower extremities. When combined with
damaged blood vessels, diabetic neuropathy can lead to diabetic foot.
Other forms of diabetic neuropathy may present as mononeuritis or
autonomic neuropathy. Diabetic nephropathy is characterized by damage to
the kidney, which can lead to chronic renal failure, eventually
requiring dialysis. Diabetes mellitus is the most common cause of l
adult kidney failure worldwide. A high glycemic diet (i.e., a diet that
consists of meals that give high postprandial blood sugar) is known to
be one of the causative factors contributing to the development of
obesity.<br />
Type 2 diabetes is characterized by insulin resistance and/or
inadequate insulin secretion in response to elevated glucose level.
Therapies for type 2 diabetes are targeted towards increasing insulin
sensitivity (such as TZDs), hepatic glucose utilization (such as
biguanides), directly modifying insulin levels (such as insulin, insulin
analogs, and insulin secretagogues), increasing increttn hormone action
(such as exenatide and sitagliptin), or inhibiting glucose absorption
from the diet (such as alpha glucosidase inhibitors) [Nature 2001 , 414,
821-827],<br />
Glucose is unable to diffuse across the cell membrane and requires
transport proteins. The transport of glucose into epithelial cells is
mediated by a secondary active cotransport system, the sodium-D-glucose
co-transporter (SGLT), driven by a sodium- gradient generated by the
Na+/K+-ATPase. Glucose accumulated in the epithelial cell is further
transported into the blood across the membrane by facilitated diffusion
through GLUT transporters [Kidney International 2007, 72, S27-S35].<br />
SGLT belongs to the sodium/glucose co-transporter family SLCA5. Two
different SGLT isoforms, SGLT1 and SGLT2, have been identified to
mediate renal tubular glucose reabsorption in humans [Curr. Opinon in
Investigational Drugs (2007): 8(4), 285-292 and references cited
herein]. Both of them are characterized by their different substrate
affinity. Although both of them show 59% homology in their amino acid
sequence, they are functionally different. SGLT1 transports glucose as
well as galactose, and is expressed both in the kidney and in the
intestine, while SGLT2 is found exclusively in the S1 and S2 segments of
the renal proximal tubule.<br />
As a consequence, glucose filtered in the glomerulus is reabsorbed
into the renal proximal tubular epithelial cells by SGLT2, a
low-affinity/high-capacity system, residing on the surface of epithelial
cell lining in S1 and S2 tubular segments. Much smaller amounts of
glucose are recovered by SGLT1 , as a high-affinity/low-capacity system,
on the more distal segment of the proximal tubule. In healthy human,
more than 99% of plasma glucose that is filtered in the kidney
glomerulus is reabsorbed, resulting in less than 1 % of the total
filtered glucose being excreted in urine. It is estimated that 90% of
total renal glucose absorption is facilitated by SGLT2; remaining 10 %
is likely mediated by SGLT1 [J. Parenter. Enteral Nutr. 2004, 28,
364-371].<br />
SGLT2 was cloned as a candidate sodium glucose co-transporter, and
its tissue distribution, substrate specificity, and affinities are
reportedly very similar to those of the low-affinity sodium glucose
co-transporter in the renal proximal tubule. A drug with a mode of
action of SGLT2 inhibition will be a novel and complementary approach to
existing classes of medication for diabetes and its associated diseases
to meet the patient’s needs for both blood glucose control, while
preserving insulin secretion. In addition, SGLT2 inhibitors which lead
to loss of excess glucose (and thereby excess calories) may have
additional potential for the treatment of obesity.<br />
Indeed small molecule SGLT2 inhibitors have been discovered and the
anti-diabetic therapeutic potential of such molecules has been reported
in literature [T-1095 (Diabetes, 1999, 48, 1794-1800, Dapagliflozin
(Diabetes, 2008, 57, 1723-1729)].<br />
<h1>
<span style="color: red;">SYNTHESIS</span></h1>
<a href="https://newdrugapprovals.files.wordpress.com/2015/11/imgf000132_0001.png"><img alt="imgf000132_0001" class="alignnone wp-image-15770" height="219" src="https://newdrugapprovals.files.wordpress.com/2015/11/imgf000132_0001.png?w=839&h=288" width="640" /></a><br />
<a href="https://newdrugapprovals.files.wordpress.com/2015/11/imgf000135_0001.png"><img alt="imgf000135_0001" class="alignnone wp-image-15771" height="149" src="https://newdrugapprovals.files.wordpress.com/2015/11/imgf000135_0001.png?w=827&h=193" width="640" /></a><br />
<h1>
<span style="color: red;">PATENT</span></h1>
WO 2011048112<br />
<a href="https://www.google.com/patents/WO2011048112A1?cl=en">https://www.google.com/patents/WO2011048112A1?cl=en</a><br />
<span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Gregory+Raymond+Bebernitz%22">Gregory Raymond Bebernitz</a>, </span><span class="patent-bibdata-value-list"><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Mark+G.+Bock%22">Mark G. Bock</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Dumbala+Srinivas+Reddy%22">Dumbala Srinivas Reddy</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Atul+Kashinath+Hajare%22">Atul Kashinath Hajare</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Vinod+Vyavahare%22">Vinod Vyavahare</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Sandeep+Bhausaheb+Bhosale%22">Sandeep Bhausaheb Bhosale</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Suresh+Eknath+Kurhade%22">Suresh Eknath Kurhade</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Videsh+Salunkhe%22">Videsh Salunkhe</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Nadim+S.+Shaikh%22">Nadim S. Shaikh</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Debnath+Bhuniya%22">Debnath Bhuniya</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22P.+Venkata+Palle%22">P. Venkata Palle</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Lili+Feng%22">Lili Feng</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Jessica+Liang%22">Jessica Liang</a></span>, </span><br />
<span class="patent-bibdata-value"><a href="https://www.google.com/url?id=c2rXBgABERAJ&q=http://patentscope.wipo.int/search/en/WO2011048112&usg=AFQjCNGN7OC9-iVjVCY7rMJRz6peaY5goA">Patentscope</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/url?id=c2rXBgABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DWO%26NR%3D2011048112A1%26KC%3DA1%26FT%3DD&usg=AFQjCNH4S_aWc7gGRvePk_XqBKmLxwFkfA">Espacenet</a></span><br />
Example 61-62:<br />
<div class="patent-image">
<a href="https://patentimages.storage.googleapis.com/WO2011048112A1/imgf000135_0001.png"><img alt="Figure imgf000135_0001" class="patent-full-image" height="140" id="imgf000135_0001" src="https://patentimages.storage.googleapis.com/WO2011048112A1/imgf000135_0001.png" width="608" /></a></div>
Ex. 61<br />
Example 61 : Acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester<br />
Step I: To a stirred solution of acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3- (2,3-dihydro-benzo[1
,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.0 g,
15.74 mmol) in toluene (200 mL) was added tricyclohexylphosphine (1.76
g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9
mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol). The
reaction mixture was degassed for 45 min then palladium (II) acetate
(529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction
mixture was cooled to room temperature, and water was added. The
resulting mixture was extracted with ethyl acetate, (2 X 200 mL), washed
with water and brine, then dried over sodium sulfate, concentrated and
purified by column chromatography to furnish acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester
(5.4 g).<br />
Example 62:
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-
ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol<br />
Step II: To a stirred solution of acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester
(9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 mL) was added
lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room
temperature, the volatiles were evaporated under reduced pressure. The
resulting residue was taken up in ethyl acetate (150 mL) and washed with
brine (75 mL), brine containing 5 mL of 5% aqueous KHS0<sub>4</sub> (75
mL), and brine (20 mL) again, then dried over sodium sulfate and
concentrated to furnish
(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro- benzo[1
,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(6.59)<br />
<br />
<strong><span style="color: red;"><em>H NMR (400 MHz, CD<sub>3</sub>OD):
δ 1.07 (t, J = 7.6 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.34- 3.50 (m,
4H), 3.68 (dd, J = 12.0, 5.6 Hz, 1 H), 3.85-3.91 (m, 3H), 4.08 (d, J =
9.6 Hz, 1 H), 4.17 (s, 4H), 6.53-6.58 (m, 2H), 6.68 (d, J – 8.4 Hz, 1
H), 7.15-7.25 (m, 3H).</em></span></strong><br />
<strong><span style="color: red;"><em>MS (ES) m z 434.2 (M+18).</em></span></strong><br />
<h1>
<strong><em><span style="color: red;">PICK UP IDEAS FROM HERE</span></em></strong></h1>
<br />
Examples 57-58:<br />
<div class="patent-image">
<a href="https://patentimages.storage.googleapis.com/WO2011048112A1/imgf000132_0001.png"><img alt="Figure imgf000132_0001" class="patent-full-image" height="204" id="imgf000132_0001" src="https://patentimages.storage.googleapis.com/WO2011048112A1/imgf000132_0001.png" width="604" /></a></div>
Ex. 57 Ex. 58<br />
Step I: To a stirred solution of 2-bromo-5-iodobenzoic acid (25.0 g,
76.48 mmol) in dichloromethane (200 mL) was added oxalyl chloride (10.3
mL, 114.74 mmol) at 0 °C followed by D F (0.9 mL). After complete
addition, the reaction mixture was stirred at room temperature for 3h.
Volatiles were evaporated under reduced pressure to furnish
2-bromo-5-iodo-benzoyl chloride (26.4 g). The crude product was used for
the next step immediately.<br />
Step II: To a stirred solution of 2-bromo-5-iodo-benzoyl chloride
(26.4 g, 76.56 mmol) in dichloromethane (250 mL) was added benzo(1
,4)-dioxane (10.41 g, 76.26 mmol) at 0 °C. To this reaction mixture,
AICI<sub>3</sub> (40.78 g, 305.47 mmol) was added in portions. After
stirring overnight at room temperature, the reaction mixture was poured
into crushed ice. The resulting mixture was extracted with
dichloromethane (500 mL X 2). The dichloromethane layers were combined
and washed with water (200 mL), saturated aqueous sodium bicarbonate
solution (200 mL X 2), and brine (200 mL), then dried over sodium
sulfate and concentrated. The solid product was triturated with hexanes,
and the triturated product was dried under vacuum to furnish
(2-bromo-5-iodo-phenyl)-(2,3- dihydro-benzo[1 ,4]dioxin-6-yl)-methanone
(30 g).<br />
<sup>1</sup>H N R (400 MHz, DMSO-D<sub>6</sub>): δ 4.29-4.37 (m, 4H),
7.02 (d, J = 8.4 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 7.18-7.19 (m, 1
H), 7.53 (d, J = 8.4 Hz, 1 H), 7.77-7.81 (m, 1 H), 7.82 (d, J = 2.0 Hz, 1
H).<br />
Step III: To a stirred solution of
(2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1 ,4]dioxin- 6-yl)-methanone
(30.0 g, 67.4 mmol) in trifluoroacetic acid (100 mL) was added
triethylsilane (86.2 mL, 539.3 mmol) followed by triflic acid (6.0 mL,
67.42 mmol ) at room temperature. After stirring for 25 min at room
temperature, volatiles were evaporated under reduced pressure. The
resulting residue was taken up in ethyl acetate and washed with
saturated aqueous sodium bicarbonate solution (200 mL X 2), water (200
mL), and brine (200 mL), then dried over sodium sulfate, concentrated
and purified by silica gel column chromatography to furnish
6-(2-bromo-5-iodo-benzyl)-2,3- dihydro-benzo[1 ,4]dioxine (26.5 g). H
NMR (400 MHz, DMSO-D<sub>6</sub>): δ 3.90 (s, 4H), 4.2 (s, 2H), 6.65
(dd, J = 8.4 Hz, J = 2.0 Hz, H), 6.68 (d, J = 2.0 Hz, 1 H), 6.77 (d, J =
8.4 Hz, H), 7.39 (d, J = 8.4 Hz, 1 H), 7.50 (dd, J = 8.4 Hz, J = 2.4 Hz
1 H), 7.67 (d, J = 2.8 Hz, 1 H).<br />
Step IV: To a stirred solution of
6-(2-bromo-5-iodo-benzyl)-2,3-dihydro- benzo[1 ,4]dioxine (26.5 g, 61.47
mmol) in THF:toluene 2:1 (300 mL) was added 1.6 M solution of n-BuLi in
hexanes (42.3 mL, 67.62 mmol) at -78 °C. The reaction mixture was
stirred for 1 h, and then transferred to a stirred solution of
2,3,4,6-tetrakis-O- (trimethylsilyl)-D-glucopyranone (28.69 g, 61.47
mmol) in toluene (100 mL) at -78 °C. After stirring for 1 h, 0.6 N
methanesulfonic acid in methanol (265 mL) was added dropwise and stirred
the reaction mixture for 16 h at room temperature. Reaction was
quenched by the addition of aq. NaHC0<sub>3</sub> solution (~75 mL) and
extracted with ethyl acetate (250 mL X 3), dried over sodium sulfate,
concentrated and purified by silica gel column chromatography to furnish
(3R,4S,5S,6R)-2-[4-Bromo-3-(2,3-dihydro- benzo[1
,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-
3,4,5-triol (28.4 g)<br />
Example 57:
[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1 ,4-
benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate<br />
Step V: To a stirred solution of
(3R,4S,5S,6R)-2-[4-bromo-3-(2,3-dihydro- benzo[1
,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-
triol (28.4 g, 57.1 mmol) in acetonitrile-dichloromethane 1 :1 (250 mL)
was added triethylsilane (36.5 mL, 228.4 mmol) and boron trifluoride
diethyletharate complex (14.1 mL, 114.2 mmol) at 10 °C. After stirring
for 4 h at 10°C, the reaction was quenched with saturated aqueous sodium
bicarbonate (~ 100 mL). The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate (3 X 150 mL). The organic
layers were combined and dried over sodium sulfate, concentrated to
furnish (3R,4R,5S,6R)-2- [4-bromo-3-(2,3-dihydro-benzo[1
,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-
tetrahydro-pyran-3,4,5-triol (28.4 g). Crude product was used for next
reaction without purification. Example 58:
[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2<sub>!</sub>3-dihydro-1,4-
benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate Step
V: To a stirred solution of (3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-
benzo[ 1 ,4]dioxin-6-yl methyl)-phenyl]-6-hydroxymethyl-tetrahyd
ro-pyran-3,4 , 5-triol (28.4 g, 60.81 mmol) in dichloromethane (300 mL)
was added pyridine (40 mL, 486.5 mmol), acetic anhydride (50 mL, 486.5
mmol) and DMAP (740 mg, 6.08 mmol) at room temperature. After stirring
for 2 h, volatiles were evaporated under reduced pressure. The resulting
residue was taken up in ethyl acetate (500ml) and washed with 1 N HCI
(200 mL X 2) followed by brine (200ml), then dried over sodium sulfate
and<br />
concentrated. The resulting crude compound was dissolved in ethanol
(320 mL) at 65 °C and allowed to cool to room temperature while
stirring. Light yellow solid formed was filtered and washed with cold
ethanol (150 mL) followed by hexane (200 mL) to get acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1
,4]dioxin- 6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester powder
(22.5 g, purity 98%).<br />
<br />
<br />
<h1>
<span style="color: red;">COCRYSTAL</span></h1>
Example 75: 1:1 Proline Co-crvstal with
f2S.3R.4R.5S.6R¾-2-r3-f2.3-Dihvdro-
benzori.41dioxin-6-ylmethyl)-4-ethyl-phenvn-6-hvdroxymethyl-tetrahydro-pyran-
3.4.5-triol<br />
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-
phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62) was
completely amorphous initially but formed a crystalline complex with
proline. This was confirmed by powder X-ray diffraction (PXRD) analysis.
The stiochiometry of Example 62 and L- proline in the co-crystal
prepared by method 1 was found to be 1 :1 by NMR<br />
spectroscopy & HPLC. Characterization data for co-crystals of
Example 62 and proline prepared by method 1 is shown in Table 3.
Relative intensities of the most prominent powder x-ray diffraction
peaks for co-crystals of Example 62 and proline are shown in Table 3A.<br />
Table 3<br />
<img alt="" height="314" id="imgf000166_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2010065747@@@id00000006457022@@@8044906@@@imgf000166_0001.gif" width="492" /><br />
Table 3A<br />
<img alt="" height="55" id="imgf000166_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2010065747@@@id00000006457022@@@8044906@@@imgf000166_0002.gif" width="494" /><br />
3.70 15.78 18.36 25.18<br />
9.68 10.68 18.88 36.33<br />
11.07 21.21 20.42 69.29<br />
14.26 14.81 21.18 27.94<br />
14.80 22.97 22.50 12.25<br />
15.40 4 98 23.78 33.08<br />
16.12 8.45 24.56 6.92<br />
16.59 18.78 25.79 21.69<br />
17.31 100.0 27.46 8.90<br />
17.60 20.35 31.97 7.65<br />
17.98 47.20 32.46 5.98<br />
<br />
<h1>
<span style="color: red;"> 1:1 Proline Co-crvstal</span></h1>
Example 77: 1:1 Proline Co-crvstal with
(2S.3R.4R.5S.6Ri-2-f3-(2.3-Dihvdro- benzoh
.41dioxin-6-ylmethvh-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran-
3.4.5-triol<br />
Method 2:<br />
<span style="color: red;">1 :1 Co-Crvstals of Example 62 with L-Proline</span><br />
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-
6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62,
1500mg,3.6mmol), L- proline (415mg, 3.6mmol) and ethanol (23 ml_) were
added to a 50 mL 3-neck round bottom flask equipped with nitrogen
purging, magnetic stirring bar,<br />
thermometer pocket & calcium chloride guard tube and the mixture
was stirred at 25-30°C for 30 min., then heat to reflux. A clear
solution was observed which was refluxed for 30 min., then slowly cool
to 25-30°C causing percipitation. Di- isopropyl ether (DIPE, 23 mL) was
added while maintaining the mixture at 25-30°C and stirring continuously
for additional one to two hours at the same temperature. The
precipitate was collected by filtration using vacuum (Nitrogen
atmosphere), and the filter cake was washed with ethanol-DIPE mixture (1
:1 v/v, 10ml) followed by DIPE (23 mL). The product was vacuum dried at
65-70°C for 5-6 hrs.<br />
1:1 Proline Co-crvstal (ΔΗ 53 J/g) was observed by differential
scanning calorimetry (DSC) and is shown in Fig. 1. A powder X-ray
diffraction (PXRD) spectrum is shown in Fig. 2.<br />
<br />
<h1>
<span style="color: red;">2:1 Proline Co-crvstal</span></h1>
Example 78: 2:1 Proline Co-crvstal with
f2S.3R.4R.5S.6R>-2-r3-f2.3-Pihvdro-benzof1.41dioxin-6-ylmethvH-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran-
3.4.5-triol<br />
Method 3: 1 :2 Co-Crvstals of Example 62 with L-Proline<br />
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(Example 62, 1 kg) was added to 15 L of ethanol with agitation while
maintaining the mixture at 20-25 °C. The mixture was stirred for 10 min
at 20-25 °C, then L-proline (537 gm) was added while maintaining the
mixture at 20-25 °C. The mixture was stirred at this temperature for 30
min., then heated to reflux and refluxed for 30 min. The mixture was
slowly cooled to 25-30°C then stired for 1 hr. DIPE (15 L) was added
while maintaining the temperature at 25-30 °C and the mixture was
stirred at this temperature for 1 hr. The precipitated product was
collected by filtration and the product was washed with DIPE (5 L). The
product was air dried at 65-70 °C to yield 1.22 kg<br />
(79%) of a 1 :2 co-crystal of Example 62 : L-proline. A melting point
176°C (ΔΗ 85 J/g) was observed by differential scanning calorimetry
(DSC) and is shown in Fig.<br />
3. A powder X-ray diffraction (PXRD) spectrum is shown in Fig. 4. Relative<br />
intensities of the most prominent powder x-ray diffraction peaks for
the 1 :2 co- crystals of Example 62 and proline are shown in Table 5.<br />
Table 5<br />
<img alt="" height="165" id="imgf000169_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2010065747@@@id00000006457022@@@8044906@@@imgf000169_0001.gif" width="496" /><br />
<a href="https://newdrugapprovals.files.wordpress.com/2015/11/lik-066.png"><img alt="lik 066" class="alignnone wp-image-15789" height="405" src="https://newdrugapprovals.files.wordpress.com/2015/11/lik-066.png?w=630&h=405" width="630" /></a><br />
<h1>
<span style="color: red;">PATENT</span></h1>
WO 2012140597<br />
<a href="http://www.google.co.in/patents/WO2012140597A1?cl=en">http://www.google.co.in/patents/WO2012140597A1?cl=en</a><br />
. TABLE 2:<br />
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000041_0001.png"><img alt="Figure imgf000041_0001" class="patent-full-image" src="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000041_0001.png" height="704" id="imgf000041_0001" width="548" /></a></div>
<div class="patent-image">
Intermediate 2: (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-<br />
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000049_0001.png"><img alt="Figure imgf000049_0001" class="patent-full-image" src="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000049_0001.png" height="156" id="imgf000049_0001" width="636" /></a></div>
Intermediate 2<br />
Intermediate 1<br />
Step I: To a stirred solution of acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3- (2,3-dihydro-benzo[1
,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester
(Intermediate 1 , 10.0 g, 15.74 mmol) in toluene (200 mL) was added<br />
tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium
phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and
ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassed
for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added.
After refluxing overnight, the reaction mixture was cooled to room
temperature, and water was added. The resulting mixture was extracted
with ethyl acetate, (2 X 200 ml_), washed with water and brine, then
dried over sodium sulfate, concentrated and purified by column
chromatography to furnish acetic acid<br />
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-tetrahydro-pyran-2-ylmethyl ester
(5.4 g).<br />
Step II: To a stirred solution of acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester
(9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 ml.) was added
lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room
temperature, the volatiles were evaporated under reduced pressure. The
resulting residue was taken up in ethyl acetate (150 ml.) and washed
with brine (75 ml_), brine containing 5 ml. of 5% aqueous KHS0<sub>4</sub>
(75 ml_), and brine (20 ml.) again, then dried over sodium sulfate and
concentrated to furnish
(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1
,4]dioxin-6-ylmethyl)-
phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.5 g)<br />
<sup>1</sup>H NMR (400 MHz, CD<sub>3</sub>OD): δ 1.07 (t, J = 7.6 Hz,
3H), 2.57 (q, J = 7.6 Hz, 2H), 3.34- 3.50 (m, 4H), 3.68 (dd, J = 12.0,
5.6 Hz, 1 H), 3.85-3.91 (m, 3H), 4.08 (d, J = 9.6 Hz, 1 H), 4.17 (s,
4H), 6.53-6.58 (m, 2H), 6.68 (d, J = 8.4 Hz, 1 H), 7.15-7.25 (m, 3H).<br />
MS (ES) m/z 434.2 (M+18).<br />
Example 3: Synthesis of phosphoric acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-
ylmethyl ester diethyl ester<br />
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000059_0002.png"><img alt="Figure imgf000059_0002" class="patent-full-image" src="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000059_0002.png" height="148" id="imgf000059_0002" width="456" /></a></div>
To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1
,4]dioxin-6-ylmethyl)-
4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(Intermediate 2, 500 mg, 1.2 mmol) in pyridine (5 ml) was added
diethylchlorophosphate (0.27 ml, 1 .9 mmol) at -40°C. After stirring for
1 h at same temperature, reaction was quenched with the addition of 1 N
HCI and extracted with ethyl acetate (2 X 10 ml). Combined organic
layers were washed with brine (10 ml), dried over sodium sulfate,
concentrated and purified by preparative HPLC to give 220 mg of
phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl
ester diethyl ester as a white solid. <sup>1</sup>H NMR (400 MHz, CD<sub>3</sub>OD):
δ 1.07 (t, J = 7.6 Hz, 3H), 1.15 (td J = 7.2, 1.2 Hz, 3H), 1.22 (td, J =
6.8, 0.8 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.36-3.46 (m, 3H),
3.53-3.55 (m, 1 H),3.89 (s, 2H), 3.96-4.11 (m, 5H), 4.17 (s, 4H),
4.18-4.22 (m 1 H), 4.30-4.34 (m, 1 H), 6.52 (d, J = 2.0 Hz, 1 H),6.57
(dd, J = 8.4, 2.4 Hz, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 7.15- 7.22(m,
3H). MS (ES) m/z 553.3 (M+1 ).<br />
Example 4: Synthesis of disodium salt of phosphoric acid mono-
{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-
3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester<br />
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000061_0001.png"><img alt="Figure imgf000061_0001" class="patent-full-image" src="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000061_0001.png" height="112" id="imgf000061_0001" width="604" /></a></div>
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000061_0002.png"><img alt="Figure imgf000061_0002" class="patent-full-image" src="http://patentimages.storage.googleapis.com/WO2012140597A1/imgf000061_0002.png" height="104" id="imgf000061_0002" width="144" /></a></div>
To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1
,4]dioxin-6-
ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(Intermediate 2, 1.0 g, 2.4 mmol) in THF (15 ml) was added a solution of
Diethyl-phosphoramidic acid di- tert-butyl ester (780 mg, 3.12 mmol) in
THF (5 ml) at 0°C followed by a solution of tetrazole (435 mg, 6.2
mmol) in DCM (12.5 ml). After stirring for 5 min at same temperature, it
was stirred at room temperature for 20 min. Reaction mixture was cooled
to -40 °C and added a solution of m-CPBA (830 mg, 4.8 mmol) in DCM (5
ml). The reaction mixture was stirred at same temperature for 5 min and
then at room temperature for 2 h. Reaction mixture was cooled to 0°C and
quenched by the addition of 10% sodium bisulfite solution (5 ml). This
was extracted with ether (3 X 10 ml). Combined organic layer was washed
with brine (5 ml), dried over sodium sulfate and concentrated to give
700 mg of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6-
[3-(2,3-dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-
pyran-2-ylmethyl ester.<br />
To the stirred solution of phosphoric acid di-tert-butyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3- dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-
ylmethyl ester (500 mg) in methanol (20 ml) was added amberlyst 15 ion
exchange resin (250 mg) and refluxed for overnight. Reaction mixture was
cooled to room temperature, filtered through celite bed and filtrate
was concentrated to give 300 mg of phosphoric acid
mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-
phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester. The crude
material was taken up for next reaction.<br />
To a solution of phosphoric acid
mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-
ylmethyl} ester (300 mg, 0.6 mmol) in methanol (5 ml) was added 1 N
sodium bicarbonate solution (80 mg, 0.7 mmol) in water. After stirring
at room temperature for 2 h, the volatiles were evaporated under reduced
pressure. The resulting solid was triturated with diethyl ether. The
resulting residue was purified by preparative HPLC to give 95 mg of
disodium salt of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-
dihydro-benzo[1
,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-
ylmethyl} ester.<br />
<sup>1</sup>H NMR (400 MHz, CD<sub>3</sub>OD): δ 1.06 (t, J = 7.4 Hz,
3H), 2.56 ( q, J = 7.3 Hz, 2H), 3.34- 3.41 (m, 2H), 3.49 (t, J = 8.8
Hz, 1 H), 3.81-3.88 (m, ,3H), 3.92-3.99 (m, 1 H), 4.05 (d, J = 9.3 Hz, 1
H), 4.16 (s, 4H), 4.20-4.25 (m, 1 H), 6.54 (m, 2H), 6.67 (d, J = 7.8
Hz, 1 H), 7.12-7.21 (m, 3H). MS (ES) m/z 497.1 (M+1 ) for phosphoric
acid.<br />
<img alt="" height="154" src="https://d0.awsstatic.com/logos/customers/Novartis-logo.jpg" width="640" /><br />
<br /></div>
<h1>
<span style="color: red;">PATENT</span></h1>
<br />
SEE INDIAN PATENT<br />
IN 2009DE02173<br />
Glycoside derivatives and uses thereof<br />
<br />
<h1>
<span style="color: red;">REFERENCES</span></h1>
Pediatric investigation plan (PIP) decision:
(S)-Pyrrolidine-2-carboxylic acid compound with
(2S,3R,4R,5S,6R)-2-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
(2:1) ( LIK066) (EMEA-001527-PIP01-13)<br />
European Medicines Agency (EMA) Web Site 2014, July 24<br />
Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD)
assessment of LIK066 in healthy subjects and in patients with type 2
diabetes mellitus (T2DM) (NCT01407003)<br />
ClinicalTrials.gov Web Site 2011, August 07<br />
<a href="http://www.google.co.in/patents/WO2012140597A1?cl=en#">WO2012140597</a><br />
<span class="searchhit"><a href="https://www.google.com/patents/WO2011048112A1?cl=en">WO2011048112</a></span><br />
IN 2009DE02173<br />
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<td class="patent-data-table-td ">Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof</td>
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<td class="patent-data-table-td ">Hideki Fujikura</td>
<td class="patent-data-table-td ">Glucopyranosyloxy benzylbenzene
derivatives, medicinal compositions containing the same and
intermediates for the preparation of the derivatives</td>
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<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/WO2001074834A1?cl=en">WO2001074834A1</a></td>
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<td class="patent-data-table-td ">Squibb Bristol Myers Co</td>
<td class="patent-data-table-td ">O-aryl glucoside sglt2 inhibitors and method</td>
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<td class="patent-data-table-td ">O-pyrazole glucoside sglt2 inhibitors and method of use</td>
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<td class="patent-data-table-td ">Andrew Thomas Bach</td>
<td class="patent-data-table-td ">Heterocyclic compounds and methods of use</td>
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of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole,
topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide,
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<td class="patent-data-table-td ">Novel glucitol derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes</td>
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<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/WO2006054629A1?cl=en">WO2006054629A1</a></td>
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<td class="patent-data-table-td ">Kissei Pharmaceutical</td>
<td class="patent-data-table-td ">1-SUBSTITUTED-3-β-D-GLUCOPYRANOSYLATED NITROGENOUS HETERO- CYCLIC COMPOUNDS AND MEDICINES CONTAINING THE SAME</td>
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<td class="patent-data-table-td patent-date-value">3 Aug 2007</td>
<td class="patent-data-table-td patent-date-value">7 Feb 2008</td>
<td class="patent-data-table-td ">Daiichi Sankyo Co Ltd</td>
<td class="patent-data-table-td ">Benzyl phenyl glucopyranoside derivative</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/WO2011048112A1?cl=en">WO2011048112A1</a><span class="patent-tooltip-anchor"> *</span></td>
<td class="patent-data-table-td patent-date-value">19 Oct 2010</td>
<td class="patent-data-table-td patent-date-value">28 Apr 2011</td>
<td class="patent-data-table-td ">Novartis Ag</td>
<td class="patent-data-table-td ">Glycoside derivatives and uses thereof</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US20030114390">US20030114390</a><span class="patent-tooltip-anchor"> *</span></td>
<td class="patent-data-table-td patent-date-value">4 Oct 2002</td>
<td class="patent-data-table-td patent-date-value">19 Jun 2003</td>
<td class="patent-data-table-td ">Washburn William N.</td>
<td class="patent-data-table-td ">C-aryl glucoside SGLT2 inhibitors and method</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US20040018998">US20040018998</a></td>
<td class="patent-data-table-td patent-date-value">21 Sep 2001</td>
<td class="patent-data-table-td patent-date-value">29 Jan 2004</td>
<td class="patent-data-table-td ">Hideki Fujikura</td>
<td class="patent-data-table-td ">Glucopyranosyloxybenzylbenzene derivatives and medicinal compositions containing the same</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US20060009400">US20060009400</a></td>
<td class="patent-data-table-td patent-date-value">28 Jun 2005</td>
<td class="patent-data-table-td patent-date-value">12 Jan 2006</td>
<td class="patent-data-table-td ">Boehringer Ingelheim International Gmbh</td>
<td class="patent-data-table-td ">D-xylopyranosyl-substituted phenyl
derivatives, medicaments containing such compounds, their use and
process for their manufacture</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US20060019948">US20060019948</a></td>
<td class="patent-data-table-td patent-date-value">15 Jul 2005</td>
<td class="patent-data-table-td patent-date-value">26 Jan 2006</td>
<td class="patent-data-table-td ">Boehringer Ingelheim International Gmbh</td>
<td class="patent-data-table-td ">Methylidene-D-xylopyranosyl- and
oxo-D-xylopyranosyl-substituted phenyl derivatives, medicaments
containing such compounds, their use and process for their manufacture</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US20060025349">US20060025349</a></td>
<td class="patent-data-table-td patent-date-value">27 Jul 2005</td>
<td class="patent-data-table-td patent-date-value">2 Feb 2006</td>
<td class="patent-data-table-td ">Boehringer Ingelheim International Gmbh</td>
<td class="patent-data-table-td ">D-xylopyranosyl-phenyl-substituted cycles, medicaments containing such compounds, their use and process for their manufacture</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US20060035841">US20060035841</a></td>
<td class="patent-data-table-td patent-date-value">9 Aug 2005</td>
<td class="patent-data-table-td patent-date-value">16 Feb 2006</td>
<td class="patent-data-table-td ">Boehringer Ingelheim International Gmbh</td>
<td class="patent-data-table-td ">D-xylopyranosyl-phenyl-substituted cycles, medicaments containing such compounds, their use and process for their manufacture</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US20060074031">US20060074031</a></td>
<td class="patent-data-table-td patent-date-value">30 Sep 2005</td>
<td class="patent-data-table-td patent-date-value">6 Apr 2006</td>
<td class="patent-data-table-td ">Boehringer Ingelheim International Gmbh</td>
<td class="patent-data-table-td ">D-pyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US20060293252">US20060293252</a></td>
<td class="patent-data-table-td patent-date-value">14 Aug 2006</td>
<td class="patent-data-table-td patent-date-value">28 Dec 2006</td>
<td class="patent-data-table-td ">Sanofi-Aventis Deutschland Gmbh</td>
<td class="patent-data-table-td ">Novel Thiophene Glycoside Derivatives,
Processes for The Preparation, Medicaments Comprising These Compounds,
and The Use Thereof</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US20080027014">US20080027014</a></td>
<td class="patent-data-table-td patent-date-value">26 Jul 2007</td>
<td class="patent-data-table-td patent-date-value">31 Jan 2008</td>
<td class="patent-data-table-td ">Tanabe Seiyaku Co., Ltd.</td>
<td class="patent-data-table-td ">Novel SGLT inhibitors</td>
</tr>
</tbody>
</table>
</div>
<div class="patent-section patent-tabular-section">
<table class="patent-data-table">
<thead class="patent-data-table-thead">
<tr class="patent-data-table">
<th class="patent-data-table-th">Citing Patent</th>
<th class="patent-data-table-th">Filing date</th>
<th class="patent-data-table-th">Publication date</th>
<th class="patent-data-table-th">Applicant</th>
<th class="patent-data-table-th">Title</th>
</tr>
</thead>
<tbody>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/WO2015032272A1?cl=en">WO2015032272A1</a><span class="patent-tooltip-anchor"> *</span></td>
<td class="patent-data-table-td patent-date-value">19 Aug 2014</td>
<td class="patent-data-table-td patent-date-value">12 Mar 2015</td>
<td class="patent-data-table-td ">Jiangsu Hansoh Pharmaceutical Co., Ltd.</td>
<td class="patent-data-table-td ">C-aryl glucoside derivative, preparation method for same, and medical applications thereof</td>
</tr>
<tr>
<td class="patent-data-table-td citation-patent"><a href="http://www.google.co.in/patents/US9034921">US9034921</a></td>
<td class="patent-data-table-td patent-date-value">1 Jun 2012</td>
<td class="patent-data-table-td patent-date-value">19 May 2015</td>
<td class="patent-data-table-td ">Green Cross Corporation</td>
<td class="patent-data-table-td ">Diphenylmethane derivatives as SGLT2 inhibitors</td>
</tr>
</tbody>
</table>
</div>
<br />
<br />
INVENTORS OF LIK 066<br />
<span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Gregory+Raymond+Bebernitz%22">Gregory Raymond Bebernitz</a>, </span><span class="patent-bibdata-value-list"><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Mark+G.+Bock%22">Mark G. Bock</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Dumbala+Srinivas+Reddy%22">Dumbala Srinivas Reddy</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Atul+Kashinath+Hajare%22">Atul Kashinath Hajare</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Vinod+Vyavahare%22">Vinod Vyavahare</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Sandeep+Bhausaheb+Bhosale%22">Sandeep Bhausaheb Bhosale</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Suresh+Eknath+Kurhade%22">Suresh Eknath Kurhade</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Videsh+Salunkhe%22">Videsh Salunkhe</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Nadim+S.+Shaikh%22">Nadim S. Shaikh</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Debnath+Bhuniya%22">Debnath Bhuniya</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22P.+Venkata+Palle%22">P. Venkata Palle</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Lili+Feng%22">Lili Feng</a>, </span><span class="patent-bibdata-value"><a href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Jessica+Liang%22">Jessica Liang</a></span>, </span><br />
<table cellpadding="2" cellspacing="3" id="detailPCTtableHeader" style="height: 277px; width: 531px;">
<tbody>
<tr>
<td valign="TOP"><br /></td>
<td><span class="notranslate" id="PCTinventors"><b>BEBERNITZ, Gregory, Raymond</b>; (US).<br />
<b>BOCK, Mark, G.</b>; (US).<br />
<b>REDDY, Dumbala Srinivas</b>; (IN).<br />
<b>HAJARE, Atul Kashinath</b>; (IN).<br />
<b>VYAVAHARE, Vinod</b>; (IN).<br />
<b>BHOSALE, Sandeep Bhausaheb</b>; (IN).<br />
<b>KURHADE, Suresh Eknath</b>; (IN).<br />
<b>SALUNKHE, Videsh</b>; (IN).<br />
<b>SHAIKH, Nadim, S.</b>; (IN).<br />
<b>BHUNIYA, Debnath</b>; (IN).<br />
<b>PALLE, P., Venkata</b>; (IN).<br />
<b>FENG, Lili</b>; (US).<br />
<b>LIANG, Jessica</b>; (US) </span></td>
</tr>
</tbody>
</table>
<a class="lightview" href="http://aurigene.com/wp-content/uploads/2014/02/IMG-20140228-WA0002.jpg" rel="" target="" title=""><img alt="IMG-20140228-WA0002" class="alignnone size-full wp-image-1821" src="http://aurigene.com/wp-content/uploads/2014/02/IMG-20140228-WA0002.jpg" height="160" title="" width="129" /></a>Mark G Bock<br />
<span class="notranslate" id="PCTinventors"><b>BEBERNITZ, Gregory, Raymond….PIC NOT AVAILABLE<br />
</b></span><br />
<span class="notranslate"><b><br /></b></span>
<span class="notranslate"><b><br /></b></span>
<span class="notranslate"><img alt="Image result for SRINIVASAREDDY NCL" height="438" src="http://academic.ncl.res.in/ep_admin/webroot/files/page/ds.reddy/image/PRONAY/HOME/DSC_0043(1).jpg" width="640" /></span><br />
<br />
Dr. Srinivasa Reddy<br />
<img alt="" class="spotlight" src="https://fbcdn-sphotos-f-a.akamaihd.net/hphotos-ak-xpa1/v/t1.0-9/155776_108037479264418_7169875_n.jpg?oh=de4440095aa003a02f59e88d975a894e&oe=56F356EE&__gda__=1455315635_e565257b3820a258ca6ac4f6cee1f907" />NADEEM SHAIKH<br />
<br />
<img alt="Venkata Palle" height="200" src="https://media.licdn.com/mpr/mpr/shrinknp_400_400/p/6/000/2a4/35f/2c80b70.jpg" width="200" /><span class="fn"><span class="full-name" dir="auto">Venkata Palle</span></span><br />
<br />
ONLY FEW…………………….<br />
//////<br />
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<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
//////////<br />
see..........<a href="http://newdrugapprovals.org/2015/11/16/lik-066-novartis-for-the-treatment-of-type-2-diabetes/">http://newdrugapprovals.org/2015/11/16/lik-066-novartis-for-the-treatment-of-type-2-diabetes/</a></div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-302770220608373834.post-44692939755735136662015-11-17T04:20:00.002-08:002015-11-17T04:20:42.692-08:00AZD 1080<div dir="ltr" style="text-align: left;" trbidi="on">
<img alt="" class="irc_mi" height="127" src="http://image.ec21.com/image/yu41884905/oimg_GC08132851_CA08134471/AZD1080.jpg" width="235" />.<br />
<div class="pro_title01">
<h1>
AZD 1080<span class="p_title"> </span></h1>
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile<br />
2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile<br />
<div class="new_title">
AZD1080 is a selective, orally active, brain permeable <b>GSK3</b> inhibitor, inhibits human GSK3α and GSK3β with <b>K<sub>i</sub></b> of 6.9 nM and 31 nM, respectively, shows >14-fold selectivity against CDK2, CDK5, CDK1 and Erk2.</div>
</div>
<span class="t_txt">Cas 612487-72-6, AZD1080,</span><br />
AZD-1080, a glycogen synthase kinase 3 (GSK-3) inhibitor, had been in
early clinical trials for the treatment of Alzheimer’s type dementia by
AstraZeneca<br />
<table class="patent-bibdata patent-drawings-missing" style="height: 52px; width: 119px;">
<tbody>
<tr class="patent-bibdata-list-row ">
<td><br /></td>
</tr>
<tr class="patent-bibdata-list-row ">
<td class="patent-bibdata-heading"><br /></td>
<td><span class="patent-bibdata-value-list"><span class="patent-bibdata-value"><a href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Astrazeneca+Ab%22">Astrazeneca Ab</a></span></span></td>
</tr>
</tbody>
</table>
<h1>
<span style="color: red;">PATENTS</span></h1>
WO 2003082853<br />
<a href="http://www.google.com/patents/WO2003082853A1?cl=en">http://www.google.com/patents/WO2003082853A1?cl=en</a><br />
<h1>
<span style="color: red;">PAPER</span></h1>
Organic Process Research & Development (2008), 12(3), 540-543.<br />
<a href="http://pubs.acs.org/doi/abs/10.1021/op800020r">http://pubs.acs.org/doi/abs/10.1021/op800020r</a><br />
<div id="absImg">
<img alt="Abstract Image" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2008/oprdfk.2008.12.issue-3/op800020r/production/images/medium/op-2008-00020r_0001.gif" /></div>
<div class="articleBody_abstractText">
A mild and robust method for the
large-scale palladium-catalysed cyanation of aryl bromides has been
developed. The reaction is sensitive to cyanide poisoning of the
catalyst, and it was found that the order of adding the reagents had a
strong impact on the performance of the reaction. Addition of the
cyanide source to a preheated mixture of the other reagents was critical
for achieving a robust and scaleable process. This improved protocol
allowed the reaction to be run to full conversion within 3 h at 50 °C on
a 6.7 kg scale. Furthermore, it led to the identification of several
new efficient catalysts for the reaction.</div>
<div class="articleBody_abstractText">
2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile (<b>2</b>) (5.2 kg, 15.6 mol), 90% yield with a purity of >90% by HPLC. <sup>1</sup>H NMR (<i>d</i><sub>6</sub>-DMSO, 400 MHz) δ 14.79 (broad s, 1H), 10.86 (broad s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.83 (d, <i>J</i> = 8.8 Hz, 1H), 7.27 (dd,<i>J</i> = 8.0, 0.9 Hz, 1H), 7.01 (d, <i>J</i> = 8.0 Hz, 1H), 3.57 (t, <i>J</i> = 4.4 Hz, 4H), 3.36 (s, 2H), 2.36 (broad s, 4H); <sup>13</sup>C NMR (<i>d</i><sub>6</sub>-DMSO,
100 MHz) δ 168.8, 148.6, 141.8, 137.0, 136.1, 125.4, 123.9, 122.3,
121.1, 118.8, 118.3, 108.7, 101.3, 84.6, 66.1, 58.4, 52.8. MS (ES) <i>m</i>/<i>z</i> [M + 1] 335.</div>
<h1>
<span style="color: red;">PAPER</span></h1>
Topics in Organometallic Chemistry (2012), 42(Organometallics as Catalysts in the Fine Chemical Industry), 125-134.<br />
<a href="http://link.springer.com/chapter/10.1007%2F3418_2011_25">http://link.springer.com/chapter/10.1007%2F3418_2011_25</a><br />
<br />
<br />
<h1>
<span style="color: red;">PATENT</span></h1>
<a href="https://www.google.co.in/patents/WO2007089193A1?cl=en">https://www.google.co.in/patents/WO2007089193A1?cl=en</a><br />
<div class="patent-image">
<a href="https://patentimages.storage.googleapis.com/WO2007089193A1/imgf000005_0001.png"><img alt="Figure imgf000005_0001" class="patent-full-image" height="296" id="imgf000005_0001" src="https://patentimages.storage.googleapis.com/WO2007089193A1/imgf000005_0001.png" width="652" /></a></div>
In the above scheme, preferably Rl is bromo and X is chloro.<br />
<br />
<br />
Synthesis of 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl] lH-indole-5-carbonitrile <span style="color: red;">citrate</span><br />
Example 14<br />
2-Hydroxy-3-r5-(moφholin-4-ylmethyl)pyridin-2-yl1 lH-indole-5-carbonitrile <span style="color: red;">citrate salt</span>
2-Hydroxy-3-[5-(moφholin-4-ylmethyl)pyridin-2-yl]
lH-indole-5-carbonitrile (5.14 kg, 15.4 mol) was suspended in ethanol
(54 L) at room temperature. The suspension was heated to an inner
temperature of 70<sup>0</sup>C and a solution of citric acid (3.424 kg,
17.82 mol, 1.300 eq)) in water (103 L) was added keeping the inner
temperature above 65<sup>0</sup>C. The mixture was heated to reflux.
After this the resulting solution was mixed with activated charcoal
(0.412 kg) and reflux continued for 3.5 h after which the reaction
mixture was clear filtered at 83<sup>0</sup>C followed by cooling to
room temperature over 20 h. After filtration the precipitate was washed
twice with a cold mixture of ethanol/water (6.9 L/13.7 L). Drying under
vacuum at 5O<sup>0</sup>C gave 6.648 kg, 82.2% yield of
2-hydroxy-3-[5-(morpholin-
4-ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile citrate having a purity
of at least 98%. The palladium content was less than 1 ppm and the zinc
content was lower than 10 ppm. <sup>1</sup>H NMR (Jd-DMSO<sub>3</sub>
400 MHz) δ 14.7 (br s, 1 H), 11.55 (s, 1 H), 10.98 (s, IH), 8.31 (s, 1
H), 8.08 (br d, J= 1.84Hz, IH), 8.02 (s, IH), 7.90 (br d, J = 8.92Hz, 1
H), 7.31 (d, J = 8.0 Hz, 1 H), 7.02 (d, J= 8.0Hz), 4.28 (s, 2 H), 3.97
(m, 2 H), 3.94 (m, 2H), 3.35 (m, 9H), 3.32 (m, 2H) ppm; <sup>13</sup>C
NMR (d6-DMSO, 400MHz) δ 168.9, 148.5, 142.7, 139.8, 137.5,126.4, 124.9,
124.8, 120.9, 119.4, 118.4, 113.3, 109.0, 101.6, 85.7, 63.1, 55.5, 50.3,
40.1, 39.9, 39.7, 39.2, 39.0, 38.8ppm; MS (ES) m/z [M<sup>+</sup>+l] 335.<br />
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-302770220608373834.post-77054167864439514152015-09-06T02:18:00.001-07:002015-09-06T02:18:25.331-07:00Bococizumab<div dir="ltr" style="text-align: left;" trbidi="on">
<br />
<img alt="" src="http://imgt.org/mAb-DB/images/formats/IgG2-kappa.png" /><br />
<br />
Bococizumab<br />
PF-04950615, RN-316, RN316<br />
<a href="http://www.genenames.org/data/hgnc_data.php?hgnc_id=20001">PCSK9</a>
(proprotein convertase subtilisin/kexin type 9, neural
apoptosis-regulated convertase 1, NARC1, NARC-1, proproteine convertase
9, PC9) [<i>Homo sapiens</i>]<br />
IgG2 – kappa<br />
Hypercholesterolemia<br />
Cardiovascular diseases<br />
STRUCTURAL FORMULA<br />
Heavy chain<br />
QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYYMHWVRQA PGQGLEWMGE 50<br />
ISPFGGRTNY NEKFKSRVTM TRDTSTSTVY MELSSLRSED TAVYYCARER 100<br />
PLYASDLWGQ GTTVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY 150<br />
FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSNFGTQTYT 200<br />
CNVDHKPSNT KVDKTVERKC CVECPPCPAP PVAGPSVFLF PPKPKDTLMI 250<br />
SRTPEVTCVV VDVSHEDPEV QFNWYVDGVE VHNAKTKPRE EQFNSTFRVV 300<br />
SVLTVVHQDW LNGKEYKCKV SNKGLPSSIE KTISKTKGQP REPQVYTLPP 350<br />
SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPMLDSDGS 400<br />
FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPGK 444<br />
Light chain<br />
DIQMTQSPSS LSASVGDRVT ITCRASQGIS SALAWYQQKP GKAPKLLIYS 50′<br />
ASYRYTGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCQQ RYSLWRTFGQ 100′<br />
GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150′<br />
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200′<br />
LSSPVTKSFN RGEC 214′<br />
Disulfide bridges location<br />
22-96 22”-96” 23′-88′ 23”’-88”’ 132-214′ 132”-214”’<br />
134′-194′ 134”’-194”’ 145-201 145”-201” 220-220” 221-221”<br />
224-224” 227-227” 258-318 258”-318” 364-422 364”-422”<br />
<h3>
<a href="https://www.google.co.in/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&ved=0CCoQFjAA&url=http%3A%2F%2Fwww.ama-assn.org%2Fresources%2Fdoc%2Fusan%2Fbococizumab.pdf&ei=Twm9Up6cIsGOrQeA84GICQ&usg=AFQjCNEGpU2SguVUAHVX2DfHBD6UEJWggg&sig2=9w774Hucdr32uYE5p2bPaw&bvm=bv.58187178,d.bmk"><em>Bococizumab</em> nonproprietary drug name</a></h3>
<a href="http://www.ama-assn.org//resources/doc/usan/bococizumab.pdf">bococizumab</a><br />
RN-316, PF-04950615<br />
target-PC9<br />
USAN (AB-55) BOCOCIZUMAB<br />
PRONUNCIATION boe” koe siz’ ue mab<br />
THERAPEUTIC CLAIM Treatment of dyslipidemia<br />
CHEMICAL NAME<br />
1. Immunoglobulin G2, anti-(human neural apoptosis-regulated proteinase<br />
1)(human-Mus musculus monoclonal PF-04950615 heavy chain), disulfide<br />
with human-Mus musculus monoclonal PF-04950615 light chain, dimer<br />
2. Immunoglobulin G2-kappa, anti-[human proprotein convertase
subtilisin/hexin type 9 (neural apoptosis-regulated convertase 1, PC9)],
humanized mouse monoclonal antibody; gamma 2 heavy chain (1-444)
[humanized VH (Homo sapiens IGHV1-46-1*03 (90.8%) -(IGHD)-IGHJ6*01)
[8.8.11] (1-118)-Homo sapiens IGHG2*01
CH2A100>S(327),CH2P101>S(328) (119-444)] (132-214′)-<br />
disulfide with kappa light chain (1′-214′) [humanized V-KAPPA (Homo
sapiensIGKV1-39*01 (88.2%)-IGKJ2*01 [6.3.9] (1′-107′)-IGKC*01
(108′-214′)]; dimer<br />
(220-220”:221-221”:224-224”:227-227”)-tetrakisdisulfide<br />
MOLECULAR FORMULA C6414H9918N1722O2012S54<br />
MOLECULAR WEIGHT 145.1 kDa<br />
TRADEMARK None as yet<br />
SPONSOR Pfizer, Inc.<br />
CODE DESIGNATIONS RN316, PF-04950615<br />
CAS REGISTRY NUMBER 1407495-02-6<br />
WHO NUMBER 9840<br />
<b>Bococizumab</b><sup class="reference" id="cite_ref-1"><a href="https://en.wikipedia.org/wiki/Bococizumab#cite_note-1">[1]</a></sup> (<b>RN316</b>)<sup class="reference" id="cite_ref-2"><a href="https://en.wikipedia.org/wiki/Bococizumab#cite_note-2">[2]</a></sup> is a drug in development by <a href="https://en.wikipedia.org/wiki/Pfizer" title="Pfizer">Pfizer</a> targeting <a href="https://en.wikipedia.org/wiki/PCSK9" title="PCSK9">PCSK9</a> to reduce <a class="mw-redirect" href="https://en.wikipedia.org/wiki/LDL" title="LDL">LDL</a> <a href="https://en.wikipedia.org/wiki/Cholesterol" title="Cholesterol">cholesterol</a>.<sup class="reference" id="cite_ref-3"><a href="https://en.wikipedia.org/wiki/Bococizumab#cite_note-3">[3]</a></sup><br />
<img alt="" src="http://www.dddmag.com/sites/dddmag.com/files/Pfizer_logo.jpg" /><br />
<h2>
<span class="mw-headline" id="Description">Description</span></h2>
Bococizumab is a <a href="https://en.wikipedia.org/wiki/Monoclonal_antibody" title="Monoclonal antibody">monoclonal antibody</a> that inhibits <a href="https://en.wikipedia.org/wiki/PCSK9" title="PCSK9">PCSK9</a>, a <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a> that interferes with the removal of <a class="mw-redirect" href="https://en.wikipedia.org/wiki/LDL" title="LDL">LDL</a>. LDL levels are a major risk factor for <a href="https://en.wikipedia.org/wiki/Cardiovascular_disease" title="Cardiovascular disease">cardiovascular disease</a>.<br />
<h2>
<span class="mw-headline" id="Clinical_trials">Clinical trials</span></h2>
A phase 2b study of <a href="https://en.wikipedia.org/wiki/Statin" title="Statin">statin</a>
patients was presented at the 2014 American College of Cardiology.
Monthly or bimonthly injections resulted in significantly reduced <a class="mw-redirect" href="https://en.wikipedia.org/wiki/LDL-C" title="LDL-C">LDL-C</a> at week 12.<br />
The <a href="https://en.wikipedia.org/wiki/Phases_of_clinical_research" title="Phases of clinical research">Phase 3</a> SPIRE trials plan to enroll 17,000 patients to measure <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cardiovascular" title="Cardiovascular">cardiovascular</a> risk. High risk and statin intolerant subjects will be included.<br />
<img alt="" src="http://image.slidesharecdn.com/11-roe-pcsk9inhibitors-140428073411-phpapp02/95/prevention-2014-pcsk9-inhibitors-9-638.jpg?cb=1424440665" /><br />
<h2>
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist">
<ol class="references">
<li id="cite_note-1"><span class="reference-text"><span class="citation web"><a class="external text" href="http://www.ama-assn.org/resources/doc/usan/x-pub/bococizumab.pdf" rel="nofollow">“Statement On A Nonproprietary Name Adopted By The USAN Council: Bococizumab”</a> (PDF). <a href="https://en.wikipedia.org/wiki/American_Medical_Association" title="American Medical Association">American Medical Association</a>.</span></span></li>
<li id="cite_note-2"> <span class="reference-text"><span class="citation journal"><a href="https://en.wikipedia.org/wiki/World_Health_Organization" title="World Health Organization">World Health Organization</a> (2013). <a class="external text" href="http://www.who.int/medicines/publications/druginformation/innlists/PL110.pdf" rel="nofollow">“International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 110”</a>(PDF). <i>WHO Drug Information</i> <b>27</b> (4).</span></span></li>
<li id="cite_note-3"> <span class="reference-text"><span class="citation news"><a class="external text" href="http://press.pfizer.com/press-release/bococizumab-rn316-significantly-reduced-ldl-cholesterol-statin-treated-adults-high-cho" rel="nofollow">“Bococizumab (RN316) Significantly Reduced LDL Cholesterol In Statin-Treated Adults With High Cholesterol In A Phase 2b Study”</a><span class="reference-accessdate">. Retrieved <span class="nowrap">29 December</span> 2014</span>.</span></span></li>
</ol>
</div>
<br />
<table class="infobox">
<caption>Bococizumab<sup><a href="https://en.wikipedia.org/wiki/Nomenclature_of_monoclonal_antibodies" title="Nomenclature of monoclonal antibodies">?</a></sup></caption>
<tbody>
<tr>
<th colspan="2"><a href="https://en.wikipedia.org/wiki/Monoclonal_antibody#Applications" title="Monoclonal antibody">Monoclonal antibody</a></th>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/File:Engineered_monoclonal_antibodies.svg" title="File:Engineered monoclonal antibodies.svg">Type</a></th>
<td>Whole antibody</td>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/Monoclonal_antibody#Production" title="Monoclonal antibody">Source</a></th>
<td><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Humanized" title="Humanized">Humanized</a> (from <a href="https://en.wikipedia.org/wiki/Mouse" title="Mouse">mouse</a>)</td>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/Antigen" title="Antigen">Target</a></th>
<td>Proprotein convertase subtilisin/kexin type 9 (<a href="https://en.wikipedia.org/wiki/PCSK9" title="PCSK9">PCSK9</a>)</td>
</tr>
<tr>
<th colspan="2">Clinical data</th>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th>
<td>
<div class="plainlist">
<ul>
<li>Investigational</li>
</ul>
</div>
</td>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />
administration</a></th>
<td><a href="https://en.wikipedia.org/wiki/Subcutaneous_injection" title="Subcutaneous injection">Subcutaneous injection</a></td>
</tr>
<tr>
<th colspan="2">Identifiers</th>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Registry Number</a></th>
<td><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=1407495-02-6&rn=1" rel="nofollow">1407495-02-6</a></span></td>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th>
<td>None</td>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th>
<td>SID: <span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=194168554" rel="nofollow">194168554</a></span></td>
</tr>
<tr>
<th scope="row"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/IUPHAR/BPS" title="IUPHAR/BPS">IUPHAR/BPS</a></th>
<td><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7730" rel="nofollow">7730</a></span></td>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th>
<td><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL3137349" rel="nofollow">CHEMBL3137349</a></span></td>
</tr>
<tr>
<th colspan="2">Chemical data</th>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th>
<td><a href="https://en.wikipedia.org/wiki/Carbon" title="Carbon">C</a><sub>6414</sub><a href="https://en.wikipedia.org/wiki/Hydrogen" title="Hydrogen">H</a><sub>9918</sub><a href="https://en.wikipedia.org/wiki/Nitrogen" title="Nitrogen">N</a><sub>1722</sub><a href="https://en.wikipedia.org/wiki/Oxygen" title="Oxygen">O</a><sub>2012</sub><a href="https://en.wikipedia.org/wiki/Sulfur" title="Sulfur">S</a><sub>54</sub></td>
</tr>
<tr>
<th scope="row"><a href="https://en.wikipedia.org/wiki/Molecular_mass" title="Molecular mass">Molecular mass</a></th>
<td>145.1 <a class="mw-redirect" href="https://en.wikipedia.org/wiki/KDa" title="KDa">kDa</a></td>
</tr>
</tbody>
</table>
//////</div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com3tag:blogger.com,1999:blog-302770220608373834.post-61251117654968538812015-07-17T19:34:00.002-07:002015-07-17T19:34:52.363-07:00Triphala : A Digestive Miracle<div dir="ltr" style="text-align: left;" trbidi="on">
<img alt="" src="http://www.herbalbloom.com/images/triphala1.jpg" /><br />
<img alt="" src="http://upload.wikimedia.org/wikipedia/commons/thumb/7/7f/Phyllanthus_officinalis.jpg/220px-Phyllanthus_officinalis.jpg" /><br />
<i><a href="http://en.wikipedia.org/wiki/Emblica_officinalis" title="Emblica officinalis">Emblica officinalis</a></i><br />
<table>
<tbody>
<tr>
<th colspan="2"><i>Terminalia bellirica</i></th>
</tr>
<tr>
<td colspan="2"><a href="http://en.wikipedia.org/wiki/File:Terminalia_bellirica.jpg"><img alt="" height="165" src="http://upload.wikimedia.org/wikipedia/commons/thumb/7/74/Terminalia_bellirica.jpg/220px-Terminalia_bellirica.jpg" width="220" /></a>
</td>
</tr>
</tbody>
</table>
<table>
<tbody>
<tr>
<th colspan="2"><i>Terminalia chebula</i></th>
</tr>
<tr>
<td colspan="2"><a href="http://en.wikipedia.org/wiki/File:Harra_%28Terminalia_chebula%29_leafless_tree_at_23_Mile,_Duars,_WB_W_IMG_5905.jpg"><img alt="" height="338" src="http://upload.wikimedia.org/wikipedia/commons/thumb/f/ff/Harra_%28Terminalia_chebula%29_leafless_tree_at_23_Mile%2C_Duars%2C_WB_W_IMG_5905.jpg/220px-Harra_%28Terminalia_chebula%29_leafless_tree_at_23_Mile%2C_Duars%2C_WB_W_IMG_5905.jpg" width="220" /></a></td>
</tr>
</tbody>
</table>
<img alt="" src="http://www.goherbalsupplements.com/images/triphala-mix.jpg" /><br />
<b>Triphala</b> (<a href="http://en.wikipedia.org/wiki/Help:IPA_for_English" title="Help:IPA for English">/</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">t</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">r</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">iː</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">ˈ</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">f</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">ɑː</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">l</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">ə</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English" title="Help:IPA for English">/</a> or <a href="http://en.wikipedia.org/wiki/Help:IPA_for_English" title="Help:IPA for English">/</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">t</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">r</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">iː</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">ˈ</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">f</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">æ</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">l</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English">ə</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English" title="Help:IPA for English">/</a>; <a href="http://en.wikipedia.org/wiki/Hindi" title="Hindi">Hindi</a>/<a href="http://en.wikipedia.org/wiki/Sanskrit" title="Sanskrit">Sanskrit</a>: त्रिफला, <i>triphalā</i> <a href="http://en.wikipedia.org/wiki/Help:IPA_for_Hindi_and_Urdu" title="Help:IPA for Hindi and Urdu">[trɪˈpʰɐlaː]</a>, “three fruits”)<sup id="cite_ref-formulary_1-0"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-formulary-1">[1]</a></sup> is an <a href="http://en.wikipedia.org/wiki/Ayurvedic" title="Ayurvedic">Ayurvedic</a><sup id="cite_ref-McIntyre2005_2-0"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-McIntyre2005-2">[2]</a></sup> <a href="http://en.wikipedia.org/wiki/Herb" title="Herb">herbal</a> <a href="http://en.wikipedia.org/wiki/Rasayana" title="Rasayana">rasayana</a> formula consisting of equal parts of three <a href="http://en.wikipedia.org/wiki/Myrobalans" title="Myrobalans">myrobalans</a>, taken without seed: <a href="http://en.wikipedia.org/wiki/Amalaki" title="Amalaki">Amalaki</a> (<i><a href="http://en.wikipedia.org/wiki/Emblica_officinalis" title="Emblica officinalis">Emblica officinalis</a></i>), <a href="http://en.wikipedia.org/wiki/Beleric" title="Beleric">Bibhitaki</a> (<i><a href="http://en.wikipedia.org/wiki/Terminalia_bellirica" title="Terminalia bellirica">Terminalia bellirica</a></i>), and <a href="http://en.wikipedia.org/wiki/Haritaki" title="Haritaki">Haritaki</a> (<i><a href="http://en.wikipedia.org/wiki/Terminalia_chebula" title="Terminalia chebula">Terminalia chebula</a></i>).<sup id="cite_ref-formulary_1-1"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-formulary-1">[1]</a></sup><br />
<h2>
Medicinal use</h2>
In traditional Ayurvedic medicine, Triphala is used for:<br />
<ul>
<li>immune system stimulation<sup id="cite_ref-juss_3-0"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-juss-3">[3]</a></sup></li>
<li>improvement of digestion<sup id="cite_ref-nadkarni_4-0"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-nadkarni-4">[4]</a></sup><sup id="cite_ref-formulary_1-2"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-formulary-1">[1]</a></sup></li>
<li>relief of constipation<sup id="cite_ref-nadkarni_4-1"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-nadkarni-4">[4]</a></sup><sup id="cite_ref-formulary_1-3"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-formulary-1">[1]</a></sup></li>
<li>gastrointestinal tract cleansing<sup id="cite_ref-nadkarni_4-2"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-nadkarni-4">[4]</a></sup></li>
<li>relief of gas<sup id="cite_ref-formulary_1-4"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-formulary-1">[1]</a></sup></li>
<li>treatment of diabetes<sup id="cite_ref-formulary_1-5"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-formulary-1">[1]</a></sup></li>
<li>treatment of eye disease<sup id="cite_ref-formulary_1-6"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-formulary-1">[1]</a></sup></li>
</ul>
These health claims have not been yet tested in clinical trials. Even
within the practice of Ayurvedic medicine, there are controversies
about the composition (<i>amlaki, haritaki and bibhitaki</i>), preparation, and medicinal uses of Triphala.<sup id="cite_ref-Puri2003_5-0"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-Puri2003-5">[5]</a></sup><br />
The active constituents are unknown. Triphala contains several
compounds that have been proposed to be responsible for its claimed
health benefits, including gallic acid, chebulagic acid, and chebulinic
acid. <sup id="cite_ref-reddy_6-0"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-reddy-6">[6]</a></sup><sup id="cite_ref-pawar_7-0"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-pawar-7">[7]</a></sup><br />
<h2>
Contemporary research on triphala</h2>
There is preliminary evidence that Triphala contains compounds with
antioxidant properties in isolated cells and rats, however this has not
yet been demonstrated in people.<sup id="cite_ref-reddy_6-1"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-reddy-6">[6]</a></sup><sup id="cite_ref-8"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-8">[8]</a></sup><sup id="cite_ref-9"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-9">[9]</a></sup><sup id="cite_ref-10"><a href="http://en.wikipedia.org/wiki/Triphala#cite_note-10">[10]</a></sup><br />
<em>Triphala, </em>widely used by natural Ayurvedic healers in India
for thousands of years, contains 3 different fruits: Harada, Amla and
Bihara. The word <em>“T</em><em>riphala”</em>literally means “three fruits”. The combination of these three fruits cleanses the gastro-intestinal tract in a <em>natural</em> and <em>gentle</em> way. Basically our “bathroom experience” becomes a better one That is the best way I can put it!!<br />
<strong><em>Why should we cleanse?</em></strong><br />
It’s always a good idea to cleanse! Get rid of toxins that build up
in our bodies so that our bodies can function most efficiently and have
that bright glowing skin we all crave and want! More energy and feel
less bloated!<br />
<img alt="" src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcQznRpnWvFj4dWikbZBG-yeYScXm3Mw4_Na1oGu5FgmgmFykn0K" /><br />
And I’m not talking about cleansing with juicing or not eating. No
no, that’s a whole other conversation. I absolutely believe in still
eating a healthy diet while “cleansing”/taking Triphala.<br />
I have suggested Triphala to many clients, students and friends and
all of them have seen results. You can call it a form of laxative if
you’d like but this is totally safe and gentle on the body. Yes, we are
all different but seems like this one might be a miracle worker and
work for everyone!<br />
<em>Suggested use</em>: Take one pill before bedtime. *Take on and
off for a period of time OR once in a while when you feel you need it.
I usually take it when I feel I need a cleanse- about one or two times a
week (usually when I have consumed a bigger meal or more food than
usual).<br />
<strong>Benefits of Triphala:</strong><br />
<ul>
<li>detoxify and cleanses the colon of toxins</li>
<li>removes excess fats</li>
<li>purifies the blood</li>
<li>removes toxins from the liver</li>
<li>reduces some forms of cholesterol (serum cholesterol)</li>
<li>reduces high blood pressure</li>
<li>high nutritional value: including high levels of vitamin C</li>
<li>high in antioxidants</li>
<li>strengthens hair roots and enriches hair color</li>
</ul>
<img alt="Triphala" src="http://ayurveda.iloveindia.com/pics/triphala.jpg" /><br />
<img alt="" height="403" src="http://www.trulyorganicfoods.com/prodimages/triphala-giant.jpg" width="480" /><br />
<strong><em>The three fruits contained in Triphala are </em></strong><br />
<strong><em>Amalaki (Indian Gooseberry), </em></strong><br />
<strong><em>Haritaki (Indian Gallnut or Terminalia chebula), </em></strong><br />
<strong><em>and Bibhitaki (Beleric Myrobalan or Terminalia bellerica).</em></strong><br />
<h3>
The prokinetic cleanser</h3>
An immensely popular Ayurvedic herbal formula,<strong>Triphala</strong>(<em>Terminalia chebula,Terminalia bellirica and Emblica officinalis</em>)
is an effective bowel cleanser. It combines the goodness of Indian
Gooseberry, Belleric Myrobalan and Chebulic Myrobalan, which work
together to produce effective bowel movements.<br />
The herbal compound provides overall support for digestion and helps
ensure that the digestive tract works at optimal levels. Triphala
relieves constipation and regularizes the digestive system, without
disrupting the fluid-electrolyte balance in the body.<br />
The herbs that make up Triphala are found in abundance in India.<br />
Triphala, the well-known traditional Ayurvedic formulation, makes an
excellent skin tonic. It is one of the most popular Ayurvedic medicinal
herbs, prescribed by a number of Ayurvedic practitioners. Triphala
literally means ‘three fruits’. The three fruits contained in Triphala
are Amalaki (Indian Gooseberry), Haritaki (Indian Gallnut or Terminalia
chebula), and Bibhitaki (Beleric Myrobalan or Terminalia bellerica).
Since Triphala is tridoshic – equally balancing for Vata, Pitta and
Kapha – it is beneficial for all skin types. Triphala nourishes the
skin, both directly and indirectly. Amla (Indian gooseberry), one of the
three ingredients in Triphala, is the richest known natural source of
Vitamin C. Apart from the rich source of Vitamin C, Triphala also
contains calcium – an important nutrient that helps enhance skin clarity
and brings dull, tired skin to life.<br />
Preparation Of Triphala Rasayana<br />
Triphala Rasayana is usually prepared by mixing triphala with equal
quantity of madhuka (mahua tree), tavakshir (East Indian arrowroot)
pippali (long pepper), saindhava (long salt), and each one of the loha
(iron), suvarna (gold), vacha (Acorus calamus) with either honey, ghee
or sugar, in equal quantity.<br />
Benefits Of Triphala<br />
Triphala Rasayana is beneficial is promoting ojas, the finest product of
digestion that prevents the occurrence of many diseases, creates luster
and make the skin exude its natural glow and radiance.<br />
It nourishes both the body and the mind, thereby promoting longevity of
life. Therefore, Triphala Rasayana is very much beneficial for adults
and children alike.<br />
The Rasayana is especially beneficial for eyes. In case one has problems
in eye sight, opting for Triphala Rasayana would be the best bet.<br />
The Rasayana creates a balance in the cholesterol level, by removing ama from the fat tissue.<br />
It helps in the purification of urinary tract, thereby helping the prevention of urinary tract diseases.<br />
It also strengthens and cleanses the liver, which is one of its main
functions. This ensures that the liver, one of the important parts of
the body, stays healthy. It can also be said that the consumption of
Rasayana prevents diseases related to the functioning of liver.<br />
The medicine also helps the management of weight. Thus, it is beneficial for people, who want to loose weight.<br />
It enhances the thirteen agnis (digestive fires), especially the main digestive fire in the stomach.<br />
Triphala Rasayana is helpful in pacifying Kapha and Pitta. If taken on a
regular basis, the Rasayana can be a powerful anti-aging medicine.<br />
People suffering from skin inflammation, heat, infection, obesity will find the consumption of Triphala Rasayana as beneficial.<br />
Diseases such as fatigue and anemia can be effectively cured by the
regular consumption of Triphala Rasayana, if taken according to the
prescribed doses.<br />
<ol>
<li id="cite_note-formulary-1"> Ayurvedic pharmacopoeia committee. The
Ayurvedic Formulary of India, Part I, 2nd English ed. New Delhi:
Controller of Publications; 2003</li>
<li id="cite_note-McIntyre2005-2"> Anne McIntyre (7 September 2005). <a href="http://books.google.com/books?id=QLin14nRVBsC&pg=PA278" rel="nofollow"><i>Herbal treatment of children: Western and Ayurvedic perspectives</i></a>. Elsevier Health Sciences. pp. 278–. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/9780750651745" title="Special:BookSources/9780750651745">9780750651745</a>. Retrieved 24 July 2010.</li>
<li id="cite_note-juss-3"> Juss SS. Triphala – the wonder drug. Indian Med Gaz 1997;131:94-6.</li>
<li id="cite_note-nadkarni-4"> Nadkarni AK. Indian Materia Medica. 3rd ed. Mumbai: Popular Press; 1976. p. 1308-15.</li>
<li id="cite_note-Puri2003-5"> Harbans Singh Puri (2003). <a href="http://books.google.com/books?id=aQh25X9mzjAC&pg=PA30" rel="nofollow"><i>Rasayana: ayurvedic herbs for longevity and rejuvenation</i></a>. CRC Press. pp. 30–. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/9780415284899" title="Special:BookSources/9780415284899">9780415284899</a>. Retrieved 24 July 2010.</li>
<li id="cite_note-reddy-6"> Reddy TC, Aparoy P, Babu NK, Kalangi SK,
Reddanna P (May 2010). “Kinetics and Docking Studies of a COX-2
Inhibitor Isolated from Terminalia bellerica Fruits”. <i>Protein Pept Lett</i>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/20441561" rel="nofollow">20441561</a>.</li>
<li id="cite_note-pawar-7"> Pawar V, Lahorkar P, Anantha Narayana DB.
Development of a RP-HPLC method for analysis of Triphala curna and its
applicability to test variations in Triphala curna preparations. Indian J
Pharm Sci [serial online] 2009 [cited 2010 Aug 1];71:382-6. Available
from:<a href="http://www.ijpsonline.com/text.asp?2009/71/4/382/57286" rel="nofollow">http://www.ijpsonline.com/text.asp?2009/71/4/382/57286</a></li>
<li id="cite_note-8"> Mahesh R, Bhuvana S, Begum VM (August 2009).
“Effect of Terminalia chebula aqueous extract on oxidative stress and
antioxidant status in the liver and kidney of young and aged rats”. <i>Cell Biochem. Funct.</i> <b>27</b> (6): 358–63. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a href="http://dx.doi.org/10.1002%2Fcbf.1581" rel="nofollow">10.1002/cbf.1581</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/19548245" rel="nofollow">19548245</a>.</li>
<li id="cite_note-9"> Sandhya T, Lathika KM, Pandey BN, <i>et al.</i> (October 2006). “Protection against radiation oxidative damage in mice by Triphala”. <i>Mutat. Res.</i> <b>609</b> (1): 17–25.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a href="http://dx.doi.org/10.1016%2Fj.mrgentox.2006.05.006" rel="nofollow">10.1016/j.mrgentox.2006.05.006</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/16860592" rel="nofollow">16860592</a>.</li>
<li id="cite_note-10"> Srikumar R, Parthasarathy NJ, Manikandan S,
Narayanan GS, Sheeladevi R (February 2006). “Effect of Triphala on
oxidative stress and on cell-mediated immune response against noise
stress in rats”. <i>Mol. Cell. Biochem.</i> <b>283</b> (1-2): 67–74. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a href="http://dx.doi.org/10.1007%2Fs11010-006-2271-0" rel="nofollow">10.1007/s11010-006-2271-0</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/16444587" rel="nofollow">16444587</a>.</li>
</ol>
</div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-302770220608373834.post-69183040000115602302015-05-08T02:15:00.001-07:002015-05-08T02:15:21.314-07:00ELIGLUSTAT<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Eliglustat.svg" class="" height="210" src="http://upload.wikimedia.org/wikipedia/commons/thumb/b/b0/Eliglustat.svg/1280px-Eliglustat.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="474" /></div>
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ELIGLUSTAT TARTRATE</div>
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THERAPEUTIC CLAIM Treatment of lysosomal storage disorders</div>
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CHEMICAL NAMES</div>
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1. Octanamide, N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-<br />pyrrolidinylmethyl)ethyl]-, (2R,3R)-2,3-dihydroxybutanedioate (2:1)</div>
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2. bis{N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(pyrrolidin-1-<br />ylmethyl)ethyl]octanamide} (2R,3R)-2,3-dihydroxybutanedioate</div>
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MOLECULAR FORMULA C23H36N2O4 . ½ C4H6O6</div>
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MOLECULAR WEIGHT 479.6</div>
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MANUFACTURER Genzyme Corp.</div>
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CODE DESIGNATION Genz-112638</div>
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CAS REGISTRY NUMBER 928659-70-5</div>
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<b>Eliglustat</b> (<a href="http://en.wikipedia.org/wiki/International_Nonproprietary_Name" style="color: #0c5390; text-decoration: none;" title="International Nonproprietary Name">INN</a>, <a href="http://en.wikipedia.org/wiki/United_States_Adopted_Name" style="color: #0c5390; text-decoration: none;" title="United States Adopted Name">USAN</a>;<span class="reference" id="cite_ref-1" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Eliglustat#cite_note-1" style="color: #0c5390; text-decoration: none;">[1]</a></span> trade name <b>Cerdelga</b>) is a treatment for <a href="http://en.wikipedia.org/wiki/Gaucher%27s_disease" style="color: #0c5390; text-decoration: none;" title="Gaucher's disease">Gaucher’s disease</a>developed by <a href="http://en.wikipedia.org/wiki/Genzyme" style="color: #0c5390; text-decoration: none;" title="Genzyme">Genzyme Corp</a> that was approved by the FDA August 2014.<span class="reference" id="cite_ref-2" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Eliglustat#cite_note-2" style="color: #0c5390; text-decoration: none;">[2]</a></span> Commonly used as the <a href="http://en.wikipedia.org/wiki/Tartrate" style="color: #0c5390; text-decoration: none;" title="Tartrate">tartrate</a> <a href="http://en.wikipedia.org/wiki/Salt_(chemistry)" style="color: #0c5390; text-decoration: none;" title="Salt (chemistry)">salt</a>, the compound is believed to work by inhibition of<a href="http://en.wikipedia.org/wiki/Ceramide_glucosyltransferase" style="color: #0c5390; text-decoration: none;" title="Ceramide glucosyltransferase">glucosylceramide synthase</a>.<span class="reference" id="cite_ref-3" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Eliglustat#cite_note-3" style="color: #0c5390; text-decoration: none;">[3]</a></span><span class="reference" id="cite_ref-4" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Eliglustat#cite_note-4" style="color: #0c5390; text-decoration: none;">[4]</a></span></div>
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In March 2015, eliglustat tartrate was approved in Japan for the treatment of Gaucher disease. Eliglustat tartrate was described specifically within the US FDA’s Orange Booked listed US6916802, which is set to expire in April 2022.</div>
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In May 2015, the Orange Book also listed that eliglustat tartrate had Orphan Drug Exclusivity and New Chemical Entity exclusivity until 2019 and 2021, respectively.</div>
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it having been developed and launched as eliglustat tartrate by Genzyme (a wholly owned subsidiary of Sanofi), under license from the University of Michigan.</div>
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Eliglustat tartrate is known to act as inhibitors of glucosylceramide synthase and glycolipid, useful for the treatment of Gaucher’s disease type I and lysosome storage disease.</div>
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<a href="http://newdrugapprovals.wordpress.com/2013/02/16/genzyme-announces-positive-new-data-from-two-phase-3-studies-for-oral-eliglustat-tartrate-for-gaucher-disease/" rel="bookmark" style="color: #0c5390; text-decoration: none;" title="Permanent Link to Genzyme Announces Positive New Data from Two Phase 3 Studies for Oral Eliglustat Tartrate for Gaucher Disease">Genzyme Announces Positive New Data from Two Phase 3 Studies for Oral Eliglustat Tartrate for Gaucher Disease</a></h2>
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<a href="http://www.kegg.jp/Fig/drug/D09894.gif" style="color: #0c5390; text-decoration: none;"><img alt="" border="0" height="105" src="http://www.kegg.jp/Fig/drug_small/D09894.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="306" /></a><br />Eliglustat tartrate (USAN)<div style="margin-bottom: 10px;">
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CAS:928659-70-5</div>
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February 15, 2013</div>
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Genzyme , a Sanofi company (EURONEXT: SAN and NYSE: SNY), today announced positive new data from the Phase 3 ENGAGE and ENCORE studies of eliglustat tartrate, its investigational oral therapy for Gaucher disease type 1. The results from the ENGAGE study were presented today at the 9th Annual Lysosomal Disease Network WORLD Symposium in Orlando, Fla. In conjunction with this meeting, Genzyme also released topline data from its second Phase 3 study, ENCORE. Both studies met their primary efficacy endpoints and together will form the basis of Genzyme’s registration package for eliglustat tartrateThe data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease”The company is developing eliglustat tartrate, a capsule taken orally, to provide a convenient treatment alternative for patients with Gaucher disease type 1 and to provide a broader range of treatment options for patients and physicians. Genzyme’s clinical development program for eliglustat tartrate represents the largest clinical program ever focused on Gaucher disease type 1 with approximately 400 patients treated in 30 countries.“The data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease,” said Genzyme’s Head of Rare Diseases, Rogerio Vivaldi MD. “We are excited about this therapy’s potential and are making excellent progress in our robust development plan for bringing eliglustat tartrate to the market.”<b>ENGAGE Study Results:</b>In ENGAGE, a Phase 3 trial to evaluate the safety and efficacy of eliglustat tartrate in 40 treatment-naïve patients with Gaucher disease type 1, improvements were observed across all primary and secondary efficacy endpoints over the 9-month study period. Results were reported today at the WORLD Symposium by Pramod Mistry, MD, PhD, FRCP, Professor of Pediatrics & Internal Medicine at Yale University School of Medicine, and an investigator in the trial.The randomized, double-blind, placebo-controlled study had a primary efficacy endpoint of improvement in spleen size in patients treated with eliglustat tartrate. Patients were stratified at baseline by spleen volume. In the study, a statistically significant improvement in spleen size was observed at nine months in patients treated with eliglustat tartrate compared with placebo. Spleen volume in patients treated with eliglustat tartrate decreased from baseline by a mean of 28 percent compared with a mean increase of two percent in placebo patients, for an absolute difference of 30 percent (p<0.0001).</div>
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<a href="http://www.wikigenes.org/e/ref/e/20439622.html" style="color: #0c5390; text-decoration: none;">http://www.wikigenes.org/e/ref/e/20439622.html</a></div>
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<img alt="Genzyme" height="50" src="http://www.gaucherdisease.org/images/logo_genzyme.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="200" /></h1>
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Eliglustat tartate (Genz-112638)</h1>
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<strong>What is Eliglustat?</strong></div>
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<li style="list-style-type: square;">Eliglustat is a new investigational phase 3 compound from Genzyme Corporation that is being studied for type 1 Gaucher Disease.</li>
<li style="list-style-type: square;">Eliglustat works as a substrate reduction therapy by reducing glucocerebroside. formation.</li>
<li style="list-style-type: square;">This product is an oral agent (i.e. a pill) that is taken once or twice a day in contrast to an IV infusion for enzyme replacement therapy. Enzyme replacement therapy focuses on replenishing the enzyme that is deficient in Gaucher Disease and breaks down glucocerebroside that accumulates.</li>
<li style="list-style-type: square;">The clinical trials for eliglustat tartate are sponsored by Genzyme Corporation.<img alt="" border="0" class=" alignleft" height="170" src="http://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&deposited=t&sid=135626643" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; float: left; height: auto; margin: 3px 15px 10px 0px; max-width: 100%; vertical-align: middle;" title=" zoom the structure" width="170" /></li>
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<img alt="" height="310" src="http://patentimages.storage.googleapis.com/WO2013059119A1/imgf000024_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="648" /></div>
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Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.</div>
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Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.</div>
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Formula I</div>
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Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.</div>
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Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.</div>
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<span style="color: maroon;">U.S. patent No. 7,196,205</span> (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:</div>
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(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,</div>
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(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,</div>
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(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,</div>
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(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.</div>
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U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. <span style="color: maroon;">2012/296088</span> disclose processes for preparation of eliglustat and intermediates thereof.</div>
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U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.</div>
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WO 2015059679</div>
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<tr><td style="padding: 5px 0px;"></td><td style="padding: 5px 0px;" width="100%">Process for the preparation of eliglustat free base – comprising the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat.</td></tr>
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<tr><td style="padding: 5px 0px;"></td><td style="padding: 5px 0px;" width="100%">Dr Reddy’s Laboratories Ltd</td></tr>
<tr><td style="padding: 5px 0px;"></td><td style="padding: 5px 0px;" width="100%">New crystalline eliglustat free base Form R1 and a process for its preparation are claimed. Also claimed is a process for the preparation of eliglustat free base which comprises the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat.Further eliglustat oxalate, its crystalline form, and a process for the preparation of crystalline eliglustat oxalate, are claimed.</td></tr>
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Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.</div>
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Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.</div>
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Formula I</div>
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Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.</div>
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Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.</div>
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U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:</div>
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(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,</div>
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(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,</div>
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(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,</div>
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(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.</div>
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U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.</div>
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U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.</div>
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Example 1 : Preparation of 5-phenyl morpholine-2-one hydrochloride</div>
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To a (S) + phenyl glycinol (100g) add N, N-diisopropylethylamine (314ml) and acetonitrile (2000ml) under nitrogen atmosphere at room temperature. It was cooled to 10- 15° C. Phenyl bromoacetate (172.4g) dissolved in acetonitrile (500ml) was added to the above solution at 15° C over a period of 30 min. The reaction mixture is allowed to room temperature and stirred for 16-20h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at a water bath</div>
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temperature less than 25<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span> C to get a residue. The residue was dissolved in ethyl acetate (1000ml) and stirred for 1 h at 15-20°C to obtain a white solid. The solid material obtained was filtered and washed with ethyl acetate (200ml). The filtrate was dried over anhydrous sodium sulphate (20g) and concentrated under reduced pressure at a water bath temperature less than 25° C to give crude compound (1000g) as brown syrup. The Crude brown syrup is converted to HCI salt by using HCI in ethyl acetate to afford 5-phenyl morpholine-2-one hydrochloride (44g) as a white solid. Yield: 50%, Mass: m/z = 177.6; HPLC (% Area Method): 90.5%</div>
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Example 2: Preparation of (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4] dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one.</div>
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5-phenyl morpholine-2-one hydrochloride (100g) obtained from above stage 1 is dissolved in toluene (2500ml) under nitrogen atmosphere at 25-30<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span>C. 1 ,4-benzodioxane-6-carboxaldehyde (185.3g) and sodium sulphate (400g) was added to the above solution and the reaction mixture was heated at 100-105<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span>C for 72h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span> C to get a residue. The residue was cooled to 10°C, ethyl acetate (2700ml) and 50% sodium bisulphate solution (1351 ml) was added to the residue and stirred for 1 h at 10<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span>C to obtain a white solid. The obtained white solid was filtered and washed with ethyl acetate. The separated ethyl acetate layer was washed with water (1000ml), brine (1000ml) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure at a water bath temperature of 45-50°C to get a crude material. The obtained crude material is triturated with diethyl ether (1500ml) to get a solid material which is filtered and dried under vacuum at room temperature for 2-3h to afford (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (148g) as a yellow solid. Yield: 54%, Mass: m/z = 487.7; HPLC (% Area Method): 95.4 %</div>
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Example 3: Preparation of (2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 ”^henyl-ethy^</div>
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(1 R,3S,5S,8aS)-1 <span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">!</span>3-Bis-(2′<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">!</span>3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (70g) obtained from above stage 2 was dissolved in chloroform (1400ml) at room temperature. It was cooled to 0-5°C and pyrrolidone (59.5ml) was added at 0-5°C over a period of 30 minutes. The reaction mixture was allowed to room temperature and stirred for 16-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature of 40-45°C to obtain a crude. The obtained crude was dissolved in methanol (1190ml) and 1 N HCI (1 190ml) at 10-15° C, stirred for 10 minutes and heated at 80-85°C for 7h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C.The aqueous layer was extracted with ethyl acetate and the organic layer was washed with 1 N HCI (50ml). The aqueous layer was basified with saturated sodium bicarbonate solution up to p<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">H</span> 8-9 and extracted with ethyl acetate (3x70ml). The combined organic layers was washed with brine (100ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50-55<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span>C to afford (2S,3R,1″S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (53g) as a yellow foamy solid. Yield: 90%, Mass: m/z = 412.7, HPLC (% Area Method): 85.1 %</div>
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Example 4: Preparation of (1 R,2R,1 “S)-1-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2″-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol.</div>
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(2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (2.5g) obtained from above stage 3 dissolved in Tetrahydrofuran (106ml) was added to a solution of Lithium aluminium hydride (12.2g) in tetrahydrofuran (795ml) at 0°C and the reaction mixture was heated at 60-65°C for 10h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 5- 10°C and quenched in saturated sodium sulphate solution (100ml) at 5-10°C. Ethyl acetate was added to the reaction mass and stirred for 30-45 min. The obtained solid is filtered through celite bed and washed with ethyl acetate. Filtrate was dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span>C to afford (1 R,2R, 1″S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2″-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (43.51 g) as a yellow gummy liquid. The crude is used for the next step without further purification. Yield: 85%, Mass: m/z = 398.7, HPLC (% Area Method): 77 %</div>
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Example 5: Preparation of (1 R, 2R)-2-Amino-1-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol.</div>
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(1 R,2R,1 “S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2″-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (40g) obtained from above stage 4 was dissolved in methanol (400ml) at room temperature in a 2L hydrogenation flask. Trifluoroacetic acid (15.5ml) and 20% Pd (OH) <span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span> (40g) was added to the above solution under nitrogen atmosphere. The reaction mixture was hydrogenated under H<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>, 10Opsi for 16-18h at room temperature. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was filtered through celite bed and washed with methanol (44ml) and water (44ml). Methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C and the aqueous layer was washed with ethyl acetate. The aqueous layer was basified with 10M NaOH till the P<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">H</span> reaches 12-14 and then extracted with dichloromethane (2x125ml). The organic layer was dried over anhydrous sodium sulphate (3gm) and concentrated under reduced pressure at a water bath temperature of 45°C to obtain a gummy liquid. The gummy liquid was triturated with methyl tertiary butyl ether for 1 h to get a white solid, which is filtered and dried under vacuum at room temperature to afford (1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (23g) as a white solid. Yield: 82.3%, Mass (m/zj: 278.8, HPLC (% Area Method): 99.5%, Chiral HPLC (% Area Method): 97.9%</div>
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Example 6: Preparation of Eliglustat {(1 R, 2R)-Octanoic acid[2-(2′,3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1-ylmethyl-ethyl]-amide}.</div>
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(1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span> C. Octanoic acid N-hydroxy succinimide ester (13.0 g)was added to the above reaction mass at 10-15<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span> C and stirred for 15 min. The reaction mixture was stirred at room temperature for 16h-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 15°C and diluted with 2M NaOH solution (100 ml_) and stirred for 20 min at 20 °C. The organic layer was separated and washed with 2M sodium hydroxide (3x90ml).The organic layer was dried over anhydrous sodium sulphate (30g) and concentrated under reduced pressure at a water bath temperature of 45<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span>C to give the crude compound (20g).The crude is again dissolved in methyl tertiary butyl ether (25 ml_) and precipitated with Hexane (60ml). It is stirred for 10 min, filtered and dried under vacuum to afford Eliglustat as a white solid (16g). Yield: 74%, Mass (m/zj: 404.7 HPLC (% Area Method): 97.5 %, ELSD (% Area Method): 99.78%, Chiral HPLC (% Area Method): 99.78 %.</div>
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Example 7: Preparation of Eliglustat oxalate.</div>
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Eliglustat (5g) obtained from above stage 6 is dissolved in Ethyl acetate (5ml) at room temperature under nitrogen atmosphere. Oxalic acid (2.22g) dissolved in ethyl acetate (5ml) was added to the above solution at room temperature and stirred for 14h. White solid observed in the reaction mixture was filtered and dried under vacuum at room temperature for 1 h to afford Eliglustat oxalate as a white solid (4g). Yield: 65.46%, Mass (m/zj: 404.8 [M+H] <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+></span> HPLC (% Area Method): 95.52 %, Chiral HPLC (% Area Method): 99.86 %<br />……………………………..</div>
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Nmr predict</div>
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<img alt="N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide H-NMR spectrum" class="" height="718" src="http://pic11.molbase.net/nmr/nmr_image/2014-09-06/001/571/702/491833-29-5-1h.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="729" /></div>
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13 C NMR</div>
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<img alt="N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide C-NMR spectrum" class="" height="717" src="http://pic11.molbase.net/nmr/nmr_image/2014-09-06/001/571/702/491833-29-5-13c.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="741" /></div>
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CAS NO. 491833-29-5, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide</div>
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C-NMR spectral analysis</div>
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………………..</div>
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<a href="http://www.google.com/patents/WO2013059119A1?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/WO2013059119A1?cl=en</a></div>
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<a href="http://patentimages.storage.googleapis.com/WO2013059119A1/imgf000024_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000024_0001" class="patent-full-image" height="292" id="imgf000024_0001" src="http://patentimages.storage.googleapis.com/WO2013059119A1/imgf000024_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="612" /></a></div>
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<a href="http://www.google.com/patents/US7196205" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/US7196205</a></div>
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Compound 7</div>
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(1R,2R)-Nonanoic acid[2-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide</div>
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<a href="http://patentimages.storage.googleapis.com/US7196205B2/US07196205-20070327-C00026.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure US07196205-20070327-C00026" class="patent-full-image" height="286" id="EMI-C00026" src="http://patentimages.storage.googleapis.com/US7196205B2/US07196205-20070327-C00026.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="292" /></a></div>
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This compound was prepared by the method described for Compound 6 using Nonanoic acid N-hydroxysuccinimide ester. Analytical HPLC showed this material to be 98.4% pure. mp 74–75° C.</div>
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<span style="color: red;"><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>H NMR (CDCl<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span>) δ 6.86–6.76 (m, 3H), 5.83 (d, J=7.3 Hz, 1H), 4.90 (d, J=3.3 Hz, 1H), 4.24 (s, 4H), 4.24–4.18 (m, 1H), 2.85–2.75 (m, 2H), 2.69–2.62 (m, 4H), 2.10 (t, J=7.3 Hz, 2H), 1.55–1.45 (m, 2H), 1.70–1.85 (m, 4H), 1.30–1.15 (m, 10H), 0.87 (t, J=6.9 Hz, 3H) ppm.</span></div>
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Intermediate 4(1R,2R)-2-Amino-1-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-3-pyrrolidin-1-yl-propan-1-ol</div>
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<a href="http://patentimages.storage.googleapis.com/US7196205B2/US07196205-20070327-C00023.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure US07196205-20070327-C00023" class="patent-full-image" height="223" id="EMI-C00023" src="http://patentimages.storage.googleapis.com/US7196205B2/US07196205-20070327-C00023.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="297" /></a></div>
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Intermediate 3 (5.3 g, 13.3 mmol) was dissolved in methanol (60 mL). Water (6 mL) and trifluoroacetic acid (2.05 m/L, 26.6 mmol, 2 equivalents) were added. After being placed under nitrogen, 20% Palladium hydroxide on carbon (Pearlman’s catalysis, Lancaster or Aldrich, 5.3 g) was added. The mixture was placed in a Parr Pressure Reactor Apparatus with glass insert. The apparatus was placed under nitrogen and then under hydrogen pressure 110–120 psi. The mixture was stirred for 2–3 days at room temperature under hydrogen pressure 100–120 psi. The reaction was placed under nitrogen and filtered through a pad of celite. The celite pad was washed with methanol (100 mL) and water (100 mL). The methanol was removed by rotoevaporation. The aqueous layer was washed with ethyl acetate three times (100, 50, 50 mL). A 10 M NaOH solution (10 mL) was added to the aqueous layer (pH=12–14). The product was extracted from the aqueous layer three times with methylene chloride (100, 100, 50 mL). The combined organic layers were dried with Na<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>SO<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">4</span>, filtered and rotoevaporated to a colorless oil. The foamy oil was vacuum dried for 2 h. Intermediate 4 was obtained in 90% yield (3.34 g).</div>
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Intermediate 3(1R,2R,1″S)-1-(2′,3′-Dihydro-benzo[1,4]dioxin-6′-yl)-2-(2″-hydroxy -1′-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol</div>
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<a href="http://patentimages.storage.googleapis.com/US7196205B2/US07196205-20070327-C00022.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure US07196205-20070327-C00022" class="patent-full-image" height="299" id="EMI-C00022" src="http://patentimages.storage.googleapis.com/US7196205B2/US07196205-20070327-C00022.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="297" /></a></div>
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To a 3-neck flask equipped with a dropping funnel and condenser was added LiAlH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">4</span>(Aldrich, 1.2 g, 31.7 mmol, 2.5 equivalents) and anhydrous THF (20 mL) under nitrogen. A solution of Intermediate 2 (5.23 g, 12.68 mmol) in anhydrous THF (75 mL) was added dropwise to the reaction over 15–30 minutes. The reaction was refluxed under nitrogen for 9 hours. The reaction was cooled in an ice bath and a 1M NaOH solution was carefully added dropwise. After stirring at room temperature for 15 minutes, water (50 mL) and ethyl acetate (75 mL) was added. The layers were separated and the aqueous layer was extracted twice with ethyl acetate (75 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL). After drying with Na<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>SO<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">4 </span>the solution was filtered and rotoevaporated to yield a colorless to yellow foamy oil. Intermediate 3 was obtained in 99% yield (5.3 g).</div>
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<table class="infobox" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 500px;"><caption style="font-size: 14px; margin: 10px 0px; text-transform: uppercase;">ELIGLUSTAT</caption><tbody>
<tr><td colspan="2" style="padding: 5px 0px;"><a class="image" href="http://en.wikipedia.org/wiki/File:Eliglustat.svg" style="color: #0c5390; text-decoration: none;"><img alt="Eliglustat.svg" height="98" src="http://upload.wikimedia.org/wikipedia/commons/thumb/b/b0/Eliglustat.svg/220px-Eliglustat.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="220" /></a><div style="margin-bottom: 10px;">
</div>
<div style="margin-bottom: 10px;">
<a class="image" href="http://en.wikipedia.org/wiki/File:Eliglustat.svg" style="color: #0c5390; text-decoration: none;"><img alt="Eliglustat.svg" height="98" src="http://upload.wikimedia.org/wikipedia/commons/thumb/b/b0/Eliglustat.svg/220px-Eliglustat.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="220" /></a></div>
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<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">SYSTEMATIC (<a class="mw-redirect" href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" style="color: #0c5390; text-decoration: none;" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC</a>) NAME</th></tr>
<tr><td colspan="2" style="padding: 5px 0px;"><i>N</i>-[(1<i>R</i>,2<i>R</i>)-1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]octanamide</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CLINICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Trade_name" style="color: #0c5390; text-decoration: none;" title="Trade name">TRADE NAMES</a></th><td style="padding: 5px 0px;">Cerdelga</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" style="color: #0c5390; text-decoration: none;" title="Regulation of therapeutic goods">LEGAL STATUS</a></th><td style="padding: 5px 0px;"><div class="plainlist">
<ul style="margin: 0px 0px 14px 36px; padding: 0px;">
<li style="list-style-type: square;"><small style="font-size: 9.60000038146973px;"><abbr style="border-bottom-style: dotted; border-bottom-width: 1px; cursor: help;" title="United States">US</abbr>:</small><a href="http://en.wikipedia.org/wiki/Prescription_drug" style="color: #0c5390; text-decoration: none;" title="Prescription drug"><span class="Unicode">℞</span>-only</a></li>
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<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">IDENTIFIERS</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/CAS_Registry_Number" style="color: #0c5390; text-decoration: none;" title="CAS Registry Number">CAS REGISTRY NUMBER</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=491833-29-5&rn=1" rel="nofollow" style="color: #0c5390; text-decoration: none;">491833-29-5</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" style="color: #0c5390; text-decoration: none;" title="Anatomical Therapeutic Chemical Classification System">ATC CODE</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/ATC_code_A16" style="color: #0c5390; text-decoration: none;" title="ATC code A16">A16</a><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.whocc.no/atc_ddd_index/?code=A16AX10" rel="nofollow" style="color: #0c5390; text-decoration: none;">AX10</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/PubChem" style="color: #0c5390; text-decoration: none;" title="PubChem">PUBCHEM</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=23652731" rel="nofollow" style="color: #0c5390; text-decoration: none;">CID 23652731</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/ChemSpider" style="color: #0c5390; text-decoration: none;" title="ChemSpider">CHEMSPIDER</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.chemspider.com/Chemical-Structure.28475348.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">28475348</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/ChEBI" style="color: #0c5390; text-decoration: none;" title="ChEBI">CHEBI</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:82752" rel="nofollow" style="color: #0c5390; text-decoration: none;">CHEBI:82752</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CHEMICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Chemical_formula" style="color: #0c5390; text-decoration: none;" title="Chemical formula">FORMULA</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Carbon" style="color: #0c5390; text-decoration: none;" title="Carbon">C</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">23</span><a href="http://en.wikipedia.org/wiki/Hydrogen" style="color: #0c5390; text-decoration: none;" title="Hydrogen">H</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">36</span><a href="http://en.wikipedia.org/wiki/Nitrogen" style="color: #0c5390; text-decoration: none;" title="Nitrogen">N</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span><a href="http://en.wikipedia.org/wiki/Oxygen" style="color: #0c5390; text-decoration: none;" title="Oxygen">O</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">4</span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Molecular_mass" style="color: #0c5390; text-decoration: none;" title="Molecular mass">MOLECULAR MASS</a></th><td style="padding: 5px 0px;">404.543 g/mol</td></tr>
</tbody></table>
</div>
</div>
<div class="reflist">
<ol class="references" style="margin: 0px 0px 14px 36px; padding: 0px;">
<li id="cite_note-1" style="list-style-type: decimal;"><span class="reference-text"><a class="external free" href="https://download.ama-assn.org/resources/doc/usan/x-pub/eligustat.pdf" rel="nofollow" style="color: #0c5390; text-decoration: none;">https://download.ama-assn.org/resources/doc/usan/x-pub/eligustat.pdf</a></span></li>
<li id="cite_note-2" style="list-style-type: decimal;"><span class="reference-text"><a class="external free" href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm410585.htm" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm410585.htm</a></span></li>
<li id="cite_note-3" style="list-style-type: decimal;"> <span class="reference-text">Lee, L.; Abe, A.; Shayman, J. A. (21 May 1999). “Improved Inhibitors of Glucosylceramide Synthase”. <i>Journal of Biological Chemistry</i> <b>274</b>(21): 14662–14669.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1074%2Fjbc.274.21.14662" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1074/jbc.274.21.14662</a>.</span></li>
<li id="cite_note-4" style="list-style-type: decimal;"> <span class="reference-text">Shayman, JA (Aug 1, 2010). “ELIGLUSTAT TARTRATE: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease.”.<i>Drugs of the future</i> <b>35</b> (8): 613–620.<a class="mw-redirect" href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="color: #0c5390; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/22563139" rel="nofollow" style="color: #0c5390; text-decoration: none;">22563139</a>.</span></li>
</ol>
</div>
<table class="patent-data-table" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 500px;"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/WO2008150486A2?cl=en" style="color: #0c5390; text-decoration: none;">WO2008150486A2</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">May 30, 2008</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Dec 11, 2008</td><td class="patent-data-table-td " style="padding: 5px 0px;">Genzyme Corp</td><td class="patent-data-table-td " style="padding: 5px 0px;">2-acylaminopropoanol-type glucosylceramide synthase inhibitors</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/WO2009045503A1?cl=en" style="color: #0c5390; text-decoration: none;">WO2009045503A1</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Oct 3, 2008</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Apr 9, 2009</td><td class="patent-data-table-td " style="padding: 5px 0px;">Genzyme Corp</td><td class="patent-data-table-td " style="padding: 5px 0px;">Method of treating polycystic kidney diseases with ceramide derivatives</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/WO2010014554A1?cl=en" style="color: #0c5390; text-decoration: none;">WO2010014554A1</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Jul 27, 2009</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Feb 4, 2010</td><td class="patent-data-table-td " style="padding: 5px 0px;">Genzyme Corporation</td><td class="patent-data-table-td " style="padding: 5px 0px;">Glucosylceramide synthase inhibition for the treatment of collapsing glomerulopathy and other glomerular disease</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/WO2010039256A1?cl=en" style="color: #0c5390; text-decoration: none;">WO2010039256A1</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Oct 2, 2009</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Apr 8, 2010</td><td class="patent-data-table-td " style="padding: 5px 0px;">Genzyme Corporation</td><td class="patent-data-table-td " style="padding: 5px 0px;">2-acylaminopropoanol-type glucosylceramide synthase inhibitors</td></tr>
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SWEDEN</div>
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<img alt="A golden medallion with an embossed image of Alfred Nobel facing left in profile. To the left of the man is the text " class="" height="637" src="http://upload.wikimedia.org/wikipedia/en/thumb/e/ed/Nobel_Prize.png/220px-Nobel_Prize.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="648" /></div>
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<img alt="A black and white photo of a bearded man in his fifties sitting in a chair." class="" height="811" src="http://upload.wikimedia.org/wikipedia/commons/thumb/6/6e/AlfredNobel_adjusted.jpg/170px-AlfredNobel_adjusted.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="615" /></div>
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Alfred Nobel had the unpleasant surprise of reading his own obituary, titled <i>The merchant of death is dead</i>, in a French newspaper.</div>
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<img alt="Map of sweden europe" class="" height="391" src="https://www.google.co.in/maps/vt/data=RfCSdfNZ0LFPrHSm0ublXdzhdrDFhtmHhN1u-gM,iHReY0FkWq2gTMnQDVK0BEtqI75LqhpM91uFX_bMinCGRf6t5ptQI16hDMtMVlKXsKfSJX8XIlkBUsXacrz4R6tXVOa5RsGWh9wTs8uJL9f5lh5Tn28-QzV0-uF6BfdVwz7pPPMmyqs8qj-T848PqKwYtAiPdPya8xhHORcK-ocPf20A-g-pm-QdUXPKghfcvD-JFLe1_fO3Is6GoP44CZkmap37iMaEZ6hM" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="611" /></div>
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<img alt="" class="" height="409" src="http://upload.wikimedia.org/wikipedia/en/archive/4/4c/20140526092805!Flag_of_Sweden.svg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="642" /></div>
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<img alt="" class="" height="410" src="http://kids.nationalgeographic.com/content/dam/kids/photos/Countries/Q-Z/sweden-map.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="635" /></div>
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<img alt="" class="" height="403" src="http://www.nth-mobile.com/wp-content/uploads/2013/12/Sweden-11.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="639" /></div>
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<img alt="" class="" height="399" src="https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcSrpf1MFOXPYQRexGv2qFoFUgUh7SEXM90dG4gNctuBFj0z_u6biw" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="625" /></div>
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<img alt="" class="" height="425" src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcQapsUwV1k2yuDVNWuZNnFDTuGs2b1EbL4slP0-J8PvO57V5L3E" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="626" /></div>
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<img alt="" class="" height="427" src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcQlPGaIl0rKgwbwYZ63FcTuIZvkCkzoVJ8eaNzJ0tAtTuZvTeFtjw" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="631" />Nyköping (Sweden)-houses.</div>
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<img alt="" class="" height="427" src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcQH8N9iK4z-lfsBsYbg8m6D27njD_ozmhsG9dXJ-gI_-kaSLQ6D" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="628" />Fjallbacka, a colorful fishing Village along the west coast of Sweden</div>
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<img alt="" class="" height="285" src="https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcQ65TphE5TpN0KFfE43wLndt5D3xKx0pbfdHkRRCgx6ex8wMSn8bA" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="644" />Knights Island, Stockholm, Sweden</div>
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<img alt="" class="" height="487" src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcT2hjhKN8f6UjWHhcWCl2U_OCGZ5gHK7n_gqteTzUE4ddzPWlRz" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="641" />Sweden Stockholm</div>
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<img alt="" class="" height="486" src="https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcQkOcOgpufSHFaz4TNZxWKLyxb8IcWEi2FvbsSCe7k0d8b5MQ8-lA" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="639" />Europe Örby Änger – Sweden</div>
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<img alt="" class="" height="473" src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcQRWoQLkuI8XNGy0ZCG3ciyHUlhJ1duM0D3HtbxptVE296cBfvjWA" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="622" /></div>
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<img alt="" class="" height="480" src="http://blog.food-programme.eu/files/2009/10/home-suede.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="634" />Despite the cold weather, public came and enjoyed different activities. The famous chef, Paul Svensson who works in one of the fanciest and most famous …</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-302770220608373834.post-24228063984364875902015-04-10T02:22:00.000-07:002015-04-27T22:11:58.926-07:00Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities<div dir="ltr" style="text-align: left;" trbidi="on">
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<tr><td bgcolor="#FFF9DF" style="cursor: text; font-family: Verdana, Arial, Helvetica, sans-serif; font-size: 11px; margin: 8px;" valign="top">YANG Hongliang, XU Guoxing, BAO Meiying, ZHANG Dapeng, LI Zhiwei, PEI Yazhong<br />
<a data-mce-href="http://www.cjcu.jlu.edu.cn/EN/abstract/abstract25459.shtml" href="http://www.cjcu.jlu.edu.cn/EN/abstract/abstract25459.shtml" target="_blank"><b>Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities</b></a><br />
<img alt="" data-mce-src="http://www.cjcu.jlu.edu.cn/fileup/PIC/20141129110543.jpg" src="http://www.cjcu.jlu.edu.cn/fileup/PIC/20141129110543.jpg" style="border: 0px; cursor: default;" vspace="5" /></td></tr>
<tr><td bgcolor="#EBEBEB" style="cursor: text; font-family: Verdana, Arial, Helvetica, sans-serif; font-size: 11px; margin: 8px;" valign="top">2014 Vol. 35 (12): 2584-2592 [<a href="https://www.blogger.com/null"><span data-mce-style="text-decoration: underline;" style="text-decoration: underline;">Abstract</span></a>] ( <span data-mce-style="color: red;" style="color: red;">781 </span>) [<a data-mce-href="http://www.cjcu.jlu.edu.cn/EN/volumn/volumn_1608.shtml#" href="http://www.cjcu.jlu.edu.cn/EN/volumn/volumn_1608.shtml#"><span data-mce-style="text-decoration: underline;">HTML</span></a> 0KB] [<a data-mce-href="http://www.cjcu.jlu.edu.cn/EN/article/downloadArticleFile.do?attachType=PDF&id=25459" href="http://www.cjcu.jlu.edu.cn/EN/article/downloadArticleFile.do?attachType=PDF&id=25459"><span data-mce-style="text-decoration: underline;">PDF</span></a> 2464KB] (<span data-mce-style="color: red;" style="color: red;">116 </span>)<br />
<b>doi</b>: <a data-mce-href="http://dx.doi.org/10.7503/cjcu20140333" href="http://dx.doi.org/10.7503/cjcu20140333">10.7503/cjcu20140333</a></td></tr>
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<a data-mce-href="http://www.cjcu.jlu.edu.cn/" href="http://www.cjcu.jlu.edu.cn/">Chemical Journal of Chinese Universities</a> <img alt="" data-mce-src="http://www.cjcu.jlu.edu.cn/images/dao.gif" src="http://www.cjcu.jlu.edu.cn/images/dao.gif" style="border: 0px; cursor: default;" /> <a data-mce-href="http://www.cjcu.jlu.edu.cn/EN/article/showTenYearVolumnDetail.do?nian=2014" href="http://www.cjcu.jlu.edu.cn/EN/article/showTenYearVolumnDetail.do?nian=2014">2014</a>, <b><a data-mce-href="http://www.cjcu.jlu.edu.cn/EN/article/showTenYearVolumnDetail.do?nian=2014" href="http://www.cjcu.jlu.edu.cn/EN/article/showTenYearVolumnDetail.do?nian=2014">Vol. 35</a></b> <img alt="" data-mce-src="http://www.cjcu.jlu.edu.cn/images/dao.gif" src="http://www.cjcu.jlu.edu.cn/images/dao.gif" style="border: 0px; cursor: default;" /> <a data-mce-href="http://www.cjcu.jlu.edu.cn/EN/volumn/volumn_1608.shtml" href="http://www.cjcu.jlu.edu.cn/EN/volumn/volumn_1608.shtml">Issue (12)</a>: 2584-2592 DOI: 10.7503/cjcu20140333</div>
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<b>Abstract</b> Based on the X-ray co-crystal structures of reported allosteric kinase inhibitors bound to their corresponding protein kinases, a pharmacophore model was proposed. To examine the validity of this hypothesis, 21 new pyridinylisoxazole derivatives were designed and synthesized. Their structures were confirmed using 1H NMR, 13C NMR and MS data. Their inhibitory effects against human breast cancer cell(MCF-7) proliferation were evaluated. Preliminary results indicated that some of these pyridinylisoxazole derivatives possess potent anti-proliferative activities, with IC50 data in the micromolar range. The mechanism-of-action of these compounds is under investigation.</div>
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<tr><td align="left" height="40" style="border: 1px dashed rgb(187, 187, 187); cursor: text; font-size: 11px; margin: 8px;">Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities</td></tr>
<tr><td align="left" height="30" style="border: 1px dashed rgb(187, 187, 187); cursor: text; font-size: 11px; margin: 8px;">YANG Hongliang<sup>1</sup>, XU Guoxing<sup>1</sup>, BAO Meiying<sup>2</sup>, ZHANG Dapeng<sup>1</sup>, LI Zhiwei<sup>1</sup>, PEI Yazhong<sup>1</sup></td></tr>
<tr><td align="left" height="30" style="border: 1px dashed rgb(187, 187, 187); cursor: text; font-size: 11px; margin: 8px;">1. The Center for Combinatorial Chemistry and Drug Discovery, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China;<br />
2. Changchun Discovery Sciences Co. Ltd., Changchun 130012, China</td></tr>
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<tr><td height="24" style="border: 1px dashed rgb(187, 187, 187); cursor: text; font-family: Verdana, Arial, Helvetica, sans-serif; font-size: 11px; margin: 8px;">YANG Hongliang,XU Guoxing,BAO Meiying et al. Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities[J]. Chemical Journal of Chinese Universities, 2014, 35(12): 2584-2592.</td></tr>
<tr><td bgcolor="#f1f1f1" height="25" style="border: 1px dashed rgb(187, 187, 187); cursor: text; font-family: Verdana, Arial, Helvetica, sans-serif; font-size: 11px; margin: 8px;"><b>URL:</b></td></tr>
<tr><td height="24" style="border: 1px dashed rgb(187, 187, 187); cursor: text; font-family: Verdana, Arial, Helvetica, sans-serif; font-size: 11px; margin: 8px;"><a data-mce-href="http://www.cjcu.jlu.edu.cn/EN/10.7503/cjcu20140333" href="http://www.cjcu.jlu.edu.cn/EN/10.7503/cjcu20140333">http://www.cjcu.jlu.edu.cn/EN/10.7503/cjcu20140333</a> <b> OR</b> <a data-mce-href="http://www.cjcu.jlu.edu.cn/EN/Y2014/V35/I12/2584" href="http://www.cjcu.jlu.edu.cn/EN/Y2014/V35/I12/2584">http://www.cjcu.jlu.edu.cn/EN/Y2014/V35/I12/2584</a></td></tr>
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DHAKA BANGLADESH</div>
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<img alt="" class="" src="http://media.web.britannica.com/eb-media/16/64716-004-71C4497C.gif" height="640" id="irc_mi" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" /></div>
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<img alt="" class="" src="http://chada.com.au/wp-content/uploads/2013/03/Dhakanews_w1020_image01.jpg" height="358" id="irc_mi" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" /></div>
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<img alt="" class="irc_mut" height="426" src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcRfZ6uzwopsjhx9O6Ajw57PDIv_NY-3FIeY2oj3pixG0KyweBBJGw" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" /></div>
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<img alt="" class="irc_mut" height="492" src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcRXKxtUzUJqiVcAstEn1WlhXe8nHbqNtMOtTeHiC9Zis_VFJIz-vg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" /></div>
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<img alt="" class="" src="http://www.hotelclub.com/blog/wp-content/uploads/2009/12/Dhaka-Bangladesh-9.jpg" height="479" id="irc_mi" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" /></div>
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<img alt="" class="" src="http://www.bestourism.com/img/items/big/6929/Bangladesh_Dhaka_8417.jpg" height="426" id="irc_mi" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" /></div>
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<img alt="" class="" src="http://upload.wikimedia.org/wikipedia/commons/c/c4/Steamers_in_Sadarghat_Dhaka.jpg" height="436" id="irc_mi" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" />.</div>
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<span class="irc_su" dir="ltr">Steamers and ferries in Sadarghat Port</span></div>
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<img alt="" class="" src="http://upload.wikimedia.org/wikipedia/commons/6/62/Dhaka-Bangladesh.jpg" height="422" id="irc_mi" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" /><span class="irc_su" dir="ltr">Kawran Bazar</span></div>
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<img alt="" class="" height="625" id="irc_mi" src="https://www.happytellus.com/img/dhaka/bangladesh-dhaka_69.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" />.</div>
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<img alt="" class="" src="http://cdn.c.photoshelter.com/img-get2/I00003BxpAvFzp28/fit=1000x750/dryfish-market-dhaka-bangladesh-7.jpg" height="427" id="irc_mi" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" /><span class="irc_su" dir="ltr">Dry fish sellers at the Karwan Dry Fish Market (Bazar), Dhaka, Bangladesh.</span></div>
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<img alt="" class="" height="426" id="irc_mi" src="https://www.wodumedia.com/wp-content/uploads/2012/11/Bangladeshi-vendors-display-for-sale-traditional-food-items-for-breaking-fast-on-the-first-day-of-holy-Ramadan-at-Chalk-Bazar-market-in-Dhaka-Bangladesh-on-August-2-2011.-AP-PhotoPavel-Rahman.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="640" /></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-302770220608373834.post-23291520433974426792015-04-09T05:56:00.002-07:002015-04-09T05:56:53.240-07:00VENLAFAXINE PART 2/3<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="" src="http://www.animatedimages.org/data/media/696/animated-update-image-0024.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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part 1………<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html" style="color: #0c5390; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html</a> / <a href="http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/</a></div>
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part 2……..<a href="http://newdrugapprovals.org/2015/04/09/venlafaxine-22/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2015/04/09/venlafaxine-22/</a></div>
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PART 3…..<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html" style="color: #0c5390; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html</a></div>
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<a href="http://www.google.com/patents/WO2008059525A2?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/WO2008059525A2?cl=en</a></div>
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WILL BE UPDATED………..</div>
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<img alt="" src="http://www.chemdrug.com/databases/SYNTHESIS/SYN/10/10072103a.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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PAPER</div>
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<i><strong>RSC Adv.</strong></i>, 2014,<strong>4</strong>, 14468-14470</div>
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<span class="DOILink"><strong>DOI: </strong>10.1039/C4RA00840E</span></div>
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<a href="http://pubs.rsc.org/en/content/articlelanding/2014/ra/c4ra00840e#!divAbstract" style="color: #0c5390; text-decoration: none;">http://pubs.rsc.org/en/content/articlelanding/2014/ra/c4ra00840e#!divAbstract</a></div>
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A protecting group free asymmetric total synthesis of (−)-venlafaxine is reported. The strategy employs Sharpless epoxidation and regio-selective epoxide ring opening by an <em>in situ</em>generated Gilman reagent as key steps. This paper reports a 53% overall yield in 6 steps for total synthesis of (−)-venlafaxine.</div>
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<img alt="Graphical abstract: A protecting group free and scalable approach towards total synthesis of (−)-venlafaxine" class="" height="156" id="imgGALoader" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=C4RA00840E" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" title="Graphical abstract" width="604" /></div>
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<img alt="" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2014/RA/c4ra00840e/c4ra00840e-s2_hi-res.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<a href="http://www.google.com/patents/EP2181982B1?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/EP2181982B1?cl=en</a></div>
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<img alt="" class="" height="268" src="http://patentimages.storage.googleapis.com/EP2181982B1/imgb0002.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="970" /></div>
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<b><span style="text-decoration: underline;">Examples:</span></b><b><span style="text-decoration: underline;">Example 1</span> – Preparation of venlafaxine from <i>N,N</i>-didesmethyl venlafaxine hydrochloride</b></div>
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A 50 % aqueous NaOH solution (4 ml, 74 mmol) was added to a stirred solution of N,N-didesmethyl venlafaxine hydrochloride (5.72 g, 20 mmol) in water (16 ml) at room temperature. Formic acid (98 %, 11.5 ml, 305 mmol) and 37 % aqueous solution of formaldehyde (8.4 ml, 113 mmol) were added to this mixture. The mixture was stirred under reflux temperature and the conversion was completed in 5 h (HPLC: 98.67 area %). Then the solution was cooled to room temperature and adjusted with 50 % aequous NaOH to pH 12. The mixture was extracted twice with 66 ml of isopropyl acetate. The collected organic phases were washed three times with water (66 ml). The isolated solution of venlafaxine base was very pure (HPLC: 98.9 area%).</div>
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<b><span style="text-decoration: underline;">Example 2 –</span> Preparation of venlafaxine hydrochloride form I from the solution of venlafaxine base in isopropyl acetate</b></div>
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To the solution of venlafaxine base in isopropyl acetate from example 1 (66 ml, 10 mmol) 5 ml of 2 M aqueous HCl were added. The mixture was heated and water was removed by azeotropic distillation using a Dean-Starck trap. When all water was removed from the mixture, the product began slowly to crystallize. The obtained suspension was heated under reflux temperature for 1.5 h, then cooled and filtered. 2.75 g (88 % from N,N-didesmethyl venlafaxine hydrochloride) of pure venlafaxine hydrochloride form I (HPLC: 99.65 area %) were obtained.</div>
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<b><span style="text-decoration: underline;">Example 3</span> (exemplary) – Preparation of venlafaxine hydrochloride form I from the solution of venlafaxine base in isopropyl acetate</b></div>
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The solution of venlafaxine in isopropyl acetate from example 1 (66 ml, 10 mmol) was concentrated to ½ of the volume. Then 10 to 50 mg of venlafaxine hydrochloride form I was added to the solution. Subsequently, a 2.5 M solution of HCl in ethanol (4.0 ml) was slowly added within 30 min. After the whole amount of acid was added, the obtained suspension was stirred for another 2 h. Then the mixture was filtered and the product was washed with isopropyl acetate and dried. We obtained 2.69 g (86 % from<i>N,N</i>-didesmethyl venlafaxine hydrochloride) of pure venlafaxine hydrochloride form I (HPLC: 99.65 area %).</div>
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…………………..</div>
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PATENT</div>
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<a href="http://www.google.com/patents/WO2006035457A1?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/WO2006035457A1?cl=en</a></div>
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Venlafaxine is known by the chemical name 1-[2-dimethylamino-1-(4 methoxyphenyl ethyl Cyclohexanol hydrochloride and structure of formula (V).</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000002_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000002_0001" class="patent-full-image" height="128" id="imgf000002_0001" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000002_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="272" /></a></div>
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(V)</div>
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Venlafaxine is a useful pharmaceutical agent as an antidepressant. Venlafaxine, the intermediates in the manufacture of Venlafaxine, the process of preparing said Venlafaxine and their intermediates are well known from US Patents 4,535,186, US Patent No. 6,350,912, and CN 1225356.</div>
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Further International Publication No. WO03/050074 discloses the manufacture of Venlafaxine Hydrochloride and crystalline polymorphs Form I, Form II, Form III and optically pure (R) and (S) enantiomers exhibiting different crystalline structures of Venlafaxine hydrochloride. The preparation of all the forms of Venlafaxine and their inter-conversion are also described in said WO03/0500074 publication. U.S. Patents 4535186, 4761501 disclose a process for manufacture of 1-[2- amino-i-(p-methoxyphenyl) ethyljcyclohexanol (free base of formula IV), an intermediate produced during the preparation of Venlafaxine in two stages by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of n- butyl lithium (Stage 1) to form 1-[cyano(p-methoxyphenyl) methyl] Cyclohexanol of formula III</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000003_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" height="92" id="imgf000003_0001" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000003_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="240" /></a></div>
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(111)</div>
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This process is commonly used for the preparation of formula III. The US Patent 4,535,186 produces a yield of about 30% based on p-methoxyphenyl acetonitrile.</div>
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WO/03/050074 suggests an alternate way of preparing compound of formula III without using butyl lithium i.e. by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of alkali metal hydroxide in a mixture of toluene and hexane. The publication WO/03/050074 also suggests a material yield of 74% based upon p-methoxyphenyl acetonitrile and purity.</div>
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The drop wise addition of butyl lithium to p-methoxyphenyl acetonitrile is hazardous and hence it requires skill and safety measures to be taken by the person skilled in the art for handling butyl lithium over the addition period to avoid any accidents during the preparation process.</div>
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The second stage i.e. conversion of compound of formula III to formula IV described in US patent US 4,535,186 is by hydrogenating compound of formula III using Rhodium on alumina. The catalyst Rhodium is recycled by filtering and washing the catalyst with ethanol and the combined filtrate evaporated and dried under vacuum yielding free base as an oil. However, the cost of Rhodium catalyst is very high and hence the catalyst has to be recovered.</div>
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WO/02/500017 suggests the use of a Nickel or cobalt catalyst for the hydrogenation, which is highly economical when compared with the Rhodium catalyst as suggested by US Patent No. 4,535,186. The International Publication WO/02/500017 teaches that the hydrogenation reaction of Stage Il may be carried out in the presence of an organic solvent preferably an alcohol. The international publication also suggests the pretreatment of the catalyst with ethanol.</div>
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The US Patent 4,535,186 describes the third stage in the process of preparing Venlafaxine i.e. conversion of compound of formula IV (free base) to compound V i.e. Venlafaxine by methylating the compound of formula IV (free base) with a mixture of formaldehyde and formic acid in water.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000004_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" height="124" id="imgf000004_0001" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000004_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="200" /></a></div>
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(IV)</div>
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US Patent Publication No. 2005/0033088 describes a process for preparing phenylethylamine derivative, an intermediate of Venlafaxine hydrochloride; said process comprising steps of reduction of compound of formula III with palladium on charcoal in an organic acid selected from formic acid, acetic acid or propionic acid, preferably acetic acid in an autoclave at a pressure of 5 to 25 kg/cm2 preferably 10 to 15 kg/cm2 at a temperature in the range of 30 to 75°C, preferably at 50 to 55°C till the hydrogenation substantially complete, filtering the palladium catalyst and evaporating the filtrate. Extracting the filtrate with halogenated hydrocarbon solvent and purifying the same. The process also describes the preparation of Venlafaxine hydrochloride without isolation of freebase.</div>
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The route of synthesis for Venlafaxine (formula V) and intermediate of Venlafaxine (formula IV) is depicted in the following scheme:</div>
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Step -I</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000008_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000008_0001" class="patent-full-image" height="108" id="imgf000008_0001" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000008_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="552" /></a></div>
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(I) (II) (III) Step-ll</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000009_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000009_0001" class="patent-full-image" height="124" id="imgf000009_0001" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000009_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="556" /></a></div>
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…………..(III) ……………………(IV)</div>
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Step-ll I</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000009_0002.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000009_0002" class="patent-full-image" height="136" id="imgf000009_0002" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000009_0002.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="576" /></a></div>
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(IV) (V)</div>
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Accordingly, the present invention relates to an improved process for the preparation of compound of formula IV</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000009_0003.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000009_0003" class="patent-full-image" height="120" id="imgf000009_0003" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000009_0003.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="252" /></a></div>
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(IV)</div>
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comprising the step of hydrogenating a compound of formula</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000010_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000010_0001" class="patent-full-image" height="96" id="imgf000010_0001" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000010_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="240" /></a></div>
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(Hi)</div>
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in the presence of toluene, water, and a catalyst wherein the said process yields 66% formula (IV) with 99% HPLC purity.</div>
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The compound of formula IV is further methylated using formaldehyde and formic acid mixture to form Venlafaxine (formula V) followed by the treatment with HCL gas dissolved in Isopropanol.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000010_0002.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000010_0002" class="patent-full-image" height="136" id="imgf000010_0002" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000010_0002.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="576" /></a></div>
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(IV) (V)</div>
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According to the preferred embodiment of the present invention, nickel catalyst, preferably Raney nickel catalyst is used. The catalyst is washed in water to remove the alkali. No pretreatment of the nickel catalyst is required.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000011_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000011_0001" class="patent-full-image" height="124" id="imgf000011_0001" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000011_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="556" /></a></div>
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(HI) (IV)</div>
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According to another embodiment of the present invention, compound of formula IV is prepared by hydrogenating compound of formula III in the presence of Raney Nickel and water. According to another embodiment of the present invention, compound of formula III is prepared by charging p-methoxyphenyl acetonitrile into butyl lithium at -70 to -75°C and tetrahydrofuran; cooling the reaction mixture to about -50°C to -75<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C; adding cyclohexanone at a temperature below -50<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C quenching with ice and saturated ammonium chloride solution below 0<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">°</span>C; and stirring and filtering the product of formula (III) wherein the said process yields 89% of compound of formula III with 99.8% purity. The reaction scheme is depicted as follows:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000012_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000012_0001" class="patent-full-image" height="108" id="imgf000012_0001" src="http://patentimages.storage.googleapis.com/WO2006035457A1/imgf000012_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="552" /></a></div>
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…………(I) …………(H)………………………………. (III)</div>
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Example 1 :</div>
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Preparation of 1-[cyano-(4-methoxyphenyl) methyl Icvclohexanol.</div>
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In a 2 ltr 4 necked round bottom flask equipped with a overhead stirrer, thermometer and dropping funnel, 100 ml dry THF followed by 210 ml Butylithium (1.6 M solution in Hexane) was charged. The reaction mixture was cooled to – 70<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. Added gradually a solution of 50 gm p-methoxyphenyl acetonitrile dissolved in 50 ml dry THF at -70 to -75°C. After 30 min, added solution of 33.1 gm Cyclohexanone in 50 ml THF. After the addition, maintained at -65 to -70<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C and monitored by TLC. After 4 hrs, reaction mixture was gradually added over mixture of ice and 150 ml saturated ammonium chloride solution below 0°C and adjusted pH to 7 with dilute Hydrochloric acid. Stirred for 1 hr and filtered the product. Washed the product with 200 ml hexane and dried to obtain 74.3 gm. (The yield based on p-methoxyphenyl acetonitrile 89%, Melting range 123- 125°C, HPLC purity of 99.8%).</div>
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Example 2:</div>
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Preparation of 1-[2-amino-(4-methoxyphenyl) ethyl] Cyclohexanol acetate</div>
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In an autoclave are charged 100 gm 1-[cyano(4- methoxyphenyl)ethyl]cyclohexanol, 100 ml toluene and 400 ml water at RT. Stirred and cooled to 10°C. Charged 20 gm Raney Nickel (which was prewashed with water to make it free of Alkali) and 100 ml liquor ammonia (20%). Then pressurized the autoclave with hydrogen to 4 – 5 kg pressure and maintained for 120 minutes below 12<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. Then the reaction temperature slowly raised to bout 50<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C along with the increase in the hydrogen pressure to 7 to 8 kg. Maintained between 45 – 50°C for 8 hr. After the completion of the reaction, cooled the reaction to RT, released the hydrogen pressure and charged 400 ml toluene. Filtered the catalyst and washed bed with 100 ml toluene. Separated the organic layer from the filtrate. The organic layer was washed with 10% Sodium chloride solution. To the organic layer was added 40 ml methanol followed by 10 ml acetic acid. Stirred for 15 minutes and then again charged 10 ml acetic acid. Then heated to 75-8O<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C and maintained for 15 minutes. Cooled to 0 – 5<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. Filtered the product. Washed the product with 100 ml ethyl acetate and dried: 83.5 gm (Yield 66%, Melting range 164-166°C, HPLC purity 99%).</div>
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Example 3:</div>
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Preparation of H2-dimethylamino-1-(4-methoxyphenyl) ethvH Cyclohexanol Hydrochloride</div>
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To a stirred solution of 100 gm of 1-[2-amino-(4-methoxyphenyl) ethyl] Cyclohexanol acetate in 300 ml water was added 117 gm of formic acid (88%) and 91 gm of formaldehyde (40% solution). The solution was heated to 98°C and maintained for 20 hrs. Reaction mixture was cooled to about 10<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C and added 500 ml ethyl acetate. The pH was adjusted to about 7 with sodium hydroxide solution and further to 10 – 10.5 with ammonium hydroxide solution. Layers were separated. Aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with water. Combined organic extract was stirred with activated carbon (5 gm) and filtered. Filtrate was concentrated in vacuum to completely remove ethyl acetate. Residue was dissolved in isopropanol (300 ml) and acidified at 30<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C (pH 1-1.5) with the solution of HCI in isopropanol. Temperature was then raised to 60<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C and maintained for 60 to 90 min. The reaction mass was cooled under agitation to 10°C and maintained under agitation at 10°C for 60 min. Product was isolated by filtration. Finally it was washed with isopropanol and dried at 60°C.</div>
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Dry wt. : 85 gm (84% yield, HPLC 99.9% purity with all individual impurities below 0.1% concentration). This material exhibited following characteristic x-ray powder diffraction pattern with characteristic peaks expressed in d-values (A) at.</div>
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(The abbreviations in brackets mean : (vs) = Relative intensity above 80%; (s) = 30% – 80%; (m) = 15% – 30%; <span class="wp-smiley wp-emoji wp-emoji-wordpress" style="display: inline-block !important; min-height: 1.2em; overflow: hidden; position: relative !important; text-indent: 9999px; vertical-align: bottom; white-space: nowrap; width: 1.35em;" title="(w)">(w)</span> = 8% to 15% and (vw) = below 8%.) 2.23 (VW), 2.29(VW), 2.32 (VW)<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">1</span>2.35(VW), 2.38(VW), 2.43(VW), 2.46(VW), -2.48(VW)<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">1</span>2.55(M), 2.64(W), 2.69(W), 2.73(VW), 2.8(W), 2.83(W), 2.88(W), 2.93(VW), 3.09(VW), 3.12(M), 3.26(VM), 3.31(VM), 3.38(W), 3.45(VW), 3.5(VW), 3.55(M), 3.69(VW), 3.87(VW), 3.99(VW), 4.07(M), 4.18(S), 4.35(VS), 4.48(VW), 4.68(M), 5.1 (VW), 5.27(W), 5.42(VW), 5.55(VW), 5.63(M), 5.68(M), 5.76(VW), 6.5(S), 6.95(VS), 8.65(VW), 10.56(M), 13.06(M).</div>
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Example 4 :</div>
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Preparation of 1-f2-amino-(4-methoxyphenyl) ethyl] Cyclohexanol acetate (IV)</div>
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In an autoclave charged 150 gm 1-[cyano(4-methoxyphenyl)ethyl]cyclohexanol, and 675 ml water at RT. Stirred and cooled to 1O<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. Charged 30 gm Raney Nickel (prewashed with water to make it free of Alkali) and 150 ml liquor Ammonia (20%). Then pressurized the autoclave with hydrogen to 4 – 5 kg pressure and maintaind for 120 minutes below 12°C. After completion of 120 minutes slowly raised the temperature to about 50<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C along with the increase in the hydrogen pressure to 7 to 8 kg. Maintained between 45 – 5O<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C for about 20 hrs. Monitored reaction by TLC to ensure disappearance of starting material. After the completion of the reaction cooled the reaction to RT, released the hydrogen pressure and filtered through celite bed. Washed bed with 300 ml toluene. To the filtrate added 300 ml toluene. Shaken well and separated the organic layer. The organic layer was washed with 5% Sodium chloride solution. To the organic layer was added 45 ml methanol and 15 ml acetic acid. Stirred for 15 minutes and then again charged 15 ml acetic acid. Then heated to 75-8O<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C and maintained for 15 mins. Cooled to 0 – 5°C. Filtered the product. Washed the product with 100 ml ethyl acetate and dried: 104 gm (Yield 53%, Melting range 152-153°C, HPLC purity 90%).</div>
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……………….</div>
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PATENT</div>
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<a href="http://www.google.com/patents/WO2008059525A2?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/WO2008059525A2?cl=en</a></div>
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Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonin. It has been reported that its (-) enantiomer is a more potent inhibitor of norepinephrine synaptosomal uptake while its (+) enantiomer is more selective in inhibiting serotonin uptake (J. Med. Chem. 1990, 33(10), 2899-2905) In humans, venlafaxine is transformed by a metabolic pathway into two minor metabolites, N-desmethylvenlafaxine of formula II, N,O-di- desmethylvenlafaxine of formula IV and one major metabolite, O-desmethylvenlafaxine of formula III.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000003_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" height="156" id="imgf000003_0001" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000003_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="536" /></a></div>
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formula I formula II</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000003_0002.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000003_0002" class="patent-full-image" height="160" id="imgf000003_0002" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000003_0002.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="536" /></a></div>
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formula III formula IV</div>
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In the literature there are several processes reported for the synthesis of venlafaxine of formula I and venlafaxine hydrochloride of formula Ia.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000003_0003.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000003_0003" class="patent-full-image" height="160" id="imgf000003_0003" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000003_0003.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="224" /></a></div>
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formula Ia</div>
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The synthesis of venlafaxine from 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile (hereinafter called as cyano-intermediate and represented by formula V) involving two step synthesis is known in the prior art.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000004_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" height="124" id="imgf000004_0001" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000004_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="228" /></a></div>
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formula V</div>
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US 4,535,186 discloses the preparation of venlafaxine of formula I by the reaction of p- methoxyphenylacetonitrile with cyclohexanone at -78 <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C in the presence of n-butyllithium as a base which yields 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile of formula V. Reduction of the cyano-intermediate under hydrogen pressure with rhodium on alumina catalyst gives l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol. N-Methylation of the amino compound is accomplished employing formaldehyde and formic acid (Eschweiler- Clarke reaction) to give venlafaxine of formula I.</div>
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The reaction is as shown in the Scheme- 1.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000005_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000005_0001" class="patent-full-image" height="124" id="imgf000005_0001" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000005_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="616" /></a></div>
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Reduction</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000005_0002.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000005_0002" class="patent-full-image" height="116" id="imgf000005_0002" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000005_0002.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="20" /></a></div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000005_0003.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000005_0003" class="patent-full-image" height="156" id="imgf000005_0003" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000005_0003.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="220" /></a></div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000005_0004.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000005_0004" class="patent-full-image" height="124" id="imgf000005_0004" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000005_0004.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="356" /></a></div>
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Scheme-1</div>
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Another prior art reference, Zhou Jinpei et.al, J. China Pharm. University, 1999, 30(4), 249- 50) discloses the preparation of venlafaxine starting from anisole. Anisole is acylated to the chloroacetyl derivative, which is then animated using N,N-dirnethylamine. The carbonyl group of this compound is reduced to the alcohol using KBH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">4</span> and is converted to the bromo- derivative using PBr<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span> which in turn when reacted with Mg and cyclohexanone undergoes a Grignard reaction to provide venlafaxine of formula I.</div>
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The reaction is as shown in the Scheme-2.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000006_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000006_0001" class="patent-full-image" height="408" id="imgf000006_0001" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000006_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="620" /></a></div>
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Scheme-2</div>
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US 2005033088 discloses a two step process for venlafaxine starting from the cyano- intermediate. The cyano-intermediate is reduced in the presence of palladium on charcoal in acetic acid at a hydrogen pressure of 5-25 kg/cm<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">2</span> at a temperature in the range of 30-75 <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. The product of step 1 is N-methylated using formic acid, formaldehyde solution at a temperature of 90-98 <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C for 19 hrs to yield venlafaxine, which is then converted to its hydrochloride salt.</div>
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WO2006035457 also discloses a process of making venlafaxine and its intermediates. The process comprises the step of hydrogenating the cyano-intermediate in the presence of toluene, water, and Raney nickel where in the said process yields 66% of an intermediate with 99% HPLC purity. This reaction is carried out at 10-12 <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C and at 4-5 kg/cm<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">2</span> of hydrogen pressure for 2 hrs and further at 50 <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C at 7-8 kg/cm<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">2</span> for 7-8 hrs. This intermediate is N-methylated using formaldehyde and formic acid mixture to form venlafaxine, which is treated with IPA/HC1 to get venlafaxine hydrochloride.</div>
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US 6,350,912 discloses a one pot process for the preparation of venlafaxine in 15-28 % yield from the cyano-intermediate. In the said patent venlafaxine has been prepared by the reduction of cyano-intermediate in the presence of Raney nickel and without isolation of intermediate l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol</div>
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CN 1850781 discloses a process for the preparation of venlafaxine by following steps: (1) carrying out condensation of 4-methoxyphenylacetonitrile and cyclohexanone in presence of base to obtain 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile, (2) reacting 2-(l- hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile with cuprous chloride and dimethylamine to obtain 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)-N,N- dimethylacetimidamide, and (3) reacting 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)- N,N-dimethylacetimidamide with KBH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">4</span> to obtain 1 – [2-dimethylamino)- 1 -(4-methoxyphenyl) ethyl)cyclohexanol (venlafaxine).</div>
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The reaction is as shown in the Scheme-3.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000008_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000008_0001" class="patent-full-image" height="376" id="imgf000008_0001" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000008_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="616" /></a></div>
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Scheme-3</div>
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The processes disclosed in the prior art have many disadvantages. Most of the prior art processes employ formaldehyde as a reactant for N-methylation step which is known to be a carcinogen. Acute exposure of the same is highly irritating to the eyes, nose and throat. Ingestion of formaldehyde is fatal and long term exposure causes respiratory problems and skin irritation.</div>
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Another disadvantage is the formation of an impurity (represented by formula VI), which is formed during N-methylation step using formaldehyde as a reagent.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000009_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000009_0001" class="patent-full-image" height="160" id="imgf000009_0001" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000009_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="224" /></a></div>
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formula VI</div>
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As may be appreciated, all the above well-known processes share the same strategy of synthesis, consisting of two steps for the synthesis of venlafaxine from cyano-intermediate or are prepared in one pot with poor yield.</div>
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Yet another drawback of the processes disclosed in the prior art is the use of expensive catalysts like rhodium on alumina and use OfBF<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span> etherate which is highly corrosive.</div>
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The prior art references disclose the synthesis of alkoxyphenylethyldimethylamine from alkoxyphenylacetonitrile using excess dimethylamine and palladium catalyst in methanol solution which is firstly reported by Kindler and Hensse. (1. Kindler and Hesse; Arch. Pharm., 1933, 271, 439. 2. Johannes S. Buck, Richard Baltzly and Walter S. Ide; J. Am. Chem. Soc. 1938, 60(8), 1789-1792; 3. Albert J. Schuster and Eugene R. Wagner; J. Labelled Compounds and Radiopharmaceuticals 1992, XXXIII(3), 213-217).</div>
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The reaction is as shown in the Scheme-5.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000010_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000010_0001" class="patent-full-image" height="156" id="imgf000010_0001" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000010_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="480" /></a></div>
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Scheme-5</div>
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According to an aspect of the invention there is provided a novel single step process for the synthesis of venlafaxine of formula I and N-desmethylvenlafaxine of formula II from 2-(l- hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile of formula V comprising reaction of 2- (l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile with an alkylamine and/or its salt in a solvent in the presence of a transition metal catalyst, under hydrogen atmosphere.</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000011_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000011_0001" class="patent-full-image" height="136" id="imgf000011_0001" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000011_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="592" /></a></div>
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formula I formula II formula V DETAILED DESCRIPTION OF THE INVENTION</div>
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The present invention describes a single step process for venlafaxine and its analog starting from the cyano-intermediate. The present invention circumvents the difficulties encountered in the prior art and is an economically viable process.</div>
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The present invention particularly relates to a single step synthesis of venlafaxine of formula I, and N-desmethylvenlafaxine of formula II from the cyano-intermediate of formula V.</div>
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The reaction of the present invention is as shown in Scheme-4:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000012_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000012_0001" class="patent-full-image" height="148" id="imgf000012_0001" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000012_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="536" /></a></div>
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formula V formula L R = CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span> (Venlafaxine) formula II. R = H (N-desmethylvenlafaxine)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000012_0002.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000012_0002" class="patent-full-image" height="224" id="imgf000012_0002" src="http://patentimages.storage.googleapis.com/WO2008059525A2/imgf000012_0002.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="216" /></a></div>
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formula Ia. R = CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span>, X = Cl formula Ha. R = H, X = Cl</div>
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Example-1:</div>
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General procedure for synthesis of venlafaxine and N-desmethylvenlafaxine To the, stirred solution of 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile (1.0 equiv.) in methanol (10-20 volumes), alkylamine (3-5 equiv.) was added and the mixture was stirred for 5-10 minutes to get a clear solution. Palladium catalyst (10-50 wt %) was added under nitrogen atmosphere to the above reaction mixture. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atmospheric pressure.) at room temperature for 5 to 40 hrs. The progress of the reaction was monitored by TLC and HPLC. After completion of the reaction, the catalyst was filtered through celite and washed with methanol. The combined filtrate was concentrated to dryness under reduced pressure and the residue was poured in water. The aqueous layer was basifϊed with 10% aq. NaOH to pH 8-10 and extracted with ethyl acetate (3 times). The combined ethyl acetate layers were washed with brine and dried over sodium sulphate. Ethyl acetate was evaporated under vacuum to obtain the title compound.</div>
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Example-2: <span style="color: red;">Venlafaxine</span></div>
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To the stirred solution of 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile (20.0 g, 1 equiv.) in methanol (460.0 ml), dimethylamine hydrochloride (26.6 g, 4 equiv.) was added and the mixture was stirred for 5-10 minutes at room temperature to obtain a clear solution. 5% Palladium on alumina (4.0 g, 20 wt %) was added under nitrogen to the above clear solution. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atmospheric pressure.) at room temperature for 20 hrs. After completion of the reaction product was isolated by the procedure as described in Example- 1 above to obtain light yellow viscous liquid (18.Og) which was directly converted to its hydrochloride salt using IPA/HC1. HPLC purity of the crude reaction mixture (18.Og) = 81.64%.</div>
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<span style="color: red;">Venlafaxine-free base:</span></div>
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<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>H NMR in CDCl<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span> (300 MHz): δ 7.05 (d, 2H), 6.81 (d, 2H), 3.79 (s, 3H), 3.27 (t, IH), 2.94 , (dd, IH), 2.31 (s, 6H), 2.28 (dd, IH), 1.71-0.94 (m, 10H). 1<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3</span>C NMR in CDCl<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span>: δ 158.16,’ 132.65, 130.01, 113.20, 74.14, 61.14, 55.05, 51.52, 45.37, 37.99, 31.07, 25.91, 21.52, 21.23.</div>
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IR (KBr): 3152, 2980, 2941, 2895, 1728, 1607, 1512, 1462, 1439, 1358, 1279, 1204, 1186, 1177, 1146, 1103, 1040, 1011, 968, 851 cm<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">“1</span>. HPLC Purity: 99.37 % (area %). GC-MS: 178 (M+H<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>).</div>
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<span style="color: red;">Venlafaxine hydrochloride salt:</span></div>
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<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>H NMR in D<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>O (300 MHz): δ 7.23 (d, 2H), 6.91 (d, 2H), 3.71 (s, 3H), 3.54 (t, IH), 3.48 (dd, IH), 2.97 (dd, IH), 2.69 (s, 6H), 1.41-1.0 (m, 10H).</div>
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<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">13</span>C NMR in D<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>O: δ 158.52, 130.86, 128.16, 114.25, 73.23, 58.26, 55.25, 50.38, 44.87, 41.41, 35.07, 33.34, 24.76, 21.08, 20.86.</div>
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IR (KBr): 3321, 2941, 2928, 2675, 2644, 2623, 2611, 2587, 2521, 2482, 2359, 2330, 1512, 1441, 1242, 1179, 1038, 829 cm<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">“1</span>. HPLC Purity: 99.64 % (area %). GC-MS: 178 (M+H<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>).</div>
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Example-3:<span style="color: red;"> N-Desmethyl venlafaxine</span> To the stirred solution of 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile (20.0 g, 1 equiv.) in methanol (350.0 ml), monomethylamine hydrochloride (27.7 g, 4 equiv.) was added and the mixture was stirred for 5-10 minutes at room temperature to obtain a clear solution. 5% Palladium on alumina (4.0 g, 20 wt %) was added under nitrogen to the above clear solution. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atmospheric pressure.) at room temperature for 24 hrs. After completion of the reaction product was isolated by the procedure as described in Example- 1 above to obtain light yellow viscous liquid (18.5g) which was directly converted to its hydrochloride salt using IPA/HCl.</div>
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HPLC conversion to N-desmethylvenlafaxine (in the crude reaction mixture = 18.5g): 35.46%. <span style="color: red;">N-Desmethyl venlafaxine-free base:</span></div>
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<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>H NMR in CDCl<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span> (300 MHz): δ 7.23 (d, 2H), £91 (d, 2H), 3.71 (s, 3H), 3.54 (t, IH), 3.48 (dd, IH), 2.97 (dd, IH), 2.69 (s, 3H), 1.41-1.0 (m, 10H)</div>
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<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/WO2003050074A1?cl=en" style="color: #0c5390; text-decoration: none;">WO2003050074A1</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Mar 19, 2002</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Jun 19, 2003</td><td class="patent-data-table-td " style="padding: 5px 0px;">Cadila Healthcare Ltd</td><td class="patent-data-table-td " style="padding: 5px 0px;">Manufacture of venlafaxine hydrochloride and crystalline polymorphs thereof</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/US4535186" style="color: #0c5390; text-decoration: none;">US4535186</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Oct 26, 1983</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Aug 13, 1985</td><td class="patent-data-table-td " style="padding: 5px 0px;">American Home Products Corporation</td><td class="patent-data-table-td " style="padding: 5px 0px;">2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives</td></tr>
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* Cited by examiner</div>
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<span class="patent-section-title">REFERENCED BY</span></div>
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<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/WO2008059525A2?cl=en" style="color: #0c5390; text-decoration: none;">WO2008059525A2</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Oct 1, 2007</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">May 22, 2008</td><td class="patent-data-table-td " style="padding: 5px 0px;">Calyx Chemicals And Pharmaceut</td><td class="patent-data-table-td " style="padding: 5px 0px;">An improved process for the preparation of venlafaxine and its analogs</td></tr>
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<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/WO2006035457A1?cl=en" style="color: #0c5390; text-decoration: none;">WO2006035457A1</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Sep 16, 2005</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Apr 6, 2006</td><td class="patent-data-table-td " style="padding: 5px 0px;">Amoli Organics Ltd</td><td class="patent-data-table-td " style="padding: 5px 0px;">A process for the manufacture of venlafaxine and intermediates thereof</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/US4535186" style="color: #0c5390; text-decoration: none;">US4535186</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Oct 26, 1983</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Aug 13, 1985</td><td class="patent-data-table-td " style="padding: 5px 0px;">American Home Products Corporation</td><td class="patent-data-table-td " style="padding: 5px 0px;">2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/US6350912" style="color: #0c5390; text-decoration: none;">US6350912</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Feb 28, 2001</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Feb 26, 2002</td><td class="patent-data-table-td " style="padding: 5px 0px;">Council Of Scientific And Industrial Research</td><td class="patent-data-table-td " style="padding: 5px 0px;">One pot process for the preparation of 1-[2-dimethylamino-(4-methoxyphenyl)-ethyl]cyclohexanol</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/US20050033088" style="color: #0c5390; text-decoration: none;">US20050033088</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Jun 7, 2004</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Feb 10, 2005</td><td class="patent-data-table-td " style="padding: 5px 0px;">Dr. Reddy’s Laboratories Limited</td><td class="patent-data-table-td " style="padding: 5px 0px;">Catalytic hydrogenation of phenylacetonitrile using palladium on carbon supports</td></tr>
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<tr><td class="patent-data-table-td " style="padding: 5px 0px;">1</td><td class="patent-data-table-td " style="padding: 5px 0px;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="padding: 5px 0px;">CHAVAN S P ET AL: “<a href="http://scholar.google.com/scholar?q=%22An+efficient+and+green+protocol+for+the+preparation+of+cycloalkanols%3A+a+practical+synthesis+of+venlafaxine%22" style="color: #0c5390; text-decoration: none;">An efficient and green protocol for the preparation of cycloalkanols: a practical synthesis of venlafaxine</a>” TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 45, no. 39, 20 September 2004 (2004-09-20), pages 7291-7295, XP004558985 ISSN: 0040-4039</td></tr>
<tr><td class="patent-data-table-td " style="padding: 5px 0px;">2</td><td class="patent-data-table-td " style="padding: 5px 0px;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="padding: 5px 0px;">J.S. BUCK ET AL: “<a href="http://scholar.google.com/scholar?q=%22beta-Phenylethylamine+Derivatives.+Tertiary+and+quaternary+salts%22" style="color: #0c5390; text-decoration: none;">beta-Phenylethylamine Derivatives. Tertiary and quaternary salts</a>” J.AM.CHEM.SOC., 1938, pages 1789-1792, XP002478651 cited in the application</td></tr>
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<tr class="patent-data-table"><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CITING PATENT</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">FILING DATE</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">PUBLICATION DATE</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">APPLICANT</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">TITLE</th></tr>
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<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/WO2010100520A1?cl=en" style="color: #0c5390; text-decoration: none;">WO2010100520A1</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Mar 4, 2009</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Sep 10, 2010</td><td class="patent-data-table-td " style="padding: 5px 0px;">Hikal Limited</td><td class="patent-data-table-td " style="padding: 5px 0px;">A process for preparation of phenethylamine derivative</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.com/patents/WO2011124190A2?cl=en" style="color: #0c5390; text-decoration: none;">WO2011124190A2</a></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Apr 6, 2011</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">Oct 13, 2011</td><td class="patent-data-table-td " style="padding: 5px 0px;">Zentiva, K.S.</td><td class="patent-data-table-td " style="padding: 5px 0px;">Method of producing 4-(2-(substituted)-1-(1-hydroxycyclohexyl)ethyl)phenols by o- demethylation of their methylethers by means of inodorous aromatic thiols</td></tr>
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part 1………<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html" style="color: #0c5390; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html</a> / <a href="http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/</a></div>
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part 2……..<a href="http://newdrugapprovals.org/2015/04/09/venlafaxine-22/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2015/04/09/venlafaxine-22/</a></div>
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PART 3…..<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html" style="color: #0c5390; font-size: 13.3333330154419px; line-height: 21.3333320617676px; outline-offset: -2px; outline: -webkit-focus-ring-color auto 5px; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html</a></div>
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SEE ALSO</div>
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<a href="http://www.google.com/patents/WO2008059525A2?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/WO2008059525A2?cl=en</a></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-302770220608373834.post-11349968960633095492015-04-09T05:55:00.000-07:002015-04-09T05:55:08.769-07:00VENLAFAXINE PART 1/3<div dir="ltr" style="text-align: left;" trbidi="on">
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<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html" style="color: #6c1b00; text-decoration: none;">VENLAFAXINE PART 1/3</a></h3>
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<img alt="Venlafaxine structure.svg" src="http://upload.wikimedia.org/wikipedia/commons/thumb/7/7d/Venlafaxine_structure.svg/357px-Venlafaxine_structure.svg.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><br /><img height="605" src="http://upload.wikimedia.org/wikipedia/commons/2/28/Venlafaxine-3D-balls.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><div align="left" style="font-size: 13.3333330154419px; margin-left: 0pt;">
<span style="font-family: Arial; font-size: 13px;"><br /></span></div>
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<span style="font-family: Arial; font-size: 13px;">Venlafaxine</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>CAS :</b> 93413-69-5</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>CAS Name:</b> 1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Additional Names:</b> (±)-1-[</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">-[(dimethylamino)methyl]-<i>p</i>-methoxybenzyl]cyclohexanol; <i>N,N</i>-dimethyl-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethylamine; venlafexine</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Molecular Formula:</b> C</span><span style="font-family: Arial; font-size: 11px;">17</span><span style="font-family: Arial; font-size: 13px;">H</span><span style="font-family: Arial; font-size: 11px;">27</span><span style="font-family: Arial; font-size: 13px;">NO</span><span style="font-family: Arial; font-size: 11px;">2</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Molecular Weight:</b> 277.40</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Percent Composition:</b> C 73.61%, H 9.81%, N 5.05%, O 11.54%</span></div>
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<img height="180" src="http://www.miguelprudencio.com/animated%20links%202.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" width="320" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><div align="left" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 13.333333015442px; margin-left: 0px;">
SEE</div>
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part 1………<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html" style="color: #0c5390; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html</a> / <a href="http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/</a></div>
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part 2……..<a href="http://newdrugapprovals.org/2015/04/09/venlafaxine-22/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2015/04/09/venlafaxine-22/</a></div>
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PART 3…..<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html" style="color: #0c5390; font-size: 13.3333330154419px; line-height: 21.3333320617676px; outline-offset: -2px; outline: -webkit-focus-ring-color auto 5px; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html</a></div>
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SEE ALSO</div>
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<a href="http://www.google.com/patents/WO2008059525A2?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/WO2008059525A2?cl=en</a></div>
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<b>Venlafaxine</b> (<a class="mw-redirect" href="http://en.wikipedia.org/wiki/Brand_name" style="background: none; color: #0b0080; text-decoration: none;" title="Brand name">brand names</a>: <b>Effexor</b>, <b>Effexor XR</b> and <b>Trevilor</b>) is an <a href="http://en.wikipedia.org/wiki/Antidepressant" style="background: none; color: #0b0080; text-decoration: none;" title="Antidepressant">antidepressant</a> of the <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Serotonin-norepinephrine_reuptake_inhibitor" style="background: none; color: #0b0080; text-decoration: none;" title="Serotonin-norepinephrine reuptake inhibitor">serotonin-norepinephrine reuptake inhibitor</a> (SNRI) class.<sup class="reference" id="cite_ref-pmid3790168_3-0" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-pmid3790168-3" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[3]</a></sup><sup class="reference" id="cite_ref-pmid1976813_4-0" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-pmid1976813-4" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[4]</a></sup><sup class="reference" id="cite_ref-pmid11750180_5-0" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-pmid11750180-5" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[5]</a></sup> This means it increases the concentrations of the neurotransmitters <a href="http://en.wikipedia.org/wiki/Serotonin" style="background: none; color: #0b0080; text-decoration: none;" title="Serotonin">serotonin</a> and <a href="http://en.wikipedia.org/wiki/Norepinephrine" style="background: none; color: #0b0080; text-decoration: none;" title="Norepinephrine">norepinephrine</a> in the body and the brain. First introduced by <a href="http://en.wikipedia.org/wiki/Wyeth" style="background: none; color: #0b0080; text-decoration: none;" title="Wyeth">Wyeth</a> in 1993, now marketed by <a href="http://en.wikipedia.org/wiki/Pfizer" style="background: none; color: #0b0080; text-decoration: none;" title="Pfizer">Pfizer</a>, it is <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Licensed" style="background: none; color: #0b0080; text-decoration: none;" title="Licensed">licensed</a> for the treatment of <a href="http://en.wikipedia.org/wiki/Major_depressive_disorder" style="background: none; color: #0b0080; text-decoration: none;" title="Major depressive disorder">major depressive disorder</a> (MDD), <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Generalised_anxiety_disorder" style="background: none; color: #0b0080; text-decoration: none;" title="Generalised anxiety disorder">generalised anxiety disorder</a> (GAD), <a href="http://en.wikipedia.org/wiki/Panic_disorder" style="background: none; color: #0b0080; text-decoration: none;" title="Panic disorder">panic disorder</a> and <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Social_phobia" style="background: none; color: #0b0080; text-decoration: none;" title="Social phobia">social phobia</a>.<sup class="reference" id="cite_ref-BNF_6-0" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-BNF-6" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[6]</a></sup><sup class="reference" id="cite_ref-AMH_7-0" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-AMH-7" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[7]</a></sup></div>
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Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis have shown venlafaxine, alongside <a href="http://en.wikipedia.org/wiki/Mirtazapine" style="background: none; color: #0b0080; text-decoration: none;" title="Mirtazapine">mirtazapine</a>, <a href="http://en.wikipedia.org/wiki/Escitalopram" style="background: none; color: #0b0080; text-decoration: none;" title="Escitalopram">escitalopram</a> and <a href="http://en.wikipedia.org/wiki/Sertraline" style="background: none; color: #0b0080; text-decoration: none;" title="Sertraline">sertraline</a> were significantly more efficacious.<sup class="reference" id="cite_ref-8" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-8" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[8]</a></sup> Remission rates (defined as a HAM-D score of 7 or less) were 58% for venlafaxine plus mirtazapine.<sup class="reference" id="cite_ref-9" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-9" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[9]</a></sup></div>
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The rate of life-threatening or lethal outcomes for suicidal overdoses of venlafaxine is lower than for the <a href="http://en.wikipedia.org/wiki/Tricyclic_antidepressant" style="background: none; color: #0b0080; text-decoration: none;" title="Tricyclic antidepressant">TCAs</a>, <a href="http://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor" style="background: none; color: #0b0080; text-decoration: none;" title="Monoamine oxidase inhibitor">MAOIs</a> and <a href="http://en.wikipedia.org/wiki/Bupropion" style="background: none; color: #0b0080; text-decoration: none;" title="Bupropion">bupropion</a>and comparable to several of the <a href="http://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor" style="background: none; color: #0b0080; text-decoration: none;" title="Selective serotonin reuptake inhibitor">SSRIs</a>.<sup class="reference" id="cite_ref-10" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-10" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[10]</a></sup> It is metabolised in the body into another antidepressant drug called <a href="http://en.wikipedia.org/wiki/Desvenlafaxine" style="background: none; color: #0b0080; text-decoration: none;" title="Desvenlafaxine">desvenlafaxine</a> (<i>O</i>-desmethylvenlafaxine) which is also sold as an antidepressant, under the brand name Pristiq.<sup class="reference" id="cite_ref-11" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-11" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[11]</a></sup></div>
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Both venlafaxine and <a href="http://en.wikipedia.org/wiki/Paroxetine" style="background: none; color: #0b0080; text-decoration: none;" title="Paroxetine">paroxetine</a> have been linked to the most severe discontinuation symptomes.</div>
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In 2007, venlafaxine was the sixth most commonly prescribed antidepressant on the U.S. retail market, with 17.2 million prescriptions.<sup class="reference" id="cite_ref-12" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-12" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[12]</a></sup></div>
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<span class="mw-headline" id="Chemistry">Chemistry</span></h2>
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The <a href="http://en.wikipedia.org/wiki/Chemical_structure" style="background: none; color: #0b0080; text-decoration: none;" title="Chemical structure">chemical structure</a> of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride, and it has the <a href="http://en.wikipedia.org/wiki/Empirical_formula" style="background: none; color: #0b0080; text-decoration: none;" title="Empirical formula">empirical formula</a> of C<sub style="font-size: 11.1999998092651px; line-height: 1;">17</sub>H<sub style="font-size: 11.1999998092651px; line-height: 1;">27</sub>NO<sub style="font-size: 11.1999998092651px; line-height: 1;">2</sub>. It is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioid <a href="http://en.wikipedia.org/wiki/Analgesic" style="background: none; color: #0b0080; text-decoration: none;" title="Analgesic">analgesic</a> <a href="http://en.wikipedia.org/wiki/Tramadol" style="background: none; color: #0b0080; text-decoration: none;" title="Tramadol">tramadol</a>, and more distantly to the newly released opioid <a href="http://en.wikipedia.org/wiki/Tapentadol" style="background: none; color: #0b0080; text-decoration: none;" title="Tapentadol">tapentadol</a>, but not to any of the conventional antidepressant drugs, including <a href="http://en.wikipedia.org/wiki/Tricyclic_antidepressant" style="background: none; color: #0b0080; text-decoration: none;" title="Tricyclic antidepressant">tricyclic antidepressants</a>, SSRIs, MAOIs, or <a href="http://en.wikipedia.org/wiki/Reversible_inhibitor_of_monoamine_oxidase_A" style="background: none; color: #0b0080; text-decoration: none;" title="Reversible inhibitor of monoamine oxidase A">RIMAs</a>.<sup class="reference" id="cite_ref-QJM2003-Whyte_66-0" style="font-size: 11.1999998092651px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-QJM2003-Whyte-66" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[66]</a></sup></div>
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<img height="282" src="http://upload.wikimedia.org/wikipedia/commons/c/c7/Venlafaxine_Enantiomers_Structural_Formulae.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /></div>
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<table class="infobox" style="background-color: #f9f9f9; border: 1px solid rgb(170, 170, 170); clear: right; color: black; font-family: sans-serif; font-size: 12.3199996948242px; line-height: 1.5em; margin: 0.5em 0px 0.5em 1em; padding: 0.2em; width: 22em;"><caption style="font-size: 15.3999996185303px; font-weight: bold; padding: 0.2em;">Venlafaxine</caption><tbody>
<tr><td colspan="2" style="text-align: center; vertical-align: top;"><a class="image" href="http://en.wikipedia.org/wiki/File:Venlafaxine_structure.svg" style="background: none; color: #0b0080; text-decoration: none;"><img alt="Venlafaxine structure.svg" data-file-height="367" data-file-width="357" height="226" src="http://upload.wikimedia.org/wikipedia/commons/thumb/7/7d/Venlafaxine_structure.svg/220px-Venlafaxine_structure.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/7/7d/Venlafaxine_structure.svg/330px-Venlafaxine_structure.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/7/7d/Venlafaxine_structure.svg/440px-Venlafaxine_structure.svg.png 2x" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative; vertical-align: middle;" width="220" /></a></td></tr>
<tr><td colspan="2" style="text-align: center; vertical-align: top;"><a class="image" href="http://en.wikipedia.org/wiki/File:Venlafaxine-3D-balls.png" style="background: none; color: #0b0080; text-decoration: none;"><img alt="Venlafaxine-3D-balls.png" data-file-height="1041" data-file-width="1100" height="208" src="http://upload.wikimedia.org/wikipedia/commons/thumb/2/28/Venlafaxine-3D-balls.png/220px-Venlafaxine-3D-balls.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/2/28/Venlafaxine-3D-balls.png/330px-Venlafaxine-3D-balls.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/2/28/Venlafaxine-3D-balls.png/440px-Venlafaxine-3D-balls.png 2x" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative; vertical-align: middle;" width="220" /></a></td></tr>
<tr><th colspan="2" style="background: rgb(221, 221, 221); text-align: center; vertical-align: top;">Systematic (<a class="mw-redirect" href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" style="background: none; color: #0b0080; text-decoration: none;" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC</a>) name</th></tr>
<tr><td colspan="2" style="text-align: center; vertical-align: top;"><span style="font-size: 11px;">(<i>RS</i>)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol</span></td></tr>
<tr><th colspan="2" style="background: rgb(221, 221, 221); text-align: center; vertical-align: top;">Clinical data</th></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Trade_name" style="background: none; color: #0b0080; text-decoration: none;" title="Trade name">Trade names</a></th><td style="vertical-align: top;">Effexor XR, Effexor, Trevilor</td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" style="background: none; color: #0b0080; text-decoration: none;" title="American Society of Health-System Pharmacists">AHFS</a>/<a href="http://en.wikipedia.org/wiki/Drugs.com" style="background: none; color: #0b0080; text-decoration: none;" title="Drugs.com">Drugs.com</a></th><td style="vertical-align: top;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.drugs.com/monograph/venlafaxine.html" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">monograph</a></span></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" style="background: none; color: #0b0080; text-decoration: none;" title="Regulation of therapeutic goods">Licence data</a></th><td style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Daily_Med" style="background: none; color: #0b0080; text-decoration: none;" title="Daily Med">US Daily Med</a>:<span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=b23637e5-d37f-41b5-ba76-fc053e903bc2" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">link</a></span></td></tr>
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<a href="http://en.wikipedia.org/wiki/Pregnancy_category" style="background: none; color: #0b0080; text-decoration: none;" title="Pregnancy category">Pregnancy<br />category</a></div>
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<li style="border: none; margin: 0px; padding: 0px;"><small><abbr style="border-bottom-style: dotted; border-bottom-width: 1px; cursor: help;" title="Australia">AU</abbr>:</small> B2</li>
<li style="border: none; margin: 0px; padding: 0px;"><small><abbr style="border-bottom-style: dotted; border-bottom-width: 1px; cursor: help;" title="United States">US</abbr>:</small> C</li>
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<a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" style="background: none; color: #0b0080; text-decoration: none;" title="Regulation of therapeutic goods">Legal status</a></div>
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<li style="border: none; margin: 0px; padding: 0px;"><small><abbr style="border-bottom-style: dotted; border-bottom-width: 1px; cursor: help;" title="Australia">AU</abbr>:</small> <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Standard_for_the_Uniform_Scheduling_of_Drugs_and_Poisons#Schedule_4_Prescription_Only_Medicine" style="background: none; color: #0b0080; text-decoration: none;" title="Standard for the Uniform Scheduling of Drugs and Poisons">Prescription Only (S4)</a></li>
<li style="border: none; margin: 0px; padding: 0px;"><small><abbr style="border-bottom-style: dotted; border-bottom-width: 1px; cursor: help;" title="Canada">CA</abbr></small>: <a href="http://en.wikipedia.org/wiki/Prescription_drug" style="background: none; color: #0b0080; text-decoration: none;" title="Prescription drug"><span class="Unicode">℞</span>-only</a></li>
<li style="border: none; margin: 0px; padding: 0px;"><small><abbr style="border-bottom-style: dotted; border-bottom-width: 1px; cursor: help;" title="United Kingdom">UK</abbr>:</small> <a href="http://en.wikipedia.org/wiki/Prescription_drug" style="background: none; color: #0b0080; text-decoration: none;" title="Prescription drug">POM</a></li>
<li style="border: none; margin: 0px; padding: 0px;"><small><abbr style="border-bottom-style: dotted; border-bottom-width: 1px; cursor: help;" title="United States">US</abbr>:</small> <a href="http://en.wikipedia.org/wiki/Prescription_drug" style="background: none; color: #0b0080; text-decoration: none;" title="Prescription drug"><span class="Unicode">℞</span>-only</a></li>
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</td></tr>
<tr><th scope="row" style="vertical-align: top;"><div style="line-height: 1.2em; padding: 0.1em 0px;">
<a href="http://en.wikipedia.org/wiki/Route_of_administration" style="background: none; color: #0b0080; text-decoration: none;" title="Route of administration">Routes of<br />administration</a></div>
</th><td style="vertical-align: top;">Oral</td></tr>
<tr><th colspan="2" style="background: rgb(221, 221, 221); text-align: center; vertical-align: top;">Pharmacokinetic data</th></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Bioavailability" style="background: none; color: #0b0080; text-decoration: none;" title="Bioavailability">Bioavailability</a></th><td style="vertical-align: top;">42±15%<sup class="reference" id="cite_ref-TGA_1-0" style="font-size: 9.85599994659424px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-TGA-1" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[1]</a></sup></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Plasma_protein_binding" style="background: none; color: #0b0080; text-decoration: none;" title="Plasma protein binding">Protein binding</a></th><td style="vertical-align: top;">27±2% (parent compound), 30±12% (active metabolite,<a href="http://en.wikipedia.org/wiki/Desvenlafaxine" style="background: none; color: #0b0080; text-decoration: none;" title="Desvenlafaxine">desvenlafaxine</a>)<sup class="reference" id="cite_ref-DM_2-0" style="font-size: 9.85599994659424px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-DM-2" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[2]</a></sup></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Drug_metabolism" style="background: none; color: #0b0080; text-decoration: none;" title="Drug metabolism">Metabolism</a></th><td style="vertical-align: top;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/Hepatic" style="background: none; color: #0b0080; text-decoration: none;" title="Hepatic">Hepatic</a> (~50% of the parent compound is metabolised on first pass through the liver)<sup class="reference" id="cite_ref-TGA_1-1" style="font-size: 9.85599994659424px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-TGA-1" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[1]</a></sup><sup class="reference" id="cite_ref-DM_2-1" style="font-size: 9.85599994659424px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-DM-2" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[2]</a></sup></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Biological_half-life" style="background: none; color: #0b0080; text-decoration: none;" title="Biological half-life">Half-life</a></th><td style="vertical-align: top;">5±2 h (parent compound for immediate release preparations), 15±6 h (parent compound for extended release preparations), 11±2 h (active metabolite)<sup class="reference" id="cite_ref-TGA_1-2" style="font-size: 9.85599994659424px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-TGA-1" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[1]</a></sup><sup class="reference" id="cite_ref-DM_2-2" style="font-size: 9.85599994659424px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-DM-2" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[2]</a></sup></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Excretion" style="background: none; color: #0b0080; text-decoration: none;" title="Excretion">Excretion</a></th><td style="vertical-align: top;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/Renal" style="background: none; color: #0b0080; text-decoration: none;" title="Renal">Renal</a> (87%; 5% as unchanged drug; 29% as<a href="http://en.wikipedia.org/wiki/Desvenlafaxine" style="background: none; color: #0b0080; text-decoration: none;" title="Desvenlafaxine">desvenlafaxine</a> and 53% as other metabolites)<sup class="reference" id="cite_ref-TGA_1-3" style="font-size: 9.85599994659424px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-TGA-1" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[1]</a></sup><sup class="reference" id="cite_ref-DM_2-3" style="font-size: 9.85599994659424px; line-height: 1; unicode-bidi: -webkit-isolate;"><a href="http://en.wikipedia.org/wiki/Venlafaxine#cite_note-DM-2" style="background: none; color: #0b0080; text-decoration: none; white-space: nowrap;">[2]</a></sup></td></tr>
<tr><th colspan="2" style="background: rgb(221, 221, 221); text-align: center; vertical-align: top;">Identifiers</th></tr>
<tr><th scope="row" style="vertical-align: top;"><div style="line-height: 1.2em; padding: 0.1em 0px;">
<a href="http://en.wikipedia.org/wiki/CAS_Registry_Number" style="background: none; color: #0b0080; text-decoration: none;" title="CAS Registry Number">CAS Registry Number</a></div>
</th><td style="vertical-align: top;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=93413-69-5&rn=1" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">93413-69-5</a></span><sup style="font-size: 9.85599994659424px; line-height: 1;"> <img alt="Yes" data-file-height="600" data-file-width="600" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th scope="row" style="vertical-align: top;"><div style="line-height: 1.2em; padding: 0.1em 0px;">
<a href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" style="background: none; color: #0b0080; text-decoration: none;" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></div>
</th><td style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/ATC_code_N06" style="background: none; color: #0b0080; text-decoration: none;" title="ATC code N06">N06</a><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.whocc.no/atc_ddd_index/?code=N06AX16" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">AX16</a></span></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/PubChem" style="background: none; color: #0b0080; text-decoration: none;" title="PubChem">PubChem</a></th><td style="vertical-align: top;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5656" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">CID 5656</a></span></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/DrugBank" style="background: none; color: #0b0080; text-decoration: none;" title="DrugBank">DrugBank</a></th><td style="vertical-align: top;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.drugbank.ca/drugs/DB00285" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">DB00285</a></span><sup style="font-size: 9.85599994659424px; line-height: 1;"> <img alt="Yes" data-file-height="600" data-file-width="600" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/ChemSpider" style="background: none; color: #0b0080; text-decoration: none;" title="ChemSpider">ChemSpider</a></th><td style="vertical-align: top;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.chemspider.com/Chemical-Structure.5454.html" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">5454</a></span><sup style="font-size: 9.85599994659424px; line-height: 1;"> <img alt="Yes" data-file-height="600" data-file-width="600" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" style="background: none; color: #0b0080; text-decoration: none;" title="Unique Ingredient Identifier">UNII</a></th><td style="vertical-align: top;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=GRZ5RCB1QG" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">GRZ5RCB1QG</a></span><sup style="font-size: 9.85599994659424px; line-height: 1;"> <img alt="Yes" data-file-height="600" data-file-width="600" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/ChEBI" style="background: none; color: #0b0080; text-decoration: none;" title="ChEBI">ChEBI</a></th><td style="vertical-align: top;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9943" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">CHEBI:9943</a></span><sup style="font-size: 9.85599994659424px; line-height: 1;"> <img alt="Yes" data-file-height="600" data-file-width="600" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/ChEMBL" style="background: none; color: #0b0080; text-decoration: none;" title="ChEMBL">ChEMBL</a></th><td style="vertical-align: top;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL637" rel="nofollow" style="background: none !important; color: #663366; padding: 0px !important; text-decoration: none;">CHEMBL637</a></span><sup style="font-size: 9.85599994659424px; line-height: 1;"> <img alt="Yes" data-file-height="600" data-file-width="600" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="background: rgb(221, 221, 221); text-align: center; vertical-align: top;">Chemical data</th></tr>
<tr><th scope="row" style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Chemical_formula" style="background: none; color: #0b0080; text-decoration: none;" title="Chemical formula">Formula</a></th><td style="vertical-align: top;"><a href="http://en.wikipedia.org/wiki/Carbon" style="background: none; color: #0b0080; text-decoration: none;" title="Carbon"><span style="color: black; font-weight: bold;">C</span></a><sub style="font-size: 9.85599994659424px; line-height: 1;">17</sub><a href="http://en.wikipedia.org/wiki/Hydrogen" style="background: none; color: #0b0080; text-decoration: none;" title="Hydrogen"><span style="color: #4d4d4d; font-weight: bold;">H</span></a><sub style="font-size: 9.85599994659424px; line-height: 1;">27</sub><a href="http://en.wikipedia.org/wiki/Nitrogen" style="background: none; color: #0b0080; text-decoration: none;" title="Nitrogen"><span style="color: navy; font-weight: bold;">N</span></a><a href="http://en.wikipedia.org/wiki/Oxygen" style="background: none; color: #0b0080; text-decoration: none;" title="Oxygen"><span style="color: #742323; font-weight: bold;">O</span></a><sub style="font-size: 9.85599994659424px; line-height: 1;">2</sub></td></tr>
<tr><th scope="row" style="vertical-align: top;"><div style="line-height: 1.2em; padding: 0.1em 0px;">
<a href="http://en.wikipedia.org/wiki/Molecular_mass" style="background: none; color: #0b0080; text-decoration: none;" title="Molecular mass">Molecular mass</a></div>
</th><td style="vertical-align: top;">277.402 g/mol</td></tr>
</tbody></table>
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<img src="http://images.rxlist.com/images/rxlist/effexor1.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Derivative Type:</b> Hydrochloride</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>CAS :</b> 99300-78-4</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Manufacturers' Codes:</b> Wy-45030</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Trademarks:</b> Effexor (Wyeth)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Molecular Formula:</b> C</span><span style="font-family: Arial; font-size: 11px;">17</span><span style="font-family: Arial; font-size: 13px;">H</span><span style="font-family: Arial; font-size: 11px;">27</span><span style="font-family: Arial; font-size: 13px;">NO</span><span style="font-family: Arial; font-size: 11px;">2</span><span style="font-family: Arial; font-size: 13px;">.HCl</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Molecular Weight:</b> 313.86</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Percent Composition:</b> C 65.06%, H 8.99%, N 4.46%, O 10.20%, Cl 11.30%</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Properties:</b> White to off-white crystalline solid from methanol/ethyl acetate, mp 215-217°. Soly (mg/ml): 572 water. Partition coefficient (octanol/water): 0.43.</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Melting point:</b> mp 215-217°</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Log P:</b> Partition coefficient (octanol/water): 0.43</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Derivative Type:</b> (+)-Form</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Properties:</b> Crystals from ethyl acetate, mp 102-104°. [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D25</span><span style="font-family: Arial; font-size: 13px;"> +27.6° (c = 1.07 in 95% ethanol).</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Melting point:</b> mp 102-104°</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Optical Rotation:</b> [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D25</span><span style="font-family: Arial; font-size: 13px;"> +27.6° (c = 1.07 in 95% ethanol)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Derivative Type:</b> (+)-Form hydrochloride</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Manufacturers' Codes:</b> Wy-45655</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Properties:</b> Crystals from methanol/ether, mp 240-240.5°. [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D25</span><span style="font-family: Arial; font-size: 13px;"> -4.7° (c = 0.945 in ethanol).</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Melting point:</b> mp 240-240.5°</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Optical Rotation:</b> [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D25</span><span style="font-family: Arial; font-size: 13px;"> -4.7° (c = 0.945 in ethanol)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Derivative Type:</b> (-)-Form</span></div>
<div align="left" style="font-size: 13.3333330154419px; margin-left: 0pt;">
<span style="font-family: Arial; font-size: 13px;"><b>Properties:</b> Crystals from ethyl acetate, mp 102-104°. [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D25</span><span style="font-family: Arial; font-size: 13px;"> -27.1° (c = 1.04 in 95% ethanol).</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Melting point:</b> mp 102-104°</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Optical Rotation:</b> [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D25</span><span style="font-family: Arial; font-size: 13px;"> -27.1° (c = 1.04 in 95% ethanol)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Derivative Type:</b> (-)-Form hydrochloride</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Manufacturers' Codes:</b> Wy-45651</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Properties:</b> Crystals from methanol/ether, mp 240-240.5°. [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D25</span><span style="font-family: Arial; font-size: 13px;"> +4.6° (c = 1.0 in ethanol).</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Melting point:</b> mp 240-240.5°</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Optical Rotation:</b> [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D25</span><span style="font-family: Arial; font-size: 13px;"> +4.6° (c = 1.0 in ethanol)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Therap-Cat:</b> Antidepressant.</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Keywords:</b> Antidepressant; Serotonin Noradrenaline Reuptake Inhibitor (SNRI).</span></div>
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<span style="font-family: Arial; font-size: 13px;">1H NMR</span></div>
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<br />HSQC<br /><img alt="Image" height="480" src="http://specdb.wishartlab.com/system/documents/files/000/036/546/original/051008_P00_02_2DHSQC_322_Assigned20121204-19426-g7107r.png?1354676482" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><br /><img alt="Displaying image.png" height="631" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.5&disp=emb&realattid=ii_14c98e50eb127574&attbid=ANGjdJ9JdRIw2ilG8Xtd245EVIugD6vAD9BDPjUWWOY0cJIW6EfH10iaatG0_FLsNPRueltM1V0MpFF7LEYPlPkXdYrKAj5Z5OX85m4r0XLArFtDsoaKGrSYlLjSZUA&sz=w944-h932&ats=1428495416057&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><br /><img alt="Displaying image.png" height="640" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.6&disp=inline&realattid=ii_14c98e582f89e131&safe=1&attbid=ANGjdJ-uhzor-slBZRqYfiuSK5RAeTM_47HSPQ2EVliHb1__n44u6fscKRQx8Cc9Yjk-mL5vISq2zaHulMsfsEJNEBVCSpql54JxDErQMrMCSw1ig7Ex0rU97yZ8UTw&ats=1428495416064&rm=14c98f622341f54f&zw&sz=w1342-h523" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="545" /><br /><br /><br /><br /><img alt="Displaying image.png" height="640" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.9&disp=inline&realattid=ii_14c98e60ec6b5296&safe=1&attbid=ANGjdJ8Ya-Ohycxnz7Zbsxe-gbv9wdvFL03r43ZtI346K2JFzu9VJt92NRj1J7_3s6yBRoaTc7hcZG4d1VMLFJvwMH5CGFsNi9BLv7ybQksJe5z4CBE4b-ViJuigCwc&ats=1428495416065&rm=14c98f622341f54f&zw&sz=w1342-h523" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="562" /><br /><br /><img alt="Displaying image.png" height="637" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.19&disp=emb&realattid=ii_14c98e6dc65df5c9&attbid=ANGjdJ-YCRnT1ToNNtNm4q5vcNXPhpAxmOiRBBCPuqYPikKoqYJK7-bQdoSoR51sGVSZZdxUyLmxhdexAPkx8tobrVgNjBA1eSiBrwQvHw3zL1PWtyWDQvjORz_ht6A&sz=w944-h940&ats=1428495416057&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><br /><br /><br /><img alt="Displaying image.png" height="640" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.8&disp=emb&realattid=ii_14c98e364e9e095f&attbid=ANGjdJ_ZmBiT4mHRKXbHoPnTfXclYzs8_XqwA8clRcwbeUts0aHTtCSb_427wlOfEcBFudhKV8S2fqJBmV2dqX2jzzvCvdd3G82mOyu0CKuTFh9vL2oZvWOaKLChLUk&sz=w882-h944&ats=1428495416057&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="597" /><br /><br /><br /><img alt="Displaying image.png" height="640" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.13&disp=emb&realattid=ii_14c98e7344d394c3&attbid=ANGjdJ9mMNwy7pvBEURR9v4-RCcIQQrEP2VGPqNrAoQCdPbkbPfT1wrIKbRWrEiGbmhWJAoVEyvHw5BmHWDlx5_5ptZgmtGBfuzxSdEhKMK1fDXBczQEBIJZP0iyj9M&sz=w816-h944&ats=1428495416057&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="553" /><br /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.1&disp=emb&realattid=ii_14c98e789d8964b2&attbid=ANGjdJ-NDujd8uo3hn7F7bSdZ-12738SEDJMGy-SO-1ox7S8GLBNeksHvZJrb-QMF10F3dGKSFv6p_QAZt8bxJ0hHRu9-V-8ylT_l3sKkr-qM-yjOTtdkKQhTA7RjWo&sz=w822-h944&ats=1428495416057&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.14&disp=emb&realattid=ii_14c98e7f0ccb15c5&attbid=ANGjdJ8_liyQjW0yGud7q5lRuTMXTeT0V8fgRd3zUUxfqMAJFBhgU2ic263uRd3bjd2IH9m2ge5eaNcQa2ME_qmCnC6XGzz7n-QC_CEk7sGbWjHnASRvNTNM0HUe9PE&sz=w944-h468&ats=1428495416057&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.10&disp=emb&realattid=ii_14c98e82b6560d9a&attbid=ANGjdJ9mj_JcbtQTN3aQ80uVY8viNzR0k5xMw0hsrg0PHW1GECgFZf2JVZ1tmHAH5dlS04LDAVCZcLUfoiB7EmeAnsU6_0QTWd1TZrS1TcbhcXyaIyCLuXRyVmNbFhc&sz=w844-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.20&disp=emb&realattid=ii_14c98e87f644eb0c&attbid=ANGjdJ8F9mQP6qnzWfKwRaKBFJvwwqwDTwirw0GCysCCFuA8FUHpGz_1adI1_W4RShsbIk9DDWAx0KoJIzHhFQZQaJgjwRCMSOFM31i1EHSRRww8JNe7h28yqQ0KcwA&sz=w944-h938&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.2&disp=emb&realattid=ii_14c98e8c75172df1&attbid=ANGjdJ9MXVFJBYxFGDvrqczyWkvxGCq8XH6o20SVAQGy0LnxUF4Eemw_W-LMXNy5wJo4hAoFijRGC4eIZk8aOR3s3IXYQPcNOK1H3FM-8DMNvuYR-Nhp79PGiH_DECo&sz=w844-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.17&disp=emb&realattid=ii_14c98e96c8b888a2&attbid=ANGjdJ8EXfsxvsWPPQuZgeRo1X17sPXtQT75eGvjgrUjU0T4CV1R4Ji3hHoiLTwaFpm8o-mjtgkvfqeBn9kaf9R-KpQ3vtLRycdz1_efbxlq-Ij1zJe5lZ_Wsff6OVg&sz=w936-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.7&disp=emb&realattid=ii_14c98eafdac472bf&attbid=ANGjdJ9u-penjAZs2m2bh8Is11ruReIx6QfnnAU7uh0tN-EVe0AgcojMtspMDg6G3VsU68EoFr-xV556STpDFkdDnYBoM7i4AVjkiJGVpj0ikP90XHcdm7p9zPLmwqY&sz=w944-h388&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.21&disp=emb&realattid=ii_14c98eba62c2e9b1&attbid=ANGjdJ-j5KSoxHS2vz0D-8q9XUtDxzp_EKTwwVSCxwy8b6HRjswdlsE2Z7oHjDCMTppxdc0saIxwcXspQoFt3JGVUvwzOFNcFHyA9w_Pu5BU7oZQAGkh5g6gqIiZjxQ&sz=w862-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><br /><img alt="Displaying image.png" height="640" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.16&disp=emb&realattid=ii_14c98ec78da66c34&attbid=ANGjdJ_5Qsyc-nMT6uvh4HmV84CbZvrJWsY0Iv0DdCvNv0ROCo2nJA0v-I72F4yGSjdCyxrEaQ8grMBHqziwCl_opeH7T2oIyQ8D5aP9tu0tL0HgOdN_PpYAbcMC5Uc&sz=w532-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="360" /><br /><br /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.4&disp=emb&realattid=ii_14c98ed9147e9303&attbid=ANGjdJ8mY3SfGaW3iZ75dy5c3djlJCNNQnRF29eU58m2HHDcIszzlHDu3K0eUbCrIVrXcMupPfGvvlxrsy0dysPXsyjTfOlKOPZYgKWzex7QG4OuAxEQeJVu7bnO244&sz=w866-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.22&disp=emb&realattid=ii_14c98f4b9fc9dab1&attbid=ANGjdJ8uWZaXc40l0O_-O9eE1Uet1QE7ZfShsmBc9OnaD9hGonZef92yGXdzLVccASVR8oPviOv4lqW_D7A3g9HxV2r3qeN2OONy5VHizJ72NVKoKHBrvV9ZDhdD-30&sz=w646-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><img alt="Displaying image.png" height="640" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.3&disp=emb&realattid=ii_14c98f50a3efaa13&attbid=ANGjdJ_bbJCyCGJPeT34YV3iiUGWmGybIxeiHrAaRw6YzN7hYnQVCwRTjgWmEP444VfFXyw39vO8kOmVH_DF0Faf-yHMiVbpkSpcfVY0OaMPKYYDG_fjXVY25eoq3-8&sz=w678-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="460" /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.18&disp=emb&realattid=ii_14c98ee35a34bac0&attbid=ANGjdJ9HFy-CLTvXHBaU_cWBBOjB0Onf96SDuvIixJyoME42flTNlVkXHvPQZWojcfXSgSYHFYPKEbs-IDuUxEgnk67xu4r9hi1hkkqPdMy95p4n2GD0ERtzIYueFTg&sz=w812-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><img alt="Displaying image.png" height="640" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.12&disp=emb&realattid=ii_14c98f5b6230c2a6&attbid=ANGjdJ95U6XWFzX9nWUprrj8L3_JluTUet2lWw4mR4T2S6vSx86JgJS18HeO1X1Q-f44QGQbufvYg-US34ERBdeODecBrMC58umRvHiC6JN23_Cd9LutklVdvrZ9itI&sz=w608-h944&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="410" /><br /><br /><br /><br /><img alt="Displaying image.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.11&disp=emb&realattid=ii_14c98efc552190a8&attbid=ANGjdJ-uFmplRNU6qI-z0kdz_0zyscs3C3j33g920P5Cvq9nK7B99CC_QL151SPG5cWrZ3nXGYSbYHMYbZ3ePdIcgbq-uS7ToOYrcdSIWZ3aw7TfoURPR0sTJHitlSg&sz=w666-h768&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><br /><br /><br /><a href="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.15&disp=emb&realattid=ii_14c98f60ccc63b7f&attbid=ANGjdJ_43wkgn19t-Ohaq0UgGGAHLo8GKUsrom1MrziT5xR8vyaa-3rHcwF_G0kzF-FfOwGTRbzqWU07yqBQW4uare51QaBc4EiF_ff85VAMOzu3oJucT4Qg_jmqxc4&sz=w726-h854&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" imageanchor="1" style="clear: left; color: #6c1b00; float: left; margin-bottom: 1em; margin-right: 1em; text-decoration: none;"><img alt="Displaying image.png" border="0" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c98f622341f54f&attid=0.15&disp=emb&realattid=ii_14c98f60ccc63b7f&attbid=ANGjdJ_43wkgn19t-Ohaq0UgGGAHLo8GKUsrom1MrziT5xR8vyaa-3rHcwF_G0kzF-FfOwGTRbzqWU07yqBQW4uare51QaBc4EiF_ff85VAMOzu3oJucT4Qg_jmqxc4&sz=w726-h854&ats=1428495416058&rm=14c98f622341f54f&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" /></a><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br />1H NMR PREDICT OF HCL<br /><br /><br /><br /><img alt="Venlafaxine hydrochloride NMR spectra analysis, Chemical CAS NO. 99300-78-4 NMR spectral analysis, Venlafaxine hydrochloride H-NMR spectrum" height="579" src="http://pic11.molbase.net/nmr/nmr_image/2014-07-19/000/024/868/99300-78-4-1h.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><br />13C NMR PREDICT OF HCL<br /><br /><img alt="Venlafaxine hydrochloride NMR spectra analysis, Chemical CAS NO. 99300-78-4 NMR spectral analysis, Venlafaxine hydrochloride C-NMR spectrum" height="579" src="http://pic11.molbase.net/nmr/nmr_image/2014-07-19/000/024/868/99300-78-4-13c.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><br /><br /><br /><br /><br /><br /><br /><img alt="Venlafaxine" src="http://www.druglead.com/cds/structure/Venlafaxine.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br />BASE<br /><br /><br /><br /><img alt="Venlafaxine NMR spectra analysis, Chemical CAS NO. 93413-69-5 NMR spectral analysis, Venlafaxine H-NMR spectrum" height="537" src="http://pic11.molbase.net/nmr/nmr_image/2014-07-19/000/025/576/93413-69-5-1h.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><br /><br /><img alt="Venlafaxine NMR spectra analysis, Chemical CAS NO. 93413-69-5 NMR spectral analysis, Venlafaxine C-NMR spectrum" height="537" src="http://pic11.molbase.net/nmr/nmr_image/2014-07-19/000/025/576/93413-69-5-13c.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><br /><br /><br /><br /><br /><div align="left" style="font-size: 13.3333330154419px; margin-left: 0pt;">
<span style="font-family: Arial; font-size: 13px;"><b>Literature References:</b> </span></div>
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<span style="font-family: Arial; font-size: 13px;">Serotonin noradrenaline reuptake inhibitor (SNRI). Prepn: G. E. M. Husbands <i>et al.,</i> <b>EP</b> <b>112669</b>; <b>US</b><b>4535186</b> (1984, 1985 both to Am. Home Prods.); </span></div>
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<span style="font-family: Arial; font-size: 13px;"><br /></span></div>
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<span style="font-family: Arial; font-size: 13px;">and resolution of isomers: J. P. Yardley <i>et al.,</i> <i>J. Med. Chem.</i> <b>33,</b> 2899 (1990). Receptor binding studies: E. A. Muth <i>et al.,</i> <i>Biochem. Pharmacol.</i> <b>35,</b> 4493 (1986). </span></div>
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<span style="font-family: Arial; font-size: 13px;">HPLC determn in biological fluids: D. R. Hicks<i>et al.,</i> <i>Ther. Drug Monit.</i> <b>16,</b> 100 (1994).</span></div>
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<span style="font-family: Arial; font-size: 13px;"><br /></span></div>
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<span style="font-family: Arial; font-size: 13px;">Clinical pharmacokinetics: K. J. Klamerus <i>et al.,</i> <i>J. Clin. Pharmacol.</i> <b>32,</b> 716 (1992). </span></div>
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<div align="left" style="font-size: 13.3333330154419px; margin-left: 0pt;">
<span style="font-family: Arial; font-size: 13px;">Clinical trial in major depression: E. Schweizer <i>et al.,</i> <i>J. Clin. Psychopharmacol.</i> <b>11,</b> 233 (1991). </span></div>
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<span style="font-family: Arial; font-size: 13px;"><br /></span></div>
<div align="left" style="font-size: 13.3333330154419px; margin-left: 0pt;">
<span style="font-family: Arial; font-size: 13px;">Review of pharmacology and clinical efficacy in depression: S. A. Montgomery, <i>J. Clin. Psychiatry</i> <b>54,</b> 119-126 (1993). </span></div>
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<div align="left" style="font-size: 13.3333330154419px; margin-left: 0pt;">
<span style="font-family: Arial; font-size: 13px;">Clinical trial in generalized anxiety disorder: A. J. Gelenberg <i>et al.,</i> <i>J. Am. Med. Assoc.</i> <b>283,</b> 3082 (2000).</span></div>
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<h2 style="background: none rgb(255, 255, 255); border-bottom-color: rgb(170, 170, 170); border-bottom-style: solid; border-bottom-width: 1px; color: #516c00; font-family: 'Linux Libertine', Georgia, Times, serif; font-size: 20px; font-stretch: normal; font-weight: normal; line-height: 1.3; margin: 1em 0px 0.25em; overflow: hidden; padding: 0px; position: relative;">
<span class="mw-headline" id="External_links">External links</span><span class="mw-editsection" style="-webkit-user-select: none; display: inline-block; font-family: sans-serif; font-size: xx-small; line-height: 1em; margin-left: 1em; unicode-bidi: -webkit-isolate; vertical-align: baseline; white-space: nowrap;"><span class="mw-editsection-bracket" style="color: #555555; margin-left: 0px; margin-right: 0px;">[</span></span><span class="mw-headline" id="Drug_information" style="font-family: sans-serif; font-size: 14px; line-height: 1.6;">Drug information</span></h2>
<ul style="background-color: white; color: #252525; font-family: sans-serif; line-height: 22.3999996185303px; list-style-image: url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%0A%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20version%3D%221.1%22%20width%3D%225%22%20height%3D%2213%22%3E%0A%3Ccircle%20cx%3D%222.5%22%20cy%3D%229.5%22%20r%3D%222.5%22%20fill%3D%22%2300528c%22%2F%3E%0A%3C%2Fsvg%3E%0A); margin: 0.3em 0px 0px 1.6em; padding: 0px;">
<li style="border: none; margin: 0px 0px 0.1em; padding: 0px;"><a class="external text" href="http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106481.htm" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">U.S. Food and Drug Administration information on Effexor</a></li>
<li style="border: none; margin: 0px 0px 0.1em; padding: 0px;"><a class="external text" href="http://www.medicines.org.uk/EMC/medicine/8609/XPIL/Efexor+XL/" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">Efexor patient information leaflet (UK)</a></li>
<li style="border: none; margin: 0px 0px 0.1em; padding: 0px;"><a class="external text" href="http://web.archive.org/web/20060917025217/http://www.wyeth.com/content/ShowLabeling.asp?id=100" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">Effexor XR prescribing information for healthcare professionals (pdf) (USA only)</a> Archived from the <a class="external text" href="http://www.wyeth.com/content/ShowLabeling.asp?id=100" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">original</a> on 17 September 2006.</li>
<li style="border: none; margin: 0px 0px 0.1em; padding: 0px;"><a class="external text" href="http://www.rxlist.com/cgi/generic/venlafax_pi.htm" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">Detailed Patient/Parent Information on Effexor</a></li>
<li style="border: none; margin: 0px 0px 0.1em; padding: 0px;"><a class="external text" href="http://www.merck.com/mmpe/lexicomp/venlafaxine.html#N18219E" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">List of international brand names for Venlafaxine</a></li>
<li style="border: none; margin: 0px 0px 0.1em; padding: 0px;"><a class="external text" href="http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Venlafaxine" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">U.S. National Library of Medicine: Drug Information Portal -Venlafaxine</a></li>
</ul>
<h3 style="background: none rgb(255, 255, 255); border-bottom-style: none; font-family: sans-serif; line-height: 1.6; margin: 0.3em 0px 0px; overflow: hidden; padding-bottom: 0px; padding-top: 0.5em; position: relative;">
<span class="mw-headline" id="Diagnostic_tools">Diagnostic tools</span></h3>
<ul style="background-color: white; color: #252525; font-family: sans-serif; line-height: 22.3999996185303px; list-style-image: url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%0A%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20version%3D%221.1%22%20width%3D%225%22%20height%3D%2213%22%3E%0A%3Ccircle%20cx%3D%222.5%22%20cy%3D%229.5%22%20r%3D%222.5%22%20fill%3D%22%2300528c%22%2F%3E%0A%3C%2Fsvg%3E%0A); margin: 0.3em 0px 0px 1.6em; padding: 0px;">
<li style="border: none; margin: 0px 0px 0.1em; padding: 0px;"><a class="external text" href="http://www.qjmed.oxfordjournals.org/cgi/content/full/96/9/635" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity</a></li>
</ul>
<h3 style="background: none rgb(255, 255, 255); border-bottom-style: none; font-family: sans-serif; line-height: 1.6; margin: 0.3em 0px 0px; overflow: hidden; padding-bottom: 0px; padding-top: 0.5em; position: relative;">
<span class="mw-headline" id="Patient_experiences">Patient experiences</span></h3>
<span data-mce-style="color: #800000;" style="color: maroon; font-style: inherit; font-weight: inherit; line-height: 1.7;"></span><br /><ul style="background-color: white; color: #252525; font-family: sans-serif; line-height: 22.3999996185303px; list-style-image: url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%0A%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20version%3D%221.1%22%20width%3D%225%22%20height%3D%2213%22%3E%0A%3Ccircle%20cx%3D%222.5%22%20cy%3D%229.5%22%20r%3D%222.5%22%20fill%3D%22%2300528c%22%2F%3E%0A%3C%2Fsvg%3E%0A); margin: 0.3em 0px 0px 1.6em; padding: 0px;">
<li style="border: none; margin: 0px 0px 0.1em; padding: 0px;"><a class="external text" href="http://www.nytimes.com/2007/05/06/magazine/06antidepressant-t.html?_r=1&ei=5087%0A&em=&en=cdeb03773a3deee0&ex=1178596800&pagewanted=all&oref=slogin" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">Stutz, Bruce "Self-Nonmedication" New York Times Magazine May 6, 2007</a></li>
<li style="border: none; margin: 0px 0px 0.1em; padding: 0px;"><a class="external text" href="http://web.archive.org/web/20130421232047/http://sideeffectsofeffexor.org" rel="nofollow" style="background: linear-gradient(transparent, transparent) 100% 50% no-repeat, url(data:image/svg+xml,%3C%3Fxml%20version%3D%221.0%22%20encoding%3D%22UTF-8%22%3F%3E%3Csvg%20xmlns%3D%22http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%22%20width%3D%2210%22%20height%3D%2210%22%3E%3Cg%20transform%3D%22translate%28-826.429%20-698.791%29%22%3E%3Crect%20width%3D%225.982%22%20height%3D%225.982%22%20x%3D%22826.929%22%20y%3D%22702.309%22%20fill%3D%22%23fff%22%20stroke%3D%22%2306c%22%2F%3E%3Cg%3E%3Cpath%20d%3D%22M831.194%20698.791h5.234v5.391l-1.571%201.545-1.31-1.31-2.725%202.725-2.689-2.689%202.808-2.808-1.311-1.311z%22%20fill%3D%22%2306f%22%2F%3E%3Cpath%20d%3D%22M835.424%20699.795l.022%204.885-1.817-1.817-2.881%202.881-1.228-1.228%202.881-2.881-1.851-1.851z%22%20fill%3D%22%23fff%22%2F%3E%3C%2Fg%3E%3C%2Fg%3E%3C%2Fsvg%3E) 100% 50%; color: #663366; padding-right: 13px; text-decoration: none;">Effexor Side Effects</a></li>
</ul>
</div>
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<span data-mce-style="color: #800000;" style="color: maroon; font-style: inherit; font-weight: inherit; line-height: 1.7;">P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.</span></div>
<div class="autores" style="font-family: 'Open Sans', 'Helvetica Neue', Helvetica, Arial, sans-serif; font-size: 14px; line-height: 23.7999992370605px; margin-bottom: 0.825em;">
<span data-mce-style="color: #0000ff;" style="color: blue; font-style: inherit; font-weight: inherit; line-height: 1.7;">P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.</span></div>
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<span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;">P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.</span></div>
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<img src="http://dc387.4shared.com/img/8J_qf002/13189b1e778/Chicken-Animation.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" />COCK WILL TEACH YOU NMR</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-302770220608373834.post-38284485091333083692015-04-09T05:53:00.001-07:002015-04-09T05:53:06.720-07:00VENLAFAXINE PART 3/3<div dir="ltr" style="text-align: left;" trbidi="on">
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<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html" style="color: #6c1b00; text-decoration: none;">VENLAFAXINE PART 3/3</a></h3>
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<img height="180" src="http://www.miguelprudencio.com/animated%20links%202.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="320" /><br /><br /><div align="left" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 13.333333015442px; margin-left: 0px;">
SEE</div>
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part 1………<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html" style="color: #0c5390; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html</a> / <a href="http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/</a></div>
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part 2……..<a href="http://newdrugapprovals.org/2015/04/09/venlafaxine-22/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2015/04/09/venlafaxine-22/</a></div>
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PART 3…..<a href="http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html" style="color: #0c5390; font-size: 13.3333330154419px; line-height: 21.3333320617676px; outline-offset: -2px; outline: -webkit-focus-ring-color auto 5px; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html</a></div>
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SEE ALSO</div>
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<a href="http://www.google.com/patents/WO2008059525A2?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/WO2008059525A2?cl=en</a></div>
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PAPER</div>
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<i><strong>RSC Adv.</strong></i>, 2014,<strong>4</strong>, 14468-14470</div>
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<span class="DOILink"><strong>DOI: </strong>10.1039/C4RA00840E</span></div>
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<a href="http://pubs.rsc.org/en/content/articlelanding/2014/ra/c4ra00840e#!divAbstract" style="color: #0c5390; text-decoration: none;">http://pubs.rsc.org/en/content/articlelanding/2014/ra/c4ra00840e#!divAbstract</a></div>
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A protecting group free asymmetric total synthesis of (−)-venlafaxine is reported. The strategy employs Sharpless epoxidation and regio-selective epoxide ring opening by an <em>in situ</em>generated Gilman reagent as key steps. This paper reports a 53% overall yield in 6 steps for total synthesis of (−)-venlafaxine.</div>
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<img alt="Graphical abstract: A protecting group free and scalable approach towards total synthesis of (−)-venlafaxine" class="" height="156" id="imgGALoader" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=C4RA00840E" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 4px solid rgb(238, 238, 238); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; box-sizing: border-box; height: auto; max-width: 100%; padding: 8px; vertical-align: middle;" title="Graphical abstract" width="604" /></div>
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<img alt="" height="426" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2014/RA/c4ra00840e/c4ra00840e-s2_hi-res.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 4px solid rgb(238, 238, 238); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; box-sizing: border-box; height: auto; max-width: 100%; padding: 8px; vertical-align: middle;" width="640" /></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-302770220608373834.post-61180336794701754082015-04-03T06:59:00.000-07:002015-04-04T05:10:18.837-07:00Levetiracetam industrial process<div dir="ltr" style="text-align: left;" trbidi="on">
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2 pyrolidinone</div>
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ethyl 2 bromo butyrate</div>
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<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"> (R)-(+)-alpha-methyl-<wbr></wbr>benzylamine</span></div>
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ethyl chloro formate</div>
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<span style="font-family: Arial, sans-serif;"><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">US4943639.</span></span></div>
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<span style="color: red; font-family: Arial, sans-serif;"><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;"><a href="http://www.google.co.in/patents/US4943639">http://www.google.co.in/patents/US4943639</a></span></span></div>
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cut paste</div>
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note.............<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;">racemic (±)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetic acid is obt by rxn of 2 pyrolidinone with ethyl 2 bromo acetate</span></div>
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<span style="background-color: #f1f1f1; line-height: 16px;"><span style="color: red;">+/-)-(R,S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester. CAS# 33978-83-5</span></span></div>
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EXAMPLE 1<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"> </span>(a) Preparation of the (R)-alpha-methyl-benzylamine salt of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetic acid<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"></span><br />
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8.7 kg (50.8 moles) of racemic (±)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetic acid are suspended in 21.5 liters of anhydrous benzene in a 50 liter reactor. To this suspension is added gradually a solution containing 3.08 kg (25.45 moles) of (R)-(+)-alpha-methyl-<wbr></wbr>benzylamine and 2.575 kg (25.49 moles) of triethylamine in 2.4 liters of anhydrous benzene. This mixture is then heated to reflux temperature until complete dissolution It is then cooled and allowed to crystallize for a few hours. 5.73 kg of the (R)-alpha-methyl-benzylamine salt of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetic acid are thus obtained.</div>
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Melting point: 148°-151° C. Yield: 77.1%.</div>
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This salt may be purified by heating under reflux in 48.3 liters of benzene for 4 hours. The mixture is cooled and filtered to obtain 5.040 kg of the desired salt. Melting point: 152°-153.5° C. Yield: 67.85%.</div>
(b) Preparation of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetic acid<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"></span><br />
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5.04 kg of the salt obtained in (a) above are dissolved in 9 liters of water. 710 g of a 30% sodium hydroxide solution are added slowly so that the pH of the solution reaches 12.6 and the temperature does not exceed 25° C. The solution is stirred for a further 20 minutes and the alpha-methylbenzylamine liberated is extracted repeatedly with a total volume of 18 liters of benzene.</div>
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The aqueous phase is then acidified to a pH of 1.1 by adding 3.2 liters of 6N hydrochloric acid. The precipitate formed is filtered off, washed with water and dried.</div>
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The filtrate is extracted repeatedly with a total volume of 50 liters of dichloromethane. The organic phase is dried over sodium sulfate and filtered and evaporated to dryness under reduced pressure.</div>
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The residue obtained after the evaporation and the precipitate isolate previously, are dissolved together in 14 liters of hot dichloromethane. The dichloromethane is distilled and replaced at the distillation rate, by 14 liters of toluene from which the product crystallizes.</div>
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The mixture is cooled to ambient temperature and the crystals are filtered off to obtain 2.78 kg of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetic acid.</div>
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Melting point: 125.9° C. [alpha]<sub>D</sub> <sup>20</sup> =-26.4° (c=1, acetone). Yield: 94.5%.</div>
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(c) Preparation of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetamide</div>
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34.2 g (0.2 mole) of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetic acid are suspended in 225 ml of dichloromethane cooled to -30° C. 24.3 g (0.24 mole) of triethylamine are added dropwise over 15 minutes. The reaction mixture is then cooled to -40° C. and 24.3 g (0.224 mole) of ethyl chloroformate are added over 12 minutes. Thereafter, a stream of ammonia is passed through the mixture for 41/2 hours. The reaction mixture is then allowed to return to ambient temperature and the ammonium salts formed are removed by filtration and washed with dichloromethane. The solvent is distilled off under reduced pressure. The solid residue thus obtained is dispersed in 55 ml toluene and the dispersion is stirred for 30 minutes and then filtered. The product is recrystallized from 280 ml of ethyl acetate in the presence of 9 g of 0,4 nm molecular sieve in powder form.</div>
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24.6 g of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetamide are obtained.</div>
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Melting point: 115°-118° C. [alpha]<sub>D</sub> <sup>25</sup> =-89.7° (c=1, acetone). Yield: 72.3%.</div>
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Analysis for C<sub>8</sub> H<sub>14</sub> N<sub>2</sub> O<sub>2</sub> in % calculated: C 56.45. H 8.29. N 16.46. found: 56.71. 8.22. 16.48.</div>
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The racemic (±)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetic acid used in this synthesis has been prepared in the manner described below.</div>
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A solution containing 788 g (19.7 moles) of sodium hydroxide in 4.35 liters of water is introduced over 2 hours into a 20 liter flask containing 3.65 kg (18.34 moles) of ethyl (±)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetate at a temperature not exceeding 60° C. When this addition is complete, the temperature of the mixture is raised to 80° C. and the alcohol formed is distilled off until the temperature of the reaction mixture reaches 100° C.</div>
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The reaction mixture is then cooled to 0° C. and 1.66 liter (19.8 moles) of 12N hydrochloric acid is added over two and a half hours. The precipitate formed is filtered off, washed with 2 liters of toluene and recrystallized from isopropyl alcohol. 2.447 kg of racemic (±)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetic acid, melting at 155°-156° C., are thus obtained. Yield: 78%.</div>
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Analysis for C<sub>8</sub> H<sub>13</sub> NO<sub>3</sub>, in % calculated: C 56.12. H 7.65. N 8.18. found: 55.82. 8.10. 7.97.</div>
EXAMPLE 2<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"> </span>(a) Preparation of ethyl (S)-4-[[1-(aminocarbonyl)<wbr></wbr>propyl]amino]butyrate<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"></span><br />
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143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (S)-2-amino-butanamide hydrochloride ([alpha]<sub>D</sub> <sup>25</sup> : +26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.</div>
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The reaction mixture is maintained at 80° C. for 10 hours and then filtered hot to remove the triethylamine salts. The filtrate is then evaporated under reduced pressure and 59 g of an oily residue consisting essentially of the monoalkylation product but containing also a small amount of dialkylated derivative are obtained.</div>
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The product obtained in the crude state has been used as such, without additional purification, in the preparation of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetamide by cyclization.</div>
(b) Preparation of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetamide<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"></span><br />
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54 g of the crude product obtained in a) above are dissolved in 125 ml of toluene in the presence of 2 g of 2-hydroxypyridine. The mixture is heated at 110° C. for 12 hours.</div>
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The insoluble matter is filtered off hot and the filtrate is then evaporated under reduced pressure.</div>
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The residue is purified by chromatography on a column of 1.1 kg of silica (column diameter: 5 cm; eluent: a mixture of ethyl acetate, methanok and concentrated ammonia solution in a proportion by volume of 85:12:3).</div>
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The product isolated is recrystallized from 50 ml of ethyl acetate to obtain 17.5 g of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetamide.</div>
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Melting point: 117° C. [alpha]<sub>D</sub> <sup>25</sup> : -90.0° (c=1, acetone). Yield: 41%.</div>
EXAMPLE 3<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"> </span>(a) Preparation of (S)-N-[1(aminocarbonyl)propyl]<wbr></wbr>-4-chlorobutanamide<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"></span><br />
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345.6 g (2.5 moles) of ground potassium carbonate are mixed with 138.5 g (1 mole) of (S)-2-amino-butanamide hydrochloride in 2.5 liters of acetonitrile. The reaction mixture is cooled to 0° C. and a solution of 129.2 g (1.2 mole) of 4-chlorobutyryl chloride in 500 ml of acetonitrile is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 1.2 liter of anhydrous ether for 30 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 225 ml of ether and dried in vacuo to obtain 162.7 g of (S)-N-[1-(aminocarbonyl)propy]<wbr></wbr>-4-chlorobutanamide.</div>
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Melting point: 118°-123° C. [alpha]<sub>D</sub> <sup>25</sup> : -18° (c=1, methanol). Yield: 78.7%.</div>
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The crude product thus obtained is very suitable for the cyclization stage which follows. It can however be purified by stirring for one hour in anhydrous ethyl acetate.</div>
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Melting point: 120°-122° C. [alpha]<sub>D</sub> <sup>25</sup> : -22.2° (c=1, methanol).</div>
(b) Preparation of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetamide<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"></span><br />
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6.2 g (0.03 mole) of (S)-N-[1(aminocarbonyl)propyl]<wbr></wbr>-4-chlorobutamine and 0.484 g (0.0015 mole) of tetrabutylammonium bromide are mixed in 45 ml of dichloromethane at 0° C. under a nitrogen atmosphere. 2.02 g (0.036 mole) of potassium hydroxide powder are added over 30 minutes, at such a rate that the temperature of the reaction mixture does not exceed +2° C. The mixture is then stirred for one hour, after which a further 0.1 g (0.0018 mole) of ground potassium hydroxide is added and stirring continued for 30 minutes at 0° C. The mixture is allowed to return to ambient temperature. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue obtained is recrystallized from 40 ml of ethyl acetate in the presence of 1.9 g of 0,4 nm molecular sieve. The latter is removed by hot filtration to give 3.10 g of (S)-alphaethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetamide.</div>
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Melting point: 116.7° C. [alpha]<sub>D</sub> <sup>25</sup> : -90.1° (c=1, acetone). Yield: 60.7%.</div>
EXAMPLE 4<span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"> </span>Preparation of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetamide......<span style="background-color: red;">leve<wbr></wbr>tiracetam</span><span style="font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"></span><br />
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This example illustrates a variant of the process of Example 3, in which the intermediate 4-chlorobutanamide obtained in situ is not isolated. 84 g of anhydrous sodium sulfate are added to a suspension of 69.25 g (0.5 mole) of (S)-2-amino-butanamide hydrochloride in 600 ml of dichloromethane at ambient temperature. The mixture is cooled to 0° C. and 115 g of ground potassium hydroxide are added, followed by 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. A solution of 77.5 g of 4-chlorobutyryl chloride in 100 ml of dichlorometha is added dropwise at 0° C., wih vigorous stirring. After 5 hours' reaction, a further 29 g of ground potassium hydroxide are added. Two hours later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. The resultant mixture is filtered and the filtrate evaporated under reduced pressure. The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0,4 nm molecular sieve in powder form are added. This mixture is heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 63 g of (S)-alpha-ethyl-2-oxo-1-<wbr></wbr>pyrrolidineacetamide.</div>
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Melting point: 117° C. [alpha]<sub>D</sub> <sup>25</sup> : -91.3° (c=1, acetone). Yield: 74.1%.</div>
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(±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide a key levetiracetam intermediate</h3>
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<span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">(±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide </span><br />
<span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;"><br /></span><span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">methyl (±)-(R,S)-alpha-ethyl-2-oxo-l -pyrrolidine acetate with (+)-(R)-(l-phenylethyl)- amine in toluene in the presence of a base such as sodium hydride or methoxide; crystallization- induced dynamic resolution of the resultant (±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide</span><br />
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<span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewControl1_formview_WrapTitle">(R)-(+)-1-Phenylethylamine</span></h1>
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33978-83-5<br />
1-Pyrrolidineacetic acid, α-ethyl-2-oxo-, methyl ester<br />
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<img alt="Ebd414139" src="http://www.ebuychem.com/product_pic/EBD414139.png?id=817" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br />
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1004767-60-5<br />
1-Pyrrolidineacetamide, α-ethyl-2-oxo-<i>N</i>-[(1<i>R</i>)-1-phenylethyl]-<br />
(±)-(R.S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide<br />
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Example 1</div>
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<span style="color: red;">(±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide. </span><br />
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In a 100 ml reactor equipped with mechanical stirring, thermometer and bubble condenser, 13.4 g of <span style="color: red;">(±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester</span> (71.6 mmol), 8.8 g of<span style="color: red;"> (+)-(R)-(l-phenylethyl)-amine</span> (72.5 mmol) and 45 ml of tetrahydrofuran were charged. 3.4 g of NaH (60% dispersion in mineral oil, 85.6 mmol) was added in small portions under nitrogen atmosphere. Reaction mixture was maintained at room temperature for about 2 h. Then, it was heated up to 35<sup>0</sup>C and kept under stirring overnight. Reaction was controlled by TLC (Rf = 0.5, AcOEt/silica gel).</div>
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At reaction completed, one night at 35°C temperature, reaction mixture was cooled to room temperature and 30 ml of water was slowly charged. It was transferred into a separatory funnel and was diluted with 30 ml of water and 80 ml of dichloromethane. Phases were separated and the aqueous one was washed with 50 ml of dichloromethane. Collected organic phases were washed with an aqueous acid solution, dried on Na<sub>2</sub>SO<sub>4</sub>, filtered and concentrated under vacuum. 19.5 g of an oil residue was obtained which slowly solidified. Solid was suspended in 20 ml of a hexane/dichloromethane 9/1 v/v mixture. It was then filtered, washed with 10 ml of the same solvent mixture and dried at 40<sup>0</sup>C to give 12.1 g of the title compound (44.1 mmol, 61.6% yield) as dry solid.</div>
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<sup>1</sup>H NMR (400.13 MHz, CDCl<sub>3</sub>, 25 <sup>0</sup>C): δ (ppm, TMS)<br />
7.35-7.19 (1OH, m),<br />
6.49 (2H, br s),<br />
5.09-5.00 (2H, m),<br />
4.41 (IH, dd, J = 8.3, 7.4 Hz),<br />
4.36 (IH, dd, J = 8.6, 7.1 Hz),<br />
3.49 (IH, ddd, J = 9.8, 7.7, 6.6 Hz),<br />
3.41 (IH, ddd, J = 9.8, 7.7, 6.2 Hz),<br />
3.30 (IH, ddd, J = 9.6, 8.3, 5.5 Hz),<br />
3.13 (IH, ddd, 9.7, 8.5, 6.1 Hz), 2.47-2.38 (2H, m), 2.41 (IH, ddd, J = 17.0, 9.6, 6.3 Hz), 2.26 (IH, ddd, 17.0, 9.5, 6.6 Hz), 2.10-1.98 (2H, m), 2.01-1.89 (IH, m), 1.99-1.88 (IH, m), 1.98-1.85 (IH, m), 1.88-1.78 (IH, m), 1.75- 1.62 (IH, m), 1.72-1.59 (IH, m), 1.45 (3H, d, J = 7.1 Hz), 1.44 (3H, d, J = 7.1 Hz), 0.90 (3H, t, J = 7.4 Hz), 0.86 (3H, t, J = 7.4 Hz). <sup> </sup><br />
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<sup>13</sup>C NMR (100.62 MHz, CDCl<sub>3</sub>, 25 <sup>0</sup>C): δ (ppm, TMS)<br />
176.05 (CO), 176.00 (CO), 169.08 (CO),<br />
168.81 (CO), 143.59 (C<sub>qua</sub>t),<br />
143.02 (C<sub>qua</sub>t), 128.66 (2 x CH), 128.55 (2 x CH),<br />
127.33 (CH), 127.19 (CH), 126.05 (2 x CH),<br />
125.80 (2 x CH), 56.98 (CH), 56.61 (CH),<br />
48.90 (CH), 48.84 (CH), 44.08 (CH<sub>2</sub>),<br />
43.71 (CH<sub>2</sub>), 31.19 (CH<sub>2</sub>), 31.07 (CH<sub>2</sub>), 22.08 (CH<sub>3</sub>),<br />
22.04 (CH<sub>3</sub>), 21.21 (CH<sub>2</sub>), 20.68 (CH<sub>2</sub>),<br />
18.28 (CH<sub>2</sub>), 18.08 (CH<sub>2</sub>), 10.50 (CH<sub>3</sub>), 10.45 (CH<sub>3</sub>).<br />
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Example 2 (±)-(R.S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide (alternative 1).</div>
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In a 500 ml reactor equipped with mechanical stirring, thermometer and condenser, 24.2 g of (+)-(R)-(l-phenylethyl)-amine (199.51 mmol) and 40 ml of toluene were charged. By keeping the reaction mixture at 0<sup>0</sup>C temperature under nitrogen atmosphere, 9.5 g of NaH (60% mineral oil suspension, 237.50 mmol) was added in small portions. At the same temperature, 190.0 g of a toluene solution of (±)-(R,S)- alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (19.28% equal to 36.63 g, 197.77 mmol) was charged. Reaction mixture was then heated up to 35°C and maintained in that condition till complete disappearing of methyl ester reagent (about 14 h; checked by HPLC).</div>
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At reaction completed, reaction mixture was cooled and when room temperature was reached, 100 ml of water was slowly charged. Aqueous phases were separated and extracted with toluene (2 x 75 ml). Collected organic phases were treated with acid water till neuter pH. Solvent was evaporated and residue was suspended in about 100 ml of heptane for about 30 minutes. Product was isolated by filtration and dried in oven at 40<sup>0</sup>C temperature under vacuum overnight to give 45.2 g of the title compound (164.54 mmol, 83.2% yield, d.e. 0.0%) as white dusty solid.<br />
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Example 3</div>
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(±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide (alternative 2).</div>
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In a 500 ml reactor equipped with mechanical stirring, thermometer and Dean-Stark distiller, 24.2 g of (+)-(R)-(l-phenylethyl)-amine (199.51 mmol) and 40 ml of toluene were charged. By keeping the reaction mixture at 0<sup>0</sup>C temperature, 42.7 g of sodium methoxide (30% solution in methanol, 237.14 mmol) was added under nitrogen atmosphere. At the same temperature, 190.0 g of a toluene solution of (±)- (R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (19.28% equal to 36.63 g, 197.77 mmol) was charged. Reaction mixture was then heated up to 65- 70<sup>0</sup>C and maintained in that condition till complete disappearing of methyl ester reagent (about 4 h; checked by HPLC). After a work-up carried out according to the procedure described in example 2, 40.2 g of the title compound (146.53 mmol, 74.1% yield, d.e. 0.0%) as white dusty solid was obtained.</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-302770220608373834.post-63870667740521379592015-03-29T00:57:00.000-07:002015-03-29T00:57:02.388-07:00TELAPREVIR<div dir="ltr" style="text-align: left;" trbidi="on">
<img height="392" src="http://upload.wikimedia.org/wikipedia/commons/4/4d/Telaprevir.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" width="640" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">TELAPREVIR</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">MF C36H53N7O6</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"> MolWeight: 679.85</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">CAS No.: 402957-28-2</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">NMR..........</span><a href="http://www.abmole.com/download/vx-950-hnmr.pdf" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://www.abmole.com/download/vx-950-hnmr.pdf</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">AND</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://file.selleckchem.com/downloads/nmr/S153802-Telaprevir-NMR-Selleck.pdf" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://file.selleckchem.com/downloads/nmr/S153802-Telaprevir-NMR-Selleck.pdf</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
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13C NMR</div>
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<i><strong>Chem. Commun.</strong></i>, 2010,<span style="padding-right: 2px;"></span><strong>46</strong>, 7918-7920</div>
<br style="background-color: white; color: #cd0066; font-family: Arial, Helvetica, sans-serif; font-size: 12px; line-height: 20px;" /><span class="DOILink" style="background-color: white; color: #cd0066; float: left; font-family: Arial, Helvetica, sans-serif; font-size: 12px; line-height: 20px; padding: 0px; width: 505px;"><strong>DOI: </strong>10.1039/C0CC02823A</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://pubs.rsc.org/en/Content/ArticleLanding/2010/CC/c0cc02823a#!divAbstract" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://pubs.rsc.org/en/Content/ArticleLanding/2010/CC/c0cc02823a#!divAbstract</a><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">'</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
<div style="background-color: white; color: #222222; font-family: Arial; font-size: 12px; line-height: 18px;" xmlns="http://www.rsc.org/schema/rscart38">
A very short and efficient synthesis of the important <annref idrefs="ann2">drug</annref> candidate telaprevir, featuring a biocatalytic desymmetrization and two multicomponent reactions as the key steps, is presented. The classical issue of lack of stereoselectivity in Ugi- and Passerini-type reactions is circumvented. The atom economic and convergent nature of the synthetic strategy require only very limited use of protective <annref idrefs="ann3">groups</annref>.</div>
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<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Telaprevir (1). 250 l of saturated K2CO3 was added to a solution of 14 (0.514 g, 0.75 mmol) in MeOH (20 ml) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature resulting in a pale yellow suspension. After full conversion (as judged by TLC analysis), the reaction mixture was washed with 20 ml brine, the aqueous layer was washed again with 10 ml CH2Cl2 (2x). The organic layers were collected, dried with MgSO4 and concentrated in vacuo, to yield a pale yellow solid. The yellow solid was dissolved in CH2Cl2 (10 ml) and Dess-Martin periodinane (0.650 g, 1.532 mmol) was added at room temperature. The reaction mixture was stirred overnight before adding saturated NaHCO3 solution (10 ml) and saturated Na2S2O3 solution (10 ml). This mixture was stirred for 10 minutes, separated and the aqueous layers were washed with EtOAc (2 x 10 ml). The organic layers were collected, dried with MgSO4 and concentrated in vacuo to give the crude product as an 83:13:4 mixture of diastereomers. After silica gel flash chromatography (1% MeOH in CH2Cl2), 1 (0.412 mg, 0.61 mmol, 80%) was obtained as a white solid.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR (500.23 MHz, DMSO-d6): δ = 9.19 (d, J = 1.4 Hz, 1H), 8.91 (d, J = 24.5 Hz, 1H), 8.76 (dd, J = 1.5, 2.5 Hz, 1H), 8.71 (d, J = 5.3 Hz, 1H), 8.49 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 4.94 (m, 1H), 4.68 (dd, J = 6.5, 9.0 Hz, 1H), 4.53 (d, J = 9.0 Hz, 1H), 4.27 (d, J = 3.5 Hz, 1H), 3.74 (dd, J = 8.0, 10 Hz, 1H), 2.74 (m, 1H), 3.64 (d, J = 3.5 Hz, 1H), 0.92 (s, 9H), 0.87 (t, 3H), 0.84-1.40 (m, 23H), 0.65 (m, 2H), 0.56 (m, 2H); </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"></span><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">13C NMR (125.78 MHz, CDCl3): δ = 197.0 (C), 171.8 (C), 170.4 (C), 169.0 (C), 162.1 (C), 161.9 (C), 147.9 (CH), 144.0 (C), 143.4 (CH), 56.4 (CH), 56.3 (CH), 54.2 (CH), 53.4 (CH), 42.3 (CH), 41.3 (CH), 32.1 (CH), 31.8 (CH), 31.6 (CH), 29.1 (CH), 28.0 (CH), 26.4 (CH3); </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"></span><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">max (cm -1 ): 3302 (m), 2928 (m), 2858 (w), 1658 (s), 1620 (s), 1561 (s), 1442 (m); </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"></span><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">HRMS (ESI, 4500 V): m/z calcd. for C36H53N7O6Na + ([M + Na] + ) 702.3950, found 702.3941. </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><img src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2012/MD/c2md20089a/c2md20089a-s45.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; 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Reference:</h3>
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<span style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><a href="http://www.google.com.ar/patents/WO2011103932A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com.ar/patents/WO2011103932A1?cl=en</a></span><br /><div num="p0138" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
t mpound XVIII,</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000023_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000023_0001" class="patent-full-image" file="imgf000023_0001.tif" he="45" height="180" id="imgf000023_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000023_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="89" width="356" /></a></div>
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(XVIII).</div>
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This compound, which also known as Telaprevir, could be prepared in higher yields and with higher efficiency than any previously disclosed processes. Furthermore, the chiral information used for the preparation was derived from readily available simple building blocks, making the process a highly effective approach to such prolyl dipeptides and similar peptidomimetics.</div>
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<div num="p0141" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
EXAMPLE 22</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000044_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000044_0001" class="patent-full-image" file="imgf000044_0001.tif" he="29" height="116" id="imgf000044_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000044_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="72" width="288" /></a></div>
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(5)-Methyl 2-cyclohexyl-2-(pyrazine-2-carboxamido)acetate (9).</div>
<div num="p0244" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Pyrazinecarboxylic acid (2.72 g, 21.9 mmol) was added to a solution of L- cyclohexylglycine methyl ester (4.13 g, 19.9 mmol) in CH<sub>2</sub>CI<sub>2</sub> (100 ml) at room temperature under N<sub>2</sub>, forming a white suspension. Triethylamine (6.33 ml, 4.62 g, 45.8 mmol) was added, followed by benzotriazol-l-yloxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (BOP; 9.69 g, 21.9 mmol), which turned the reaction mixture from purple to an orange solution. After two days of stirring at room temperature the reaction mixture was washed two times with 50 ml saturated Na<sub>2</sub>CC>3, followed by the washing of the aqueous layers with CH<sub>2</sub>CI<sub>2</sub> (2 <sup>χ</sup> 50 ml). The organic layers were collected and dried with MgSC , followed by concentration in vacuo. Purification by silica gel flash chromatography (c-Hex:EtOAc = 2: 1 with 0.5% triethylamine) afforded 9 (5.28 g, 19.03 mmol, 96%) as a yellow oil that solidified upon standing to give a white solid.</div>
<div num="p0245" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[a f° = +42.5 (c= 1.13, CHC1<sub>3</sub>); *H NMR (250.13 MHz, CDCI3) δ = 9.39 (d, J= 1.25 Hz, 1H), 8.76 (d, J = 2.5 Hz, 1H), 8.57 (t, J = 1.5 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 4.74 (dd, J= 5.5, 9.3 Hz, 1H), 3.78 (s, 3H), 1.96 (m, 1H), 1.77 (m, 5H), 1.24 (m, 5H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): δ= 172.0 (C), 162.8 (C), 147.4 (CH), 144.5 (CH), 144.1 (C), 142.7(CH), 57.0 (CH), 52.3 (CH<sub>3</sub>), 41.2 (CH), 29.7 (CH<sub>2</sub>), 28.4 (CH<sub>2</sub>), 26.0 (CH<sub>2</sub>); IR (neat): v^cm ) = 3374 (m), 2920 (s), 2845 (w), 1740 (s), 1665 (s); HRMS (ESI, 4500 V): m/z calcd. for Ci<sub>4</sub>Hi<sub>9</sub>N<sub>3</sub>03Na<sup>+</sup> ([M + Na]<sup>+</sup>) 300.1319, found 300.1319.</div>
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Example 23 :</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000045_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000045_0001" class="patent-full-image" file="imgf000045_0001.tif" he="27" height="108" id="imgf000045_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000045_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="34" width="136" /></a></div>
<div num="p0248" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid (10). A solution of 1 M NaOH (12 ml, 12 mmol) was added to a solution of 9 (2.77 g, 10 mmol) in THF (25 ml) at 0°C. MeOH was added to the formed suspension, to give a clear, colorless solution. The reaction mixture was stirred overnight at room temperature, followed by concentration in vacuo. The pH of the aqueous layer was set on 3.5 with a 1 M KHSO<sub>4</sub> solution and was extracted with EtOAc (2 <sup>χ</sup> 25 ml). The mixture was dried with Na<sub>2</sub>S04, filtered, and concentrated in vacuo, to give 10 (2.49 g, 9.45 mmol, 95%) as a white solid.</div>
<div num="p0249" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[a £° = +50.9 (c= 1.06, CHC1<sub>3</sub>); H NMR (250.13 MHz, CDCI3): δ = 9.38 (d, J = 1.5</div>
<div num="p0250" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Hz, 1H), 8.78 (d, J= 2.5 Hz, 1H), 8.58 (dd, J= 1.5, 2.5 Hz, 1H), 8.27 (d, J= 9.0, 1H), 4.77 (dd, J = 4.3, 5.0 Hz, 1H), 2.00 (m, 1H), 1.76 (m, 5H), 1.37 (m, 5H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): δ = 175.7 (C), 163.0 (C), 147.2 (CH), 144.3 (CH), 144.2 (C), 142.0 (CH), 56.9 (CH), 40.9 (CH), 29.7 (CH<sub>2</sub>), 28.1 (CH<sub>2</sub>), 25.9 (CH<sub>2</sub>); IR (neat): v<sub>max</sub> (cm<sup>4</sup>) = 3383 (m), 2928 (s), 2852 (w), 1713 (m), 1676 (s), 1518 (s); HRMS (ESI, 4500 V): m/z calcd. For Ci<sub>3</sub>H<sub>17</sub>N<sub>3</sub>0<sub>3</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 286.1162, found 286.1158.</div>
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Example 23 :</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000046_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000046_0001" class="patent-full-image" file="imgf000046_0001.tif" he="29" height="116" id="imgf000046_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000046_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="49" width="196" /></a></div>
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(S)-methyl 2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)-acetamido)-3,3- dimethylbutanoate (11). 10 (0.653 g, 4.5 mmol) was added to a solution of H-Tle- OMe (0.653 g, 4.5 mmol) in DMF (40 ml). l-Ethyl-3-(3-dimethylaminopropyl)- carbodiimide-HCl (EDOHC1; 0.919 g, 6.75 mmol) was added to this colorless solution followed by 1 -hydroxy-7-azabenzotriazole (HOAt; 1.035 g, 5.4 mmol) giving a bright yellow solution. The reaction mixture was stirred for 3 days and afterwards concentrated in vacuo. The formed yellow solid was dissolved in EtOAc, washed with 40 ml saturated aqueous ammonium chloride solution and 40 ml of saturated aqueous NaHCC>3 solution. The organic layers were collected, dried with MgSC^ and concentrated in vacuo to give 11 (1.48 g, 3.78 mmol, 84%) as a white solid.</div>
<div num="p0254" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[a f° = -2.0 (c= 1.0, CHC1<sub>3</sub>); ¾ NMR (250.13 MHz, CDC1<sub>3</sub>): δ = 9.39 (d, J = 1.5 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.55 (dd, J = 2.4, 1.8 Hz, 1H), 8.29 (d, J = 8.1, 1H), 6.40 (d, J= 9.3 Hz, 1H), 4.46 (m, 2H), 3.74 (s, 3H), 1.81 (m, 1H), 1.76 (m, 4H), 1.24 (m, 6H), 0.96 (s, 12H); <sup>13</sup>C NMR (62.90 MHz, CDC1<sub>3</sub>): δ = 171.7 (C) , 170.4 (C), 163.0 (C), 147.5 (CH), 144.5 (CH), 144.2 (C), 142.7 (CH), 60.2 (CH<sub>3</sub>), 58.4 (CH), 51.9 (CH), 40.5 (CH), 31.7 (C), 29.7 (CH<sub>2</sub>), 28.7 (CH<sub>2</sub>), 26.6 (CH<sub>3</sub>), 25.9 (CH<sub>2</sub>); IR (neat): v„(cm<sup>J</sup>) = 3350 (m), 2928 (m), 2853 (w), 1738 (s), 1686 (s), 1640 (s), 1520 (s); HRMS (ESI, 4500 V): m/z calcd. for C<sub>2</sub>oH<sub>3</sub>oN<sub>4</sub>04Na<sup>+</sup> ([M + Na]<sup>+</sup>) 413.2159, found 413.2169.</div>
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Example 24:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000047_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000047_0001" class="patent-full-image" file="imgf000047_0001.tif" he="32" height="128" id="imgf000047_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000047_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="53" width="212" /></a></div>
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(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoic acid (2). A solution of 1 M NaOH (0.94 ml, 0.94 mmol) was added to a solution of 11 (0.31 g, 0.78 mmol) in THF (3 ml) at 0°C. MeOH was added to the formed suspension, to give a clear and colourless solution. The reaction mixture was stirred overnight at room temperature, followed by concentration in vacuo. The pH of this aqueous layer was set to 3.5 with 1 M KHSO<sub>4</sub> and subsequently extracted with EtOAc (2 <sup>χ</sup> 10ml). The mixture was dried with Na<sub>2</sub>S0<sub>4</sub>, filtered, and concentrated in vacuo, to give 2 (0.28 g, 0.75 mmol, 95%) as a white solid.</div>
<div num="p0258" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[a f° = +21.7 (c= 1.015, CHC1<sub>3</sub>); *H NMR (250.13 MHz, CDC1<sub>3</sub>): δ = 9.39 (d, J= 1.3</div>
<div num="p0259" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Hz, 1H), 8.77 (d, J = 2.5 Hz, 1H), 8.57 (dd, J = 1.5, 2.5 Hz, 1H), 8.35 (d, J = 9 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 4.45 (t, J = 8.8 Hz, 1H), 4.42 (d, J = 9.2 Hz, 1H), 1.94 (m, 1H), 1.71 (m, 5H), 1.20 (m, 5H), 1.01 (s, 9H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): δ = 173.4 (C), 170.5 (C), 163.3 (C), 147.4 (CH), 144.4 (CH), 144.2 (C), 142.8 (CH), 58.4 (CH), 51.9 (CH), 40.4 (CH), 34.7 (C), 29.8 (CH<sub>2</sub>), 28.6 (CH<sub>2</sub>), 26.6 (CH<sub>3</sub>), 25.8 (CH<sub>2</sub>); IR (neat): v„(cm ) = 3335 (w), 2930 (m), 1726 (m), 1663 (s), 1514 (s); HRMS (ESI, 4500 V): m/z calc. for Ci<sub>9</sub>H<sub>29</sub>N<sub>4</sub>0<sub>4</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 399.2003, found 399.2013.</div>
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Example 25:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000047_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000047_0002" class="patent-full-image" file="imgf000047_0002.tif" he="23" height="92" id="imgf000047_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000047_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="32" width="128" /></a></div>
<div num="p0262" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(5)-2-formamido-l-pentanol (12). (5)-2-amino-l-pentanol (1.00 g, 9.7 mmol) was dissolved in ethylformate (7.84 ml, 7.19 g, 97 mmol). This reaction mixture was refluxed at 80 °C for 4 hours, followed by stirring overnight at room temperature. The colourless solution was concentrated in vacuo and stirred for 1 hour in a 10 mol% K<sub>2</sub>C0<sub>3</sub> in MeOH (25 ml). Afterwards, the pH was set to 7 with DOWEX 50wx8, followed by filtration and concentration in vacuo to give 12 (1.26 g, 9.61 mmol, 99%). [a f° = -29.6 (c = 1.15, CHCI<sub>3</sub>); H NMR (250.13 MHz, CDC1<sub>3</sub>): δ = 8.20 (s, 1H), 5.81 (bs, 1H), 4.04 (m, 1H), 2.11 (b, 1H), 1.47 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): 161.8 (C), 65.1 (CH<sub>2</sub>), 50.6 (CH), 33.2 (CH<sub>2</sub>), 19.2 (CH<sub>2</sub>), 13.9 (CH<sub>3</sub>); IR (neat): v<sub>max</sub> (cm ) = 3248 (s), 2957 (m), 1651 (s), 1528 (m), 1381 (m); HRMS (ESI, 4500 V): m/z calcd. for C<sub>6</sub>Hi<sub>3</sub>N0<sub>2</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 154.0838, found 154.0835.</div>
<div num="p0263" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 26:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000048_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000048_0001" class="patent-full-image" file="imgf000048_0001.tif" he="34" height="136" id="imgf000048_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000048_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="74" width="296" /></a></div>
<div num="p0141" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">(5)-2-formamidopentanal. (7). Dess-Martin periodinane (5.514 g, 13 mmol) was added to a solution of (5)-2-formamido-l-pentanol (12, 1.31 g, 10 mmol) in CH</span><sub style="line-height: 21.3333339691162px;">2</sub><span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">C1</span><sub style="line-height: 21.3333339691162px;">2</sub><span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;"> (100 ml) at room temperature. The white suspension was stirred for 2 days and subsequently 35 ml MeOH was added and stirred for 30 minutes. The resulting suspension was filtrated and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography (cHex:EtOAc = 1 :4) to give 7 (1.08 g,</span></div>
<div num="p0265" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
8.29 mmol, 83%) as a white solid. NMR analysis indicates that 7 is in equilibrium with its cyclic dimer.</div>
<div num="p0266" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[a f° = +37.6 ( c= 0.745, CHC1<sub>3</sub>); <sup>l</sup>U NMR assigned to the monomer (250.13 MHz, CDCI<sub>3</sub>): δ = 8.22 (s, 1H), 7.84 (s, 1H), 7.10 (m, 1H), 5.31 (m, 1H), 1.52 (m, 4H), 0.95 (m, 3H); <sup>13</sup>C NMR assigned to the monomer (100.61 MHz, CDC13): 198.8 (CH), 161.7 (CH), 57.4 (CH), 30.8 (CH<sub>2</sub>), 18.4 (CH<sub>2</sub>), 13.7 (CH<sub>3</sub>); <sup>l</sup>H NMR assigned to the dimer (400.13 MHz, CDC1<sub>3</sub>) 8.22 (s, 2H), 5.26 (m, 2H), 3.72 (m, 2H) 1.52 (m, 8H), 0.95 (m, 6Η;) <sup>13</sup>C NMR (100.61 MHz, CDCI3) assigned to the dimer: 161.7 (CH), 89.8 (CH), 63.1 (CH), 30.8 (CH2), 18.4 (CH2), 13.7 (CH3); IR (neat): <sub>Vmax</sub> (cm ): 3325 (s), 2959 (s), 1649 (s), 1530 (s), 1381 (m), 1123 (w); HRMS (ESI, 4500 V): m/z calc. for C<sub>6</sub>Hi<sub>2</sub>N0<sub>2</sub> <sup>+</sup> ([M + H]<sup>+</sup>) 130.0863, found 130.0858.</div>
<div num="p0267" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
It was noted that the dimer exists as a mixture of diastereomers.</div>
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Example 27:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000049_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000049_0001" class="patent-full-image" file="imgf000049_0001.tif" he="28" height="112" id="imgf000049_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000049_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="34" width="136" /></a></div>
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(35)-2-acetoxy- V-cyclopropyl-3-formamidohexanoyl amide (13). From 7: Aldehyde 7 (0.892 g, 6.91 mmol) was added to a solution of cyclopropyl isocyanide (0.410 g, 6.12 mmol) in CH<sub>2</sub>C1<sub>2</sub> (110 ml) and stirred for 5 minutes at room temperature. Acetic acid (0.711 ml, 0.747 g, 12.44 mmol) was added and the yellow reaction mixture was stirred for 3 days at room temperature. The reaction mixture was washed twice with 100 ml saturated Na<sub>2</sub>C03, followed by drying with Na<sub>2</sub>S04 and concentration in vacuo. The crude was purified by silica gel flash chromatography (5% MeOH in CH<sub>2</sub>C1<sub>2</sub>, 1% triethylamine). (3S)-2-acetoxy-N-cyclopropyl-3- formamidohexanoyl amide (0.99 g, 3.87 mmol, 56%) was obtained as a white solid as a 78:22 mixture of diastereomers.</div>
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From 12: Dess Martin periodinane (5.66 g, 12.3 mmol) was added to a solution of (S)-N-(l hydroxypentan-2-yl)formamide (1.15 g, 8.8 mmol) in CH<sub>2</sub>C1<sub>2</sub> (12 ml) at room temperature. The white suspension was stirred for 60 minutes and subsequently cyclopropyl isocyanide (0.74 g, 10.0 mmol) was added and stirred for 48 hours. The resulting suspension was filtrated and washed twice with 10 ml saturated Na<sub>2</sub>C03, followed by drying with Na<sub>2</sub>SC>4 and concentration in vacuo. The crude product was purified by silica gel flash chromatography (5% MeOH in CH<sub>2</sub>CI<sub>2</sub>, 1% triethylamine) to give 13 (1.34 g, 5.22 mmol, 60%) as a pale yellow solid as a 78:22 mixture of diastereomers.</div>
<div num="p0272" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
*H NMR (130 °C, 400.13 MHz, DMSO-i¾: δ = 8.03 (s, 1H), 7.52 (m, 1H), 7.30 (m, 1H), 4.89 (d, J= 4.4, 1H), 4.28 (m, 1H), 2.65 (m, 1H), 2.17(s, 3H), 1.27-1.47 (m, 4H), 0.89 (t, J= 7.2, 3H), 0.63 (m, 2H), 0.48 (m, 2H); <sup>13</sup>C NMR (125.78 MHz, DMSO-i <sub>6</sub>): δ = 169.8 (C), 168.5 (C), 160.6 (CH), 74.4 (CH), 47.5 (CH), 22.2 (CH), 18.4 (CH<sub>3</sub>), 13.6 (CH<sub>3</sub>), 5.7 (CH<sub>2</sub>); IR (neat): v<sub>max</sub> (cm ) 3283 (s), 2961 (w), 1744 (m), 1661 (s), 1530 (s), 1238 (s); HRMS (ESI, 4500 V): m/z calcd. for Ci<sub>2</sub>H<sub>2</sub>oN<sub>2</sub>0<sub>4</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 279.1315, found 279.1325.</div>
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Example 28:</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000050_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000050_0001" class="patent-full-image" file="imgf000050_0001.tif" he="31" height="124" id="imgf000050_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000050_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="32" width="128" /></a></div>
<div num="p0275" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(35)-2-acetoxy-7V-cyclopropyl-3-isocyano-hexanoyl amide (4). N- methylmorpholine (0.57 ml, 0.562 g, 5.56 mmol) was added to a solution of (5)-l- (cyclopropylamino)-3-formamido-l-oxohexan-2-yl acetate (0.713 g, 2.78 mmol) in CH<sub>2</sub>CI<sub>2</sub> (40 ml) at room temperature. The reaction mixture was cooled to -78 °C and triphosgene (0.289 g, 0.97 mmol) was quickly added and stirred for 5 minutes at this temperature. The resulting yellow solution was warmed up to -30 °C and was stirred for another 3 h. Subsequently, the reaction was quenched with water and extracted twice with CH<sub>2</sub>CI<sub>2</sub> (40 ml). The organic layers were collected, dried with Na<sub>2</sub>SC>4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (2% MeOH in CH<sub>2</sub>C1<sub>2</sub>) to give 4 (0.578 g, 2.42 mmol, 87%) as a white solid. <sup>l</sup>U NMR (250.13 MHz, CDC1<sub>3</sub>): δ = 6.28 (s, 1H), 5.25 (d, J = 2.5 Hz, 1H), 4.2 (m, 1H), 2.74 (m, 1H), 2.24 (s, 3H), 1.55 (m, 4H), 0.96 (m, 3H), 0.84 (m, 2H), 0.60 (m, 2H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): δ= 169.7 (C), 168.3 (C), 74.4 (CH), 47.5 (CH), 22.0 (CH), 20.6 (CH<sub>3</sub>), 18.5 (CH<sub>2</sub>), 13.5 (CH<sub>3</sub>), 5.5 (CH<sub>2</sub>); IR (neat): <sub>Vmas</sub>(cm ): 3267 (s), 2959 (m), 1745 (m), 1643 (s), 1512 (m), 1221 (s); HRMS (ESI, 4500 V): m/z calcd. for Ci<sub>2</sub>H<sub>18</sub>N<sub>2</sub>0<sub>3</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 261.1210, found 261.1214.</div>
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<br /></div>
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<br /></div>
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<br /></div>
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<br /></div>
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<div num="p0276" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 29:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000051_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000051_0001" class="patent-full-image" file="imgf000051_0001.tif" he="36" height="144" id="imgf000051_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000051_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="79" width="316" /></a></div>
<div num="p0278" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Compound 14. Isocyanide 4 (0.549 g, 2.3 mmol) was dropwise added to a solution of imine 3 (0.252 g, 2.3 mmol) and carboxylic acid 2 (0.602 g, 1.60 mmol) in CH<sub>2</sub>C1<sub>2</sub> (5 ml) at room temperature. This yellow solution was stirred for 72 hours and afterwards diluted with 5 ml CH<sub>2</sub>C1<sub>2</sub>. The reaction mixture was washed twice with saturated Na<sub>2</sub>C0<sub>3</sub> solution (10 ml) and twice with saturated NH<sub>4</sub>CI. The organic layers were collected, dried with MgS04 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (5% MeOH in CH<sub>2</sub>C1<sub>2</sub>) to give 14 (0.876 g, 1.21 mmol, 76%) as a mixture of diastereomers.</div>
<div num="p0279" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
lU NMR (500.23 MHz, CDC1<sub>3</sub>): δ = 9.50 (s, 1H), 8.75 (d, J = 2.5, 1H), 8.59 (s, 1H), 8.35 (d, J = 9.0, 1H), 6.84 (d, J= 9.0, 1H), 6.44 (s, 1H), 5.20 (d, J= 3.0, 1H), 4.74 (d, J= 9.5, 1H), 4.58 (t, J = 7.5, 1H), 4.38 (m, 1H), 3.37 (d, J= 6.0, 1H), 2.82 (m, 1H), 2.69 (m, 1H), 2.11 (s, 3H), 1.26 (s, 2H), 0.97 (s, 9H), 0.86 (m, 3H), 0.84-2.00 (m, 21H), 0.76 (m, 2H), 0.51 (m, 2H);<sup>13</sup>C NMR (125.78 MHz, CDC1<sub>3</sub>): δ = 170.5 (C), 169.3 (C), 162.9 (C), 147.4 (CH), 144.6 (CH), 144.2 (C), 142.8 (CH), 74.4 (CH), 66.6 (CH), 58.3 (CH), 56.6 (CH), 54.5 (CH<sub>2</sub>), 44.9 (CH), 43.0 (CH), 41.3 (CH), 35.5 (C), 26.4 (CH<sub>3</sub>), 20.8 (CH<sub>3</sub>), 19.1 (CH<sub>2</sub>), 13.8 (CH<sub>3</sub>), 6.6 (CH<sub>2</sub>); v<sub>max</sub> (cm<sup>4</sup>): 3306 (m), 2928 (m), 2931 (m), 1743 (w), 1655 (s), 1520 (m), 1219 (m); HRMS (ESI, 4500 V): m/z calcd. for C<sub>3</sub>8H<sub>5</sub>7N<sub>7</sub>0<sub>7</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 746.4212, found 746.4107.</div>
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<br /></div>
<div num="p0279" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 30:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000052_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000052_0001" class="patent-full-image" file="imgf000052_0001.tif" he="32" height="128" id="imgf000052_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000052_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="74" width="296" /></a></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<span style="color: #222222;">Telaprevir (1). 250 μΐ of saturated K<sub>2</sub>C0<sub>3</sub> was added to a solution of 14 (0.514 g, 0.75 mmol) in MeOH (20 ml) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature resulting in a pale yellow suspension. After full conversion (as judged by TLC analysis), the reaction mixture was washed with 20 ml brine, the aqueous layer was washed again with 10 ml CH<sub>2</sub>C1<sub>2</sub> (2x). The organic layers were collected, dried with MgS0<sub>4</sub> and concentrated in vacuo, to yield a pale yellow solid. The yellow solid was dissolved in CH<sub>2</sub>CI<sub>2</sub> (10 ml) and Dess-Martin periodinane (0.650 g, 1.532 mmol) was added at room temperature. The reaction mixture was stirred overnight before adding saturated NaHC0<sub>3</sub> solution (10 ml) and saturated Na<sub>2</sub>S<sub>2</sub>0<sub>3</sub> solution (10 ml). This mixture was stirred for 10 minutes, separated and the aqueous layers were washed with EtOAc (2 x 10 ml). The organic layers were collected, dried with MgSC^ and concentrated in vacuo to give the crude product as an 83: 13:4 mixture of diastereomers. After silica gel flash chromatography (1% MeOH in CH<sub>2</sub>C1<sub>2</sub>), 1 (0.412 mg, 0.61 mmol, 80%) was obtained as a white solid. <sup>l</sup>U </span><span style="color: red;">NMR (500.23 MHz, DMSO-i¾: 5 = 9.19 (d, J= 1.4 Hz, 1H), 8.91 (d, J= 24.5 Hz, 1H), 8.76 (dd, J = 1.5, 2.5 Hz, 1H), 8.71 (d, J= 5.3 Hz, 1H), 8.49 (d, J= 9.2 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 4.94 (m, 1H), 4.68 (dd, J= 6.5, 9.0 Hz, 1H), 4.53 (d, J = 9.0 Hz, 1H), 4.27 (d, J = 3.5 Hz, 1H), 3.74 (dd, J = 8.0, 10 Hz, 1H), 2.74 (m, 1H), 3.64 (d, J = 3.5 Hz, 1H), 0.92 (s, 9H), 0.87 (t, 3H), 0.84-1.40 (m, 23H), 0.65 (m, 2H), 0.56 (m, 2H); </span></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<sup><span style="color: red;"><br /></span></sup></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<span style="color: red;"><sup>13</sup>C NMR (125.78 MHz, CDC1<sub>3</sub>): δ = 197.0 (C), 171.8 (C), 170.4 (C), 169.0 (C), 162.1 (C), 161.9 (C), 147.9 (CH), 144.0 (C), 143.4 (CH), 56.4 (CH), 56.3 (CH), 54.2 (CH), 53.4 (CH), 42.3 (CH), 41.3 (CH), 32.1 (CH), 31.8 (CH), 31.6 (CH), 29.1 (CH), 28.0 (CH), 26.4 (CH<sub>3</sub>); (cm<sup>4</sup>): 3302 (m), 2928 (m), 2858 (w), 1658 (s), 1620 (s), 1561 (s), 1442 (m); </span></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<span style="color: red;"><br /></span></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<span style="color: red;">HRMS (ESI, 4500 V): m/z calcd. for C<sub>3</sub>6H<sub>5</sub>3N<sub>7</sub>0<sub>6</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 702.3950, found 702.3941.</span></div>
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<br /></div>
<div>
<div style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
..................</div>
<div num="p0014" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
telaprevir according to Formula 1</div>
<div num="p0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000004_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000004_0002" class="patent-full-image" file="imgf000004_0002.tif" he="33" height="132" id="imgf000004_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000004_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="85" width="340" /></a></div>
<div style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
<br /></div>
<span style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><a href="http://www.google.im/patents/WO2013135870A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2013135870A1?cl=en</a></span><br /><div style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
<br /></div>
<div num="p0004" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telaprevir is a protease inhibitor that can be used as antiviral drug. By way of example, telaprevir inhibits the hepatitis C virus NS3-4A serine protease.</div>
<div num="p0005" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Although some processes for the synthesis of telaprevir or its pharmaceutical acceptable salts are available, it is an object of the present invention to provide an alternative process, in particular an enhanced process that overcomes at least one of the problems of the prior art processes.</div>
<div num="p0006" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Y. Yip et al. Bioorg. Med. Chem. Lett., 2004, 14, 5007 discloses the preparation of a 1 :1 mixture of isomers defined by Formula 5a (see Scheme 1 ) which isomers appear to have a stereochemical configuration other than that of telaprevir. WO 2007/022459 A2 discloses a process for preparing telaprevir, wherein in a first coupling step, a bicyclic pyrrolidine derivative is reacted with a protected amino acid, followed by a stepwise extension of the chain of the amino acid to provide a tripeptide as shown in Formula 2. Subsequently, a β-amino acid is added to the carbon chain-end opposite to said previously built chain. Finally, telaprevir is obtained in an oxidation step. Turner et al. (Chemical Communications 2010, 46(42), 7918) discloses a process for the preparation of teiaprevir by applying an Ugi reaction type process which reacts a compound of Formula 2</div>
<div num="p0007" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000003_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" file="imgf000003_0001.tif" he="34" height="136" id="imgf000003_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000003_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="50" width="200" /></a></div>
<div num="p0008" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
a chiral imine, namely (3aS,6aR)-1 ,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole, which is obtained by enzyme technology and is thus difficult to prepare and is instabile and a relatively unstable isonitrile derivative of formula 4.</div>
<div num="p0009" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Summary of the invention The known processes for the preparation of teiaprevir are based on long linear sequences or require the use of labile, highly reactive agents and specific enzymes. The process described herein may for example allow to avoid the use of said labile, highly reactive reactants and specific enzymes. It was surprisingly found within the context of the present invention that teiaprevir may be prepared in a smaller number of process steps in a convergent manner by using stabile precursors (see an example process in Figure 1 ). The present invention may also contribute to preserving the desired stereochemical configuration during the process of preparing teiaprevir. In particular, it has been found that the desired stereochemical configuration may be preserved during the process of peptide bond formation in the compound according to Formula 5 when using the coupling agents described herein, in particular when using 2, 4,6-tripropyl-1 ,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (T3P) or related compounds in dichloromethane. It is also possible to use a combination of a diimide coupling reagent, including but not being limited to dicyclohexylcarbodiimide (DCC), diispropylcarbodiimide (DIC) and 1-ethyl-3-(3- dimethy!aminopropyl)carbodiimide hydrochloride (EDC), with 1-hydroxy-benzotriazole (HOBt) or 1-hydroxy-7-aza-benzotriazole (HOAt) or related reagents for preparing teiaprevir. It has been found that the coupling agents are particularly effective when used in the presence of a lewis acid such as a copper salt. It was also unexpectedly found that the choice of solvent for carrying out the coupling reaction may further enhance the preservation of the stereochemical configuration during peptide bond formation in the compound according to Formula 5.</div>
<div num="p0010" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Furthermore, the expensive compound according to Formula 3</div>
<div num="p0011" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000004_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" file="imgf000004_0001.tif" he="20" height="80" id="imgf000004_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="23" width="92" /></a></div>
<div num="p0012" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
3</div>
<div num="p0013" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
is used at a later stage of the process compared to the process of WO 2007/022459 A2, namely for coupling to the compound according to Formula 2 which already represents a dipeptide. Considering the yields of the single process steps, a smaller amount of the compound according to Formula 3 is required according to the invention, and, thus, the process may be less costly. Compared to the above method of Turner et al., it is not required to use a toxic and instable isonitrile compound. It has also been found that the process for preparing telaprevir may provide an advantage since fewer impurities such as epimeric forms and other byproducts may be formed.</div>
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<br /></div>
<div num="p0122" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1b - (1S,3aR,6aS)-tert-butyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 dimethylbutanovDoctahydrocvclopentafclpyrrole-l- carboxylate (5b)</div>
<div num="p0123" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000021_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000021_0001" class="patent-full-image" file="imgf000021_0001.tif" he="32" height="128" id="imgf000021_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000021_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="160" width="640" /></a></div>
<div num="p0124" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 41 mg of 2 (0.11 mmol, 1 eq.) and 1 ml. of DCM is added. Then, 29 mg of 3b (0.16 mmol, 1.5 eq.) are added. After stirring for 5 min 190μΙ of T3P (50% in EtOAc, 0.32 mmol, 3 eq.) are added and the reaction mixture is stirred for 21 h at room temperature.</div>
<div num="p0125" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction is then diluted with DCM and quenched with water. The aqueous layer is separated and re-extracted with DCM. The combined organic layers are washed with brine, dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (26 mg, 43% yield), (d.r. = 7.5:1 ).</div>
<div num="p0126" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1c - (1S,3aR.6aS)-tert-butyl 2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 dimethylbutanoyl)octahvdrocvclopentarc1pyrrole-1- carboxylate (5b)</div>
<div num="p0127" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000021_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000021_0002" class="patent-full-image" file="imgf000021_0002.tif" he="32" height="128" id="imgf000021_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000021_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="161" width="644" /></a></div>
<div num="p0128" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 1g of 2 (2.66 mmol, 1 eq.) and 20 ml_ of DCM is added. Then, 0.73g of 3b (3.98 mmol, 1.5 eq.) are added. After stirring for 5 min 4.75mL of T3P (50% in EtOAc, 7.98 mmol, 3 eq.) are added and the reaction mixture is stirred for 21 h at room temperature. The reaction is then quenched with water. The aqueous layer is separated and re-extracted with DCM. The combined organic layers are washed with sat. NaHC0<sub>3</sub>-solution, brine and then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (0.70g, 49% yield), (d.r. = 5.6:1 ).</div>
<div num="p0129" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1d - (1S,3aR,6aS)-tert-butyl 2-gS)-2-((S)-2-cvclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3.3 dimethylbutanoyl)octahvdrocvclopentaMpyrrole-1- carboxylate (5b)</div>
<div num="p0130" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000022_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000022_0001" class="patent-full-image" file="imgf000022_0001.tif" he="32" height="128" id="imgf000022_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000022_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="160" width="640" /></a></div>
<div num="p0131" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 1.0g of 2 (2.66 mmol, 1 eq.) and 0.58g of 3b (3.19 mmol, 1.2 eq), then 8 mL of DMF is added and the mixture cooled to 0°C using an ice-bath. In a second flask, 0.36g CuCI<sub>2</sub> (2.66 mmol, 1 eq.) are dispersed in 5mL DMF, cooled to 0°C and the previously prepared solution is added to it. Now, 0.36g HOBt (2.66 mmol, 1 eq.) and 2.0g EDC HCI (10.43 mmol, 4 eq.) are added and the mixture is then stirred at r.t. for 16h.</div>
<div num="p0132" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction is then quenched with 10ml_ 10% NH<sub>3</sub>-solution and then extracted 4 times with a total of 60mL of EtOAc. The combined organic layers are then washed 3 times with dilute hydrochloric acid, once with sat. NaHC0<sub>3</sub>-solution and brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (0.78g, 54% yield), (d.r. = 53 : 1 ).</div>
<div num="p0133" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1e - (1S.3aR.6aS)-tert-butyl 2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 dimethylbutanoyl)octahvdrocvclopentarclpyrrole-1- carboxylate (5b)</div>
<div num="p0134" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000022_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000022_0002" class="patent-full-image" file="imgf000022_0002.tif" he="32" height="128" id="imgf000022_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000022_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="161" width="644" /></a></div>
<div num="p0135" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 1.25g PS-supported HOBt (1.07 mmol/mg) and 0.30g of 3b (1.65 mmol, 1.2 eq) and 0.36g CuCI<sub>2</sub> (2.66 mmol, 1 eq.). Then 15 ml_ of DMF are added and the mixture cooled to 0°C using an ice-bath, while mixing with a mechanical stirrer. In a second flask, 0.5g of 2 (1.3 mmol, 1 eq.) and 1.0g EDC HCI (5.21 mmol, 4 eq.) are dispersed in 12mL DMF, cooled to 0°C and added to the previously prepared solution. The mixture is then stirred at r.t. for 22h.</div>
<div num="p0136" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction is then filtered and the filter washed with 15mL DMF. 50ml_ EtOAc are added to the filtrate, followed by 35ml_ 5% NH<sub>3</sub>-solution. The aqueous layer is then separated and extracted 3 times with a total of 45ml_ of EtOAc. The combined organic layers are then washed once with 10% NH<sub>3</sub>-solution, dilute hydrochloric acid, sat. NaHC0<sub>3</sub>-solution and brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (0.43g, 61 % yield), (d.r. = 18 : 1 ).</div>
<div num="p0137" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1f - (1S.3aR,6aS)-tert-butyl 2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 dimethylbutanovDoctahydrocvclopentafclpyrrole-l- carboxylate (5b)</div>
<div num="p0138" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000023_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000023_0001" class="patent-full-image" file="imgf000023_0001.tif" he="32" height="128" id="imgf000023_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000023_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="160" width="640" /></a></div>
<div num="p0139" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 2.0g of 2 (5.3 mmol, 1 eq.) and 1.17g of 3b (6.4 mmol, 1.2 eq), then 10 mL of DMF is added and the mixture cooled to 0°C using an ice-bath, then 0.72g CuCI<sub>2</sub> (5.3 mmol, 1 eq.) are added. In a second flask 0.72g HOBt (5.3 mmol, 1 eq.) and 1.34g DIC (10.6 mmol, 2 eq.) are dissolved in 5mL DMF, cooled to 0°C and added to the previously prepared solution. The mixture is then stirred at r.t. for 5h.</div>
<div num="p0140" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction is then quenched with 30mL 2% NH<sub>3</sub>-solution and then extracted 3 times with a total of 60ml_ of EtOAc. The combined organic layers are then washed 3 times with a total of 60mL of dilute hydrochloric acid, once with 20ml_ sat. NaHC0<sub>3</sub>-solution and 20ml_ of brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (2.59g, 90% yield), (d.r. = 340 : 1 )</div>
<div num="p0141" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1g - Use of HOAT as anti-isomerisation reagent</div>
<div num="p0142" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
To 4.4ml of a 0.6M HOAT solution in DMF (1.1eq, 2.63mmol) were added 0.6ml DMF.</div>
<div num="p0143" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Afterwards 1g of 2 (90% content, 1eq, 2.39mmol), 567mg of 3b (1.3eq, 3.11 mmol) and 391 mg DIC (1.3eq, 3.11 mmol) were added at room temperature. The reaction was stirred at room temperature for 23h. After 19h 86% conversion to 5b, with a d.r. 3.9/1 was observed. After 23h, with 87% conversion to 5b, and a d.r. 4.1/1 the conversion had stalled and the product was not isolated. Example 1 h - Use of CuCI? with in situ generation of AOC-Et from its HCI salt</div>
<div num="p0144" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
353mg water free CuCI<sub>2</sub> (1.1 eq, 2.63mmol) was dissolved in 5ml DMF. To the solution 1 g 2 (90% content, 1 eq, 2.39mmol), 683mg 3b. HCI (1 .3eq, 3.1 1 mmol), 315mg NMM (1.3eq,</div>
<div num="p0145" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
3.1 1 mmol) and 391 mg DIC (1.3eq, 3.1 1 mmol) were added at room temperature. The reaction mixture was stirred at room temperature. After two hours 2.6area% 2 was detected and yield was 96.5% (calculated via internal standard). After 5h less than 0.5area% 2 was detected and yield was 98.1 %. d.r. at both IPCs was 108/1.</div>
<div num="p0146" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1 i - HOAT without CuCI? in DMF</div>
<div num="p0147" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
To a solution of 0.5g 2 (90%, 1 eq, 1 .19mmol) and 179mg HOAT (1.1eq, 1.32mmol) in 2.5ml DMF 284mg 3b (1.3eq, 1 .55mmol) was added. Afterwards</div>
<div num="p0148" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
241 μΙ DIC (1 .3eq, 1.55mmol) was added. Reaction was stirred at room temperature. After2.5h 91 % conversion and DR of 4.3/1 was observed. After 5h complete conversion</div>
<div num="p0149" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Was observed and DR of 4.1/1. No work was performed.</div>
<div num="p0150" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1j - HOAT without CuCI, in THF/MED</div>
<div num="p0151" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
To a suspension of 0.5g 2 (90, 1 eq. 1.19mmol) and 179mg HOAT (1 .1 eq, 1 ,32mmol) in 2.5ml of a 1/1 mixture of THF/MED (methylene chloride) 284mg 3b (1.3eq, 1.55mmol) was added. Afterwards, 241 μΙ DIC (1.3eq, 1 .55mmol) was added. Reaction was stirred at room</div>
<div num="p0152" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
temperature. After2.5h 7.5% conversion and DR of 6.7/1 was observed. After 5h 80 conversion was observed and DR of 6.2/1 . After 19h 86% conversion and DR of 6.0/1 was found. No work was performed. Example 1 k - HOAT with CuCI? in DMF</div>
<div num="p0153" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
177mg CuCI<sub>2</sub> (1 .1 eq, 1 .31 mmol) was dissolved in 2.5ml DMF. To the solution 0.5g 2 (90%, 1 eq, 1.19mmol), 179mg HOAT (1.1 eq, 1 .32mmol), 284mg 3b (1.3eq, 1.55mmol) and 241 μΙ DIC (1.3eq, 1.55mmol) was added. The reaction was stirred at room temperature for 13h. 95% conversion and DR of 48/1 was observed. No work up was performed.</div>
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Example 11 - Substochiometric amounts of CuCI? in DMF without HOAT</div>
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177mg CuCI<sub>2</sub> (0.55eq, 1.31 mmol) was dissolved in 5ml DMF. To the solution 1.0g 2 (90%, 1 eq, 2.39mmol), 683mg 3b.HCI (1.3eq, 3.11 mmol), 340μΙ NMM (1.3eq, 3.11 mmol) and 481 μΙ DIC (1.3eq, 3.11 mmol) was added. The reaction was stirred at room temperature for 4.5h, complete conversion and DR of 76/1 was observed. No separated work up was performed. Example 2a - Synthesis of the compound according to Formula 7</div>
<div num="p0156" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1S.3aR.6aS)-2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)octahvdrocvclopentarclpyrrole-1 -carboxylic acid (7)</div>
<div num="p0157" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000025_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000025_0001" class="patent-full-image" file="imgf000025_0001.tif" he="31" height="124" id="imgf000025_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000025_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="143" width="572" /></a></div>
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A round-bottom flask was charged with 6g of 5b (11.08 mmol, 1 eq.) and 85mL of THF and 26mL of H<sub>2</sub>0 was added. Then 2.20g LiOH H<sub>2</sub>0 (52.43 mmol, 4.7 eq.) were added and the mixture was stirred at r.t. for 18h.</div>
<div num="p0159" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Then 50ml_ EtOAc and 50mL H<sub>2</sub>0 were added, and the aqueous layer separated. The organic layer was washed once more with 40ml_ H<sub>2</sub>0. To the combined aqueous layers 50ml_ of EtOAc were added, and by slow addition of 2M HCI the pH was adjusted to 1.89. After separation of the aqueous layer, it was extracted once more with 50ml_ EtOAc, and the combined organic layers washed with brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo.</div>
<div num="p0160" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Purification by flash chromatography yielded 7 (4.83g, 85% yield).</div>
<div num="p0161" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 2b - Synthesis of the compound according to Formula 7</div>
<div num="p0162" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)octahvdrocvclopenta[c1pyrrole-1 -carboxylic acid (7)</div>
<div num="p0163" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000026_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000026_0001" class="patent-full-image" file="imgf000026_0001.tif" he="28" height="112" id="imgf000026_0001" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000026_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="157" width="628" /></a></div>
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A round bottom flask is charged with 2.0g of 2 (5.3 mmol, 1 eq.) and 1.17g of 3b (6.4 mmol, 1.2 eq), then 10 mL of DMF is added and the mixture cooled to 0°C using an ice-bath, then 0.72g CuCI<sub>2</sub> (5.3 mmol, 1 eq.) are added. In a second flask 0.72g HOBt (5.3 mmol, 1 eq.) and 1 .34g DIC (10.6 mmol, 2 eq.) are dissolved in 3ml_ DMF, cooled to 0°C and added to the previously prepared solution. The mixture is then stirred at r.t. for 5h.</div>
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The reaction is then quenched with 30mL 2% NH<sub>3</sub>-solution and then extracted 3 times with a total of 70ml_ of EtOAc. The combined organic layers are then washed with 15mL 2% NH<sub>3</sub>- solution, 1 time with 20ml_ 1 M HCI, 3 times with a total of 60ml_ of dilute hydrochloric acid, once with 20ml_ sat. NaHC0<sub>3</sub>-solution and 20ml_ of brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. The residue (compound 5b - 2.59g, 4.78 mmol, 1 eq.) was dissolved in 27ml_ of a 1 :1 mixture THF/H<sub>2</sub>0. Then 0.48g NaOH (1 1.95 mmol, 2.5 eq.) were added and the mixture was stirred at r.t. for 18h.</div>
<div num="p0166" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Then 20ml_ EtOAc and 10ml_ H<sub>2</sub>0 were added, and the aqueous layer separated. The organic layer was washed once more with 20ml_ H<sub>2</sub>0. To the combined aqueous layers 20ml_ of EtOAc were added, and by slow addition of 2M HCI the pH was adjusted to 1.27. After separation of the aqueous layer, it was extracted once more with 20ml_ EtOAc, and the combined organic layers washed with brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo to give 7 (2.82g, 93% yield). Trace metal analysis using ICP-OES showed residual copper < 1 ppm, wherein the following method was used:</div>
<div num="p0167" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Digestion: about 250mg of sample material was digested under pressure with a mixture of HNO<sub>3</sub>+HCI in a closed quartz container which can be heated by microwave radiation.</div>
<div num="p0168" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Determination of Cu:</div>
<div num="p0169" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Measurement was performed with ICP-OES at 324,754nm, Axialplasm, simultaneous background correction; calibration with external standards, certified elemental standard of Merck, Device: Fabr. Thermo Electron, Type: IRIS Intrepid XSP II, Duo. Example 2c - Synthesis of the compound according to Formula 7</div>
<div num="p0170" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1 S,3aR,6aSV2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3.3- dimethylbutanoyl)octahvdrocyclopenta[clpyrrole-1 -carboxylic acid (7)</div>
<div num="p0171" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000027_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000027_0001" class="patent-full-image" file="imgf000027_0001.tif" he="27" height="108" id="imgf000027_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000027_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="156" width="624" /></a></div>
<div num="p0172" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
7.07g water free CuCI<sub>2</sub> (1.1eq, 52.6mmol) was dissolved in 100ml DMF. To the solution 20g of 2 (90% content, 1eq, 47.82mmol), 10.51g of 3b (d.r. = 9:1) (1.2eq, 57.38mmol), 6.3ml NMM (1.2eq, 57.38mmol) and 9.6ml DIC (1.3eq, 62.16mmol) were added at 0°C. the reaction mixture was warmed to 40°C in 1.5h and stirred at that temperature until complete conversion was observed. To the reaction mixture isopropyl acetate was added followed by the addition of 10% HCI. The organic phase was separated and washed with 5% ammonia and 2% NaCI. The organic solvent was removed to dryness and 26.95g was isolated as a diasteromeric mixture of 9:1 detected via NMR.</div>
<div num="p0173" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
6g of this material was dissolved in 15ml ethanol and 15ml water. To the mixture 1.15g sodium hydroxide was added. The reaction mixture was stirred at room temperature until no further conversion was observed. Ethanol was removed via distillation and water was added. The basic aqueous phase was washed with isopropyl acetate, the organic phase was re-extracted with water. To the combined aqueous phase Isopropyl acetate was added an pH was adjusted to 1.5 via addition of 10% HCI. The organic phase was separated and solvent was removed to dryness to yield 5.29g of compound 7 as a single diastereomer according to NMR analysis.</div>
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Example 2d - Use of CuCI? as anti isomerisation reagent (without any triazol reagent) 353mg water free CuCI<sub>2</sub> (1.1eq, 2.63mmol) was dissolved in 5ml DMF. To the solution 1g 2 (90% content, 1eq, 2.39mmol), 567mg 3b (1.3eq, 3.11 mmol) and 391 mg DIC (1.3eq,</div>
<div num="p0175" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
3.1 1 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 19h full conversion to 5b with d.r. 116/1 was observed. To the reaction mixture 50ml of ethyl acetate was added and the occurring precipitation was removed via filtration. The organic phase was washed with 5% ammonia and the aqueous phase was reextracted with 50ml ethyl acetate. The combined organic phase was washed with 40ml 2M HCI and 40ml brine. After drying with sodium sulfate and filtration the organic solvent was removed via evaporation. The solid residue was dissolved in 20ml methylene chloride and again the solvent was removed to dryness. After drying (rt, 40mbar), 1.373g of a slightly yellow amorphous solid (NMR content 81.6%, yield 86.4%).</div>
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Example 3 - Synthesis of the compound according to Formula 6</div>
<div num="p0177" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1S,3aR,6aSV2-((S)-2- SV2-cvclohexyl-2-(pyrazine-2-carboxamido)acetamidoV3,3- dimethylbutanoyl)-N-((S)-1-(cvclopropylamino)-2-hvdroxy-1-oxohexan-3- yl)octahvdrocvclopentarclpyrrole-1-carboxamide (6)</div>
<div num="p0178" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000028_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000028_0001" class="patent-full-image" file="imgf000028_0001.tif" he="30" height="120" id="imgf000028_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000028_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="168" width="672" /></a></div>
<div num="p0179" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round-bottom flask was charged with 11.87g of 7 (23.11 mmol, 1 eq.), 5.32g of EDC<sup>*</sup>HCI (27.73mmol, 1.2 eq.), 3,74g of HOBt (27.73 mmol, 1.2 eq.) and 80 mL DCM were added. The mixture was cooled with an ice-bath and a suspension of 5.66g of 4 (25.42mmol, 1.1 eq.) in 50 mL of DCM containing 2.75g NEt<sub>3</sub> (27.73 mmol, 3.88mL, 1.2 eq.) was added. This mixture was then stirred at r.t. for 6h when conversion was complete.</div>
<div num="p0180" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction was quenched by addition of 50ml_ H<sub>2</sub>0, followed by dropwise addition of 6M HCI to adjust the pH to 1.45. The aqueous layer was separated and extracted once with 50ml_ DCM. The combined organic layers were washed with 50ml_ sat. NaHC0<sub>3</sub> solution and 50mL brine, dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash</div>
<div num="p0181" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
chromatography yielded 6 (14.89g, 94% yield).</div>
<div num="p0182" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 4 - Synthesis of the compound according to Formula 1</div>
<div num="p0183" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1S,3aR,6aS)-2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3.3- dimethylbutanoyl)-N-((S)-1-(cvclopropylamino)-1 ,2-dioxohexan-3- yl)octahvdrocvclopentaFclpyrrole-1-carboxamide (Telaprevir) (1)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000029_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000029_0001" class="patent-full-image" file="imgf000029_0001.tif" he="30" height="120" id="imgf000029_0001" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000029_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="167" width="668" /></a></div>
<div num="p0184" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round-bottom flask was charged with 2.00g of 6 (2.93 mmol, 1 eq.) and 20mL of DCM and then cooled with an ice-bath. 200μΙ of 15% KBr-solution and 800μΙ of sat. NaHC0<sub>3</sub>-solution were added, followed by 1 1 mg of TEMPO (0.07mmol, 0.025 eq.) and 600μΙ 10% NaOCI- solution. After stirring at r.t. for 18h, another 1.2ml_ of 10% NaOCI-solution were added - after another 2h the reaction was complete.</div>
<div num="p0185" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction mixture was then diluted with 10mL of H<sub>2</sub>0. After separation of the aqueous layer it was extracted with 10ml_ of DCM. The combined organic layers were washed with 10ml_ of 1 % Na<sub>2</sub>S0<sub>3</sub> and 10ml_ of H<sub>2</sub>0, dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo.</div>
<div num="p0186" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The residue was then stirred in 40ml_ Et<sub>2</sub>0, filtered, washed with 10ml_ of cold Et<sub>2</sub>0 and then dried in vacuo to give crystalline 1 (1 .41g, 71 %).</div>
<div num="p0187" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Cited literature</div>
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WO 2007/022459 A2; Turner et al. (Chemical Communications 2010, 46(42), 7918); WO2010/126881 ; Y. Yip et al. Bioorg. Med. Chem. Lett., 2004, 14, 5007; Harbeson, S. L. et al. J. Med. Chem. 1994, 37, 2918-2929.</div>
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<br /></div>
<table class="patent-data-table" style="background-color: white; border-bottom-color: rgb(209, 209, 209); border-bottom-width: 2px; border-collapse: collapse; border-style: none none solid; color: #333333; font-family: Arial, sans-serif; font-size: 13.2799997329712px; line-height: 18px; margin: 10px 0px 0px 18px;"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.im/patents/WO2007022459A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2007022459A2</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 Aug 2006</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">22 Feb 2007</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Vertex Pharma</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Processes and intermediates</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.im/patents/WO2010126881A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2010126881A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">27 Apr 2010</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">4 Nov 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Vertex Pharmaceuticals Incorporated</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Processes and intermediates</td></tr>
</tbody></table>
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PATENT</div>
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<span style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><a href="http://www.google.im/patents/WO2010126881A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2010126881A1?cl=en</a></span><br /><br /><br /><br /><br /><br /><div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000050_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000050_0001" class="patent-full-image" file="imgf000050_0001.tif" he="23" height="92" id="imgf000050_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000050_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="129" width="516" /></a></div>
<div num="p0391" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
5 6 7 8 (rac)</div>
<div num="p0392" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000050_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000050_0002" class="patent-full-image" file="imgf000050_0002.tif" he="16" height="64" id="imgf000050_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000050_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="132" width="528" /></a></div>
<div num="p0393" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
9 10 1</div>
<div num="p0394" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Scheme I</div>
<br /><br /><div num="p0400" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Scheme II</div>
<div num="p0401" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000052_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000052_0001" class="patent-full-image" file="imgf000052_0001.tif" he="124" height="496" id="imgf000052_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000052_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="137" width="548" /></a></div>
<br /><br /><br /><br /><div num="p0418" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
a cyclopropylamide of Formula 18 is prepared using the Passeπni reaction (see, e.g., A. Doemling et al., Angew. Chem., 2000, 1 12, 3300-3344). Scheme IV</div>
<div num="p0419" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000054_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000054_0001" class="patent-full-image" file="imgf000054_0001.tif" he="60" height="240" id="imgf000054_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000054_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="113" width="452" /></a></div>
<br /><br /><div num="p0424" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Scheme V</div>
<div num="p0425" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000056_0001" class="patent-full-image" file="imgf000056_0001.tif" he="82" height="328" id="imgf000056_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="151" width="604" /></a></div>
<div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000056_0002" class="patent-full-image" file="imgf000056_0002.tif" he="24" height="96" id="imgf000056_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="87" width="348" /></a></div>
<div num="p0426" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
34</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0003.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000056_0003" class="patent-full-image" file="imgf000056_0003.tif" he="63" height="252" id="imgf000056_0003" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="99" width="396" /></a></div>
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<div num="p0109" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The invention further relates to a process for piepaπng a compound of Formula 4</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000014_0001" class="patent-full-image" file="imgf000014_0001.tif" he="33" height="132" id="imgf000014_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="100" width="400" /></a></div>
<div num="p0110" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[0060] In some embodiments, the process for preparing compounds of Formula 4 includes the steps of i) providing an N-alkoxycarbonyl-S-azabicycloP 3 0]octane, ii) forming a 2-anion of the N-alkoxycarbonyl-3-azabicyclo[3 3 0]octane in the presence of a chelating agent, iii) treating the anion of step ii) with carbon dioxide to produce a cis /trans mixture of N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole- l-carboxyhc acids, iv) treating the mixture of step iii) with a strong base to produce an essentially pure trans- N-alkoxycarbonyl-octahydrocyclopenta[c]ρyrrole-l -carboxyhc acid, v) forming a salt of the carboxylic acid with an optically active amine, vi) crystallizing the salt, vii) esteπfying the salt provided in step vi), viii) removing the N-alkoxycarbonyl gioup to produce (lS,3aR,6aS)-f-butyl- octahydiocyclopenta[c)pyiτole-l -carboxylate, /-butyl ester, ix) reacting the bicyclic of step viii) with a protected amino acid of Formula 26,</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000014_0002" class="patent-full-image" file="imgf000014_0002.tif" he="16" height="64" id="imgf000014_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="24" width="96" /></a></div>
<div num="p0111" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
26 wherein Z is an amine protecting group, in the piesence of a coupling reagent, to pioduce an amide-ester of Formula 27,</div>
<div num="p0112" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0003.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000014_0003" class="patent-full-image" file="imgf000014_0003.tif" he="30" height="120" id="imgf000014_0003" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="47" width="188" /></a></div>
<div num="p0113" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
27 x) removing the protecting group Z from the amide-ester of step ix) to produce the amino compound of Formula 28,</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0001" class="patent-full-image" file="imgf000015_0001.tif" he="21" height="84" id="imgf000015_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="36" width="144" /></a></div>
<div num="p0114" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
28 xi) reacting the amino compound of Formula 28 with a protected amino acid of Formula 29</div>
<div num="p0115" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Z-HN^<sub>/</sub>CO<sub>2</sub>H</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0002" class="patent-full-image" file="imgf000015_0002.tif" he="14" height="56" id="imgf000015_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="10" width="40" /></a></div>
<div num="p0116" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
29 in the presence of a coupling reagent to produce a tripeptide of Formula 30;</div>
<div num="p0117" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0003.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0003" class="patent-full-image" file="imgf000015_0003.tif" he="28" height="112" id="imgf000015_0003" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="53" width="212" /></a></div>
<div num="p0118" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
30 xii) removing the protecting group Z in the tripeptide of Formula 30 to produce a free amino-tripeptide of Formula 31;</div>
<div num="p0119" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0004.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0004" class="patent-full-image" file="imgf000015_0004.tif" he="28" height="112" id="imgf000015_0004" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0004.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="51" width="204" /></a></div>
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31 xiii) reacting the amino-tripeptide of Formula 31 with pyrazine-2-carboxylic acid in the presence of a coupling reagent to produce an amide-tripeptide ester of Formula 33;</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0005.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0005" class="patent-full-image" file="imgf000015_0005.tif" he="29" height="116" id="imgf000015_0005" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0005.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="60" width="240" /></a></div>
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33 xiv) hydrolyzing the ester of the amide-tripeptide ester of Formula 33 to produce an amide-tripeptide acid of Formula 34;</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000016_0001" class="patent-full-image" file="imgf000016_0001.tif" he="28" height="112" id="imgf000016_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="64" width="256" /></a></div>
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34</div>
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XV) reacting the amide-tπpeptide acid of Formula 34 with an aminohydroxy-amide of Formula 18</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000016_0002" class="patent-full-image" file="imgf000016_0002.tif" he="17" height="68" id="imgf000016_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="27" width="108" /></a></div>
<span style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">18 in the piesence of a coupling reagent to produce a hydroxy-tetrapeptide of Formula 35, and</span><br /><div num="p0125" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0003.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000016_0003" class="patent-full-image" file="imgf000016_0003.tif" he="33" height="132" id="imgf000016_0003" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="105" width="420" /></a></div>
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35 xvi) oxidizing the hydroxy gioup of Formula 35 to produce the compound of Formula 4</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0004.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000016_0004" class="patent-full-image" file="imgf000016_0004.tif" he="33" height="132" id="imgf000016_0004" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0004.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="99" width="396" /></a></div>
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Example 13: (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-l-(cyclopropylamino)-l,2- dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-l -carboxamide (4)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000085_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000085_0001" class="patent-full-image" file="imgf000085_0001.tif" he="24" height="96" id="imgf000085_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000085_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="152" width="608" /></a></div>
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35 <sub>4</sub></div>
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Method 1</div>
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[00256] A 500 inL 3-neck round bottomed flask equipped with an overhead stirrer, condenser, thermocouple, and nitrogen outlet was purged with nitrogen for several minutes A methylene chloride solution of the hydroxyamide peptide amide 35 (128 64 g, 16-17wt%, 20 6 g and 30 mmol of 35) in methylene chloride was added to the reaction flask, followed by the addition of 15% w/w aq NaBr (13 mL) and 7 5% w/w aq NaHCO<sub>3</sub> (52 mL) The solution was cooled to 5±3 <sup>0</sup>C in an ice bath TEMPO (0 7 g) dissolved in methylene chloride (3 mL) was added to the reaction mixture In a separate Erlenmeyer flask, 10- 13% NaOCI solution (23 25 mL, titer = 108 mg/mL, 2 51 g, 33 7 mmol, 1 12 molar eq ) was diluted with water (70 mL) The NaOCI solution was charged to the reaction mixture via addition funnel at a rate that maintained the temperature below 8 <sup>0</sup>C The reaction mixture was allowed to stir at 5±3 <sup>0</sup>C for lhour The layers were separated and the organic layer was quenched with 10% (w/w) aq Na<sub>2</sub>SOs (100 mL) and washed with water (100 mL) The organic phase was reduced to dryness at reduced pressure and the solid triturated with ethyl acetate (100 mL) and filtered on a Buchner funnel to give the title compound Method 2</div>
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[00257] TEMPO (1 09 g, 6 95 mmol) was added to the methylene chloπde solution of 35 from Example 12, Method 2, followed by a solution of sodium bicarbonate (21 89 g, 260 5 mmol) in water (400 mL) and the mixture cooled to 0-5 <sup>0</sup>C A solution of sodium hypochlorite (122 17 g, 11 64 wt%, 191 04 mmol) was added over 2 hours while maintaining a temperature of 0-5 <sup>0</sup>C The mixture was stirred for 1 hour at 0-5 <sup>0</sup>C, then the phases separated The organic phase was washed with water (500 mL), 1 wt% aqueous sodium bisulfite (500 mL) and water (500 mL), then polish filtered The mixture was distilled at 38- 42 <sup>0</sup>C, 710 mm Hg, to a volume of about 320 mL Ethyl acetate (44 mL) was added followed immediately by 1 5 g of seed ciystals of 4 and the mixture was stirred for 15 minutes at 38-42 <sup>0</sup>C Ethyl acetate (800 mL) was added over 3 hours while maintaining a temperature of 38-42 <sup>0</sup>C The mixture was then distilled at 38-42 <sup>0</sup>C, 200-250 mm Hg, to a volume of about 400 mL Additional ethyl acetate (200 mL) was added over 0 5 hour The resultant slurry was cooled over 1 hour to 20-25 <sup>0</sup>C and stirred an additional hour at the same temperature The mixture was filtered and the filter cake washed with ethyl acetate (twice, 300 mL each) and dned under vacuum with a nitrogen bleed at 45-55 <sup>0</sup>C to give the title compound 4 as a white solid. Method 3</div>
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[00258] TEMPO (0 06 eq) was added to the CH<sub>2</sub>CI<sub>2</sub> solution of 35 from Example 12, method 3, and the solution was stirred at 20-25 <sup>0</sup>C until all TEMPO dissolved To this solution was added a solution of NaHCOi (1 5 eq ) in water (4 vol ) The resulting biphasic mixture was cooled to 0-5 <sup>0</sup>C While maintaining the reaction temperature at 0-5 <sup>0</sup>C, a 10-13 wt% NaOCl solution (1 10 eq ) was added over 2-3 hours and the mixture stirred for additional one hour The layers were separated and the organic layer was washed at 0-5 <sup>0</sup>C with H<sub>2</sub>O (5 vol ), 1 wt% Na<sub>2</sub>SO<sub>3</sub> (5 vol ), and H<sub>2</sub>O (5 vol ) Glacial acetic acid (0 12 eq ) was added to the solution of compound 4 in CH<sub>2</sub>Cl<sub>2</sub> to stabilize compound 4</div>
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Example 14: Recrystallization of Compound of Formula 4.</div>
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[00259] The solution of Compound 4 from Example 13, Method 3, was filtered through Cehte, and the filtrate solution was reduced to 3 1 -3 3 volumes by vacuum distillation at lower than 20 <sup>0</sup>C After distillation, the solution was brought to 38-42<sup>0</sup>C before EtOAc (0 80 vol ) was added, followed by the addition of Compound 4 seed (1 5 wt% relative to 34, Example 12) The resulting mixture was stirred for 15 minutes at 38-42 <sup>0</sup>C EtOAc (8 vol ) was added over 3 hours to this mixture while maintaining a temperature of 38-42 <sup>0</sup>C The total volume of the slurry was then reduced to 3 9-4 1 volumes by vacuum distillation at 38- 42 <sup>0</sup>C To this mixture was added EtOAc (2 vol ) over 30 minutes while maintaining the batch temperature at 38-42 <sup>0</sup>C The resulting slurry was then cooled to 20-25 <sup>0</sup>C over 1 hour and stirred at 20-25 <sup>0</sup>C for additional 1 hour. The slurry was filtered. The filter cake was washed with EtOAc (twice, 3 vol. each) and dried under vacuum with a nitrogen bleed at 45- 55 <sup>0</sup>C for 6 hours.</div>
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[00260] To the dried filter cake was added 2.2-2.4 volumes of CH<sub>2</sub>Ch to a total volume of 3.1-3.3 volumes. The mixture was broughl to 38-42 <sup>0</sup>C to give a homogeneous solution. EtOAc (0.80 vol) was added, followed by the addition of Compound 4 seed ( 1.5 wt% relative to 34, Example 12). The resulting mixture was stirred for 15 minutes at 38-42 <sup>0</sup>C. EtOAc (8 vol.) was added over 3 hours to this mixture while maintaining a temperature of 38-42 <sup>0</sup>C. The total volume of the slurry was then reduced to 3.9-4.1 volumes by vacuum distillation at 38-42<sup>0</sup>C. EtOAc (2 vol.) was added over 30 minutes to this mixture while maintaining the batch temperature at 38-42°C. The resulting slurry was then cooled to 20-25 <sup>0</sup>C over 1 hour and stirred at 20-25 <sup>0</sup>C for additional one hour. The slurry was filtered and the filter cake was washed with EtOAc (twice, 3 vol. each) and dried under vacuum with a nitrogen bleed at 45-55 <sup>0</sup>C for 12 hour to give purified Compound 4. <sup>1</sup>H NMR (500 MHz, CDCI3) 0.78 (m, 2H), 0.87 (m, 2H), 0.91 (s, 9H), 0.91 (t Lobscured], 3H), 0.98 (m, 4H), 1.08 (m, IH), 1.20 (m, 4H), 1.29 (m, IH), 1.40 (m, IH), 1..42 (m, 2H), 1.46 (m, IH), 1.48 (m, IH), 1.60 (m, IH), 1.70 (m, IH), 1.79 (m, IH), 1.83 (m, 2H), 1.88 (m, IH), 1.94 (m, IH), 2.67 (m, IH), 2.89 (bs, IH), 2.96 (bs, IH), 3.63 (d, IH), 3.99 (d, IH), 4.70 (s, IH), 4.82 (d, IH), 4.89 (t, IH), 5.65 (bs, IH), 7.74 (bs, IH), 8.00 (bs, I H), 8.06 (bs, IH), 8.29 (bs, IH), 8.60 (s, IH), 8.77 (s, I H), 9.42 (s, IH).</div>
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Example 15: (lS,3a#,6aS)-2-((,S>2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-Λ'-((S)-l-(cyclopropylamino)-l,2-dioxo- hexan-3-yl)octahydrocyclopenta[c]pyrrole-l-carboxamide (4)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000087_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000087_0001" class="patent-full-image" file="imgf000087_0001.tif" he="36" height="144" id="imgf000087_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000087_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="81" width="324" /></a></div>
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PATENT</div>
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<span style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><a href="http://www.google.im/patents/WO2007022459A2?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2007022459A2?cl=en</a></span><br /><br /><br /><br /><br /><div num="p0286" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1: N-/-butyloxycarbonyI-3-azabicycIo[3.3.0]octane (6)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000050_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000050_0001" class="patent-full-image" file="imgf000050_0001.tif" he="27" height="108" id="imgf000050_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000050_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="55" width="220" /></a></div>
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6</div>
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Method 1</div>
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[00177] To a 2 L 3-necked round-bottom flask under nitrogen fitted with a mechanical stirrer, a 500 niL addition funnel, and a thermometer was charged 3-azabicyclo[3.3.0]nonane hydrochloride (100 g, 0.677 mol), potassium carbonate (187 g, 1.35 mol), /-butyl methyl ether (220 mL) and water (160 mL), with stirring. The mixture was cooled to 14-16 °C. In a separate 500 mL erylenmeyer flask was charged Boc<sub>2</sub>O (di-t-butyl dicarbonate) (145 g, 0.644 mol) and t-butyl methyl ether (190 mL). The mixture was stirred until complete dissolution was obtained. The solution was poured into the addition funnel and added to the above reaction mixture, keeping the reaction temperature below 25 °C. Water (290 mL) was added to dissolve solids, and the mixture was stirred for 10-15 minutes. After separating the lower aqueous phase, the organic phase was washed with 5% aq. NaHSO<sub>4</sub> (twice, 145 mL each), then water (145 mL). The organic phase was concentrated and methyl t-butyl ether was added (1.3 L) to give a solution of the title compound in t-butyl methyl ether. See, e.g., R.Griot, HeIv. CMm. Acta., 42, 67 (1959).</div>
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Method 2</div>
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[00178] A solution of potassium carbonate (187 g, 1.35 mol) in water (160 mL) was added to a mixture of 3-azabicyclo[3.3.0]octane hydrochloride (100 g, 0.677 mol) and t-butyl methyl ether (220 mL), and the resultant mixture was cooled to 14-16 °C. A solution of Boc<sub>2</sub>O (145 g, 0.644 mol) in t-butyl methyl ether (190 mL) was added while maintaining a temperature below 35 <sup>0</sup>C. After the addition, the mixture was stirred for 1 hour then filtered. The solids were washed with MTBE (50 mL). The phases were separated and the organic phase washed with 5% aq. NaHSO<sub>4</sub> (twice, 145 mL each) and water (145 mL) and concentrated to 300 mL under vacuum. MTBE (300 mL) was added and the mixture concentrated to remove water to less than 550 ppm. The concentrate was diluted with MTBE (400 mL) to provide a solution of the title compound in MTBE.</div>
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Example 2: mc-2-(/-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (7)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000051_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000051_0001" class="patent-full-image" file="imgf000051_0001.tif" he="30" height="120" id="imgf000051_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000051_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="66" width="264" /></a></div>
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6 7</div>
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Method 1</div>
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[00179] The solution from Example 1, Method 1, was charged to a 5 L 4-necked flask fitted with a mechanical stirrer, an addition funnel, a ReactIR probe, and a thermometer. 3,7- Dipropyl-3,7-diazabicyclo[3.3.1]nonane (183 g, 0.88 mol) was charged to the flask. Data collection was started on the ReactIR instrument, and the solution was cooled to -72 to -75 <sup>0</sup>C. sec-Butyllithium (600 mL, 1.6 M in cyclohexane) was slowly added to the reaction mixture, keeping the reaction temperature below -69 <sup>0</sup>C. The addition was monitored with the ReactIR instrument, and the addition was stopped after the absorbance at 1698 cm<sup>"1</sup> had disappeared and the absorbance at 1654 cm<sup>"1</sup> ceased to increase for three consectutive scans (2-minute intervals). The solution was agitated for 3 hours at -75 to -72 °C. A 10% mixture of CO<sub>2</sub> in nitrogen was carefully sparged into the reaction mixture, keeping the reaction temperature below -70 °C. The sparge was stopped after the absorbance for CO<sub>2</sub> appeared in the ReactIR spectrum (2350 cm<sup>"1</sup>). The mixture was warmed to 0-5 <sup>0</sup>C, and a solution of 30 wt% NaHSO<sub>4</sub>(1.4 L) was added. The mixture was warmed to 22-25 °C and stirred for 30 minutes. The aqueous phase was separated and the organic phase washed with water (700 mL). The aqueous phase was decanted and the organic phase concentrated to provide the title compound.</div>
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Method 2</div>
<div num="p0297" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00180] A solution of 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane (183 g, 0.87 mol) in</div>
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MTBE (300 mL) was added to the solution of N-t-butyloxycarbonyl-3- azabicyclo [3.3.0] octane from Example 1, Method 2 in a flask fitted with a mechanical stirrer, an addition funnel, a ReactIR probe, and a thermometer and the mixture was cooled to -75 to</div>
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-72 <sup>0</sup>C. A solution of sec-butyllithium (510 mL, 1.6 M) was added, keeping the reaction temperature below -70 °C, until the absorbance at 1698 cm<sup>"1</sup> had disappeared and the absorbance at 1654 cm<sup>"1</sup> ceased to increase. The solution was stirred for 3 hours at -75 to -72</div>
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°C. The reaction mixture was sparged with 10% CO<sub>2</sub> in N<sub>2</sub> keeping the reaction temperature e ow - /υ "U. lne sparge was stoppe w en t e a sor ance or <sub>2</sub> appears in the eact spectrum (2339 cm<sup>"1</sup>). The mixture was warmed to 0-5 °C and a solution of 30 wt% NaHSO<sub>4</sub> (1.4 L) was added and the mixture was warmed to 22-25 °C then stirred 30 minutes. The phases were separated and the aqueous phase was checked to make sure the pH was lower than 3. The organic phase was washed with water (700 mL) then concentrated to 300 mJL Ethyl acetate (1.7 L) was added and the mixture concentrated to 300 mL twice to give a solution of the title compound in ethyl acetate.</div>
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Example 3: (S)-l,2,3,4-tetrahydronaphthalen-l-aminium (lS,3aR,6aS)-2-(f- butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (9a)</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000052_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000052_0001" class="patent-full-image" file="imgf000052_0001.tif" he="28" height="112" id="imgf000052_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000052_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="104" width="416" /></a></div>
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8 9a</div>
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Method 1</div>
<div num="p0305" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00181] Ethyl acetate (2.3 L) was added to the residue of Example 2, method 1, and the mixture filtered through a pad of Celite<sup>®</sup>. (S)-1 ,2,3,4-tetrahydro-l-naphthylamine (56.7 g, 0.385 mol) was added and the solution was stirred for 3-4 hours at 22-25 <sup>0</sup>C. The mixture was filtered and the solids were rinsed with ethyl acetate (200 mL). The solids were dried at 20-30 <sup>0</sup>C under vacuum for 4 hours to give 99.02 g of product (73% yield, 90% ee by chiral HPLC).</div>
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[00182] To a 3-necked RBF fitted with a temperature contoller, a mechanical stirrer, a reflux condenser, and a nitrogen bubbler, was charged the (S)-l,2,3,4-tetrahydro-l- naphthylammonium salt (88.98g, 0.22 mol), ethyl acetate (712 mL), and 2-propanol (666 mL). The mixture was warmed to 70-75 <sup>0</sup>C with stirring. The mixture was stirred for 15-30 minutes, then cooled to -5 to -10 °C over 1 hour. The resultant slurry was filtered and the solids were rinsed with cold ethyl acetate (180 mL). The solids were dried in vacuo at 35-40 °C to give 7.37 g of a white solid (83% yield, 98% ee).</div>
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Method 2</div>
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[00183] The ethyl acetate solution of racemic N-t-butyloxycarbonyl-3- azabicyclo[3.3.0]octane-2-carboxylic acid from Example 2, Method 2, was added to a solution of (S)-l,2,3,4-tetrahydro-l-naphthylamine (56.7 g, 0.385 mol) in ethyl acetate (300 mL). The mixture was strirred for 3-4 hours at 22-25 °C, then filtered, and the solids washed with ethyl acetate (200 mL). The product was dried at 20-30 °C under vacuum for 4 hours to give the title compound (99.02 g, 36% yield) with a 95 to 5 diasteromer ratio. [00184] A mixture of the salt as prepared above (89.0 g), ethyl acetate, and 2-propanol was warmed to 70-75 <sup>0</sup>C until complete dissolution. The mixture was cooled to -5 to -10 <sup>0</sup>C over two hours and stirred for 3-4 hours. The mixture was filtered and the product dried at 35-40 <sup>0</sup>C to give the title compound (73.7g, 83% yield, >99.5% ee).</div>
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Example 4: (R)-l-phenylethanaminium (lS,3aR,6aS)-2-(f- butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (9b)</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000053_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000053_0001" class="patent-full-image" file="imgf000053_0001.tif" he="28" height="112" id="imgf000053_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000053_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="106" width="424" /></a></div>
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8 9b</div>
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[00185] To a soution of racemic N-t-butyloxycarbonyl-3-azabicyclo[3.3.0]octane-2- carboxylic acid (4.66 g) in ethyl acetate (100 mL) was added (R)-α-methylbenzylamine (56.7 g) and the solution was stirred for 16 hr at 22-25 °C. The mixture was filtered and the solids were rinsed with ethyl acetate. The solids were dried at 20-30 °C under vacuum for 4 hours to give 1.47 g of product (43%, 82% ee, 92:8 ratio of exorendo diastereomers).</div>
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Example 5: (lS,3aR,6aS)-tf-butyl octahydrocyclopenta[c]pyrrole-l-carboxylate, t- butylester, oxalate</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000053_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000053_0002" class="patent-full-image" file="imgf000053_0002.tif" he="32" height="128" id="imgf000053_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000053_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="116" width="464" /></a></div>
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9a</div>
<div num="p0316" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
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[00186] A mixture of the (S)- 1 ,2,3 ,4-tetrahydro- 1 -naphthylammonium salt prepared as in</div>
<div num="p0318" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 3, Method 1 (81.7 g, 0.203 mol), /-butyl methyl ether (400 mL) and 5% NaHSO<sub>4</sub>- H<sub>2</sub>O (867 mL, 0.304 mol) was stirred for 30 minutes until all solids were dissolved. The organic phase was washed with water (334 mL) then concentrated to 259 mL. /-Butyl methyl ether (334 mL) was added and the solution was concentrated again to 259 mL. The addition- concentration process was repeated twice more. After the final concentration, t-BuOH (158 mL) and dimethylaminopyridine (5.04 g, 41.3 mmol) were added. A solution of BoC<sub>2</sub>O (67.6 g, 0.31 mol) in t-butylmethyl ether (52.0 mL) was added. After stirring for 5 hours at ambient temperature, /-butyl methyl ether (158 mL) and 5% aqueous NaHSO<sub>4</sub>-H<sub>2</sub>O (260 mL) were added and the resultant mixture was stirred. The organic phase was washed with 5% aqueous NaCl (twice, 260 mL each). The organic phase was concentrated to 320 mL, and tetrahydrofuran (320 mL) was added. The organic phase was concentrated again to 320 mL, and tetrahydrofuran (320 mL) was added. After concentrating to 320 mL once more, methane sulfonic acid (80.1 g, 0.62 mol) was added and the solution was stirred at ambient temperature for 4.5 hours. The reaction mixture was added to a 30% aqueous solution of K<sub>2</sub>CO<sub>3</sub> (571 mL) and stirred. The aqueous phase was extracted with isopropyl acetate (320 mL). The combined organic phases were concentrated to 320 mL, and isopropyl acetate (320 mL) was added. The organic solution was concentrated again to 320 mL. The organic phase was washed with water (320 mL). Isopropyl acetate (320 mL) was added to the organic phase and the solution was concentrated to 192 mL. Isopropyl acetate (320 mL) was added a second time, and the organic solution was concentrated to 192 mL. A solution of oxalic acid (24.1 g, 267 mmol) in isopropyl acetate (448 mL) was added to the orgam<sup>'</sup>c solution over 2 hours. The mixture was stirred for 2-4 hours, and the slurry was filtered. The white solids were rinsed with isopropyl acetate (100 mL) and dried at 35-40 <sup>0</sup>C under vacuum to yield 52.6 g of the title compound (85% yield).</div>
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Method 2</div>
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[00187] A mixture of (S)- 1 ,2,3,4-tetrahydro- 1 -naphthylammonium salt as prepared by the method of Example 3, Method 2 (148 g, 0.609 mol), t-butyl methyl ether (726 mL) and 5% NaHSO<sub>4</sub>-H<sub>2</sub>O (1.58 L, 0.913 mol) was stirred until all of the solids had dissolved. The phases were separated and the organic phase washed with water (726 mL). The organic phase was concentrated to about 400 mL. t-Butyl methyl ether (726 mL) was added and the mixture concentrated to 590 mL. The addition of t-butyl methyl ether and concentration was repeated to give a final volume of 350 mL. Dimethylaminopyridine (8.42 g, 68.9 mmol) and t-butyl alcohol(260 mL) were added, followed by addition of a solution of BoC<sub>2</sub>O (112 g, 0.52 mol) in MTBE (88 mL) over 0.5 hour. The mixture was stirred for 5 hours at 22-25 <sup>0</sup>C.</div>
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A solution of 5% sodium bisulfate in water was added and the mixture stirred for 0.5 hour. The organic phase was washed with 5% sodium chloride (twice, 440 mL each) and concentrated to 270 mL. Tetrahydrofuran (540 mL) was added and the mixture concentrated to 270 mL; this procedure was repeated twice more to give a final volume of 270 mL. Methane sulfonic acid (67 mL) was added over 0.5 hour while maintaining a temperature of lower than 30 °C and the mixture stirred at 22-25 °C for 12 hours. The mixture was added to a 30% aqueous solution of pottassium carbonate (478 mL) while maintaining a temperature of 22-25 °C. The mixture was filtered, the phases separated and the aqueous phase extracted with isopropyl acetate (twice, 540 mL each). The organic phase was concentrated to 270 mL, then twice evaporated with isopropyl acetate (540 ml) to give a final volume of 540 mL. The organic phase was washed with water (twice, 540 mL), then twice evaporated with isopropyl acetate (320 mL) to give a final volume of 320 mL. Additional isopropyl acetate (429 mL) was added followed by addition of a solution of oxalic acid (40.4 g, 0.448 mol) in t- butylmethyl ether (321 mL) over 2 hours maintaining a temperature of 22-25 <sup>0</sup>C. The mixture was stirred for 3 hours at 22-25 <sup>0</sup>C then filtered. The filter cake was washed with isopropyl acetate (100 mL) and the prouduct dried at 35-40 °C under vacuum to give the title compound as a white solid (88.4g, 81%).</div>
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Example 6: (lS,3aR,6aS)-*-butyl 2-((S)-2-(benzyloxycarbonylamino)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (27)</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000055_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000055_0001" class="patent-full-image" file="imgf000055_0001.tif" he="33" height="132" id="imgf000055_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000055_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="166" width="664" /></a></div>
<div num="p0324" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
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[00188] A 3-L 3-neck round bottomed flask equipped with an overhead stirrer, condenser, thermocouple, and nitrogen outlet was purged with nitrogen for several minutes. In a separate flask, sulfuric acid (46.2 mL, 0.867 mol) was diluted with 442 mL of water. The solution was allowed to cool slightly. Cbz-L-tert-Leucine dicyclohexylamine salt (330.0 g, 0.739 mol) was charged to the reaction flask. t-Butyl methyl ether (1620 mL) was added to the reactor, and the mixture was stirred to suspend the salt. The acid solution prepared above was added to the reactor over about 10 minutes, keeping the temperature at 20±5 °C. The mixture was stirred at room temperature for approximately 1 hour, then diluted slowly with water (455 mL). Agitation was stopped, and the layers were allowed to settle. The lower (aqueous) phase was withdrawn to provide 1100 mL colorless solution of pH 1. To the organic phase remaining in the flask was charged additional water (200 mL). The mixture was stirred at room temperature for approximately lhour. Agitation was stopped, and the layers were allowed to settle. The lower (aqueous) phase was withdrawn to provide 50OmL colorless solution of pH 2. The organic phase was heated to about 35 °C, diluted with DMF (300 mL), and concentrated under reduced pressure to the point at which distillation slowed significantly, leaving a concentrate of about 500 mL. The concentrate was transferred without rinsing to a 1-L Schott bottle. The concentrate, a clear colorless solution, weighed 511.6 g. Based on solution assay analysis and the solution weight, the solution contained 187.2 g (0.706 mol) Cbz-L-tørt-Leucine.</div>
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[00189] To a 5-L 4-neck round bottomed flask equipped with an overhead stirrer, thermocouple, addition funnel and nitrogen inlet were charged HOBT<sup>»</sup>H<sub>2</sub>O (103.73 g, 0.678 mol, 1.20 molar eq.), EDC-HCl (129.48 g, 0.675 mol, 1.20 molar eq.) and DMF (480 mL). The slurry was cooled to 0-5 <sup>0</sup>C. A 36.6 wt% solution of the acid of Cbz-L-tert-Leucine in DMF (491.3 g, 0.745 mol, 1.32 molar eq.) was added over 47 minutes to the reaction mixture while keeping the temperature at 0-5 °C. The reaction mixture was stirred for 1 hour and 27 minutes. A solution of 3-azabicyclo(3.3.0)octane-2-carboxylic acid /-butyl ester in isopropyl acetate (28.8 wt%, 414.3 g, 0.564 mol) was added over 53 minutes while keeping the reaction temperature at 0-5.1 <sup>0</sup>C. The reaction mixture was warmed to 20±5 °C over about lhour. 4- Methylmorpholine (34.29 g, 0.339 mol, 0.60 molar eq.) was added over 5 minutes. The reaction mixture was agitated for 16 hours then isopropyl acetate (980 mL) was added to the reaction solution. A solution of histamine*2HCl (41.58 g, 0.226 mol, 0.40 molar eq.) in water (53.02 g) was added to the reaction mixture within 4 minutes, followed by 4- methylmorpholine (45.69 g, 0.45 mol, 0.80 molar eq.). The reaction mixture was sampled after 3.5 hours. Water (758 mL) was added, the mixture stirred for about 20 minutes, then allowed to settle for 11 minutes. The phases were separated. The aqueous phase was extracted with isopropyl acetate (716 mL) and the organic phases were combined. IN aq. HCl was prepared by adding 37 wt% hydrochloric acid (128.3 mL) to water (1435 ml). The organic phase was washed for about 20 minutes with the IN hydrochloric acid. A 10wt% aq. K<sub>2</sub>CO<sub>3</sub> solution was prepared by dissolving K<sub>2</sub>CO<sub>3</sub> (171 g, 1.23 mol, 2.19 molar eq.) in water (1540 mL). The organic phase was washed with the 10 wt% aq. K<sub>2</sub>CO<sub>3</sub> solution for about 20minutes. The final clear, very slightly yellow organic solution, weighing 1862.1 g, was sampled and submitted for solution assay. Based on the solution assay and the weight of the solution, the solution contained 238.3 g (0.520 mol) of product of the title compound. <sup>1</sup>H NMR (DMSO-d<sub>6</sub>, 500 MHz): δ 7.37 ppm (5 H, s), 7.25-7.33 ppm (1 H, m), 5.03 ppm (2 H<sub>3</sub> s), 4.17 ppm (1 H, d), 3.98 ppm (1 H, d), 3.67-3.75 ppm (2 H, m), 2.62-2.74 ppm (1 H, m), 2.48-2.56 ppm (1 H, m), 1.72-1.89 ppm (2 H, m), 1.60-1.69 ppm (1 H, m), 1.45-1.58 ppm (2 H, m), 1.38 ppm (9 H, s), 1.36-1.42 ppm (1 H, m), 0.97 ppm (9 H, s).</div>
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Method 2</div>
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[00190] A solution of potassium carbonate (73.3 g) in water (220 mL) was added to a suspension of (IS, 2S,5R) 3-azabicyclo[3.3.0]octane-2-carboxylic, t-butylester, oxalate (80.0 g,) in isopropyl acetate (400 mL) while maintaining a temperature of about 20 <sup>0</sup>C. The mixture was stirred for 0.5 hour, tha phases separated and the organic phase washed with 25% w/w aqueous potassium carbonate (80 mL) to give a slution of the free base. In a separate flask, aqueous sulfuric acid (400 mL, 0.863 M) was added to a suspension of Cbz-t- leucine dicyclohexylamine salt (118.4g) in /-butylmethyl ether (640 mL) while maintaing a temperature of about 20 <sup>0</sup>C. The mixture was stirred for 0.5 hour, the phases separated and the organic phase washed with water (200 mL). The phase were separated and N- methylmorpholine (80 mL) was added to the organic phase which was concentrated under reduced pressure at 40 <sup>0</sup>C to 80 mL to give the free acid as a solution in N-methyl morpholine. This solution was added to a mixture of EDC* HCl (50.8 g) HOBt hydrate (40,6 g) in N-methylmorpholine (280 mL) at 0-10 <sup>0</sup>C. The mixture was stirred for 1 hour at about 5 <sup>0</sup>C. The solution of 3-azabicyclo[3.3.0]octane-2-carboxylic, t-butylester from above was added at 0-20 <sup>0</sup>C followed by N-methylmorpholine (32 mL). The mixture was stired for 6 hour then diluted with isopropyl acetate (600 mL) followed by IN HCl (400 mL). After stirring 0.5 hour, the phases were separated and the organic phase washed with 25% w/w aqueous potassium carbonate (400 mL) and water (80 mL). The mixture was stirred for about 1 hour and the phases separated to give a solution of the title compound in isopropyl acetate.</div>
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Method 3</div>
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[00191] (IS, 2S,5R) 3-azabicyclo[3.3.0]octane-2-carboxylic, /-butylester, oxalate (1.0 eq.) was suspended in isopropyl acetate (6 vol.) and a solution of potassioum carbonate (3.0 eq.) in water (3.5 vol.) was added at 20-25<sup>0</sup>C. The mixture was stirred for 3 hours then the phases separated. The organic phase was washed with water (2 vol.). [00192] Cbz-Meucine dicyclohexylamine salt (1.05 eq.) was suspended in isopropyl acetate (6 vol.) and sulfuric acid (1.3 eq.) in water (5 vol.) was added at 20-25<sup>0</sup>C. The mixture was stirred for 30 minutes, the phases separated, and the organic phase washed twice with water (2.5 vol each).</div>
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[00193] The two solutions from above were combined and then cooled to 0-5<sup>0</sup>C. HOBt hydrate (1.1 eq.) and EDC (1.1 eq.) were suspended in the mixture and the mixture stirred for 6 hours. The mixture was washed with water (5 vol.) and the resulting organic phase treated with L-lysine (1 eq.) and-N-methylmorpholine (NMM) (2 eq.) at 20-25<sup>0</sup>C to destroy excess activated ester. The mixture was then washed with 5% potassium carbonate (5 vol.), IN hydrochloric acid (5 vol.), 5% potassium carbonate (5 vol.) and twice with water (5 vol. each) to give a solution of the title compound in isopropyl acetate.</div>
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Example 7: (lS,3aR,6aS)-*-butyI 2-((S)-2-amino-3,3-dimethyIbutanoyl)- octahydrocyclopenta[c]pyrrole-l-carboxylate (28)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000058_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000058_0001" class="patent-full-image" file="imgf000058_0001.tif" he="23" height="92" id="imgf000058_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000058_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="104" width="416" /></a></div>
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Method 1</div>
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[00194] A 1 L Buchi hydrogenator was purged with nitrogen three times. A 307.8 g portion of a 12.8 wt% solution of (lS,3aR,6aS)-t-butyl 2-((S)-2-(benzyloxycarbonylamino)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (as prepared by the method of Example 6, Method 1) in isopropyl acetate (39.39 g, 0.086 mol) was charged to the reactor. Isopropyl acetate (100 mL) was added to the reactor. A slurry of 50% water and wet 20% Pd(OH)<sub>2</sub>/carbon (3.97 g) in isopropyl acetate (168 mL) was prepared and charged to the reactor and agitation was started. The reactor was pressurized to 30 psig with nitrogen gas and vented down to atmospheric pressure. This was repeated twice. The reactor was pressurized to 30 psig with hydrogen and vented down to atmospheric pressure. This was repeated twice. The reactor was pressurized to 30 psig with hydrogen and stirred at ambient temperature for 1 hour. The mixture was filtered using a Buchner funnel with a Whatman # 1 filter paper to remove catalyst. The filter cake was washed with isopropyl acetate (80 mL). The procedure was repeated twice more using 617 g and 290.6 g of the 12.8 wt% solution of the starting Cbz compound. The material from the three hydrogenations were combined and distilled under reduced pressure (28" Hg). The resultant solution (468.68 g) was assayed for the title compound (23.2%, 98.9 % purity).</div>
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<sup>1</sup>H NMR (DMSO-d<sub>6</sub>, 500 MHz): δ 3.96 ppm (1 H, d), 3.67 ppm (1 H, dd), 3.53 ppm (1 H, dd), 3.19 ppm (1 H<sub>5</sub> s), 2.66-2.75 ppm (1 H, m), 2.49-2.53 ppm (1 H, m), 1.75-1.92 ppm (2 H, m), 1.66-1.74 ppm (1 H, m), 1.48-1.60 ppm (4 H, m), 1.38 ppm (9 H, s), 1.36-1.42 ppm (1 H<sub>5</sub> m), 0.91 ppm (9 H<sub>5</sub> s)</div>
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Method 2</div>
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[00195] The solution of the Cbz derivative 27 from Example 6, Method 2, was added to 20% Pd(OH)<sub>2</sub>/water (50%, 12.2 g) in a hydrogenation apparatus. The apparatus was pressurized to 30 psi with hydrogen then stirred for 2 hr at about 20 <sup>0</sup>C. The mixture was filtered to remove the catalyst, the filter cake washed with isopropyl acetate (160 mL). The combined filtrates were evaporated with about 4 volumes of heptane at 40 <sup>0</sup>C 2 to 3 times to remove the isopropyl acetate. The resultant slurry was cooled to 0 <sup>0</sup>C, filtered and the product dried under vacuum to give the title compound (78.8 g, 98.3% purity).</div>
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Method 3</div>
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[00196] Asolution of (1 S,3aR,6aS)-t-butyl 2-((S)-2-amino-3<sub>5</sub>3-dimethylbutanoyl)- octahydrocyclopenta[c]pyrrole-l-carboxylate in isopropyl acetate from Example 6, Method 3<sub>5</sub> was added to 20% Pd(OH)<sub>2</sub> (2 wt% loading, 50% wet) and the mixture was hydrogenated at 2 bar and 20-25 <sup>0</sup>C for 2 hours. The catalyst was removed by filtration and washed with isopropyl acetate (2 vol.). The filtrate was concentrated to 10 vol. under reduced pressure at 40 <sup>0</sup>C to give a solution of the title compound in isopropyl acetate.</div>
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Example 8: (lS,3aR,6aS)-*-butyl 2-((S)-2-((S)-2-(benzyloxycarbonylamino)-2- cycIohexylacetamido)-3,3-dimethyIbutanoyl)octahydrocyclopenta[c]pyrrole-l- carboxylate (30)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000059_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000059_0001" class="patent-full-image" file="imgf000059_0001.tif" he="32" height="128" id="imgf000059_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000059_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="139" width="556" /></a></div>
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Method 1 [00197] To a 3 L 3-neck round bottomed flask equipped with an overhead stirrer, thermocouple, addition funnel, nitrogen outlet and ice/water bath was charged HOBt*H<sub>2</sub>O (51.74 g; 0.338 mol, 1.05 molar eq.), EDCΗC1 (64.8 g; 0.338 mol, 1.05 molar eq.) followed by DMF (197.1 g, 208.8 mL) and agitation was started. The slurry was cooled to 0-5 <sup>0</sup>C, then a solution of the acid 29 (98.45 g; 0.338 mol, 1.05 molar eq.) in DMF (172.4 g; 182.9 mL) was prepared and charged to the addition funnel. This was added over about 30 minutes to the batch, maintaining the temperature at 0-5 <sup>0</sup>C. Once addition was complete the reaction mixture was agitated at 0-5 °C for 2 hours. The solution of the amine 28 in isopropyl acetate (450 g solution; containing 104.4 g of acid 29, 0.322mol) was charged to an addition funnel and added drop wise over lhour maintaining the temperature at 0-5 <sup>0</sup>C. Sample analysis indicated incomplete reaction and additional EDC hydrochloride (3.89 g) was added. After 3 hours, analysis of a sample showed 1.8% amine 28 remained. A slurry of HOBT»H<sub>2</sub>O (2.59 g; 0.0169 mol), and EDC»HC1 (3.24 g; 0.0169 mol) was prepared in DMF (10.44 mL) and cooled to 0-5 <sup>0</sup>C . A solution of acid 29 (4.92 g; 0.169 mol) in DMF (10.44 mL) was prepared and added to the slurry of EDC<sup>»</sup>HC1 and HOBT in DMF over 30minutes, maintaining the reaction temperature at 0-5 <sup>0</sup>C. The mixture was stirred for 1 hour at 0-5 <sup>0</sup>C then added to the original mixture maintaining 0-5 <sup>0</sup>C. The mixture was stirred for 14 hours at about 25 <sup>0</sup>C. A solution of histamine<sup>»</sup>2HCl (11.84 g; 0.064 mol) in water (8.9 mL) was prepared and added to the reaction mixture over 5-10 minutes. A charge of 4- methylmorpholine (13.01 g; 0.129 mol) was added to the batch over about 10 minutes, maintaining the batch temperature at 20±5 <sup>0</sup>C. The reaction mixture was diluted with isopropyl acetate (443 mL), followed by water (585 mL). A solution of potassium carbonate (57.8 g) in water (585 mL) was added and the mixture was stirred for 0.5 hour. The layers were separated the aqueous layer was extracted twice with isopropyl acetate (twice, 235 mL each). The combined organic phases were washed with 18 % aqueous HCl in water (585 mL), then NaHCO<sub>3</sub> (43.25 g) in water (585 mL). The layers were separated to give a light yellow solution of product 30 in isopropyl acetate weighing 1159.3 g (1275 mL) containing 16.0 w/w % 30 in isopropyl acetate.</div>
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<sup>1</sup>H NMR (DMSO-d<sub>6</sub>, 500 MHz): δ 7.74 (IH, d), 7.36 (5H, m), 7.34-7.26 (IH, m), 5.01 (2H, s), 4.51 (IH, d), 4.02 (IH, t), 3.96 (IH, d), 3.73 (IH, m), 3.66 (IH, m), 3.68 (IH, m), 2.53 (IH, m), 1.86-1.76 (2H, m), 1.70-1.30 (1OH, m), 1.39 (9H, s), 1.15-0.85 (5H, m), 0.96 (9H, s).</div>
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Method 2</div>
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[00198] A solution of Cbz acid 29 (59.62 g) in N-methylpyrrolidone (126 mL) was added to a suspension of EDCHCL (39.23 g) HOBt hydrate (31.34 g) in N-methylpyrrolidone (221 mL) while maintaining a temperature of about 0 <sup>0</sup>C. After the addition, the mixture was stirred for 1.5 hours at about 0 <sup>0</sup>C. A solution of the amine 28 (63.24 g, as prepared in Example 7, Method 2) in isopropyl acetate (632 mL) was added to the mixture maintaining a temperature of about 0 <sup>0</sup>C. After the addition the mixture was allowed to warm to room temperature and stirred for 5 hours. A solution of potassium carbonate (20.17g) in water (316 mL) was added while maintaining a temperature of about 20 <sup>0</sup>C. The mixture was vigorously stirred for 0.5 hour. The phases were separated and the organic phase vigorously stirred with potassium carbonate (105.3 g) in water (316 mL). The organic phase was separated and washed with IN HCl (316 mL), and then water (158 mL) to give a 12.7% w/w solution of the title compound 30 in isopropyl acetate.</div>
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Method 3 I</div>
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[00199] To a solution of (1 S,3aR,6aS)-t-butyl 2-((S)-2-amino-3,3-dimethylbutanoyl)- octahydrocyclopenta[c]pyrrole-l-carboxylate (1 eq) in isopropyl acetate (10 vol) was added NMP (5 vol) followed by EDC (1.15 eq), HOBT hydrate (1.0 eq) and (S)-2- (benzyloxycarbonylamino)-2-cyclohexylacetic acid (29, 1.05 eq) and the suspension was stirred at 20-25<sup>0</sup>C for 4 hr. The mixture was washed with 5% potassium carbonate (5 vol). A mixture of glycine (1 eq), NMM (2 eq) and water (1 vol) was added and the mixture stirred for 4 hr. The mixture was then washed with 5% potassium carbonate (5 vol), IN hydrochloric acid (5 vol), 5% potassium carbonate (5 vol) and twice with water (5 vol each) to give a solution of the title compound in isopropyl acetate.</div>
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Example 9: (lS,3aR,6aS)-fert-butyl 2-((S)-2-((S)-2-amino-2-cyclohexylacetamido)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (31)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000061_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000061_0001" class="patent-full-image" file="imgf000061_0001.tif" he="32" height="128" id="imgf000061_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000061_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="137" width="548" /></a></div>
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Method 1</div>
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[00200] A 60-gallon hasteloy hydrogenating reactor was charged with a solution of the Cbz peptide 30 (15.1 kg) in isopropyl acetate (109 kg). This solution was reduced under vacuum at 50 <sup>0</sup>C to 68 L. The mixture was then cooled to 25±5 °C and MeOH (15.4 kg) added. This mixture was drained into a container and the reactor was dried. To the dried reactor was charged Pd(OH)<sub>2</sub>/C (20%, 1.51 kg). The solution containing the Cbz peptide 30 was added to W 2</div>
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the reactor and blanketed with hydrogen (30 psi). The reaction was stirred at 20±5 °C and at 150-220 rpm for 2 hours. After completion, a slurry of activated carbon (0.97 kg) in isopropyl acetate (6.8 kg) was added batch and the mixture stirred for 15 minutes. The mixture was filtered over Celite<sup>®</sup> (2.0 kg) via Sparkler filter and through a 0.1 -um cartridge filter. The reactor was rinsed with isopropyl acetate (33.0 kg) and the rinse was combined with the reaction mixture. The system was rinsed additionally with a mixture of isopropyl acetate (25.6 kg) and MeOH (5.73 kg). The combined organics were reduced under vacuum at 65 °C to 30 L. The solution was cooled to 20-30 °C and heptane added (30.8 kg). Distillation was instituted again and the mixture reduced to 30 L. This procedure was repeated for a total of 4 heptane additions (as above) and solvent reductions (as above). The mixture was cooled to 0-5 <sup>0</sup>C and the product filtered and washed with heptane (12.6 kg). The wet solid (14.0 kg) was dried under vacuum at 15-20 <sup>0</sup>C to constant weight to give the title compound (10.17 kg).</div>
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<sup>1</sup>H NMR (DMSOd<sub>6</sub>, 500 MHz): δ 7.97 (IH, d), 4.49 (IH<sub>5</sub> d), 3.96 (IH, d), 3.76 (IH, m), 3.67 (IH, m), 3.05 (IH, d), 2.70 (IH, m), 2.53 (IH, m), 1.87-1.77 (2H, m), 1.7-1.3 (1OH, m), 1.39 (9H, s), 1.2-0.85 (5H, m), 0.96 (9H, s).</div>
<div num="p0355" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 2</div>
<div num="p0356" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00201] The solution of compound 30 from Example 8, Method 1, was added to 50% wet 20 wt% Pd(OH)<sub>2</sub> on carbon (3.16 g) in a pressure reactor. The reactor was pressurized at 30 psi with hydrogen and the mixture stirred for about 1 hour. The catalyst was filtered, the filter washed with isopropyl acetate and the combined organics distilled to about 65 mL. The mixture was evaporated with heptane (316 mL) several times until analysis indicates <0.5% isopropyl acetate. The resultant slurry is diluted to about 320 mL then warmed to reflux. The solution was slowly cooled to about 5 <sup>0</sup>C, the suspension stirred for 1 hour then filtered. The filter cake was washed with about 65 mL of heptane and the product dried under vacuum at 30<sup>0</sup>C to give the title compound (80.16 g) as a white solid.</div>
<div num="p0357" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 3</div>
<div num="p0358" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00202] The solution of (1 S,3aR,6aS)-t-butyl 2-((S)-2-((S)-2-(benzyloxycarbonylamino)-2- cyclohexylacetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole- 1 -carboxylate in isopropyl acetate from Example 9, Method 3, was added to 20% Pd(OH)<sub>2</sub> (2 wt% loading, 50% wet) and the mixture hydrogenated at 2 bar and 20-25 <sup>0</sup>C for 2 hour. The catalyst was removed by filtration and washed with isopropyl acetate (1 vol.). The solvent was exchanged by distillation twice with heptane (8.6 vol.) at reflux. The mixture was cooled to 78 <sup>0</sup>C over 1 hour, then to 22 <sup>0</sup>C over 2 hours. After 1 hour at 22 <sup>0</sup>C the suspension was filtered and the cake washed with heptane (3.2 vol.) and the product dried under vacuum at 30 <sup>0</sup>C with a nitrogen purge to give the title compound.</div>
<div num="p0359" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 10: (lS,3aR,6aSH-butyl 2-((S)-2-((S)-2-cycIohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocycIopenta[c]pyrrole-l- carboxylate (33)</div>
<div num="p0360" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000063_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000063_0001" class="patent-full-image" file="imgf000063_0001.tif" he="33" height="132" id="imgf000063_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000063_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="165" width="660" /></a></div>
<div num="p0361" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
<div num="p0362" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00203] To a 10OmL round bottomed flask was added pyrazine-2-carboxylic acid 32 (1.6070 g, 12.95 mmol) and DMF (4 mL). The slurry was stirred at 20-25 <sup>0</sup>C. Meanwhile, a solution of CDI was prepared by combining CDI (2.1012 g, 12.96 mmol, 1 molar eq.) and DMF (8.80 g, 9.3 mL) in a 25 mL flask. Mild heating (30 °C) aided in dissolution. The CDI solution was cooled to 20-25 <sup>0</sup>C and added to the slurry of pyrazine-2-carboxylic acid. Stirring was continued for 1.5 hours to assure complete activation of the acid as carbon dioxide was produced as a byproduct. Meanwhile, the amine 31 (5.0002 g, 10.78 mmol) was dissolved in DMF (14.15 g, 15 mL) with mild warming to 30 °C aided in the dissolution of the material. This solution was cooled to 20-25 °C. The activated pyrazine solution was also cooled to about 15 <sup>0</sup>C. The solution of compound 31 was added to the activated pyrazine carboxylic acid while maintaining the temperature at 30 <sup>0</sup>C for about 1 hour. The solution was allowed to cool to 20-25 <sup>0</sup>C then added to a solution of potassium carbonate (0.25 g) in water (100 mL) at 0 <sup>0</sup>C. The mixture was filtered and washed with water (four times, 50 mL each). The filter cake was dried under vacuum beginning at 20-25 °C and warmed to 30 <sup>0</sup>C after 24hours until the cake was constant weight to give the title compound (5.99 g). <sup>1</sup>H NMR (DMSO-d<sub>6j</sub> 500 MHz): δ 9.19 ppm (1 H, d, J =1.3 Hz), 8.90 ppm (1 H, d, J = 2.5 Hz), 8.76 ppm (1 H, dd, J = 2.4 Hz, 1.5 Hz), 8.50 ppm (1 H, d, J = 9.2 Hz)<sub>5</sub> 8.22 ppm (1 H, d, J = 9.0 Hz), 4.68 ppm (1 H, dd, J = 9.1 Hz, 6.6 Hz)<sub>5</sub> 4.53 ppm (1 H, d, J = 9.0 Hz), 3.96 ppm (1 H<sub>5</sub> d, J = 4.2 Hz), 3.73 ppm (1 H<sub>5</sub> dd, J = 10.5 Hz, 7.5 Hz), 3.68 ppm (1 H, dd, J = 10.6 ppm, 3.4 ppm), 2.68-2.74 ppm (1 H, m), 2.52-2.58 ppm (1 H, m), 1.70-1.88 ppm (3 H, m), 1.51-1.69 ppm (7 H, m), 1.31-1.44 ppm (2 H, m), 1.39 ppm (9 H, s), 1.00-1.19 ppm (4 H<sub>5</sub> m), 0.97 ppm (9 H, s), 0.91-0.97 ppm (1 H, m).</div>
<div num="p0363" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method!</div>
<div num="p0364" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00204] Oxalyl chloride (11.29 mL) was added to a solution of pyrazine-2-carboxylic acid 32 and N-methylmorpholine (59.28 mL) in methylene chloride (150 mL) at about 30 <sup>0</sup>C. The mixture was stirred for 0.5 hour, then a solution of the amine 31 (50.0 g) in methylene chloride (150 mL) was added at about 30 <sup>0</sup>C. After 0.5 hour, the mixture was washed with water (250 mL). The aqueous phase was extracted with methylene chloride (100 mL) to give a solution of the title compound in methylene chloride which was used directly in the next step (Example 11, Method 2).</div>
<div num="p0365" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 11: (lS)-2-((S)-2-((S)-2-cyclohexyI-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (34)</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000064_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000064_0001" class="patent-full-image" file="imgf000064_0001.tif" he="32" height="128" id="imgf000064_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000064_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="162" width="648" /></a></div>
<div num="p0367" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
<div num="p0368" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00205] Concentrated HCl (150 g, 0.015 mol, 1.2 molar eq.) was slowly added at 0 °C to a stirred solution of the pyrazinyl peptide 33 (50.0 g) in formic acid (100. Og). After 3.3 hours, the reaction mixture was diluted with 166.5 g of ice water. Methylene chloride (100 mL) was added and the reaction was stirred for 10 minutes to dissolve the product. The phases were separated and the aqueous layer extracted with methylene chloride (100 mL). The combined organic phases were washed with water (75 mL) then concentrated to about 1/3 volume at 50 <sup>0</sup>C, 1 atm. Toluene (100 mL) was added at room temperature and the homogeneous solution was evaporated under vacuum at <56 <sup>0</sup>C to about 1/3 volume. The mixture was cooled to 20- 25 <sup>0</sup>C as a precipitate formed. Heptane (75 mL) was slowly added and the slurry stirred for 10-15 minutes. The slurry was filtered and the filter cake was washed with heptane (50 mL). The solids were dried under vacuum at 20-25 °C to give the title compound (15.19 g).</div>
<div num="p0369" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 2 [00206] The methylene chloride solution of the starting compound 33 from Example 10, Method 2, was cooled to 0-5 <sup>0</sup>C then concentrated HCl (200 mL) was added while maintaining a temperature of <10 <sup>0</sup>C. The mixture was stirred for 3 hours, then diluted with water (200 mL) while maintaining a temperature of < 10 <sup>0</sup>C. The phases were separated and the aqueous phase extracted with methylene chloride (100 mL). The combined organic phases were washed with water (100 mL) and the aqueous wash phase extracted with methylene chloride. The combined organic extracts were refluxed under an inverse Dean- Stark trap to azeotrope water. The mixture was concentrated by distillation to a minimum volume then diluted with toluene (500 mL) then concentrated by distillation at atmospheric pressure to 250 mL. The mixture was slowly cooled to 20 <sup>0</sup>C over about 6 hours. The resultant slurry was filtered, the filter cake washed with toluene (100 mL) then dried at about 45 <sup>0</sup>C in a vacuum oven to provide the title compound (64.7 g) as a pale yellow powder containing about 17 % toluene.</div>
<br /><br /><br /><br /><br /><br /><div num="p0370" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 12: (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-l-(cyclopropylamino)-2- hydroxy-l-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-l-carboxamide (35)</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000065_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000065_0001" class="patent-full-image" file="imgf000065_0001.tif" he="64" height="256" id="imgf000065_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000065_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="106" width="424" /></a></div>
<div num="p0372" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
<div num="p0373" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00207] A 500 mL 3-neck round bottomed flask equipped with an overhead stirrer, condenser, thermocouple, and nitrogen outlet was purged with nitrogen for several minutes. The peptide-acid 34 (25.0 g, 0.049 mol), EDC-HCl (10.35 g, 0.054 mol, 1.1 molar eq.), and HOBt-H<sub>2</sub>O (8.27 g, 0.054 mol, 1.1 molar eq.) were charged to the flask followed by 175 mL of methylene chloride. The mixture was stirred at room temperature for lhour then added over 20 minutes to a suspension of hydroxyamide-amine 18 (11.1 g, 0.054 mol, 1.1 molar eq.) in methylene chloride (75 mL) while maintaining a temperature below 10 °C. Upon W 2</div>
<div num="p0374" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
complete addition, N-methylmorpholine (5.94 mL, 0.054 mol, 1.1 molar eq.) was added in 2 portions. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched by the addition OfNaHCO<sub>3</sub> (8.0 g) in 200 mL of water. The phases were separated and the organic layer washed with water (175 mL), 0.5 N aq. HCl (200 mL), water (three times, 200 mL each) and saturated NaCl (200 mL) to give a 16% by weight methylene chloride solution of the title compound 35 of 100 A% purity (molar yield 100%).</div>
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Method 2</div>
<div num="p0376" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00208] N-methylmorpholine (38.19 mL, 347.3 mmol) was added to a mixture of the peptide-acid 34 (100.0 g, 89.2 wt%, 173.7 mmol), HOBt hydrate (26.79 g, 87.6 wt%, 173.7 mmol), EDCI (36.62 g, 191.04 mmol), and the hydroxyamide-amine 18 in methylene chloride over 30 minutes while maintaining a temperature of 0-5 <sup>0</sup>C. After the addition, the mixture was warmed to 20 <sup>0</sup>C and stirred for 5 hours. The mixture was then diluted with water (500 mL) and stirred for about 0.5 hour. The phases were separated and the organic phase washed with IN HCl (500 mL), 5 wt% aqueous sodium bicarbonate (500 mL) to give a solution of the title compound in methylene chloride, 98.5% AUC purity, 95% solution yield.</div>
<div num="p0377" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 3</div>
<div num="p0378" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00209] Peptide acid 34 (1.00 eq.), EDCI (1.10 eq.), HOBt hydrate (1.00 eq.), and hydroxyamine 18<sup>«</sup>HC1 (1.05 eq.) were suspended in CH<sub>2</sub>Cl<sub>2</sub> (5 vol.) and the mixture was cooled to 0-5 <sup>0</sup>C. NMM (2.0 eq) was added over 30-60 minutes while maintaining the reaction temperature below 5°C. The reaction mixture was warmed to 20-25 °C over 30 minutes and stirred for additional 5 hours. The reaction was washed with water (5 vol.), IN HCl (5 vol), and 5 wt% aqueous NaHCO<sub>3</sub> (5 vol.) to provide a solution of the title compound in CH<sub>2</sub>Cl<sub>2</sub>.</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-302770220608373834.post-41304404230935329802015-03-24T05:57:00.002-07:002015-03-24T05:57:56.942-07:00Uprosertib (GSK-2141795)<div dir="ltr" style="text-align: left;" trbidi="on">
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<strong style="font-style: inherit; line-height: 1.7;"><img alt="" class="" data-mce-src="http://www.medkoo.com/Anticancer-trials/structures/GSK2141795%20structure.gif" height="190" id="irc_mi" src="http://www.medkoo.com/Anticancer-trials/structures/GSK2141795%20structure.gif" style="border: 1px solid rgb(221, 221, 221); font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; margin-top: 0.4em; max-width: 100%; padding: 6px;" width="415" /></strong></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000390_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" height="342" id="imgf000390_0002" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="415" /></a></div>
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<strong style="font-style: inherit; line-height: 1.7;">Uprosertib (GSK-2141795)</strong></div>
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GSK 2141795C</div>
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N-[(1S)-1-(aminomethyl)-2-(3,4-difluorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)furan-2-carboxamide</div>
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N-[(2S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-2-methylpyrazol-3-yl)furan-2-carboxamide</div>
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2-Furancarboxamide, <em style="font-weight: inherit; line-height: 1.7;">N</em>-[(1<em style="font-weight: inherit; line-height: 1.7;">S</em>)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1<em style="font-weight: inherit; line-height: 1.7;">H</em>-pyrazol-5-yl)-</div>
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Λ/-{(1 S)-2-amino-1-r(3,4-difluorophenyl)methyllethyl}-5-chloro-4-(4- chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide</div>
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N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1Hpyrazol-5-yl)-2-furancarboxamide.</div>
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<span lang="EN-US" style="font-style: inherit; font-weight: inherit; line-height: 1.7;"><span class="style37" style="font-style: inherit; font-weight: inherit; line-height: 1.7;"> </span>Cas 1047634-65-0</span> (GSK-2141795); BASE</div>
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CAS 1047635-80-2 (GSK-2141795 HCl salt)</div>
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<strong style="font-style: inherit; line-height: 1.7;"><span lang="EN-US" style="font-style: inherit; font-weight: inherit; line-height: 1.7;">Synonym:</span></strong> GSK-2141795; GSK2141795; GSK 2141795; GSK795; GSK-795; GSK 795. Uprosertib. UNII ZXM835LQ5E</div>
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<strong style="font-style: inherit; line-height: 1.7;">IUPAC/Chemical name: </strong></div>
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N-((S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)furan-2-carboxamide</div>
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C18H16Cl2F2N4O2<br style="font-style: inherit; font-weight: inherit; line-height: 1.7;" />Exact Mass: 428.06184<br style="font-style: inherit; font-weight: inherit; line-height: 1.7;" />Molecular Weight: 429.25</div>
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Elemental Analysis: C, 50.37; H, 3.76; Cl, 16.52; F, 8.85; N, 13.05; O, 7.45</div>
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Mechanims of Action:Akt inhibitor<br style="font-style: inherit; font-weight: inherit; line-height: 1.7;" />Indication:Cancer Treatment<br style="font-style: inherit; font-weight: inherit; line-height: 1.7;" />Drug Company:GlaxoSmithKline</div>
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PHASE 2... CANCER</div>
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<span id="ctl16_lblTermName" style="font-style: inherit; font-weight: inherit; line-height: 1.7;"><span class="style37" style="font-style: inherit; font-weight: inherit; line-height: 1.7;"> Uprosertib, also known as</span> <span class="style37" style="font-style: inherit; font-weight: inherit; line-height: 1.7;">GSK2141795 and GSK795, is an </span></span><span class="style37" style="font-style: inherit; font-weight: inherit; line-height: 1.7;">orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity.</span></div>
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<span class="style37" style="font-style: inherit; font-weight: inherit; line-height: 1.7;">The National Cancer Institute (NCI) is evaluating the compound in phase II clinical studies for the treatment of endometrial carcinoma and multiple myeloma in combination with trametinib.</span></div>
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GSK-2141795, an oral AKT inhibitor, is in early clinical trials at GlaxoSmithKline for the treatment of solid tumors and lymphoma. The company is conducting phase II clinical trials for the treatment of patients with BRAF wild-type mutation melanoma and for the treatment of recurrent or persistent cervical cancer in combination with trametinib.</div>
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<span class="style37" style="font-style: inherit; font-weight: inherit; line-height: 1.7;">Akt inhibitor GSK2141795 binds to and inhibits the activity of Akt, which may result in inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents.</span></div>
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QC data:</div>
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<img alt="" data-mce-src="http://www.medkoo.com/Anticancer-trials/structures/pdf.jpg" height="18" src="http://www.medkoo.com/Anticancer-trials/structures/pdf.jpg" style="border: 1px solid rgb(221, 221, 221); font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; margin-top: 0.4em; max-width: 100%; padding: 6px;" width="20" />View NMR, View HPLC, View MS ...... MEDKOO</div>
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<img alt="Uprosertib.png" class="structure-img" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=51042438&t=l" height="398" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=51042438&t=l" style="border: 1px solid rgb(221, 221, 221); font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; margin-top: 0.4em; max-width: 100%; padding: 6px;" title="A structure of Uprosertib" width="398" /></div>
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PATENT</div>
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<tr style="font-style: inherit; font-weight: inherit; line-height: 1.7;"><th style="border: 1px dashed rgb(187, 187, 187); color: #666666; font-family: inherit; font-size: 10px; font-style: inherit; font-weight: 500; letter-spacing: 0.1em; line-height: 2.6em; text-transform: uppercase;">PATENT</th><th style="border: 1px dashed rgb(187, 187, 187); color: #666666; font-family: inherit; font-size: 10px; font-style: inherit; font-weight: 500; letter-spacing: 0.1em; line-height: 2.6em; text-transform: uppercase;">SUBMITTED</th><th style="border: 1px dashed rgb(187, 187, 187); color: #666666; font-family: inherit; font-size: 10px; font-style: inherit; font-weight: 500; letter-spacing: 0.1em; line-height: 2.6em; text-transform: uppercase;">GRANTED</th></tr>
<tr style="font-style: inherit; font-weight: inherit; line-height: 1.7;"><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;">Inhibitors of AKT Activity [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2011071182" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2011071182" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;" title="Go to PubChem Patent View page for this patent">US2011071182</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;">2011-03-24</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;"> </td></tr>
<tr style="font-style: inherit; font-weight: inherit; line-height: 1.7;"><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;">INHIBITORS OF Akt ACTIVITY [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2010267759" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2010267759" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;" title="Go to PubChem Patent View page for this patent">US2010267759</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;">2010-10-21</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;"> </td></tr>
<tr style="font-style: inherit; font-weight: inherit; line-height: 1.7;"><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;">INHIBITORS OF AKT ACTIVITY [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2009209607" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2009209607" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;" title="Go to PubChem Patent View page for this patent">US2009209607</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;">2009-08-20</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;"> </td></tr>
<tr style="font-style: inherit; font-weight: inherit; line-height: 1.7;"><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;">INHIBITORS OF Akt ACTIVITY [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2010041726" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2010041726" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;" title="Go to PubChem Patent View page for this patent">US2010041726</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;">2010-02-18</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;"> </td></tr>
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<span class="style11" lang="EN-US" style="font-style: inherit; font-weight: inherit; line-height: 1.7;"> <span class="style58" style="font-style: inherit; font-weight: inherit; line-height: 1.7;"><strong style="font-style: inherit; line-height: 1.7;">More information about this drug</strong></span></span></div>
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The chemical structures of <a data-mce-href="http://www.medkoo.com/Anticancer-trials/GSK-2110183.htm" href="http://www.medkoo.com/Anticancer-trials/GSK-2110183.htm" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">Afuresertib (GSK-2110183)</a> and <a data-mce-href="http://www.medkoo.com/Anticancer-trials/GSK-2141795.htm" href="http://www.medkoo.com/Anticancer-trials/GSK-2141795.htm" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">GSK-2141795</a> are very similar as shown below:</div>
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<tr style="font-style: inherit; font-weight: inherit; line-height: 1.7;"><td class="style33" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit; font-style: inherit; font-weight: inherit; line-height: 1.7; padding: 6px 10px 6px 0px;"><img alt="GSK-2110183 and Afuresertib structures" data-mce-src="http://www.medkoo.com/Anticancer-trials/structures/GSK-2110183%20and%20Afuresertib%20structures.gif" height="212" longdesc="https://wordpress.com/post/46419963/GSK-2110183%20and%20Afuresertib%20structures" src="http://www.medkoo.com/Anticancer-trials/structures/GSK-2110183%20and%20Afuresertib%20structures.gif" style="border: 1px solid rgb(221, 221, 221); font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="670" /></td></tr>
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Fig 1. chemical structures of <a data-mce-href="http://www.medkoo.com/Anticancer-trials/GSK-2110183.htm" href="http://www.medkoo.com/Anticancer-trials/GSK-2110183.htm" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">Afuresertib (GSK-2110183)</a> and <a data-mce-href="http://www.medkoo.com/Anticancer-trials/GSK-2141795.htm" href="http://www.medkoo.com/Anticancer-trials/GSK-2141795.htm" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">GSK-2141795</a></div>
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<span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;">PATENT</span></div>
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WO 2008098104 OR EP2117523</div>
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<a data-mce-href="http://www.google.com/patents/EP2117523A1?cl=en" href="http://www.google.com/patents/EP2117523A1?cl=en" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://www.google.com/patents/EP2117523A1?cl=en</a></div>
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Scheme 2</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000048_0001.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000048_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000048_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000048_0001.png" height="72" id="imgf000048_0001" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000048_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="404" /></a></div>
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11-1 I-2</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000048_0002.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000048_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000048_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000048_0002.png" height="80" id="imgf000048_0002" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000048_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="516" /></a></div>
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II-3 II-4</div>
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Reagents: (a) PyBrop, (i-Pr)<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>NEt, 1 ,1-dimethylethyl (2-amino-3- phenylpropyl)carbamate, DCM, RT; (b) 5-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-1- methyl-1 H-pyrazole, K<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>CO<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>, Pd(PPh<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>)<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>, dioxane/H<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>O; (c) TFA / DCM, RT.</div>
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<span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;">Preparation 7</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000080_0001.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000080_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000080_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000080_0001.png" height="247" id="imgf000080_0001" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000080_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="398" /></a></div>
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Preparation of 5-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-1 -methyl-1 H-pyrazole</div>
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To a solution of 1 -methyl pyrazole (4.1 g, 50 mmole) in THF (100 ml.) at 0<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 ml_, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 0<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C over 1 hour. The reaction was diluted with saturated NH<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>CI solution and extracted with DCM. The organic fractions were washed with H<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>O (2 x 100 ml_), dried over Na<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>SO<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">4</span> and concentrated under vacuum to afford a tan solid (8.0 g, 77%) which was used without further purification. LCMS (ES) m/z 127 (M+H)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span> for [RB(OH)<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>]; <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">1</span>H NMR (CDCI<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H).</div>
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Example . .24</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000390_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" height="254" id="imgf000390_0002" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="309" /></a>UPROSERTIB</div>
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Preparation Λ/-{(1 S)-2-amino-1-r(3,4-difluorophenyl)methyllethyl}-5-chloro-4-(4- chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide</div>
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a) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0001.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000391_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0001.png" height="322" id="imgf000391_0001" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="391" /></a></div>
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A solution of methyl 4-bromo-2-furancarboxylate (470 mg, 2.29 mmol), potassium carbonate (1584 mg, 11.46 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (525 mg, 2.52 mmol)[prepared according to Preparation 7] and bis-(tri-t-butylphosphine)Palladium (0) (58.6 mg, 0.12 mmol) in 1 ,4-dioxane (9.55 ml) and water (1.9 ml) was stirred at 80 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C. After 1 hr, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over I^^SOφ concentrated and purified via column chromatography (30% EtOAc in hexanes) affording the title compound (124 mg, 0.60 mmol, 26 % yield) as a white powder: LCMS (ES) m/e 206 (M+H)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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b) methyl 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylate</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0002.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000391_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0002.png" height="327" id="imgf000391_0002" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="381" /></a></div>
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A solution of methyl 4-(1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylate (412 mg, 2.0 mmol) and N-chlorosuccinimide (267 mg, 2.0 mmol) in DMF (10 ml.) was heated at 75 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C for 30 minutes. Another batch of N-chlorosuccinimide (267 mg, 2.0 mmol) was added. After 1 hr, the mixture was concentrated and purified using silica gel and eluting with 0-55% ethyl acetate / hexane to afford the title compound as a white solid (225 mg, 0.82 mmol, 71 % yield) : LCMS (ES) m/e 276 (M+H)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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c) 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylic acid</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0003.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0003.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000391_0003" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0003.png" height="353" id="imgf000391_0003" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000391_0003.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="411" /></a></div>
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A solution of methyl 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2- furancarboxylate (224 mg, 0.82 mmol) in 6N sodium hydroxide (1.36 ml, 8.2 mmol) and tetrahydrofuran (5 ml) was stirred at 70 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>O-DCM. The aqueous phase was adjusted to pH ~4 and then washed several times with DCM. The combined organic fractions were dried over Na<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>SO<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">4</span> and concentrated affording the title compound (201 mg, 0.77 mmol, 94 % yield) as a yellow oil: LCMS (ES) m/e 262 (M+H)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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d) 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1- [(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-furancarboxamide</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000392_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" height="305" id="imgf000392_0001" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="404" /></a></div>
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To a solution of 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2- furancarboxylic acid (200 mg, 0.77 mmol)[prepared according to the procedure of Preparation 6], 2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1 H-isoindole-1 ,3(2H)- dione (254 mg, 0.80 mmol) and N,N-diisopropylethylamine (0.40 ml, 2.30 mmol) in DCM (10 ml) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (536 mg, 1.15 mmol). After stirring at ambient temperature for 20 hrs, the mixture was concentrated and purified with silica gel column eluting with gradient (0-50% ethyl acetate/hexanes) to afford the title compounds as an off-white foamy solid (304 mg, 0.54 mmol, 71 % yield): LCMS (ES) m/e 560(M+H)+.</div>
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e)<span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;"> Λ/-{(1 S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1- methyl-1 /-/-pyrazol-5-yl)-2-furancarboxamide</span></div>
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To a solution of 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-N-{(1S)-2- (3,4-difluorophenyl)-1 -[(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2- furancarboxamide (304 mg, 0.54 mmol) in methanol (5 ml) at 25 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C was added hydrazine (0.08 ml, 2.7 mmol) dropwise. After 12h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1 % NH<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>OH)). The free base was converted to the HCI salt by addition of excess 4M HCI in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCI salt of the title compound as a yellow solid:</div>
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<span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;">LC-MS (ES) m/z 430(M+H)<span style="bottom: 1ex; color: #222222; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>,</span></div>
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<span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;"><span style="bottom: 1ex; color: #222222; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">1</span>H NMR (400 MHz, MeOD) δ ppm 2.91 - 3.05 (m, 2 H) 3.17 - 3.28 (m, 2 H) 3.81 (s, 3 H) 4.57 (d, J=9.60 Hz, 1 H) 7.12 (br. s., 1 H) 7.18-7.28 (m., 2 H) 7.36-7.39 (m, 1 H) 7.58 (s, 1 H).</span></div>
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<span data-mce-style="color: #000080;" style="color: navy; font-style: inherit; font-weight: inherit; line-height: 1.7;">SYNTHESIS ELABORATED</span></div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2015/03/wp_0003111.jpg" href="https://newdrugapprovals.files.wordpress.com/2015/03/wp_0003111.jpg" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="WP_000311" class="alignnone wp-image-12492" data-mce-src="https://newdrugapprovals.files.wordpress.com/2015/03/wp_0003111.jpg?w=300" height="659" src="https://newdrugapprovals.files.wordpress.com/2015/03/wp_0003111.jpg?w=300" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; margin-top: 0.4em; max-width: 100%; padding: 6px;" width="879" /></a></div>
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<span data-mce-style="color: #000080;" style="color: navy; font-style: inherit; font-weight: inherit; line-height: 1.7;">STEP A</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000261_0002.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000261_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000261_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000261_0002.png" height="273" id="imgf000261_0002" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000261_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; margin-top: 0.4em; max-width: 100%; padding: 6px;" width="401" /></a></div>
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4,5-dibromo-2-furancarboxylic acid in methanol , sulfuric acid methyl 4,5-dibromo-2-furancarboxylate LCMS (ES) m/e 283 (M+H)+</div>
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<span data-mce-style="color: #000080;" style="color: navy; font-style: inherit; font-weight: inherit; line-height: 1.7;">STEP B</span></div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2015/03/imgf000261_0002.png" href="https://newdrugapprovals.files.wordpress.com/2015/03/imgf000261_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="imgf000261_0002" class="alignnone wp-image-12497" data-mce-src="https://newdrugapprovals.files.wordpress.com/2015/03/imgf000261_0002.png?w=300" height="261" src="https://newdrugapprovals.files.wordpress.com/2015/03/imgf000261_0002.png?w=300" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="395" /></a></div>
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methyl 4,5-dibromo-2-furancarboxylate and isopropylmagnesium chloride ,to give methyl 4-bromo-2-furancarboxylate</div>
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LCMS (ES) m/e 204,206 (M, M+2)+</div>
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<span data-mce-style="color: #000080;" style="color: navy; font-style: inherit; font-weight: inherit; line-height: 1.7;">STEP C</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0001.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000262_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0001.png" height="272" id="imgf000262_0001" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; margin-top: 0.4em; max-width: 100%; padding: 6px;" width="399" /></a></div>
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methyl 4-bromo-2-furancarboxylate and NCS in N,N-dimethylformamide methyl 4-bromo-5-chloro-2-furancarboxylate LCMS (ES) m/e 238,240,242 (M, M+2, M+4)+</div>
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<span data-mce-style="color: #000080;" style="color: navy; font-style: inherit; font-weight: inherit; line-height: 1.7;">STEP D</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0002.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000262_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0002.png" height="321" id="imgf000262_0002" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="390" /></a></div>
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methyl 4-bromo-5-chloro-2-furancarboxylate , 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole prepared according to<span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;">Preparation 7</span>], potassium carbonate and bis(tri-t-butylphosphine)paliadium(0) in 1,4-dioxane (19.14 ml) and water ......methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate obtained. LCMS m/e ES 240, 242 (M, M+2)+</div>
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<span data-mce-style="color: #000080;" style="color: navy; font-style: inherit; font-weight: inherit; line-height: 1.7;">STEP E</span></div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2015/03/imgf000261_00021.png" href="https://newdrugapprovals.files.wordpress.com/2015/03/imgf000261_00021.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="imgf000261_0002" class="alignnone wp-image-12498" data-mce-src="https://newdrugapprovals.files.wordpress.com/2015/03/imgf000261_00021.png?w=300" height="315" src="https://newdrugapprovals.files.wordpress.com/2015/03/imgf000261_00021.png?w=300" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="390" /></a></div>
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a) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid.</div>
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A solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate [prepared according to Example</div>
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<span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;">127]</span> and n-chlorosuccinimide (166 mg, 1.25 mmol) yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid. LCMS (ES) m/e 261,263 (M, M+2)+</div>
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<span data-mce-style="color: #000080;" style="color: navy; font-style: inherit; font-weight: inherit; line-height: 1.7;">STEP F</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000392_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" height="308" id="imgf000392_0001" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="408" /></a></div>
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Reacting 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid [prepared according to the procedure of <span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;">Preparation 6</span>], <span data-mce-style="color: #993300;" style="color: #993300; font-style: inherit; font-weight: inherit; line-height: 1.7;">2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione</span> and N,N-diisopropylethylamine in DCM was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate .......obtd</div>
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5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-furancarboxamide. <span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;">the uproserib precursor</span></div>
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LCMS (ES) m/e 560(M+H)+</div>
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NOTE STRUCTURE OF<span data-mce-style="color: #993300;" style="color: #993300; font-style: inherit; font-weight: inherit; line-height: 1.7;"> 2-[(2S)-2-amino-3-(2,4-difluoro phenyl)propyl]-1H-isoindole-1,3(2H)-dione</span></div>
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<img alt="" data-mce-src="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0001.png" src="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0001.png" style="border: 1px solid rgb(221, 221, 221); font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; margin-top: 0.4em; max-width: 100%; padding: 6px;" /></div>
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SEE<a data-mce-href="http://www.google.com/patents/WO2010093885A1?cl=en" href="http://www.google.com/patents/WO2010093885A1?cl=en" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"> http://www.google.com/patents/WO2010093885A1?cl=en</a></div>
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Preparation 1</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0001.png" href="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000036_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0001.png" height="356" id="imgf000036_0001" src="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="401" /></a></div>
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Preparation of 2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl1-1 /-/-isoindole-1 ,3(2H)-dione a) 1 ,1-dimethylethyl [(1 S)-2-(3,4-difluorophenyl)-1-(hydroxymethyl)ethyl]carbamate</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0002.png" href="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000036_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0002.png" height="192" id="imgf000036_0002" src="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000036_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="403" /></a></div>
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To a solution of Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3,4-difluoro-L-phenylalanine (2.0 g, 6.7 mmol) in THF (35 ml.) at 0 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C stirred was added BH<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>-THF (30 ml_, 30 mmol- 1 M in THF). After 12h, the reaction was quenched with AcOH:MeOH (1 :4, 20 ml.) and partitioned between saturated aqueous NaHCO<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">3</span> and CHCI<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>. The aqueous phase was then extracted several times with CHCI<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>. The combined organic fractions were concentrated and the resulting white solid (7.0 g, 74%) used without further purification: LCMS (ES) m/e 288 (M+H)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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b) 1 ,1-dimethylethyl {(1 S)-2-(3,4-difluorophenyl)-1-[(1 ,3-dioxo-1 ,3-dihydro-2/-/-isoindol-2- yl)methyl]ethyl}carbamate</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000037_0001.png" href="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000037_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000037_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000037_0001.png" height="317" id="imgf000037_0001" src="http://patentimages.storage.googleapis.com/WO2010093885A1/imgf000037_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="392" /></a></div>
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To a solution of 1 ,1-dimethylethyl [(1 S)-2-(3,4-difluorophenyl)-1-</div>
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(hydroxymethyl)ethyl]carbamate (2.65 g, 9.22 mmol), polymer bound triphenylphosphine (5.33 g, 1 1.5 mmol, 2.15 mmol/g) and phthalimide (1.63 g, 10.9 mmol) in THF (50 ml.) at 25 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C was added diisopropyl azodicarboxylate (1.85 ml_, 11.3 mmol). After stirring at RT for 1 h, the reaction solution was filtered and concentrated. The residue was adsorbed onto silica and purified via column chromatography to yield product (0.33 g) as a white solid: LCMS (ES) m/z 417 (M+H)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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c) 2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1 H-isoindole-1 ,3(2H)-dione</div>
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To a solution of 1 ,1-dimethylethyl {(1S)-2-(3,4-difluorophenyl)-1-[(1 ,3-dioxo-1 ,3- dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (0.33 g, 0.79 mmol) in CHCI<span style="font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>:MeOH (10:3, 13 mL) at RT was added 4M HCI in dioxane (5 mL, 20 mmol). After 12h, the solvents were removed and affording the title compound (0.29 g, quant.) as a white HCI salt which was used without further purification: LCMS (ES) m/z 317 (M+H)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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<span data-mce-style="color: #000080;" style="color: navy; font-style: inherit; font-weight: inherit; line-height: 1.7;">FINAL STEP</span></div>
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<span data-mce-style="color: #ff0000;" style="color: red; font-style: inherit; font-weight: inherit; line-height: 1.7;"> conversion of precursor to uprosertb</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"> <img alt="Figure imgf000392_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" height="144" id="imgf000392_0001" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000392_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="196" /> </a>UPROSERTIB PRECURSOR GIVES<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"> <img alt="Figure imgf000390_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" height="124" id="imgf000390_0002" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000390_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="152" /> </a>UPROSERTIB</div>
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N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1Hpyrazol-5-yl)-2-furancarboxamide.</div>
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5-chloro-4-(4-chloro-1-methyl-1Hpyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-<br style="font-style: inherit; font-weight: inherit; line-height: 1.7;" />yl)methyl]ethyl}-2-furancarboxamide in methanol (5 ml) AND hydrazine .....N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1Hpyrazol-5-yl)-2-furancarboxamide.</div>
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SYNTHESIS OF INTERMEDIATES</div>
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Example 127</div>
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<br class="patent-full-image" id="imgf000261_0001" style="font-style: inherit; font-weight: inherit; line-height: 1.7;" />a) methyl 4,5-dibromo-2-furancarboxylate</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000261_0002.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000261_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000261_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000261_0002.png" height="257" id="imgf000261_0002" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000261_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="377" /></a></div>
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To a solution of 4,5-dibromo-2-furancarboxylic acid (25 g, 93 mmol) in methanol (185 ml) was added sulfuric acid (24.7 ml, 463 mmol). The resulting solution stirred at 50 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C over 12h. The solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over I^^SOφ concentrated and used directly without further purification providing methyl 4,5-dibromo-2-furancarboxylate (23.67 g, 83 mmol, 90 % yield), LCMS (ES) m/e 283, 285, 287 (M, M+2, M+4)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.b) methyl 4-bromo-2-furancarboxylate Br</div>
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To a solution of methyl 4,5-dibromo-2-furancarboxylate (3.3 g, 1 1.62 mmol) in tetrahydrofuran (46 ml) at -40 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C was added isopropylmagnesium chloride (6.97 ml, 13.95 mmol). After 1 h, Water (11 ml) was added and the solution warmed to 25 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SOφ concentrated and purified by column chromatography (3% EtOAc in hexanes) affording methyl 4-bromo-2-furancarboxylate (1.4 g, 6.49 mmol, 56 % yield) as a yellow solid: LCMS (ES) m/e 205, 207 (M, M+2)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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c) methyl 4-bromo-5-chloro-2-furancarboxylate</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0001.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000262_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0001.png" height="289" id="imgf000262_0001" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="424" /></a></div>
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A solution of methyl 4-bromo-2-furancarboxylate (1.4 g, 6.83 mmol) and NCS (0.912 g, 6.83 mmol) in N,N-dimethylformamide (13.7 ml) was stirred in a sealed tube for 1 h at 100 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C. After 1 h, the solution was partitioned between DCM- H2O and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over I^^SOφ concentrated and purified via column chromatography (2-10% EtOAc in hexanes) affording methyl 4-bromo-5-chloro-2- furancarboxylate (1.348 g, 5.12 mmol, 75 % yield) as a white solid: LCMS (ES) m/e 238, 240, 242 (M, M+2, M+4)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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d) methyl 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylate</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0002.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0002.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000262_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0002.png" height="300" id="imgf000262_0002" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000262_0002.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="365" /></a></div>
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A solution of methyl 4-bromo-5-chloro-2-furancarboxylate (1.1 g, 4.59 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.05 g, 5.05 mmol)[prepared according to Preparation 7], potassium carbonate (3.17 g, 22.97 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.117 g, 0.23 mmol) in 1 ,4- dioxane (19.14 ml) and water (3.83 ml) was stirred at 80 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C in a sealed tube for 1 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SOφ concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2- furancarboxylate (800 mg, 2.53 mmol, 55 % yield) as a yellow oil: LCMS m/e ES 240, 242 (M, M+2)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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e) 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylic acid</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000263_0001.png" href="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000263_0001.png" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;"><img alt="Figure imgf000263_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000263_0001.png" height="300" id="imgf000263_0001" src="http://patentimages.storage.googleapis.com/WO2008098104A1/imgf000263_0001.png" style="border: 1px solid rgb(221, 221, 221); color: #222222; font-style: inherit; font-weight: inherit; height: auto; line-height: 1.7; max-width: 100%; padding: 6px;" width="389" /></a></div>
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A solution of methyl 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2- furancarboxylate (300 mg, 1.25 mmol) in 6N sodium hydroxide (4.16 ml, 24.93 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70 <span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">0</span>C in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ~4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylic acid (267 mg, 0.59 mmol, 47 % yield) as a white foam: LCMS (ES) m/e 265 (M+H)<span style="bottom: 1ex; font-size: 10px; font-style: inherit; font-weight: inherit; height: 0px; line-height: 1; position: relative; vertical-align: baseline;">+</span>.</div>
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1: Dumble M, Crouthamel MC, Zhang SY, Schaber M, Levy D, Robell K, Liu Q, Figueroa DJ, Minthorn EA, Seefeld MA, Rouse MB, Rabindran SK, Heerding DA, Kumar R. Discovery of Novel AKT Inhibitors with Enhanced Anti-Tumor Effects in Combination with the MEK Inhibitor. PLoS One. 2014 Jun 30;9(6):e100880. doi: 10.1371/journal.pone.0100880. eCollection 2014. PubMed PMID: 24978597; PubMed Central PMCID: PMC4076210.</div>
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2: Pachl F, Plattner P, Ruprecht B, Médard G, Sewald N, Kuster B. Characterization of a chemical affinity probe targeting Akt kinases. J Proteome Res. 2013 Aug 2;12(8):3792-800. doi: 10.1021/pr400455j. Epub 2013 Jul 3. PubMed PMID: 23795919.</div>
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3: Pal SK, Reckamp K, Yu H, Figlin RA. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs. 2010 Nov;19(11):1355-66. doi: 10.1517/13543784.2010.520701. Epub 2010 Sep 16. Review. PubMed PMID: 20846000; PubMed Central PMCID: PMC3244346.</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-302770220608373834.post-40293349998153377172015-03-07T04:46:00.003-08:002015-03-07T04:46:39.750-08:00FDA approves new antifungal drug Cresemba<div dir="ltr" style="text-align: left;" trbidi="on">
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Isavuconazonium sulfate</div>
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<a href="http://links.govdelivery.com/track?type=click&enid=ZWFzPTEmbWFpbGluZ2lkPTIwMTUwMzA2LjQyNTQ3MDIxJm1lc3NhZ2VpZD1NREItUFJELUJVTC0yMDE1MDMwNi40MjU0NzAyMSZkYXRhYmFzZWlkPTEwMDEmc2VyaWFsPTE3MDg1ODcwJmVtYWlsaWQ9YW1jcmFzdG9AZ21haWwuY29tJnVzZXJpZD1hbWNyYXN0b0BnbWFpbC5jb20mZmw9JmV4dHJhPU11bHRpdmFyaWF0ZUlkPSYmJg==&&&100&&&http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm437106.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery" style="color: #0c5390; text-decoration: none;" target="_blank">FDA approves new antifungal drug Cresemba</a></div>
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03/06/2015 02:10 PM EST</div>
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The U.S. Food and Drug Administration today approved Cresemba (isavuconazonium sulfate), a new antifungal drug product used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections.</div>
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.syn……<a href="http://newdrugapprovals.org/2013/10/02/isavuconazole-basilea-reports-positive-results-from-study/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2013/10/02/isavuconazole-basilea-reports-positive-results-from-study/</a></div>
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The U.S. Food and Drug Administration today approved Cresemba (isavuconazonium sulfate), a new antifungal drug product used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections.</div>
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Aspergillosis is a fungal infection caused by Aspergillus species, and mucormycosis is caused by the Mucorales fungi. These infections occur most often in people with weakened immune systems.</div>
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Cresemba belongs to a class of drugs called azole antifungal agents, which target the cell wall of a fungus. Cresemba is available in oral and intravenous formulations.</div>
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“Today’s approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.</div>
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Cresemba is the sixth approved antibacterial or antifungal drug product designated as a Qualified Infectious Disease Product (QIDP). This designation is given to antibacterial or antifungal drug products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act.</div>
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As part of its QIDP designation, Cresemba was given priority review, which provides an expedited review of the drug’s application. The QIDP designation also qualifies Cresemba for an additional five years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act. As these types of fungal infections are rare, the FDA also granted Cresemba orphan drug designations for invasive aspergillosis and invasive mucormycosis.</div>
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The approval of Cresemba to treat invasive aspergillosis was based on a clinical trial involving 516 participants randomly assigned to receive either Cresemba or voriconazole, another drug approved to treat invasive aspergillosis. Cresemba’s approval to treat invasive mucormycosis was based on a single-arm clinical trial involving 37 participants treated with Cresemba and compared with the natural disease progression associated with untreated mucormycosis. Both studies showed Cresemba was safe and effective in treating these serious fungal infections.</div>
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The most common side effects associated with Cresemba include nausea, vomiting, diarrhea, headache, abnormal liver blood tests, low potassium levels in the blood (hypokalemia), constipation, shortness of breath (dyspnea), coughing and tissue swelling (peripheral edema). Cresemba may also cause serious side effects including liver problems, infusion reactions and severe allergic and skin reactions.</div>
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Cresemba is marketed by Astellas Pharma US, Inc., based in Northbrook, Illinois.</div>
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