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BHV-7000 is under investigation in clinical trial NCT06419608 (Efficacy and Safety Study of BHV-7000 Monotherapy in Major Depression).
Opakalim (also known as BHV-7000) is an investigational, small-molecule medication that acts as a selective activator of Kv7.2 and Kv7.3 potassium channels. Developed by Biohaven Pharmaceuticals, it targets a clinically validated pathway to regulate neuronal hyperexcitability, primarily for the treatment of epilepsy and focal seizures.
Key Characteristics
Mechanism of Action: It opens Kv7.2/7.3 potassium channels. This stabilizes electrical activity in the brain. Unlike older class drugs, it has minimal to no (GABA_A) receptor activity.
Safety Benefit: Its precision prevents typical central nervous system side effects. Patients experience much lower rates of somnolence, fatigue, and severe dizziness compared to other anti-seizure medications.
Administration: It is taken orally once a day. It requires no titration period before reaching therapeutic dosing.
Current Clinical Status
Refractory Focal Epilepsy: The drug is undergoing phase 2/3 clinical evaluation. The pivotal RISE 3 study completed patient enrollment, with high-profile top-line efficacy data anticipated in the second half of 2026.
Idiopathic Generalized Epilepsy (IGE): Recent clinical data highlights a three-fold prolongation in the time to a second generalized tonic-clonic seizure compared to a placebo.
Other Explored Indications: While it is actively tested for conditions like bipolar disorder and erythromelalgia (pain), an exploratory phase 2 trial for major depressive disorder failed to meet its primary goals.
Opakalim (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name; developmental code names BHV-7000, BPN-25203, and KB-3061) is a highly selectiveKv7.2 and Kv7.3potassium channel opener which is under development for the treatment of bipolar disorders, epilepsy, partial epilepsies, major depressive disorder, erythromelalgia, pain, infantile spasms, and mood disorders.[1][2][3][4] It is taken orally.[1] The drug was originated by Channel Biosciences and was under development by Biohaven Pharmaceuticals or Biohaven Therapeutics.[1][2] As of April 2026, it is in phase 2/3clinical trials for bipolar disorders, epilepsy, and partial epilepsies, phase 2 trials for major depressive disorder, and phase 1 trials for erythromelalgia and pain, whereas no recent development has been reported for infantile spasms and mood disorders.[1][2] A phase 2 trial for major depressive disorder failed to meet its primary efficacy endpoint, resulting in focus more on epilepsy instead.[3]
Study to Determine if BHV-7000 is Effective and Safe in Adults With Refractory Focal Onset EpilepsyCTID: NCT06309966Phase: Phase 2/Phase 3Status: Active, not recruitingDate: 2026-07-01
A Study to Determine if BHV-7000 is Effective and Safe in Adults With Refractory Focal Onset EpilepsyCTID: NCT06132893Phase: Phase 2/Phase 3Status: RecruitingDate: 2026-05-01
Long-term Safety and Tolerability of BHV-7000CTID: NCT06443463Phase: Phase 2Status: Enrolling by invitationDate: 2026-05-01
A Phase 1b Study of BHV-7000 in Participants With Inherited ErythromelalgiaCTID: NCT07262268Phase: Phase 1Status: Enrolling by invitationDate: 2026-04-08
Long-term Safety Study of BHV-7000 in Participants With Major Depressive Disorder (MDD)CTID: NCT06423781Phase: Phase 2Status: CompletedDate: 2026-04-01
A Study to Determine if BHV-7000 is Effective and Safe in Adults With Idiopathic Generalized Epilepsy With Generalized Tonic-clonic SeizuresCTID: NCT06425159Phase: Phase 2/Phase 3Status: TerminatedDate: 2026-03-24
Efficacy and Safety Study of BHV-7000 Monotherapy in Major DepressionCTID: NCT06419608Phase: Phase 2Status: CompletedDate: 2026-01-07
Pelorosso C, Balestrini S, Guerrini R (May 2026). "Potassium channel agonists emerging as treatment options for focal epilepsy: are we breaking new ground?". Expert Opinion on Emerging Drugs: 1–8. doi:10.1080/14728214.2026.2675274. hdl:2158/1473832. PMID42153277.
Pong AW (December 2025). "Expanding the toolkit: An update on the evolution of new therapies for Lennox-Gastaut Syndrome". Seminars in Pediatric Neurology. 56 101242. doi:10.1016/j.spen.2025.101242. PMID41371876.
In combination with fulvestran, to treat hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer without a PIK3CA mutation detected following progression on or after treatment with at least one line of endocrine therapy in the metastatic setting
Gedatolisib, sold under the brand name Revtorpyk, is an anti-cancer drug used for the treatment of breast cancer.[1] It is under development by Celcuity, Inc. Gedatolisib is a kinase inhibitor.[1] The mechanism of action is accomplished by binding the different p110 catalytic subunit isoforms of PI3K and the kinase site of mTOR.[2] Gedatolisib is administered by intravenous infusion.[1]
Gedatolisib was approved for medical use in the United States in July 2026.[1][3]
Medical uses
Gedatolisib is indicated in combination with fulvestrant, with or without palbociclib, for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer without a PIK3CA mutation detected following progression on or after treatment with at least one line of endocrine therapy in the metastatic setting.[1]
Preparation of 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with N,N-dimethylpiperidin-4-amine (51 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (30.6 mg, 52% yield); MS (ESI) m/z=616.7.
Preparation of 1-(4-(4-(dimethylamino) piperidine-1-carbonyl)phenyl-3-(4-(4,6- dimorpholino-1 ,3,5-triazine-2-yl)phenyl) urea (9)
To a slurry of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)phenyl)ureido)benzoic acid (7, 45.5 g, 0.09 mol) in dry THF (1.6 L) heated to 50 0C was added N,N'-carbonyl diimidazole (28 g, 0.17 mol). The reaction mixture was heated for 2 hours and followed by dimethylaminopiperidine (8, 23.5 g, 0.18 mol) and stirred at 53 0C for 16 hours. The reaction mixture was cooled to the room temperature and filtered. The cake was washed with 2-propanol and air-dried to give 97 % pure white powder in 88% yield (49.2 g, 0.08 mol). To the solids stirred in dimethyl acetamide (DMAC, 165 ml) at 70° C for 1 hour was added 2-propanol (640 ml) and the mixture was stirred at 65 0C for additional 1 hour. The solids were filtered, washed with 2-propanol and dried in a vacuum oven at 700C for 16 hour to give crystalline white powder (45 g) with >99% purity. The above-mentioned work up process and crystallization procedure gave a Pd residue of 20 ppm. Alternate procedures for the formation of 1-(4-(4-(dimethylamino) piperidine-1 - carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl) urea (9)
To the solution of 4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl) aniline (4, 18 g, 0.052 mol) in dichloromethane (300 ml) was added methyl 4-isocyanato benzoate (5, 10.5 g, 0.061 mol) and the reaction mixture was stirred for 5 hours. The separated solids were filtered, washed with ether and air dried to give beige solids (21 g, 0.04 mol). Yield 77%. 90 % pure by HPLC; Mass: 520.1 (M+H). Preparation of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (7)
The mixture of methyl 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)ureido)benzoate (6, 21 g, 0.04mol) and lithium hydroxide monohydrate (3.8 g, 0.09 mol) in THF (120 ml), MeOH (60 ml), and water (60 ml) was heated at 80 0C for 3 hours. The dark brown solution was cooled to room temperature and made acidic with concentrated HCI. The solids were filtered, washed with water, washed with acetone , washed with ether, and dried in a vacuum oven at 60 0C for 48 hours to give off white solids of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (19.2 g, 0.038 mol). Mass: 506.3 (M+H)+; Yield.94%. 1 -(4-(4-(dimethylamino) piperidine-1 -carbonyl)phenyl-3-(4-(4,6-dimorpholino- 1 ,3,5-triazine-2-yl)phenyl) urea (9)
The suspension of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (7, 17 g, 33.66 mmol) and N-(3-dimethylaminopropyl)ethyl carbodiimide hydrochloride (9.5 g, 49.5 mmol) in THF (200 ml) and acetonitrile (50 ml) was stirred for 10 min and followed by addition of 1-hydroxybenzotriazole hydrate (6.4 g, 47.88 mmol). The reaction mixture was stirred for 30 min and 4-dimethylaminopiperidine (8, 8.86 g, 69.2 mmol) was added by drops. After being stirred for additional 16 hours, the reaction mixture was concentrated to min. The solids were filtered and washed thoroughly with water (very fine suspension). The cake was slurred in hot ethanol, filtered and dried in a vacuum oven at 68 0C for 16 hours to give off white solids (10.3 g, 16.77 mmol). M. p. 238-240 0C. 99 % pure. Mass: 616.3 (M+H)+; Yield 50 %.
PATENT
WO 2009143317
WO 2010096619
WO 2012148540
WO 2014151147
PATENT
US 20170119778
PAPER
Journal of Medicinal Chemistry (2010), 53(6), 2636-2645
The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure−activity relationships and the in vitro and in vivo activity of analogues in this series are described.
Preparation of 1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4- yl-1,3,5-triazin-2-yl)phenyl]urea (26)
MS (ESI) m/z = 616.7. HRMS: calcd for C32H41N9O4 + H+, 616.335 43; found (ESI-FTMS, [M + H]+), 616.334 24. Purity by analytical HPLC 99.3%. (Prodigy ODS3, 0.46 cm × 15 cm, 20 min gradient acetonitrile in water, trifluoroacetic acid, detector wavelengths, 215 and 254 nm.) 1H NMR (DMSO-d6) δ 1.29−1.36 (m, 6H), 2.6 (m, 4H), 2.9 (m,1H), 3.3 (m, 4H), 3.6 (m, 8H), 3.7 (m, 8H), 7.3 (d, J = 8.3 Hz, 2H), 7.51−7.57 (m, 4H), 8.3 (d, J = 8.3 Hz 2H), 8.9 (s, 1H), 9.0 (s, 1H) ppm. Anal. Calcd for C32H41N9O4: C 62.42%, H 6.71%, N 20.47%. Found: C 62.34%, H 6.67%, N 20.39%.
A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.
Khafizova, G.; Potoski, J. R. PCT Int. Appl. WO 2010096619, 2010.
Venkatesan, A. M.; Chen, Z.; Dehnhardt, C. M.; Dos Santos, O.; Delos Santos, E. G.; Zask, A.; Verheijen, J. C.; Kaplan, J. A.; Richard, D. J.; Ayral-Kaloustian, S.; Mansour, T. S.; Gopalsamy, A.; Curran, K. J.; Shi, M. PCT Int. Appl. WO 2009143317, 2009.
REFERENCES
1: Gedaly R, Galuppo R, Musgrave Y, Angulo P, Hundley J, Shah M, Daily MF, Chen C, Cohen DA, Spear BT, Evers BM. PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation. J Surg Res. 2013 Nov;185(1):225-30. doi: 10.1016/j.jss.2013.05.016. Epub 2013 May 25. PubMed PMID: 23769634.
3: Dehnhardt CM, Venkatesan AM, Chen Z, Delos-Santos E, Ayral-Kaloustian S, Brooijmans N, Yu K, Hollander I, Feldberg L, Lucas J, Mallon R. Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8. doi: 10.1016/j.bmcl.2011.06.063. Epub 2011 Jun 21. PubMed PMID: 21763134.
4: Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15. PubMed PMID: 21325073.
5: Venkatesan AM, Chen Z, dos Santos O, Dehnhardt C, Santos ED, Ayral-Kaloustian S, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Chaudhary I, Mansour TS. PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73. doi: 10.1016/j.bmcl.2010.07.104. Epub 2010 Jul 30. PubMed PMID: 20797855.
6: Venkatesan AM, Dehnhardt CM, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, Khafizova G, Brooijmans N, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Gibbons J, Abraham RT, Chaudhary I, Mansour TS. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010 Mar 25;53(6):2636-45. doi: 10.1021/jm901830p. PubMed PMID: 20166697.
Clinical trial number NCT01420081 for "A Study Of Two Dual PI3K/mTOR Inhibitors, PF-04691502 And PF-05212384 In Patients With Recurrent Endometrial Cancer" at ClinicalTrials.gov
Clinical trial number NCT01925274 for "A Study Of PF-05212384 Plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS And NRAS Wild Type Metastatic Colorectal Cancer" at ClinicalTrials.gov
Clinical trial number NCT02438761 for "PF-05212384 (PKI-587) for t-AML/MDS or de Novo Relapsed or Refractory Acute Myeloid Leukemia (AML)" at ClinicalTrials.gov
Clinical trial number NCT03698383 for "Phase II Study of Herzuma® Plus Gedatolisib in Patients With HER-2 Positive Metastatic Breast Cancer" at ClinicalTrials.gov
Clinical trial number NCT03911973 for "Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast Cancers" at ClinicalTrials.gov
Clinical trial number NCT03065062 for "Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the PI3K/mTOR Inhibitor Gedatolisib (PF-05212384) for Patients With Advanced Squamous Cell Lung, Pancreatic, Head & Neck and Other Solid Tumors" at ClinicalTrials.gov
Clinical trial number NCT02626507 for "Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/HER2- Breast Cancer" at ClinicalTrials.gov
World Health Organization (2015). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 73". WHO Drug Information. 29 (1). hdl:10665/331088.
External links
Clinical trial number NCT05501886 for "Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer (VIKTORIA-1) (VIKTORIA-1)" at ClinicalTrials.gov
To treat adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer after receiving a ROS1 kinase inhibitor
FDA 2026, APPROVALS 2026, Jideytro, NVL-520, NUV-520, NU-520, NVL 520, NUV 520, NU 520, MX5KQV5XHC
Zidesamtinib (sold under the brand name Jideytro) is an oral, highly selective, next-generation kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) on July 22, 2026, to treat adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who have previously been treated with at least one ROS1 kinase inhibitor. Developed originally by Nuvalent and subsequently acquired by GSK, it represents a major milestone as GSK's first approved therapeutic targeting lung cancer.
Mechanism of Action
Zidesamtinib functions by targeting and inhibiting the receptor tyrosine kinase c-ros oncogene 1 (ROS1). It is custom-engineered to solve the primary clinical challenges that limit previous therapies:
Overcoming Resistance Mutations: It binds tightly to wild-type ROS1 and remains robustly active against a broad array of treatment-emergent point mutants. This includes G2032R (the most common solvent-front resistance mutation), as well as S1986Y/F, L2026M, and D2033N mutations.
Blood-Brain Barrier Penetration: It features high central nervous system (CNS) penetrance to effectively treat and control brain metastases, which are frequent in aggressive ROS1-positive cancers.
TRK-Sparing Design: Unlike older dual-acting inhibitors, it deliberately avoids inhibiting the structurally similar tropomyosin receptor kinase (TRK) family. This minimizes off-target TRK-related neurological toxicities like severe dizziness and ataxia.
Clinical Trial Outcomes
The FDA approval was heavily supported by data from the ongoing global, single-arm, Phase 1/2 ARROS-1 clinical trial (N=117 heavily pretreated patients):
Overall Response: Delivered an Objective Response Rate (ORR) of 44% in patients who had exhausted alternative TKI options.
Subgroup Efficacy: Achieved a 51% ORR in patients who had received only one prior ROS1 inhibitor, a 54% ORR in those harboring the G2032R mutation, and an intracranial ORR of 48% for patients with active brain metastases.
Durability: Showed prolonged disease control, with a 12-month duration of response (DOR) rate standing at 69%.
Administration and Side Effects
Jideytro is formulated as an oral tablet taken once daily, with or without food. It demonstrates a highly tolerable safety profile, with only a 10% dose reduction rate and a 2% treatment discontinuation rate due to adverse events.
Common Adverse Reactions (≥ 15%): Edema (swelling), peripheral neuropathy, constipation, fatigue, and dyspnea (shortness of breath).
Warnings & Precautions: Includes risks of mild CNS reactions (dizziness, cognitive alterations), QTc interval prolongation, skeletal fractures, pancreatic toxicity, and interstitial lung disease (ILD)/pneumonitis.
Zidesamtinib, sold under the brand name Jideytro, is an anti-cancer medication used for the treatment of previously treated locally advanced or metastatic ROS1+ non-small cell lung cancer.[1][2][3] It is taken by mouth once daily.[1][2][3]
Medical uses
Indication
Zidesamtinib is a prescription medicine used to treat adults with non-small cell lung cancer that has spread within the chest or other parts of the body and is caused by an abnormal ROS1 gene, and who have received a ROS1 kinase inhibitor.[1][2][3]
Mechanism of action
Zidesamtinib is a kinase inhibitor that works by blocking ROS1, an abnormal protein that drives some lung cancers to grow, including forms that have become resistant to earlier ROS1 treatments.[4] Jideytro also works on the related proteins ALK and TRK. In laboratory and animal studies, Zidesamtinib stopped cancer cells with ROS1 changes from growing and slowed tumor growth, including tumors in the brain.[2]
[00548] Synthesis of Compound 5. To a reactor was charged THF (10 vol ), water (1 vol ), followed by Compound 6 (850.0 g, 2.68 mol, 1 equiv.) and Compound 7 (534.0 g, 3.22 mol, 1.2 equiv ) at 20~30°C. The solids were completely dissolved at 20~30°C while stirring for 15 min and K2CO3 (1.11 kg, 3 equiv.) was added in portions over 10-15 min at 20~30°C. The reaction mixture was fully refdled with nitrogen, and was added Pd(dppf)C12 (78.5 g, 0.04 equiv.) in one portion under nitrogen. The reaction mixture was fully refdled with nitrogen again, then heated to 60-65 °C and stirred at 60~65°C for 16 h under nitrogen. The reaction mixture was cooled to 20~30°C, fdtered through a 10 cm celite pad (2X, 2.4 kg celite). The combined fdtrates were washed with EtOAc (10 vol., 21 L) and separated. The organic phase was washed with water (5 vol., 10.5 L) and separated. The organic phase was stirred for 1 h at 40-45°C in 5 w% aqueous L-cysteine (2.0 eq., 1.61 kg in 30.6 kg water) and separated. The organic phase was washed with water (5 vol., 10.5 L) and separated. The resulting organic phase was concentrated at 45-50°C in vacuum to afford crude product as a light brown oil (2.28 kg). To the crude product was charged MTBE (228 mL, 0.1 vol. relative to crude product), heated to 50°C over 15 min, followed by isopropyl ether (2.28 L, 1 vol.) dropwise over 1 h at 45~50°C, then cooled to 10°C over 2 h. A large amount of solids came out and the resulting slurry was stirred for 2 h at 10-15°C. The solids were collected by fdtration, dried in oven at 45°C for 16 h to get crude Compound 5 as a pale-yellow solid (1.67 kg, 96.3% /220 nm, >99.9%/220 nm chiral purity). 1.67 kg of crude Compound 5 was purified by silica gel chromatography (EtOAc/ n-heptane=l: 1, 2.5X silica gel, 100-200 meshes) to get Compound 5 as an off-white solid (1.58 kg, 99.6%/220 nm, >99.9%/220 nm chiral purity, 97.9 w%, 72% yield). H NMR (400 MHz, DMSO) 5 7.44 (dd, J = 10.5, 2.5
[00549] In another example, a similar procedure was run in a 0.5:2 biphasic mixture of toluene and water (2.5 vol.) with a catalystic amount (e.g. 0.002 mol equiv.) Pd(Amphos)C12 (instead of 0.04 mol equiv. of PdidppfhCE) used as the catalyst. Potassium phosphate (K3PO4 3 H2O) substituted potassium carbonate (K2CO3) 3.0 mol equiv. as the base, and the amount of Compound 7 employed was 1.02 mol equiv. The improved process was conducted at 50 °C. At the end of the reaction, the organic layer was fdtered and treated with activated carbon and concentrated, and the final material was crystallized from toluene/heptane/water to give Compound 5 in 92% yield and 99.9% purity.
[00550] Synthesis of Compound 3. To a 50 L reactor was charged dichloromethane (11.25 L), Compound 5 (750 g, >99.9%/220 nm chiral purity) and triethylamine (920.0 g) at r t. (20~30°C). The resulting mixture was refilled with nitrogen and cooled to 0°C. To it was added a solution of MS2O (793.0 g) in dichloromethane (3.75 L) drop-wise over 45 min while keeping the temperature at 0~5°C. The reaction mixture was stirred at 0~5°C for 1 h under nitrogen. The reaction mixture was quenched with cooled water (7.5 L) at 5~15°C and separated. The organic phase was washed with cooled water (3.75 L) and separated. The organic phase was dried over anhydrous Na2SC>4, filtered and concentrated at 25~30°C in vacuum to around 2 vol., then switched to n-heptane (2.25 L) and concentrated at 25~30°C in vacuum to around 2 vol. of Compound 3 in n-heptane. n-heptane /EtOAc (3.0 L, lOv/lv) was added to the above mixture and the mixture was slurried for 1 h at 0~10°C under nitrogen and filtered. The filter cake was washed with n-heptane (1.5 L), dried in vacuum at 25~30°C for 5 h to afford Compound 3 as an off-white solid (845 g, 98.9 w%, 99.98%/220 nm chiral purity, 91% yield). H NMR (400 MHz, CDC13) 5 7.35 (dd, J = 9.6, 2.5 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.12 (s, 1H), 7.08 (td, J = 8.3, 2.6 Hz, 1H), 5.78 (d, J = 6.4 Hz, 1H), 4.21 (s, 3H), 4.05 (q, J = 7.3 Hz, 2H), 3.90 - 3.76 (m, 2H), 2.78 (s, 3H), 1.58 (d, J = 6.5 Hz, 3H), 1.40 (t, J = 7.3 Hz, 3H). MS (ESI, m/z): 408.20 (M + H)+.
[00551] In another example, triethylamine base (1.3 mol equiv.), MS2O (1.2 mol equiv.), and dichloromethane solvent (10 vol) were used. The reaction mixture was quenched with aqueous sodium bicarbonate to remove excess MS2O, and crystallization from dichloromenthane/hexane results in 98% yield with 100% purity of Compound 3.
[00552] Synthesis of Compound 2. A 20 L reactor was refilled with nitrogen, then charged with DMA (12.6 L) at r.t. (20~25°C) To the reactor was charged Compound 4 (390.0 g) and Compound 3 (840.0 g, 99.98%/220 nm chiral purity) in one portion at 20~25°C through a dry nitrogen flow. The reaction mixture was heated to 35°C over 15 min and stirred for 5-10 min at 35~40°C to get a clear solution. To the reaction mixture was charged powder K3PO4 (875.0 g) in one portion at 35~45°C. After complete addition, the resulting mixture was heated to 60°C over 20 min and stirred at 58~63°C for 1.5 h through a dry nitrogen flow. The reaction mixture was cooled to 25~30°C, filtered through a celite pad (5 cm, 1.5 kg) and rinsed the filter cake with EtOAc (2 L, 2-3 vol.). The filtrate was poured into water (16.8 L, 20 vol.) at 0-10°C, extracted with EtOAc (10 L, 12 vol.) and separated. The aqueous phase was extracted with EtOAc (5 L, 6 vol.). The combined organic phases were washed with water (5 L*3, 6 vol. *3), concentrated at 50°C in vacuum to afford crude product as a gray solid (956 g). The crude product was dissolved in EtOAc (950 mL, 1 vol. relative to crude product) at 35~40°C, then was added dropwise n-heptane (950 mL, 1 vol. relative to crude product) at 30~40°C over 20 min. The resulting mixture was cooled to 20~25°C over 30 min and stirred for 1 h at 30-40°C. Some solids came out slowly and n-heptane (1.9 L, 2 vol. relative to crude product) was added dropwise to the slurry mixture at 20~25°C over 30 min. The precipitates were stirred at 15~20°C for 3 h and filtered. The filter cake was washed with n-heptane (1.5 L) and dried in oven at 45-50°C for 16 h to afford Compound 2 as a pale-yellow solid (743 g, 98.6%/220 nm, 96.9 w%, 99.98%/220 nm chiral purity, 0.48%KF, 72% yield). H NMR (400 MHz, DMSO) 5 7.54 (dd, J = 10.2, 2.7 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.42 (s, 1H), 7.31 (dd, J = 8.5, 5.8 Hz, 1H), 7.22 (td, J = 8.4, 2.7 Hz, 1H), 7.17 (s, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.14 (s, 2H), 5.47 (q, J = 6.0 Hz, 1H), 4.22 (s, 3H), 4.02 (q, J = 7.3 Hz, 2H), 3.78 (q, J = 16.1 Hz, 2H), 1.40 (d, J = 6.3 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H). MS (ESI, m/z): 500.30 (M + H)+.
[00553] In another example, a process was developed where Compound 4 (1.1 mol equiv. to Compound 3) was used. Potassium phosphate base (K2PO4, 4. 1 mol equiv.) and DMA (16 vol.) were substituted with cesium carbonate (CS2CO3, 2.2 mol equiv.) and NMP (5.6 vol.). The reaction was carried out at 20~30°C. Following completion of the reaction, the crude product was precipitated with water. The material was then dissolved in ethyl acetate, washed with water, and treated with activated carbon. The product is subsequently crystallized from toluene/ethyl acetate/heptane to give Compound 2 in 80% yield and 99.9% purity.
[00554] Synthesis of Compound 1. To a reactor was charged t-AmOH (20 vol.), Compound 2 (700.0 g, 99.99% chiral purity) and potassium pivalate (588.0 g). The reaction mixture was fully refilled with nitrogen. To the reaction mixture was added cataCXium A (120.4 g) and Pd(OAc)2 (37.8 g) at r.t. under nitrogen. The resulting mixture was heated to 100°C and stirred for 18 h under nitrogen. The reaction mixture was cooled to 30°C , filtered through a celite pad and washed the filter cake with EtOAc (3 vol.). The filtrate was washed with water (5 vol. *2) and separated. The upper organic phase was concentrated in vacuum to afford a brown oil. The oil was dissolved in EtOAc (27 L) then added 5w% aqueous L-cysteine (0.98 kg in 18.6 kg water), stirred for 1 h at 40~45°C and separated. The organic phase was washed with water (6.75 L) and separated. 5w% aqueous L-cysteine (0.98 kg in 18.6 kg water) was charged to the above organic phase, stirred for 1 h at 40~45°C and separated. The organic phase was washed with water (6.75 L.) and separated. The organic phase was concentrated in vacuum at 45~50°C to afford a brown solid (1.12 kg). The crude solid (1.12 kg) was further purified by silica gel chromatography eluted with EtOAc/DCM (dry loading, 3X, 100-200 meshes, EtOAc:DCM=l : 1) to afford a pale-yellow solid ( 1.02 kg). The solid was dissolved in EtOAc (600 mL, 2 vol.) at 50~60°C, then was added n-heptane (1.8 L, 6 vol.) dropwise over 50 min at 50~60°C. A large of solids came out during addition. The resulting slurry was cooled to 15~20°C over 50 min and stirred for 30 min at 15~20°C. The slurry was concentrated in vacuum at 45~50°C to 2-3 vol. mixture, n-heptane (1.2 L, 4 vol.) was added to the
above mixture (2-3 vol.), concentrated in vacuum at 45~50°C to 2-3 vol. mixture. The mixture was cooled to 10~15°C over 2 h, stirred at 10~15°C for 1 h and filtered. The filtered cake was rinsed with n-heptane (600 mb) and dried in vacuum at 50°C for 20 h to afford Form 1 of Compound 1 as an off-white solid (280 g, 99.0%). H NMR (400 MHz, DMSO) 57.79 (dd, J = 10.3, 2.2 Hz, 1H), 7.58 (s, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.24 - 7.16 (m, 2H), 6.13 (s, 2H), 6.08 (d, J = 1.7 Hz, 1H), 5.31 - 5.23 (m, 1H), 4.16 (s, 3H), 4.05 - 3.94 (m, 2H), 3.78 (d, J = 15.6 Hz, 1H), 2.98 (d, J = 15.5 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H). MS (ESI, m/z): 420.30 (M + H)+. XRPD (FIG. 1), TG/DTA (FIG. 2), DSC (FIG. 3), DVS (FIG. 4), and FT-IR (FIG. 5) results for a sample of Form 1 were obtained.
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