871038-72-1 (monopotassium salt)IUPAC Name:- N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)
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- Raltegravir Pharmacokinetics
i. Benzylchloroformate, N,N-diisopropylethylamine, Methyl tert-butyl ether, 20 – 25 °C, 16 h, ii. Hydroxyl amine, Water, 60 °C, 3 h, iii. Dimethyl acetylenedicarboxylate, methanol, Room temperature 2 h then Xylene 90 °C, 2 h, iv. Magnesium methoxide, dimethyl sulfoxide, Methyl iodide, 20 - 25 °C, 2 h, v. 4-fluorobenzyl amine, ethanol, 72 °C, 2 h, vi. 5% Pd/C, methanol, Molybdate sulfuric acid, Hydrogen gas, 50 °C, 3 h, vii. 5-methyl-1,3,4-oxadiazole-2-carbonylchloride, N-methylmorpholine, Tetrahydrofuran, 0 – 5 °C, 2 h
|preparation of Raltegravir is described in US patent 2006122205A1 and also in WO2006060730. Accordingly, 2-amino-2-methyl-propanenitrile 1 was reacted with benzylchloroformate in presence of N,N-diisopropylethylamine using methyl tert-butyl ether as solvent at ambient temperature to give benzyl N-(1-cyano-1-methyl-ethyl)carbamate 2. Treatment of 2 with hydroxyl amine using water as solvent at elevated temperature give benzyl N-[(2Z)-2-amino-2-hydroxyimino-1,1-dimethyl-ethyl]carbamate 3. The compound 3 was further cyclized with dimethyl acetylenedicarboxylate using methanol as solvent at higher temperature to give methyl 2-(1-benzyloxycarbonylamino-1-methyl-ethyl)-5-hydroxy-6-oxo-1H-pyrimidine-4-carboxylate 4. Compound 4 was then methylated with methyl iodide in presence of magnesium methoxide as base and dimethyl sulfoxide as solvent at ambient temperature to give methyl 2-(1-benzyloxycarbonylamino-1-methyl-ethyl)-5-hydroxy-1-methyl-6-oxo-pyrimidine-4-carboxylate 5. Compound 5 on condensing with 4-fluorobenzyl amine using ethanol as solvent result in to benzyl N-[1-[4-[(4-fluorophenyl)methylcarbamoyl]-5-hydroxy-1-methyl-6-oxo-pyrimidin-2-yl]-1-methyl-ethyl]carbamate 6, which underwent benzyloxy-decarboxylation on hydrogenating with hydrogen gas in presence of 5% Palladium on carbon catalyst and molybdate sulfuric acid using methanol as solvent to give 2-(1-amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-5-hydroxy-1-methyl-6-oxo-pyrimidine-4-carboxamide 7. The final step involves condensation of 7 with 5-methyl-1,3,4-oxadiazole-2-carbonylchloride in presence of N-methylmorpholine as base using tetrahydrofuran as solvent at slightly lower temperature to afford N-[1-[4-[(4-fluorophenyl)methylcarbamoyl]-5-hydroxy-1-methyl-6-oxo-pyrimidin-2-yl]-1-methyl-ethyl]-5-methyl-1,3,4-oxadiazole-2-carboxamide also called Raltegravir 8.|