Synthesis Of Anti - HCV Drug TMC - 435 Intermediates

Hepatitis C virus(HCV) is the main cause of chronic liver disease worldweidely. Most of the infected individuals may develop to chronic hepatitis after initial acute infection, HCV therapy has became the focus of medical research and development with the number of patients involved. Currently, HCV therapy has the disadvantages of limited efficacy, obvious side effects and the poorly tolerated in many patients. Simeprevir(TMC-435) is a new type of protease inhibitor, which is developed by Janssen and Mediver. In September 2013, Simeprevir, that the trade name is Sovriad, was on the market in Japan.The main purpose of the paper is to design and optimize a new synthetic route of the important intermediate of Simeprevir(TMC-435). On the basis of the literature, one new synthetic route of the target compound was designed and optimized through conditional experiments.2-Methyl-3-amino-4-acethylanisole, the intermediate I, was synthesized from starting material 2-methyl-3-nitro phenol through phenolic hydroxyl methylation, Friedel-Crafts reaction catalyzed by aluminium trichloride and reduction by iron powder. 4-Isopropylthiazole-2-formyl chloride, the intermediate II, was synthesized from oxalyl chloride and 4-isopropyl-thiazole-2-formic acid, which was obtained from 3-methyl-2-butanone by bromination, cyclization with thiourea, Sandmeyer reaction in the presence of tert-Butyl nitrite, cyano-substitution with Copper(I) cyanide, and hydrolysis reaction.N-(2-Methyl-3-methoxy-6-acetylphenyl)-4-isopropyl-thiazole-2-carboxamide was prepared from intermediate II and intermediate I through N-acylation reaction. Finally, the target compound, the key intermediate of Simeprevir was prepared through cyclization with t-BuOK as the base.The experiments have proved that the new route has the advantages of simple operation, low cost, high yield, less pollution and is suitable for industrial preparation. The chemical structures of the target and intermediate compounds were confirmed by 1H-NMR, IR and so on.