The Synthetic Research Of Asunaprevir

Asunaprevir is a kind of new drug as a NS3/4A protease inhibitor, which is useful for the treatment of hepatitis C virus. It is researched and developed by an American company BRISTOL-MYERS SQUIBB Company. As a kind of NS3/4A protease inhibitor, Asunaprevir is a new kind of anti-HCV drugs.The chemical name of Asunaprevir is (1R,2S)-N-[(1,1-Dimethylethox-y)carbonyl]-3-methyl-L-valyl-(4R)-4-[(7-chloro-4-methoxy-1-isoquinolin yl)oxy]-L-prolyl-1-amino-N-(cyclopropylsulfonyl)-2-ethenylcyclopropanec arboxamide. This paper conducted a study on the synthesis of Asunaprevir, and optimized the process of the intermediates of Asunaprevir; And desigined a synthesis process of the key intermediate of Asunaprevir which provided a basic synthesis process for the future industrial production.In this paper, the research is divided into for parts as listed:First, the new synthesis process of the key intermediate 1,7-Dichloro-4-methoxy isoquinoline. And use 4-Chlorocinnamic acid as starting material, get the key intermediate 1,7-Dichloro-4-methoxy isoquinoline, desigined a new synthesis process of 1,7-Dichloro-4-methoxyisoquinoline, and optimized the process in lab, the process need 5 steps, compared with the original route, raw material is easily available, mild reaction conditions and the total yield reached 46.23%; Second, explored a simple and feasible method of resolution of N-Boc-(1 R,2S)/(1 S,2R)-1-Amino-2-vinylcy-clopropane carb-oxylic acid methyl ester, it used benzaldehyde and glycine ethyl ester hydrochloride as the starting material, synthesized the racemizated product, then separate to get the target configuration with chemical method, the ee value reached 99.4%. The process need 3 steps, compared with the original route, it is simple, reaction condition are warm, suitable for industrialized production; Third, we designed a route by using 3-chloro-propanol as the starting material, successfully synthesized intermediate cyclopropyl sulfonamide, the new route need 5 steps and the total yield is 56.14%;. Finally, after the successful synthesis of the intermediate compounds, we synthesized of the target product Asunaprevir.This research is based on the research of new synthetic route, mean while optimize the reaction route to be green, environmentally friendly, security, stability, suitable for industrial production.