Process for the preparation of perindopril

摘要

A process for preparing perindopril comprising: coupling a substituted benzyl ester of (2S, 3aS, 7aS) -2-carboxyoctahydroindole (I) with N-[(S)-1-carbethoxybutyl]-(S)-alanine (II) in the presence of N,N-dicyclohexyl carbodiimide (DCC) and l-hydroxybenzotriazole (HOBT),where R is a halo, C1-C4 alkoxy or nitro substituent, to form ester (III); and converting ester (III) to perindopril or a pharmaceutically acceptable salt thereof. This deprotection may be effected by hydrogenolysis using a noble metal catalyst such as palladium on carbon. A process for preparing perindopril including the formation of aralkyl esters of (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid by formation of the acid chloride with thionyl chloride followed by reaction with an aralkyl alcohol, or esterification with an aralkyl alcohol in the presence of p-toluenesulfonic acid is claimed. A process for preparing perindopril including the formation of (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid from an alkali metal salt of S-indoline-2-carboxylic acid by hydrogenation at 5-20 bar is claimed. A process for preparing perindopril including the formation of N-[(S)-1-carbethoxybutyl]-(S)-alanine (II) from norvaline ethyl ester and pyruvic acid under catalytic hydrogenation conditions is also claimed.