Method for synthesis of (2S,3aS,7aS)-perhydroindole-2-carboxylic acid and esters thereof; and use in the synthesis of perindopril

摘要

Preparation of (2S, 3aS, 7aS)-perhydroindole-2-carboxylic acid (I) and its esters (I) is new. Preparation of (2S, 3aS, 7aS)-perhydroindole-2-carboxylic acid (I) and its esters by condensation of (2-oxocyclohexyl) acetic acid (III) with (S)-phenyl glycinol (IV) to form the tricyclic lactam (V) as a diastereoisomeric salt. (V) is then reduced in the presence of a Lewis acid to form (VI) and the 2-hydroxy-1-phenyl group removed to form (VII). Reaction of (VII) with triflic anhydride or an alkylating agent leads to the formation of (VIII). Compounds of formula (VIII) then undergo cyanation to form (IX), which is hydrolyzed to form (X). R = H, benzyl, or 1-6C alkyl; and R1 = trimethylsulfonate or 1-6C alkyl. Independent claims are included for the following: (1) Intermediates of formula (IX) and (X); and (2) Preparing perindopril using (I) prepared by the new process.