Novel method for synthesising derivatives of (2s,3as,7as)-1-[(s)-alanyl]-octahydro,-1h-indole-2-carboxylic acid and the use thereof for perindopril synthesis

A process for the synthesis of compounds of formula (I):

• wherein R1 represents hydrogen, linear or branched (C1-C6)alkyl or benzyl, and R2 represents a protecting group,
• wherein 1-(1-cyclohexen-1-yl)-pyrrolidine of formula (III)
• is reacted with a serine compound of formula (IV)
• wherein R1 is as defined for formula (I) and R3 represents a protecting group,
• to yield a compound of formula (V):
• the amine function of the compound of formula (V) is deprotected and the deprotected intermidiate thus obtained is subjected to dehydration, to yield a compound of formula (VI):
• which is reacted with an alanine compound of formula (VII):
• wherein R2 is as defined for formula (1),
• in an organic solvent,
• in the presence of an amount of dicyclohexylcarbodiimide of from 1 to 1.2 mol per mol of compound of formula (V) used and an amount of triethylamine of from 1 to 1.2 mol per mol of compound of formula (V) used and optionally in the presence of 1-hydroxybenzotriazole,
• at a temperature of from 20 to 50° C.,
• to yield, after isolation and recrystallisation, a compound of formula (VIII):
• which is hydrogenated in the presence of a catalyst,
• under a hydrogen pressure of from 1 to 30 bars, to yield, after optional deprotection or reprotection of the acid function, the compound of formula (I).