Novel method for synthesising perindopril and the pharmaceutically acceptable salt thereof

摘要

Preparation of perindopril (I) involves reacting 1-(1-cyclohexen-1-yl)-pyrrolidine (II) with a serine derivative (III); deprotecting the obtained cyclohexyl-serine derivative (IV), cyclizing and dehydrating; reacting the obtained hexahydroindole derivative (V) with N-((S)-1-ethoxycarbonyl-butyl)-(S)-alanine (VI); and hydrogenating and deprotecting the obtained hexahydroindole derivative (VII). Industrial production of (2S,3aS,7aS)-1-((2S)-2-((1S)-1-(ethoxycarbonyl)-butylamino)-propionyl)-octahydro-1H-indole-2-carboxylic acid of formula (I) or its salt (specifically the tert. butylamine salt) involves: (1) reacting 1-(1-cyclohexen-1-yl)-pyrrolidine (II) with an iodo-serine derivative of formula (III); (2) deprotecting the obtained cyclohexyl-serine derivative of formula (IV) then cyclizing and dehydrating; (3) reacting the obtained hexahydroindole derivative of formula (V) (optionally in mineral or organic acid addition salt form) with N-((S)-1-ethoxycarbonyl-butyl)-(S)-alanine (VI) in ethyl acetate at 20-77degreesC in presence of 0.4-0.6 moles 1-hydroxy-benzotriazole, 1-1.2 moles dicyclohexyl carbodiimide and 0.25-1.2 moles triethylamine (all based on (V)); and (4) subjecting the obtained 1-(N-substituted alanyl)-hexahydroindole derivative of formula (VII) (after isolation) to hydrogenation under a pressure of 1-30 (preferably 1-10) bars in presence of a catalyst (e.g. palladium, platinum, rhodium or nickel), followed by deprotection, to give (I). R1 = acid-protecting group; R2 = amino-protecting group.