Novel method for synthesizing (2S, 3AS, 7AS) -1-(S) -alanyl -octahydro-1H-indole-2-carboxylic acid derivatives and use thereof in perindopril synthesis

摘要

Synthesis of 1-alanyl-octahydroindole derivatives (I) involves reacting 1-(1-cyclohexen-1-yl)-pyrrolidine (III) with an iodo-serine derivative (IV); deprotecting the product (V), cyclizing and dehydrating; reacting the obtained hexahydroindole derivative (VI) with alanine derivative (VII); and hydrogenating the obtained 1-alanyl-hexahydroindole derivative (VIII). Industrial synthesis of (2S,3aS,7aS)-1-((S)-alanyl)-octahydro-1H-indole-2-carboxylic derivatives of formula (I) involves: (1) reacting 1-(1-cyclohexen-1-yl)-pyrrolidine (III) with an iodo-serine derivative of formula (IV); (2) deprotecting the obtained cyclohexyl-serine derivative of formula (V) then cyclizing and dehydrating; (3) reacting the obtained hexahydroindole derivative of formula (VI) with an alanine derivative of formula (VII) in an organic solvent (e.g. tetrahydrofuran or ethyl acetate) at 20-50degreesC in presence of 1-1.2 moles (based on (V)) of each of dicyclohexyl carbodiimide and triethylamine; and (4) subjecting the obtained 1-alanyl-hexahydroindole derivative of formula (VIII) (after isolation and recrystallization) to hydrogenation under a pressure of 1-30 (preferably 1-10) bars in presence of a catalyst (e.g. palladium, platinum, rhodium or nickel), optionally followed by deprotection and reprotection of the acid function, to give (I). R1 = H, 1-6C alkyl or benzyl; R2, R3 = amino-protecting groups. An Independent claim is also included for the praparation of perindopril or it salt from (I).