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

摘要

Synthesis of (2S,3aS,7aS)-1-((S))-alanyl-octahydro-1H-indole-2-carboxylic acid derivatives (I) comprises reacting 2,7-oxepanedione with an amino acid derivative to give a ketone which is cyclized to give a lactam. The lactam is converted to an indole derivative which is then reacted with an alanine derivative to give 2,3,4,5,6,7-hexahydro-1H-indole derivative which is hydrogenated to give (I). Industrial synthesis of (2S,3aS,7aS)-1-((S))-alanyl-octahydro-1H-indole-2-carboxylic acid derivatives of formula (I) by: (i) reacting 2,7-oxepanedione with a compound of formula (IV) in the presence of zinc or zinc/copper amalgam to give, after deprotection of the amine function, a compound of formula (V); (ii) cyclizing (V) with a chlorination agent such as thionyl chloride or oxalyl chloride or a peptide coupling agent to give a compound of formula (VI); (iii) coupling (VI) in the presence of titanium to give a compound of formula (VII); (iv) reacting (VII) with an alanine derivative of formula (VIII) in an organic solvent such as THF or ethyl acetate in the presence of 1-1.2 moles of dicyclohexylcarbodiimide per mole of (VII), and optionally in the presence of 1-hydroxybenzotriazole at 20-50 degrees C with an acid chloride of formula (VIIIb) to give, after isolation followed by recrystallization, a compound of formula of formula (IX); (v) hydrogenating (IX) in the presence of a catalyst such as palladium, platinum, rhodium or nickel and a hydrogen pressure of 1-30 bars, to give, after optional deprotection of the acid group, (I). R1 = H or 1-6C alkyl or benzyl; R'1 = benzyl or 1-6C alkyl; R3 = amine protecting group which is not the same as R1'; and X = Br or I.