Novel method for the synthesis of perindopril and the pharmaceutically acceptable salts thereof

• Main Authors: CLAUDE FUGIER, THIERRY DUBUFFET, PASCAL LANGLOIS
• Format: Patent
• Language: English
• Published: 13.03.2008
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PEPTIDES; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES

Industrial synthesis of perindopril (I) involves: (a) reacting a (2S, 3aS, 7aS)-octahydro-1H-indole-2-carboxylic acid compound (II) with a 2(R)-substituted propionyl chloride (III) in presence of base; and (b) reacting the obtained (2S, 3aS, 7aS)-1-(2-substituted propionyl)-octahydro-1H-indole-2-carboxylic acid compound (IV) with ethyl (2S)-2-aminopentanoate (V) to give (I) (if necessary after deprotection). Some compounds (IV) are new. Industrial synthesis of perindopril of formula (I) or its salts involves: (a) reacting (2S, 3aS, 7aS)-octahydro-1H-indole-2-carboxylic acid (or its ester) of formula (II) with a 2(R)-substituted propionyl chloride of formula (III) in presence of base; and (b) reacting the obtained (2S, 3aS, 7aS)-1-(2-substituted propionyl)-octahydro-1H-indole-2-carboxylic acid (or its ester) of formula (IV) with ethyl (2S)-2-aminopentanoate of formula (V) to give (I) (if necessary after deprotection). R = H, benzyl or 1-6C alkyl; G = Cl, Br, OH, p-toluenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy. An Independent claim is included for intermediates of formula (IV; G = Cl, p-toluenesulfonyloxy or methanesulfonyloxy).