Process for the preparation of perindopril
AssigneeCipla Limited
InventorsRajendra Kankan, Dharmaraj Rao
Life of this patent
Estimating the term…
Abstract
A process for preparing perindopril (III) or a pharmaceutically acceptable salt thereof, which process comprises a substituted benzyl ester of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (I) with N-[(S)-carbethoxybutyl]-(S)-alanine (II) where R represents a halo, C1-4 alkoxy or nitro substituent.
Claims34
A process for preparing perindopril, or a pharmaceutically acceptable salt thereof, which process comprises coupling a substituted benzyl ester of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (I) with N-[(S)-carbethoxybutyl]-(S)-alanine (II):
- where R represents a halo, C1-4alkoxy or nitro substituent, to form the ester of formula III, wherein the coupling is carried out in the presence of N,N-dicyclohexyl carbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT):
- and converting the ester of formula III to perindopril or a pharmaceutically acceptable salt thereof.
2-35. (canceled)
A process for preparing perindopril, or a pharmaceutically acceptable salt thereof, which includes an intermediate process step wherein an aralkyl ester of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid is prepared by reaction of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid with an aralkyl alcohol, wherein either said (2S,3aS,7aS)-octahydroindole-2-carboxylic acid is treated with an excess of the alcohol and thionyl chloride, excess alcohol is distilled off and the residue treated with a solvent to obtain the aralykyl ester of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid as a hydrochloride;
- or said (2S,3aS,7aS)-octahydroindole-2-carboxylic acid is treated with an excess of the alcohol and heated with toluene using a molar quantity p-toluene sulphonic acid, to obtain the aralkyl ester of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid as a salt, and converting the salt to the base, preferably by treatment with ammonia.
A process for preparing perindopril, or a pharmaceutically acceptable salt thereof, which includes an intermediate process step which comprises conversion of an alkali metal salt of S-indoline-2-carboxylic acid to (2S,3aS,7aS)-octahydroindole-2-carboxylic acid by hydrogenation at a pressure of from 5 to 20 bar.
A process for preparing perindopril, or a pharmaceutically acceptable salt thereof, which includes an intermediate process step which comprises condensation of norvaline ethyl ester with pyruvic acid to yield N-[(S)-1-carbethoxybutyl]-(S)-alanine (II), wherein said condensation is carried out under catalytic hydrogenation and said catalyst and any inorganic salts present in the reaction medium are removed by filtration to obtain a filtrate, the filtrate is concentrated and N-[(S)-1-carbethoxybutyl]-(S)-alanine is isolated by precipitation by the addition of a solvent selected from acetone, acetonitrile and ethyl acetate.
Dependencies are inferred from the claim text.