Enzymatic synthesis of ivabradine midbody and application in the synthesis of ivabradine and addition salts thereof

Abstract

Preparing an optically pure (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid compound (I), comprises enantioselective enzymatically esterifying a racemic acid or 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (a), using a lipase or esterase, in a mixture of an alcohol and an organic cosolvent, at a temperature of 25-40[deg] C, where (a) is not pure, has a concentration of 5-500 g / l, and has an enzyme / substrate (E / S) ratio of 10 / 1:1 / 100. Preparing an optically pure (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid compound (I), comprises enantioselective enzymatically esterifying a racemic acid or 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (a), using a lipase or esterase, in a mixture of an alcohol of formula (ROH) and an organic cosolvent, at a temperature of 25-40[deg] C, where (a) is not pure, has a concentration of 5-500 g / l, and has an enzyme / substrate (E / S) ratio of 10 / 1:1 / 100. R : linear or branched 1-6C-alkyl, preferably methyl. Independent claims are included for: (1) process-II for preparing an optically pure compound of formula (S)3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid compound of formula (II) by enantioselective enzymatic hydrolysis of the racemic ester or ester compound of formula (b) using the lipase or esterase, in water and in a buffer solution of pH 5-8 or in a mixture of organic solvent and water or buffer at a temperature of 25-40[deg] C, where (b) is not pure, and has E / S ratio of 10 / 1:1 / 100; and (2) process-III for preparing ((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-trien-7-ylmethyl)-methyl-amine compound (III) comprising either hydrolyzing 3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (IV) to form (a), enzymatically esterifying (a) to form (I), converting (I) into an optically pure (S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid methylamide amide (c) and reducing (c), or hydrolyzing (IV) to form (a), alkylating (a) to form (b), enzymatically hydrolyzing (b) to obtain (II), converting (II) into (c), and reducing (c). [Image].

Description

technical field [0001] The present invention relates to the method for enzymatically synthesizing the compound of formula (I): [0002] [0003] where R 1 stands for hydrogen atom or C 1 -C 6 Alkyl group, preferably methyl, [0004] It also relates to its role in the synthesis of ivabradine or 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octane-1,3,5- Trien-7-yl]methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine Use of -2-ketones, their addition salts with pharmaceutically acceptable acids, and their hydrates [0005] Background technique [0006] Ivabradine and its addition salts with pharmaceutically acceptable acids, more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, which These compounds can be used to treat or prevent various clinical manifestations of myocardial ischemia, such as angina pectoris, myocardial infarction and related rhythm disturbances, an...

AI Technical Summary

Problems solved by technology

[0022] This very low yield is caused by the low yield (4-5%) of the resolution step of the edematous amine of formula (VII)

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