Method for enzymatic synthesis of (7S)-3,4-dimethoxybicyclo(4.2.0)octa-1,3,5-triene-7-carboxylic acid or the esters thereof, and use for the synthesis of ivabradine and the salts thereof

摘要

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].