ENZYMATIC SYNTHESIS METHOD OF (7S)-3,4-DIMETHOXY BICYCLO[4.2.0]OCTA-1,3,5-TRIENE-7-CARBOXYLIC ACID, AND APPLICATION IN SYNTHESIS OF IVABRADINE AND SALT THEREOF

摘要

PROBLEM TO BE SOLVED: To provide a synthesis method of ivabradine and an addition salt thereof with a pharmaceutically acceptable acid.SOLUTION: A synthesis method of an ivabradine synthesis intermediate compound represented by the formula (I) is provided. In the synthesis method, in a mixture of an organic solvent with an aqueous solution having a pH of 5 to 10, a corresponding racemic nitrile with a concentration of 1 to 500 g per 1 liter of the solvent mixture is enantioselectively enzymic hydrolyzed with rhodococcus-rhodochrous nitrilase overexpressed in another organism having a competent biosystem in an E/S ratio of 1/1 to 1/100 at a temperature of 25°C to 40°C.