PROCESS FOR THE ENZYMATIC SYNTHESIS OF (7S)-3,4-DIMETHOXYBICYCLO[4.2.0]OCTA-1,3,5-TRIENE-7-CARBOXYLIC ACID OR ESTERS THEREOF, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE AND SALTS THEREOF

摘要

PURPOSE: A method for enzymatic synthesis of esters is provided to obtain a compound of the chemical formula (III) using an effective process for getting a high yield, especially in a dissolution step. CONSTITUTION: A synthesizing method of the optically pure compound of the chemical formula (Ia) is as follows. Racemic acid of the chemical formula (X) or optically impure other acids is enzymatic esterified enantioselectively by adding lipase or esterase to a mixture of alcohol ROH and organic co-solvent at a E/S ratio of 10/1-1/100 in concentration of the compound of the chemical formula (X) of 5-500 g/L per a liter of the solvent mixture under a temperature of 25-40°C. A synthesizing method of a compound of the chemical formula (III) is as follows. Racemic acid of the chemical formula (X) is formed by hydrolyzing nitrile of the chemical formula (IV). Optically pure acid of the chemical formula (Ia) is obtained by enzymatically esterifying the racemic acid. The acid is converted into the optically pure amide of the chemical formula (XII), and then the amide is obtained by reduction.