SYNTHESIS OF CHIRAL INTERMEDIATES USEFUL IN PREPARING PHARMACOLOGICALLY ACTIVE COMPOUNDS

摘要

A process is disclosed for preparing (R)-2-hydroxy-4-phenylbutyronitrile of formula (I) wherein * signifies the (R) stereoisomer; and Ph is the phenyl group C6H5, which process comprises reacting, in a biphasic system, 3-phenylpropionaldehyde of formula (X): with a cyanide compound in the presence of (R)-hydroxynitrilase, wherein the reaction is carried out a temperature below (10)°C. Preferably, the reaction is carried out at a temperature in the range of from -(5)° to (0)°C. The compounds of formula (I) thereby prepared are useful in the preparation of the family of ACE inhibitors known as 'prils', of the general formula (A): wherein R' is hydrogen or C1-C2 alkyl and R'' is selected from a large number of possible moieties. Example of 'prils' include lisinopril, cilazapril, enalapril, benazepril, ramipril, delapril, enalaprilat, imidapril, spirapril, trandolapril and others. These 'prils' compounds are chiral compounds, only one of their diastereomers being pharmacologically active. Use of a chiral intermediate (I) thereby avoids the necessity to isolate and purify the active 'pril' diastereomer, rather than using a racemic mixture, for pharmaceutical/medical applications.