Process for the preparation of nebivolol

摘要

The present invention relates to a novel process for the synthesis of the Nebivolol product depicted in Scheme 1, comprised of a reduced number of high-yield steps, and characterized by the enzymatic resolution of the chroman ester precursor.;

主权项

1. A method for the synthesis of d-Nebivolol and/or l-Nebivolol of the following formulas comprising the following steps: a) hydrolyzing a mixture of enantiomers of the 6-fluoro-2-carboxylic acid ester (1), wherein R1 is a linear or branched C1-5 alkyl group by a stereoselective enzymatic hydrolysis reaction to give a mixture of R acid (2) and S ester (3); b) using thus obtained acid (2) and ester (3) for the synthesis respectively of mixtures of epoxides (RR) and (RS) (4) and (SS) and (SR) (5); c) resolving the mixtures of epoxides (4) and (5) to obtain respectively amino alcohol RS (6)+epoxide RR (7) and amino alcohol SR (8)+epoxide SS (9); d) reacting amino alcohols (6) and (8) with epoxides (7) and (9) to obtain l-benzyl Nebivolol (10) and d-benzyl Nebivolol (11); and e) removing the benzyl protecting group; wherein in step (a), hydrolysis is carried out to give the mixture of R acid (2) with an enantiomeric excess of >70% and of S ester (3) with an enantiomeric excess of >70%; in step (c), the mixtures of epoxides (4) and (5) are kinetically resolved by reacting them with benzylamine in a sterically hindered alcohol; and the enzymatic hydrolysis reaction is carried out by an esterase obtained from genus Ophiostoma.