Lipase-Catalyzed Kinetic Resolution of Alcohols as Intermediates for the Synthesis of Heart Rate Reducing Agent Ivabradine

Ivabradine (Corlanor®), is a chiral benzocycloalkane currently employed and commercialized for the treatment of chronic stable angina pectoris reduction in sinus tachycardia. The eutomer (S)-ivabradine usually produced via resolution intermediates, by employing enantiopure auxiliary molecules or through preparative HPLC separations. Recently, more sustainable biocatalytic approaches have been reported literature preparation amine precursor. In this work, we report on novel biocatalyzed pathway, study key alcohol intermediate used as precursor amine. After screening several enzymatic reaction conditions, different lipases esterases both esterification hydrolysis reactions, best result was achieved with Pseudomonas cepacia Lipase final product obtained up to 96:4 enantiomeric ratio (e.r.) an ivabradine This enantiomer then efficiently converted into desired facile three step synthetic sequence.