Ivabradine (Corlanor®), is a chiral benzocycloalkane currently employed and commercialized for the treatment of chronic stable angina pectoris and for the reduction in sinus tachycardia. The eutomer (S)-ivabradine is usually produced via chiral resolution of intermediates, by employing enantiopure auxiliary molecules or through preparative chiral HPLC separations. Recently, more sustainable biocatalytic approaches have been reported in literature for the preparation of the chiral amine precursor. In this work, we report on a novel biocatalyzed pathway, via a resolution study of a key alcohol intermediate used as a precursor of the chiral amine. After screening several enzymatic reaction conditions, employing different lipases and esterases both for the esterification and hydrolysis reactions, the best result was achieved with Pseudomonas cepacia Lipase and the final product was obtained in up to 96:4 enantiomeric ratio (e.r.) of an ivabradine alcohol precursor. This enantiomer was then efficiently converted into the desired amine in a facile three step synthetic sequence.
Kinetic Resolution of Enantiomers in Enantiomerically Enriched 2-Alkanol by Pseudomonas cepacia Lipase Catalyzed Transesterification with Vinyl Acetate in Organic Solvent.