A Facile, One-Pot Synthesis of Lacidipine Using in Situ Generation of Wittig Intermediates

Abstract

An improved, one-pot process for the preparation of lacidipine (1) via an efficient in situ generation of Wittig intermediates is reported. Generation of ylide (4) by dehydrobromination of phosphonium salt (3) followed by in situ condensation of 4 with o-phthalaldehyde (5) to yield corresponding olefin (6) and its subsequent reaction with crotonate derivative (7) in the same pot furnished the drug substance 1 with an overall yield of about 51% over the reported yield of about 24% starting from the corresponding ylide. The present work overcomes the challenges associated with prior art processes such as chromatographic purifications, handling of unstable intermediates, and formation of byproducts as potential impurities. The interesting insights on the safety aspects of the process, drawn through calorimetric studies, rendered the successful implementation of the process at manufacturing facility.