Pilot Plant Preparation of an αvβ3 Integrin Antagonist. Part 1. Process Research and Development of a (S)-β-Amino Acid Ester Intermediate: Synthesis via a Scalable, Diastereoselective Imino-Reformatsky Reaction

Described are four process research investigations directed toward discerning a scalable, enantioselective method for preparing (S)-β-amino acid ester 3, a key intermediate to the αvβ3 integrin antagonist 1. Reported are an asymmetric Michael reaction approach, attempts to enantioselectively hydrogenate an enamine, resolution of (±)-3 via diastereomeric salt formation, and a synthetic route employing a novel, diastereoselective imino-Reformatsky reaction. This last research initiative proved successful and was employed as the enabling route to initial API supply. Process development of this enabling chemistry is reported. The technical issues researched and optimized were (1) the necessity of employing MEM-protection for high yield and diastereoselectivity in the imino-Reformatsky reaction, (2) the reaction kinetics of MEM chloride hydrolysis and the application of these data to an on-scale quench procedure, (3) the efficient formation of the (S)-phenylglycinol imine 15 in NMP and a dehydration of this pr...