Described are four process research investigations directedtoward discerning a scalable, enantioselective method forpreparing (
S)-
-amino acid ester
3, a key intermediate to the
v3 integrin antagonist
1. Reported are an asymmetric Michaelreaction approach, attempts to enantioselectively hydrogenatean enamine, resolution of (±)-
3 via diastereomeric salt formation, and a synthetic route employing a novel, diastereoselectiveimino-Reformatsky reaction. This last research initiative provedsuccessful and was employed as the enabling route to initialAPI supply. Process development of this enabling chemistry isreported. The technical issues researched and optimized were(1) the necessity of employing MEM-protection for high yieldand diastereoselectivity in the imino-Reformatsky reaction, (2)the reaction kinetics of MEM chloride hydrolysis and theapplication of these data to an on-scale quench procedure, (3)the efficient formation of the (
S)-phenylglycinol imine
15 inNMP and a dehydration of this product solution on-scale,employing molecular sieves, (4) a calorimetric study of theReformatsky reaction and the application of these data, (5) thereplacement of Pb(OAc)
4 with NaIO
4 and the use of methylamine to sequester competing oxazolidine formation, and (6)further development of the isolation and purification protocolfor the ethyl ester,
p-TsOH salt of (
S)-
3. The results andchallenges associated with two campaigns in which the potentialcommercial process was practiced are discussed.