Enzymatic Hydrolysis of a Prochiral 3-Substituted Glutarate Ester, an Intermediate in the Synthesis of an NK 1 /NK 2 Dual Antagonist

An enzymatic process for desymmetrization of the prochiral diethyl 3-[3',4'-dichlorophenyl]glutarate, 1, an intermediate in the synthesis of a series of neurokinin (NK) receptor antagonists, has been developed and scaled up. The transformation catalyzed by Candida antarctica lipase B in either the free or the immobilized form was carried out at 100 g/L of substrate and proceeded with an average conversion of 97%. In the pilot plant, the process produced 200 kg of 2 in 3 batches with ee >99% and an average isolated yield of 80%. The immobilized enzyme preparation was particularly effective, achieving over 70,000 enzyme turnovers per batch.