Development of a Sustainable Chemoenzymatic Process for (S)-Pregabalin Synthesis via Nitrilase-Catalyzed Hydrolysis and Continuous Flow Racemization

A chemoenzymatic process combing nitrilase-catalyzed hydrolysis and continuous flow racemization was developed for highly efficient manufacturing of (S)-pregabalin. Nitrilase was immobilized on epoxy resin and employed for the biosynthesis of (S)-3-cyano-5-methylhexanoic acid ((S)-CMHA), the precursor of (S)-pregabalin. Isobutylsuccinonitrile (IBSN) (700 mM) was converted to (S)-CMHA with a conversion of 45.3% and ee of 99.5%. Meanwhile, the unreacted (R)-IBSN was continuously racemized by the gamma-alumina-based solid base catalysts (ASBCs) in a packed bed reactor, and an outstanding space-time yield of 6.76 mol L-1 day(-1) was achieved. Moreover, the ASBCs exhibited excellent operational stability in the racemization system and retained 85.9% catalytic activity after 20 days of continuous racemization operation. (S)-CMHA was subsequently separated and purified by a membrane separation system in 95% yield and was hydrogenated in one step to (S)-pregabalin in a yield of 88%. These obtained results exhibited the efficiency of the chemoenzymatic process and the great potential for industrialization of (S)-pregabalin.