Development of a Sustainable Chemoenzymatic Process for (<i>S</i>)-Pregabalin Synthesis via Nitrilase-Catalyzed Hydrolysis and Continuous Flow Racemization
Chao-Ping Lin, Chenhui Xu, Fanyu Meng, Shiping Song, Zhe‐Ming Wu, Ren‐Chao Zheng, Yu‐Guo Zheng
Abstract
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 γ-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.