外消旋化
普瑞巴林
水解
化学
连续流动
催化作用
硝化酶
对映选择合成
有机化学
组合化学
生化工程
医学
工程类
麻醉
作者
Lin Chen,Chenhui Xu,Fanbin Meng,Shiping Song,Zhe‐Ming Wu,Ren‐Chao Zheng,Yu‐Guo Zheng
标识
DOI:10.1021/acs.oprd.3c00441
摘要
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.
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