期刊
ORGANIC PROCESS RESEARCH & DEVELOPMENT
卷 23, 期 9, 页码 2042-2049出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.9b00285
关键词
pregabalin; nitrilase; chemoenzymatic route; isobutylsuccinonitrile; immobilization
资金
- Zhejiang Provincial Natural Science Foundation [LR19B060001]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT13096]
An efficient chemoenzymatic route has been developed for the synthesis of optically active pregabalin (PGB) from isobutylsuccinonitrile (IBSN). (S)-3-cyano-5-methylhexanoic acid ((S)-CMHA), a critical chiral intermediate of PGB, was synthesized using regio- and enantioselective hydrolysis of IBSN by immobilized Escherichia coli cells harboring nitrilase BrNIT from Brassica rapa. The catalytic performances of immobilized cells were investigated, and high enantioselectivity (E > 150) and substrate conversion (>41.1%) were obtained at a substrate loading of 100 g/L by immobilized cells after 12 batches of reaction. The unreacted (R)-IBSN was recycled by racemization with a high yield of 94.5%, and the resultant (S)-CMHA was hydrogenated directly to the desired PGB with a high purity of 99.6% and optical purity of 99.4%. The input of raw materials and E factor of this chemoenzymatic route were demonstrated to be much lower than those of the first- and second-generation routes for PGB synthesis.
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