Chemoenzymatic synthesis of gabapentin by combining nitrilase-mediated hydrolysis with hydrogenation over Raney-nickel |
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| Affiliation: | 1. Center of Excellence for Modern Analytical Technologies (CEMAT), Zhejiang Huahai Pharmaceutical Co. Ltd., Xunqiao, Linhai, Zhejiang, 317204, PR China;2. Quality Control Department of Chuannan Site, Zhejiang Huahai Pharmaceutical Co. Ltd., Duqiao, Linhai, Zhejiang, 317016, PR China;3. Huahai US, Inc., 700 Atrium Drive, Somerset, NJ, 08873, USA;1. Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China;2. National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Center for Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 Xi Qi Dao, Tianjin Airport Economic Area, Tianjin, 300308, China;1. Department of Chemistry, Jawaharlal Nehru Technological University, Kakinada 533003, India;2. Department of Chemistry, Jawaharlal Nehru Technological University, Anantapur 515002, India;1. State Key Laboratory of Materials-Oriented Chemical Engineering, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, PR China;2. Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University, Nanjing 211816, PR China;1. Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, PR China;2. Engineering Research Center of Bioconversion and Biopurification of Ministry of Education, Zhejiang University of Technology, Hangzhou 310014, PR China |
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| Abstract: | An efficient chemoenzymatic process is devised for synthesizing high-purity gabapentin. 1-Cyanocyclohexaneacetic acid was first produced in 0.94 M from 1.0 M 1-cyanocycloalkaneacetonitrile by a greatly improved nitrilase from Acidovorax facilis ZJB09122, resulting in a commercially attractive bioprocess with an outstanding space-time yield of 461 g/L/day. The resulting aqueous 1-cyanocycloalkaneacetic acid was then directly converted to 2-azaspiro [4.5] decan-3-one without further purification in subsequent hydrogenation by Raney-nickel, followed by simple chemical steps to afford gabapentin in high purity and 77.3% overall yield from 1-cyanocyclohexylacetonitrile. The simplicity of the process makes this new pathway suitable for large-scale preparation. |
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