- Nitrilase-catalyzed selective hydrolysis of dinitriles and green access to the cyanocarboxylic acids of pharmaceutical importance
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To further explore its synthetic applications, the nitrilase bll6402 from Bradyrhizobium japonicum strain USDA110 has been examined toward the hydrolysis of various dinitriles. It has been found that nitrilase bll6402 effectively hydrolyzed α,ω-dinitriles to ω-cyanocarboxylic acids, and the selectivity was independent of the substrate chain length. This feature is distinct from all the known nitrilases of various sources. Nitrilase bll6402 was thus applied to the synthesis of 1-cyanocycloalkaneacetic acids, the useful precursors for the synthesis of gabapentin and its analogues.
- Zhu, Dunming,Mukherjee, Chandrani,Biehl, Edward R.,Hua, Ling
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- Enzymatic production of key intermediate of gabapentin by recombinant amidase from Pantoea sp. with high ratio of substrate to biocatalyst
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1-Cyanocyclohexaneacetic acid is the key intermediate of gabapentin. A novel bioprocess catalyzed by amidase was developed for efficient production of 1-cyanocyclohexaneacetic acid from 1-cyanocyclohexaneacetamide, which can be prepared with high efficiency by nitrile hydratase-catalyzed regioselective hydration of 1-cyanocyclohexaneacetonitrile. Kinetic analysis and molecular docking of three recombinant amidase demonstrated that amidase (Pa-Ami) from Pantoea sp. was the most robust biocatalyst for hydrolysis of 1-cyanocyclohexaneacetamide with the kcat/Km value of 208.2 ± 16.2 mM-1 s-1. Some key parameters of the bioprocess, such as substrate loading, catalyst loading and product inhibition, were investigated. Enzymatic hydrolysis of 80 g/L of 1-cyanocyclohexaneacetamide was completed within 20 min using 1 g/L wet whole cells of recombinant Escherichia coli BL21, leading to high ratio of substrate to catalyst (S/C-ratio, 80) and high space-time yield (5794.7 gproduct L-1 d-1). These encouraging results indicated the great potential of Pa-Ami in practical production of gabapentin.
- Wu, Zhe-Ming,Zheng, Ren-Chao,Ding, Xu,Jin, Jian-Qiang,Zheng, Yu-Guo
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- Chemoenzymatic synthesis of gabapentin by combining nitrilase-mediated hydrolysis with hydrogenation over Raney-nickel
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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.
- Xue, Ya-Ping,Wang, Ying-Peng,Xu, Zhe,Liu, Zhi-Qiang,Shu, Xin-Rui,Jia, Dong-Xu,Zheng, Yu-Guo,Shen, Yin-Chu
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- A PROCESS FOR THE PREPARATION OF GABAPENTIN
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The present invention provides an improved process for the preparation of a compound of formula (I),
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- PROCESS FOR PREPARING GABAPENTIN
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A process for preparing gabapentin of formula 1, which comprises Formula (I) converting 1-allyl-cyclohexanecarboxaldehyde into 1-allyl-cyclohexanecarbonitrile; ozonizing 1-allyl-cyclohexanecarbonitrile to obtain 1-cyano-cyclohexaneacetaldehyde; acetalizing 1-cyano-cyclohexaneacetaldehyde with a suitable acetalizing agent to give the corresponding acetal and converting the latter into gabapentin.
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Page/Page column 17
(2008/06/13)
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- Process for preparing a cyclic amino acid anticonvulsant compound
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An improved process for the preparation of a cyclic amino acid by a novel synthesis is described where benzonitrile is treated with an alkali metal and an amine under Birch reduction conditions to generate in situ an anionic intermediate which is alkylated with an α-haloacetic acid moiety which is subsequently converted to the desired product, as well as valuable intermediates used in the process.
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- Process for cyclic amino acid anticonvulsant compounds
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An improved process for the preparation of cyclic amino acids by a novel synthesis is described where a dinitrile derivative is converted in two steps to the desired products, as well as valuable intermediates used in the process.
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- Process for cyclic amino acid anticonvulsant compounds
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An improved process for the preparation of cyclic amino acids by a novel synthesis is described where a dinitrile derivative is converted in two steps to the desired products, as well as valuable intermediates used in the process.
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- Process for the preparation of cyclic amino acids and intermediates useful in the process
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Processes for the preparation of cyclic amino acid derivatives useful in the treatment of cerebral diseases such as epilepsy are disclosed. Novel intermediates useful in processes are also disclosed.
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