Abstract
Abstract An industrial one-pot, two-step bioprocess catalyzed by nitrile hydratase (NHase) and amidase was developed for ( S )-2,2-dimethylcyclopropanecarboxamide ( 1 ), the key chiral intermediate of cilastatin. The key unit operations of the whole process including fermentative production of enzymes, biotransformation, isolation of product, and recycling of by-product were reported for the first time. The volumetric enzyme activities of NHase and amidase in 1000-L fermentor were enhanced to 351,000 and 5880 U/L, respectively. The two-step, one-pot biotransformation of rac -2,2-dimethylcyclopropanecarbonitrile ( 2 ) took full advantage of both enzymes, leading to accumulation of ( S )- 1 in 47% yield and 99.6% ee . ( S )- 1 and the by-product ( R )-2,2-dimethylcyclopropanecarboxylic acid ( 3 ) were obtained with yields of 38% and 45%, respectively, by a novel macroporous resin adsorption chromatography. Moreover, the total yield of ( S )- 1 was further increased to 53% after one recycling of ( R )-3. The new bioprocess dramatically improved process efficiency compared with the chemical route by elimination of six synthetic steps and proved to be a superior and more cost-effective approach towards ( S )- 1 .
Published Version
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