95310-88-6Relevant academic research and scientific papers
Enzymatic synthesis of a key intermediate for rosuvastatin by nitrilase-catalyzed hydrolysis of ethyl (R)-4-cyano-3-hydroxybutyate at high substrate concentration
Yao, Peiyuan,Li, Jianjiong,Yuan, Jing,Han, Chao,Liu, Xiangtao,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
, p. 271 - 275 (2015)
An enzymatic method for the synthesis of ethyl (R)-3-hydroxyglutarate from ethyl (R )-4-cyano-3-hydroxybutyate was developed by using free and immobilized recombinant Escherichia coli BL21(DE3)pLysS harboring a nitrilase gene from Arabidopsis thaliana (AtNIT2). The hydrolysis of ethyl (R)-4-cyano-3-hydroxybutyate proceeded with the freely suspended cells of the biocatalyst under the optimized conditions of 1.5 molL-1 (235.5 gL-1) substrate concentration and 6.0 wt% loading of wet cells at pH 8.0 and 25 °C, with 100% conversion obtained in 4.5 h. Furthermore, immobilization of the whole cells enhanced their substrate tolerance, stability, and reusability. Under the optimized conditions (100 mmolL-1 tris(hydroxymethyl) aminomethane hydrochloride buffer, pH 8.0, 25 °C), the immobilized biocatalyst could be reused for up to 16 batches, with a biocatalyst productivity of 55.6 ggwet cells-1 and a spacetime productivity of 625.5 gL-1 d-1. These results demonstrated that the immobilized whole cells might be used as a biocatalyst in the industrial production of ethyl (R)-3-hydroxyglutarate, a key intermediate for the synthesis of rosuvastatin.
Integrated Biocatalysis in Multistep Drug Synthesis without Intermediate Isolation: A de Novo Approach toward a Rosuvastatin Key Building Block
Metzner, Richard,Hummel, Werner,Wetterich, Frank,K?nig, Burghard,Gr?ger, Harald
supporting information, p. 635 - 638 (2015/06/30)
In this contribution, we report the chemoenzymatic preparation of a key building block for the active pharmaceutical ingredient rosuvastatin, one of the "top 5 blockbuster drugs" with a worldwide market value of 6.25 billion USD in 2012, via a seven-step synthesis without isolation of intermediates and with incorporation of two highly efficient biotransformations. This chemoenzymatic process reaches excellent space-time yields by using high substrate concentrations (several hundred grams per liter), emphasizing the potential of biocatalysis for industrial processes related to pharmaceutical drug synthesis and the compatibility of enzyme chemistry with classical organic synthesis.
Efficient biosynthesis of ethyl (R)-3-hydroxyglutarate through a one-pot bienzymatic cascade of halohydrin dehalogenase and nitrilase
Yao, Peiyuan,Wang, Lei,Yuan, Jing,Cheng, Lihua,Jia, Rongrong,Xie, Meixian,Feng, Jinhui,Wang, Min,Wu, Qiaqing,Zhu, Dunming
, p. 1438 - 1444 (2015/06/30)
An effective one-pot bienzymatic synthesis of ethyl (R)-3-hydroxyglutarate (EHG) from ethyl (S)-4-chloro-3-hydroxybutyrate (ECHB) was achieved by using recombinant Escherichia coli cells expressing separately or co-expressing a mutant halohydrin dehalogenase gene from Agrobacterium radiobacter AD1 and a nitrilase gene from Arabidopsis thaliana. The activity of nitrilase was inhibited by high concentration of ECHB and NaCN. Consequently, the one-pot one-step process was implemented by fed-batch of ECHB and NaCN with high accumulative product concentration (up to 0.9 mol L-1). The biotransformation of ECHB to EHG was successfully achieved at 1.2 mol L-1 substrate concentration by a one-pot two-step process. As such, this one-pot bienzymatic transformation should be useful in synthesizing these important optical pure β-hydroxycarboxylic acids.
Enantioselective hydrolysis of diethyl 3-hydroxyglutarate to ethyl (S)-3-hydroxyglutarate by immobilized Candida antarctica lipase B
Dong, Hua-Ping,Wang, Ya-Jun,Zheng, Yu-Guo
scheme or table, p. 90 - 94 (2011/01/03)
Optically pure ethyl (S)-3-hydroxyglutarate [(S)-3-EHG] is used as a key precursor for synthesis of a variety of pharmaceutically important compounds. In this work, we established an efficient procedure for enantioselectively hydrolyzing diethyl 3-hydroxyglutarate (3-DHG) to optically active (S)-3-EHG employing immobilized Candida antarctica lipase B (Novozym 435). Under the optimized conditions: pH 7.0, agitation speed 200 rpm, temperature 40 °C, 3-DHG concentration 0.15 mol L-1, and enzyme loading 7 g L -1, (S)-3-EHG was prepared in above 95% ee value and 98.5% yield, and the reaction was free from external mass transfer and intra-particle diffusion limitations and kinetically controlled. The inhibitions of substrate (3-DHG) and product (3-EHG) were excluded because both displayed no decline in activity at elevated concentrations within the given ranges. In addition, ethanol, a byproduct of the reaction, inhibited lipase B following an uncompetitive inhibition pattern. The kinetic constants were obtained through non-linear regression, with values of Vmax 1.29 mmol min-1 g -1, Km 0.06 mol L-1, and Ki 0.37 mol L-1, respectively.
Bifunctional chiral synthons via biochemical methods. 5. Preparation of (S)-ethyl hydrogen-3-hydroxyglutarate, key intermediate to (R)-4-amino-3-hydroxybutyric acid and L-carnitine
Gopalan,Sih
, p. 5235 - 5238 (2007/10/02)
Microbial enantioselective hydrolysis of diethyl-3-hydroxyglutarate afforded (S)-ethyl hydrogen-3-hydroxyglutarate, which was transformed into (R)-4-amino-3-hydroxybutyric acid and L-carnitine, via a Curtius and Hunsdiecker rearrangement, respectively.
