全细胞生物催化邻氯扁桃腈不对称合成(R)-邻氯扁桃酸

摘要

(R)-o-chloromandelic acid is the key precursor for the synthesis of clopidogrel. The nitrilase from Labrenzia aggregate(LaN) was utilized as the catalyst,and o-chlorobutyronitrile(2-Cl-MN) racemate as substrate,which could theoretically provide 100% yield of 2-Cl-MA due to the efficient in situ racemization of residual(S)-o-chloromandelonitrile. Then,the primary product was simply extracted and recrystallized to obtain 2-Cl-MA with an optical purity of more than 99.9%. Finally,the effects of substrate concentration, reaction temperature and pH on the catalytic activity and enantioselectivity of LaN nitrilase were optimized. The yield of (R)-2-Cl-MA reached to 68.6 g/L within 35 h,and the yield was showed to be 86.4% and 99.9% enantioselectivity,under the optimum reaction conditions. It provide a practical way of large-scale production of (R)-2-Cl-MA.%(R)-邻氯扁桃酸((R)-2-Cl-MA)是制备抗凝血集药物氯吡格雷的关键中间体.以Labrenzia aggregate(LaN)来源的腈水解酶作为催化剂,邻氯扁桃腈(2-Cl-MN)消旋体作为底物.2-Cl-MN在水相中能够自发消旋,使得两种构型的底物均能转化成(R)-2-Cl-MA,因而能提供100%的产物得率.反应产物经过简单的萃取、重结晶后即可得到光学纯度高达99.9%的产物.实验系统优化了底物浓度、反应温度、pH等反应条件对LaN腈水解酶的活性和对映体选择性的影响.在最优反应条件下采用分批补料的反应方式,使得(R)-2-Cl-MA的产量在35 h内达到68.6 g/L,产率86.4%,99.9% ee.为规模化生产(R)-2-Cl-MA提供了一条实用途径.