Experiment and simulation on kinetic resolution of (R,S)‐2‐chloromandelic acid by enzymatic transesterification

Abstract

Optically pure 2‐chloromandelic acid (ClMA) is a very important chiral drug intermediate for synthesis of (S)‐clopidogrel, belonging to the platelet aggregation inhibitor. Enantioselective resolution of (R,S)‐2‐chloromandelic acid was carried out in organic solvent through irreversible transesterification catalyzed by lipase AK with vinyl acetate acting as the acyl donor. Effects of various conditions on enantioselectivity and activity of lipase were investigated, including organic solvents, temperature, water content, substrate ratio, enzyme loading, and reaction time. Based on homogeneous reaction and Ping‐Pong bi‐bi mechanism, a quantitative model was constructed to simulate and optimize the reaction process. Under the optimal conditions, excellent results were obtained with high conversion of (R)‐2‐ClMA (c R, ≥98.85%) and large enantiomeric excess of substrate (ee s, ≥98.15%). There is a good agreement between predicted values and experiment data, which indicates that the established method is a powerful tool for optimization of the enantioselective transesterification process for enantiomers separation.

Resolution of (R,S)‐1‐(4‐methoxyphenyl)ethanol by lipase‐catalyzed stereoselective transesterification and the process optimization

“…When the reaction time is higher than 2 h, the further extension of time can hardly improve ee S , but can slightly enhance c ; however, the increase in c is mainly due to the conversion of the slow‐reaction enantiomer (indicated by a slight decrease in ee P ), which will reduce the resolution efficiency. The above observations are consistent with the theoretical expectation and the literature reports 22,23 . The required time for the optimal resolution results is reduced than the previous work 12–14 …”

Synthesis of mitomycin analogs catalyzed by coupling of laccase with lipase and the kinetic model

“…proposed a semi‐empirical kinetic model which accurately predicted the hydrolysis performance of laccase‐treated wheat straw. A quantitative Ping‐Pong bi‐bi mechanism model was constructed to simulate and optimize the reaction process . Using Approximate Bayesian Computation, kinetic constants in the Michaelis–Menten model was obtained .…”