Lipase/VOSO₄ Catalyzed Dynamic Kinetic Resolution To Prepare Chiral Intermediates Of Cetines

With the increase in the number of people who are depressed worldwide,there is an increasing demand for high-efficiency and low-toxicity antidepressants.The existing microbial cell or enzyme-catalyzed latent chiral ketone reduction method for preparing atomoxetine chiral intermediates mainly has the problems of long reaction time,low conversion rate,inability to tolerate high concentrations of substrates,and high cost.Therefore,it is of great significance to develop a green and efficient method for the synthesis of atomoxetine chiral intermediates.In this paper,inexpensive and easily available VOSO₄ was used as a racemization catalyst to construct a lipase/VOSO₄ dynamic kinetic resolution（DKR）system to prepare the chiral intermediate of antidepressant tomoxetine（R）-3-chlorophenylpropane alcohol.Optimize reaction conditions through single factor and response surface methodology（RSM）,and study the effect of reaction time,enzyme dosage,the mass ratio of lipase/VOSO₄,solvent properties,acyl donor type,internal and external diffusion on the substrate conversion rate and product enantiomeric excess（e.e）in DKR,and improve DKR efficiency.In this paper,the kinetic resolution（KR）of racemic 3-chlorophenylpropanol catalyzed by a lipase is first carried out.The lipase used is a cross-linked immobilized lipase prepared by our team,mainly investigated the influence of solvent,acyl donor type,water activity,enzyme amount,reaction temperature,reaction time,rotation speed,enzyme particle size on the conversion rate and ee value,and optimized the main influencing factors by response surface method.Finally,the optimal reaction conditions for KR are determined,which lays the foundation for DKR exploration.Based on the study of KR reaction conditions,the reaction conditions of the lipase/VOSO₄ dynamic kinetics resolution system were studied to investigate the mass ratio of lipase/VOSO₄,the way of adding VOSO₄,particle size of immobilized lipase and VOSO₄,reaction stirring speed,initial substrate concentration,reaction time,reaction temperature on DKR.The response surface method was used to optimize the reaction conditions to determine the optimal ratio.The final DKR reaction conditions were as follows:the substrate 3-chlorophenylpropanol was 2.5 mmol,the molar ratio of ethyl acetate to the substrate was 0.96,and the reaction temperature was 66.89℃,the reaction time was 30.71 h,the toluene was 4m L,the mass ratio of lipase/VOSO₄ was 3.5,the rotation speed was 200 rpm,the final substrate 3-chlorophenylpropanol conversion rate reached 59%,and the product enantiomeric excess value up to more than 96%.