Enzymatic hydrolysis by immobilized lipase applied to a new prototype anti-asthma drug

摘要

The last step of the production of 4-ethyl-(2-(l,3-dioxo-l,3-dihydro-2-isoindoylyl))-phenoxy acetic acid (LASSBio 482),designed to act as an anti-asthma drug,was performed by enzymatic hydrolysis of the methyl ester.Reactions were performed in a three-phase system with a solid biocatalyst (Lipozyme~R RMIM),an organic solvent phase (ethyl acetate) and an aqueous phase (saturated Na_2CO_3 solution).In order to optimize the reaction conditions,experimental design techniques were used.The variables studied were the amount of enzyme,the reaction temperature and the total volume of saturated Na2CO3 solution.The experimental results were analysed statistically and the main effects of the variables were computed and analysed.Dynamic experiments were then performed under optimised reaction conditions for different initial enzyme concentrations (0.5,0.9 and 1.4 U_(HLipozyme)/mL solvent).An empirical nonlinear model was then proposed to describe the process,and experimental data were used to estimate the model parameters.The optimised reaction conditions were 20 mg Lipozyme~R (0.9U_H/mL_(solvent),5.0 mL Na_2CO_3 (sat),a temperature of 40 deg C and batch reaction time of 6h.The results showed that enzymatic hydrolysis is a promising technique for the synthesis of the desired product.