Resolution Of α-Cyano-3-Phenoxybenzyl Acetate Via Lipase-Catalyzed Asymmetric Transesterification In Organic Media

The recent development, the synthetic techniques and the analytical methods of chiral pharmaceuticals were introduced. The research and application of the biocatalysis in organic media and the enzyme-catalyzed transesterification were outlined. The synthetic research progresses of S- -Cyano-3-phenoxybenzyl alcohol (S-CPBA) --an important chiral building block for the preparation of many high-level activity pyrethroids insecticides were reviewed. In this article the lipase-catalyzed asymmetric transesterification of a-Cyano-3- phenoxybenzyl acetate (CPBAc) for the synthesis of S-CPBA in organic media was studied. The effects of lipases from different sources, different solvents and alcohols on the reaction, and the kinetics of the reaction were investigated for the first time.The racemic compound CPBAc were resolved by transesterification when lipase showed highly enantioselectivity that one of enantiomer was deacylated preferably, one of the probable process was schemed as flow:The concentration of CPBAc was determined by GC with a flame ionization detector and a capillary column. The concentrations and e.e% of the enantiomers of CPBA were analyzed by HPLC with a chiral HPLC column and a UV detector. The best chromatographic conditions were optimized by a series of experiments.36 lipases from different sources were screened, 10 of them showed higher catalytic activity and were screened again, lipases of 7#, 10#, 13# showed higher enantioselectivity. 15 different organic solvents include mixed solvents and 14 different alcohols were compared, THF and dichloromethane were the best organic media, and methanol was the best acyl accepter. Thus the preferable system for theasymmetric reaction were :7#, THF, methanol and 7#, dichloromethane, methanol. When the reaction carried out in the optimum systems above, several factors that affecting the reaction were investigated in detail. The results indicated that trace water(0-1.0%) is desired in the reaction; >1:0.5 is the ideal molar ratio of CPBAc: alcohol for the reaction; 35-45 is a nice choice for the reaction ; Shorten the reaction time (<4days) would decreased the decomposition of the product; when the rate of the shaker >200rpm, the external diffusion limitation of the reaction would be omitted; 10mg/ml lipase is enough when 337.08mmol/l CPBAc is used ; The inhibitions of substrate and product were observed; >90% of the catalytic activity of the lipase was loss after 4 and 24 runs of use in dichloromethane and THF respectively. When the reaction carried out in THF for preparation a 43.85% yield of S-CPBA with >98%e.e. was obtained. The deaction of the lipase in THF was studied, the deaction equation is expressedas follow: The reaction mechanism was hypothesized to be a ping-pong bi-bi reaction with dead-end inhibition by both substrates. The initial rate equation for the asymmetric transesterification is:The parameters of the equation were calculated via a simplex program of C++: Vm=61.98mmoll-1hr-1,KmAs=314.64mmoll-1,KiB=1263.47mmoll-1,,KmB=77.81mmoll-1, KiA=3076.87mmoll-1,and the relative error is calculated to be 10.23%,...