Study On The Preparation Of Chiral Intermediates Of Citine Antidepressants

(S)-3-chloro-1-phenylpropanol is a key chiral intermediate for the preparation of citine antidepressants.The existing chemical asymmetric reduction of pre-chiral ketones,microbial cell-catalyzed reduction of carbonyl ketones for the preparation of chiral secondary alcohols suffer from high costs,harsh reaction conditions,low yields,environmental pollution and more difficult industrial scale-up production.Therefore,the search for efficient and low-cost methods for the preparation of high enantiomer purity(S)-3-chloro-1-phenylpropanols is of great relevance for the process production of citine antidepressants.In this paper,a reaction system for the preparation of(S)-3-chloro-1-phenylpropyl alcohol by kinetic resolution of racemic esters catalyzed by lipase in an emulsion system was established,and high enantiomer purity of(S)-3-chloro-1-phenylpropanol was obtained by kinetic resolution.The synthetic reaction of racemic 3-chloro-1-phenylpropyl acetate was firstly investigated.The effects of the reaction solvent,acylation reagent,catalyst,reaction temperature,catalyst dosage,substrate concentration and reaction time on the conversion were investigated,and the optimal conditions for the synthesis reaction were obtained by response surface optimization: 5m L of acetic anhydride substrate was used as solvent,the substrate 3-chloro-1-phenylpropanol concentration was 0.5 mol/L,the amount of catalyst 4-dimethylpyridine was 0.34 g,and reacted at a constant temperature of 53.5°C and 150 rpm for 2.3 hours.The conversion of 3-chloro-1-phenylpropanol under these conditions was greater than95% and the yield of the product 3-chloro-1-phenylpropyl acetate was greater than 85%.Based on the synthetic study,the kinetic hydrolysis resolution of racemic 3-chloro-1-phenylpropyl acetate catalyzed by lipase was carried out.The effects of the reaction medium,catalyst,surfactant,substrate concentration,enzyme dosage,reaction temperature,reaction time and other factors on the conversion and ee values were investigated,and the main factors were optimized by response surface methodology.The reaction conditions were determined as follows: the substrate 3-chloro-1-phenylpropyl acetate at a concentration of 0.15 mol/L,Tween 80 at a concentration of 0.3 mg/m L and lipase enzyme activity was 300 U/m L,was prepared as an emulsion in phosphate buffer and reacted at a constant temperature of 53.7°C and 200 rpm for 27.6 hours.The final substrate conversion was 48.5% and the ee value of the product(S)-3-chloro-1-phenylpropanol was over 95.8%.