有机相酶催化转酯化反应拆分西酞普兰中间体

利用脂肪酶催化的不对称转酯反应成功远程拆分具有季碳手性中心的西酞普兰中间体4-4-(二甲基氨基)-1-(4’-氟苯基)-1-羟基丁基]-3-(羟基甲基)苄腈(1). 以乙酸乙烯酯作为酰基供体, 通过筛选酶和溶剂, 确定最佳脂肪酶及溶剂分别为Candida antarctica lipase B (Novozym 435)和乙腈; 并在该反应体系中考察了反应温度、二醇1与酰基供体的比例、酶浓度和摇床转速等对反应的影响, 确定优化的反应条件为: 温度30 ℃, 二醇1与酰基供体的物质的量比为1∶5, 酶浓度为10 mg/mL, 摇床转速200 r/min. 分别考察二醇1浓度为60和180 mmol/L的反应情况, 均具有较高的选择性和反应速度. 实验结果表明酶能够多次重复利用.

Resolution of Citalopram Intermediate by Enzyme-Catalyzed Enantioselective Transesterification in Organic Media

The lipase-catalyzed remote kinetic resolution of 4-4-(dimethylamino)-1-(4-fluorophenyl)- 1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile (1), a useful intermediate of citalopram with a quater-nary chiral center, was studied. Through screening, the preferable system for the asymmetric reaction was: Candida antarctica lipase B (Novozym435) as a catalyst, acetonitrile as a solvent and vinyl acetate as an acyl donor. The influence of various parameters on the enzymatic resolution was studied. The optimal con-dition was as follows: temperature of 30 ℃, the molar ratio of diol 1 to vinyl acetate 1 to 5, 10 mg/mL li-pase, and 200 r/min rotation speed. Reaction curves of 180 and 60 mmol/L diol 1 concentrations ensured the high reaction rate and enantioselectivity. Reusability study ensured the operational stability of lipase over repeated cycles.