普瑞巴林手性中间体的合成工艺研究

以异戊醛和丙二酸二乙酯为原料,经过Knoevenagel缩合反应,合成普瑞巴林中间体2-羧乙基-5-甲基-2-己烯酸乙酯(Ⅰ),再通过与氰化钠的加成反应,合成普瑞巴林中间体2-羧乙基-3-氰基-5-甲基己酸乙酯(Ⅱ),利用酶Lipoprime 50T进行生物拆分,得到普瑞巴林手性中间体(3S)-2-羧乙基-3-氰基-5-甲基己酸(Ⅲ),GC检测e.e.为99.0%。改进并优化合成工艺,Ⅰ收率由78%提高至88.5%,Ⅱ收率90%提高至99%。

Process improvement for the synthesis of chiral intermediates of pregabalin

A process is reported for stereoselectively hydrolyzing one enantiomer of rac-3-cyano-2-carboxyethyl-5-methylhexanoic acid ethyl ester for (S)-2-cyano-5-methyl-2-hexanoic acid ethyl ester,an important chiral intermediate of (S)-(+)2-aminomethyl-5-methylhexanoic acid (pregabalin).Our route begins with the Knoevenagel condensation of isovaleraldehyde and diethyl malonate,followed by the addition reaction with sodium cyanide to give the key intermediate Ⅰ.Compound Ⅰ can be stereoselectively hydrolyzed to form (3S)-2-carboxyethyl-3-cyano-5-methylhexanoic acid.GC assay:e.e.p=99%.After synthetic method was improved and optimized,the yields were increased from 78.0% to 88.5% for Ⅰ and from 90.0% to 99.0% for Ⅱ,respectively.