Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.
School of Medicine and Life Sciences, Xinyu University, Xinyu, China.
Chirality. 2021 Feb;33(2):62-71. doi: 10.1002/chir.23286. Epub 2020 Dec 3.
Brivaracetam is a structural derivative of the chiral drug levetiracetam and has been approved for the adjuvant treatment of partial epilepsy. As a new antiepileptic drug, it is widely used in a variety of epilepsy models. In this study, a novel lipase M16 derived from Aspergillus oryzae WZ007 was cloned, expressed, and used for chiral resolution. Lipase M16 has a high enantioselectivity to the racemic substrate (R,S)-methyl 2-propylsuccinate 4-tert-butyl ester, and the intermediate (R)-2-propylsuccinic acid 4-tert-butyl ester of brivaracetam was obtained efficiently. Under optimal conditions, the enantiomeric excess of substrate was up to 99.26%, and the e.e. was 96.23%. The conversion and apparent E value were 50.63% and 342.48, respectively. This study suggests a new biocatalytic resolution via lipase M16 for preparing the brivaracetam chiral intermediate and its potential application in the pharmaceutical industry.
布瓦西坦是手性药物左乙拉西坦的结构衍生物，已被批准用于部分癫痫的辅助治疗。作为一种新型抗癫痫药物，它被广泛应用于多种癫痫模型。本研究克隆、表达了来源于米曲霉 WZ007 的新型脂肪酶 M16，并将其用于手性拆分。脂肪酶 M16 对(R,S)-甲基 2-丙基琥珀酸 4-叔丁酯的对映体具有较高的选择性，可高效获得布瓦西坦的手性中间体(R)-2-丙基琥珀酸 4-叔丁酯。在最佳条件下，底物的对映体过量值可达 99.26%，对映体过量值为 96.23%。转化率和表观 E 值分别为 50.63%和 342.48。本研究通过脂肪酶 M16 为制备布瓦西坦手性中间体提供了一种新的生物催化拆分方法，并为其在制药工业中的潜在应用提供了参考。
