盐酸依格列汀合成工艺研究

Synthetic Process of Evogliptin Hydrochloride

关键词:  依格列汀  糖尿病  手性拆分  回收

Key words:  evogliptin  diabetes  chiral resolution  recycling

摘要:

研究盐酸依格列汀（1）的合成工艺。方法 以2，4，5-三氟苯乙酸为原料，经缩合、氨化、NaBH₄还原3步反应得到消旋依格列汀，再经酒石酸拆分、盐酸成盐得到目标产物盐酸依格列汀。其中，拆分后所得的另一对映异构体S-依格列汀通过N-氯代、消除后顺利回收烯胺中间体。结果 制备工艺总收率26.9%，化学纯度为99.9%，光学纯度ee值为99.8%；烯胺中间体回收率为92.3%（以拆分所得依格列汀剩余的对映异构体量计算）。结论 该工艺收率高，步骤短，成本低廉、操作简便，适应工业化生产。此外，本文也为手性胺类药物的高效制备提供了一种极具吸引力的策略。

Abstract:

OBJECTIVE To study the synthetic process of evogliptin hydrochloride (1). METHODS Rac-evogliptin was synthesized from 2,4,5-trifluoro phenyl acetic acid through condensation, amination, and NaBH₄ reduction in three steps. After resolution of rac-evogliptin with L-(+)-tartaric acid and susequent salification process, the corresponding desired evogliptin hydrochloride was produced. In addition, another (S)-enantiomer could be recycled substantially as enamine intermediate via N-chlorination and elimination in two steps. RESULTS The yield of evogliptin hydrochloride was 26.9%. The purity of the target product was 99.9% with excellent enantioselectivity (99.8% ee). The recovery rate of enamine intermediate was 92.3% based on the resolution yield of the remaining enantiomers. CONCLUSION This synthetic process is a satisfactory way with high yield, simple synthetic route, low-cost, convenient operation for industrial production. Moreover, this mothod also provides an efficient and attractive strategy for the preparation of chiral amine drugs.