磷酸西格列汀的合成工艺改进

Improved synthesis of sitagliptin phosphate

目的改进磷酸西格列汀的合成方法。方法以2,4,5-三氟苯乙酸为原料,经缩合、水解得到3-氧代-(2,4,5-三氟苯基)丁酸甲酯,该甲酯与手性苯乙胺反应,经硼氢化钠还原,再经缩合、脱保护、成盐得到磷酸西格列汀。结果与结论提供了一条简捷高效且适合工业化生产磷酸西格列汀的工艺路线,7步反应的总收率为39.5%。关键还原步骤以廉价的硼氢化钠为还原剂,使本工艺避免了使用有毒、昂贵试剂,符合绿色化学的原则。

An improved synthesis of sitagliptin phosphate w as reported in this paper. The key enamine intermediate 6 w as prepared from starting material 2,4,5-trifluorophenyl acetic acid（ 2） via condensation w ith M eldrum ＇s acid,methanolysis under room temperature and condensation w ith α-phenethylamine 6,diastereoseletive reduction by Na BH4 under mild condition to give chiral amine,w hich w as aminolyzed in the presence of DIPEA to give intermediate 8. The title product sitagliptin phosphate w as afforded from 8 via deprotection and salification in isopropyl alcohol（ IPA）. The procedure enclosed here w as an efficient and economical route to a practical synthesis of stagliptin phosphate（ 39. 5% yield in 7 steps）. The use of Na BH4,as a cheap reducing reagent avoided expensive and toxic reagents,which followed the principles of green chemistry.