千克级DPP-4抑制剂氢溴酸替格列汀工艺改进

Kilogram scaleimproved procedure of teneligliptin hydrobromideas DPP-4 inhibitor

摘要:

以（2S)-4-氧代-2-（3-噻唑烷基羰基)-1-吡咯烷羧酸叔丁酯（Ⅱ）和1-（3-甲基-1-苯基-1H-吡唑-5-基)哌嗪（Ⅲ）为原料，三乙酰氧基硼氢化钠(V)为还原剂，仅用甲苯为溶剂，通过胺化还原、脱保护成盐、析晶改进了千克级DPP-4抑制剂氢溴酸替格列汀的合成工艺。采用FTIR, LC-MS, XRD, 1HNMR及旋光仪对产物进行了表征和测试。胺化还原和脱保护成盐反应的最佳合成工艺条件为：n(Ⅱ)∶n(Ⅲ)∶n(V)=1.0∶1.0∶1.5，反应时间2~3 h。在该条件下，中间体3-({（2S,4S)-1-叔丁氧羰基-4-[4-（3-甲基-1-苯基-1H-吡唑-5-基)-1-哌嗪基]-2-吡咯烷基}甲酰基)噻唑烷(Ⅳ)的纯度98.40%；n(Ⅱ)∶n(Ⅲ)∶n(HBr)=1.0∶1.0∶3.5，反应时间4 h，析晶温度为0~5 ℃，总收率为88.33%，纯度为99.95%，[]20D=-32.5°。

Abstract:

Kilogram scale teneligliptin hydrobromide, a DPP-4 inhibitor, was synthesized by amination reduction, de-protection, salt formation, and crystallization using (2S)-4-oxo-2-(3-thiazolidinylcarbonyl)-1-pyrrolidinecarboxylicacid tert-butyl ester (Ⅱ) and 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl) piprazine (Ⅲ) as raw materials, sodium triacetoxyborohydride as reducing agent and only toluene as solvent. The structure and properties of the product were characterized by FTIR, LC-MS, XRD, 1HNMR and polarimeter. The optimum synthetic conditions of amination reduction, de-protection and salt formation were as follows: n(Ⅱ)∶n(Ⅲ)∶n(V)=1.0∶1.0∶1.5, and reaction time 2~3 h. Under these conditions, the purity of obtained the product 3-({(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}formyl) thiazolidine (Ⅳ) with the of 98.40%; n(Ⅱ)∶n(Ⅲ)∶n(HBr)=1.0∶1.0∶3.5, reaction time 4 h and crystallized at 0~5 ℃ with the total yield of 88.33% and the purity of 99.95%, []20D=-32.5°.