Process improvement of kilogram scale teneligliptin hydrobromide as DPP-4 inhibitor

被引：0

作者：

Gu, Na ^{[1
]}

Zhang, Jiufeng ^{[2
]}

Yao, Tong ^{[2
]}

Mao, Liangang ^{[2
]}

Li, Linzhe ^{[3
]}

Zhang, Zhenming ^{[1
,4
]}

机构：

[1] School of Environmental and Chemical Engineering, Jiangsu Ocean University, Lianyungang,222005, China

[2] Lianyungang Jari Pharmaceutical Co., Ltd., Lianyungang,222005, China

[3] School of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang,222005, China

[4] Jiangsu Institute of Marine Resources, Lianyungang,222005, China

来源：

Jingxi Huagong/Fine Chemicals | 2021年 / 38卷 / 03期

关键词：

Amines - Bromine compounds - Sodium compounds;

D O I：

10.13550/j.jxhg.20200766

中图分类号：

学科分类号：

摘要：

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 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 of 2~3 h. Under these conditions, the HPLC purity of 3-({(2S, 4S)-1-tert-butoxycarbonyl-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}formyl) thiazolidine (Ⅳ) was 98.40%. Under the conditions of n(Ⅱ):n(Ⅲ):n(HBr)=1.0:1.0:3.5, reaction time of 4 h, and crystallized temperature of 0~5℃, the overall yield and HPLC purity of the product were 88.33% and 99.95%, respectively, specific rotation [a]D20 was -32.5°. © 2021, Editorial Office of FINE CHEMICALS. All right reserved.

引用

页码：572 / 577