DPP-Ⅳ抑制剂特力利汀的合成工艺改进  

Improved synthesis of DPP-Ⅳ inhibitor of teneligliptin

作　　者：刘进[1] 吴迪[1] 李鹏程[1] 徐登智 徐莉英[1] 宫平[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2016年第5期390-393,401,共5页Chinese Journal of Medicinal Chemistry

摘　　要：目的合成DPP-Ⅳ抑制剂特力利汀并进行工艺优化。方法以N-Boc哌嗪、双乙烯酮为原料,经过缩合、环化和脱保护得到中间体1-(3-甲基-1-苯基-1H-吡唑-5-基)哌嗪;以反式-4-羟基-L-脯氨酸为原料,经过Fmoc保护、氧化、缩合反应得到中间体3-[(2S)-1-(9H-芴-9-基甲氧羰基)-4-氧代吡咯烷-2-基羰基]噻唑烷;这两个中间体经还原胺化、脱保护基制得抗糖尿病药特力利汀,总收率为47.2%(以反式-4-羟基-L-脯氨酸计),纯度为99.1%(HPLC法)。结果与结论特力利汀的结构经MS、IR、1H-NM R和13C-NM R谱确证,所确定的合成路线原料廉价易得,反应条件温和,后处理简单,收率较高,为中试放大生产奠定了基础。Teneligliptin,an orally active DPP-Ⅳ inhibitor,is effective for the treatment of type 2 diabetes. An improved synthetic process of teneligliptin has been developed in this paper. Taking N-Boc-piperazinyl and diketene as the starting material,the key intermediate 1-（ 3-methyl-1-phenyl-1H-pyrazol-5-yl） piperazine was synthesized via acylation,condensation,cyclization and Boc-deprotection. Another key intermediate（ 2S）-（ 9H-fluoren-9-yl-methyl）-4-oxo-2-（ 1,3-thiazolidin-3-ylcarbonyl） pyrrolidine-1-carboxylate was prepared starting from trans-（ 2S,4R）-4-hydroxy-proline,followed by N-Fmoc-protection,condensation,oxidation.Finally,the target product teneligliptin was gained by reductive amination and deprotection. The total yield of teneligliptin was 47. 2%（ calculated from trans-（ 2S,4R）-4-hydroxy-proline）,and its purity was 99. 1%.The structure of teneligliptin was confirmed by MS,IR,1H-NMR and13C-NMR. The synthetic route is of many advantages,such as inexpensive starting materials,mild reaction conditions,simple work-up,and high yield,which established a good foundation for large-scale production.

关 键 词：特力利汀 DPP-Ⅳ抑制剂 工艺改进 抗糖尿病药 

分 类 号：R914.5[医药卫生—药物化学]