外周大麻素Ⅰ型(CB1)受体拮抗剂TM38837的合成  

Synthesis of peripherally CB1 receptor inhibitor TM38837

作　　者：邴绍辉 陈伟[2] 郑志兵[1,2] 

机构地区：[1]广西医科大学药学院,广西南宁530021 [2]军事医学科学院毒物药物研究所,北京100850

出　　处：《中国药物化学杂志》2014年第1期19-22,共4页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(81102308)

摘　　要：目的合成外周大麻素Ⅰ型受体拮抗剂TM38837。方法以2-正丁酰噻吩、六甲基二硅基胺基锂和乙二酸二乙酯为起始原料,经过成锂盐、环化、取代、Sonogashira偶合、水解、酰胺化6步反应制得目标产物TM38837。结果与结论目标化合物和中间体的结构经1H-NMR、MS谱确证,总收率为14.8%(以2-正丁酰噻吩计)。The synthesis of TM38837, a CB1 receptor inhibitor, has been accomplished via 6 steps according to the literature. Treatment of 2-butyrylthiophene with diethyl oxalate in the presence of LiHMDS gave rise to lithium salt 2 in 72% yield ,which in turn was coupled with 2,4-dichlorophenylhydrazine hydrochloride in ethanol followed by intramolecular cyclization under refluxing acetic acid to provide ester 3 in 46% yield over two steps. Regioselective bromination of ester 3 was smoothly effected using NBS in acetonitrile to af ford the corresponding 5-bromo ester 4 in 95 % yield. Compound 4 was treated with 1 -ethynyl-4- （ trifluorom ethyl） benzene dissolved in triethylamine and THF in the presence of PdC12 （PPh3 ）：/CuI to afford product 5 in 71% yield through Sonogashira coupling. Compound 5 was subjected to basic hydrolysis under standard conditions to give carboxylic acid 6 in 91% yield, which was then treated with trimethylacetyl chloride to ac tivate the carboxylic group followed by coupling with 1-aminopiperidine to furnish the desired product TM38837 in 74% yield.

关 键 词：外周大麻素I型(CB1)受体 拮抗剂 TM38837 化学合成 外周选择性 

分 类 号：R914.5[医药卫生—药物化学]