氟两相体系中2-正丙基-4-甲基-6-甲氧羰基苯并咪唑的合成  

Synthesis of 2-(n-Propyl)-4-methyl-6-methoxycarbonylbenzimidazole in Fluorous Biphasic System (FBS)

作　　者：陶锋 易文斌[2] 

机构地区：[1]亚邦医药研究所有限公司,江苏常州213163 [2]南京理工大学化工学院,江苏南京210094

出　　处：《精细化工》2007年第8期809-812,共4页Fine Chemicals

基　　金：中国博士后科学基金(20060400942)~~

摘　　要：2-正丙基-4-甲基-6-甲氧羰基苯并咪唑是合成替米沙坦药物的重要中间体。在氟两相体系中,在不用乙酸的条件下,3-甲基-4-丁酰氨基-5-氨基苯甲酸甲酯以高产率转化为2-正丙基-4-甲基-6-甲氧羰基苯并咪唑。考察了催化剂种类及用量、全氟溶剂、反应温度和氟相循环使用对缩合反应的影响。结果表明,全氟辛基磺酸镱〔Yb(OPf)3〕和全氟萘烷(C10F18)分别是最好的催化剂和氟溶剂。在x〔Yb(OPf)3〕=0.3%,反应温度80℃,反应时间2 h的条件下,2-正丙基-4-甲基-6-甲氧羰基苯并咪唑产率为94%。含有催化剂的氟相通过简单的相分离,就可回收利用。19FNMR、GC-MS和UV-Vis检测结果显示没有催化剂或氟溶剂的损失。含有催化剂的氟相的UV-Vis光谱图分析说明,Yb(OPf)3在使用前后活性没有变化。原子发射光谱(ICP)显示,催化剂被完全(99.9%)回收,氟相重复使用10次,缩合产率从94%降至90%。2-（n-Propyl） 4-methyl-6-methoxycarbonylbenzimidazole （ Ⅰ ） is an important intermediate of telmisartan pharmaceutical. Methyl 3-methyl4-butyrylamino-5-aminobenzoate was efficiently converted into Ⅰ in fluorous biphasic system （FBS） without acetic acid. It was found that Yb（OPf）3 and C10F18 were the best catalyst and fluorous solvent respectively for the reaction. Yield of I could be up to 94% at 80 ℃ for 2 h with x[ Yb（OPf） 3 ] = 0. 3%. By simple phase separation,the fluorous phase containing only the catalyst could be directly reused next time. Based on 19F NMR and UV - Vis and GC - MS data, no loss of catalyst or fluorous solvent to the organic phase can be detected, and no organic compounds can be found in the fluorous phase. There is no significant difference between the UV - Vis spectra of the initial and recovered fluorous phases, indicating that Yb（ OPf）3 is recovered unaltered after the condensation reaction. The catalyst was completely （ 〉 99% ） recovered as determined by atomic emission spectrometry. The fluorous phase containing only catalyst can be reused up to ten times with only a slight decrease in yields from 94% to 90%.

关 键 词：2-正丙基-4-甲基-6-甲氧羰基苯并咪唑 替米沙坦 氟两相体系 全氟溶剂 全氟辛基磺酸镱 药物中间体 

分 类 号：TQ203[化学工程—有机化工] O614.33[理学—无机化学]