马西替坦关键中间体5-(4-溴苯基)-4,6-二氯嘧啶的合成  

Synthesis of Macitentan Key Intermediate 5-(4-Bromophenyl)-4,6-dichloropyrimidine

作　　者：丁利红 王珣 张耀光 肖艳华[1] DING Lihong;WANG Xun;ZHANG Yaoguang;XIAO Yanhua(Key Laboratory of Green Chemical Engineering Process of Ministry of Education,Hubei Key Laboratory of Novel Reactors and Green Chemical Technology,School of Chemical Engineering and Pharmacy,Wuhan Institute of Technology,Wuhan 430074,China)

机构地区：[1]武汉工程大学化工与制药学院、绿色化工过程教育部重点实验室、新型反应器与绿色化学工艺湖北省重点实验室,湖北武汉430074

出　　处：《化学与生物工程》2024年第8期52-55,共4页Chemistry & Bioengineering

基　　金：国家自然科学基金青年科学基金项目(22004095)。

摘　　要：以4-溴苯乙酸甲酯(Ⅱ)和碳酸二甲酯为原料,经克莱森(Claisen)缩合反应得到2-(4-溴苯基)-丙二酸-1,3-二乙酯(Ⅲ),化合物Ⅲ再与甲脒盐酸盐环合得到5-(4-溴苯基)嘧啶-4,6-二醇(Ⅳ),化合物Ⅳ经氯代反应得到目标化合物5-(4-溴苯基)-4,6-二氯嘧啶(Ⅰ);通过1 HNMR对中间体和目标化合物进行了表征,并对合成工艺进行了优化。^(1)HNMR分析结果表明,所得中间体和目标化合物均与目标物一致;在最优工艺条件下,3步总收率达到43.6%。该工艺原料廉价易得,反应条件温和,后处理简单,易于大规模工业化生产。First,2-(4-bromophenyl)-malonicacid-1,3-diethyl ester(Ⅲ)was obtained from methyl 4-bromophenylacetate(Ⅱ)and dimethyl carbonate by Claisen condensation reaction.Then,5-(4-bromophenyl)pyrimidine-4,6-diol(Ⅳ)was obtained from compoundⅢcycled with formamidine hydrochloride.Finally,the target compound 5-(4-bromophenyl)-4,6-dichloropyrimidine(Ⅰ)was obtained by chlorination of compoundⅣ.Moreover,we characterized the intermediates and target compound by 1 HNMR.The results of ^(1)HNMR analysis show that all intermediates and the target compound are consistent with the targets.The three-step total yield reaches 43.6%under the optimal synthesis conditions.The process has the advantages of cheap raw materials,mild reaction conditions,simple post-treatment,and it is easy for large-scale industrial production.

关 键 词：马西替坦 内皮素受体拮抗剂 中间体 合成 

分 类 号：TQ463[化学工程—制药化工]