离子液体催化合成阿立哌唑关键中间体  

Synthesis of a Key Intermediate of Aripiprazole Catalyzed by the Ionic liquid

作　　者：张稳 陈道鹏[1] 杜康 杨相平[1] 许向阳 ZHANG Wen;CHEN Daopeng;DU Kang;YANG Xiangping;XU Xiangyang(Jiangsu Key Lab.of Central Nervous System Drug Research and Development,Jiangsu Nhwa Pharmaceutical Co.,Ltd.,Xuzhou 221116)

机构地区：[1]江苏恩华药业股份有限公司,江苏省中枢神经药物研究重点实验室,江苏徐州221116

出　　处：《中国医药工业杂志》2023年第9期1327-1329,共3页Chinese Journal of Pharmaceuticals

基　　金：江苏省中枢神经药物研究重点实验室资助项目(BM2019004)。

摘　　要：以间氨基苯酚(2)为原料,与3-氯丙酰氯(3)发生酰化反应,得3-氯-N-(3-羟基苯基)丙酰胺(4),用盐酸三乙胺-三氯化铝离子液体催化4分子内Friedel-Crafts烷基化反应,得阿立哌唑关键中间体7-羟基-3,4-二氢-2(1H)-喹啉酮(1)。通过对主要工艺参数的优化,确认了Friedel-Crafts烷基化的优化反应条件如下:4、盐酸三乙胺和三氯化铝投料的物质的量比为1.1∶1.0∶5.5,反应温度为120~130℃,反应时间10 h。在上述条件下,1的催化合成可成功放大至公斤级规模,产品纯度达99.7%,总收率58.2%(以2计)。该方法条件温和、后处理简单、产品纯度高、工艺稳定,适合工业化放大。In this study,the key intermediate of aripiprazole,7-hydroxy-3,4-dihydro-2(1H)-quinolone(1),was obtained by intramolecular Friedel-Crafts alkylation reaction of 3-chloro-N-(3-hydroxyphenyl)propionamide(4)using triethylamine hydrochloride-aluminum chloride ionic liquid.Compound 4 was synthesized by acylation reaction between m-aminophenol(2)and 3-chloropropionyl chloride(3).Through the optimization of the main process parameters,the reaction conditions of the Friedel-Crafts alkylation were confirmed as the following:the amount of substance ratio of 3-chloro-N-(3-hydroxyphenyl)propionamide,triethylamine hydrochloride and aluminum chloride was 1.1∶1.0∶5.5,and reaction temperature was 120-130℃,while reaction time was 10 h.Under the above conditions,the product was successfully scaled up to the kilogram scale.The purity of the product was up to 99.7%with the total yield of 58.2%(based on 2).This method had mild conditions,simple post-processing,high product purity,stable process,which was suitable for industrialization.

关 键 词：阿立哌唑 离子液体 Friedel-Crafts烷基化 中间体 

分 类 号：R749.4[医药卫生—神经病学与精神病学] TQ460.6[医药卫生—临床医学]