盐酸丁卡因的合成工艺改进  

Process Improvement on Synthesis of Tetracaine Hydrochloride

作　　者：李文丽[1] 赵杰[1] 许志刚 张彩霞 

机构地区：[1]重庆能源职业学院,石油化工检测中心,重庆402260 [2]西南大学材料与能源学部,重庆400715

出　　处：《精细化工》2018年第2期272-277,共6页Fine Chemicals

基　　金：重庆市教委科学技术研究项目(批准号:KJ1505501)~~

摘　　要：以对氨基苯甲酸乙酯（苯佐卡因,EPABA）为原料,经过N-烷基化、水解、酯化三步反应得到盐酸丁卡因。采用FTIR、^1HNMR和HPLC对产物进行了表征。对N-烷基化过程、水解条件、酯化条件进行了优化。结果表明：盐酸丁卡因被成功合成。N-烷基化的最佳工艺条件为：反应温度60℃,n（三乙胺）∶n（EPABA）∶n（1-溴丁烷）=1.2∶1.0∶4.6,在此条件下合成对丁氨基苯甲酸乙酯（Ⅰ）,产品收率为75.62%;与现有工艺路线相比,在生成关键中间体Ⅰ时成功减少了双丁基化副产物的产生;水解反应的最佳合成条件为：n（Na OH）∶n（Ⅰ）=1.4∶1.0、反应温度为50℃、反应时间为8 h,在此条件下合成对丁氨基苯甲酸（Ⅱ）的收率为99.78%;当n[（β-氯乙基）二甲胺盐酸盐,Ⅲ]∶n（Ⅱ）=1.3∶1.0、反应温度为116℃、溶剂为甲基异丁基酮时,合成了盐酸丁卡因,收率为85.07%。Tetracaine hydrochloride was synthesized from ethylp-aminobenzoate （EPABA） via Nalkylation, hydrolysis and esterifieation. FTIR, 1HNMR and HPLC were used to characterize and analyze the structure and purity of the products. The reaction conditions of N-alkylation, hydrolysis and esterification were optimized. The results showed that tetraeaine hydrochloride was successfully synthesized. The optimal process conditions of N-alkylation were reaction temperature 60 ℃, molar ratio of triethylamine, EPABA and 1-bromobutane = 1.2：1.0：4.6. Under these conditions, the yield of ethyl 4-（butylamino） benzoate （ Ⅰ ） was up to 75.62%. Compared with the present technology route for the synthesis of intermediate I ,this new method could reduce the production of dibutyl by-products. The optimal synthesis conditions of hydrolysis were obtained. When the reaction temperature was 50 ℃, the molar ratio of sodium hydroxide to ethyl 4- （hutylamino） benzoate was 1.4 ： 1.0, and the reaction time was 8 hours,the yield of 4-（butylamino）benzoic acid （ Ⅱ ） was 99.78%. When the esterifieation was performed at 116 ℃ by using isohutyl methyl ketone as solvent with 1.3：1. 0 molar ratio of 2- dimethylaminoethyl chloride hydroehloride to 4- （butylamino） benzoic acid,, tetraeaine hydroehloride in 85.07% yield was obtained.

关 键 词：苯佐卡因 对丁氨基苯甲酸 (β-氯乙基)二甲胺盐酸盐 盐酸丁卡因 医药与日化原料 

分 类 号：R625[医药卫生—整形外科]