丁卡因合成工艺研究  

Research on the Synthesis Process of Tetracaine

作　　者：赵珂 孙会谦 王瑞 霍彩霞 ZHAO Ke;SUN Huiqian;WANG Rui;HUO Caixia(School of Pharmacy,Inner Mongolia Medical University,Hohhot 010013,China;Beijing Green Pharmaceutical Technology Co.,Ltd.,Beijing 101399,China)

机构地区：[1]内蒙古医科大学药学院,内蒙古呼和浩特010013 [2]北京格林意锐医药科技有限责任公司,北京101399

出　　处：《山东化工》2025年第4期29-32,共4页Shandong Chemical Industry

摘　　要：以对氨基苯甲酸为起始原料经酯化、N-烷基化、水解、再酯化四步反应得到丁卡因。采用^(1)H NMR和HPLC对产物进行了表征。对反应温度、物料种类及物质的量比等关键参数进行了优化。起始原料采用价格低廉的化工品对氨基苯甲酸,通过酯化反应得到对氨基苯甲酸乙酯(Ⅰ)物质的量收率为98.30%;在合成对丁氨基苯甲酸乙酯(Ⅱ)时选择位阻比三乙胺较大的N,N-二异丙基乙胺(DIPEA)为碱,物质的量收率为82.82%。Ⅱ在2倍水和2倍乙醇的混合溶剂体系中水解,对丁氨基苯甲酸(Ⅲ)的物质的量收率为98.60%;丁卡因合成的最佳反应条件是选择5倍甲苯作溶剂,n(Ⅲ)∶n(N,N-二甲基氯乙胺盐酸盐,Ⅳ)∶n(K_(2)CO_(3))=1.0∶1.2∶2.0,于85~95℃反应10 h,物质的量收率为89.68%。结果表明:丁卡因收率明显提高,总收率为72%,HPLC纯度为99.95%。Tetracaine was obtained by a four-step reaction of esterification,N-alkylation,hydrolysis,and re-esterification with p-aminobenzoic acid as the starting material.^(1)H NMR and HPLC were used to analyze the products'structure and purity.Key parameters such as reaction temperature,material type,and molar ratio were optimized.The starting material was 4-aminobenzoic acid,a low-cost chemical product,and the molar yield of ethyl-p-aminobenzoate(Ⅰ)was obtained by esterification reaction with a molar yield of 98.30%.In the synthesis of ethyl 4-(butylamino)benzoate(Ⅱ),N,N-diisopropylethylamine(DIPEA)with a larger steric hindrance than triethylamine was selected as the base,and the molar yield was 82.82%.Ⅱwas hydrolyzed in a mixed solvent system of 2 times water and 2 times ethanol,and the molar yield of 4-(butylamino)benzoic acid(Ⅲ)was 98.60%;The optimal reaction conditions for the synthesis of tetracaine were to select 5 times toluene as the solvent,n(Ⅲ)∶n(N,N-diisopropylethylamine hydrochloride,IV)∶n(K_(2)CO_(3))=1.0∶1.2∶2.0,and react at 85~95℃for 10 h,and the yield of the substance was 89.68%.The results showed that the yield of tetracaine was significantly improved,the total yield was 72%,and the HPLC purity was 99.95%.The process has the advantages of cheap and easy availability of raw materials,mild reaction conditions,strong operability,simple post-processing,and no special equipment requirements,and is suitable for industrial production.

关 键 词：对氨基苯甲酸 丁卡因 合成工艺 

分 类 号：TQ460[化学工程—制药化工] R914[医药卫生—药物化学]