盐酸丁卡因的合成改进
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R625

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重庆教委科学技术研究项目(批准号:KJ1505501)


Improvements on the Synthesis of Tetracaine Hydrochloride
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Project Foundation of Chongqing Municipal Education Committee (No.KJ1505501)

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    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粗品,产品收率 高达85.09%。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、酯化条件进行了反应条件优化。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)=1.2:1:4.6 ,合成对丁氨基苯甲酸乙酯(I),产品收率为75.69%;与现有工艺路线相比,在生成关键中间体对丁氨基苯甲酸乙酯(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:原料配比为n(NaOH)∶n(对丁氨基苯甲酸乙酯)=1.4:1、反应温度为50℃、反应时间为8h, 合成对丁氨基苯甲酸(Ⅱ),产品收率为99.78%;酯化反应的最佳反应条件为:原料配比为n〔(β-氯乙基)二甲胺盐酸盐〕: n(对丁氨基苯甲酸) =1.3:1、反应温度为116℃、溶剂为甲基异丁基甲酮,合成盐酸丁卡因,产品收率为85.09%。

    Abstract:

    Tetracaine hydrochloride was synthesized from N-alkylation,hydrolysis and esterification through three-step reactions,The yield of tetracaine hydrochloride was up to 85.09 %. FTIR,1HNMR and HPLC were used to characterize and analyze the structure and purity of the products.The reaction conditions were optimized, which was studied with the reaction of N-alkylation,hydrolysis and esterification. The results show that,tetracaine hydrochloride is successfully synthesized. The optimal process conditions of N-alkylation, under which the yield of ethyl 4-(butylamino) benzoate( I) is up to 75.69%, are as follows: at 60℃, and with the ratio of triethylamine, benzocaine and 1- bromobutane is 1.2:1:4.6. Compared with the present technology route,the new method has successed in reducing the formation of dibutyl by-product, during formed the key intermediate of ethyl 4-(butylamino)benzoate(I). The optimal synthesis conditions of hydrolysis, are as follows: at 50℃, and with the ratio of sodium hydroxide and ethyl 4-(butylamino)benzoate is 1.4:1. We can get the target product in 8 hours. The production of 4-(butylamino)benzoic acid (Ⅱ)with a 99.78% yield. The optimal reaction conditions of esterification, are as follows: at 116℃, and with the ratio of 2-dimethylaminoethyl chloride hydrochloride and 4-(butylamino)benzoic acid is 1.3:1. The solvent methyl isobutyl ketone ensures the production of tetracaine hydrochloride with a 85.09% yield.

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李文丽.盐酸丁卡因的合成改进[J].精细化工,2018,35(2):

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  • 收稿日期:2016-06-12
  • 最后修改日期:2017-08-08
  • 录用日期:2017-08-23
  • 在线发布日期: 2018-02-06
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