雷芬那辛合成工艺优化  

Synthesis process optimization of Revefenacin

作　　者：魏岚[1] 郑丽丽 WEI Lan;ZHENG Lili(School of Medical Nursing,Minxi Vocational&Technical College,Longyan Fujian 364021)

机构地区：[1]闽西职业技术学院医学护理学院,福建龙岩364021

出　　处：《辽宁师专学报（自然科学版）》2024年第2期95-103,共9页Journal of Liaoning Normal College(Natural Science Edition)

基　　金：闽西职业技术学院科研立项项目(KJMY2310)。

摘　　要：探究雷芬那辛合成新工艺.以4-羟基哌啶盐酸盐为原料,经过亲核取代反应生成4-氯甲酸哌啶盐酸盐,然后与邻氨基联苯经过亲核取代反应生成哌啶-4-基[1,1′-联苯]-2-氨基甲酸酯,再与2-氯-N-甲基-1-胺盐酸盐反应生成1-(2-甲基氨基)乙基)哌啶-4-基[1,1′-联苯]-2-基氨基甲酸酯,最后经过缩合反应生成雷芬那辛.实验结果表明:合成REV-1的最佳反应溶剂为N-甲基吡咯烷酮,合成REV-2的最佳碱为碳酸钾,合成REV-3的最佳反应温度为80℃,合成REV-4的最佳缩合剂为EDCI/HOBT.所得产品纯度为99.6%,总收率为59.5%,雷芬那辛及中间体经过核磁表征,结构正确.该合成工艺的条件温和、合成率较高,对环境污染较小,是合成雷芬那辛的新选择.This paper explored a new synthesis process of revefenacin.Using 4-hydroxypiperidine hydrochloride as raw material,4-chloroformate piperidine hydrochloride was synthesized by nucleophilic substitution reaction,then piperidine-4-yl[1,1′-biphenyl].-2-carbamate was synthesized by nucleophilic substitution reaction with o-aminobiphenyl,and reacted again with 2-chloro-n-methyl-1-amine hydrochloride to produce 1-(2-(methylamino-ethyl)piperidine-4-yl[1,1′-biphenyl].-2-yl carbamate,and finally revefenacin was generated through condensation reaction.The experimental results showed that the optimal reaction solvent for the synthesis of REV-1 was N-methylpyrrolidone,the optimal base for the synthesis of REV-2 was potassium carbonate,the optimal reaction temperature for the synthesis of REV-3 was 80℃,and the optimal condensation mixture for the synthesis of REV-4 was EDCI/HOBT.The purity of the obtained product was 99.6%,the total yield was 59.5%,and the revefenacin and the intermediate were characterized by nuclear magnetic resonance with the correct structure.The synthesis process has mild conditions,high synthesis rate and less pollution to the environment,which is a new choice for the synthesis of Revefenacin.

关 键 词：雷芬那辛 慢性阻塞性肺病 合成工艺优化 

分 类 号：R914.5[医药卫生—药物化学]