雷芬那辛合成工艺优化

Synthesis process optimization of Revefenacin

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.

Abstract

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-(methylaminoethyl)piperidine-4-yl[1,1'-biphenyl]-2-ylcarbamate, 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

Key words

Revefenacin / Chronic Obstructive Pulmonary Disease / optimization of synthesis process

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基金资助

闽西职业技术学院科研立项项目(KJMY2310)