马来酸氯苯那敏的绿色合成工艺研究

Study on the green synthesis process of chlorpheniramine maleate

摘要

马来酸氯苯那敏,又称扑尔敏,是临床上常用的丙胺类H₁受体拮抗剂.本研究以对氯苯乙腈为起始原料,通过缩合、脱氰、缩合及成盐反应步骤,对马来酸氯苯那敏的合成工艺进行了系统优化.关键创新在于脱氰环节采用廉价无机碱水溶液替代传统浓硫酸体系,实现了对氰基转化路径的精准控制,有效抑制过度水解和碳化等副反应,减少高盐废水的产生,符合绿色化学原则.同时成功完成50kg级中试放大,产品总收率达70.0%以上,主成分含量超过99.0%,单一杂质低于0.1%,总杂质不超过0.3%,符合《中华人民共和国药典》(2025年版)要求,且反应条件温和、操作简便,具备良好的产业化应用前景.

Abstract

Chlorpheniramine maleate, or chlorphenamine, is a widely used propylamine-type H ₁ receptor antagonist. This study details a systematically optimized synthesis of chlorpheniramine maleate from p-chlorophenylacetonitrile through a four-step sequence: condensation, decyanation, condensation, and salification. The process innovation centers on a critically improved decyanation step by substituting concentrated sulfuric acid with an inexpensive aqueous inorganic base. This novel approach affords precise control over the cyano conversion pathway, effectively suppresses undesirable side reactions, drastically reduces high-salt aqueous waste, and conforms to the principles of green chemistry. The process's industrial viability was validated through a successful 50 kg pilot-scale run, delivering an overall yield of over 70.0%. The resulting chlorpheniramine maleate exhibited exceptional purity (the main component purity exceeding 99.0%, with any single impurity below 0.1%, and total impurities not exceeding 0.3%), fully complying with the Pharmacopoeia of the People's Republic of China (2025 Edition). Combined with its mild reaction conditions and operational simplicity, this process demonstrates strong potential and commercial viability for industrial-scale application.

关键词

氯苯那敏 / 工艺研究 / 脱氰反应 / 绿色 / 产业化

Key words

chlorpheniramine maleate / process study / decyanation reaction / green / industrialization

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基金资助

国家自然科学基金(82003585)

河南省科技攻关项目(242102230095)

河南省高校基础研究专项(23ZX009)

河南师范大学优秀科技创新团队(2022TD03)