瑞替加滨的简易合成方法

摘要以5-氟-2-硝基苯胺为起始原料，经亲核取代、氢化还原和酰化反应合成了瑞替加滨，并对反应工艺条件进行了优化。中间产物2-氨基-4-（4-氟苄胺基）硝基苯的优化条件为：以三乙胺为缚酸剂，n（5-氟-2-硝基苯胺）∶n（4-氟苄胺）∶n（三乙胺）=1.0∶1.2∶1.3，反应温度为90℃，反应时间为8 h，得中间产物，收率可达92.94%。瑞替加滨合成的优化条件为：以四氢呋喃为溶剂，钯碳（Pd/C，5%）为催化剂，氢压为101.325 kPa，反应温度为35℃，氢化还原反应3 h后，在15℃下滴加盐酸溶液后继续氢化还原反应，此后不经分离与氯甲酸乙酯直接进行酰化反应得粗品，粗品经乙醇/正己烷混合溶剂精制，得到目标产物瑞替加滨，总收率43.09%，质量分数可达99.9%（HPLC），其化学结构经元素分析、¹H NMR、¹³C NMR和ESI-MS确证。该合成工艺方法操作简单，稳定可靠，原料易得，催化剂可以回收再用，有效地降低了生产成本，有利于工业化生产。

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	訾晨瑞
	陈立功
	王东华
	闫喜龙
	李阳
	徐蕊

关键词：癫痫；瑞替加滨；合成

Abstract： Retigabine was synthesized from 5-fluoro-2-nitroaniline through three steps including nucleophilic substitution, reduction and acylation reaction. The reaction conditions of each reaction step were optimized. The optimized conditions for intermediate 2-amino-4-(4-fluoro benzylamino) nitrobenzene are as follows:Triethylamine as base, n(5-fluoro-2-nitroaniline):n(4-Fluorobenzylamine):n(triethylamine)=1.0:1.2:1.3, 90℃, 8 h, the yield of intermediate is 92.94%. The optimized synthesis process for Retigabine are as follows:Tetrahydrofuran as solvent, Pd/C(5%) as catalyst, nitro reduction reaction was conducted at 35℃ for 3 h under a hydrogen pressure of 101.325 kPa, then hydrochloric acid solution was dropwisely added under 15℃ to complete the reduction, followed by acylation with ethyl chloroformate without separation, the target product Retigabine was obtained by ethanol/n-hexane mixture solvent recrystallization with 43.09% overall yield and 99.9% purity (HPLC). The final product was confirmed by elemental analysis, ¹H NMR, ¹³C NMR and ESI-MS. The synthesis method is simple and stable, the material is feasible, and the catalyst can be recycled, which is cost-reducing and suitable for industrial production.

Keywords： epilepsy； Retigabine； synthesis

Received 2016-12-08;

Corresponding Authors: 王东华,E-mail:dhwang022@163.com Email: dhwang022@163.com

About author: 訾晨瑞(1981-),男,在职硕士研究生,工程师,现从事新药合成及新药质量控制方面的研究。

引用本文:

訾晨瑞, 陈立功, 王东华, 闫喜龙, 李阳, 徐蕊.瑞替加滨的简易合成方法[J]. 化学工业与工程, 2018,35(6): 13-19

Zi Chenrui, Chen Ligong, Wang Donghua, Yan Xilong, Li Yang, Xu Rui.A Simple Synthesis Method of Retigabine[J]. Chemcial Industry and Engineering, 2018,35(6): 13-19

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