A Simple Synthesis Method of Retigabine

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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.

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	Articles by authors
	Zi Chenrui
	Chen Ligong
	Wang Donghua
	Yan Xilong
	Li Yang
	Xu Rui

Keywords： epilepsy； Retigabine； synthesis

Received 2016-12-08;

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Zi Chenrui, Chen Ligong, Wang Donghua, Yan Xilong, Li Yang, Xu Rui.A Simple Synthesis Method of Retigabine[J] Chemcial Industry and Engineering, 2018,V35(6): 13-19

[1] DeBoer H M, Mula M, Sander J W. The global burden and stigma of epilepsy[J/OL]. Epilepsy Behavior, 2008, 12(4):540-546
[2] Czuczwar P, Wojtak A, Cioczek-Czuczwar A, et al. Retigabine:The newer potential antiepileptic drug.[J]. Pharmacological Reports, 2010, 62(2):211-219
[3] US FDA. FDA approves Potiga to treat seizures in adults[EB/OL].http:\\www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm 258834.htm
[4] Rundfeldt C. The new anticonvulsant retigabine (D-23129) acts as an opener of K+channels in neuronal cells[J]. European Journal of Pharmacology, 1997, 336(2/3):243-249
[5] Sills G J, Rundfeldt C, Butler E, et al. A neurochemical study of the novel antiepileptic drug retigabine in mouse brain[J]. Pharmacological Research the Official Journal of the Italian Pharmacological Society, 2000, 42(6):553-557
[6] 牛丽萍, 宗利, 武杰, 等. 一种合成瑞替加滨的方法:CN, 103570587[P]. 2014-02-12
[7] 孟月垒, 张宪美, 谈敦潮, 等. 瑞替加滨中间体的制备方法和瑞替加滨的制备方法:CN, 103342648A[P]. 2013-10-09
[8] 朱磊, 王佳乐, 王浦海. 瑞替加滨的合成工艺改进[J]. 中国药物化学杂志, 2014, 24(1):31-33 Zhu Lei, Wang Jiale, Wang Puhai. Improved synthesis of retigabine[J]. Chinese Journal of Medicinal Chemistry, 2014, 24(1):31-33(in Chinese)
[9] 王浦海, 王佳乐, 朱磊, 等. 一种瑞替加滨的合成方法:CN, 103724231A[P]. 2014-04-16
[10] 祁金龙, 张超, 吴茵, 等. 瑞替加滨的合成[J]. 中国医药工业杂志, 2013, 44(3):223-225 Qi Jinlong, Zhang Chao, Wu Yin, et al. Synthesis of retigabine[J]. Chinese Journal of Pharmaceuticals, 2013, 44(3):223-225(in Chinese)
[11] 郑建兵, 王向军, 李贵杰, 等. 瑞替加滨及其中间体的制备方法:CN, 103373941A[P]. 2013-10-30
[12] 容志欢. 瑞替加滨及其相关物质的合成方法研究[D]. 石家庄:河北医科大学, 2015 Rong Zhihuan. Study on the synthesis of retigabine and its related impurities[D]. Shijiazhuang:Hebei Medical University, 2015(in Chinese)
[13] 谌伦华, 蔡祖安, 张志强, 等. 一种瑞替加滨中间体的简单合成方法:CN, 101921195A[P]. 2010-12-22
[14] 曹云峰, 王辉, 王俊臣. 瑞替加滨的合成工艺改进[J]. 广州化工, 2015, 43(6):95-97 Cao Yunfeng, Wang Hui, Wang Junchen. Improvement for synthesis of retigabine[J]. Guangzhou Chemical Industry, 2015, 43(6):95-97(in Chinese)
[15] Hans-Reinhold Dieter. Phamaceutically active 1,2,4-triamino-benzene derivatives, process for their preparation and pharmaceutical compositions containing them:US, 5384330[P]. 1995-01-24
[16] 张明森, 黄凤兴, 梁泽生, 等. 精细有机化工中间体全书[M]. 北京:化学工业出版社, 2007