瑞替加滨的合成工艺改进

Improved synthesis of retigabine

目的改进抗癫痫药瑞替加滨的合成工艺。方法以对硝基苯胺(2)为起始原料,首先与氯甲酸乙酯反应得到N-(4-硝基苯基)氨基甲酸乙酯(3),3经还原、氨基保护、硝化、脱保护制得N-(2-硝基-4-氨基苯基)氨基甲酸乙酯(6),6与对氟苯甲醛反应生成N-[2-硝基-4-(4-氟苯基亚甲基氨基)苯基]氨基甲酸乙酯(7),7不经分离直接以NaBH4还原制得N-[2-硝基-4-(4-氟苯基甲基氨基)苯基]氨基甲酸乙酯(8),最后8经三氯化铁/水合肼还原制得抗癫痫药物瑞替加滨。结果与结论目标化合物的结构经IR、1H-NMR、13C-NMR和HRMS(ESI)谱确证。改进后的工艺操作简单,反应选择性高,成本低,利于工业化生产,总收率为62%(以对硝基苯胺计)。

Retigabine, as a new kind of mechanism of action of potassium ion channel opener, was used for anti-epileptic. In this paper, a six-step procedure from p-nitrophenylamine as starting material was used to synthesize the desired compound through a series of reactions, such as substitution, reduction, protection, ni tration, deprotection, addition and elimination reaction and reduction. The process expressed a higher selectiv ity than that of the former methods described, and the overall yield was 62 %. The structure of retigabine was characterized by IR, 1H-NMR, 13C-NMR and HRMS （ESI）. The improved process has the advantages of low cost, high selectivity and mild reaction for industrial production.