托匹司他的合成工艺

Synthesis of Topiroxostat

在碘化亚铜和氰化锌存在下,异烟酸甲酯-N-氧化物与二甲胺基甲酰氯反应,生成化合物2-氰基异烟酸甲酯,经肼解得到2-氰基异烟肼,再与4-氰基吡啶缩合得到托匹司他粗品,与对甲苯磺酸一水合物反应成对甲苯磺酸盐,加入碳酸钾解离得标题化合物纯品,总收率41%。改进后的工艺原料易得,反应条件温和,工艺路线短,适合工业化生产。

Methyl isonicotinate-N-oxide reacted with dimethylcarbamyl chloride in the presence of cuprous iodide and zinc cyanide to give methyl 2-cyanopyridine-4-carboxylate, followed by hydrazinolysis to obtain 2-cyano isoniazide, then the latter was condensed with 4-cyanopyridine, followed by reaction with p-toluenesulfonic acid monohydrate and dissociation by potassium carbonate, the anti-hyperuricemia drug topiroxostat was prepared with an overall yield of 41%. This method started from cheap and easily obtained raw materials, with mild reaction conditions, short synthetic route and good potential for industrial application.