目的 对molidustat的合成工艺进行研究。方法 以4,6-二氯嘧啶为原料,先后引入吗啉、肼取代基,制备获得中间体4-(6-肼基嘧啶-4-基)吗啉(2);1H-1,2,3-三氮唑和溴乙酸乙酯为原料,经烃基化、缩合反应,制备获得中间体(Z/E)-3-(二甲基氨基)-2-(1H-1,2,3-三氮唑-1-基)丙烯酸乙酯(4)。中间体2和4在三氟乙酸的催化下,经环合反应制备得到molidustat(5),然后经成盐反应得到其钠盐(6)。结果 合成了目标化合物molidustat及其钠盐,并利用¹H-NMR、MS确证了结构。此路线的总收率为31.5%。结论 该合成工艺步骤短,操作简单,可适应未来工业化放大生产,具有良好的应用前景。

Objective To study the synthetic technology of molidustat.Methods 4,6-Dichloro pyrimidine was used as starting material to synthesize intermediate 4-(6-hydrazine pyrimidine-4-yl)morpholine (2) by introducing morpholine and hydrazine group successively. 1H-1,2,3-Triazole and ethyl bromoacetate were used as starting materials to synthesize intermediate (Z/E)-3-(dimethyl amine)-2-(1H-1,2,3-triazole-1-yl)ethyl acrylate (4) by hydrocarbylation and condensation reactions. Molidustat (5) was synthesized by cyclization reaction with intermediates2and4, and sodium of molidustat (6) was synthesized by saltforming reaction.Results The target compound and its sodium were synthesized and characterized by ¹H-NMR and MS. The total yield of this synthetic route was 31.5%.Conclusion The synthetic process with simple operation and simplified method is applicable to pilot manufacture, and has a good application prospect.

中国医学科学院放射医学研究所发展基金资助项目(1537);协和青年基金资助项目(3332015102)