molidustat的合成工艺研究  

Synthetic technology of molidustat

作　　者：魏会强[1] 刘洋[2] 于江[3] 尚海花[1] 樊赛军[1] 李祎亮[1] 

机构地区：[1]中国医学科学院北京协和医学院放射医学研究所天津市放射医学与分子核医学重点实验室,天津300192 [2]武警总医院药剂科,北京100039 [3]天津医科大学,天津300070

出　　处：《现代药物与临床》2016年第4期411-414,共4页Drugs & Clinic

基　　金：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)

摘　　要：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 intermediates 2 and 4, 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.

关 键 词：molidustat 肾性贫血 有机合成 

分 类 号：R914[医药卫生—药物化学]