目的 對(duì)molidustat的合成工藝進(jìn)行研究。方法 以4,6-二氯嘧啶為原料,先后引入嗎啉、肼取代基,制備獲得中間體4-(6-肼基嘧啶-4-基)嗎啉(2);1H-1,2,3-三氮唑和溴乙酸乙酯為原料,經(jīng)烴基化、縮合反應(yīng),制備獲得中間體(Z/E)-3-(二甲基氨基)-2-(1H-1,2,3-三氮唑-1-基)丙烯酸乙酯(4)。中間體2和4在三氟乙酸的催化下,經(jīng)環(huán)合反應(yīng)制備得到molidustat(5),然后經(jīng)成鹽反應(yīng)得到其鈉鹽(6)。結(jié)果 合成了目標(biāo)化合物molidustat及其鈉鹽,并利用¹H-NMR、MS確證了結(jié)構(gòu)。此路線的總收率為31.5%。結(jié)論 該合成工藝步驟短,操作簡(jiǎn)單,可適應(yīng)未來工業(yè)化放大生產(chǎn),具有良好的應(yīng)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.

中國醫(yī)學(xué)科學(xué)院放射醫(yī)學(xué)研究所發(fā)展基金資助項(xiàng)目(1537);協(xié)和青年基金資助項(xiàng)目(3332015102)