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目的研究FLT3激酶抑制剂奎扎替尼(quizartinib,AC220)的合成工艺。方法以对硝基苯乙酮为原料,经溴代反应得到中间体2-溴-4’-硝基苯乙酮(3);以对苯醌和硫脲为起始原料,经缩合、环合、取代和还原得到重要中间体7-(2-吗啉-4-基-乙氧基)-2-(4-氨基苯基)咪唑并[2,1-b]苯并噻唑(7);以氰基频那酮为起始原料,经缩合、取代反应得到重要中间体5-叔丁基异口恶唑-3-氨基甲酸苯酯(9);中间体7和中间体9经取代反应得到目标化合物奎扎替尼。结果与结论目标化合物的结构经1H-NM R、13C-NM R和M S谱确证。该合成路线总收率为52.5%(以对苯醌计),纯度为99.4%(HPLC法)。新工艺路线所用原料相对廉价易得、操作简便、收率较高,可为工业化生产提供参考。
Objective To study the synthesis of FLT3 kinase inhibitor quizartinib (AC220). Methods The p-nitroacetophenone was used as the starting material to obtain the intermediate 2-bromo-4’-nitroacetophenone (3) via bromination reaction. The p-benzoquinone and thiourea were used as starting materials, The synthesis, substitution and reduction give the important intermediate 7- (2-morpholin-4-yl- ethoxy) -2- (4- aminophenyl) imidazo [ ; To cyano cyanogenone as the starting material, by condensation, the reaction was converted to an important intermediate 5-tert-butyl isooxazole-3-carbamate (9); intermediate 7 and intermediate 9 obtained by the substitution reaction The target compound is quetiapinib. Results and Conclusions The structure of the target compound was confirmed by 1H-NMR, 13C-NMR and MS spectra. The overall yield of the synthetic route was 52.5% (based on p-benzoquinone) and the purity was 99.4% (HPLC method). The raw materials used in the new process route are relatively cheap and easy to obtain, easy to operate and high in yield, which can provide reference for industrialized production.