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目的合成mTOR通路抑制剂Wye-125132,确立一条适用于工业化生产的合成路线。方法以巴比妥酸为原料经Vilsmeier-Haack甲酰化、氯代反应合成中间体2,4,6-三氯-嘧啶-5-甲醛2,以1,4-环己二酮单乙二醇缩酮为原料,经3步反应得到中间体5,化合物2与5缩合后,再经取代反应合成关键中间体7。以对溴苯胺为原料经3步反应得侧链9,将9与7经Suzuki偶联反应得目标产物1。中间体及目标化合物的结构经MS和1H-NMR确认。结果与讨论新的合成路线反应总收率为13.2%,产物纯度为99.77%。新的合成路线具有原料易得、操作简便、反应条件温和、无需柱层析等优点,适合工业化生产。
Objective To synthesize Wye-125132, an inhibitor of mTOR pathway, to establish a synthetic route suitable for industrial production. Methods Barbituric acid was used as the starting material to form the intermediate 2,4,6-trichloro-pyrimidine-5-carbaldehyde by Vilsmeier-Haack formylation and chlorination reaction. Alcohol ketal as raw material, the intermediate 5 is obtained through 3 steps, the condensation of the compounds 2 and 5 is followed by the substitution reaction to synthesize the key intermediate 7. The reaction of side-chain 9 with p-bromoaniline as the starting material was carried out in three steps and the target product 1 was obtained through the Suzuki coupling of 9 and 7. The structures of intermediates and target compounds were confirmed by MS and 1H-NMR. Results and Discussion The new synthetic route showed a total yield of 13.2% and a purity of 99.77%. The new synthetic route has the advantages of readily available raw materials, simple operation, mild reaction conditions and no need for column chromatography, which is suitable for industrialized production.