摘要
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,and to establish a synthetic route for industrial production. Methods Barbituric acid was used as the raw material to synthesize the intermediate 2,4,6-trichrolopyrimidine-5-carbaldehyde 2 via Vilsmeier-Haack and chlorination reaction,while intermediate 5 was prepared via 3-step reaction from 1,4-dioxaspiro-[4,5]decan-8-one. The condensation of 2 and 5 was followed by substitution reaction to obtain the key intermediate 7. The side chain 9 was prepared by 3-step reaction from bromine aniline. Then the title product 1 was obtained with the reaction of Suzuki cross-coupling of 7 and 9. The structures of intermediate and target compounds were confirmed by MS and1H-NMR. Results and Conclusion Compared with the method reported in the literature,this new synthesis method possesses some advantages,such as ready availablity of raw materials,simple operation,mild reaction conditions and easy disposal of products. The total yield is 13. 2%,and the purity of the target compound is 99. 77%.
出处
《军事医学》
CAS
CSCD
北大核心
2016年第8期643-645,685,共4页
Military Medical Sciences
基金
中国博士后科学基金面上资助项目(2015M572756)
