1-(3-氟苯基)-2-(6-甲氧基-2-(1-(3,4,5-三甲氧基苯基)乙烯基)苯并呋喃-5-基)乙烯合成工艺优化及活性初探

Optimization in Synthesis Process and Preliminary Study on Activity of 1-(3-Fluorophenyl)-2-(6-methoxy-2-(1-(3,4,5-trimethoxyphenyl)vinyl)benzofuran-5-yl)ethylene

以4-甲氧基水杨醛为原料、乙腈为溶剂,通过溴代、碘代、Rap-Stoermer偶联、Heck偶联4步反应合成了目标化合物1-(3-氟苯基)-2-(6-甲氧基-2-(1-(3,4,5-三甲氧基苯基)乙烯基)苯并呋喃-5-基)乙烯,通过单因素实验对关键步骤碘代反应条件进行了优化,通过^(1)HNMR、^(13)CNMR、MS对目标化合物的结构进行了表征,并对目标化合物的微管蛋白和PI3K双靶点抑制活性进行了初步研究。结果表明,碘代反应最佳条件为:以对甲苯磺酸一水合物为催化剂、反应温度25℃、反应时间10 h、碘代试剂用量n(4-甲氧基水杨醛)∶n(N-碘代丁二酰亚胺)为1∶1.0、溶剂用量n(4-甲氧基水杨醛)∶V(乙腈)为1∶3(mmol∶mL),在此条件下碘代反应产率为70.6%;通过分子对接验证了目标化合物具有双靶点抑制活性,其对微管蛋白的抑制活性高于对PI3K的抑制活性。

Using 4-methoxy salicylaldehyde as a raw material and acetonitrile as a solvent,we synthesized the target compound 1-(3-fluorophenyl)-2-(6-methoxy-2-(1-(3,4,5-trimethoxyphenyl)vinyl)benzofuran-5-yl)ethylene by a four-step reaction of bromination,iodination,Rap-Stoermer coupling,and Heck coupling.Moreover,we optimized the reaction conditions of the key step iodination by single-factor experiments,and characterized the structure of the target compound by ^(1)HNMR,^(13)CNMR,and MS.Furthermore,we preliminarily studied the double-target inhibitory activity of tubulin and PI3K.The results show that the optimal conditions of iodination reaction are obtained as follows:p-toluene sulfonate monohydrate as the catalyst,the reaction temperature of 25℃,the reaction time of 10 h,n(4-methoxy salicylaldehyde)∶n(N-iodo succinimide)of 1∶1.0,and n(4-methoxy salicylaldehyde)∶V(acetonitrile)of 1∶3(mmol∶mL).Under above conditions,the yield of iodination reaction is 70.6%.The double-target inhibitory activity of target compound is verified by molecular docking,indicating the inhibitory activity on tubulin is higher than that on PI3K.