间苯二酚类热休克蛋白90抑制剂关键中间体5-异丙基-2,4-二甲氧基苯甲醛合成研究  

Synthesis of 5-Isopropyl-2,4-Dimethoxybenzaldehyde as the Key Intermediate of Resorcinol HSP90 Inhibitors

作　　者：王薇 薛从建 陈秋缘 刘巧燕 李心忠 刘洋[3,5] WANG Wei;XUE Chongjian;CHEN Qiuyuan;LIU Qiaoyan;LI Xinzhong;LIU Yang(Department of Clinical Medicine, Fujian Medical University, Fuzhou 350004, China;The Graduate School, Fujian Medical University, Fuzhou 350122, China;Department of Medicinal Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China;Ocean College of Minjiang University, Fuzhou 350108, China;Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122, China)

机构地区：[1]福建医科大学临床医学部,福州350004 [2]福建医科大学研究生院,福州350122 [3]福建医科大学药学院药物化学系,福州350122 [4]闽江学院海洋学院,福州350108 [5]福建省天然药物药理学重点实验室,福州350122

出　　处：《福建医科大学学报》2021年第5期373-376,共4页Journal of Fujian Medical University

基　　金：福建省天然药物药理学重点实验室(福建医科大学)开放课题(FJNMP-202001);福建医科大学大学生创新创业训练计划资助项目(C19040)。

摘　　要：目的合成间苯二酚类热休克蛋白90(HSP90)抑制剂的关键中间体5-异丙基-2,4-二甲氧基苯甲醛,为该类抑制剂的高效制备和改造奠定基础。方法以2,4-二羟基苯乙酮为起始原料,先与碘甲烷O-烷基化反应得到2,4-二甲氧基苯乙酮,后与甲基溴化镁加成得到2-(2,4-二甲氧基苯基)丙-2-醇,三乙基硅烷还原该醇为1-异丙基-2,4-二甲氧基苯,最后Vilsmeier-Haack-Arnold甲酰化反应得到目标化合物5-异丙基-2,4-二甲氧基苯甲醛。结果以2,4-二羟基苯乙酮为原料,经过四步反应成功合成5-异丙基-2,4-二甲氧基苯甲醛,产率均>90%,总产率为86.3%,目标产物的结构经核磁氢谱和碳谱确证。结论优化后的合成条件操作简单,简化了合成步骤,目标中间体的产率提高,成本降低。Objective To synthesize the key intermediate of resorcinol type HSP90 inhibitors,which may lay a foundation for the high-efficiency preparation and modification of this kind of HSP90 inhibitors.Methods 2,4-dimethoxyacetophenone was synthesized by O-alkylation of 2,4-dihydroxyacetophenone with methyl iodide,then 2-(2,4-dimethoxyphenyl)propanol was synthesized by addition of 2,4-dimethoxyacetophenone with methyl magnesium bromide,which was reduced to 1-isopropyl-2,4-dimethoxybenzene by triethylsilane,and finally 5-isopropyl-2,4-dimethoxybenzaldehyde was synthesized by Vilsmeier-Haack-Arnold formylation.Results 5-isopropyl-2,4-dimethoxybenzaldehyde was successfully synthesized from 2,4-dihydroxyacetophenone through four steps.The yield was more than 90%and the total yield was 86.3%.The structure of the target product was confirmed by ^(1)H NMR and ^(13)C NMR.Conclusion The optimized synthesis conditions are simple,the synthesis steps are simplified,the yield of target intermediates is increased,and the cost is reduced.

关 键 词：5-异丙基-2 4-二甲氧基苯甲醛 HSP90抑制剂 间苯二酚 合成 

分 类 号：O62[理学—有机化学]