2,4-二苄氧基-5-异丙烯基苯甲酸的合成工艺研究
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摘要
以2,4-二羟基苯甲酸甲酯为原料,经过"一锅法"的Friedel-Crafts反应和Fries重排、亲核取代反应、Wittig反应和酯水解4步操作,合成了非安莎霉素(AT13387)的重要中间体2,4-二苄氧基-5-异丙烯基苯甲酸(1)。其结构经~1H NMR、~(13)C NMR和MS确证。探讨了反应体系、投料比、反应温度和溶剂对化合物1合成过程中各步得率的影响,确定了化合物1合成的最适宜工艺条件,其总收率为65.8%。
An important intermediate of non-ansamycin(AT13387), 2,4-dibenzyloxy-5-isopropenyl benzoic acid(1), was prepared via one-pot of Friedel-Crafts reaction and Fries rearrangement, nucleophilic substitution, Wittig reaction and hydrolysis of ester using the 2,4-dihydroxy-benzoic acid methyl ester as starting material. The structure of compound 1 was confirmed by ~1H NMR,~(13)C NMR and MS. The comprehensive investigations on the optimization of reaction system, the rate of ingredients, reaction temperature and solvent on the yield of compound 1 were conducted. The overall yield was 65.8%.
An important intermediate of non-ansamycin(AT13387), 2,4-dibenzyloxy-5-isopropenyl benzoic acid(1), was prepared via one-pot of Friedel-Crafts reaction and Fries rearrangement, nucleophilic substitution, Wittig reaction and hydrolysis of ester using the 2,4-dihydroxy-benzoic acid methyl ester as starting material. The structure of compound 1 was confirmed by ~1H NMR,~(13)C NMR and MS. The comprehensive investigations on the optimization of reaction system, the rate of ingredients, reaction temperature and solvent on the yield of compound 1 were conducted. The overall yield was 65.8%.
引文
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[3] Patel B H,Barrett A G M.Total synthesis of resorcinol amide hsp 90 inhibitor AT13387[J].The Journal of Organic Chemistry,2012,77(24):11 296-11 301
[4] Stuart C M,Helen F L,Martyn F,et al.Preparation of N-benzoylisoindoline derivatives and analogs as analgesics:UK,WO 2008/044027A2[P].2008-04-17
[5] Liang C,Gu L,Yang Y,et al.Alternate synthesis of HSP90 inhibitor AT13387[J].Synthetic Communications,2014,44(16):2 416-2 425
[6] Martyn F,Francis L J,Thomas T N,et al.Hydrobenzamide derivatives as inhibitors of Hsp90:UK,WO 2008/044034A1[P].2008-04-17
[7] Alexander R D,Sanjeev R,Rajashree J.Pharmaceutical formulation comprising AT13387:JP,WO 2015/140624A1[P].2015-09-24
[8] Jiang F,Wang H,Jin Y,et al.Novel tetrahydropyrido [4,3-d] pyrimidines as potent inhibitors of chaperone heat shock protein 90[J].Journal of Medicinal Chemistry,2016,59(23):10 498-10 519
[9] 郭冠群,杨明仙.从分子中正电荷分数探讨常用溶剂的极性顺序[J].色谱,1996,14(4):267-270Guo Guanqun,Yang Mingxian.Evaluation of polar order of common solvents from fraction of positive charge in molecules[J].Chinese Journal of Chromatography,1996,14(4):267-270(in Chinese)