摘要
目的改进分裂原激活/胞外信号调节激酶的激酶(MEK)抑制剂PD198306的合成工艺。方法以四氯邻苯二甲酸酐为起始原料,经5步反应制备3,4,5三-氟-2[(2甲-基-4-碘苯)氨基]苯甲酸(7);以N-羟基逐乙酸乙酯为起始原料,经3步反应制得O-环丙甲基羟胺盐酸盐(11);3,4,5-三氟-2[(2-甲基-4-碘苯)氨基]苯甲酸(7)与O-环丙甲基羟胺盐酸盐(11)缩合得到目标化合物PD198306。结果与结论目标化合物结构经1H-NMR、M S谱确证,总收率为13.67%。与现有工艺相比,新工艺操作简单,成本降低。
An improved synthesis method of the MEK inhibitor PD198306 was developed.PD198306 was synthisized through condensing reaction between the intermediate 7 and 11.The intermediate 3,4,5-trifluoro-2-[（2-methyl-4-iodobenzene）amino]-benzoic acid（7） was obtained from intermediate 6,which was synthisized from tetrachlorophthalic anhydride via aniline protection,fluorination,deprotection and decarboxylation,with 4-iodo-2-methylaniline catalyzed by lithium amide.The another intermediate O-（cyclopropylmethyl）-hydroxylamine hydrochloride（11） was synthisized from N-hydroxy-ethyl acetate by successively reacting with sodium methanolate,（bromomethyl） cyclopropane and hydrochloric acid aqueous.The total yield of PD198306 synthesied from tetrachlorophthalic anhydride is 13.67%.Compared with the existing technology,the improved synthesis method showed a lot of advantages,such as the towardly temperature of condensation reaction which was raised to the room temperature（lit.-20 ℃）,a shorter reaction time which was reduced to 1.5 h（lit.23 h）,a easier and simplified synthesis process,a higher reaction yield,85%,and with much lower synthesis cost of PD198306.
出处
《中国药物化学杂志》
CAS
CSCD
2011年第4期286-289,共4页
Chinese Journal of Medicinal Chemistry
基金
国家自然科学基金项目(30873135)
