尼达尼布的合成-学兔兔 www.xuetutu.com.pdfVIP

学兔兔 2015年第23卷 合成化学 Vo1．23，2015 第8期，763～766 Chinese Joumal of Synthetic Chemistry No．8，763—766 · 制药技术· 尼达尼布的合成 贾本立h，朱 雄仆，陈仁杰h，袁 铎h，徐云根h (1．中国药科大学a．药化教研室；b．医药化工研究所，江苏南京 210009) 摘要：间硝基苯甲酸甲酯(1)与氯乙酸甲酯反应制得4-甲氧基羰基甲基-3一硝基苯甲酸甲酯(2)；2依次经催化 氢化、乙酰化及与原苯甲酸三乙酯反应制得关键中间体(E)-1-乙酰基_3_．(乙氧基一苯基一甲烯基)-2一氧．2，3一二 氢．1U-n~l哚一6一羧甲酸甲酯(5)；Ⅳ．甲基对硝基苯胺依次经氯乙酰化、取代和催化氢化反应制得Ⅳ_(4-氨基苯 基)．Ⅳ_甲基．2．(4．甲基哌嗪．1．基)乙酰胺(9)；5和9经拼合合成了治疗特发性肺纤维化药尼达尼布，总收率 22．O％，纯度99．4％，其结构经 H NMR和MS确证。 关 键 词：尼达尼布；特发性肺纤维化；合成 中图分类号：R914．5；O621．3 文献标识码：A DOI：10．15952／j．cnki．cjsc．1005—1511．2015．08．0763 Synthesis of Nintedanib JIA Ben．1ih， ZHU Xiong ， CHEN Ren-jieh， YUAN Duoh， XU Yun—gen (a．Department of Medicinal Chemistry；b．Medicinal and Chemical Institute， 1．China Pharmaceutical University，Nanjing 210009，China) Abstract：4一Methoxycarbonylmethyl一3一nitrobenzoic acid methyl ester(2)was synthesized by reaction of 3-nitrobenzoic acid methyl ester with methyl chloroacetate．The key intermediate，(E)一1-acetyl一3一 (ethoxy—phenyl—methylene)-2一oxo-2，3-dihydro一1H-indole-6一carboxylic acid methyl ester(5)，was synthesized by a three—step reaction of hydrogenation，acetylation and reaction with ortho-benzoic acid triethyl ester from 2．Ⅳ．(4一aminopheny1)·N-methyl-2一(4一methylpiperazin一1一y1)acetamide(9)was synthesized by a three—step reaction of acylchlorination，substitution and hydrogenation from N-meth— yl-4一nitro—benzenamine．Nintedanib with an overall yield of 22．0％ and purity of 99．4％ was synthe— sized by reaction of 5 with 9．The structure was confirmed by H NMR and MS． Keywords：Nintedanib；idiopathic pulmonar