尼达尼布的合成  

Synthesis of Nintedanib

作　　者：贾本立[1] 朱雄[2] 陈仁杰[1] 袁铎[1] 徐云根[1] 

机构地区：[1]中国药科大学药化教研室,江苏南京210009 [2]中国药科大学医药化工研究所,江苏南京210009

出　　处：《合成化学》2015年第8期763-766,共4页Chinese Journal of Synthetic Chemistry

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-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-苯基-甲烯基)-2-氧-2,3-二氢-1H-吲哚-6-羧甲酸甲酯(5);N-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N-(4-氨基苯基)-N-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22.0%,纯度99.4%,其结构经1H NMR和MS确证。4-Methoxycarbonylmethyl-3-nitrobenzoic acid methyl ester（2） was synthesized by reaction of 3-nitrobenzoic acid methyl ester with methyl chloroacetate. The key intermediate, （E）-1-acetyl-3- （ ethoxy-phenyl-methylene ） -2-oxo-2,3-dihydro-1H-indole-6-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. N-（ 4-aminophenyl ） -N-methyl-2-（ 4-methylpiperazin-l-yl ） acetamide （ 9 ） was synthesized by a three-step reaction of acylchlorination, substitution and hydrogenation from N-meth- yl-4-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 l H NMR and MS.

关 键 词：尼达尼布 特发性肺纤维化 合成 

分 类 号：R914.5[医药卫生—药物化学] O621.3[医药卫生—药学]