文献类型：期刊文献

中文题名：尼达尼布的合成新方法

英文题名：A New Synthetic Method of Nintedani

作者：赵菲熠[1];邵玲艳[1];郭瑛[1];冀亚飞[1]

机构：[1]华东理工大学药学院,上海200237

年份：2017

卷号：25

期号：9

起止页码：784

中文期刊名：合成化学

外文期刊名：Chinese Journal of Synthetic Chemistry

收录：CSTPCD;;CSCD:【CSCD_E2017_2018】；

基金：国家自然科学基金资助项目(21476074;21676088)

语种：中文

中文关键词：N-甲基4一硝基苯胺;4-氯-3-硝基苯甲酸;尼达尼布;特发性肺纤维化;酪氨酸激酶抑制剂;一锅煮;药物合成

外文关键词：N-methyl-4-nitro aniline; 4-chlorine-3-nitro benzoic acid; Nintedanib; idiopathic pulmonary fibrosis; tyrosine kinase inhibitor; one-pot; drug synthesis

摘要：以N-甲基-4-硝基苯胺作为起始原料,依次经氯乙酰化、取代及氢化还原反应制得关键中间体N-(4-氨基苯基)-甲基-2-(4-甲基-1-哌嗪基)乙酰胺(4);以4-氯-3-硝基苯甲酸为原料,依次经酯化、取代、氢化还原及环合反应制得6-甲氧羰基-2-吲哚酮(8);8与原苯甲酸三乙酯和乙酸酐经"一锅煮"反应制得中间体1-乙酰基-3-甲氧基(苯基)亚甲烯基-2-氧代吲哚环-6-羧酸甲酯(9);4和9进行取代反应的同时脱除保护,经"一锅煮"反应合成尼达尼布,总收率57.2%,其结构经~1H NMR,^(13)C NMR和MS(ESI)确证。
N-methyl-4-nitro aniline was subjected to a sequential chloroacetylation, nucleophilic sub- stitution and catalytic hydrogenation sequence achieving a key intermediate N-（4-aminophenyl）-N- methyl-2- （4-metrylpiperazin-1 -yl） chloroacetamide （ 4 ）. 6-Methoxycarbonyl-2-oxindole （ 8 ） was pre- pared from 4-chlorine-3-nitro benzoic acid via a four-step reaction of esterification, nucleophilic substi- tution, catalytic hydrogenation and cyclization. Then, another key intermediate, methyl-l-（acetyl）-3- [ methoxy （phenyl） methylene ] -2-oxoindoline-6-carboxylate （ 9 ） was prepared by a ＂one-pot＂ process of compound 8 in the presence of triethyl orthobenzoate and acetic anhydride. Nintedanib with an overall yield of 57.2% was synthesized via a ＂one-pot＂ process of substitution of 4 with 9 and then depro- tection. The structure was confirmed by ^1H NMR, ^13C NMR and MS（ESI）.