尼达尼布的合成新方法

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，¹³C NMR和MS(ESI)确证。

A New Synthetic Method of Nintedani

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-1-( 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 over-all 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).