奈妥吡坦药物的中间体合成工艺优化

Process optimization of intermediate synthesis for Netupitant production

以N-叔丁基-6-氯烟酰胺(化合物2)为原料,经1,4-加成与氧化、缩合、N-去烷基化、Hofmann重排反应,采用叠缩工艺合成了(6-(4-甲基哌嗪-1-基)-4-(邻甲苯)吡啶-3-基)氨基甲酸甲酯(化合物1)。化合物2与邻甲苯基氯化镁反应后,经I2氧化生成N-叔丁基-6-氯-4-邻甲苯基烟酰胺(化合物3)。化合物3与N-甲基哌嗪发生缩合反应得到N-叔丁基-6-(4-甲基哌嗪-1-基)-4-邻甲苯基烟酰胺(化合物4)。在MeSO3H作用下,化合物4发生去烷基化反应得到6-(4-甲基哌嗪-1-基)-4-(邻甲苯基)烟酰胺(化合物5)。在KOH/MeOH溶液中,化合物5与PhI(OAc)2发生Hofmann重排反应生成化合物1,总收率达到67.4%。

The synthetic process of methyl(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)carbamate(compound 1) was studied via 1,4-addition and oxidation, condensation, N-dealkylation and Hofmann rearrangement reactions using N-(tert-butyl)-6-chloronicotinamide(compound 2) as the raw material. N-(tert-butyl)-6-chloro-4-(o-tolyl)nicotinamide(compound 3) was obtained from compound 2 by reaction with o-tolylmagnesium chloride and followed by I2 oxidation. Condensation reaction between compound 3 and N-methyl pyrizine gave 6-(4-methylpiperazin-1-yl)-4-(o-tolyl)nicotinamide(compound 4). N-dealkylation reaction of compound 4 resulted in 6-(4-methylpiperazin-1-yl)-4-(o-tolyl)nicotinamide(compound 5) in the presence of MeSO3 H. Compound 1 was obtained from compound 5 reacting with PhI(OAc)2 in KOH/MeOH solution by Hofmann rearrangement with a total yield of 67.4%.