瑞戈非尼有关物质的制备

Preparation of the Related Substances of Regorafenib

为控制瑞戈非尼的质量,制备8个工艺杂质:4-[3-氟-4-[[(2-甲胺甲酰基)吡啶-4-基]氨基]苯氧基]-N-甲基吡啶-2-甲酰胺(7)、4-氨基-3-(4-氨基-3-氟苯氧基)苯酚(8)、4-[4-氨基-3-(4-氨基-3-氟苯氧基)苯氧基]-N-甲基吡啶-2-甲酰胺(9)、N,N’-双[[3-氟-4-(2-甲胺基羰基吡啶-4-基)氧基]苯基]脲(10)、4-[4-[[4-氯-3-(三氟甲基)-苯基]氨基甲酰胺基]-3-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰胺基]-3-氟苯氧基]苯氧基]-N-甲基吡啶-2-甲酰胺(11)、[4-氯-3-(三氟甲基)苯胺基]甲酸乙酯(12)、[4-氯-3-(三氟甲基)苯胺基]甲酸(13)及4-[[4-[4-氯-3-(三氟甲基)苯基]氨基甲酰胺基]苯氧基]-N-甲基吡啶-2-甲酰胺(15)。其中有关物质8、10、12及13未见文献报道。以上有关物质的结构均经~1H NMR和MS确证,可作为瑞戈非尼质量研究的对照物。

To perform the quality control of regorafenib,eight related substances were prepared. These substances were 4-[3-fluoro-4-[[2-(methylcarbamoyl)pyridin-4-yl]amino]phenoxy]-N-methylpyridin-2-carboxamide(7), 4-amino-3-(4-amino-3-fluorophenoxy)phenol(8), 4-[4-amino-3-(4-amino-3-fluorophenoxy)phenoxy]-Nmethylpyridin-2-carboxamide(9), N,N’-bis[[3-fluoro-4-[[2-(methylamino)carbonyl]-4-pyridinyl]oxy]phenyl]-urea(10), 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]aminoformamido]-3-[4-[[4-chloro-3-(trifluoromethyl)-phenyl]-aminoformamido]-3-fluorophenoxy]phenoxy]-N-methylpyridin-2-carboxamide(11), ethyl [4-chloro-3-(trifluoromethyl)-phenyl]carbamate(12),[4-chloro-3-(trifluoromethyl)phenyl]carbamic acid(13), and4-[[4-[4-chloro-3-(trifluoromethyl)phenyl]aminoformamido]phenoxy]-N-methylpyridin-2-carboxamide(15). The related substances 8, 10, 12 and 13 have not been reported in literature. The structures of the above related substances were confirmed by ~1H NMR and MS, which could be used for conference of regorafenib quality control.