塞瑞替尼有关物质的合成

Synthesis of the Related Substances of Ceritinib

根据塞瑞替尼(1)结构及合成工艺,制备了8个有关物质:5-氯-2-异丙氧基-N-[2-(异丙基磺酰基)苯基]-4-嘧啶胺(有关物质A)、5-氯-4-[[2-(异丙基磺酰基)苯基]氨基]-2-嘧啶醇(有关物质B)、5-氯-N^(2)-[2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基]-N^(4)-[2-(异丙基亚硫酰基)苯基]-2,4-嘧啶二胺(有关物质C)、5-氯-N^(2)-[2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基]-N^(4)-[2-(丙基磺酰基)苯基]-2,4-嘧啶二胺(有关物质D)、5-氯-N^(4)-[2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基]-N^(2)-[2-(异丙基磺酰基)苯基]-2,4-嘧啶二胺(有关物质E)、2-[[5-氯-4-[[2-(异丙基磺酰基)苯基]-氨基]嘧啶-2-基]氨基]-4-甲基-5-(哌啶-4-基)苯酚(有关物质F)、4-[4-[4-[[5-氯-4-[[2-(异丙基磺酰基)苯基]-氨基]-嘧啶-2-基]氨基]-5-异丙氧基-2-甲基苯基]哌啶-1-基]戊-2-酮(有关物质G)、5-氯-N^(2)-[4-[1-[5-氯-4-[[2-(异丙基磺酰基)苯基]胺基]嘧啶-2-基]哌啶-4-基]-2-异丙氧基-5-甲基苯基]-N^(4)-[2-(异丙基磺酰基)苯基]-2,4-嘧啶二胺(有关物质H),且经^(1)H NMR和MS结构确证。

Eight related substances of ceritinib(1)were prepared according to its structure and synthetic process,namely 5-chloro-2-isopropoxy-N-[2-(isopropylsulfonyl)phenyl]pyrimidin-4-amine(related substance A),5-chloro-4-[[2-(isopropylsulfonyl)phenyl]amino]pyrimidin-2-ol(related substance B),5-chloro-N^(2)-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]-N^(4)-[2-(isopropylsulfinyl)phenyl]pyrimidine-2,4-diamine(related substance C),5-chloro-N^(2)-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]-N^(4)-[2-(propylsulfonyl)phenyl]pyrimidine-2,4-diamine(related substance D),5-chloro-N^(4)-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]-N^(2)-[2-(isopropylsulfonyl)phenyl]-pyrimidine-2,4-diamine(related substance E),2-[[5-chloro-4-[[2-(isopropylsulfonyl)phenyl]amino]pyrimidin-2-yl]amino]-4-methyl-5-(piperidin-4-yl)phenol(related substance F),4-[4-[4-[[5-chloro-4-[[2-(isopropylsulfonyl)-phenyl]amino]pyrimidin-2-yl]amino]-5-isopropoxy-2-methylphenyl]piperidin-1-yl]pentan-2-one(related substance G),5-chloro-N^(2)-[4-[1-[5-chloro-4-[[2-(isopropylsulfonyl)phenyl]amino]pyrimidin-2-yl]piperidin-4-yl]-2-isopropoxy-5-methylphenyl]-N^(4)-[2-(isopropylsulfonyl)phenyl]pyrimidine-2,4-diamine(related substance H).And their structures were confirmed by^(1)H NMR and MS.