妥卡替尼的合成研究

以2-氨基-4-氯吡啶为起始原料，经过缩合、取代、环合、乌尔曼反应和水合肼还原硝基5步反应得到中间体4-(1,2,4]三唑并1,5-a]吡啶-7-氧基)-3-甲基苯胺，总收率28.8%。2-氨基-5-硝基苯腈先与N,N-二甲基甲酰胺二甲基缩醛（DMF-DMA）缩合，再与4-(1,2,4]三唑并1,5-a]吡啶-7-氧基)-3-甲基苯胺环合得到N-3-甲基-4-(1,2,4]三唑并1,5-a]吡啶-7-氧基)苯基]-6-硝基-4-喹唑啉胺，再经硝基还原得到N4-3-甲基-4-(1,2,4]三唑并1,5-a]吡啶-7-氧基)苯基]-4,6-喹唑啉二胺，三步收率47.4%。同时，采用二硫化碳和2-氨基-2-甲基-1-丙醇为原料，经两步反应制备4,5-二氢-4,4-二甲基-2-(甲硫基)噁唑三氟甲磺酸盐，收率68.6%。最后，N4-3-甲基-4-(1,2,4]三唑并1,5-a]吡啶-7-氧基)苯基]-4,6-喹唑啉二胺和4,5-二氢-4,4-二甲基-2-(甲硫基)噁唑三氟甲磺酸盐以三乙胺为碱进行缩合反应得到妥卡替尼，收率62.8%，HPLC纯度99.08%。采用1HNMR、13CNMR和HRMS等对产物结构进行了表征。该合成路线原料廉价易得，为妥卡替尼的放大生产提供理论依据。

The synthesis of tucatinib

The intermediate 4-(1,2,4]triazolo1,5-a]pyridin-7-yloxy)-3-methylaniline was obtained from 2-amino-4-chloropyridine with a total yield of 28.8% through five steps of condensation, substitution, cyclization, Ullmann reaction and reduction of nitro group. Secondly, 2-amino-5-nitrobenzonitrile was used as starting materials to synthesize the target intermediate N4-3-methyl-4-(1,2,4]triazolo1,5-a]pyridin-7-yloxy)phenyl]-4,6-quinazolinediamine via condensation, cyclization and reduction reaction with a total yield of 47.4%. In addition, 4,5-dihydro-4,4-dimethyl-2-(methylthio)oxazole trifluoromethanesulfonate was prepared in two steps under mild conditions in 68.6% yield using carbon disulfide and 2-amino-2-methyl-1-propanol as raw material. Finally, tucatinib was obtained from N4-3-methyl-4-(1,2,4]triazolo1,5-a] pyridin-7-yloxy)phenyl]-4,6-quinazolinediamine and 4,5-dihydro-4,4-dimethyl-2-(methylthio)oxazole trifluoromethanesulfonate using triethylamine as base with a yield of 62.8% and HPLC purity of 99.08%. The structures of the products were characterized by 1HNMR, 13CNMR and HRMS analysis. The raw materials are cheap and easy to obtain. This synthetic route provides a theoretical basis for the scale-up production of tucatinib.