Optimized Synthesis Of Irbinitinib

Irbinitinib(Tucatinib),a HER2 tyrosine kinase inhibitor,developed by Array BioPharma and Cascadian Therapeutics company.It is mainly used for treating rare metastatic breast cancer.Due to its unique mechanism of action,its has low drug resistance.At the same time,irbinitinib has also been proven to be used in combination with other drugs,thereby playing a role in high efficiency and dose reducing.In this paper,based on the related literature and reports at home and abroad,aiming at the problems existing in the existing routes,the synthesis routes of 4-([1,2,4]triazolo[1,5-a]pyridine-7-alkoxy)-3-methylaniline(8)and 4,4-dimethyl-2-methylthioalkyl-4,5-dihydroxazol-trifluoromethylsulfonate(50)and drug irbinitinib were designed and optimized,and the reactions of each step involved were carried out It can meet the requirements of environmental protection and has the potential to enlarge production.The synthesis of irbinitinib was carried out by the aggregation scheme.The compound N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylphenyl)quinazoline-4,6-diamine(47)and compound 4,4-dimethyl-2-methylthioalkyl-4,5-dihydroxazolyltrifluoromethylsulfonate(50)were prepared by addition elimination reaction.Among them,the synthesis of4-([1,2,4]triazolo[1,5-a]pyridine-7-alkoxy)-3-methylaniline(8)and 4,4-dimethyl-2-methylthioalkyl-4,5-dihydroxazolyltrifluoromethylsulfonate(50)is mainly involved 4-([1,2,4]triazolo[1,5-a]pyridine-7-alkoxy)-3-methylaniline(8)was synthesized by nucleophilic substitution of 2-methyl-4-nitrophenol(43)with 4-chloro-2-nitropyridine(44),followed by reaction with DMF-DMA and hydroxylamine hydrochloride,followed by intramolecular cyclization and Pd/C hydrogenation reduction.In addition to the first nucleophilic substitution reaction at 150?,the rest of the four reactions were in the range of 20-75?,in which the solid intermediates were recrystallized and purified,and the final product purity reached 99.1%by HPLCSynthesis of 4,4-dimethyl-2-methylsulfanyl-4,5-dihydrooxazole trifluoromethanesulfonate(50)as key intermediate,select compound 2-amino-2-methyl-1-propanol(5)as raw material,by reacting with compound bis(1 H-imidazol-1-y l)methanone(6),the target product 4,4-dimethyl-2-methylthioalkyl-4,5-dihydroxazoletrifluoromethylsulfonate(50)was prepared by nucleophilic addition elimination and methylation.The two-step yield was 67.1%.The reaction process was carried out at room temperature.Finally,4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-alkoxy)-3-methylaniline(8)was synthesized by the reaction of 2-amino-5-nitrobenzonitrile(2)with DMF-DMA,and then with 4,4-dimethyl-2-methylthioalkyl-4,5-dihydroxazolyl-4,6-diamine(3)by ring formation and Pd/C hydrogenation The final compound irbinitinib(1)was prepared by addition and elimination reaction.The yield of the three-step reaction is 58%,and the reaction process is at room temperature or 75-125?.The solid is purified by recrystallization.The final product is confirmed by 1H NMR and MS.The purity of HPLC is more than 99.5%,and the total yield is 17%.Based on the related literatures and data,the synthesis mechanisms of each reactions are discussed and analyzed,and the reaction conditions are screened in this thesis.