Study On Synthesis Process Of Brigatinib

Lung cancer is a serious threat to human health,non-small-cell lung cancer(NSCLC)accounts for about 85%of all lung cancers,Brigatinib,a second-generation anaplastic lymphoma kinase(ALK)inhibitor plays an important role in the treatment of NSCLC,it can effectively inhibit the mutations of drug resistance to Crizotinib.In addition,Brigatinib is also indicated for fibrosarcoma,diffuse large B-cell lymphoma,and anaplastic large cell lymphoma,it can be seen that Brigatinib has a good market prospect.The synthetic routes reported in the literature were summarized and analyzed,developed a new synthetic route,using 5-fluoro-2-nitroanisole as raw material,it is substituted with 4-piperidone hydrate hydrochloride to synthesize 1-(3-methoxy-4-nitr obenzene)piperidine-4-ketone(D),compounds D and N-methylpiperazine were reducti ve amination using sodium triacetoxyborohydride as reducing agent and dichloromet hane as solvent,the final productwas then reduced by zinc powder to 2-methoxy-4-[4-(4-methylpiperazine-1-yl)piperidine-1-yl]aniline(3);Diethyl phosphite and methyl magnesium bromide were formalized to synthesize dimethyl phosphine oxides(A),t he Buchwald-Hartwig reaction ofcompound A with o-iodoaniline was carried out in the presence of palladium acetate,4,5-diphenylphosphine-9,9-dimethylxanthracene as double catalyst,potassium phosphate as base,and N,N-dimethylformamide as solvent,finally,the last step product was substituted with 2,4,5-trichloropyrimidine to synthesize 2,5-dichloro-N-[2-(dimethylphosphonyl)phenyl]pyrimidine-4-amine(2).Compound 2 and compound3 were substituted in trifluoroacetic acid and ethylene glycol monomethyl ether to synthesize Brigatinib,the optimized route increased the total yield from 37.3%to 40.4%,in the synthesis of compound E,sodium triacetox yborohydride is substitutedfor sodiumcyanoborohydride,thus avoiding the formation of toxic by-products,when compound 2 and compound 3 were substituted,the mic rowave heating reaction wasreplacedby trifluoroacetic acid and ethylene glycol mon omethyl ether,which simplified the operation process.The structures of the synthesized compounds and the target compound were confirmed by~1H-NMR...