雄激素受体拮抗剂MDV3100的合成研究

Synthesis of Androgen Receptor Antagonists MDV3100

以3-三氟甲基-4-腈基-苯胺和二硫化碳为原料制备异硫氰酸酯4-异硫氰基-2-三氟甲基苯腈(2),以2-氟-4-硝基甲苯为原料,经氧化、酰胺化、催化氢化制得N-甲基-2-氟-4-氨基苯甲酰胺(5),5与2-溴异丁酸乙酯反应得到2-(3-氟-4-甲胺甲酰苯基)胺基苯胺-2-甲基丙酸乙酯(6),2和6在无水N,N-二甲基甲酰胺溶液中缩合得到MDV3100(1),结构经MS和1H NMR确证,总收率18%(以2-氟-4-硝基苯甲酸计,n/n)。

4-Isothiocyanato-2-(trifluoromethyl)benzonitrile(2) was synthesized from 4-amino-2-(trifluoromethyl)benzonitrile and carbon disulfide.4-Amino-2-fluoro-N-methylbenzamide(5) was synthesized starting from 2-fluoro-1-methyl-4-nitro-benzoic acid via oxidation,amidation and reduction.2-(3-Fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropanoate(6) was produced by Hofmann alkylation of 5.Combination of 2 and 6 in dry DMF produced MDV3100(1) in overall yield of 18%.The structures were confirmed by MS and 1H NMR.