|
【结 构 式】 
|
【药物名称】Defactinib Hydrochloride 【化学名称】N-Methyl-4-[4-[3-[N-methyl-N-(methylsulfonyl)amino]pyrazin-2-ylmethylamino]-5-(trifluoromethyl)pyrimidin-2-ylamino]benzamide hydrochloride 【CA登记号】1073160-26-5;1073154-85-4 (as free base) 【 分 子 式 】C20H21F3N8O3S .HCl 【 分 子 量 】546.954 |
【开发单位】Pfizer, Inc. (US), licensed to Verastem, Inc. (US) 【药理作用】Dual FAK1/PYK2 Inhibitor;Treatment of non-small cell lung cancer;Treatment of malignant mesothelioma;Treatment of ovarian cancer |
合成路线1
Condensation of 3-chloropyrazine-2-carbonitrile (I) with N-methylmethanesulfonamide (II) in the presence of Cs2CO3 in acetonitrile at 80 °C gives N-(3-cyano-2-pyrazinyl)-N-methylmethanesulfonamide (III), which by nitrile reduction using H2 over Pd/C in methanolic ammonia, followed by treatment with AcOH in EtOAc provides the primary amine (IV). Condensation of 2,4-dichloro-5-(trifluoromethyl) pyrimidine (V) with 4-amino-N-methylbenzamide (VI) by means of ZnBr2 and Et3N in DCE/t-BuOH affords diaryl amine (VII). Finally, (aminomethyl)pyrazine (IV) is coupled with chloropyrimidine (VII) in the presence of DIEA in DCE/t-BuOH at 80 °C and the resulting free base is treated with HCl in MeOH .
| 【1】 Luzzio, M.J., Autry, C.L., Bhattacharya, S.K. et al. (Pfizer Products Inc. ). Sulfonyl amide derivatives for the treatment of abnormal cell growth. US 2014100368; US 8247411; EP 2146779; US 2013005964; JP 2010524914; CN 103951658; US 2011166120; US 8440822; WO 2008129380. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 42535 | 3-chloro-2-pyrazinecarbonitrile | 55557-52-3 | C5H2ClN3 | 详情 | 详情 |
| (II) | 67859 | N-methylmethanesulfonamide | 1184-85-6 | C2H7NO2S | 详情 | 详情 |
| (III) | 67860 | N-(3-cyano-2-pyrazinyl)-N-methylmethanesulfonamide | C7H8N4O2S | 详情 | 详情 | |
| (IV) | 67861 | N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide acetate | C7H12N4O2S.C2H4O2 | 详情 | 详情 | |
| (V) | 67477 | 2,4-dichloro-5-(trifluoromethyl)pyrimidine | 3932-97-6 | C5HCl2F3N2 | 详情 | 详情 |
| (VI) | 67862 | 4-amino-N-methylbenzamide | 6274-22-2 | C8H10N2O | 详情 | 详情 |
| (VII) | 67863 | 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide | C13H10ClF3N4O | 详情 | 详情 | |
| (VIII) | 67864 | N-methyl-4-((4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide | C20H21F3N8O3S | 详情 | 详情 |