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【结 构 式】 
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【药物名称】MDV-3100；NC-54 【化学名称】4-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluoro-N-methylbenzamide 【CA登记号】 【 分 子 式 】C21H16F4N4O2S 【 分 子 量 】464.436 |
【开发单位】Medivation, Inc. (US); licensed worldwide for codevelopment and cocommercialization to Astellas Pharma, Inc. (JP) 【药理作用】Androgen Receptor Antagonist；Prostate Cancer Therapy |
合成路线1
Oxidation of 2-fluoro-4-nitrotoluene (I) by means of periodic acid and CrO3 affords 2-fluoro-4-nitrobenzoic acid (II), which by chlorination with SOCl2 in DMF at –5 °C, followed by condensation with methylamine, yields 2-fluoro-N-methyl-4-nitrobenzamide (III). Reduction of the nitro group in compound (III) with Fe in refluxing AcOH/EtOAc gives amine (IV), which is then condensed with pure acetone cyanohydrin (V) in the presence of anhydrous MgSO4 at 80 °C to provide 4-(1-cyano-1-methylethylamino)-2-fluoro-Nmethylbenzamide (VI). Finally, compound (VI) is condensed with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (VII) (prepared by reaction of 4-amino-2-(trifluoromethyl)benzonitrile (VIII) with thiophosgene in H2O) in DMF heated to 100 °C under microwave irradiation, and then cyclized by means of HCl in refluxing MeOH .
| 【1】 Sawyers, C.L., Jung, M.E., Chen, C.D., Ouk, S., Welsbie, D., Tran, C., Wongvipat, J., Yoo, D. (University of California, Oakland). Diarylhydantoin compounds. EP 1893196, JP 2008540523, US 2007004753, US 7709517, WO 2006124118. |
| 【2】 Jung, M., Yoo, D., Sawyers, C.L., Tran, C. (University of California, Oakland). Diarylthiohydantoin compounds. EP 2013187, JP 2009531449, US 2007254933, US 2008139634, WO 2007127010. |
| 【3】 Jung, M.E., Ouk, S., Yoo, D., Sawyers, C.L., Chen, C., Tran, C., Wongvipat, J. Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). J Med Chem 2010 53(10): 2779-96. |
| 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) | 55902 | 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene | 1427-07-2 | C7H6FNO2 | 详情 | 详情 |
| (II) | 55903 | 2-Fluoro-4-nitrobenzoic acid | 403-24-7 | C7H4FNO4 | 详情 | 详情 |
| (III) | 68796 | 2-fluoro-N-methyl-4-nitrobenzamide | C8H7FN2O3 | 详情 | 详情 | |
| (IV) | 67496 | 4-amino-2-fluoro-N-methylbenzamide | C8H9FN2O | 详情 | 详情 | |
| (V) | 18029 | Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile | 75-86-5 | C4H7NO | 详情 | 详情 |
| (VI) | 68797 | 4-(1-cyano-1-methylethylamino)-2-fluoro-N-methylbenzamide | C12H14FN3O | 详情 | 详情 | |
| (VII) | 68798 | 4-isothiocyanato-2-(trifluoromethyl)benzonitrile；4-Cyano-3-trifluoromethylphenylisothiocyanate | 143782-23-4 | C9H3F3N2S | 详情 | 详情 |
| (VIII) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |