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【结 构 式】 
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【药物名称】Regorafenib;BAY-73-4506 【化学名称】4-[4-[3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide 【CA登记号】755037-03-7 【 分 子 式 】C21H15ClF4N4O3 【 分 子 量 】482.815 |
【开发单位】Bayer AG (DE) 【药理作用】Broad-Spectrum Kinase Inhibitor；Oncolytic |
合成路线1
Chlorination of picolinic acid (I) with SOCl2 in the presence of DMF at 72 °C gives 4-chloropyridine-2-carbonyl chloride hydrochloride (II), which is then esterified with MeOH to afford the corresponding methyl ester (III). Aminolysis of ester (III) with methylamine in MeOH gives 4-chloro-N-methylpyridine-2-carboxamide (IV) , which can also be prepared by direct amidation of acid chloride (II) with methylamine in THF/MeOH or by Minisci reaction of 4-chloropyridine (V) with N-methylformamide (VI) in the presence of H2SO4, H2O2 and FeSO4·7H2O . Condensation of chloropicolinamide (IV) with 4-amino-3-fluorophenol (VII) –prepared by reduction of 3-fluoro-4-nitrophenol (VIII) by means of H2 and Pd/C in EtOAc– in the presence of t-BuOK in DMAc at 100 °C provides the 4-phenoxypyridine derivative (IX), which is finally coupled with 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (X) in toluene .
| 【1】 Scott, W.J., Joel, R., Ridel, B. et al. (Bayer Healthcare LLC). omega-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors. US 2002042517. |
| 【2】 Dumas, J., Lynch, M., Scott, W.J., Ladouceur, G., Wilhelm, S. (Bayer Pharmaceuticals Corp.). Diaryl ureas with kinase inhibiting activity. CA 2526617, EP 1636585, JP 200751103, US 2007020704, WO 2004113274. |
| 【3】 Dumas, J., Wilhelm, S., Boyer, S., Riedl, B. (Bayer Pharmaceuticals Corp). Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions. EP 1663978, JP 2006528196, US 2005038080, WO 2005009961. |
| 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) | 29950 | 2-pyridinecarboxylic acid；picolinic acid;Pyridine-2-carboxylic acid | 98-98-6 | C6H5NO2 | 详情 | 详情 |
| (II) | 49908 | 4-chloropyridine-2-carbonyl chloride hydrochloride;(4-Chloro-2-pyridinecarbonyl Chloride Hydrochloride);4-Chloro-2-pyridinecarbonyl Chloride Hydrochlorid | 51727-15-2 | C6H3Cl2NO.HCl | 详情 | 详情 |
| (III) | 68688 | methyl 4-chloropicolinate hydrochloride | C7H6ClNO2.HCl | 详情 | 详情 | |
| (IV) | 49910 | 4-chloro-N-methyl-2-pyridinecarboxamide；4-chloro-N-methylpyridine-2-carboxamide;4-chloro-N-methylpicolinamide;4-Chloro-N-methylpicolinamide;2-(N-Methylcarbamoyl)-4-chloropyridine;4-Chloropyridine-2-carboxylicacid methylamide;N-Methyl-4-chloro-2-pyridinecarboxamide;N-Methyl-4-chloropicolinamide | 220000-87-3 | C7H7ClN2O | 详情 | 详情 |
| (V) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (VI) | 68689 | N-methylformamide;Methylformamide;Monomethylformamide;N-Methylformimidic acid;N-Monomethylformamide | 123-39-7 | C2H5NO | 详情 | 详情 |
| (VII) | 68690 | 4-amino-3-fluorophenol;3-Fluoro-4-aminophenol | 399-95-1 | C6H6FNO | 详情 | 详情 |
| (VIII) | 68691 | 3-fluoro-4-nitrophenol;2-Fluoro-4-hydroxy-1-nitrobenzene;4-Nitro-3-fluorophenol | 394-41-2 | C6H4FNO3 | 详情 | 详情 |
| (IX) | 68692 | 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide；4-(4-amino-3- fluorophenoxy)-N-methyl-2-Pyridinecarboxamide;4-(4-Amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide;4-(4-Amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide | 757251-39-1 | C13H12FN3O2 | 详情 | 详情 |
| (X) | 37868 | 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene; 4-chloro-3-(trifluoromethyl)phenyl isocyanate | 327-78-6 | C8H3ClF3NO | 详情 | 详情 |