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【结 构 式】 
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【药物名称】Sorafenib, BAY-43-9006 【化学名称】4-[4-[3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido]phenoxy]-N-methylpyridine-2-carboxamide 【CA登记号】284461-73-0 【 分 子 式 】C21H16ClF3N4O3 【 分 子 量 】464.83487 |
【开发单位】Bayer (Originator), Onyx (Codevelopment) 【药理作用】Colorectal Cancer Therapy, Leukemia Therapy, Liver Cancer Therapy, Melanoma Therapy, Myelodysplastic Syndrome Therapy, Myeloid Leukemia Therapy, Oncolytic Drugs, Renal Cancer Therapy, Solid Tumors Therapy, Inhibitors of Signal Transduction Pathways, Raf Kinase Inhibitors, Vascular Endothelial Growth Factor (VEGF) Inhibitors |
合成路线1
Reaction of picolinic acid (I) with hot thionyl chloride in DMF gives 4-chloropyridine-2-carbonyl chloride (II), which is treated with methanol to give ester (III). Subsequent displacement of the methyl ester function with methylamine provides amide (IV). Alternatively, acid chloride (II) is directly converted into amide (IV) by reaction with a cold solution of methylamine. In a different synthetic procedure, amide (IV) can be obtained from 4-chloropyridine (V) via the Menisci reaction using N-methylformamide and hydrogen peroxide in the presence of FeSO4 and H2SO4. Coupling of the amide (IV) with potassium 4-aminophenolate (VI) -obtained by treatment of 4-aminophenol (VII) with potassium tert-butoxide- in hot DMF yields the pyridyloxyaniline (VIII). Aniline (VIII) is finally condensed with either 4-chloro-3-(trifluoromethyl)phenyl isocyanate (IX) in CH2Cl2 or 4-chloro-3-(trifluoromethyl)aniline (X) by means of CDI in CH2Cl2.
| 【1】 Sorbera, L.A.; Castaner, J.; Bozzo, J.; Leeson, P.A.; BAY-43-9006. Drugs Fut 2002, 27, 12, 1141. |
| 【2】 Monahan, M.-K.; Sibley, R.; Natero, R.; Dumas, J.; Bankston, D.; Riedl, B.; A scaleable synthesis of BAY 43-9006: A potent Raf kinase inhibitor for the treatment of cancer. Org Process Res Dev 2002, 6, 6, 777. |
| 【3】 Smith, R.A.; Monahan, M.-K.; Riedl, B.; Scott, W.J.; Khire, U.; Lowinger, T.B.; Natero, R.; Sibley, R.N.; Wood, J.E.; Renick, J.; Dumas, J. (Bayer Corp.); omega-Carboxy aryl substd. diphenyl ureas as p38 kinase inhibitors. WO 0041698 . |
| 【4】 Lowinger, T.B.; Monahan, M.-K.; Dumas, J.; Scott, W.J.; Khire, U.; Wood, J.E.; Renick, J.; Riedl, B.; Smith, R.A.; Natero, R.; Sibley, R.N. (Bayer Corp.); omega-Carboxyaryl substd. diphenyl ureas as raf kinase inhibitors. EP 1140840; WO 0042012 . |
| 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) | 49909 | methyl 4-chloro-2-pyridinecarboxylate | 24484-93-3 | C7H6ClNO2 | 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) | 49911 | potassium 4-aminobenzenolate | C6H6KNO | 详情 | 详情 | |
| (VII) | 49912 | 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide | 284462-37-9 | C13H13N3O2 | 详情 | 详情 |
| (VII) | 49912 | 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide | 284462-37-9 | C13H13N3O2 | 详情 | 详情 |
| (VIII) | 37868 | 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene; 4-chloro-3-(trifluoromethyl)phenyl isocyanate | 327-78-6 | C8H3ClF3NO | 详情 | 详情 |