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【结 构 式】 
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【分子编号】29950 【品名】2-pyridinecarboxylic acid；picolinic acid;Pyridine-2-carboxylic acid 【CA登记号】98-98-6 |
【 分 子 式 】C6H5NO2 【 分 子 量 】123.11124 【元素组成】C 58.54% H 4.09% N 11.38% O 25.99% |
合成路线1
该中间体在本合成路线中的序号：(Ia)This compound can be obtained in three different ways: 1) Condensation of pyridine-2-carboxylic acid (Ia, R = H), with 1-phenyl methylpiperazine (II) at 160 C. 2) Condensation of methyl pyridine-2-carboxylate (Ib, R = CH3) with 1-phenylmethylpiperazine (II) at 140 C. 3) Reaction of 1-phenylmethylpiperazine (II) with a mixed anhydride (III) formed from (Ia) and ethyl chloroformate (IV).
| 【1】 Budai, Z.; Zolyomi, G.; Synthesis of 14C and 3H specifically labelled 1-benzyl-4-picolinoylpiperazine. J Label Compd Radiopharm 1981, 18, 427-432. |
| 【2】 Budai, Z.; Mezei, T.; Lay, A.; A novel synthesis of pyridinecarboxylic acid piperazides. Acta Chim Acad Sci Hung 1980, 105, 241-246. |
| 【3】 Budai, Z.; Mezei, T.; Lay, A. (Egis Pharmaceuticals Ltd.); Preparation of pyridinecaboxylic acid piperazides. DE 2828888; GB 2001062; HU 175075 . |
| 【4】 Korosi, J.; et al. (Egis Pharmaceuticals Ltd.); Pyridine derivatives. DE 2215545; GB 1378964; HU 162396; JP 7644957 . |
| 【5】 Nogradi, M.; Piberaline. Drugs Fut 1984, 9, 1, 30. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 29950 | 2-pyridinecarboxylic acid；picolinic acid;Pyridine-2-carboxylic acid | 98-98-6 | C6H5NO2 | 详情 | 详情 |
| (Ib) | 29951 | methyl 2-pyridinecarboxylate | 2459-07-6 | C7H7NO2 | 详情 | 详情 |
| (II) | 28542 | N-Benzylpiperazine; 1-Benzylpiperazine | 2759-28-6 | C11H16N2 | 详情 | 详情 |
| (III) | 29952 | ethyl 2-oxo-2-(2-pyridinyl)acetate | C9H9NO3 | 详情 | 详情 | |
| (IV) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |
合成路线3
该中间体在本合成路线中的序号：(I)
| 【1】 Wilhelm S. 2007. Use of sorafenib for the treatment of cancers having resisunce to chemotherapeutic agents. W0 2007059155 |
| 【2】 Bankston D, Dumas J, Natero R, et al. 2002. A scaleable synthesis of BAY 43-9006: a potent raf kinase inhibitor for the treatment of cancer. Org Proc Dev, 6(6):777～781 |
| 【3】 Logers M, Gehring R, Kuhn O, et al. 2006. Process for the preparation of 4-[4-[[[[4-chloro-3-(trifluoromethyl) phenyl]amino]carbonyl]amino]phenoxy]-N-methylpyridine-2-carboxamide and its tosylate salt. WO 2006034796 |
| 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) | 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 |
| (IV) | 15715 | 4-Aminophenol | 123-30-8 | C6H7NO | 详情 | 详情 |
| (V) | 49912 | 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide | 284462-37-9 | C13H13N3O2 | 详情 | 详情 |
| (VI) | 37868 | 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene; 4-chloro-3-(trifluoromethyl)phenyl isocyanate | 327-78-6 | C8H3ClF3NO | 详情 | 详情 |
| (VII) | 66747 | 4-[4-[3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido]phenoxy]-N-methylpyridine-2-carboxamide | 284461-73-0 | C21H16ClF3N4O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)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 |