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【结 构 式】 
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【分子编号】18296 【品名】2-Fluoro-4-methylpyridine 【CA登记号】461-87-0 |
【 分 子 式 】C6H6FN 【 分 子 量 】111.1187832 【元素组成】C 64.85% H 5.44% F 17.1% N 12.61% |
合成路线1
该中间体在本合成路线中的序号：(I)Chlorination of 2-fluoro-4-picoline (I) with N-chlorosuccinimide in the presence of benzoyl peroxide furnished a 3:1:1 mixture of chloromethyl- (II), and dichloromethylpyridine (III) along with some unreacted starting material. Treatment of this mixture with NaI in refluxing acetone converted (II) into the iodomethyl compound (IV), but (I) and (III) remained unreacted. Then, the dialkylation of anthrone (V) in the presence of NaH in THF afforded the title compound, which was purified by column chromatography.
| 【1】 Earl, R.A.; Zaczek, R.; Teleha, C.A.; Fisher, B.N.; Maciag, C.M.; Marynowski, M.E.; Logue, A.R.; Tam, S.W.; Tinker, W.J.; Huang, S.M.; Chorvat, R.J.; 2-Fluoro-4-pyridinylmethyl analogues of linopirdine as orally active acetylcholine release-enhancing agents with good efficacy and duration of action. J Med Chem 1998, 41, 23, 4615. |
| 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) | 18296 | 2-Fluoro-4-methylpyridine | 461-87-0 | C6H6FN | 详情 | 详情 |
| (II) | 18297 | 4-(chloromethyl)-2-fluoropyridine | C6H5ClFN | 详情 | 详情 | |
| (III) | 18298 | 4-(dichloromethyl)-2-fluoropyridine | C6H4Cl2FN | 详情 | 详情 | |
| (IV) | 18299 | 2-fluoro-4-(iodomethyl)pyridine | C6H5FIN | 详情 | 详情 | |
| (V) | 18300 | Anthrone; 9(10H)-anthracenone | 90-44-8 | C14H10O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The radical chlorination of 2-fluoro-4-methylpyridine (I) with NCS, benzoyl peroxide and acetic acid in refluxing acetonitrile gives a mixture of the starting material (I) and its mono (II) and dichloro (III) derivatives. This mixture of (I), (II) and (III) was treated with refluxing aqueous K2CO3 , which selectively hydrolyzes the monochloro derivative (II) to afford 2-fluoro-4-(hydroxymethyl)pyridine (IV). The compound (IV), which is easily separated from unreacted (I) and dichloro compound (III), is treated with methanesulfonyl chloride and TEA in ethyl acetate to provide the corresponding mesylate (V). The reaction of (V) with NaI in THF gives 2-fluoro-4-(iodomethyl)pyridine (VI), which is finally condensed with anthrone (VII) by means of lithium tert-butoxide in THF.
| 【1】 Pesti, J.A.; et al.; Efficient pyridinylmethyl functionalization: Synthesis of 10,10-bis[2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (DMP 543), an acetylcholine release enhancing agent. J Org Chem 2000, 65, 23, 7718. |
| 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) | 18296 | 2-Fluoro-4-methylpyridine | 461-87-0 | C6H6FN | 详情 | 详情 |
| (II) | 18297 | 4-(chloromethyl)-2-fluoropyridine | C6H5ClFN | 详情 | 详情 | |
| (III) | 18298 | 4-(dichloromethyl)-2-fluoropyridine | C6H4Cl2FN | 详情 | 详情 | |
| (IV) | 50205 | (2-fluoro-4-pyridinyl)methanol | C6H6FNO | 详情 | 详情 | |
| (V) | 50206 | (2-fluoro-4-pyridinyl)methyl methanesulfonate | C7H8FNO3S | 详情 | 详情 | |
| (VI) | 18299 | 2-fluoro-4-(iodomethyl)pyridine | C6H5FIN | 详情 | 详情 | |
| (VII) | 18300 | Anthrone; 9(10H)-anthracenone | 90-44-8 | C14H10O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Condensation of the anion resulting from 2-fluoro-4-methylpyridine (I) and LDA with N-methoxy-N-methyl-3-trifluoromethylbenzamide (II) afforded ketone (III). Subsequent alpha-oximination of (III) with tert-butyl nitrite and HCl provided the required E-oxime (IV) as the major isomer. Cyclization of (IV) with N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde (V) and ammonium acetate in refluxing AcOH afforded hydroxyimidazole (VI). Further reduction of (VI) to imidazole (VII) was carried out with titanium trichloride. Methylation of the imidazole ring of (VII) by treatment with N,N-dimethylformamide dimethylacetal in boiling toluene gave rise to a mixture of both N-methylated imidazoles, from which the desired compound (VIII) was isolated by column chromatography as the minor isomer. Nucleophilic displacement of the fluoropyridine of (VIII) by (S)-alpha-methylbenzylamine (IX) at 150 C gave the corresponding aminopyridine derivative (X). The N-benzyloxycarbonyl protecting group was finally removed by catalytic hydrogenation over Pd/C.
| 【1】 Claiborne, C.F.; Liverton, N.J.; Butcher, J.W.; et al.; Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J Med Chem 1999, 42, 12, 2180. |
| 【2】 Selnick, H.G.; Claremon, D.A.; Liverton, N.J. (Merck & Co., Inc.); Substd. imidazoles having anti-cancer and cytokine inhibitory activity. JP 1999514353; US 5717100; WO 9712876 . |
| 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) | 18296 | 2-Fluoro-4-methylpyridine | 461-87-0 | C6H6FN | 详情 | 详情 |
| (II) | 35153 | N-methoxy-N-methyl-3-(trifluoromethyl)benzamide | C10H10F3NO2 | 详情 | 详情 | |
| (III) | 35154 | 2-(2-fluoro-4-pyridinyl)-1-[3-(trifluoromethyl)phenyl]-1-ethanone | C14H9F4NO | 详情 | 详情 | |
| (IV) | 35155 | 1-(2-fluoro-4-pyridinyl)-2-[3-(trifluoromethyl)phenyl]-1,2-ethanedione 1-oxime | C14H8F4N2O2 | 详情 | 详情 | |
| (V) | 35156 | 4-Formyl-N-Cbz-piperidine; benzyl 4-formyl-1-piperidinecarboxylate | 138163-08-3 | C14H17NO3 | 详情 | 详情 |
| (VI) | 35157 | benzyl 4-[5-(2-fluoro-4-pyridinyl)-1-hydroxy-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate | C28H24F4N4O3 | 详情 | 详情 | |
| (VII) | 35158 | benzyl 4-[5-(2-fluoro-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate | C28H24F4N4O2 | 详情 | 详情 | |
| (VIII) | 35159 | benzyl 4-[5-(2-fluoro-4-pyridinyl)-1-methyl-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate | C29H26F4N4O2 | 详情 | 详情 | |
| (IX) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (X) | 35160 | benzyl 4-[1-methyl-5-(2-[[(1S)-1-phenylethyl]amino]-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate | C37H36F3N5O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Condensation of 2-fluoro-4-methylpyridine (I) with ethyl 4-fluorobenzoate (II) by means of sodium bis(trimethylsilyl)amide provides the diaryl ethanone (III). Subsequent nitrosation of ketone (III) with tert-butyl nitrite under acidic conditions furnishes oxime (IV). Cyclization of keto oxime (IV) with trimethylacetaldehyde (V) in the presence of ammonium acetate in boiling AcOH proceeds with concomitant hydrolysis of the fluoro group to produce the N-hydroxy imidazole (VI). Reduction of (VI) employing TiCl3 gives imidazole (VII). Finally, the photochemical cyclization of diarylimidazole (VII) leads to the target tetracyclic compound (1, 2).
| 【1】 Thompson, J.E.; Cubbon, R.M.; Cummings, R.T.; Wicker, L.S.; Franksun, R.; Cunningham, B.R.; Cameron, P.M.; Meinke, P.T.; Liverton, N.; Weng, Y.; DeMartino, J.A.; Photochemical preparation of a pyridone containing tetracycle: A jak protein kinase inhibitor. Bioorg Med Chem Lett 2002, 12, 8, 1219. |
| 【2】 Sinclair, P.J.; Goulet, J.L.; Hong, X.; Thompson, J.E.; Cubbon, R.M.; Cummings, R.T. (Merck & Co., Inc.); Benzimidazo[4,5-f]isoquinolinone derivs.. WO 0311285 . |
| 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) | 18296 | 2-Fluoro-4-methylpyridine | 461-87-0 | C6H6FN | 详情 | 详情 |
| (II) | 22830 | ethyl 4-fluorobenzoate | 451-46-7 | C9H9FO2 | 详情 | 详情 |
| (III) | 63664 | 1-(4-fluorophenyl)-2-(2-fluoro-4-pyridinyl)-1-ethanone | C13H9F2NO | 详情 | 详情 | |
| (IV) | 63665 | 1-(4-fluorophenyl)-2-(2-fluoro-4-pyridinyl)-1,2-ethanedione 2-oxime | C13H8F2N2O2 | 详情 | 详情 | |
| (V) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VI) | 63666 | 4-[2-(tert-butyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]-2(1H)-pyridinone | C18H18FN3O2 | 详情 | 详情 | |
| (VII) | 63667 | 4-[2-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2(1H)-pyridinone | C18H18FN3O | 详情 | 详情 |