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【结 构 式】

【分子编号】35157

【品名】benzyl 4-[5-(2-fluoro-4-pyridinyl)-1-hydroxy-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate

【CA登记号】

【 分 子 式 】C28H24F4N4O3

【 分 子 量 】540.5173328

【元素组成】C 62.22% H 4.48% F 14.06% N 10.37% O 8.88%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VI)

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
Extended Information