benzyl 4-[5-(2-fluoro-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】35158

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

【CA登记号】

【分子式】C₂₈H₂₄F₄N₄O₂

【分子量】524.5179328

【元素组成】C 64.12% H 4.61% F 14.49% N 10.68% O 6.1%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

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.

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(VII)

In a modified procedure, displacement of fluoropyridine (VII) by (S)-alpha-methylbenzylamine (IX) afforded aminopyridine derivative (XI). This was then alkylated with iodomethane and Cs2CO3 to provide the required N-methyl imidazole (X) as the major isomer, which was finally deprotected by catalytic hydrogenation over Pd/C.

参考文献中间体

合成目标

【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.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	35158	benzyl 4-[5-(2-fluoro-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate	C₂₈H₂₄F₄N₄O₂	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
(XI)	35161	benzyl 4-[5-(2-[[(1S)-1-phenylethyl]amino]-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate	C₃₆H₃₄F₃N₅O₂	详情	详情

Extended Information