-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】4-[1-Methyl-2-(4-piperidinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]-N-[1(S)-phenylethyl]pyridine-2-amine

【CA登记号】189442-43-1

【分子式】C₂₉H₃₀F₃N₅

【分子量】505.59115

【开发单位】Merck & Co. (Originator)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, p38 Protein Kinase Inhibitors, TNF-alpha Production Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

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

【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

合成路线3

Keto oxime (IV) was converted to the syn amino alcohol (XII) by palladium-catalyzed hydrogenation. Subsequent N-methylation of (XII) to give (XIV) was then achieved via formylation of the primary amine to formamide (XIII) in refluxing ethyl formate, followed by borane reduction. Acylation of the secondary amine (XIV) with N-(benzyloxycarbonyl)piperidine-4-carbonyl chloride (XV) provided amide (XVI). After Swern oxidation of the alcohol group of (XVI), the keto amide (XVII) was cyclized to the desired imidazole (VIII) in boiling ammonium formate.

参考文献中间体

【1】 Claiborne, C.F.; et al.; An efficient synthesis of tetrasubstituted imidazoles from N-(2-oxo)-amides. Tetrahedron Lett 1998, 39, 49, 8939.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	16602	ethyl formate	109-94-4	C₃H₆O₂	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
(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
(XII)	35162	(1S,2R)-2-amino-2-(2-fluoro-4-pyridinyl)-1-[3-(trifluoromethyl)phenyl]-1-ethanol		C₁₄H₁₂F₄N₂O	详情	详情
(XIII)	35163	(1R,2S)-1-(2-fluoro-4-pyridinyl)-2-hydroxy-2-[3-(trifluoromethyl)phenyl]ethylformamide		C₁₅H₁₂F₄N₂O₂	详情	详情
(XIV)	35164	(1S,2R)-2-(2-fluoro-4-pyridinyl)-2-(methylamino)-1-[3-(trifluoromethyl)phenyl]-1-ethanol		C₁₅H₁₄F₄N₂O	详情	详情
(XV)	35165	benzyl 4-(chlorocarbonyl)-1-piperidinecarboxylate		C₁₄H₁₆ClNO₃	详情	详情
(XVI)	35166	benzyl 4-[[[(1R,2S)-1-(2-fluoro-4-pyridinyl)-2-hydroxy-2-[3-(trifluoromethyl)phenyl]ethyl](methyl)amino]carbonyl]-1-piperidinecarboxylate		C₂₉H₂₉F₄N₃O₄	详情	详情
(XVII)	35167	benzyl 4-[[[(1R)-1-(2-fluoro-4-pyridinyl)-2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl](methyl)amino]carbonyl]-1-piperidinecarboxylate		C₂₉H₂₇F₄N₃O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)