4-fluoro-N-methoxy-N-methylbenzamide -Drug Synthesis Database

【结构式】

【分子编号】29514

【品名】4-fluoro-N-methoxy-N-methylbenzamide

【CA登记号】

【分子式】C₉H₁₀FNO₂

【分子量】183.1823432

【元素组成】C 59.01% H 5.5% F 10.37% N 7.65% O 17.47%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(X)

In a related procedure, 4-fluorobenzoyl chloride (IX) was converted to the corresponding Weinreb amide (X) upon treatment with N,O-dimethylhydroxylamine. Condensation of (X) with the lithium derivative of 4-[(tert-butyldimethylsilyloxy)methyl]pyridine (II) furnished the silylated hydroxy ketone (XI). This was then condensed with 4-(methylthio)benzaldehyde (VII) in the presence of cupric acetate as oxidant and ammonium acetate to produce the intermediate triaryl imidazole (VIII), which was finally oxidized as above.

参考文献中间体

合成目标

【1】 Gallagher, T.F.; et al.; Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg Med Chem 1997, 5, 1, 49.
【2】 Gallagher, T.F.; et al.; 2,4,5-Triarylimidazole inhibitors of IL-1 biosynthesis. Bioorg Med Chem Lett 1995, 5, 11, 1171.
【3】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazole derivs. and their use as cytokine inhibitors. EP 0623126; EP 0943616; JP 1995503017; US 5686455; WO 9314081 .
【4】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazoles for treating cytokine mediated disease. WO 9503297 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	22829	4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether		C₁₂H₂₁NOSi	详情	详情
(VII)	18815	4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde	3446-89-7	C₈H₈OS	详情	详情
(VIII)	55083	4-{5-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1H-imidazol-4-yl}pyridine; 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazol-2-yl]phenyl methyl sulfide		C₂₁H₁₆FN₃S	详情	详情
(IX)	17263	4-fluorobenzoyl chloride	403-43-0	C₇H₄ClFO	详情	详情
(X)	29514	4-fluoro-N-methoxy-N-methylbenzamide		C₉H₁₀FNO₂	详情	详情
(XI)	22831	2-[[tert-butyl(dimethyl)silyl]oxy]-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone		C₁₉H₂₄FNO₂Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The reaction of 4-fluorobenzoyl chloride (I) with N,O-dimethylhydroxylamine (II) in pyridine gives the N-methylhydroxamate (III), which is condensed with 5-bromo-1H-indole (IV) by means of KH and t-BuLi yielding the ketone (V). The alkylation of (V) with ethyl iodide and NaH in DMF affords (1-ethylindol-5-yl)(4-fluorophenyl)methanone (VI), which is reduced with NaBH4 in methanol to the corresponding carbinol (VII). Finally, this compound is treated with carbonyl diimidazole in THF.

参考文献中间体

合成目标

【1】 Marchand, P.; Robert, J.-M.; Palzer, M.; Delovoye-Seiller, B.; Hartmann, R.W.; Le Baut, G.; Le Borgne, M.; New selective nonsteroidal aromatase inhibitors: Synthesis and inhibitory activity of 2, 3 or 5-(alpha-azolylbenzyl)-1H-indoles. Bioorg Med Chem Lett 1999, 9, 3, 333.

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)	17263	4-fluorobenzoyl chloride	403-43-0	C₇H₄ClFO	详情	详情
(II)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(III)	29514	4-fluoro-N-methoxy-N-methylbenzamide		C₉H₁₀FNO₂	详情	详情
(IV)	13309	5-Bromo-1H-indole; 5-Bromoindole	10075-50-0	C₈H₆BrN	详情	详情
(V)	29515	(4-fluorophenyl)(1H-indol-5-yl)methanone		C₁₅H₁₀FNO	详情	详情
(VI)	29516	(1-ethyl-1H-indol-5-yl)(4-fluorophenyl)methanone		C₁₇H₁₄FNO	详情	详情
(VII)	29517	(1-ethyl-1H-indol-5-yl)(4-fluorophenyl)methanol		C₁₇H₁₆FNO	详情	详情
(VIII)	11353	1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole)	530-62-1	C₇H₆N₄O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

Acylation of the lithium derivative of 4-picoline (VI) with the Weinreb amide of 4-fluorobenzoic acid (V) yielded ketone (VII). The sodium enolate of (VII) was then alkylated with chloro ketone (IV) to afford diketone (VIII). The Paal-Knorr cyclization of diketone (VIII) in the presence of ammonium acetate in boiling HOAc led to pyrrole (IX). Finally, reduction of the benzyloxycarbonyl group of (IX) by means of LiAlH4 furnished the target N-methyl piperidine.

参考文献中间体

合成目标

【1】 De Laszlo, S.E.; Mantlo, N.B.; Ponticello, G.S.; Selnick, H.G.; Liverton, N.J. (Merck & Co., Inc.); 2-Substd. aryl pyrroles, compsns. containing such cpds. and methods of use. EP 0863757; JP 1999510510; US 5792778; WO 9705877 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	56084	benzyl 4-(2-chloroacetyl)-1-piperidinecarboxylate		C₁₅H₁₈ClNO₃	详情	详情
(V)	29514	4-fluoro-N-methoxy-N-methylbenzamide		C₉H₁₀FNO₂	详情	详情
(VI)	31150	4-methylpyridine	108-89-4	C₆H₇N	详情	详情
(VII)	45005	1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone		C₁₃H₁₀FNO	详情	详情
(VIII)	56085	benzyl 4-[4-(4-fluorophenyl)-4-oxo-3-(4-pyridinyl)butanoyl]-1-piperidinecarboxylate		C₂₈H₂₇FN₂O₄	详情	详情
(IX)	56086	benzyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrrol-2-yl]-1-piperidinecarboxylate		C₂₈H₂₆FN₃O₂	详情	详情

Extended Information