4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether -Drug Synthesis Database

【结构式】

【分子编号】22829

【品名】4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether

【CA登记号】

【分子式】C₁₂H₂₁NOSi

【分子量】223.39038

【元素组成】C 64.52% H 9.48% N 6.27% O 7.16% Si 12.57%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(II)

4-[(tert-Butyldimethylsilyloxy)methyl]pyridine (II) was prepared by silylation of 4-hydroxymethylpyridine (I) with tert-butyldimethylsilyl chloride and imidazole. Deprotonation of (II) by means of LDA in cold THF, followed by condensation with 4-fluorobenzaldehyde (III), furnished the protected diol adduct (IV), which was further desilylated upon treatment with tetrabutylammonium fluoride in THF. Oxidation of the resultant diol (V) under Swern conditions provided diketone (VI). The triaryl imidazole (VIII) was then obtained by condensation of diketone (VI) with 4-(methylsulfanyl)benzaldehyde (VII) in the presence of ammonium acetate in refluxing HOAc. Finally, oxidation of the thioether function of (VIII) with K-2S2O8 furnished the title sulfoxide.

参考文献中间体

合成目标

【1】 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 .

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)	32835	4-pyridinylmethanol	586-95-8	C₆H₇NO	详情	详情
(II)	22829	4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether		C₁₂H₂₁NOSi	详情	详情
(III)	12337	4-fluorobenzaldehyde	459-57-4	C₇H₅FO	详情	详情
(IV)	55081	2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanol		C₁₉H₂₆FNO₂Si	详情	详情
(V)	55082	1-(4-fluorophenyl)-2-(4-pyridinyl)-1,2-ethanediol		C₁₃H₁₂FNO₂	详情	详情
(VI)	37913	1-(4-fluorophenyl)-2-(4-pyridinyl)-1,2-ethanedione		C₁₃H₈FNO₂	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

合成路线2

该中间体在本合成路线中的序号：(II)

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3

该中间体在本合成路线中的序号：(I)

Condensation of 4-(tert-butyldimethylsilyloxymethyl)pyridine (I) with ethyl 4-fluorobenzoate (II) using NaHMDS gave the silyloxyketone (III). Then, cyclization of (III) with 2,6-diamino-4-methoxypyridine (IV) in the presence of H2SO4 in refluxing dimethoxyethane provided the target pyrrolopyridine.

参考文献中间体

合成目标

【1】 Henry, J.R.; Rupert, K.C.; Dodd, J.H.; Turchi, I.J.; Wadsworth, S.A.; Cavender, D.E.; Fahmy, B.; Olini, G.C.; Davis, J.E.; Pellegrino-Gensey, J.L.; Schafer, P.H.; Siekierka, J.J.; 6-Amino-2-(4-fluorophenyl)-4-methoxy-3-(4-pyridyl). J Med Chem 1998, 41, 22, 4196.

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)	22829	4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether		C₁₂H₂₁NOSi	详情	详情
(II)	22830	ethyl 4-fluorobenzoate	451-46-7	C₉H₉FO₂	详情	详情
(III)	22831	2-[[tert-butyl(dimethyl)silyl]oxy]-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone		C₁₉H₂₄FNO₂Si	详情	详情
(IV)	22832	4-methoxy-2,6-pyridinediamine; 6-amino-4-methoxy-2-pyridinylamine		C₆H₉N₃O	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Sylilated hydroxymethylpyridine (I) was condensed with ethyl 4-fluorobenzoate (II) in the presence of sodium hemamethyldisilazide to produce the silyloxy ketone (III). Subsequent reaction of (III) with diaminopyrimidine (IV) in the presence of H2SO4 in refluxing dimethoxyethane yielded the title pyrrolopyridine.

参考文献中间体

合成目标

【1】 Henry, J.R.; Rupert, K.C.; Dodd, J.H.; Turchi, I.J.; Wadsworth, S.A.; Cavender, D.E.; Schafer, P.H.; Siekierka, J.J.; Potent inhibitors of the MAP kinase p38. Bioorg Med Chem Lett 1998, 8, 23, 3335.
【2】 Dodd, J.H.; Henry, J.R.; Rupert, K. (Ortho-McNeil Pharmaceutical, Inc.); Substd. pyrrolopyridines useful in the treatment of inflammatory diseases. WO 9847899 .

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)	22829	4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether		C₁₂H₂₁NOSi	详情	详情
(II)	22830	ethyl 4-fluorobenzoate	451-46-7	C₉H₉FO₂	详情	详情
(III)	22831	2-[[tert-butyl(dimethyl)silyl]oxy]-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone		C₁₉H₂₄FNO₂Si	详情	详情
(IV)	26862	4-(benzyloxy)-2,6-pyridinediamine		C₁₂H₁₃N₃O	详情	详情

Extended Information