4-pyridinylmethanol -Drug Synthesis Database

【结构式】

【分子编号】32835

【品名】4-pyridinylmethanol

【CA登记号】586-95-8

【分子式】C₆H₇NO

【分子量】109.12772

【元素组成】C 66.04% H 6.47% N 12.84% O 14.66%

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：(I)

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：(I)

Quaternization of 4-pyridylcarbinol (I) by means of iodoethane provided pyridinium salt (II), which was reduced with NaBH4 to the tetrahydropyridine (III). Subsequent Mitsunobu coupling of (III) with 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (IV) afforded ether (V). Intramolecular cyclization of (V) to the spiro compound (VI) was effected by treatment with tributyltin hydride and azobis(isobutyronitrile). The acetamide function of (VI) was then hydrolyzed by refluxing with HCl in H2O-EtOH to furnish intermediate diamine (VII).

参考文献中间体

合成目标

【1】 Gaster, L.M.; King, F.D.; Wyman, P.A. (GlaxoSmithKline plc); Tetracyclic spiro cpds., process for their preparation and their use as 5HT1D receptor antagonists. EP 0799226; JP 1998510821; US 5972951; WO 9619477 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10925	Iodoethane;ethyl iod	75-03-6	C₂H₅I	详情	详情
(I)	32835	4-pyridinylmethanol	586-95-8	C₆H₇NO	详情	详情
(II)	32836	1-ethyl-4-(hydroxymethyl)pyridinium iodide		C₈H₁₂INO	详情	详情
(III)	32837	(1-ethyl-1,2,3,6-tetrahydro-4-pyridinyl)methanol		C₈H₁₅NO	详情	详情
(IV)	19324	1-(6-bromo-5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone		C₁₀H₁₀BrNO₂	详情	详情
(V)	32838	1-[6-bromo-5-[(1-ethyl-1,2,3,6-tetrahydro-4-pyridinyl)methoxy]-2,3-dihydro-1H-indol-1-yl]-1-ethanone		C₁₈H₂₃BrN₂O₂	详情	详情
(VI)	32839	1'-Ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]; 5-Acetyl-1'-ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]		C₁₈H₂₄N₂O₂	详情	详情
(VII)	32844	1'-Ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]		C₁₆H₂₂N₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XV)

The debenzylation of 2-(benzyloxymethyl)-5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1H-imidazole (IX) with hot aqueous HCl gives 5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1H-imidazole-2-methanol (XIII), which is condensed with chlorosulfonyl isocyanate in acetonitrile to yield carbamic acid 5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1H-imidazol-2-ylmethyl ester (XIV). Finally, this compound is alkylated with 4-(chloromethyl)pyridine (X) - obtained by reaction of 4-(hydroxymethyl)pyridine (XV) and SOCl2 in acetonitrile - by means of NaHCO3 in ethyl acetate/water.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149.
【2】 Sugimoto, H.; Fujiwara, T. (Shionogi & Co. Ltd.); Imidazole deriv.. EP 0786455; US 5910506; US 6147097; WO 9610019 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	35844	benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl]methyl ether; 2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazole		C₂₀H₂₀Cl₂N₂OS	详情	详情
(X)	10844	4-(Chloromethyl)pyridine	10445-91-7	C₆H₆ClN	详情	详情
(XIII)	63297	{5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl}methanol		C₁₃H₁₄Cl₂N₂OS	详情	详情
(XIV)	63298	{5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl}methyl carbamate		C₁₄H₁₅Cl₂N₃O₂S	详情	详情
(XV)	32835	4-pyridinylmethanol	586-95-8	C₆H₇NO	详情	详情

Extended Information