4-[[tert-butyl(dimethyl)silyl]oxy]phenol -Drug Synthesis Database

【结构式】

【分子编号】18958

【品名】4-[[tert-butyl(dimethyl)silyl]oxy]phenol

【CA登记号】

【分子式】C₁₂H₂₀O₂Si

【分子量】224.3751

【元素组成】C 64.24% H 8.98% O 14.26% Si 12.52%

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：(III)

The silylation of 4-benzyloxyphenol (I) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF gives the silyl ether (II), which is debenzylated by hydrogenation with H2 over Pd/C in ethyl acetate yielding the silylated phenol (III). The condensation of (III) with 2(S)-glycidyl 3-nitrobenzenesulfonate (IV) by means of NaH in DMF affords the glycicyl ether (V), which is treated with 2-(4-aminophenyl)ethylamine (VI) in refluxing methanol to give the addition compound (VII). The reaction of (VII) with di-tert-butyl dicarbonate in THF affords compound (VIII) with the secondary aliphatic amine protected as carbamate. Finally, the reaction of (VIII) with N-[4-(chlorosulfonyl)phenyl]-N'-hexylurea (IX) (obtained by reaction of the isocyanate (X) with hexylamine) by means of pyridine in dichloromethane, followed by deprotection with HCl provides the target product.

参考文献中间体

合成目标

【1】 Parmee, E.R.; et al.; Synthesis and activity of conformationally restrained human beta3-adrenergic receptor agonists. 213th ACS Natl Meet (April 13-17, San Francisco) 1997, Abst MEDI 031.
【2】 Fisher, M.H.; Mathvink, R.J.; Ok, H.O.; Parmee, E.R.; Weber, A.E. (Merck & Co., Inc.); Substd. phenyl sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. CA 2114712; EP 0611003; JP 1995010827; US 5451677; WO 9418161 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	26546	n-hexylamine; hexylamine	111-26-2	C₆H₁₅N	详情	详情
(I)	18956	4-(Benzyloxy)phenol; 4-Benzyloxyphenol	103-16-2	C₁₃H₁₂O₂	详情	详情
(II)	18957	[4-(benzyloxy)phenoxy](tert-butyl)dimethylsilane; benzyl 4-[[tert-butyl(dimethyl)silyl]oxy]phenyl ether		C₁₉H₂₆O₂Si	详情	详情
(III)	18958	4-[[tert-butyl(dimethyl)silyl]oxy]phenol		C₁₂H₂₀O₂Si	详情	详情
(IV)	24765	(2S)oxiranylmethyl 3-nitrobenzenesulfinoperoxoate		C₉H₉NO₆S	详情	详情
(V)	18960	tert-butyl(dimethyl)[4-[(2S)oxiranylmethoxy]phenoxy]silane; tert-butyl(dimethyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether		C₁₅H₂₄O₃Si	详情	详情
(VI)	18961	4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine	13472-00-9	C₈H₁₂N₂	详情	详情
(VII)	18962	(2S)-1-[(4-aminophenethyl)amino]-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-propanol		C₂₃H₃₆N₂O₃Si	详情	详情
(VIII)	18963	tert-butyl 4-aminophenethyl[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]carbamate		C₂₈H₄₄N₂O₅Si	详情	详情
(IX)	24770	N-[4-[(chlorooxy)sulfinyl]phenyl]-N'-hexylurea		C₁₃H₁₉ClN₂O₃S	详情	详情
(X)	24771	(chlorooxy)(4-isocyanatophenyl)oxo-lambda(4)-sulfane		C₇H₄ClNO₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

1) 4-(Benzyloxy)phenol (I) was protected as the silyl ether (II) by treatment with tert-butyldimethylsilyl chloride (TBDMS-Cl) in the presence of imidazole in DMF. Then, the benzyl group of (II) was removed by hydrogenolysis on Pd(OH)2/C to give 4-(tert-butyldimethylsilyloxy)phenol (III). This phenol was treated with NaH in DMF, and the resulting sodium phenoxide was alkylated with (S)-glycidyl 3-nitrobenzenesulfonate (IV) to provide epoxide (V) (1,2). Subsequent reaction of (V) with 4-aminophenethyl amine (VI) in refluxing MeOH gave the chiral phenoxypropanolamine (VII). Selective protection of the resultant secondary aliphatic amine with one equivalent of di-tert-butyl dicarbonate in THF afforded carbamate (VIII). Then, acylation of the aniline N atom with 4-bromobenzenesulfonyl chloride (IX) in the presence of pyridine gave sulfonamide (X). Finally, removal of both silyl ether and tert-butyl carbamate protecting groups using methanolic HCl provided the desired product.

参考文献中间体

合成目标

【1】 Weber, A.E.; Mathvink, R.J.; Perkins, L.; Hutchins, J.E.; Candelore, M.R.; Tota, L.; Strader, C.D.; Wyvratt, M.J.; Fisher, M.H.; Potent, selective benzenesulfonamide agonists of the human beta3 adrenergic receptor. Bioorg Med Chem Lett 1998, 8, 9, 1101.
【2】 Fisher, M.H.; Mathvink, R.J.; Ok, H.O.; Parmee, E.R.; Weber, A.E. (Merck & Co., Inc.); Substd. phenyl sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. CA 2114712; EP 0611003; JP 1995010827; US 5451677; WO 9418161 .

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)	18956	4-(Benzyloxy)phenol; 4-Benzyloxyphenol	103-16-2	C₁₃H₁₂O₂	详情	详情
(II)	18957	[4-(benzyloxy)phenoxy](tert-butyl)dimethylsilane; benzyl 4-[[tert-butyl(dimethyl)silyl]oxy]phenyl ether		C₁₉H₂₆O₂Si	详情	详情
(III)	18958	4-[[tert-butyl(dimethyl)silyl]oxy]phenol		C₁₂H₂₀O₂Si	详情	详情
(IV)	16259	(2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate	115314-14-2	C₉H₉NO₆S	详情	详情
(V)	18960	tert-butyl(dimethyl)[4-[(2S)oxiranylmethoxy]phenoxy]silane; tert-butyl(dimethyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether		C₁₅H₂₄O₃Si	详情	详情
(VI)	18961	4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine	13472-00-9	C₈H₁₂N₂	详情	详情
(VII)	18962	(2S)-1-[(4-aminophenethyl)amino]-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-propanol		C₂₃H₃₆N₂O₃Si	详情	详情
(VIII)	18963	tert-butyl 4-aminophenethyl[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]carbamate		C₂₈H₄₄N₂O₅Si	详情	详情
(IX)	18964	4-bromobenzenesulfonyl chloride	98-58-8	C₆H₄BrClO₂S	详情	详情
(X)	18965	tert-butyl 4-[[(4-bromophenyl)sulfonyl]amino]phenethyl[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]carbamate		C₃₄H₄₇BrN₂O₇SSi	详情	详情

Extended Information