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【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

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.

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.

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