|
【结 构 式】 
|
【分子编号】18960 【品名】tert-butyl(dimethyl)[4-[(2S)oxiranylmethoxy]phenoxy]silane; tert-butyl(dimethyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether 【CA登记号】 |
【 分 子 式 】C15H24O3Si 【 分 子 量 】280.43926 【元素组成】C 64.24% H 8.63% O 17.12% Si 10.01% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(V)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 |
合成路线3
该中间体在本合成路线中的序号：(V)2) Alternatively, amine (VI) was selectively protected as the carbamate (XI) with di-tert-butyl dicarbonate. This compound was condensed with sulfonyl chloride (IX) and pyridine to afford sulfonamide (XII), and the Boc protecting group was then removed with trifluoroacetic acid to give the primary amine (XIII). Subsequent addition of (XIII) to epoxide (V) provided the phenoxypropanolamine (XIV), and the silyl group was finally eliminated with methanolic HCl.
| 【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 |
|---|---|---|---|---|---|---|
| (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 |
| (IX) | 18964 | 4-bromobenzenesulfonyl chloride | 98-58-8 | C6H4BrClO2S | 详情 | 详情 |
| (XI) | 18966 | tert-butyl 4-aminophenethylcarbamate | C13H20N2O2 | 详情 | 详情 | |
| (XII) | 18967 | tert-butyl 4-[[(4-bromophenyl)sulfonyl]amino]phenethylcarbamate | C19H23BrN2O4S | 详情 | 详情 | |
| (XIII) | 18968 | N-[4-(2-aminoethyl)phenyl]-4-bromobenzenesulfonamide | C14H15BrN2O2S | 详情 | 详情 | |
| (XIV) | 18969 | 4-bromo-N-[4-(2-[[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]amino]ethyl)phenyl]benzenesulfonamide | C29H39BrN2O5SSi | 详情 | 详情 |