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【结 构 式】 
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【分子编号】18963 【品名】tert-butyl 4-aminophenethyl[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]carbamate 【CA登记号】 |
【 分 子 式 】C28H44N2O5Si 【 分 子 量 】516.75334 【元素组成】C 65.08% H 8.58% N 5.42% O 15.48% Si 5.43% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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：(VIII)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 |