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【结 构 式】 
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【分子编号】46257 【品名】1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)-1-ethanone 【CA登记号】 |
【 分 子 式 】C20H19F3O7S 【 分 子 量 】460.4278696 【元素组成】C 52.17% H 4.16% F 12.38% O 24.32% S 6.96% |
合成路线1
该中间体在本合成路线中的序号：(V)The condensation of 4-(trifluoromethoxy)phenol (I) with 4-fluorophenyl(methyl)sulfone (II) by means of K2CO3 in hot DMSO gives the diphenyl ether (III), which is condensed with 2,2-dimethyl-1,3-dioxolane-(R)-carboxylic acid methyl ester (IV) by means of BuLi in THF to afford the ethanone (V). The reduction of (V) with NaBH4 in ethanol yields the ethanol derivative (VI), which is dehydrated to the ethylene (VII) by means of MsCl, TEA and NaHCO3. The addition of hydroxylamine to the double bond of (VII) provides the hydroxyamine derivative (VIII) as a diastereomeric mixture that is separated by flash chromatography, affording the desired enantiomer (IX). Finally, this compound is formylated by treatment with 2,2,2-trifluoroethyl formate (X) (obtained by reaction of 2,2,2-trifluoroethanol (XI) with hot formic acid (XII)) in refluxing MTBE.
| 【1】 Curtin, M.L.; Wada, C.K.; Holms, J.H.; et al.; Phenoxyphenyl sulfone N-forylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors. J Med Chem 2002, 45, 1, 219. |
| 【2】 Curtin, M.L.; Davidsen, S.K.; Michaelides, M.R.; Steinman, D.H.; Dai, Y.; Heyman, H.R.; Holmes, J.H. (Abbott Laboratories Inc.); Reverse hydroxamate inhibitors of matrix metalloproteinases. WO 0044739 . |
| 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) | 18780 | 4-(trifluoromethoxy)phenol | 828-27-3 | C7H5F3O2 | 详情 | 详情 |
| (II) | 46256 | 4-fluorophenyl methyl sulfone; (4-fluorophenyl)(methyl)dioxo-lambda(6)-sulfane | C7H7FO2S | 详情 | 详情 | |
| (III) | 46241 | methyl(dioxo)[4-[4-(trifluoromethoxy)phenoxy]phenyl]-lambda(6)-sulfane; methyl 4-[4-(trifluoromethoxy)phenoxy]phenyl sulfone | C14H11F3O4S | 详情 | 详情 | |
| (IV) | 20917 | methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate | 52373-72-5 | C7H12O4 | 详情 | 详情 |
| (V) | 46257 | 1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)-1-ethanone | C20H19F3O7S | 详情 | 详情 | |
| (VI) | 46258 | (1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)-1-ethanol | C20H21F3O7S | 详情 | 详情 | |
| (VII) | 46259 | (Z)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethenyl 4-[4-(trifluoromethoxy)phenoxy]phenyl sulfone; (4S)-2,2-dimethyl-4-[(Z)-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethenyl]-1,3-dioxolane | C20H19F3O6S | 详情 | 详情 | |
| (VIII) | 46260 | (4S)-4-[1-(hydroxyamino)-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]-2,2-dimethyl-1,3-dioxolane; N-[1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]hydroxylamine | C20H22F3NO7S | 详情 | 详情 | |
| (IX) | 46261 | N-[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]hydroxylamine; (4S)-4-[(1S)-1-(hydroxyamino)-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]-2,2-dimethyl-1,3-dioxolane | C20H22F3NO7S | 详情 | 详情 | |
| (X) | 46245 | 2,2,2-trifluoroethyl formate | C3H3F3O2 | 详情 | 详情 | |
| (XI) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
| (XII) | 14590 | Formic acid | 64-18-6 | CH2O2 | 详情 | 详情 |