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【结 构 式】 
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【药物名称】 【化学名称】2(S)-Allyl-3(R)-[N-[1(S)-(1H-indol-3-ylcarbonyl)-2-phenylethyl]carbamoyl]-5-methylhexanehydroxamic acid 【CA登记号】 【 分 子 式 】C28H33N3O4 【 分 子 量 】475.59291 |
【开发单位】Abbott (Originator) 【药理作用】Antiarthritic Drugs, Bone Diseases, Treatment of, METABOLIC DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Osteoporosis, Matrix Metalloproteinase Inhibitors, TNF-alpha Production Inhibitors |
合成路线1
Friedel Crafts acylation of indole (II) with phenylalanine N-carboxyanhydride (I) in the presence of AlCl3 gave aminoketone (III). Subsequent condensation of (III) with the succinate building block (IV) in DMF afforded succinamide (V). Further deprotection of the tert-butyl ester of (V) by treatment with trifluoroacetic acid provided carboxylic acid (VI), which was coupled with O-tert-butyldimethylsilyl hydroxylamine (VII) in the presence of EDC and HOBt to yield, after desilylation, the target hydroxamic acid.
| 【1】 Sheppard, G.S.; Florjancic, A.S.; Giesler, J.R.; Xu, L.; Guo, Y.; Davidsen, S.K.; Marcotte, P.A.; Elmore, I.; Albert, D.H.; Terrance, J.M.; Bouska, J.J.; Goodfellow, C.L.; Morgan, D.W.; Summers, J.B.; Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg Med Chem Lett 1998, 8, 22, 3251. |
| 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) | 21645 | (4S)-4-benzyl-1,3-oxazolidine-2,5-dione | 14825-82-2 | C10H9NO3 | 详情 | 详情 |
| (II) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (III) | 21647 | (2S)-2-amino-1-(1H-indol-3-yl)-3-phenyl-1-propanone | C17H16N2O | 详情 | 详情 | |
| (IV) | 21641 | 1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2S,3R)-2-allyl-3-isobutylbutanedioate | C21H25F5O4 | 详情 | 详情 | |
| (IV) | 21655 | 4-(tert-butyl) 1-(2,3,4,5,6-pentafluorophenyl) (2R,3S)-2-isobutyl-3-(4-pentenyl)butanedioate | C23H29F5O4 | 详情 | 详情 | |
| (V) | 21649 | tert-butyl (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-(1H-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate | C32H40N2O4 | 详情 | 详情 | |
| (V) | 21656 | tert-butyl (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-(1H-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-6-heptenoate | C34H44N2O4 | 详情 | 详情 | |
| (VI) | 21650 | (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-(1H-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid | C28H32N2O4 | 详情 | 详情 | |
| (VI) | 21657 | (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-(1H-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-6-heptenoic acid | C30H36N2O4 | 详情 | 详情 | |
| (VII) | 21644 | (Aminooxy)(tert-butyl)dimethylsilane; O-[tert-Butyl(dimethyl)silyl]hydroxylamine | 41879-39-4 | C6H17NOSi | 详情 | 详情 |