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【结 构 式】 
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【药物名称】Vadimezan, AS-1404, DMXAA, 5, 6-MeXAA, NSC-640488 【化学名称】5,6-Dimethyl-9-oxoxanthene-4-acetic acid 【CA登记号】117570-53-3 【 分 子 式 】C17H14O4 【 分 子 量 】282.29873 |
【开发单位】University of Auckland (Originator), Antisoma (Licensee), Roche (Licensee), Cancer Research UK (Codevelopment) 【药理作用】ONCOLYTIC DRUGS, Solid Tumors Therapy |
合成路线1
The reaction of 2,3-dimethylaniline (I) with chloral hydrate (II) and hydroxylamine in hot aq. HCl gives the isonitrosoacetanilide (III), which is cyclized by means of hot Ms-OH or H2SO4 to yield 6,7-dimethylisatin (IV). The hydrolysis of (IV) by means of KOH and H2O2 in water affords 2-amino-3,4-dimethylbenzoic acid (V), which is diazotized with NaNO2 and H2SO4 and treated with KI to provide 2-iodo-3,4-dimethylbenzoic acid (VI). The condensation of (VI) with the sodium salt of 2-(2-hydroxyphenyl)acetic acid (VII) by means of tris[2-(2-methoxyethoxy)ethyl]amine (TDA) and CuCl in DMSO gives the precursor (VIII), which is finally cyclized by means of hot conc. aq. H2SO4 to furnish the target xanthene derivative.
| 【1】 Denny, W.A.; Atwell, G.J.; Yang, S.; An improved synthesis of 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Eur J Med Chem 2002, 37, 10, 825. |
| 【2】 Denny, W.A.; Baguley, B.C.; Atwell, G.J.; Rewcastle, G.W. (Cancer Research UK; Pfizer Inc.); Cpds. having antitumour and antibacterial properties. EP 0278176; US 5281620 . |
| 【3】 Rewcastle, G.W.; et al.; Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids. J Med Chem 1991, 34, 1, 217. |
| 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) | 23025 | 2,3-Dimethylphenylamine; 2,3-Dimethylaniline; 2,3-Xylidine | 87-59-2 | C8H11N | 详情 | 详情 |
| (II) | 14018 | 2,2,2-Trichloro-1,1-ethanediol; Chloral hydrate | 302-17-0 | C2H3Cl3O2 | 详情 | 详情 |
| (III) | 56664 | N-(2,3-dimethylphenyl)-2-(hydroxyimino)acetamide | C10H12N2O2 | 详情 | 详情 | |
| (IV) | 56665 | 6,7-dimethyl-1H-indole-2,3-dione | C10H9NO2 | 详情 | 详情 | |
| (V) | 56667 | 2-amino-3,4-dimethylbenzoic acid | 50419-58-4 | C9H11NO2 | 详情 | 详情 |
| (VI) | 56668 | 2-iodo-3,4-dimethylbenzoic acid | 129833-31-4 | C9H9IO2 | 详情 | 详情 |
| (VII) | 56666 | disodium 2-(2-oxidophenyl)acetate | C8H6Na2O3 | 详情 | 详情 | |
| (VIII) | 56669 | 2-[2-(carboxymethyl)phenoxy]-3,4-dimethylbenzoic acid | 117570-93-1 | C17H16O5 | 详情 | 详情 |