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【结 构 式】 
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【药物名称】Fanapanel, ZK-200775, MPQX 【化学名称】7-Morpholino-2,3-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxalin-1-ylmethylphosphonic acid 【CA登记号】161605-73-8 【 分 子 式 】C14H15F3N3O6P 【 分 子 量 】409.26115 |
【开发单位】Novo Nordisk (Originator), Schering AG (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, AMPA Antagonists, Kainate Antagonists |
合成路线1
The reaction of 2,4-dichloro-5-(trifluoromethyl)nitrobenzene (I) with aminomethanephosphonic acid (II) by means of NaOH in ethanol/water gives the anilinomethanephosphonic acid (III), which is condensed first with morpholine (IV) by heating at 120 C and esterified with triethyl orthoformate at 150 C yielding 5-(4-morpholinyl)-2-nitro-4-(trifluoromethyl)phenylaminomethyl phosphonic acid diethyl ester (V). The reduction of the nitro group of (V) with H2 over Pd/C in ethanol affords the corresponding amino-derivative (VI), which is cyclized with oxalic acid monoethyl ester monochloride (VII) by means of triethylamine in THF providing the quinoxaline (VIII). Finally, this compound is hydrolyzed to the free phosphonic acid with trimethylbromo silane in acetonitrile.
| 【1】 Huth, A.; Turski, L. (Schering AG); Quinoxalindione derivs., their preparation and their use in drugs. DE 4314591; DE 4344486; EP 0696288; EP 1002796; JP 1996508037; US 5750525; WO 9425469 . |
| 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) | 28301 | 1,5-dichloro-2-nitro-4-(trifluoromethyl)benzene | 400-70-4 | C7H2Cl2F3NO2 | 详情 | 详情 |
| (II) | 28302 | aminomethylphosphonic acid | 1066-51-9 | CH6NO3P | 详情 | 详情 |
| (III) | 28303 | [5-chloro-2-nitro-4-(trifluoromethyl)anilino]methylphosphonic acid | C8H7ClF3N2O5P | 详情 | 详情 | |
| (IV) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (V) | 28304 | diethyl [5-(4-morpholinyl)-2-nitro-4-(trifluoromethyl)anilino]methylphosphonate | C16H23F3N3O6P | 详情 | 详情 | |
| (VI) | 28305 | diethyl [2-amino-5-(4-morpholinyl)-4-(trifluoromethyl)anilino]methylphosphonate | C16H25F3N3O4P | 详情 | 详情 | |
| (VII) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (VIII) | 28306 | diethyl [7-(4-morpholinyl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydro-1(2H)-quinoxalinyl]methylphosphonate | C18H23F3N3O6P | 详情 | 详情 |