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【结 构 式】 
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【药物名称】RPR-118723 【化学名称】(-)-2-(6-Chloro-9-methyl-2,3-dioxo-2,3,4,9-tetrahydro-1H-indeno[1,2-b]pyrazin-9-yl)acetic acid 【CA登记号】173187-06-9, 173187-05-8 ((+)-enantiomer), 173186-99-7 (undefined isomer) 【 分 子 式 】C14H11ClN2O4 【 分 子 量 】306.70777 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, AMPA Antagonists, NMDA Glycine-Site Antagonists |
合成路线1
Knoevenagel condensation of ketone (I) with ethyl cyanoacetate followed by Michael addition of cyanoacetamide to the resulting alpha-cyanocinnamate (IIa-b) yields cyclic imide (III). Hydrolysis and decarboxylation of (III) with H2SO4 gives diacid (IV), which is cyclized by means of hot H2SO4 to provide indanone (V). Treatment of (V) with oxalyl chloride in CH2Cl2 and catalytic DMF followed by addition of EtOH affords ethyl ester (VI), which is then converted into oxime (VII) by means of t-BuONO in Et2O and HCl. Hydrogenolysis of (VII) with H2 over Pd/C in HOAc/HCl provides alpha-amino derivative (VIII). By reacting (VIII) with ethyl oxalyl chloride (A), in CH2Cl2 in presence of Et3N, (IX) was obtained and then cyclized in presence of NH4OAc in refluxing HOAc to yield pyrazino derivative (X). Finally (X) is hydrolyzed with HCl in dioxane.
| 【1】 Jimonet, P.; Ribeill, Y.; Bohme, A.; et al.; Indeno[1,2-b]pyrazin-2,3-diones: A new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity. J Med Chem 2000, 43, 12, 2371. |
| 【2】 Jimonet, P.; Ribeill, Y.; Audiau, F.; Aloup, J.-C.; Barreau, M.; Mignani, S.; Genevois-Borella, A.; Damour, D. (Aventis Pharma SA); 5H-Indeno[1,2-b]pyrazine-2,3-dione derivs., their preparation and medicinal products containing them. US 5922716; WO 9526342 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 | |
| 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 | |
| (A) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IIa) | 41464 | ethyl (Z)-3-(4-chlorophenyl)-2-cyano-2-butenoate | C13H12ClNO2 | 详情 | 详情 | |
| (IIb) | 41465 | ethyl (E)-3-(4-chlorophenyl)-2-cyano-2-butenoate | C13H12ClNO2 | 详情 | 详情 | |
| (I) | 12685 | 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone | 99-91-2 | C8H7ClO | 详情 | 详情 |
| (III) | 41466 | 4-(4-chlorophenyl)-4-methyl-2,6-dioxo-3,5-piperidinedicarbonitrile | C14H10ClN3O2 | 详情 | 详情 | |
| (IV) | 41467 | 3-(4-chlorophenyl)-3-methylpentanedioic acid | C12H13ClO4 | 详情 | 详情 | |
| (V) | 41468 | 2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetic acid | C12H11ClO3 | 详情 | 详情 | |
| (VI) | 41469 | ethyl 2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate | C14H15ClO3 | 详情 | 详情 | |
| (VII) | 41470 | ethyl 2-[5-chloro-2-(hydroxyimino)-1-methyl-3-oxo-1,3-dihydro-2H-inden-1-yl]acetate | C14H14ClNO4 | 详情 | 详情 | |
| (VIII) | 41471 | ethyl 2-(2-amino-5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate | C14H16ClNO3 | 详情 | 详情 | |
| (IX) | 41472 | ethyl 2-[[5-chloro-1-(2-ethoxy-2-oxoethyl)-1-methyl-3-oxo-2,3-dihydro-1H-inden-2-yl]amino]-2-oxoacetate | C18H20ClNO6 | 详情 | 详情 | |
| (X) | 41473 | ethyl 2-(6-chloro-9-methyl-2,3-dioxo-2,3,4,9-tetrahydro-1H-indeno[1,2-b]pyrazin-9-yl)acetate | C16H15ClN2O4 | 详情 | 详情 |