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【结 构 式】 
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【药物名称】Alprazolam, U-31889, Xanax XR, Panistat, Xanax 【化学名称】8-Chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine 【CA登记号】28981-97-7 【 分 子 式 】C17H13ClN4 【 分 子 量 】308.77296 |
【开发单位】Pfizer (Originator), Questcor (Not Determined), Fabre-Kramer (Licensee) 【药理作用】Anxiolytics, Generalized Anxiety Disorder (GAD), Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Benzodiazepines, GABA(A) BZ Site Receptor Agonists |
合成路线1
The reaction of 2,6-dichloro-4-phenylquinoline (I) with refluxing hydrazine hydrate gives 6-chloro-2-hydrazino-4-phenylquinoline (II), which is cyclocondensed with triethyl orthoacetate (A) in refluxing xylene yielding 7-chloro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline (III). The oxidation of (III) to 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (V) can be performed with sodium periodate and ruthenium dioxide in acetone-water, or first with ozone in CH2Cl2 giving 4-(2-benzoyl-4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-carboxaldehyde (IV), which is then oxidized to (V) with silver oxide in methanol. The condensation of (V) with formaldehyde in xylene at 125 C affords 5-chloro-2-(3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl)benzophenon (VI), which by reaction with PBr3 in chloroform is converted into 5-chloro-2-(3-bromoethyl-5-methyl-4H-1,2,4-triazol-4-yl)benzophenon (VII). Finally, this product is cyclized with ammonia in THF - methanol.
| 【1】 Hester, J.B. Jr.; Process for the production of triazolobenzodiazepines and intermediates. DE 2203782; FR 2124559; GB 1374822; GB 1374823; GB 1374824; GB 1374825; JP 49066679; US 3709898 . |
| 【2】 Castaner, J.; Chatterjee, S.S.; Alprazolam. Drugs Fut 1976, 1, 12, 551. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
| (I) | 34092 | 2,6-dichloro-4-phenylquinoline | C15H9Cl2N | 详情 | 详情 | |
| (II) | 34093 | 6-chloro-2-hydrazino-4-phenylquinoline | C15H12ClN3 | 详情 | 详情 | |
| (III) | 34094 | 7-chloro-1-methyl-5-phenyl[1,2,4]triazolo[4,3-a]quinoline | C17H12ClN3 | 详情 | 详情 | |
| (IV) | 34095 | 4-(2-benzoyl-4-chlorophenyl)-5-methyl-4H-1,2,4-triazole-3-carbaldehyde | C17H12ClN3O2 | 详情 | 详情 | |
| (V) | 34096 | [5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl](phenyl)methanone | C16H12ClN3O | 详情 | 详情 | |
| (VI) | 34097 | [5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]phenyl](phenyl)methanone | C17H14ClN3O2 | 详情 | 详情 | |
| (VII) | 34098 | [2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-5-chlorophenyl](phenyl)methanone | C17H13BrClN3O | 详情 | 详情 |
合成路线2
The reaction of 7-chloro-5-phenyl-1,3-dihydro-3H-1,4-benzodiazepine-2-thione (VIII) with acetylhydrazine (B) in refluxing anhydrous ethanol gives 7-chloro-5-phenyl-2-(2-acetylhydrazino)-1,3-dihydro-3H-1,4-benzodiazepine (IX), which is cyclized by heating at 250 C.
| 【1】 Hester, J.B. Jr.; 6-Phenyl-4H-S-triazolo[4,3-a][1,4]benzodiazepines. DE 2012190; DE 2065893; ES 376689; FR 2034999; GB 1291631; US 3987052 . |
| 【2】 Castaner, J.; Chatterjee, S.S.; Alprazolam. Drugs Fut 1976, 1, 12, 551. |
合成路线3
The reaction of 7-chloro-5-phenyl-2-hydrazino-1,3-dihydro-3H-1,4-benzodiazepine (X) with refluxing acetaldehyde (C) gives 7-chloro-5-phenyl-2-ethylydenhydrazino-1,3-dihydro-3H-1,4-benzodiazepine (XI), which is cyclized by refluxing in chloroform (10.5 h) or by heating at 160-72 C (10 min).
| 【1】 Hester, J.B. Jr.; Benzodiazepines and the manufacture thereof. CH 574425; DE 2242938; FR 2154474; GB 1382605; JP 48034894 . |
| 【2】 Castaner, J.; Chatterjee, S.S.; Alprazolam. Drugs Fut 1976, 1, 12, 551. |