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【结 构 式】 
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【分子编号】33561 【品名】[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methanamine; [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methylamine 【CA登记号】 |
【 分 子 式 】C16H15ClFN3 【 分 子 量 】303.7664232 【元素组成】C 63.26% H 4.98% Cl 11.67% F 6.25% N 13.83% |
合成路线1
该中间体在本合成路线中的序号：(V)The reaction of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (I) with methylamine by means of TiCl4 in refluxing benzene gives 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine (II), which by reaction with NaNO2 in acetic acid is converted into its N-nitroso derivative (III). The treatment of (III) with nitromethane and potassium tert-butoxide in DMF affords 7-chloro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine (IV), which is reduced with H2 over Raney-Ni in THF affording the 2-aminomethyl derivative (V).The acetylation of (V) with acetic anhydride in CH2Cl2 gives the acetamide (VI), which is cyclized with polyphosphoric acid at 150 C yielding 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (VII). The deshydrogenation of (VII) with MnO2 in refluxing toluene affords 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (VIII), which is finally treated with maleic acid (A) in hot ethanol.
| 【1】 Fryer, R.I.; Walser, A.; Benzo or heterocyclic fused imidazodiazepines and pharmaceutical compositions containing them. BE 0833248; DE 2540522; FR 2303016; GB 1527131; JP 51125099 . |
| 【2】 Dhaon, M.K. (Abbott Laboratories Inc.); Process for the preparation of midazolam. WO 0170744 . |
| 【3】 Thorpe, P.; Castaner, J.; Midazolam Maleate. Drugs Fut 1978, 3, 11, 822. |
| 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) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
| (I) | 33355 | 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | 2886-65-9 | C15H10ClFN2O | 详情 | 详情 |
| (II) | 33558 | N-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]-N-methylamine; 7-chloro-5-(2-fluorophenyl)-N-methyl-3H-1,4-benzodiazepin-2-amine | C16H13ClFN3 | 详情 | 详情 | |
| (III) | 33559 | N-[7-Chloro-5-(2-fluorophenyl)-3H-1,3-benzodiazepin-2-yl]-N-methyl-N-nitrosoamine | C16H12ClFN4O | 详情 | 详情 | |
| (IV) | 33560 | 7-chloro-5-(2-fluorophenyl)-2-[(Z)-nitromethylidene]-1,3-dihydro-2H-1,4-benzodiazepine | C16H11ClFN3O2 | 详情 | 详情 | |
| (V) | 33561 | [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methanamine; [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methylamine | C16H15ClFN3 | 详情 | 详情 | |
| (VI) | 33562 | N-[[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methyl]acetamide | C18H17ClFN3O | 详情 | 详情 | |
| (VII) | 33563 | 8-chloro-6-(2-fluorophenyl)-1-methyl-3a,4-dihydro-3H-imidazo[1,5-a][1,4]benzodiazepine | C18H15ClFN3 | 详情 | 详情 | |
| (VIII) | 33564 | 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine | 59467-70-8 | C18H13ClFN3 | 详情 | 详情 |