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【结 构 式】 
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【药物名称】Quazepam, Sch-161, Sch-16134, Oniria, Doral, Quazium, Selepam, Prosedar, Dormalin, Cetrane 【化学名称】7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-1-(2,2,2-trifluoroethyl)-2H-1,4-benzodiazepine-2-thione 【CA登记号】36735-22-5 【 分 子 式 】C17H11ClF4N2S 【 分 子 量 】386.80122 |
【开发单位】Schering-Plough (Originator), MedPointe (Licensee), Mitsubishi Pharma (Licensee), SSP (Licensee) 【药理作用】PSYCHOPHARMACOLOGIC DRUGS, Sedative/Hypnotics, Sleep Disorders, Treatment of, Benzodiazepines, GABA(A) BZ Site Receptor Agonists |
合成路线1
The alkylation of 2-amino-5-chloro-2'-fluorobenzophenone (II) with 2,2,2-trifluoroethyl trichloromethylsulfonate (A) gives 2-(2,2,2-trifluoroethylamino)-5-chloro-2'-fluorobenzophenone (III), which is bromoacetylated with bromoacetyl chloride (B) in refluxing benzene yielding the bromoacetanilide (IV).This compound is cyclized with NH3 in chloroform affording 7-chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (I), which by reaction with P2S5 in refluxing dioxane gives the target compound.
| 【1】 Steinman, M.; Benzodiazepines and the process for their manufacture. DE 2138773; ES 393953; FR 2102114; GB 1345938 . |
| 【2】 Steinman, M.; 1-Polyfluoroalkyl-1,4-benzodiazepin-2-thiones for effecting tranquilization, sedation and treating colvulsions. US 3920818 . |
| 【3】 Castaner, J.; Thorpe, P.; Quazepam. Drugs Fut 1978, 3, 2, 139. |
| 【4】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (A) | 33474 | 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate | 23199-56-6 | C3H2Cl3F3O3S | 详情 | 详情 |
| (I) | 33471 | 7-Chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C17H11ClF4N2O | 详情 | 详情 | |
| (II) | 32281 | 2-Amino-5-chloro-2'-fluorobenzophenone; (2-Amino-5-chlorophenyl)(2-fluorophenyl)methanone | 784-38-3 | C13H9ClFNO | 详情 | 详情 |
| (III) | 33472 | [5-Chloro-2-[(2,2,2-trifluoroethyl)amino]phenyl](2-fluorophenyl)methanone; 2-(2,2,2-Trifluoroethylamino)-5-chloro-2'-fluorobenzophenone | C15H10ClF4NO | 详情 | 详情 | |
| (IV) | 33473 | 2-bromo-N-[4-chloro-2-(2-fluorobenzoyl)phenyl]-N-(2,2,2-trifluoroethyl)acetamide | C17H11BrClF4NO2 | 详情 | 详情 |
合成路线2
The alkylation of p-chloroaniline (V) as before yields N-(2,2,2-trifluoroethyl)aniline (VI), which is then condensed with aziridine (C) affording the substituted aniline (VII). The benzoylation of (VII) with 2-fluorobenzoyl chloride (D) yields the amide (VIII), which is cyclized with P2O5 in refluxing POCl3 giving 7-chloro-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-5-(2-fluorophenyl)-1,4-benzodiazepine (IX). This compound is oxidized with RuO4 in CCl4 to give 7-chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (I), which by reaction with P2S5 in refluxing dioxane gives the target compound.
| 【1】 Steinman, M.; Benzodiazepines and the process for their manufacture. DE 2138773; ES 393953; FR 2102114; GB 1345938 . |
| 【2】 Steinman, M.; 1-Polyfluoroalkyl-1,4-benzodiazepin-2-thiones for effecting tranquilization, sedation and treating colvulsions. US 3920818 . |
| 【3】 Castaner, J.; Thorpe, P.; Quazepam. Drugs Fut 1978, 3, 2, 139. |
| 【4】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 19551 | 2-Fluorobenzoyl chloride | 393-52-2 | C7H4ClFO | 详情 | 详情 |
| (A) | 33474 | 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate | 23199-56-6 | C3H2Cl3F3O3S | 详情 | 详情 |
| (I) | 33471 | 7-Chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C17H11ClF4N2O | 详情 | 详情 | |
| (V) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (VI) | 33475 | N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline | C8H7ClF3N | 详情 | 详情 | |
| (VII) | 33476 | N(1)-(4-chlorophenyl)-N(1)-(2,2,2-trifluoroethyl)-1,2-ethanediamine; N-(2-aminoethyl)-N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine | C10H12ClF3N2 | 详情 | 详情 | |
| (VIII) | 33477 | N-[2-[4-chloro(2,2,2-trifluoroethyl)anilino]ethyl]-2-fluorobenzamide | C17H15ClF4N2O | 详情 | 详情 | |
| (IX) | 33478 | 7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine; 7-chloro-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-5-(2-fluorophenyl)-1,4-benzodiazepine | C17H13ClF4N2 | 详情 | 详情 | |
| (C) | 10151 | Ethyleneimine; Aziridine; Azirane | 151-56-4 | C2H5N | 详情 | 详情 |