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【结 构 式】 
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【药物名称】Azurene, Bromperidol, R-11333, Impromen 【化学名称】4-[4-(4-Bromophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone 【CA登记号】10457-90-6, 59453-24-6 (HCl) 【 分 子 式 】C21H23BrFNO2 【 分 子 量 】420.32536 |
【开发单位】Janssen (Originator), Formenti (Licensee) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS |
合成路线1
The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethyleneketal (II), which is condensed with 4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 1-(4-fluorophenyl)-4-(4-hydroxypiperidin-1-yl)-1-butanone ethyleneketal (IV). The Oppenauer oxidation of (IV) with 9-fluorenone and potassium tert-butoxide in hot benzene affords the piperidinone (V), which is condensed with 4-bromo-N-(trimethylsilyl)aniline (VI) by means of BuLi in hot hexane to give 4-[4-(4-aminophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone (VII). Finally, this compound is treated with CuBr2 and NO in THF.
| 【1】 Vincent, S.H.; et al.; Synthesis of [82Br]bromperidol and preliminary tissue distribution studies in the rat. J Med Chem 1980, 23, 1, 75. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (II) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (III) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (IV) | 35865 | 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol | C17H24FNO3 | 详情 | 详情 | |
| (V) | 35866 | 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinone | C17H22FNO3 | 详情 | 详情 | |
| (VI) | 35867 | N-(4-bromophenyl)(trimethyl)silanamine; N-(4-bromophenyl)-N-(trimethylsilyl)amine | C9H14BrNSi | 详情 | 详情 | |
| (VII) | 35868 | 4-[4-(4-aminophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone | C21H25FN2O2 | 详情 | 详情 | |
| (VIII) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (IX) | 35869 | C6H5Br2MgN | 详情 | 详情 |
合成路线2
The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethyleneketal (II), which is condensed with 4-(chlorophenyl)-4-hydroxypiperidine (VIII) by means of K2CO3 in hot DMF yielding 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone ethyleneketal (IX). The reaction of (IX) with HCl in methanol yields the corresponding free butanone (X), which is treated with trimethylstannyl sodium in glyme to afford the expected stannyl derivative (XI). Finally, this compound is treated with Br2 in chloroform.
| 【1】 Moerlein, S.M.; Stocklin, G.L.; Synthesis of high specific activity [75Br]- and [77Br]-bromperidol and tissue distribution studies in the rat. J Med Chem 1985, 28, 9, 1319. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (II) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (III) | 35870 | 4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine | 39512-49-7 | C11H14ClNO | 详情 | 详情 |
| (IX) | 35871 | 4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol | C23H27ClFNO3 | 详情 | 详情 | |
| (X) | 35872 | 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone | 52-86-8 | C21H23ClFNO2 | 详情 | 详情 |
| (XI) | 35873 | 1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone | C24H32FNO2Sn | 详情 | 详情 |
合成路线3
The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene-ketal (II), which is condensed with 4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 1-(4-fluorophenyl)-4-(4-hydroxypiperidin-1-yl)-1-butanone ethyle-neketal (IV). The Oppenauer oxidation of (IV) with 9-fluorenone and potassium tert-butoxide in hot benzene affords the piperidinone (V), which is condensed with 4-bromo-N-(trimethylsilyl)aniline (VI) by means of BuLi in hot hexane to give 4-[4-(4-aminophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone (VII). Finally, this compound is treated with Cu82Br2 and NO in THF.
| 【1】 Vincent, S.H.; et al.; Synthesis of [82Br]bromperidol and preliminary tissue distribution studies in the rat. J Med Chem 1980, 23, 1, 75. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (II) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (III) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (IV) | 35865 | 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol | C17H24FNO3 | 详情 | 详情 | |
| (V) | 35866 | 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinone | C17H22FNO3 | 详情 | 详情 | |
| (VI) | 35867 | N-(4-bromophenyl)(trimethyl)silanamine; N-(4-bromophenyl)-N-(trimethylsilyl)amine | C9H14BrNSi | 详情 | 详情 | |
| (VII) | 35868 | 4-[4-(4-aminophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone | C21H25FN2O2 | 详情 | 详情 | |
| (VIII) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (IX) | 35869 | C6H5Br2MgN | 详情 | 详情 |
合成路线4
The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene-ketal (II), which is condensed with 4-(chlorophenyl)-4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone ethyleneketal (IV). The reaction of (IV) with HCl in methanol yields the corresponding free butanone (V), which is treated with trimethylstannyl sodium in glyme to afford the expected stannyl derivative (VI). Finally, this compound is treated with 75Br2 or 77Br2 and dichloramin T in methanol or H2O2 in acetic acid.
| 【1】 Moerlein, S.M.; Stocklin, G.L.; Synthesis of high specific activity [75Br]- and [77Br]-bromperidol and tissue distribution studies in the rat. J Med Chem 1985, 28, 9, 1319. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (II) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (III) | 35870 | 4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine | 39512-49-7 | C11H14ClNO | 详情 | 详情 |
| (IV) | 35871 | 4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol | C23H27ClFNO3 | 详情 | 详情 | |
| (V) | 35872 | 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone | 52-86-8 | C21H23ClFNO2 | 详情 | 详情 |
| (VI) | 35873 | 1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone | C24H32FNO2Sn | 详情 | 详情 |