|
【结 构 式】 
|
【药物名称】FR-59960, FK-960 【化学名称】N-(4-Acetyl-1-piperazinyl)-4-fluorobenzamide monohydrate 【CA登记号】133920-70-4 (anhydrous) 【 分 子 式 】C13H18FN3O3 【 分 子 量 】283.30511 |
【开发单位】Fujisawa (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS |
合成路线1
This compound can be obtained by two different ways: 1) The acetylation of 1-nitrosopiperazine (I) with acetyl chloride and pyridine in dioxane gives 1-acetyl-4-nitrosopiperazine (II), which is reduced with Zn and acetic acid/water to 1-acetyl-4-aminopiperazine (III). Finally, this compound is acylated with 4-fluorobenzoyl chloride (IV) by means of triethylamine in dichloromethane. 2) The nitrosation of piperazine (V) with NaNO2/HCl in water, followed by condensation with benzyloxycarbonyl chloride (VI) by means of NaOH yields 1-(benzyloxycarbonyl)-4-nitrosopiperazine (VII), which is reduced with Zn and acetic acid/water as before to the corresponding amino derivative (VIII). The acylation of (VIII) with 4-fluorobenzoyl chloride and triethylamine in dichloromethane affords N-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-fluorobenzamide (IX), which is deprotected with HBr in acetic acid to yield N-(1-piperazinyl)-4-fluorobenzamide (X). Finally, this compound is acetylated with acetic anhydride/NaOH in water.
| 【1】 Graul, A.; Tracy, M.; Castañer, J.; FK-960. Drugs Fut 1997, 22, 8, 830. |
| 【2】 Oku, T.; Todo, E.; Yokota, Y.; Kayakiri, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New aminopiperazine derivs. EP 0436734; JP 1991510050; US 5250528; WO 9101979 . |
| 【3】 Oku, T.; Kayakiri, H.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Novel intermediate for synthetic use and process for producing aminopiperazine derivs. WO 9500502 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17260 | 1-nitrosopiperazine | C4H9N3O | 详情 | 详情 | |
| (II) | 17261 | 1-(4-nitrosopiperazino)-1-ethanone | C6H11N3O2 | 详情 | 详情 | |
| (III) | 17262 | 1-(4-aminopiperazino)-1-ethanone | C6H13N3O | 详情 | 详情 | |
| (IV) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (V) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VI) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 17266 | benzyl 4-nitrosotetrahydro-1(2H)-pyrazinecarboxylate | C12H15N3O3 | 详情 | 详情 | |
| (VIII) | 17267 | benzyl 4-aminotetrahydro-1(2H)-pyrazinecarboxylate | C12H17N3O2 | 详情 | 详情 | |
| (IX) | 17268 | benzyl 4-[(4-fluorobenzoyl)amino]tetrahydro-1(2H)-pyrazinecarboxylate | C19H20FN3O3 | 详情 | 详情 | |
| (X) | 17269 | 4-fluoro-N-piperazinobenzamide | C11H14FN3O | 详情 | 详情 |
合成路线2
The reaction of 4-nitrobenzoic acid ethyl ester (I) with 18FK in DMSO at 150 C gives 4-18Fluorobenzoic acid ethyl ester (II), which is hydrolyzed with NaOH to yield the corresponding free acid (III) Finally, this compound is condensed with 4-acetylpiperazine-1-amine (IV) by means of WSC and HOBT in DMF to afford the target labeled compound. Alternatively, 4-18Fluorobenzoic acid ethyl ester (II) can also be obtained by reaction ethyl 4-aminobenzoate triflate salt (V) with 18FK in DMSO at 120 C.
| 【1】 Murakami, Y.; et al.; Synthesis of 18F labelled FK960, a candidate anti-dementia drug, and PET studies in conscious monkeys. J Label Compd Radiopharm 2002, 45, 14, 1219. |