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【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.
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) 60542 ethyl 4-nitrobenzoate 99-77-4 C9H9NO4 详情 详情
(II) 60543 ethyl 4-fluorobenzoate C9H9FO2 详情 详情
(III) 60544 4-fluorobenzoic acid C7H5FO2 详情 详情
(IV) 17262 1-(4-aminopiperazino)-1-ethanone C6H13N3O 详情 详情
(V) 60545   C11H16O2 详情 详情
Extended Information