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【结 构 式】 
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【分子编号】20299 【品名】1-(4-nitrophenyl)piperazine 【CA登记号】6269-89-2 |
【 分 子 式 】C10H13N3O2 【 分 子 量 】207.23224 【元素组成】C 57.96% H 6.32% N 20.28% O 15.44% |
合成路线1
该中间体在本合成路线中的序号：(III)The intermediate 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) has been obtained by several related ways: 1.- The condensation of 4-bromonitrobenzene (I) with piperazine (II) gives 1-(4-nitrophenyl)piperazine (III), which is condensed with 4-bromoanisole (IV) by means of Pdo to yield 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V). Alternatively, (V) can also be obtained by condensation of (III) with 4-methoxyphenylboronic acid (VI) by means of Cu(OAc)2 in DMSO. The demethylation of (V) with HBr yields 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (VII), which is finally reduced with H2 over Pd/C to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). 2.- The condensation of piperazine (II) with 4-bromoanisole (IV) by means of Pdo gives 1-(4-methoxyphenyl)piperazine (IX), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in hot DMSO to yield intermediate 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V), already reported. 3.- The condensation of piperazine (II) with 4-(benzyloxy)phenyl bromide (X) by means of Pdo gives 1-(4-benzyloxyphenyl)piperazine (XI), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and TBAI in hot DMSO to yield 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII). The nitro group of (XII) is reduced by means of H2 (50 psi) over Pd/C in wet THF at 50? C to afford 4-[4-(4-benzyloxyphenyl)piperazin-1-yl]aniline (XIII), which is finally debenzylated with H2 (80 psi) over Pd/C in wet THF at 70? C or other drastic conditions to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). Alternatively, 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII) can also be reduced directly to the target intermediate (VIII) with H2 over Pd/C under a variety of drastic conditions.
| 【1】 Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Evans, C.A.; Goodman, A.; Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediate. Tetrahedron Lett 2002, 43, 18, 3359. |
| 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) | 26628 | 1-bromo-4-nitrobenzene | 99-99-0 | C6H4BrNO2 | 详情 | 详情 |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (IV) | 63436 | 1-bromo-4-methoxybenzene; 4-bromophenyl methyl ether | C7H7BrO | 详情 | 详情 | |
| (V) | 16314 | methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine | C17H19N3O3 | 详情 | 详情 | |
| (VI) | 39246 | 4-methoxyphenylboronic acid | 5720-07-0 | C7H9BO3 | 详情 | 详情 |
| (VII) | 16345 | 4-[4-(4-nitrophenyl)piperazino]phenol | C16H17N3O3 | 详情 | 详情 | |
| (VIII) | 17110 | 4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine | 74853-08-0 | C16H19N3O | 详情 | 详情 |
| (IX) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (X) | 43156 | 1-(benzyloxy)-4-bromobenzene; benzyl 4-bromophenyl ether | 6793-92-6 | C13H11BrO | 详情 | 详情 |
| (XI) | 64373 | 1-[4-(benzyloxy)phenyl]piperazine; benzyl 4-(1-piperazinyl)phenyl ether | C17H20N2O | 详情 | 详情 | |
| (XII) | 64372 | benzyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether; 1-[4-(benzyloxy)phenyl]-4-(4-nitrophenyl)piperazine | C23H23N3O3 | 详情 | 详情 | |
| (XIII) | 64371 | 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}aniline; 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}phenylamine | C23H25N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The benzoquinoline carboxylate ester (I) is hydrolyzed with NaOH to produce the sodium carboxylate salt (II). Activation of (II) with propane-phosphonic anhydride, followed by coupling with N-(4-nitrophenyl)piperazine (III) furnishes the corresponding amide.
| 【1】 Neumann, P.; Pfaeffli, P.; Seiler, M.P.; Swoboda, R. (Novartis AG; Novartis Deutschland GmbH); Benzo[g]quinoline derivs.. EP 0839136; JP 1999509197; US 5885988; WO 9703054 . |
| 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) | 61421 | methyl (4aS,10aR)-6-methoxy-1-methyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate | C17H23NO3 | 详情 | 详情 | |
| (II) | 61422 | (4aS,10aR)-6-methoxy-1-methyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate | C16H20NO3 | 详情 | 详情 | |
| (III) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Esterification of (4'-biphenyl)acetic acid (I) with ethanol and p-toluenesulfonic acid provides the corresponding ethyl ester (II). Subsequent carbethoxylation of (II) with diethyl carbonate (III) under Claisen's condensation conditions furnishes the biphenylmalonate (IV). Cyclization of malonate (IV) with urea (V) in the presence of NaOEt leads to 5-(4'-biphenyl)barbituric acid (VI), which is further brominated to (VII) employing Br2 in aqueous HBr. The title compound is finally obtained by displacement of the 5-bromo barbituric acid (VII) with N-(4-nitrophenyl)piperazine (VIII) in refluxing MeOH.
| 【1】 Bosies, E.; Esswein, A.; Grams, F.; Krell, H.-W.; Menta, E. (Roche Diagnostics GmbH); New barbituric acid derivs., processes for their production and pharmaceutical agents containing these cpds.. DE 19548624; EP 0869947; JP 2000505069; US 6110924; US 6472396; WO 9723465 . |
| 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) | 58170 | 2-[1,1'-biphenyl]-4-ylacetic acid | C14H12O2 | 详情 | 详情 | |
| (II) | 58171 | ethyl 2-[1,1'-biphenyl]-4-ylacetate | C16H16O2 | 详情 | 详情 | |
| (III) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (IV) | 58172 | diethyl 2-[1,1'-biphenyl]-4-ylmalonate | C19H20O4 | 详情 | 详情 | |
| (V) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (VI) | 58173 | 5-[1,1'-biphenyl]-4-yl-2,4,6(1H,3H,5H)-pyrimidinetrione | C16H12N2O3 | 详情 | 详情 | |
| (VII) | 58174 | 5-[1,1'-biphenyl]-4-yl-5-bromo-2,4,6(1H,3H,5H)-pyrimidinetrione | C16H11BrN2O3 | 详情 | 详情 | |
| (VIII) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)(S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (I) was coupled to N-(4-nitrophenyl)piperazine (II) via activation with 1,1'-carbonyldiimidazole to furnish the corresponding amide (III). Subsequent hydrogenation of the nitro group of (III) over Pd/C provided aniline (IV). This was finally condensed with S-methyl-2-thiophenethiocarboxamide (V) to yield the title amidine.
| 【1】 Chabrier de Lassauniere, P.-E.; Auguet, M.; Auvin, S.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Novel 2-(iminomethyl)amino-phenyl derivs., preparation, application as medicines and pharmaceutical compsns. containing same. EP 0973763; WO 9842696 . |
| 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) | 34833 | (2S)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxylic acid | C14H18O4 | 详情 | 详情 | |
| (II) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (III) | 34834 | [(2S)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl][4-(4-nitrophenyl)-1-piperazinyl]methanone | C24H29N3O5 | 详情 | 详情 | |
| (IV) | 34835 | [4-(4-aminophenyl)-1-piperazinyl][(2S)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]methanone | C24H31N3O3 | 详情 | 详情 | |
| (V) | 34836 | methyl 2-thiophenecarbimidothioate | C6H7NS2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)1) The reaction of 1-(4-nitrophenyl)piperazine (I) with tert-butyl dicarbonate (II) and triethylamine in dichloromethane gives 4-(4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (III), which is reduced with H2 over Pd/C, yielding the corresponding 4-amino compound (IV). The reaction of (IV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (VI), which by reaction with hydrazine is converted into the semicarbazide (VII). The cyclization of (VII) with formamidine (VIII) and triethylamine in hot 2-methoxyethanol affords the triazolone (IX), which is condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF, giving the disubstituted triazolone (XI). The deprotection, elimination of the tert-butoxycarbonyl group, of (XI) with HCl yields the monosubstituted piperazine (XII), which is finally condensed with (2R,3S)-oxirane (XIII) by means of LiClO4 in refluxing acetonitrile.
| 【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148. |
| 【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30. |
| 【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 . |
| 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) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (II) | 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 |
| (III) | 20301 | tert-butyl 4-(4-nitrophenyl)-1-piperazinecarboxylate | C15H21N3O4 | 详情 | 详情 | |
| (IV) | 20302 | tert-butyl 4-(4-aminophenyl)-1-piperazinecarboxylate | C15H23N3O2 | 详情 | 详情 | |
| (V) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (VI) | 20304 | tert-butyl 4-[4-[(phenoxycarbonyl)amino]phenyl]-1-piperazinecarboxylate | C22H27N3O4 | 详情 | 详情 | |
| (VII) | 20305 | tert-butyl 4-[4-[(hydrazinocarbonyl)amino]phenyl]-1-piperazinecarboxylate | C16H25N5O3 | 详情 | 详情 | |
| (VIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (IX) | 20307 | tert-butyl 4-[4-(5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl]-1-piperazinecarboxylate | C17H23N5O3 | 详情 | 详情 | |
| (X) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
| (XI) | 20309 | tert-butyl 4-(4-[5-oxo-1-[4-(trifluoromethoxy)benzyl]-1,5-dihydro-4H-1,2,4-triazol-4-yl]phenyl)-1-piperazinecarboxylate | C25H28F3N5O4 | 详情 | 详情 | |
| (XII) | 20310 | 4-[4-(1-piperazinyl)phenyl]-2-[4-(trifluoromethoxy)benzyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C20H20F3N5O2 | 详情 | 详情 | |
| (XIII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)2) The addition of 1-(4-nitrophenyl)piperazine (I) to the chiral oxirane (XIII) as before gives the disubstituted piperazine (XIV), which is hydrogenated with H2 over Pd/C in ethyl acetate, yielding the anilino derivative (XV). The acylation of (XV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (XVI), which is treated with hydrazine to give the semicarbazide (XVII). The cyclization of (XVII) with formamidine (VIII) as before affords the triazolone (XVIII), which is finally condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF.
| 【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148. |
| 【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30. |
| 【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 . |
| 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) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (V) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (VIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (X) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
| (XIII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (XIV) | 20312 | (2R,3R)-2-(2,4-difluorophenyl)-3-[4-(4-nitrophenyl)-1-piperazinyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C22H24F2N6O3 | 详情 | 详情 | |
| (XV) | 20313 | (2R,3R)-3-[4-(4-aminophenyl)-1-piperazinyl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C22H26F2N6O | 详情 | 详情 | |
| (XVI) | 20314 | phenyl 4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenylcarbamate | C29H30F2N6O3 | 详情 | 详情 | |
| (XVII) | 20315 | N-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-1-hydrazinecarboxamide | C23H28F2N8O2 | 详情 | 详情 | |
| (XVIII) | 20316 | 4-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C24H26F2N8O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(X)Acetylation of substituted aniline (I) with acetic anhydride in refluxing acetic acid affords acetanilide (II), which is then nitrated with HNO3:H2SO4 to provide 2-nitro derivative (III). Hydrolysis of (III) in concentrated H2SO4 gives substituted 2-nitroaniline (IV), which is then subjected to diazotization with NaNO2 and HCl in H2O and then treated with NaN3 and sodium acetate in H2O to furnish 2-nitrophenyl azide derivative (V). Cyclocondensation of azide (V) in refluxing toluene yields benzofuroxane (VI), which in turn is subjected to Beirut reaction with malonitrile (VII) in DMF in the presence of Et3N to yield 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide (VIII). The amino group of (VIII) is replaced by chlorine by using tert-butyl nitrite in acetonitrile in the presence of copper (II) chloride to give compound (IX). Finally, the target compound is obtained by reaction of (IX) with 1-(4-nitro-phenyl)piperazine (X) in dichloromethane or CHCl3 in the presence of Na2CO3 or K2CO3.
| 【1】 Jaso, A.; Montoya, M.E.; Monge, A.; Zarranz, B.; Ortega, M.A.; Tirapu, I.; Aldana, I.; Antimycobacterial activity of new quinoxaline-2-carbonitrile and quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives. Pharmazie 2001, 56, 3, 205. |
| 【2】 Monge, A.; et al.; Hypoxia-selective agents derived from quinoxaline 1, 4-di-N-oxides. J Med Chem 1995, 38, 10, 1786. |
| 【3】 Ortega, M.A.; et al.; New quinoxalinecarbonitrile 1,4-di-N-oxide derivatives as hypoxic-cytotoxic agents. Eur J Med Chem 2000, 35, 1, 21. |
| 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) | 33707 | 3,4-dimethylphenylamine; 3,4-dimethylaniline | 95-64-7 | C8H11N | 详情 | 详情 |
| (II) | 50101 | N-Acetyl-3,4-xylidine; 3,4-Dimethylacetanilide | 2198-54-1 | C10H13NO | 详情 | 详情 |
| (III) | 50102 | 4',5'-Dimethyl-2'-nitroacetanilide | C10H12N2O3 | 详情 | 详情 | |
| (IV) | 50103 | 2-Nitro-4,5-dimethylaniline; 6-Nitro-3,4-xylidine; 4,5-Dimethyl-2-nitroaniline | 6972-71-0 | C8H10N2O2 | 详情 | 详情 |
| (V) | 50104 | 1-azido-4,5-dimethyl-2-nitrobenzene | C8H8N4O2 | 详情 | 详情 | |
| (VI) | 50105 | 5,6-dimethyl-2,1,3-benzoxadiazol-1-ium-1-olate | C8H8N2O2 | 详情 | 详情 | |
| (VII) | 10610 | 2-[(4-Methoxybenzyl)oxy]acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (VIII) | 50106 | 2-amino-3-cyano-6,7-dimethyl-1,4-quinoxalinediiumdiolate | C11H10N4O2 | 详情 | 详情 | |
| (IX) | 50107 | 2-chloro-3-cyano-6,7-dimethyl-1,4-quinoxalinediiumdiolate | C11H8ClN3O2 | 详情 | 详情 | |
| (X) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |