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【结 构 式】 
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【分子编号】33593 【品名】1-(4-chlorophenyl)piperazine 【CA登记号】38869-46-4 |
【 分 子 式 】C10H13ClN2 【 分 子 量 】196.6794 【元素组成】C 61.07% H 6.66% Cl 18.03% N 14.24% |
合成路线1
该中间体在本合成路线中的序号：(C)Compound can be prepared in several different ways, all starting from 3,4-diethyl-DELTA2-1,2,4-triazolin-5-one (I): 1) The condensation of (I) with N-(3-bromopropyl)-N'-(m-chlorophenyl)piperazine (B) by means of NaNH2, NaH or sodium alcoholate in an organic solvent (DMSO, DMF, dioxane, benzene, alcohol, tetralin, etc.). 2) The condensation of (I) with 1-chloro-3-bromopropane (A) by means of sodium alcoholate in alcohol gives 1-(3-chloropropyl)-3,4-diethyl-DELTA2-1,2,4-triazolin-5-one (II), which is then condensed with an inert solvent by means of HCl acceptor. 3) The condensation of (II) with diethanolamine (C) affords 1-(3-bishydroxyethylaminopropyl)-3,4-diethyl-DELTA2-1,2,4-triazolin-5-one (III), which is then converted into the corresponding dichlorocompound (IV) by means of SOCl2. Finally, (IV) is cyclized with m-chloroaniline (E).
| 【1】 Palazzo, G.; 1-[3-(4-Metrachlorophenyl-1-piperazinyl)propyl]-3,4-diethyl-delta2-1,2,4-triazolin-5-one. DE 2351739; FR 2202702; GB 1438337; US 3857845 . |
| 【2】 de Angelis, L.; Castaner, J.; Etoperidone. Drugs Fut 1977, 2, 3, 164. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (E) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (D) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (B) | 33592 | 1-(3-bromopropyl)-4-(4-chlorophenyl)piperazine | C13H18BrClN2 | 详情 | 详情 | |
| (I) | 33588 | 4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one | 52883-26-8 | C6H11N3O | 详情 | 详情 |
| (II) | 33589 | 2-(3-chloropropyl)-4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one | C9H16ClN3O | 详情 | 详情 | |
| (III) | 33591 | 2-[3-[bis(2-hydroxyethyl)amino]propyl]-4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one | C13H26N4O3 | 详情 | 详情 | |
| (IV) | 33590 | 2-[3-[bis(2-chloroethyl)amino]propyl]-4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one | C13H24Cl2N4O | 详情 | 详情 | |
| (C) | 33593 | 1-(4-chlorophenyl)piperazine | 38869-46-4 | C10H13ClN2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reduction of 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde (I) with NaBH4 in methanol gives the corresponding carbinol (II), which is acylated with TsCl in pyridine yielding the tosylate (III). Finally, this compound is condensed with 1-(4-chlorophenyl)piperazine (IV) by means of K2CO3 in refluxing acetonitrile.
| 【1】 Brink, W.A.; Wustrow, D.J.; Belliotti, T.R.; et al.; A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: Discovery of a potential atypical antipsychotic agent. J Med Chem 1999, 42, 25, 5181. |
| 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) | 21039 | 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde | C9H7NO3 | 详情 | 详情 | |
| (II) | 36522 | 7-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one | C9H9NO3 | 详情 | 详情 | |
| (III) | 36523 | (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl 4-methylbenzenesulfonate | C16H15NO5S | 详情 | 详情 | |
| (IV) | 33593 | 1-(4-chlorophenyl)piperazine | 38869-46-4 | C10H13ClN2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The condensation of 1-(4-chlorophenyl)piperazine (I) with 2-chloroacetonitrile (II) gives 2-[4-(4-chlorophenyl)-1-piperazinyl]acetonitrile (III), which is reduced with borane/dimethylsulfide yielding the corresponding primary amine (IV). Finally, (IV) is condensed with 3-methoxybenzoyl chloride.
| 【1】 Berardi, F.; Perrone, R.; Tortorella, V.; Leopoldo, M.; Colabufo, N.A.; A structure-affinity relationship study on derivatives of N-[2-[4-(chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a high-affinity and selective D4 receptor ligand. J Med Chem 2000, 43, 2, 270. |
| 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) | 33593 | 1-(4-chlorophenyl)piperazine | 38869-46-4 | C10H13ClN2 | 详情 | 详情 |
| (II) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (III) | 36530 | 2-[4-(4-chlorophenyl)-1-piperazinyl]acetonitrile | C12H14ClN3 | 详情 | 详情 | |
| (IV) | 28561 | 2-[4-(4-chlorophenyl)-1-piperazinyl]-1-ethanamine | C12H18ClN3 | 详情 | 详情 | |
| (V) | 16760 | 3-methoxybenzoyl chloride | 1711-05-3 | C8H7ClO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The 1,3-dipolar cycloaddition of N-aminopyridinium iodide (I) to dimethyl acetylenedicarboxylate (II) afforded the pyrazolopyridine system (III). Ester groups hydrolysis and regioselective decarboxylation of (III) with hot 50% sulfuric acid gave the mono-carboxylic acid (IV), which was further esterified with ethanol and sulfuric acid. Finally, reductive amination of the ethyl ester (V) with (p-chlorophenyl)piperazine (VI) in the presence of LiAlH4 provided the target compound.
| 【1】 Lober, S.; et al.; Rationally based efficacy tuning of selective dopamine D4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl) piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213). J Med Chem 2001, 44, 17, 2691. |
| 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) | 32760 | 1-aminopyridinium iodide | C5H7IN2 | 详情 | 详情 | |
| (II) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (III) | 51036 | dimethyl pyrazolo[1,5-a]pyridine-2,3-dicarboxylate | C11H10N2O4 | 详情 | 详情 | |
| (IV) | 51037 | pyrazolo[1,5-a]pyridine-2-carboxylic acid | C8H6N2O2 | 详情 | 详情 | |
| (V) | 51038 | ethyl pyrazolo[1,5-a]pyridine-2-carboxylate | C10H10N2O2 | 详情 | 详情 | |
| (VI) | 33593 | 1-(4-chlorophenyl)piperazine | 38869-46-4 | C10H13ClN2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Lithiation of 8-azaindole (I) with n-BuLi, followed by treatment with 1,2-diiodoethane (II) affords 7-iodopyrazolopyridine (III), which is then treated with CuCN, Pd2(dba)3 and diphenylphosphinoferrocene (dppf) in refluxing dioxane to provide pyrazolo[1,5-a]pyridine-7-carbonitrile (IV). Finally, Mannich condensation of (IV) with N-(4-chlorophenyl)piperazine (V) and formaldehyde gives rise to the title piperazinomethyl derivative.
| 【1】 Aboul-Fadl, T.; Lober, S.; Gmeiner, P.; Effective and variable functionalization of pyrazolo[1,5-a]pyridines involving palladium-catalyzed coupling reactions. Synthesis 2000, 12, Suppl. 3, 1727-1732. |
| 【2】 Aboul-Fadl, T.; Gmeiner, P.; Lober, S.; Hubner, H.; Di- and trisubstituted pyrazolo[1,5-a]pyridine derivatives: Synthesis, dopamine receptor binding and ligand efficacy. Bioorg Med Chem Lett 2002, 12, 4, 633. |
| 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) | 59298 | pyrazolo[1,5-a]pyridine | C7H6N2 | 详情 | 详情 | |
| (II) | 59299 | 1,2-Diiodoethane; Ethylene Diiodide; Ethylene iodide | 624-73-7 | C2H4I2 | 详情 | 详情 |
| (III) | 59300 | 7-iodopyrazolo[1,5-a]pyridine | C7H5IN2 | 详情 | 详情 | |
| (IV) | 59301 | pyrazolo[1,5-a]pyridine-7-carbonitrile | C8H5N3 | 详情 | 详情 | |
| (V) | 33593 | 1-(4-chlorophenyl)piperazine | 38869-46-4 | C10H13ClN2 | 详情 | 详情 |