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【结 构 式】 
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【分子编号】10756 【品名】N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine 【CA登记号】92-54-6 |
【 分 子 式 】C10H14N2 【 分 子 量 】162.23464 【元素组成】C 74.03% H 8.7% N 17.27% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of phenylpiperazine (I) with epichlorhydrin (II) leads to 1-chloro-3-(1-phenyl-4-piperazinyl)-2-propanol. This intermediate is dehydrohalogenated to 1-(1-phenyl-4-piperazinyl)-2,3-epoxypropane (III) using sodium hydroxide. The epoxide is converted without further purification into the corresponding 4,5-dihydro-5-[(4-phenyl-1-piperazinyl)methyl]-2-oxazolamine (COR3224) by condensation with monosodium cyanamide salt in methanol, which permits the solubilization of all compounds. The amidine group of the oxazoline ring induces a tautomeric amino-imino equilibrium. For COR3224 it has been shown by X-ray crystallography that the amino form is preponderant in the free base, whereas the imino form predominates in salts.
| 【1】 Creuzet, M.-H.; Feniou, C.; Jarry, C.; Prat, G.; Pontagnier, H. (Societé Cortial SA); Novel 2-amino-5-aminomethyl-2-oxazolines. EP 0106776; FR 2546167 . |
| 【2】 D'Arnoux, C.; Panconi, E.; Descas, P.; Vaugien, B.; Lambrey, B.; Mosser, J.; Jarry, C.; Gomond, P.; Saudubray, F.; Roux, J.; COR3224. Drugs Fut 1991, 16, 10, 893. |
| 【3】 Ouhabi, J.; Jarry, C.; Bosc, J.J.; Carpy, A.; Crystal and molecular structure of 5-(1-aryl-4-piperazino)-methyl-2-amino-2-oxazolines with antidepressant activity. Arch Pharm 1990, 323, 157-61. |
| 【4】 Bosc, J.J.; Descas, P.; Carpy, A.; Panconi, E.; Jarry, C.; Synthesis and antidepressant activity of 5-(1-aryl-4-piperazino)methyl-2-amino-2-oxazolines. Eur J Med Chem 1992, 27, 5, 437. |
合成路线2
该中间体在本合成路线中的序号：(VII)This compound can be prepared by two related ways: 1) The diazotation of L-serine methyl ester (I) with NaNO2 - HCl gives methyl (S)-glycerate (II), which by reaction with 2,2-dimethoxypropane and p-toluenesulfonic acid (or acetone and ZnCl2) is converted to methyl (S)-O-isopropylideneglycerate (III). The reduction of (III) with LiAlH4 in refluxing ether affords (S)-2,3-O-isopropylideneglycerol (IV), which by reaction with tosyl chloride in pyridine is converted to the corresponding tosylate (V). The partial hydrolysis of (V) with HCl in acetone affords (S)-glycerol-1-tosylate (VI), which is finally condensed with 1-phenylpiperazine (VII) in refluxing benzene. 2) The partial hydrolysis of (S)-2,3-epoxypropyl tosylate (VIII) with HCl as before gives the glycerol tosylate (VI), already obtained.
| 【1】 Borsa, M.; Tonon, G.; Malandrino, S. (Dompé Farm. SpA); Optically active compounds with antitussive and central sedative activity, a process for the preparation thereof and compositions containing the same. EP 0147847; US 4699911; US 4764515 . |
| 【2】 Giani, R.; Marione, E.; Melillo, G.; Borsa, M.; Tonon, G.C.; Synthesis and pharmacological screening of new phenylpiperazinepropane derivatives and their enantiomers. Arzneim-Forsch Drug Res 1988, 38, 8, 1139-41. |
| 【3】 Prous, J.; Castaner, J.; LEVDROPROPIZINE < Rec INN >. Drugs Fut 1989, 14, 6, 522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 | |
| (I) | 20915 | methyl (2S)-2-amino-3-hydroxypropanoate | 5680-80-8 | C4H9NO3 | 详情 | 详情 |
| (II) | 20916 | methyl (2R)-2,3-dihydroxypropanoate | C4H8O4 | 详情 | 详情 | |
| (III) | 20917 | methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate | 52373-72-5 | C7H12O4 | 详情 | 详情 |
| (IV) | 12709 | [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 22323-82-6 | C6H12O3 | 详情 | 详情 |
| (V) | 20919 | [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | 23788-74-1 | C13H18O5S | 详情 | 详情 |
| (VI) | 20920 | (2R)-2,3-dihydroxypropyl 4-methylbenzenesulfonate | C10H14O5S | 详情 | 详情 | |
| (VII) | 10756 | N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine | 92-54-6 | C10H14N2 | 详情 | 详情 |
| (VIII) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 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 reaction of 1-phenylpiperazine (I) with DMF and POCl3 in dichloroethane gives 4-(4-formylpiperazin-1-yl)benzaldehyde (II), which is condensed with indolin-2-one (III) by means of piperidine in refluxing ethanol.
| 【1】 Sun, L.; et al.; Synthesis and biological evaluations of 3-substituted indolin-2-ones: A novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases. J Med Chem 1998, 41, 14, 2588. |
| 【2】 Tang, P.C.; Sun, L.; McMahon, G. (Sugen, Inc.); Indolinone cpds. for the treatment of disease. EP 0769947; JP 2000026412; US 5780496; US 5792783; US 5880141; US 5883113; US 5883116; WO 9640116 . |
合成路线4
该中间体在本合成路线中的序号：(IV)7-Hydroxy-3-methylcoumarin (III) was obtained by Perkin reaction of 2,4-dihydroxybenzaldehyde (I) and propionic anhydride (II) in the presence of sodium propionate in pyridine. Alkylation of N-phenylpiperazine (IV) with 1-bromo-3-chloropropane (V) and NaOH in acetone provided the chloropropyl compond (VI), which was finally condensed with coumarin (III) using NaH in DMF.
| 【1】 Antonello, C.; et al.; Synthesis and characterization of new methylpsoralens as potential photochemotherapeutic agents. Farmaco 1994, 49, 4, 277. |
| 【2】 Teran, C.; Santana, L.; Uriarte, E.; Fall, Y.; Unelius, L.; Tolf, B.R.; Phenylpiperazine derivatives with strong affinity for 5HT1A, D2A and D3 receptors. Bioorg Med Chem Lett 1998, 8, 24, 3567. |
| 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) | 20094 | 2,4-dihydroxybenzaldehyde | 95-01-2 | C7H6O3 | 详情 | 详情 |
| (II) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (III) | 20096 | 7-hydroxy-3-methyl-2H-chromen-2-one | C10H8O3 | 详情 | 详情 | |
| (IV) | 10756 | N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine | 92-54-6 | C10H14N2 | 详情 | 详情 |
| (V) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (VI) | 20099 | 1-(3-chloropropyl)-4-phenylpiperazine | C13H19ClN2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Condensation between 3,5-dibromotyrosine methyl ester (I) and 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine (II) in the presence of carbonyl ditriazole (CDT) furnished the asymmetric urea (III). Subsequent hydrolysis of the ester group using LiOH provided carboxylic acid (IV). This was finally coupled with N-phenylpiperazine (V) employing O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate and 1-hydroxybenzotriazole to yield the corresponding amide.
| 【1】 Eberlein, W.; Wienen, W.; Doods, H.; Rudolf, K.; Entzeroth, M.; Pieper, H.; Engel, W.; Hallermayer, G. (Dr. Karl Thomae GmbH); Modified aminoacids, pharmaceuticals containing these cpds. and methods for their production. JP 2000505100; WO 9811128 . |
| 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) | 44314 | methyl 2-amino-3-(3,5-dibromo-4-hydroxyphenyl)propanoate | C10H11Br2NO3 | 详情 | 详情 | |
| (II) | 12138 | 1-(4-Piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one; 4-(2-Keto-1-benzimidazolinyl)piperidine | 20662-53-7 | C12H15N3O | 详情 | 详情 |
| (III) | 44315 | methyl 3-(3,5-dibromo-4-hydroxyphenyl)-2-([[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]amino)propanoate | C23H24Br2N4O5 | 详情 | 详情 | |
| (IV) | 44316 | 3,5-dibromo-4-hydroxy-N-[[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]phenylalanine | C22H22Br2N4O5 | 详情 | 详情 | |
| (V) | 10756 | N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine | 92-54-6 | C10H14N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VIII)Protection of alcohol (I) by means of TBDMSCl in DMF in the presence of imidazole yields compound (II), which is then heated with triethyl orthoformate to afford N-diethoxymethyl-substituted indole (III). Removal of the O-protecting group of (III) by means of tetrabutylammonium fluoride (Bu4NF) in THF provides 2-hydroxy-methylindole derivative (IV), which is converted into the chloro derivative (V) by treatment with CCl4/PPh3 in DMF. (Diethyloxymethyl)-protected indole (V) is then loaded onto 1,2-diol functionalized Merrifield resin (VI) by means of p-TsOH in dioxane to furnish polymer-bound derivative (VII), which is converted into the desired product by first reaction with 1-phenylpiperazine (VIII) in DMF followed by final resin cleavage with HCl/dioxane. Alternatively, the desired compound can be obtained by first conversion of alcohol (I) into chloro derivative (IX) by means of CCl4/PPh3 in DMF, followed by reaction with phenylpiperazine (VIII) in DMF.
| 【1】 Hubner, H.; Kraxner, J.; Gmeiner, P.; Cyanoindole derivatives as highly selective dopamine D4 receptor partial agonists: Solid-phase synthesis, binding assays, and functional experiments. J Med Chem 2000, 43, 23, 4563. |
| 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) | 47025 | 2-(hydroxymethyl)-1H-indole-5-carbonitrile | C10H8N2O | 详情 | 详情 | |
| (II) | 47026 | 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1H-indole-5-carbonitrile | C16H22N2OSi | 详情 | 详情 | |
| (III) | 47027 | 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-(diethoxymethyl)-1H-indole-5-carbonitrile | C21H32N2O3Si | 详情 | 详情 | |
| (IV) | 47028 | 1-(diethoxymethyl)-2-(hydroxymethyl)-1H-indole-5-carbonitrile | C15H18N2O3 | 详情 | 详情 | |
| (V) | 47029 | 2-(chloromethyl)-1-(diethoxymethyl)-1H-indole-5-carbonitrile | C15H17ClN2O2 | 详情 | 详情 | |
| (VI) | 47032 | 3-methoxy-1,2-propanediol | C4H10O3 | 详情 | 详情 | |
| (VII) | 47030 | 2-(chloromethyl)-1-[4-(methoxymethyl)-1,3-dioxolan-2-yl]-1H-indole-5-carbonitrile | C15H15ClN2O3 | 详情 | 详情 | |
| (VIII) | 10756 | N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine | 92-54-6 | C10H14N2 | 详情 | 详情 |
| (IX) | 47031 | 2-(chloromethyl)-1H-indole-5-carbonitrile | C10H7ClN2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)Cyclization of (R)-serine methyl ester (I) with methyl benzimidate (II) gave oxazolidine (III). Reduction of the methyl ester function of (III) with LiAlH4 at low temperature afforded the hydroxymethyl derivative (IV), which was further activated as the mesylate (V). Displacement of the mesylate group of (V) with phenylpiperazine (VI) resulted in the formation of the disubstituted piperazine (VII). Nucleophilic ring opening of oxazolidine (VII) by azidotrimethylsilane yielded azide (VIII). Both the amide and azide functions of (VIII) were subsequently reduced with LiAlH4 to produce (IX). Hydrogenolysis of the benzyl amine (IX) over Pearlman's catalyst furnished the chiral ethylenediamine (X). The title imidazoline was finally obtained by cyclization of diamine (X) with methyl benzimidate (II) as its hydrochloride form in refluxing MeOH.
| 【1】 Einsiedel, J.; et al.; Benzamide bioisosteres incorporating dihydroheteroazole substructures: EPC synthesis and SAR leading to a selective dopamine D4 receptor partial agonist (FAUC 179). Bioorg Med Chem Lett 2001, 11, 18, 2533. |
| 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) | 21813 | methyl (2R)-2-amino-3-hydroxypropanoate | C4H9NO3 | 详情 | 详情 | |
| (II) | 52039 | methyl benzenecarboximidoate | C8H9NO | 详情 | 详情 | |
| (III) | 52040 | methyl (4R)-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C11H11NO3 | 详情 | 详情 | |
| (IV) | 52041 | [(4S)-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]methanol | C10H11NO2 | 详情 | 详情 | |
| (V) | 52042 | [(4R)-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]methyl methanesulfonate | C11H13NO4S | 详情 | 详情 | |
| (VI) | 10756 | N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine | 92-54-6 | C10H14N2 | 详情 | 详情 |
| (VII) | 52043 | 1-phenyl-4-[[(4S)-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]methyl]piperazine | C20H23N3O | 详情 | 详情 | |
| (VIII) | 52044 | N-[(1S)-2-azido-1-[(4-phenyl-1-piperazinyl)methyl]ethyl]benzamide | C20H24N6O | 详情 | 详情 | |
| (IX) | 52045 | N-[(1R)-2-amino-1-[(4-phenyl-1-piperazinyl)methyl]ethyl]-N-benzylamine; (2R)-N(2)-benzyl-3-(4-phenyl-1-piperazinyl)-1,2-propanediamine | C20H28N4 | 详情 | 详情 | |
| (X) | 52046 | (2R)-3-(4-phenyl-1-piperazinyl)-1,2-propanediamine; (1R)-2-amino-1-[(4-phenyl-1-piperazinyl)methyl]ethylamine | C13H22N4 | 详情 | 详情 |