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【结 构 式】 
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【分子编号】16172 【品名】1-[3-(trifluoromethyl)phenyl]piperazine; N-[3-(trifluoromethyl)phenyl]piperazine 【CA登记号】15532-75-9 |
【 分 子 式 】C11H13F3N2 【 分 子 量 】230.2329096 【元素组成】C 57.39% H 5.69% F 24.76% N 12.17% |
合成路线1
该中间体在本合成路线中的序号：(IV)Flibanserin may be prepared by reacting 1-(phenylvinyl)-2,3-dihydro-1H-benzimidazol-2-one (I) with 1,2-dichloroethane (II) in the presence of NaH in warm dimethylformamide. The resulting 1-(2-chloroethyl)-2,3-dihydro-1H-benzimidazol-one (III) is in turn coupled with commercially available m-trifluoromethylphenylpiperazine hydrochloride (IV) in the presence of sodium carbonate and catalytic potassium iodide in refluxing ethanol. The crude flibanserin hydrochloride (V) is then dissolved in aqueous ethanol and the pure base is precipitated upon addition of sodium hydroxide.
| 【1】 Cesana, R.; Borsini, F.; Ladinsky, H.; Ceci, A.; Giraldo, E.; Turconi, M.; Brambilla, A.; Monferini, E.; Flibanserin. Drugs Fut 1998, 23, 1, 9. |
| 【2】 Turconi, M.; Bietti, G.; Giraldo, E.; Borsini, F.; Bignotti, M. (Boehringer Ingelheim GmbH); Benzimidazolone derivatives as 5-HT1A agonists and 5-HT2 antagonists. EP 0526434; JP 1994509575; US 5576318; WO 9303016 . |
| 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) | 16169 | 1-(1-phenylvinyl)-1,3-dihydro-2H-benzimidazol-2-one | C15H12N2O | 详情 | 详情 | |
| (II) | 16170 | 1,2-dichloroethane | 107-06-2 | C2H4Cl2 | 详情 | 详情 |
| (III) | 16171 | 1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one | C9H9ClN2O | 详情 | 详情 | |
| (IV) | 16172 | 1-[3-(trifluoromethyl)phenyl]piperazine; N-[3-(trifluoromethyl)phenyl]piperazine | 15532-75-9 | C11H13F3N2 | 详情 | 详情 |
| (V) | 16173 | 1-(2-[4-[3-(trifluoromethyl)phenyl]piperazino]ethyl)-1,3-dihydro-2H-benzimidazol-2-one | C20H21F3N4O | 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 reaction of benzophenone (I) with succinodinitrile (II) by means of potassium tert-butoxide in refluxing tert-butanol, followed by a treatment with refluxing 10% sulfuric acid gives 3-(diphenylmethylene)pyrrolidine-2,5-dione (III), which is then consdensed with 4-[3-(trifluoromethyl)phenyl]piperazine (IV) and formaldehyde in refluxing ethanol.
| 【1】 López-Rodríguez, M.L.; Morcillo, M.J.; Rovat, T.K.; Fernández, E.; Sanz, A.M.; Orensanz, L.; 1-[omega-(4-Arylpiperazin-1-yl)alkyl]-3-diphenylmethylene-2,5-pyrrolidinediones as 5-HT1A receptor ligands: Study of the steric requirements of the terminal amide fragment on 5-HT1A affinity/selectivity. Bioorg Med Chem Lett 1998, 8, 6, 581. |
| 【2】 López-Rodríguez, M.L.; Morcillo, M.J.; Rovat, T.K.; Fernandez, E.; Vicente, B.; Sanz, A.M.; Hernandez, M.; Orensanz, L.; Synthesis and structure-activity relationships of a new model of arylpiperazines. 4. 1-[omega-(4-Arylpiperazin-1-yl)alkyl]-3-(diphenylmethylene)-2,5-pyrrolidinediones and -3-(9H-fluoren-9-ylidene)-2,5-pyrrolidinediones: Study of the steric requirements of. J Med Chem 1999, 42, 1, 36. |
| 【3】 K. Rovat, T.; Oesanz Muno, L.M.; Fernandez Velando, E.; Lopez Rodriguez, M.L.; Rosado Samitier, M.L.; Morcillo Ortega, M.J. (Universidad Complutense de Madrid); New imidapiperazine derivs.. ES 2094690 . |
| 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) | 18732 | benzophenone | 119-61-9 | C13H10O | 详情 | 详情 |
| (II) | 28669 | 3-(dibenzylene)-2,5-pyrrolidinedione | C17H13NO2 | 详情 | 详情 | |
| (III) | 28669 | 3-(dibenzylene)-2,5-pyrrolidinedione | C17H13NO2 | 详情 | 详情 | |
| (IV) | 16172 | 1-[3-(trifluoromethyl)phenyl]piperazine; N-[3-(trifluoromethyl)phenyl]piperazine | 15532-75-9 | C11H13F3N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The title compound is prepared by condensation between 2-chloro-1-(3,4-dihydroxy-5-nitrophenyl)ethanone (I) and 1-(3-trifluoromethylphenyl)piperazine (II) in DMF, followed by conversion to the corresponding dihydrochloride salt.
| 【1】 Learmonth, D.A.; Soares Da Silva, P.M.V.A. (Portela & Ca., SA); Novel substd. nitrocatechols, their use in the treatment of some central and peripheral nervous system disorders and pharmaceutical compsns. containing them. EP 1167342; WO 0198251 . |
合成路线4
该中间体在本合成路线中的序号：(VII)The reaction of dihydroartemisinin (I) with benzoyl chloride in pyridine gives the benzoate (II), which is treated with alyltrimethylsilane (III) and ZnCl2 in dichloroethane to yield the allyl-artemisinin derivative (IV). The ozonolysis of the vinyl group of (IV), followed by reduction with NaBH4, affords the 2-hydroxyethyl derivative (V). The reaction of (V) with Ms-Cl and TEA provides the mesylate (VI), which is finally condensed with 1-[3-(trifluoromethyl)phenyl]piperazine (VII) in refluxing benzene to furnish the target piperazinylethyl derivative.
| 【1】 Hindley, S.; Bray, P.G.; Ward, S.A.; Searle, N.L.; Park, B.K.; Davies, J.; O'Neill, P.M.; Storr, R.C.; Mechanism-based design of parasite-targeted artemisinin derivatives: Synthesis and antimalarial activity of new diamine containing analogues. J Med Chem 2002, 45, 5, 1052. |
| 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) | 54785 | (1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadecan-10-ol | C16H26O5 | 详情 | 详情 | |
| (II) | 54786 | (1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl benzoate | C23H30O6 | 详情 | 详情 | |
| (III) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (IV) | 54787 | (1R,4S,5R,8S,9R,10R,12R,13R)-10-allyl-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadecane | C19H30O4 | 详情 | 详情 | |
| (V) | 54788 | 2-[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]-1-ethanol | C18H30O5 | 详情 | 详情 | |
| (VI) | 54789 | 2-[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]ethyl methanesulfonate | C19H32O7S | 详情 | 详情 | |
| (VII) | 16172 | 1-[3-(trifluoromethyl)phenyl]piperazine; N-[3-(trifluoromethyl)phenyl]piperazine | 15532-75-9 | C11H13F3N2 | 详情 | 详情 |