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【结 构 式】 
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【药物名称】Lu-AA-21004 【化学名称】1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine hydrobromide 【CA登记号】960203-27-4；508233-74-7 (free base) 【 分 子 式 】C18H22N2S.HBr 【 分 子 量 】379.358 |
【开发单位】H. Lundbeck A/S (DK); licensed to Takeda Pharmaceutical Co., Ltd. for codevelopment and comarketing in the U.S. and Japan 【药理作用】5-HT3/7 Receptor Antagonist;5-HT1A Receptor Agonist;5-HT1B Receptor Partial Agonist;5-HT Transporter Inhibitor;Treatment of Depression;Treatment of Anxiety |
合成路线1
Condensation of 2-bromoiodobenzene (I) with 2,4-dimethylthiophenol (II) by means of either Pd2(dba)3 or Pd(dba)2, t-BuOK and DPEphos or Pd(dba)2, BINAP and t-BuONa in toluene yields 1-(2-bromophenylsulfanyl)-2,4-dimethylbenzene (III) , which alternatively can be prepared by reaction of either 1-iodo- or 1-bromo-2,4-dimethylbenzene (IVa or IVb) with 2-bromobenzenethiol (V) in the presence of Pd2(dba)3 and DPEphos . Then, aryl bromide (III) is condensed with piperazine (VI) in the presence of Pd(dba)2, BINAP and t-BuONa in toluene to give the free base (VII) , which is finally treated with HBr in MeOH , EtOAc or toluene .
The free base (VII) can be alternatively prepared in a one-pot procedure by reaction of 2-bromoiodobenzene (I) with 2,4-dimethylthiophenol (II) and piperazine (VI) in the presence of Pd(dba)2, BINAP and t-BuONa .
Reaction of 2-bromoiodobenzene (I) with N-Boc-piperazine (VIII) by means of Pd2(dba)3 and xantphos affords the arylpiperazine (IX) , which is then condensed with 2,4-dimethylthiophenol (II) in the presence of Pd2(dba)3, t-BuOK and DPEphos in toluene at 100 °C to give the thioether (X) . Finally, compound (X) is submitted to N-deprotection with HBr in refluxing H2O .
Alternatively, reaction of thioether (III) with N-Boc-piperazine (VIII) in the presence of Pd(dba)2 or Pd2(dba)3, BINAP , and optionally, t-BuONa in toluene , provides the N-Boc-protected arylpiperazine (X), which is then N-deprotected with HCl in refluxing MeOH to give the free base (VII) .
In a solid-phase method, binding of piperazine (VI) to the p-nitrophenyl carbonate resin (XI) in the presence of NMM in DMF results in the 4-[(1-piperazinyl)carboxymethyl]phenoxymethyl polystyrene (XII), which is then condensed with [η6-1,2-dichloro-benzene][η5-cyclopentadienyl] iron hexafluorophosphate (XIII) in the presence of K2CO3 in THF to afford the N,N’-disubstituted piperazine (XIV). Finally, the resin-bound piperazine (XIV) is condensed with 2,4-dimethylthiophenol (II) (previously treated with NaH), and subsequently subjected to photolytic decomplexation, and further acidic cleavage from the resin (TFA/CH2Cl2), leading to the free base (VII) .
| 【1】 Bang-Andersen, B., Faldt, A., Moerk, A. et al. (H. Lundbeck A/S). 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment. EP 2044043, JP 2009541216, JP 2010090165, US 2010297240, WO 2007144005. |
| 【2】 Bang-Andersen, B., Ruhland, T., Smith, G. et al. Discovery of Lu AA21004: A novel compound for the treatment of mood disorders. 237th ACS Natl Meet (March 22-2, Salt Lake City) 2009, Abst MEDI 103. |
| 【3】 Moore, N., Stensboel, T.B. (H. Lundbeck A/S). 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of pain or residual symptoms in depression relating to sleep and cognition. CA 2684571, EP 2142193, JP 201052501, US 2011009422, WO 2008113359. |
| 【4】 Nicolajsen, H.V., Lopez de Diego, H., Rock, M.H. (H. Lundbeck A/S). Purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine. WO 2010094285. |
| 【5】 Bang-Andersen, B., Ruhland, T., Jorgensen, M. et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (LU AA21004): A novel multimodal compound for the treatment of major depressive disorder. J Med Chem 2011 54(9): 3206-21. |
| 【6】 Smith, G.P., Pueschl, A., Moltzen, E.K., Ruhland, T., Bang-Andersen, B., Andersen, K. (H. Lundbeck A/S). Phenyl-piperazine derivatives as serotonin reuptake inhibitors. EP 1436271, EP 1749818, JP 2005505585, JP 2007031447, JP 2007051149, US 2006084662, US 2006089368, US 7138407, US 7144884, US 7148238, US 2007060574, US 7683053, US 2011009423, WO 2003029232. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 68826 | 1-iodo-2,4-dimethylbenzene;2,4-Dimethyliodobenzene;1,3-Dimethyl-4-iodobenzene;4-Iodo-m-xylene | 4214-28-2 | C8H9I | 详情 | 详情 |
| (IVb) | 68827 | 1-bromo-2,4-dimethylbenzene;2,4-Dimethylbromobenzene;4-Bromo-1,3-dimethylbenzene;4-Bromo-m-xylene | 583-70-0 | C8H9Br | 详情 | 详情 |
| (I) | 68823 | 2-bromoiodobenzene;o-Iodobromobenzene;o-Bromophenyl iodide;o-Bromoiodobenzene;2-Iodobromobenzene;2-Bromophenyliodide;2-Bromo-1-iodobenzene;1-Iodo-2-bromobenzene;1-Bromo-2-iodobenzene | 583-55-1 | C6H4BrI | 详情 | 详情 |
| (II) | 68824 | 2,4-dimethylthiophenol;2,4-Dimethylbenzenethiol | 13616-82-5 | C8H10S | 详情 | 详情 |
| (III) | 68825 | 1-(2-bromophenylsulfanyl)-2,4-dimethylbenzene;(2-bromophenyl)(2,4-dimethylphenyl)sulfane | C14H13BrS | 详情 | 详情 | |
| (V) | 52030 | 2-Bromobenzenethiol; 2-Bromothiophenol;2-bromo-benzenethio;2-Bromo thiophenol | 6320-02-1 | C6H5BrS | 详情 | 详情 |
| (VI) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VII) | 68828 | 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine | C18H22N2S | 详情 | 详情 | |
| (VIII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (IX) | 68829 | tert-butyl 4-(2-bromophenyl)piperazine-1-carboxylate;1-BOC-4-(2-Bromophenyl)piperazine;4-(2-BROMO-PHENYL)-PIPERAZINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER | 494773-35-2 | C15H21BrN2O2 | 详情 | 详情 |
| (X) | 68830 | tert-butyl 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylate | C23H30N2O2S | 详情 | 详情 | |
| (XII) | 68831 | 4-[(1-piperazinyl)carboxymethyl]phenoxymethyl polystyrene | 详情 | 详情 | ||
| (XIII) | 68832 | [η6-1,2-dichloro-benzene][η5-cyclopentadienyl]iron hexafluorophosphate | 详情 | 详情 |