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【结 构 式】 
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【分子编号】25647 【品名】4-(4-hydrazinophenyl)-4H-1,2,4-triazole 【CA登记号】 |
【 分 子 式 】C8H9N5 【 分 子 量 】175.19316 【元素组成】C 54.85% H 5.18% N 39.98% |
合成路线1
该中间体在本合成路线中的序号：(IV)Alkylation of N-Boc-piperazine (I) with bromoacetal (II) provided piperazine acetal (III). This was submitted to Fisher cyclization with 4-(1,2,4-triazol-4-yl)phenyl hydrazine (IV) in aqueous H2SO4 to afford the deprotected indole (V). Wittig reaction of 3-fluorobenzaldehyde (VII) with phosphorane prepared from (methoxymethyl)phosphonium salt (VI) and PhLi furnished the methoxyvinyl compound (VIII) as an E:Z mixture. Subsequent acid hydrolysis of the enol ether function of (VIII) yielded aldehyde (IX). The target compound was then obtained by reductive alkylation of piperazine (V) with aldehyde (IX) in the presence of NaBH3CN.
| 【1】 Chambers, M.S.; Goodacre, S.; Street, L.J.; et al.; 3-(Piperazinylpropyl)indoles: Selective, orally bioavailable h5-HT1D receptor agonists as potential antimigraine agents. J Med Chem 1999, 42, 4, 691. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 25650 | 1-fluoro-3-[(E)-2-methoxyethenyl]benzene; (E)-2-(3-fluorophenyl)ethenyl methyl ether | C9H9FO | 详情 | 详情 | |
| (VIIIb) | 53875 | (Z)-2-(3-fluorophenyl)ethenyl methyl ether; 1-fluoro-3-[(Z)-2-methoxyethenyl]benzene | n/a | C9H9FO | 详情 | 详情 |
| (I) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (II) | 25645 | 5-bromo-1-methoxypentyl methyl ether; 5-bromo-1,1-dimethoxypentane | C7H15BrO2 | 详情 | 详情 | |
| (III) | 25646 | tert-butyl 4-(5,5-dimethoxypentyl)-1-piperazinecarboxylate | C16H32N2O4 | 详情 | 详情 | |
| (IV) | 25647 | 4-(4-hydrazinophenyl)-4H-1,2,4-triazole | C8H9N5 | 详情 | 详情 | |
| (V) | 25648 | 3-[3-(1-piperazinyl)propyl]-5-(4H-1,2,4-triazol-4-yl)-1H-indole | C17H22N6 | 详情 | 详情 | |
| (VI) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (VII) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (IX) | 25651 | 3-(3-fluorophenyl)propanal | C9H9FO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Catalytic hydrogenation of 4-nitroacetanilide (I) afforded aniline (II), which was condensed with N,N-dimethylformamide azine to produce the triazolyl derivative (III). Acid hydrolysis of the acetamido group gave rise to amine (IV). Then, diazotization, followed by stannous chloride reduction of the diazonium salt, furnished the intermediate hydrazine (V).
| 【1】 Matassa, V.G.; Pengilley, R.R.; Russell, M.G.N.; et al.; 3-[3-(Piperidin-1-yl)propyl]indoles as highly selective h5-HT1D receptor agonists. J Med Chem 1999, 42, 24, 4981. |
| 【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 . |
| 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) | 36535 | N-(4-nitrophenyl)acetamide | 104-04-1 | C8H8N2O3 | 详情 | 详情 |
| (II) | 29016 | N-(4-aminophenyl)acetamide | 122-80-5 | C8H10N2O | 详情 | 详情 |
| (III) | 36536 | N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide | 154594-15-7 | C10H10N4O | 详情 | 详情 |
| (IV) | 36537 | 4-(4H-1,2,4-triazol-4-yl)phenylamine; 4-(4H-1,2,4-triazol-4-yl)aniline | C8H8N4 | 详情 | 详情 | |
| (V) | 25647 | 4-(4-hydrazinophenyl)-4H-1,2,4-triazole | C8H9N5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)5-Bromovaleryl chloride (VI) was reduced to aldehyde (VII) by means of lithium tri-tert-butoxyaluminumhydride at -78 C and subsequently converted into the dimethyl acetal (VIII) with H2SO4 in methanol (1). Alkylation of 4-hydroxypiperidine (IX) with bromoacetal (VIII) gave adduct (X). This was subjected to Fisher indolization with the hydrazine (V), yielding indole (XI). The piperidine hydroxyl group was then oxidized to the corresponding ketone (XII) using sulfur trioxide-pyridine complex in DMSO.
| 【1】 Matassa, V.G.; Pengilley, R.R.; Russell, M.G.N.; et al.; 3-[3-(Piperidin-1-yl)propyl]indoles as highly selective h5-HT1D receptor agonists. J Med Chem 1999, 42, 24, 4981. |
| 【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 25647 | 4-(4-hydrazinophenyl)-4H-1,2,4-triazole | C8H9N5 | 详情 | 详情 | |
| (VI) | 39700 | 5-bromopentanoyl chloride | 4509-90-4 | C5H8BrClO | 详情 | 详情 |
| (VII) | 43094 | 5-bromopentanal | C5H9BrO | 详情 | 详情 | |
| (VIII) | 25645 | 5-bromo-1-methoxypentyl methyl ether; 5-bromo-1,1-dimethoxypentane | C7H15BrO2 | 详情 | 详情 | |
| (IX) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (X) | 43095 | 1-(5,5-dimethoxypentyl)-4-piperidinol | C12H25NO3 | 详情 | 详情 | |
| (XI) | 43096 | 1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinol | C18H23N5O | 详情 | 详情 | |
| (XII) | 43097 | 1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinone | C18H21N5O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Hydrogenation of p-nitroacetanilide (I) over Pd/C afforded p-aminoacetanilide (II), which was converted to triazolylacetanilide (III) upon treatment with N,N-dimethylformamide azine and p-toluenesulfonic acid. Acid hydrolysis of the acetamide (III) provided triazolylaniline (IV). Subsequent diazotization of (IV), followed by SnCl2 reduction of the diazonium salt furnished hydrazine (V). Fischer indole synthesis employing (V) and dihydropyran (VI) gave rise to the indolylpropanol (VII), which was converted to the intermediate mesylate (VIII) using CH3SO2Cl and Et3N.
| 【1】 Stanton, J.A.; Showell, G.A.; Neduvelil, J.G.; Bourrain, S.; Beer, M.S.; MacLeod, A.M.; 4-Hydroxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidines: Selective h5-HT1D agonists for the treatment of migraine. Bioorg Med Chem Lett 1999, 9, 23, 3369. |
| 【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40722 | N'-[(E)-(dimethylamino)methylidene]-N,N-dimethylhydrazonoformamide | C6H14N4 | 详情 | 详情 | ||
| (I) | 36535 | N-(4-nitrophenyl)acetamide | 104-04-1 | C8H8N2O3 | 详情 | 详情 |
| (II) | 29016 | N-(4-aminophenyl)acetamide | 122-80-5 | C8H10N2O | 详情 | 详情 |
| (III) | 36536 | N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide | 154594-15-7 | C10H10N4O | 详情 | 详情 |
| (IV) | 36537 | 4-(4H-1,2,4-triazol-4-yl)phenylamine; 4-(4H-1,2,4-triazol-4-yl)aniline | C8H8N4 | 详情 | 详情 | |
| (V) | 25647 | 4-(4-hydrazinophenyl)-4H-1,2,4-triazole | C8H9N5 | 详情 | 详情 | |
| (VI) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (VII) | 36538 | 3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]-1-propanol | C13H14N4O | 详情 | 详情 | |
| (VIII) | 36539 | 3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl methanesulfonate | C14H16N4O3S | 详情 | 详情 |