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【结 构 式】 
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【分子编号】43097 【品名】1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinone 【CA登记号】 |
【 分 子 式 】C18H21N5O 【 分 子 量 】323.39784 【元素组成】C 66.85% H 6.55% N 21.66% O 4.95% |
合成路线1
该中间体在本合成路线中的序号：(XII)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2
该中间体在本合成路线中的序号：(XII)The chiral amino alcohol (XIV) was obtained by reduction of (R)-(4-fluorophenyl)glycine (XIII) with LiAlH4. Finally, reductive condensation of amino alcohol (XIII) with piperidinone (XII) provided the title compound.
| 【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 . |