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【结 构 式】 
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【药物名称】LY-334370 【化学名称】4-Fluoro-N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]benzamide fumarate 【CA登记号】182563-09-3, 182563-08-2 (free base), 199673-74-0 (monoHCl) 【 分 子 式 】C25H26FN3O5 【 分 子 量 】467.50147 |
【开发单位】Lilly (Originator), Synaptic (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, 5-HT1F Agonists |
合成路线1
Condensation of 5-nitroindole (I) with 1-methyl-4-piperidone (II) in the presence of KOH produced tetrahydropyridinyl indole (III). Subsequent catalytic hydrogenation of (III) over Pd/C gave the 5-amino-3-piperidinylindole (VI). In a related procedure, 5-aminoindole (IV) was condensed with piperidone (II), and the resulting tetrahydropyridine (V) was hydrogenated to yield (VI). Aminoindole (VI) was finally condensed with 4-fluorobenzoyl chloride (VII) to produce the corresponding amide, which was isolated as the fumarate salt.
| 【1】 Audia, J.E.; Dressman, B.A.; Droste, J.J.; Fritz, J.E.; Kaldor, S.W.; Koch, D.J.; Krushinski, J.H. Jr.; Nissen, J.S.; Rocco, V.P.; Schaus, J.M.; Thompson, D.C. (Eli Lilly and Company); 5-Substd.-3-(1,2,3,6-tetrahydropyridin-4-yl)- and 3-(piperidin-4-yl)-1H-indoles: New 5-HT1F agonists. EP 0733628; JP 1999502816; US 5708008; WO 9629075 . |
| 【2】 Johnson, K.W.; Phebus, L.A. (Eli Lilly and Company); Use of a serotonin 5-HT1F agonist in the manufacture of a medicament for treating or ameliorating the symptoms of common cold or allergic rhinitis. EP 0824917; US 5962473; WO 9806402 . |
| 【3】 Johnson, K.W.; Phebus, L.A. (Eli Lilly and Company); A method for the prevention of migraine. WO 9811895 . |
| 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) | 26916 | 5-Nitroindole; 5-nitro-1H-indole | 6146-52-7 | C8H6N2O2 | 详情 | 详情 |
| (II) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (III) | 26917 | 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-nitro-1H-indole | C14H15N3O2 | 详情 | 详情 | |
| (IV) | 26918 | Indole-5-amine; 1H-indol-5-ylamine; 5-Aminoindole | 5192-03-0 | C8H8N2 | 详情 | 详情 |
| (V) | 26919 | 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indol-5-amine | C14H17N3 | 详情 | 详情 | |
| (VI) | 26920 | 3-(1-methyl-4-piperidinyl)-1H-indol-5-amine | C14H19N3 | 详情 | 详情 | |
| (VII) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |