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【结 构 式】 
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【药物名称】SB-224289 【化学名称】1'-Methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-ylcarbonyl]-2,3,6,7-tetrahydro-5H-spiro[furo[2,3-f]indole-3,4'-piperidine] 【CA登记号】180083-23-2, 180084-26-8 (monoHCl), 180084-29-1 (monooxalate salt) 【 分 子 式 】C32H32N4O3 【 分 子 量 】520.63684 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1B Agonists, 5-HT1D Antagonists |
合成路线1
Friedel-Crafts acylation of 1-acetylindoline (I) with acetyl chloride and AlCl3 afforded ketone (II). Subsequent Baeyer-Villiger rearrangement using peracetic acid yielded acetate ester (III), which was hydrolyzed with NaOH to give phenol (IV). Bromination of (IV) with NBS in AcOH then provided bromo hydroxy indoline (V). Alkylation with 1-methyl-tetrahydropyridine-4-methanol (VI) under Mitsunobu conditions produced ether (VII). This was cyclized to the spirocyclic compound (VIII) using AIBN and tributyltin hydride in refluxing benzene. Then, amide hydrolysis in hydroalcoholic HCl gave (IX), which was finally condensed with acid chloride (X) to provide the desired amide.
| 【1】 Gaster, L.M.; et al.; The selective 5-HT1B receptor inverse agonist 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289) potently blocks terminal 5-HT autoreceptor function b. J Med Chem 1998, 41, 8, 1218. |
| 【2】 Gaster, L.; et al.; SB-224289 - a highly selective 5-HT1B receptor inverse agonist. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.259. |
| 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) | 19320 | 1-(2,3-dihydro-1H-indol-1-yl)-1-ethanone | 16078-30-1 | C10H11NO | 详情 | 详情 |
| (II) | 19321 | 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-1-ethanone | C12H13NO2 | 详情 | 详情 | |
| (III) | 19322 | 1-acetyl-2,3-dihydro-1H-indol-5-yl acetate | C12H13NO3 | 详情 | 详情 | |
| (IV) | 19323 | 1-(5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone | C10H11NO2 | 详情 | 详情 | |
| (V) | 19324 | 1-(6-bromo-5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone | C10H10BrNO2 | 详情 | 详情 | |
| (VI) | 19325 | (1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)methanol | C7H13NO | 详情 | 详情 | |
| (VII) | 19326 | 1-[6-bromo-5-[(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)methoxy]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C17H21BrN2O2 | 详情 | 详情 | |
| (VIII) | 19327 | 5-Acetyl-1'-methyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine] | C17H22N2O2 | 详情 | 详情 | |
| (IX) | 19328 | 1'-Methyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine] | C15H20N2O | 详情 | 详情 | |
| (X) | 19329 | 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carbonyl chloride | C17H13ClN2O2 | 详情 | 详情 |