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【结 构 式】 
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【药物名称】SB-236057A(hydrochloride), SB-236057 【化学名称】1'-Ethyl-5-[2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-ylcarbonyl]-2,3,6,7-tetrahydro-5H-spiro[furo[2,3-f]indole-3,4'-piperidine] 【CA登记号】180083-49-2, 180084-01-9 (monohydrochloride), 180084-02-0 (monomethanesufonate salt) 【 分 子 式 】C33H34N4O3 【 分 子 量 】534.66393 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1B Inverse Agonists |
合成路线1
Quaternization of 4-pyridylcarbinol (I) by means of iodoethane provided pyridinium salt (II), which was reduced with NaBH4 to the tetrahydropyridine (III). Subsequent Mitsunobu coupling of (III) with 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (IV) afforded ether (V). Intramolecular cyclization of (V) to the spiro compound (VI) was effected by treatment with tributyltin hydride and azobis(isobutyronitrile). The acetamide function of (VI) was then hydrolyzed by refluxing with HCl in H2O-EtOH to furnish intermediate diamine (VII).
| 【1】 Gaster, L.M.; King, F.D.; Wyman, P.A. (GlaxoSmithKline plc); Tetracyclic spiro cpds., process for their preparation and their use as 5HT1D receptor antagonists. EP 0799226; JP 1998510821; US 5972951; WO 9619477 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10925 | Iodoethane;ethyl iod | 75-03-6 | C2H5I | 详情 | 详情 | |
| (I) | 32835 | 4-pyridinylmethanol | 586-95-8 | C6H7NO | 详情 | 详情 |
| (II) | 32836 | 1-ethyl-4-(hydroxymethyl)pyridinium iodide | C8H12INO | 详情 | 详情 | |
| (III) | 32837 | (1-ethyl-1,2,3,6-tetrahydro-4-pyridinyl)methanol | C8H15NO | 详情 | 详情 | |
| (IV) | 19324 | 1-(6-bromo-5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone | C10H10BrNO2 | 详情 | 详情 | |
| (V) | 32838 | 1-[6-bromo-5-[(1-ethyl-1,2,3,6-tetrahydro-4-pyridinyl)methoxy]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C18H23BrN2O2 | 详情 | 详情 | |
| (VI) | 32839 | 1'-Ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]; 5-Acetyl-1'-ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine] | C18H24N2O2 | 详情 | 详情 | |
| (VII) | 32844 | 1'-Ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine] | C16H22N2O | 详情 | 详情 |
合成路线2
Palladium-catalyzed coupling of phenyloxadiazol derivative (VIII) with 4-boronobenzoic acid (IX) yielded biphenyl (X). Further treatment of (X) with SOCl2 afforded acid chloride (XI). This was finally condensed with amine (VII) to provide the title carboxamide.
| 【1】 Gaster, L.M.; King, F.D.; Wyman, P.A. (GlaxoSmithKline plc); Tetracyclic spiro cpds., process for their preparation and their use as 5HT1D receptor antagonists. EP 0799226; JP 1998510821; US 5972951; WO 9619477 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 32844 | 1'-Ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine] | C16H22N2O | 详情 | 详情 | |
| (VIII) | 32840 | 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole | C10H9BrN2O | 详情 | 详情 | |
| (IX) | 32841 | 4-(dihydroxyboryl)benzoic acid；4-Boronobenzoic acid；4-carboxyphenylboronic acid;4-(Dihydroxyboryl)benzoic acid | 14047-29-1 | C7H7BO4 | 详情 | 详情 |
| (X) | 32842 | 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)[1,1'-biphenyl]-4-carboxylic acid | C17H14N2O3 | 详情 | 详情 | |
| (XII) | 32843 | 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)[1,1'-biphenyl]-4-carbonyl chloride | C17H13ClN2O2 | 详情 | 详情 |