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【结 构 式】 
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【药物名称】A-205804 【化学名称】4-(4-Methylphenylsulfanyl)thieno[2,3-c]pyridine-2-carboxamide 【CA登记号】 【 分 子 式 】C15H12N2OS2 【 分 子 量 】300.40369 |
【开发单位】Abbott (Originator), Icos (Codevelopment) 【药理作用】Antiarthritic Drugs, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Anti-ICAM-1 Agents, Cell Adhesion Inhibitors, E-Selectin Inhibitors |
合成路线1
The formylation of 3,5-dichloropyridine (I) with methyl formate by means of lithium diisopropylamide (LDA) in THF gives 3,5-dichloropyridine-4-carbaldehyde (II), which is condensed with p-thiocresol (III) by means of K2CO3 in DMF (or t-BuOK in THF) yielding 3-chloro-5-(4-methylphenylsulfanyl)pyridine-4-carbaldehyde (IV). The cyclization of (IV) with methylthioglycolate (V) by means of K2CO3 in DMF affords 4-(4-methylphenylsulfanyl)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VI), which is finally treated with ammonia in methanol to obtain the target amide. Alternatively, The hydrolysis of the methyl ester (VI) with LiOH in hot isopropanol/water gives the corresponding free acid (VII), which is treated with oxalyl chloride in dichloromethane to obtain the acyl chloride (VIII). Finally, this compound is treated with NH4OH in THF/water to afford the target amide.
| 【1】 Boyd, S.A.; Stewart, A.O.; Bhatia, P.A.; et al.; Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells: Selective inhibition of ICAM-1 and E-selectin expression. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 73. |
| 【2】 Lartey, K.; Gunawardana, I.W.; Stout, D.M.; Bhatia, P.; Patel, M.V.; Staeger, M.A.; Boyd, S.A.; Mort, N.A.; Zhu, G.-D.; McCarty, C.M.; Stewart, A.O.; Arendsen, D.L.; Condroski, K.R.; Freeman, J.C. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory cpds.. WO 9962908 . |
| 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) | 35535 | 3,5-dichloropyridine | 2457-47-8 | C5H3Cl2N | 详情 | 详情 |
| (II) | 35536 | 3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde | 136590-83-5 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 25437 | 4-methylphenylhydrosulfide | 106-45-6 | C7H8S | 详情 | 详情 |
| (IV) | 35537 | 3-chloro-5-[(4-methylphenyl)sulfanyl]isonicotinaldehyde | C13H10ClNOS | 详情 | 详情 | |
| (V) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VI) | 35538 | methyl 4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridine-2-carboxylate | C16H13NO2S2 | 详情 | 详情 | |
| (VII) | 35539 | 4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridine-2-carboxylic acid | C15H11NO2S2 | 详情 | 详情 | |
| (VIII) | 35540 | 4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridine-2-carbonyl chloride | C15H10ClNOS2 | 详情 | 详情 |