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【结 构 式】 
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【分子编号】35538 【品名】methyl 4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridine-2-carboxylate 【CA登记号】 |
【 分 子 式 】C16H13NO2S2 【 分 子 量 】315.41676 【元素组成】C 60.93% H 4.15% N 4.44% O 10.14% S 20.33% |
合成路线1
该中间体在本合成路线中的序号：(VI)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 |
合成路线2
该中间体在本合成路线中的序号：(VI)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 methyl thioglycolate (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 condensed with 2,3-dihydroxypropylamine (VII) by means of NaH in DMF to obtain the target amide. Alternatively, The hydrolysis of the methyl ester (VI) with LiOH in hot isopropanol/water gives the corresponding free acid (VIII), which is treated with N-hydroxysuccinimide (IX) and DCC in dichloromethane to obtain the activated ester (X). Finally, this compound is treated with 2,3-dihydroxypropylamine (VII) in dioxane/methanol to afford the target amide. The activation of the acid (VIII) can also be performed with oxalyl chloride or EDC and HOBT.
| 【1】 Patel, S.A.; Staeger, M.A.; McCarty, C.M.; 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 74. |
| 【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) | 35544 | 1-[([4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridin-2-yl]carbonyl)oxy]-2,5-pyrrolidinedione | C19H14N2O4S2 | 详情 | 详情 |