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【结 构 式】 
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【分子编号】52017 【品名】4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C14H8BrNO3S 【 分 子 量 】350.19246 【元素组成】C 48.02% H 2.3% Br 22.82% N 4% O 13.71% S 9.16% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The formylation of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and DIEA in THF gives 3,5-dichloropyridine-4-carbaldehyde (III), which is treated with 4-bromophenol (IV) and potassium tert-butoxide in hot THF to yield the adduct (V). This compound, without isolation is cyclized with methyl 2-mercaptoacetate (VI) by means of Cs2CO3 to afford 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VII), which is hydrolyzed with LiOH in THF/water to provide the corresponding carboxylic acid (VIII). Finally, this compound is condensed with methylamine (IX) by means of EDC and HOBt in DMF to give the target amide. Alternatively, the target amide can also be obtained by direct reaction of methyl ester (VII) with methylamine (IX) in hot methanol in a sealed tube.
| 【1】 Zhu, G.-D.; et al.; Selective inhibition of ICAM-1 and E-selectin expression in human endothelial cells. 2. Aryl modifications of 4-(aryloxy)theino[2,3-c]pyridines with fine-tuning at C-2 carbamides. J Med Chem 2001, 44, 21, 3469. |
| 【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) | 45474 | methyl formate | 107-31-3 | C2H4O2 | 详情 | 详情 |
| (III) | 35536 | 3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde | 136590-83-5 | C6H3Cl2NO | 详情 | 详情 |
| (IV) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (V) | 52015 | 3-(4-bromophenoxy)-5-chloroisonicotinaldehyde | C12H7BrClNO2 | 详情 | 详情 | |
| (VI) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VII) | 52016 | methyl 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylate | C15H10BrNO3S | 详情 | 详情 | |
| (VIII) | 52017 | 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid | C14H8BrNO3S | 详情 | 详情 | |
| (IX) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The formylation of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and DIEA in THF gives 3,5-dichloropyridine-4-carbaldehyde (III), which is treated with 4-bromophenol (IV) and potassium tert-butoxide in hot THF to yield the adduct (V). This compound, without isolation is cyclized with methyl 2-mercaptoacetate (VI) by means of Cs2CO3 to afford 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VII), which is hydrolyzed with LiOH in THF/water to provide the corresponding carboxylic acid (VIII). Finally, this compound is condensed with ethanolamine (IX) by means of EDC and HOBt in DMF to give the target ethanolamide. Alternatively, the target amide can also be obtained by direct reaction of methyl ester (VII) with ethanolamine (IX) in refluxing methanol.
| 【1】 Zhu, G.-D.; et al.; Selective inhibition of ICAM-1 and E-selectin expression in human endothelial cells. 2. Aryl modifications of 4-(aryloxy)theino[2,3-c]pyridines with fine-tuning at C-2 carbamides. J Med Chem 2001, 44, 21, 3469. |
| 【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) | 45474 | methyl formate | 107-31-3 | C2H4O2 | 详情 | 详情 |
| (III) | 35536 | 3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde | 136590-83-5 | C6H3Cl2NO | 详情 | 详情 |
| (IV) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (V) | 52015 | 3-(4-bromophenoxy)-5-chloroisonicotinaldehyde | C12H7BrClNO2 | 详情 | 详情 | |
| (VI) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VII) | 52016 | methyl 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylate | C15H10BrNO3S | 详情 | 详情 | |
| (VIII) | 52017 | 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid | C14H8BrNO3S | 详情 | 详情 | |
| (IX) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |