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【结 构 式】 
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【分子编号】35542 【品名】methyl 4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylate 【CA登记号】 |
【 分 子 式 】C15H10ClNO3S 【 分 子 量 】319.76804 【元素组成】C 56.34% H 3.15% Cl 11.09% N 4.38% O 15.01% S 10.03% |
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 4-chlorophenol (III) by means of potassium tert-butoxide in THF yielding 3,5-bis(4-chlorophenoxy)pyridine-4-carbaldehyde (IV). This compound, without isolation is cyclized with methyl thioglycolate (V) by means of Cs2CO3 in DMF affording 4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VI), which is finally condensed with methylamine by means of NaH in DMF to obtain the target amide.
| 【1】 Arendsen, D.L.; Freeman, J.C.; Boyd, S.A.; et al.; Inhibitors of cell adhesion molecule expression in human endothelial cells: Modification of 2-position of 4-aryloxythieno [2,3-c]pyridines. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 75. |
| 【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) | 35543 | 4-chlorophenol | 106-48-9 | C6H5ClO | 详情 | 详情 |
| (IV) | 35541 | 3,5-bis(4-chlorophenoxy)isonicotinaldehyde | C18H11Cl2NO3 | 详情 | 详情 | |
| (V) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VI) | 35542 | methyl 4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylate | C15H10ClNO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Treatment of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and diisopropyl amine (DIPA) in THF provides carboxaldehyde (III), which is converted into ester (VI) by first condensation with 4-chlorophenol (IV) by means of tBuOK in THF followed by cyclization with methyl thioglycolate (V) and Cs2CO3. Methyl ester (VI) reacts with methanolic ammonia to yield carboxamide (VII), which is then treated with trifluoroacetic anhydride (TFAA) in pyridine to furnish carbonitrile (VIII). Finally, (VIII) is converted into the desired compound by reaction with hydroxylamine hydrochloride (NH2OH·HCl) and TEA in EtOH.
| 【1】 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) | 35543 | 4-chlorophenol | 106-48-9 | C6H5ClO | 详情 | 详情 |
| (V) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VI) | 35542 | methyl 4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylate | C15H10ClNO3S | 详情 | 详情 | |
| (VII) | 45475 | 4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide | C14H9ClN2O2S | 详情 | 详情 | |
| (VIII) | 45476 | 4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carbonitrile | C14H7ClN2OS | 详情 | 详情 |