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【结 构 式】 
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【分子编号】25742 【品名】5-chloro-2-pyridinol 【CA登记号】4214-79-3 |
【 分 子 式 】C5H4ClNO 【 分 子 量 】129.5456 【元素组成】C 46.36% H 3.11% Cl 27.37% N 10.81% O 12.35% |
合成路线1
该中间体在本合成路线中的序号：(I)Synthesis of etoricoxib via dichloropyridine (VIII): a) The bromination of 5-chloro-2-hydroxypyridine (I) with Br2 in acetic acid gives 3-bromo-5-chloro-2-hydroxypyridine (II), which is treated with benzyl bromide and Ag2CO3 in hot benzene to yield benzyl ether (III). Condensation of (III) with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene affords 2-(benzyloxy)-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (V), which is oxidized with OsO4 and sodium sulfite to furnish sulfone (VI). Treatment of (VI) with TFA provides the 2-hydroxypyridine (VII), which is reacted with POCl3 to yield 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine (VIII). b) Bromination of 2-amino-5-chloropyridine (IX) with Br2 in acetic acid provides 2-amino-3-bromo-5-chloropyridine (X), which is condensed with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene to give 2-amino-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (XI). Oxidation of compound (XI) with OsO4 as before yields sulfone (XII), which is converted into compound (VIII) by treatment first with NaNO2 and HCl and then chlorination with POCl3.
| 【1】 Castañer, R.M.; Silvestre, J.S.; Sorbera, L.A.; Castañer, J.; Etoricoxib. Drugs Fut 2001, 26, 4, 346. |
| 【2】 Friesen, R.W.; Brideau, C.; Chan, C.C.; Charleson, S.; Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.; Gauthier, J.Y.; Girard, Y.; Gordon, R.; Greig, G.M.; Riendeau, D.; Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L.J.; Young, R.N.; 2-Pyridinyl-3-(4-methylsulfonyl)phenylpyridines: Selective and orally active cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1998, 8, 19, 2777. |
| 【3】 Dube, D.; Fortin, R.; Friesen, R.; Wang, Z.; Gauthier, J.Y. (Merck Frosst Canada Inc.); Substd. pyridines as selective cyclooxygenase-2 inhibitors. EP 0912518; JP 1999514008; US 5861419; WO 9803484 . |
| 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) | 25742 | 5-chloro-2-pyridinol | 4214-79-3 | C5H4ClNO | 详情 | 详情 |
| (II) | 25743 | 3-bromo-5-chloro-2-pyridinol | C5H3BrClNO | 详情 | 详情 | |
| (III) | 25744 | benzyl 3-bromo-5-chloro-2-pyridinyl ether; 2-(benzyloxy)-3-bromo-5-chloropyridine | C12H9BrClNO | 详情 | 详情 | |
| (IV) | 18561 | 4-(methylsulfanyl)phenylboronic acid | 98546-51-1 | C7H9BO2S | 详情 | 详情 |
| (V) | 25745 | benzyl 5-chloro-3-[4-(methylsulfanyl)phenyl]-2-pyridinyl ether; 2-(benzyloxy)-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine | C19H16ClNOS | 详情 | 详情 | |
| (VI) | 25746 | 2-(benzyloxy)-5-chloro-3-[4-(methylsulfonyl)phenyl]pyridine; 4-[2-(benzyloxy)-5-chloro-3-pyridinyl]phenyl methyl sulfone | C19H16ClNO3S | 详情 | 详情 | |
| (VII) | 25747 | 5-chloro-3-[4-(methylsulfonyl)phenyl]-2-pyridinol | C12H10ClNO3S | 详情 | 详情 | |
| (VIII) | 18565 | 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine; 4-(2,5-dichloro-3-pyridinyl)phenyl methyl sulfone | C12H9Cl2NO2S | 详情 | 详情 | |
| (IX) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (X) | 18560 | 3-bromo-5-chloro-2-pyridinylamine; 3-bromo-5-chloro-2-pyridinamine | C5H4BrClN2 | 详情 | 详情 | |
| (XI) | 18562 | 5-chloro-3-[4-(methylsulfanyl)phenyl]-2-pyridinylamine; 5-chloro-3-[4-(methylsulfanyl)phenyl]-2-pyridinamine | C12H11ClN2S | 详情 | 详情 | |
| (XII) | 18563 | 5-chloro-3-[4-(methylsulfonyl)phenyl]-2-pyridinamine; 5-chloro-3-[4-(methylsulfonyl)phenyl]-2-pyridinylamine | C12H11ClN2O2S | 详情 | 详情 |