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【结 构 式】 
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【药物名称】LY-487379 【化学名称】2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(pyridin-3-ylmethyl)ethanesulfonamide 【CA登记号】353231-17-1, 353229-59-1 (hydrochloride) 【 分 子 式 】C21H19F3N2O4S 【 分 子 量 】452.45578 |
【开发单位】Lilly (Originator) 【药理作用】Anxiolytics, PSYCHOPHARMACOLOGIC DRUGS, mglu2 Agonists |
合成路线1
The reductive alkylation of 4-(2-methoxyphenoxy)aniline (I) with pyridine-3-carboxaldehyde (II) in the presence of NaBH4 leads to the N-pyridylmethyl aniline adduct (III) (1). Alternatively, 4-bromoaniline (IV) is reductively alkylated with pyridine-3-carboxaldehyde (II) to produce (V). Subsequent copper-catalyzed bromide displacement of (V) with guaiacol (VI) affords intermediate (III) (2). Finally, acylation of amine (III) with 2,2,2-trifluoroethylsulfonyl chloride (VII) gives rise to the target sulfonamide (1,2).
| 【1】 Johnson, M.P.; Baez, M.; Jagdmann, G.E.Jr.; Britton, T.C.; Large, T.H.; Callagaro, D.O.; Tizzano, J.P.; Monn, J.A.; Schoepp, D.D.; Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: Synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine. J Med Chem 2003, 46, 15, 3189. |
| 【2】 Monn, J.A.; Hornback, W.J.; Schoepp, D.D.; Dressman, B.A.; Britton, T.C.; Tizzano, J.P.; Johnson, K.W.; Henry, S.S.; Coleman, D.S.; Jagdmann, G.E.J.; Johnson, M.P.; Large, T.H.; Barda, D.A.; Fichtner, M.W. (Eli Lilly and Company); Potentiators of glutamate receptors. WO 0156990 . |
| 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) | 65013 | 4-{[2-(methyloxy)phenyl]oxy}aniline; 4-{[2-(methyloxy)phenyl]oxy}phenylamine | C13H13NO2 | 详情 | 详情 | |
| (II) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (III) | 65014 | N-(4-{[2-(methyloxy)phenyl]oxy}phenyl)-N-(3-pyridinylmethyl)amine; 4-{[2-(methyloxy)phenyl]oxy}-N-(3-pyridinylmethyl)aniline | C19H18N2O2 | 详情 | 详情 | |
| (IV) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (V) | 65015 | 4-bromo-N-(3-pyridinylmethyl)aniline; N-(4-bromophenyl)-N-(3-pyridinylmethyl)amine | C12H11BrN2 | 详情 | 详情 | |
| (VI) | 13052 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl dibenzyl phosphate | C43H45O16P | 详情 | 详情 | |
| (VII) | 65016 | 2,2,2-trifluoro-1-ethanesulfonyl chloride | C2H2ClF3O2S | 详情 | 详情 |