4-Fluoroaniline → Methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate
Reaction equation
O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C1COCC1.CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1Participants
Procedure
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (Aldrich, 2.31 g, 15 mmol) in THF (40 mL) and DMF (10 mL) at rt was added 4-fluoroaniline (1.67 g, 15 mmol), and the reaction mixture was stirred for 2.5 h. Solid precipitation was observed. To the 4-fluoroaniline adduct intermediate formed via Michael addition obtained in situ was added EDCI.HCl (3.85 g, 20 mmol) and DMAP (120 mg) at rt. The reaction mixture was stirred at rt overnight. To the reaction mixture were added 1N aq HCl (50 mL) and EtOAc (150 mL), the EtOAc layer was separated, and the aqueous layer was washed with EtOAc (150 mL), the combined EtOAc layer was dried over MgSO4 and concentrated in vacuo to obtain a semi-solid material (˜4.4 g). To this crude product were added ether (100 mL) and methanol (15 mL), stirred, and the solid was filtered to obtain the undesired solid product (870 mg). The filtrate solution was concentrated to obtain a semi-solid crude desired product (2.95 g, crude 80%) which was pure enough to use in the next step without further purification. 1H NMR (DMSO-d6) δ 8.23 (dd, 1H, J=7.2, 2.2 Hz), 7.57 (dd, 1H, J=6.6, 1.7 Hz), 7.32-7.34 (m, 2H), 7.17 (t, 2H, J=8.8 Hz), 6.32 (t, 1H, J=7.1 Hz), 3.89 (s, 3H); MS(ESI+) m/z 248.2 (M+H)+.
Workup
- customSolid precipitation
Sources & evidence
- ORD record
- ord-724e5791250d46fc9ed7ea069e93c126
- Source dataset
- uspto-grants-2008_12
- Patent number
- US07459562B2
Reaction notes
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