反应详情

2-Iodoethanol was protected as the tetrahydropyranyl ether according to a literature method [J. Org. Chem., 54(10), 2407 (1989)]. Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (383 mg, 0.95 mmol) was dissolved/suspended in dry DMF (15 mL) and the solution cooled (ice/water). NaH (42 mg, 1.05 mmol) was added, the flask placed under nitrogen, and the resulting mixture allowed to warm and stirred at R.T. for 2 h. A solution of the protected iodide (1.22 g, 4.77 mmol) in dry DMF (5 mL) was added as a single portion and the entire mixture stirred at R.T. for 15 h. Water (100 mL) was added and the resulting aqueous suspension extracted with EtOAc (3×50 mL). The combined EtOAc fractions were then washed with water (2×50 mL) and brine (50 mL), then dried (Na2SO4). The solvent was removed under reduced pressure to afford an oil which was purified by chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxylate was isolated as a transparent oil which gave a waxy solid over time (249 mg, 49%), this material was used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 9.31 (s, 1H), 8.49 (s, 1H), 7.78 (dd, J=10.2, 1.9 Hz, 1H), 7.61 (br d, J=8.6 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 5.45 (s, 1H), 4.59 (br s, 1H), 4.30 (q, J=7.0 Hz, 2H), 4.11 (t, J=5.0 Hz, 2H), 3.75 (pentet, J=5.5 Hz, 1H), 3.61-3.49 (m, 2H), 3.40-3.32 (m, 1H), 1.74-1.33 (m, 6H), 1.30 (t, J=7.1 Hz, 3H). HRMS (EI+) calcd C21H24FIN2O5 (M+) 530.0714, found 530.0704.

1. temperatureto warm
2. stirringthe entire mixture stirred at R.T. for 15 h
3. extractionthe resulting aqueous suspension extracted with EtOAc (3×50 mL)
4. washThe combined EtOAc fractions were then washed with water (2×50 mL) and brine (50 mL)
5. dry with materialdried (Na2SO4)
6. customThe solvent was removed under reduced pressure
7. customto afford an oil which
8. customwas purified by chromatography on silica gel (50% EtOAc/hexanes as eluant)