Iodoethanol → Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxylate

Participants

Reaction Steps

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.

Provenance & Evidence