Dimethylformamide → HCID 178493889, compound

Participants

Reaction Steps

To a solution of N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide bis-TFA salt (Intermediate I, Step 2, 0.210 g, 0.37 mmol) in DMF (12 mL) was added Cs2CO3 (0.61 g, 1.86 mmol, 5.0 equiv.) and the resulting slurry was stirred at room temperature for 1.5 hr, followed by the addition of cyclic sulfite ester (0.092 g, 0.45 mmol, 1.2 equiv). This mixture was stirred at 60° C. for 12 hr, cooled to room temperature, treated with additional caesium carbonate (0.86 g, 2.6 mmol, 2.0 equiv.) and cyclic sulfite ester (0.076 g, 0.37 mmol, 1.0 equiv.) and stirred at 60° C. for an additional 3.5 days. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in a 4:1 CH2Cl2/isopropanol solution (50 mL), then was washed with a saturated NaHCO3 (25 mL) and a saturated NaCl solution (25 mL), dried (anh. Na2SO4), and concentrated under reduced pressure. Trituration with MeOH afforded crystals that were washed with water, then MeOH, and dried at 50° C. under reduced pressure. The resulting solids (0.077 g) were purified by preparative HPLC to give N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide (0.52 g, 82%): TLC (9:1 CH2Cl2/MeOH+1% NH4OH in MeOH)Rf 0.35; HPLC (condition A) ret. time 4.29 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 3.09-3.41 (m, 4H), 3.48 (br d, J=11.7 Hz, 2H), 3.62-3.85 (m, 2H), 3.88-4.01 (m, 2H), 4.03 (s, 3H), 4.20-4.31 (m, 4H), 4.41 (br s, 1H), 4.52-4.62 (m, 2H), 7.50 (d, J=9.4 Hz, 1H), 7.95 (dd, J=5.3, 7.9 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 8.92 (br d, J=8.1 Hz, 1H), 8.98 (dd, J=1.1, 5.3 Hz, 1H), 9.49 (d, J=1.5 Hz, 1H).

Provenance & Evidence