4-Methylmorpholine → HCID 21089030, compound

Participants

Reaction Conditions

Reaction Steps

To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (4.0 g, 0.0086 mol) in dimethylacetamide (10.0 mL) at −20° C. was added N-methylmorpholine (1.2 g, 0.012 mol), followed by the dropwise addition of a solution of isobutylchloroformate (1.58 g, 0.012 mmol) in dichloromethane (5.0 mL). The reaction mixture was stirred for 10 min. under argon atmosphere after which it was stirred at room temperature for 20 min. The reaction mixture was then cooled to 0° C., and added R-2-amino-1-propanol (0.97 g, 1.01 mol). The resulting mixture was stirred at room temperature for 1.5 h, concentrated in vacuo, and the residue was purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=522) were combined, and freeze-dried to give a white solid. This was dissolved in dichloromethane (20 mL), washed successively with 5% sodium bicarbonate (2×15 mL), water (2×20 mL), dried (Na2SO4), and concentrated to dryness to afford the racemic title compound (2.2 g, 49%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.91(dd, 1H, J=1.6 Hz, & 6.4 Hz), 7.68 (d, 1H, J=1.6 Hz), 7.60 (m, 1H), 7.53 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.57 (abq, 2H), 4.18 (m, 1H), 3.56 (m, 2H), 2.17 (s, 3H), 2.13 (s, 3H), and 1.22(d, 3H, J=6.8 Hz); ES-HRMS m/z 522.0860 (M+H calcd for C23H23N3O4F2Br requires 522.0835). 19F NMR(CD3OD/400 MHz) −111.85(m) and −115.90 (m).

Provenance & Evidence