4-Methylmorpholine → 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy)-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide

Participants

Reaction Conditions

Reaction Steps

To a cold solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (0.8 g, 1.7 mmol) in anhydrous dimethylacetamide (3.2 mL) was added isobutyl chloroformate (0.23 mL, 1.7 mmol) followed by N-methylmorpholine (0.25 mL, 2.2 mmol). The reaction mixture stirred under argon atmosphere at 0° C. for 10 min and then at room temperature for 30 min. At which time another equivalent of N-methylmorpholine (0.29 mL, 2.5 mmol) was added to reaction mixture, followed by the addition of glycine methyl amide HCl (0.33 g, 2.5 mmol) and DMAP (ca.). The reaction mixture stirred for 2 h at room temperature and then diluted with acetonitrile/water (2:1 v/v) to be purified by reverse phase HPLC using a 10–90% acetonitrile in water containing 0.5% TFA (30 min) gradient at a 80 mL/min flow rate. The appropriate fractions (M+H m/z=521) were collected and concentrated to a reduced volume. The resulting suspension was diluted with dichloromethane (30 mL) and washed with 5% NaHCO3 (2×50 mL). The organic extracts were washed with water (2×25 mL) and dried over Na2SO4 (anhydrous). The organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (364.4 mg, 37%) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.96 (dd, 1H, J=2 Hz), 7.80 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.98 (s, 2H), 2.74 (s, 3H), 2.20 (s, 3H); ES-HRMS m/z 521.0650 (M+H C22H20BrF2N4O4 requires 521.0630).

Provenance & Evidence