Reaction Steps
To a stirred mixture of 2-amino-6-fluorobenzoic acid (5.3 g, 34 mmol) and imidazole (2.8 g, 41 mmol) in acetonitrile (60 mL), was added acetyl chloride (2.9 mL, 41 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (6.1 g, 37 mmol), imidazole (5.1 g, 75 mmol) and triphenyl phosphite (10.6 mL, 41 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give a white solid, which was stirred in methanol (50 mL) overnight. The suspension was washed with methanol (30 mL) and water (30 mL) to give 3-(5-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (7.6 g, 78% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 3.8 min (99.6%); mp: 275-277° C.; 1H NMR (DMSO-d6) δ 2.13-2.20 (m, 1H, CHH), 2.57-2.69 (m, 5H, CH3, 2CHH), 2.77-2.90 (m, 1H, CHH), 5.25 (dd, J=6, 11 Hz, 1H, NCH), 7.26 (ddd, J=0.6, 8, 11 Hz, 1H, Ar), 7.44 (d, J=8 Hz, 1H, Ar), 7.80 (dt, J=5, 8 Hz 1H, Ar), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.45, 30.57, 56.45, 109.79 (d, JC-F=6 Hz), 112.89 (d, JC-F=21 Hz), 122.64 (d, JC-F=4 Hz), 135.39 (d, JC-F=11 Hz), 148.86, 156.22, 157.46, 160.15 (d, JC-F=264 Hz), 169.38, 172.57; LCMS: MH=290; Anal Calcd for C14H12N3O3F: C, 58.13; H, 4.18; N, 14.53; F, 6.57. Found: C, 57.98; H, 4.00; N, 14.45; F, 6.73.
