反応手順
To a stirred mixture of 2-amino-3-fluorobenzoic acid (3.0 g, 19 mmol) and imidazole (1.6 g, 23 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.7 mL, 23 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 (3.2 g, 19 mmol), imidazole (2.9 g, 43 mmol) and triphenyl phosphite (6.1 mL, 23 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 purified with preparative HPLC (C18 20/80 CH3CN/H2O) to give a white solid. The white solid in DMSO (20 mL) was heated at 60° C. for 30 minutes. To the solution, was added water (10 mL). The suspension was cooled to room temperature. The suspension was filtered and washed with DMSO (4 mL) and water (20 mL) to give 3-(8-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (3.11 g, 67% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 4.7 min (99.7%); mp: 305° C. (decomp); 1H NMR (DMSO-d6) δ 2.16-2.23 (m, 1H, CHH), 2.43-2.76 (m, 5H, CH3, 2CHH), 2.79-2.92 (m, 1H, CHH), 5.32 (dd, J=6, 11 Hz, 1H, NCH), 7.46-7.53 (m, 1H, Ar), 7.67-7.73 (m, 1H, Ar), 7.84-7.94 (m, 1H, Ar), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.80, 23.67, 30.58, 56.71, 120.04 (d, JC-F=19 Hz), 121.71 (d, JC-F=4 Hz), 122.31, 126.91 (d, JC-F=8 Hz), 136.04 (d, JC-F=12 Hz), 155.93 (d, JC-F=254 Hz), 155.93, 159.62 (d, JC-F=3 Hz), 169.32, 172.57; LCMS: MH=290; Anal Calcd for C14H12N3O3F: C, 58.13; H, 4.18; N, 14.53; F, 6.57. Found: C, 57.87; H, 3.94; N, 14.35; F, 6.91.
