反应详情

To a stirred mixture of 2-amino-4-(trifluoromethyl)benzoic acid (3.0 g, 15 mmol) and imidazole (1.2 g, 18 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.3 mL, 18 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 (2.4 g, 15 mmol), imidazole (2.2 g, 32 mmol) and triphenyl phosphite (4.6 mL, 18 mmol) and heated to reflux for 22 hours. To the mixture, was added water (100 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50 mL) to give a white solid, which was dissolved in DMSO (10 mL). To the solution, was added water (3 mL) to give a suspension. The suspension was filtered and washed with DMSO (2 mL) to give a white solid. The solid was stirred in water (50 mL) at 60° C. for 2 hours, then at room temperature overnight. The suspension was filtered and washed with water (2×50 mL) to give 3-(2-methyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (1.17 g, 24% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 8.14 min (99.9%); mp: 277-279° C.; 1H NMR (DMSO-d6) δ 2.18-2.25 (m, 1H, CHH), 2.59-2.74 (m, 5H, CH3, 2CH—H), 2.81-2.88 (m, 1H, CHH), 5.34 (dd, J=6, 11 Hz, 1H, NCH), 7.80 (dd, J=2, 8 Hz, 1H, Ar), 7.96 (s, 1H, Ar), 8.24 (d, J=8 Hz, 1H, Ar), 11.09 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.54, 30.57, 56.82, 122.30 (q, JC-F=3 Hz), 122.99, 123.45 (q, JC-F=273 Hz), 123.74 (q, JC-F=4 Hz), 127.85, 134.22 (q, JC-F=32 Hz), 146.84, 156.98, 159.80, 169.24, 172.56; LCMS: MH=340; Anal Calcd for C15H12N3O3F3: C, 53.10; H, 3.57; N, 12.39; F, 16.80. Found: C, 52.55; H, 3.42; N, 12.21; F, 17.18.

1. temperatureheated
2. temperatureto reflux for 22 hours
3. filtrationThe suspension was filtered
4. washwashed with water (2×50 mL), ethyl acetate (2×50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50 mL)
5. customto give a white solid, which
6. customto give a suspension
7. filtrationThe suspension was filtered
8. washwashed with DMSO (2 mL)
9. customto give a white solid
10. customat room temperature
11. customovernight
12. filtrationThe suspension was filtered
13. washwashed with water (2×50 mL)