反应详情

To a solution of ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 46a, 1.32 g, 5.83 mmol) in N,N-Dimethylformamide (DMF) (30 ml) at 0° C. was added sodium hydride (0.5 g, 14.58 mmol) in portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled back to 0° C. and 4-bromobenzyl bromide (1.46 g, 5.83 mmol) was added. The mixture was stirred at ambient temperature for 2 hours then quenched with 1N HCl (10 ml). The aqueous solution was extracted with ethyl acetate (2×50 ml), the organic layers combined, dried over Magnesium sulfate, filtered and solvents removed with rotary evaporation. The crude residue was dissolved in 2-methoxyethanol (10 ml), place in a 20 ml microwave tube and glycine sodium salt (0.75 g, 7.7 mmol) was added. The mixture was irradiated at 150° C. for 20 minutes, diluted with water (15 ml) and acidified with 1N HCl to cause a precipitate. The precipitate was collected by filtration and dried to give the product as an off white solid (0.750 g, 1.77 mmol, 30.3%) 1H NMR (400 MHz, DMSO-d6) d ppm 15.89 (s, 1H), 12.97 (s, 1H), 10.16 (t, J=5.31 Hz, 1H), 7.55 (d, J=8.34 Hz, 2H), 7.26 (d, J=8.34 Hz, 2 H), 5.22 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.18 (m, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 425 [M+H]+.

1. temperaturecooled back to 0° C.
2. stirringThe mixture was stirred at ambient temperature for 2 hours
3. customthen quenched with 1N HCl (10 ml)
4. extractionThe aqueous solution was extracted with ethyl acetate (2×50 ml)
5. dry with materialdried over Magnesium sulfate
6. filtrationfiltered
7. customsolvents removed with rotary evaporation
8. dissolutionThe crude residue was dissolved in 2-methoxyethanol (10 ml)
9. customThe mixture was irradiated at 150° C. for 20 minutes
10. filtrationThe precipitate was collected by filtration
11. customdried