反应详情

温度

80 °C

Ethyl 1-[(6-methyl-2,3′-bipyridin-5-yl)methyl]-4-thioxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate [(Example 6, Step 2), 125 mg, 0.299 mmol], (±)-tetrahydro-2H-pyran-3-ylhydrazine hydrochloride (91.0 mg, 0.599 mmol, 2 equiv) and potassium carbonate (414 mg, 2.99 mmol, 10 equiv) were combined in ethanol (10 mL), N,N′-dimethylformamide (3 mL) and dioxane (5 mL) at ambient temperature and after 5 minutes, were warmed to 80° C. for 4 hours. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (100 mL, aqueous saturated) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 10% methanol), providing the titled compound as a deep red solid: 1H-NMR (400 MHz, CDCl3) δ 9.02 (1H, d, J=2.1 Hz), 8.93 (1H, d, J=2.3 Hz), 8.75 (1H, dd, J=4.6, 1.8 Hz), 8.51 (1H, dd, J=8.1, 1.8 Hz), 8.16 (1H, dd, J=8.1, 2.4 Hz), 7.97 (1H, dd, J=8.2, 2.3 Hz), 7.66 (1H, dd, J=8.2, 0.6 Hz), 7.50 (1H, dd, J=7.9, 4.6 Hz), 7.24 (1H, d, J=8.1 Hz), 5.97 (1H, br s), 4.70-4.62 (1H, m), 4.01-3.94 (2H, m), 3.74 (1H, ap t, J=10.7 Hz), 3.49 (1H, br m), 3.45 (1H, dd, J=11.1, 3.4 Hz), 2.60 (3H, s), 2.21-2.05 (3H, m) ppm; high resolution mass spectrometry (ES+) m/z 454.1984 [(M+H)+; calculated for C25H24N7O2: 454.1986].

1. temperatureThe mixture was cooled to ambient temperature
2. extractionextracted with ethyl acetate (2×100 mL)
3. dry with materialThe combined organic extracts were dried with sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. customThe residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 10% methanol)