反应详情

温度

90 °C

3-amino-6-chloropyridazine (420 mg, 3.23 mmol) was added to a mixture of 4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (700 mg, 1.68 mmol) which was prepared in Step D of Example 10, cesium carbonate (1.58 g, 4.85 mmol) in DMF (50 mL) and water (10 mL). The reaction mixture was deoxygenated with argon. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (66 mg, 0.081 mmol) was added and the reaction mixture was stirred at 90° C. for 1 hour, cooled, diluted with water, and extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 100% 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solution in dichloromethane) gave 4-(3,4-dichlorophenyl)-7-(6-aminopyridazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (387 mg, 60% over 2 steps): 1H NMR (CDCl3, 500 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.01 (d, J=2.0 Hz, 1H), 7.64-7.54 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.98-6.90 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 4.74 (s, 2H), 4.07 (t, J=5.5 Hz, 1H), 3.45 (dd, J=13.0, 5.5 Hz, 1H), 3.10 (dd, J=13.0, 5.5 Hz, 1H), 1.64 (s, 3H), 1.60 (s, 3H); ESI MS m/z 399 [M+H]+.

1. customThe reaction mixture was deoxygenated with argon
2. temperaturecooled
3. extractionextracted with dichloromethane (3×)
4. washThe combined organic extracts were washed with brine
5. dry with materialdried over anhydrous sodium sulfate
6. concentrationconcentrated
7. customPurification by flash column chromatography (0 to 100% 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solution in dichloromethane)