反应详情

温度

0 °C

To a solution of 6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridazin-3-ylamine (300 mg, 1.18 mmol) in trimethyl orthoformate (1.00 g, 1.04 mL, 9.46 mmol) were added 2-3 drops of trifluoroacetic acid. The reaction mixture was stirred at reflux for 2 hours and then concentrated under vacuum. The residue was dissolved in 5 mL toluene and concentrated again under vacuum. This was repeated for three times to completely remove all volatiles. The residue was dissolved in tetrahydrofuran (3 mL) and borane tetrahydrofuran complex (1M solution, 2.96 mL, 2.96 mmol) was added in portions at 0° C. The reaction mixture was stirred at 90° C. for 2 hours and the resulting brown solution was cooled down to 0° C. and 25% aqueous hydrochloric acid (1 mL) was added slowly. The mixture was stirred at 90° C. for 1 hour and then poured on 30 mL water and 30 mL ethyl acetate. Aqueous sodium hydroxide solution (25%, 2 mL) was added and the layers were separated. The aqueous layer was extracted a second time with 30 mL ethyl acetate. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Light yellow solid (119 mg, 37.6%). MS (ESI+): m/z=268.065 ([M+H]+).

1. temperatureat reflux for 2 hours
2. concentrationconcentrated under vacuum
3. dissolutionThe residue was dissolved in 5 mL toluene
4. concentrationconcentrated again under vacuum
5. customto completely remove all volatiles
6. dissolutionThe residue was dissolved in tetrahydrofuran (3 mL)
7. additionborane tetrahydrofuran complex (1M solution, 2.96 mL, 2.96 mmol) was added in portions at 0° C
8. stirringThe reaction mixture was stirred at 90° C. for 2 hours
9. stirringThe mixture was stirred at 90° C. for 1 hour
10. customthe layers were separated
11. extractionThe aqueous layer was extracted a second time with 30 mL ethyl acetate
12. washThe organic layers were washed with 30 mL brine
13. dry with materialdried over magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated under vacuum
16. customThe compound was purified by silica gel chromatography on a 20 g column
17. washeluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100)