反应详情

To a solution of 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (2.00 g, 13.0 mmol) and N,N-dimethylformamide (3 drops) in tetrahydrofuran (30 mL) was added oxalyl chloride (2.23 mL, 26.0 mmol) with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (20 mL) with stirring under ice-cooling, N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (3.27 g, 10.0 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution (50 ml) and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1, 80 mL, 40 mL×2). The organic layer was washed with water (10 mL×3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and crystallized from ethyl acetate to give the title compound (2.39 g, yield 52%) as a white solid. melting point 199° C.

1. temperaturecooling
2. stirringthe mixture was stirred at room temperature for 3 hr
3. concentrationThe reaction mixture was concentrated under reduced pressure
4. dissolutionThe residue was dissolved in N,N-dimethylacetamide (20 mL)
5. stirringwith stirring under ice-
6. temperaturecooling
7. stirringthe mixture was stirred at room temperature for 18 hr
8. extractionextracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1, 80 mL, 40 mL×2)
9. washThe organic layer was washed with water (10 mL×3)
10. concentrationconcentrated under reduced pressure
11. customThe residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30)
12. customcrystallized from ethyl acetate