反应详情

温度

25 °C

To a solution of 1-amino-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (1.08 g, 4.50 mmol) in toluene (15 mL) were added 1,1-diethoxypropionitrile (2.02 mL, 1.93 g, 13.5 mmol) and TsOH—H2O (171 mg, 0.90 mmol). The reaction mixture was heated at reflux for 12 h and then cooled to 25° C. DBU (0.81 mL, 0.822 g, 5.40 mmol) was added and the resulting dark brown mixture was heated at 80° C. for 1 h and then cooled to room temperature. The reaction mixture was poured onto dichloromethane (50 mL) and NH4Cl (sat. aq., 50 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×30 mL) and the combined organic extracts were washed with water (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10-30% methanol/dichloromethane) to provided 441 mg (40%) of compound 1C as a brown solid. HPLC: 100% at 3.383 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 246.09 [M+H]+. D Preparation of 4-Chloro-3-cyano-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (1D)

1. temperatureThe reaction mixture was heated
2. temperatureat reflux for 12 h
3. temperaturethe resulting dark brown mixture was heated at 80° C. for 1 h
4. temperaturecooled to room temperature
5. customthe layers were separated
6. extractionThe aqueous layer was extracted with dichloromethane (2×30 mL)
7. washthe combined organic extracts were washed with water (30 mL)
8. dry with materialdried over MgSO4
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customThe crude product was purified by silica gel column chromatography (10-30% methanol/dichloromethane)