反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.
实验步骤: A mixture of 150 mg (0.936 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A), 273 mg (1.03 mmol) 4,4-difluoro-3-oxobutanenitrile (Example 14A), 0.067 ml (1.17 mmol) acetic acid and 9.3 μl (0.094 mmol) piperidine in dry dichloromethane (4 ml) containing 4 Å molecular sieve was stirred under reflux for 12 h. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2-propanol (2 ml) and acetic acid (1 ml) under argon, and 510 mg (3.75 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] were added. The solution was stirred under reflux for 6 h. Upon cooling, the mixture was evaporated to dryness, and the residue was treated with toluene (4 ml) containing a small amount of p-toluenesulfonic acid. The mixture was stirred under reflux for further 12 h. Upon cooling, the mixture was evaporated to dryness again, and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient) to yield 39 mg (11% of th.) of the racemic title compound.
containing 4 Å molecular sieve
under reflux for 12 h
Then, the mixture was filtered
the filtrate was concentrated under reduced pressure
The residue was dissolved in 2-propanol (2 ml)
34, 42 (1969)] were added
The solution was stirred
under reflux for 6 h
Upon cooling
the mixture was evaporated to dryness
the residue was treated with toluene (4 ml)
containing a small amount of p-toluenesulfonic acid
The mixture was stirred
under reflux for further 12 h
Upon cooling
the mixture was evaporated to dryness again
the residue was dissolved in ethyl acetate
The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and with water
dried over sodium sulfate
concentrated under reduced pressure
The residue was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient)
来源 ID: ord-062ee56f639a4caf83fe2000865e85ad