反应详情

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.

1. additioncontaining 4 Å molecular sieve
2. temperatureunder reflux for 12 h
3. filtrationThen, the mixture was filtered
4. concentrationthe filtrate was concentrated under reduced pressure
5. dissolutionThe residue was dissolved in 2-propanol (2 ml)
6. addition34, 42 (1969)] were added
7. stirringThe solution was stirred
8. temperatureunder reflux for 6 h
9. temperatureUpon cooling
10. customthe mixture was evaporated to dryness
11. additionthe residue was treated with toluene (4 ml)
12. additioncontaining a small amount of p-toluenesulfonic acid
13. stirringThe mixture was stirred
14. temperatureunder reflux for further 12 h
15. temperatureUpon cooling
16. customthe mixture was evaporated to dryness again
17. dissolutionthe residue was dissolved in ethyl acetate
18. washThe organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and with water
19. dry with materialdried over sodium sulfate
20. concentrationconcentrated under reduced pressure
21. customThe residue was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient)