反应详情

温度

75 °C

A solution of 2,2-difluoro-1-[3-(trifluoromethyl)phenyl]propan-1-one (1.19 g, 4.99 mmol) in ethanol (15 ml) was admixed with water (1.5 ml), hydroxylamine hydrochloride (695 mg, 10.0 mmol) and sodium acetate (922 mg, 11.2 mmol) and stirred at 75° C. for 21 h. The mixture, having been cooled to room temperature, was concentrated under reduced pressure, taken up in hydrochloric acid (1M) and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The remaining solid was dissolved in tetrahydrofuran (15 ml) and cooled to 0° C. under argon. Then lithium aluminium hydride (362 mg, 9.08 mmol) was added, and the mixture was first warmed up to room temperature and then heated under reflux for 2 h. Then the reaction mixture was cooled to 0° C. and first admixed with saturated ammonium chloride solution, diluted with sodium hydroxide solution (1 M) and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue was dissolved in N,N-dimethylformamide (7.5 ml) and admixed successively with (2E)-3-[3-chloro-4-(cyclopropylcarbamoyl)phenyl]acrylic acid (250 mg, 0.94 mmol) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (270 mg, 0.97 mmol) and stirred at room temperature overnight. The reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10% acetonitrile in water to 100% acetonitrile).

1. temperatureThe mixture, having been cooled to room temperature
2. concentrationwas concentrated under reduced pressure
3. extractionextracted with ethyl acetate
4. dry with materialThe combined organic phases were dried over sodium sulphate
5. concentrationconcentrated under reduced pressure
6. dissolutionThe remaining solid was dissolved in tetrahydrofuran (15 ml)
7. temperaturecooled to 0° C. under argon
8. temperaturethe mixture was first warmed up to room temperature
9. temperatureheated
10. temperatureunder reflux for 2 h
11. temperatureThen the reaction mixture was cooled to 0° C.
12. extractionextracted with ethyl acetate
13. dry with materialThe organic phase was dried over sodium sulphate
14. filtrationfiltered
15. concentrationconcentrated to dryness under reduced pressure
16. dissolutionThe residue was dissolved in N,N-dimethylformamide (7.5 ml)
17. stirringstirred at room temperature overnight
18. extractionextracted with ethyl acetate
19. washThe organic phase was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution
20. dry with materialdried over sodium sulphate
21. filtrationfiltered
22. concentrationconcentrated to dryness under reduced pressure
23. customThe residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10% acetonitrile in water to 100% acetonitrile)