反应详情

温度

50 °C

A suspension of 3-chloro-N-((3-chloro-5-fluorophenyl)carbamothioyl)benzamide (75 g, 219 mmol) in tert-butyl methyl ether (TBME) (1.1 L) was heated to 50° C. Next, 5-(trifluoromethyl)-1H-pyrazol-3-amine (39.6 g, 262 mmol, 1.20 equiv) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) (64.2 g, 328 mmol, 1.50 equiv) were added. The resulting reaction mixture was stirred at 50° C. for 1 hour and diluted with EtOAc (1.0 L) and water (1.0 L). The organic extract was washed with a saturated, aqueous sodium chloride solution (0.5 L), dried (Na2SO4), filtered, and concentrated. The resulting residue was diluted with EtOAc (300 mL) and this mixture was warmed to 50° C., then filtered through Celite. Next, the filtrate was concentrated to approximately 75 mL and slowly diluted with hexanes (750 mL). The resulting mixture was stirred at room temperature for 1 hour and filtered. The resulting solid was heated in acetone (100 mL), filtered, diluted with hexanes (100 mL), and the resulting mixture was heated until a clear solution developed. Next, the mixture was further diluted with hexanes (300 mL) and stirred at room temperature overnight. The resulting solids were collected by filtration, rinsed with hexanes (100 mL) and dried in vacuo at room temperature to afford (25.1 g, 25% yield) of crystalline 3-chloro-N-(((3-chloro-5-fluorophenyl)amino)((5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)methylene)benzamide acetone solvate. 1H NMR analysis indicates that the molar ratio of 3-chloro-N-(((3-chloro-5-fluorophenyl)amino)((5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)methylene)benzamide to acetone is 3 to 2. 1H NMR (DMSO-d6) of the title compound: δ 13.3 (s, 1H), 10.7 (s, 1H), 10.0 (s, 1H), 7.90 (s, 1H), 7.82 (d, 1H, J=7.6), 7.69 (d, 1H, J=8.4), 7.58 (m, 2H), 7.07 (d, 1H, J=8.4), 6.03 (s, 1H), 2.05 (s, 4H, Acetone). HPLC: 97.6% purity at 26.08 min.

1. customThe resulting reaction mixture
2. extractionThe organic extract
3. washwas washed with a saturated, aqueous sodium chloride solution (0.5 L)
4. dry with materialdried (Na2SO4)
5. filtrationfiltered
6. concentrationconcentrated
7. additionThe resulting residue was diluted with EtOAc (300 mL)
8. temperaturethis mixture was warmed to 50° C.
9. filtrationfiltered through Celite
10. concentrationNext, the filtrate was concentrated to approximately 75 mL
11. additionslowly diluted with hexanes (750 mL)
12. stirringThe resulting mixture was stirred at room temperature for 1 hour
13. filtrationfiltered
14. temperatureThe resulting solid was heated in acetone (100 mL)
15. filtrationfiltered
16. additiondiluted with hexanes (100 mL)
17. temperaturethe resulting mixture was heated until a clear solution
18. additionNext, the mixture was further diluted with hexanes (300 mL)
19. stirringstirred at room temperature overnight
20. filtrationThe resulting solids were collected by filtration
21. washrinsed with hexanes (100 mL)
22. customdried in vacuo at room temperature