反应详情

N-((2-Chloro-4-fluorobenzyl)carbamothioyl)-3,4-difluorobenzamide (98.0 g, 273 mmol) and 5-amino-3-trifluoromethylpyrazole (41.3 g, 273 mmol) were dissolved in THF (546 mL). N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (57.6 g, 300 mmol) was added and the reaction was stirred at room temperature for 1 h and then heated to 40° C. for 15 h. The crude mixture was diluted with water (500 mL) and isopropyl acetate (500 mL). The organic layer was washed with brine (500 mL), dried over sodium sulfate, and concentrated. The residue was diluted with isopropyl acetate (1.3 L) and heated to 65° C. for 1 hour. The solution was allowed to cool to room temperature, filtered and the filtrate was concentrated. The residue was heated to 70° C. in acetonitrile (900 mL) and then allowed to cool to room temperature. The resulting suspension was filtered, rinsed with acetonitrile (200 mL) and dried in vacuo at 60° C. to afford 55 g (43%) of (Z)—N-(((2-chloro-4-fluorobenzyl)amino)((3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methylene)-3,4-difluorobenzamide as a white solid. 1HNMR (400 MHz, MeOH-d4) δ 7.95 (bs, 2H), 7.50 (t, 1H, J=7.2 Hz), 7.26 (m, 2H), 7.06 (t, 1H, J=7.5 Hz), 6.56 (s, 1H), 4.84 (s, 2H).

1. temperatureheated to 40° C. for 15 h
2. washThe organic layer was washed with brine (500 mL)
3. dry with materialdried over sodium sulfate
4. concentrationconcentrated
5. additionThe residue was diluted with isopropyl acetate (1.3 L)
6. temperatureheated to 65° C. for 1 hour
7. temperatureto cool to room temperature
8. filtrationfiltered
9. concentrationthe filtrate was concentrated
10. temperatureThe residue was heated to 70° C. in acetonitrile (900 mL)
11. temperatureto cool to room temperature
12. filtrationThe resulting suspension was filtered
13. washrinsed with acetonitrile (200 mL)
14. customdried in vacuo at 60° C.