反应详情

To a solution of 1-{[(4-fluorophenyl)amino]carbonyl}cyclopropanecarboxylic acid (21 g, 94.17 mmol) and DMF (0.11 mL) in THF (147 mL) was added oxalyl chloride (8.37 mL, 98.88 mmol) slowly to maintain a temperature in the range of 4° C. to 15° C. The solution was stirred at room temperature for about 2 h, then slowly added to a chilled (−10° C.) solution of 4-amino-2-fluoro phenol (14.05 g, 110.65 mmol) and 2,6-lutidine (21.90 mL) in THF (147 mL) over ˜45 min. The temperature was maintained at or below 0° C. throughout the addition. The suspension was stirred for 0.5-1 h at 0° C. EtOAc (210 mL) and H2O (147 mL) were added and the layers were separated. 1N HCl (105 mL) was added to the organic portion and the layers separated. 5% NaHCO3 (105 mL) was added to the organic portion and the layers separated. The solution was dried over Na2SO4 and concentrated to dryness. EtOAc (42 mL) was added to the residue and the resulting suspension was stirred at 55° C. for 1 h and cooled to 20° C. The suspension was stirred at room temperature overnight then cooled to 0-5° C. with stirring for 2-3 h. The solid was isolated by filtration and the cake was washed with 1:2 EtOAc/heptane (21 mL). The solid was dried under reduced pressure at 55° C. to give 28.43 g of the desired product (yield: 91%).

1. temperatureto maintain a temperature in the range of 4° C. to 15° C
2. additionslowly added to
3. temperatureThe temperature was maintained at or below 0° C.
4. additionthroughout the addition
5. stirringThe suspension was stirred for 0.5-1 h at 0° C
6. customthe layers were separated
7. addition1N HCl (105 mL) was added to the organic portion
8. customthe layers separated
9. addition5% NaHCO3 (105 mL) was added to the organic portion
10. customthe layers separated
11. dry with materialThe solution was dried over Na2SO4
12. concentrationconcentrated to dryness
13. additionEtOAc (42 mL) was added to the residue
14. stirringthe resulting suspension was stirred at 55° C. for 1 h
15. temperaturecooled to 20° C
16. stirringThe suspension was stirred at room temperature overnight
17. temperaturethen cooled to 0-5° C.
18. stirringwith stirring for 2-3 h
19. customThe solid was isolated by filtration
20. washthe cake was washed with 1:2 EtOAc/heptane (21 mL)
21. customThe solid was dried under reduced pressure at 55° C.