反应详情

A suspension of 2,6-dichloro-4-iodobenzoyl chloride (24.2 g, 72.1 mmol) in THF (25 mL), was added drop-wise over 10 minutes, to a solution of 3,5-difluoropyridin-4-ylamine (10.37 g, 79.7 mmol) in pyridine (100 mL) at a temperature of between 3 and 5° C., under nitrogen. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred overnight. The volatiles were removed under reduced pressure and the resultant residue was treated with HCl (1 N, 90 mL). The resultant suspension was stirred at room temperature for 45 minutes and the precipitate obtained was collected by filtration, washing with water before drying. The resultant solid obtained was suspended in 1N NaOH (124 mL) and MeOH (124 mL), and heated at 65° C. for 5 hours then slowly cooled to room temperature. Further MeOH (50 mL) and dioxane (100 mL) were added and the reaction mixture was heated at 75° C. overnight. The resultant mixture was cooled to room temperature and the organic solvents removed under reduced pressure. The pH of the aqueous mixture was adjusted to 4-5 by drop-wise addition of 12 N HCl, controlling the exotherm by the use of an ice-bath. The residue was left standing at room temperature for 18 hours and then the resultant solid was collected by filtration, washing with water and dried under vacuum to afford the title compound as an off-white solid (21.3 g, 83% yield). LCMS (Method D): RT=3.46 min, m/z: 429 [M+H+].

1. additionwas added drop-wise over 10 minutes
2. customat a temperature of between 3 and 5° C.
3. customThe volatiles were removed under reduced pressure
4. additionthe resultant residue was treated with HCl (1 N, 90 mL)
5. stirringThe resultant suspension was stirred at room temperature for 45 minutes
6. customthe precipitate obtained
7. filtrationwas collected by filtration
8. washwashing with water
9. custombefore drying
10. customThe resultant solid obtained
11. temperaturethen slowly cooled to room temperature
12. temperaturethe reaction mixture was heated at 75° C. overnight
13. customthe organic solvents removed under reduced pressure
14. additionThe pH of the aqueous mixture was adjusted to 4-5 by drop-wise addition of 12 N HCl
15. waitThe residue was left
16. waitstanding at room temperature for 18 hours
17. filtrationthe resultant solid was collected by filtration
18. washwashing with water
19. customdried under vacuum