反应详情

温度

55 °C

A 1000-mL flask equipped with a mechanical stirrer, thermocouple, condenser and Teflon® fluoropolymer tubing ( 1/16″ (0.16) cm I.D.×⅛″ (0.32 cm) O.D.) (positioned such that the end of the tubing was submerged below the surface of the reaction mixture) was charged with acetic acid (226 mL). A solution of aqueous sodium hydroxide (50%, 25 g) in water (85 g) was added over 15 minutes, and then 2-amino-N,3-dimethylbenzamide (50 g, 0.305 mol) (see PCT Patent Publication WO 2006/062978 for a method of preparation) was added and the mixture was heated at 55° C. A two-necked 200-mL flask fitted on one neck with a Teflon® tubing dip tube was charged with liquid bromine (50.1 g), and the other neck was connected to the Teflon® tubing on the 1000-mL flask. Nitrogen gas was then flowed through the dip tube below the surface of the liquid bromine at a rate of about 0.012 m3 (0.4 cu ft) per h for 2.5 h, during which time all of the bromine evaporated and the bromine vapor entrained in the nitrogen gas flowed out of the two-necked 200-mL flask and entered the reaction mixture through the Teflon® tubing. The reaction temperature was held at about 55° C. during the bromine vapor addition and for 30 minutes thereafter, and then cooled to 45° C. and stirred overnight. A solution of aqueous sodium hydroxide (50%, 52 g) in water (88 mL) was added to the reaction mixture at a rate of 0.8 mL/minute. After about 10% of the total volume of the sodium hydroxide solution had been added, the addition was stopped and the reaction mixture was stirred for 1 h at 45° C. After 1 h the remaining sodium hydroxide solution was added at a rate of 0.8 mL/minute. After the addition was complete, the reaction was stirred for 30 minutes at 45° C., and then cooled to 10° C. and stirred for 1 h. The mixture was filtered and the solid collected was washed with methanol (130 mL) and water (260 mL), and then dried to a constant weight in a vacuum-oven at 45° C. to give the title compound as a solid (67 g, 99.4 area % purity by HPLC, 89.7% yield) melting at 133-135° C.

1. customA 1000-mL flask equipped with a mechanical stirrer
2. customfor a method of preparation)
3. additionwas added
4. customall of the bromine evaporated
5. additionThe reaction temperature was held at about 55° C. during the bromine vapor addition and for 30 minutes
6. temperaturecooled to 45° C.
7. additionA solution of aqueous sodium hydroxide (50%, 52 g) in water (88 mL) was added to the reaction mixture at a rate of 0.8 mL/minute
8. additionAfter about 10% of the total volume of the sodium hydroxide solution had been added
9. additionthe addition
10. stirringthe reaction mixture was stirred for 1 h at 45° C
11. additionAfter 1 h the remaining sodium hydroxide solution was added at a rate of 0.8 mL/minute
12. additionAfter the addition
13. stirringthe reaction was stirred for 30 minutes at 45° C.
14. temperaturecooled to 10° C.
15. stirringstirred for 1 h
16. filtrationThe mixture was filtered
17. customthe solid collected
18. washwas washed with methanol (130 mL) and water (260 mL)
19. customdried to a constant weight in a vacuum-oven at 45° C.