Hydrochloric Acid → 5-Difluoromethympyrazine-2-carboxylic acid

Temperature

75 °C

To a mixture of potassium salt of 5-[carboxy(difluoro)methyl]pyrazine-2-carboxylic acid (IV, 1.00 g, 3.32 mmol) which was obtained from example (1-3)-B, isopropyl acetate (4 mL), and water (2 mL) were added concentrated sulfuric acid (0.60 mL, 10.8 mmol), and the organic layer was separated. The aqueous layer was re-extracted with isopropyl acetate (4 mL) followed by combining the obtained two organic layers. After stirring the mixture at 75° C. for 16.5 h, the mixture was stirred at 80° C. for 6 h and cooled to room temperature. After polish filtration of the mixture through a filter and rising the filter with isopropyl acetate (1 mL), water (4 mL) and aqueous sodium hydroxide solution (48%, 973 mg, 8.33 mmol) were added to the filtrate, and then the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid (0.83 mL, 10.0 mmol), and the resulting mixture was stirred while in ice-cooling for 17 h. The precipitated solids were collected by filtration, washed with water (0.5 mL), and dried at 50° C. under reduced pressure to afford the title compound (V, 371 mg, 64% yield) as pale brown solids.

1. customthe organic layer was separated
2. extractionThe aqueous layer was re-extracted with isopropyl acetate (4 mL)
3. customobtained two organic layers
4. stirringthe mixture was stirred at 80° C. for 6 h
5. temperaturecooled to room temperature
6. filtrationAfter polish filtration of the mixture through
7. filtrationa filter
8. additionwere added to the filtrate
9. customthe aqueous layer was separated
10. stirringthe resulting mixture was stirred while in ice-
11. temperaturecooling for 17 h
12. filtrationThe precipitated solids were collected by filtration
13. washwashed with water (0.5 mL)
14. customdried at 50° C. under reduced pressure

ORD record

ord-0def50fa63674ab78ada1647a6bccee0

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09227942B2