Hexachloroethane → 4-Chloro-6-(trifluoromethyl)nicotinic acid

Temperature

-78 °C

A solution of 2,2,6,6-tetramethylpiperidin (198.8 g, 1.41 mol) in tetrahydrofuran (1.5 L) was added n-butyl-lithium (564 mL, 1.41 mol) dropwise at −78° C. Then the mixture was stirred from −78° C.˜−30° C. for 30 minutes. Then the mixture was cooled to −78° C. and a solution of 6-(trifluoromethyl)nicotinic acid (90 g, 1.47 mol) in tetrahydrofuran (2.5 L) added dropwise at −78° C., then the mixture was stirred from −78° C.-−40° C. for 1 hour. The mixture was cooled to −78° C. and a solution of hexachloroethane (222.5 g, 0.94 mol) was added to the reaction mixture dropwise. The mixture was stirred at −78° C. for 3 hours. Aqueous ammoniumchloride (1500 mL) was added to the mixture slowly at −78° C. and the mixture was stirred at room temperature for 20 minutes. The mixture was extracted with ethyl acetate (1 L*3). The combined organic layer was concentrated and the residue was purified by silica gel chromatography eluted with dichloromethane: methanol=20:1 to yield 4-chloro-6-(trifluoromethyl)nicotinic acid (Int-11) (85 g, 80%) as a brown solid.

1. stirringthe mixture was stirred from −78° C.-−40° C. for 1 hour
2. temperatureThe mixture was cooled to −78° C.
3. stirringThe mixture was stirred at −78° C. for 3 hours
4. stirringthe mixture was stirred at room temperature for 20 minutes
5. extractionThe mixture was extracted with ethyl acetate (1 L*3)
6. concentrationThe combined organic layer was concentrated
7. customthe residue was purified by silica gel chromatography
8. washeluted with dichloromethane

ORD record

ord-b68d8cb9b1094c47bed6241c5c5a5f42

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09301526B2