The general procedure for synthesizing 5-trifluoromethylnicotinic acid from carbon dioxide and 3-bromo-5-(trifluoromethyl)pyridine is as follows:
1. 1.5 g of 3-bromo-5-(trifluoromethyl)pyridine was dissolved in 50 mL of toluene at -75 °C to prepare a solution.
2. the above solution was slowly added dropwise to a mixed system containing 9.96mL (15.9mmol) 1.6M butyl lithium hexane solution and 3.98mL (8mmol) 2M butyl magnesium chloride ethyl ether solution and 10mL THF.
3. After the dropwise addition was completed, the reaction system was kept at -75°C and continued to be stirred for 20 minutes.
4. Subsequently, 20 g (454 mmol) of dry ice was added to the reaction system and stirring was continued at -75°C for 20 minutes, then brought to room temperature and stirred for 3 hours.
5. Upon completion of the reaction, the reaction mixture was combined with 50 mL of 1 M sodium hydroxide solution and extracted twice with ether.
6. The aqueous phase was acidified to acidity with 4M hydrochloric acid and extracted with ether three times.
7. All organic phases were combined and dried with anhydrous sodium sulfate and subsequently evaporated to dryness under vacuum.
8. The residue was mixed with dichloromethane and the precipitate formed was collected by filtration.
9. Finally, the precipitate was placed in a circulating air dryer and dried at 55 °C to give the target product 5-trifluoromethylnicotinic acid.
Yield: 9% based on the theoretical value of C7H4F3NO2 (191.11).
