Carbon Dioxide → 3-Chloro-2-fluoro-5-(trifluoromethyl)benzoic acid

Temperature

50 °C

To a mixture of ethyl magnesium bromide solution (6.25 ml, 6.25 mmol, 1.25 equiv., 1M in THF) and diisopropyl amine (77.7 μl, 0.5 mmol, 0.1 equiv.) was added 3-chloro-4-fluoro-benzo trifluoride (0.99 g, 5 mmol in THF (2 ml)) at ambient temperature and the mixture was heated in an oil bath to 50° C. for 13 h. The brown clear reaction mixture was cooled to 0-5° C., was transferred into a syringe and added dropwise to a solution of CO2 (2.2 g, 50 mmol, 10 equiv.) in THF (5 ml) at −70° C. and stirred for 15 min. To the brown suspension was added HCl (1M, 14 ml) and the phases were separated. The aqueous phase was extracted with TBME (10 ml), the combined organic phases were dried over sodium sulfate, filtered, washed with TBME and the solvents were removed under vacuum to yield a dark brown oil (0.97 g of the crude product). The crude product was treated with methyl cyclohexane (4.4 ml) and heated in a pre-heated oil bath to reflux. After 5 min, a brown clear solution was obtained, the oil bath was removed, the reaction mixture was cooled to ambient temperature and the formed suspension was stirred overnight at ambient temperature. After 18 h the brown suspension was stirred in an ice bath (0-5° C.) for two hours, the obtained crystals were filtered off, the crystals were washed with cold methyl cyclohexane (1.6 ml) and the crystals were dried until weight constancy to yield the product as white crystals (0.46 g, 38.2% yield).

1. temperatureThe brown clear reaction mixture was cooled to 0-5° C.
2. customwas transferred into a syringe
3. customthe phases were separated
4. extractionThe aqueous phase was extracted with TBME (10 ml)
5. dry with materialthe combined organic phases were dried over sodium sulfate
6. filtrationfiltered
7. washwashed with TBME
8. customthe solvents were removed under vacuum
9. customto yield a dark brown oil (0.97 g of the crude product)
10. temperatureheated in a pre-heated oil bath
11. temperatureto reflux
12. waitAfter 5 min
13. customa brown clear solution was obtained
14. customthe oil bath was removed
15. temperaturethe reaction mixture was cooled to ambient temperature
16. stirringthe formed suspension was stirred overnight at ambient temperature
17. stirringAfter 18 h the brown suspension was stirred in an ice bath (0-5° C.) for two hours
18. filtrationthe obtained crystals were filtered off
19. washthe crystals were washed with cold methyl cyclohexane (1.6 ml)
20. customthe crystals were dried until weight constancy

ORD record

ord-29c87fa3b9ed4b55908307e669c9759d

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08329939B2