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

Temperature

-78 °C

To a solution of diisopropyl amine (19.79 ml, 140 mmol, 1.4 equiv.) in 100 ml THF was added at −78° C. n-BuLi (1.6 M in hexane, 81.25 ml, 130 mmol, 1.3 equiv.) within 25 min, the light yellow solution was stirred for 30 min at −78° C. and a solution of 3-chloro-4-fluoro benzotrifluoride (19.86 g, 100 mmol, 1 equiv.) in 100 ml of THF was added dropwise within 25 min keeping the temperature between −73 and −76° C. The resulting yellow solution was stirred for 1 h at −78° C., transferred into an addition funnel which was cooled with an acetone/dry ice mixture and added to a cold (−78° C.) mixture of CO2 (44.0 g, 1000 mmol, 10 equiv.) in 100 ml of THF within 1 h keeping the temperature between −75 and −78° C. Afterwards the reaction mixture was transferred into an addition funnel and added to a solution of HCl (aq., 2M, 163 ml) within 15 min at −4° C., stirred for 15 min and transferred into a separation funnel. After separation of the phases, the aqueous phase was extracted with TBME (300 ml), the combined organic phases were dried over sodium sulfate (370 g), filtered with suction on funnel with a fritted disk, washed with TBME (100 ml in total) and the TBME was removed under vacuum to yield a light yellow solid (23.48 g of crude product, 96.8% yield). The crude product was treated with methyl cyclohexane (117 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, seeding crystals (2 mg) were added and the mixture was stirred overnight at ambient temperature. After 17 h the off-white 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 (39 ml) and the crystals were dried until weight constancy to yield the product as white crystals (18.75 g, 77.3% yield).

1. customthe temperature between −73 and −76° C
2. stirringThe resulting yellow solution was stirred for 1 h at −78° C.
3. customtransferred into an addition funnel
4. customthe temperature between −75 and −78° C
5. customAfterwards the reaction mixture was transferred into an addition funnel
6. stirringstirred for 15 min
7. customtransferred into a separation funnel
8. customAfter separation of the phases
9. extractionthe aqueous phase was extracted with TBME (300 ml)
10. dry with materialthe combined organic phases were dried over sodium sulfate (370 g)
11. filtrationfiltered with suction on funnel with a fritted disk
12. washwashed with TBME (100 ml in total)
13. customthe TBME was removed under vacuum
14. customto yield a light yellow solid (23.48 g of crude product, 96.8% yield)
15. temperatureheated in a pre-heated oil bath
16. temperatureto reflux
17. waitAfter 5 min
18. customa brown clear solution was obtained
19. customthe oil bath was removed
20. temperaturethe reaction mixture was cooled to ambient temperature
21. additionseeding crystals (2 mg) were added
22. stirringthe mixture was stirred overnight at ambient temperature
23. stirringAfter 17 h the off-white suspension was stirred in an ice bath (0-5° C.) for two hours
24. filtrationthe obtained crystals were filtered off
25. washthe crystals were washed with cold methyl cyclohexane (39 ml)
26. customthe crystals were dried until weight constancy

ORD record

ord-0cf13e2694824d649d27a8cb54a15e25

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08329939B2