Trifluoromethanesulfonic acid → HCID 70922643, compound

Temperature

50 °C

A solution of 3-(trifluoromethoxy)phenol (7.13 mL, 55.0 mmol) and 3-chloropropanoyl chloride (5.5 mL, 57.6 mmol) in trifluoroacetic acid (25 mL) was stirred 15 minutes at ambient temperature, and then heated at 50° C. for 90 minutes. After stirring at ambient temperature overnight, the solution was added over 5 minutes to preheated triflic acid (20 mL) at 50° C. After 20 minutes, the mixture was removed from the oil bath, then cooled in an ice water bath. Crushed ice was added, slowly at first, keeping the temperature of the orange solution below 25° C. Eventually a solid precipitate formed, and the suspension was diluted with MTBE (200 mL). The mixture was cooled in an ice water bath. It was washed with brine and then four times with water, partially dried (Na2SO4), filtered, and concentrated. After standing overnight, the yellow mixture was dissolved in ethanol (180 mL) and added slowly over 22 minutes to 1.5 M aqueous Na2CO3 (180 mL) cooled with a water ice bath (internal temp did not exceed 15° C.). The suspension was permitted to come to ambient temperature overnight, and was then diluted with 2:1 EtOAc/hexanes (300 mL) and filtered. The solids were rinsed with more 2:1 solution (105 mL), and the aqueous phase of the filtrate was separated and extracted with 1:1 EtOAc/hexanes (3×100 mL). The combined organic phases were washed once with water (200 mL), and the aqueous phase was back-extracted once with 1:1 solution (40 mL). The organic phases were combined and washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated, chromatographed on silica (gradient elution, 5-20% Et2O/hexanes) to give the title compound (4.95 g, 21.3 mmol, 39% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.90-7.85 (m, 1H), 7.08-7.01 (m, 2H), 4.61 (dd, 2H), 2.83 (dd, 2H).

1. waitAfter 20 minutes
2. customthe mixture was removed from the oil bath
3. temperaturecooled in an ice water bath
4. additionCrushed ice was added
5. customthe temperature of the orange solution below 25° C
6. customEventually a solid precipitate formed
7. temperatureThe mixture was cooled in an ice water bath
8. washIt was washed with brine
9. dry with materialfour times with water, partially dried (Na2SO4)
10. filtrationfiltered
11. concentrationconcentrated
12. waitAfter standing overnight
13. dissolutionthe yellow mixture was dissolved in ethanol (180 mL)
14. additionadded slowly over 22 minutes to 1.5 M aqueous Na2CO3 (180 mL)
15. temperaturecooled with a water ice bath (internal temp
16. customdid not exceed 15° C.
17. waitto come to ambient temperature overnight
18. additionwas then diluted with 2:1 EtOAc/hexanes (300 mL)
19. filtrationfiltered
20. washThe solids were rinsed with more 2:1 solution (105 mL)
21. customthe aqueous phase of the filtrate was separated
22. extractionextracted with 1:1 EtOAc/hexanes (3×100 mL)
23. washThe combined organic phases were washed once with water (200 mL)
24. extractionthe aqueous phase was back-extracted once with 1:1 solution (40 mL)
25. washwashed with brine (30 mL)
26. dry with materialdried (Na2SO4)
27. filtrationfiltered
28. concentrationconcentrated
29. customchromatographed on silica (gradient elution, 5-20% Et2O/hexanes)

ORD record

ord-adf8e46113db476bafb2f8d489f4f8e1

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08859584B2