Propargyl alcohol → (E)-4-((3,5-difluoro-4-((3,3-difluoro-1-propene-1-yl)oxy)phenoxy)difluoromethyl)-4'-propyl-1,1'-bi(cyclohexane)

Temperature

50 °C

In toluene, 4-(difluoro(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)methoxy)-2,6-difluorophenol (T-1, 4.02 g, 10 mmol) prepared according to a publicly known method, propargyl alcohol (2.96 mL, 50 mmol), triethylamine (4.16 g, 30 mmol) and manganese dioxide (17.4 g, 200 mmol) were stirred at 50° C. for 14 hours. The resultant reaction suspension was allowed to cool to room temperature, and then subjected to Celite filtration, a manganese residue was washed with acetone (120 mL), and thus the resulting filtrate was concentrated. The resulting concentrated residue was dissolved into hexane, and cooled to −78° C., and a resulting deposit was sucked and taken by filtration and dried under reduced pressure to give (T-2) (4.57 g, 10 mmol) as a pale yellow solid. (T-2) contained an enal intermediate corresponding to 4.32 g (9.45 mmol, 95%) and 3-propargyloxy-2-propene-1-al corresponding to 0.25 g (0.55 mmol) (calculated from 1H-NMR). The resulting pale yellow solid (4.57 g) was dissolved in 1,2-dichloroethane (20 ml), 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (3.51 ml, 30 mmol) and a 70% hydrogen fluoride-pyridine complex (390 mL, 15 mmol) were added thereto, and the resulting mixture was heated at 70° C. for 65 hours. After completion of the reaction, the reaction mixture allowed to cool to room temperature was poured into a saturated aqueous solution of sodium hydrogencarbonate (300 mL), and extracted with chloroform (240 mL×2). Combined organic layers were dried over anhydrous magnesium sulfate, the resulting residue concentrated under reduced pressure was purified by silica gel column chromatography (elution solvent: hexane), and then the resulting white solid (2.38 g) was dissolved into hexane at room temperature and cooled to −78° C., and a precipitated crystal was sucked and taken by filtration, and then dried under reduced pressure to give 2.29 g (4.78 mmol, two steps, 47.8%) of a target compound (No. 38).

1. customThe resultant reaction suspension
2. temperatureto cool to room temperature
3. filtrationsubjected to Celite filtration
4. washa manganese residue was washed with acetone (120 mL)
5. concentrationthus the resulting filtrate was concentrated
6. dissolutionThe resulting concentrated residue was dissolved into hexane
7. temperaturecooled to −78° C.
8. filtrationtaken by filtration
9. customdried under reduced pressure
10. customto give (T-2) (4.57 g, 10 mmol) as a pale yellow solid
11. temperaturethe resulting mixture was heated at 70° C. for 65 hours
12. customAfter completion of the reaction
13. temperatureto cool to room temperature
14. extractionextracted with chloroform (240 mL×2)
15. dry with materialCombined organic layers were dried over anhydrous magnesium sulfate
16. concentrationthe resulting residue concentrated under reduced pressure
17. customwas purified by silica gel column chromatography (elution solvent: hexane)
18. dissolutionthe resulting white solid (2.38 g) was dissolved into hexane at room temperature
19. temperaturecooled to −78° C.
20. filtrationtaken by filtration
21. customdried under reduced pressure
22. customto give 2.29 g (4.78 mmol, two steps, 47.8%) of a target compound (No

ORD record

ord-aa15a997d4ec411984b286958e5103f6

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296951B2