Potassium Phosphate, Tribasic → HCID 58042453, compound

Temperature

80 °C

2-Bromo-3-(1,1-difluoroethoxy)pyridine (Preparation 266, 700 mg, 2.948 mmol), cycloproyl boronic acid (252 mg, 2.94 mmol), and potassium phosphate tribasic (1.56 g, 7.35 mmol) were suspended in a mixture of toluene (100 mL) and water (20 mL), with rapid stirring. The suspension was heated to 80° C., and the solvent de-gassed by direct bubbling of N2 gas through the suspension for 30 minutes. The reaction was then heated to 95° C., and tricyclohexyl phosphine (82 mg, 0.29 mmol), rapidly followed by palladium acetate (33 mg, 0.15 mmol), were added. The reaction was left to stir and heat at 95° C. for 18 hours. The reaction was cooled to room temperature, and filtered through a plug of arbocel, eluting with ethyl acetate. The solvent was removed to leave a dark yellow oil. Ethyl acetate was added (100 mL), and the organic phase extracted with 2M HCl solution (3×100 mL). The organic phase was discarded. Ethyl acetate (150 mL) was added to the combined aqueous layers, and solid sodium bicarbonate was added until the aqueous layer reached pH 7. The mixture was transferred to a separating funnel, the organic layer was removed and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed to leave a yellow oil. The material was purified by silica gel column chromatography eluting with 1:1 heptane:ethyl acetate to afford the title compound as a colourless oil (252 mg, 43%).

1. customthe solvent de-gassed
2. customby direct bubbling of N2 gas through the suspension for 30 minutes
3. temperatureThe reaction was then heated to 95° C.
4. additionwere added
5. waitThe reaction was left
6. temperatureheat at 95° C. for 18 hours
7. temperatureThe reaction was cooled to room temperature
8. filtrationfiltered through a plug of arbocel
9. washeluting with ethyl acetate
10. customThe solvent was removed
11. customto leave a dark yellow oil
12. extractionthe organic phase extracted with 2M HCl solution (3×100 mL)
13. additionEthyl acetate (150 mL) was added to the combined aqueous layers, and solid sodium bicarbonate
14. additionwas added until the aqueous layer
15. customThe mixture was transferred to a separating funnel
16. customthe organic layer was removed
17. extractionthe aqueous layer was extracted with ethyl acetate (2×100 mL)
18. dry with materialThe combined organic phases were dried over magnesium sulfate
19. filtrationfiltered
20. customthe solvent removed
21. customto leave a yellow oil
22. customThe material was purified by silica gel column chromatography
23. washeluting with 1:1 heptane

ORD record

ord-98378a34d1a44aa7ba500614d5db8ecd

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08592629B2