Sodium hydride → 2-Chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine

Sodium hydride (60% by weight in mineral oil) (3.08 g, 77 mmol) was placed in a 500 mL round bottom flask flushed with argon. DMF (140 mL) was added and the mixture was cooled in an ice bath. 2-Chloro-4-hydroxypyridine (7.68 g, 59.3 mmol) was then added slowly over 45 minutes. After addition of the hydroxypyridine was complete 2,4,5-trifluoronitrobenzene (10.5 g, 59.3 mmol) was added as a solution in DMF (29 mL). The mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the majority of DMF in the mixture, and was then partitioned between ethyl acetate (300 mL) and 10% aqueous lithium chloride (150 mL). A precipitate formed which was removed via suction filtration and then the layers were separated. The organic layer was washed with additional 10% aqueous lithium chloride (2×150 mL), saturated aqueous sodium bicarbonate (150 mL) and brine (150 mL). The organic layer was dried over magnesium sulfate and evaporated to yield a dark red solid which was purified by silica gel chromatography (10 to 30% ethyl acetate/hexane) to give 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (13.56 g, 80% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.45 (dd, 1H), 8.39 (d, 1H), 7.87 (dd, 1H), 7.39 (d, 1H), 7.24 (dd, 1H); MS (ESI) m/z: 287.0 (M+H+).

1. customflushed with argon
2. additionDMF (140 mL) was added
3. temperaturethe mixture was cooled in an ice bath
4. concentrationThe reaction mixture was concentrated under reduced pressure
5. customto remove the majority of DMF in the mixture
6. customwas then partitioned between ethyl acetate (300 mL) and 10% aqueous lithium chloride (150 mL)
7. customA precipitate formed which
8. customwas removed via suction filtration
9. customthe layers were separated
10. washThe organic layer was washed with additional 10% aqueous lithium chloride (2×150 mL), saturated aqueous sodium bicarbonate (150 mL) and brine (150 mL)
11. dry with materialThe organic layer was dried over magnesium sulfate
12. customevaporated
13. customto yield a dark red solid which
14. customwas purified by silica gel chromatography (10 to 30% ethyl acetate/hexane)

ORD-Eintrag

ord-d72b2b51eee742e09ce08e68e54c275d

Quelldatensatz

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08637672B2