Ethyl difluoroacetate → 1-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethanone

Temperatur

-78 °C

To 3-neck 250-mL round bottomed flask was added THF (15 mL). The mixture was cooled to −78° C. and lithium diisopropylamide, 2.0 m solution in tetrahydrofuran/heptane/ethylbenzene (5.73 ml, 11.45 mmol) was added over 1 min. To the solution was then added 2-bromo-5-fluoro-4-(triethylsilyl)pyridine (2.89 g, 9.96 mmol) in 16 mL THF over 5 min. The temperature was not allowed to go above −70° C. during the addition. After 3 h at −78° C., ethyl difluoroacetate (1.099 ml, 10.45 mmol) was added dropwise and the resulting reaction mixture was stirred at −78° C. for 2 h. The cold bath was removed and the solution was allowed to warm to −40° C. At that point the solution was quenched with a solution of saturated NH4Cl. The solution was extracted with EtOAc (2×100 mL) and the combined extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by silica gel chromatography (0.0 to 20% EtOAc/hexane, 120 g Grace column) afforded 1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethanone (0.81 g, 2.2 mmol, 22.1% yield) as a dark orange oil. MS m/z=386, 388 M+18, Calculated for C13H17BrF3NOSi: 368.26.

1. additionto go above −70° C. during the addition
2. customthe resulting reaction mixture
3. customThe cold bath was removed
4. temperatureto warm to −40° C
5. customAt that point the solution was quenched with a solution of saturated NH4Cl
6. extractionThe solution was extracted with EtOAc (2×100 mL)
7. washthe combined extracts were washed with brine
8. dry with materialdried (Na2SO4)
9. concentrationconcentrated
10. customPurification by silica gel chromatography (0.0 to 20% EtOAc/hexane, 120 g Grace column)

ORD-Eintrag

ord-1e172c45fb7c4de183c706580395a744

Quelldatensatz

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09296734B2