2-Cyano-3,5-difluoropyridine → 5-Tert-butoxy-3-fluoropyridine-2-carbonitrile

A solution (30 mL) of 3,5-difluoropyridine-2-carbonitrile (1.51 g, 10.8 mmol) in tert-butanol was added dropwise to a solution (40 mL) of sodium tert-butoxide (1.04 g, 10.8 mmol) in tert-butanol (40 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give a mixture (1.63 g) of 5-tert-butoxy-3-fluoropyridine-2-carbonitrile and 3-tert-butoxy-5-fluoropyridine-2-carbonitrile. To the obtained mixture (1.62 g, 8.34 mmol) was added 4N hydrogen chloride-dioxane (40 mL), and the mixture was stirred at 60° C. for 2 hr, and concentrated. To a solution of the obtained residue (1.46 g, 8.34 mmol) and potassium carbonate (2.31 g, 16.7 mmol) in DMF (20 mL) was added cyclopropylmethyl bromide (1.21 mL, 12.5 mmol), and the mixture was stirred at 60° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0 to 7:3) to give the title compound (365 mg, yield 23%).

1. washthe mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine
2. dry with materialdried over anhydrous sodium sulfate
3. customThe solvent was evaporated under reduced pressure
4. customthe obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1)

ORD-Eintrag

ord-9acbb14466594e2db55cf97eb9b87557

Quelldatensatz

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08501804B2