Sulfuric Acid → 3-(Pyridine-2-yl)-5-trifluoromethylpyrazole

2-(2′,4′-difluorophenyl)pyrazole (3.6 g, 20 mmol) and K3IrBr6 (6.3 g, 8 mmol) were added to a flask containing 90 ml 2-ethoxyethanol and 30 ml water. The reaction mixture was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the pale yellow precipitate was vacuum filtered and washed first with ethanol followed by heptanes. The product [2-(4′,6′-diflouorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-diflouorophenyl)pyrazole]2 was dried in vacuum oven (4.2 g, 81%). Step 2 To a 60 ml THF suspension of potassium t-butoxide (7.9 g, 59 mmol) and 2-acetylpyridine(7.1 g, 59 mmol) was added dropwise ethyl trifluoroacetate (10 g, 70 mmol) at 10° C., and the mixture was stirred at room temperature for 15 h. After the PH value of the mixture had been adjusted to 6-7 with 10% H2SO4, the solution was extracted with Et2O. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel with CH2Cl2 followed by recrystallization from ethanol to give 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (10.2 g, 81%). Step 3 Hydrazine hydrate (1.44 g, 27.7 mmol) was added dropwise to 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (5 g, 23 mmol) in 250 ml diethyl ether, and the mixture was stirred at ambient temperature for 3.5 h. Most of the solvent was evaporated and the mixture was extracted with water. The organic layer was dried (MgSO4) and evaporated to give 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 78%). Step 4 Compound 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 24 mmol) was boiled under reflux in 300 ml ethanol in the presence of conc. sulfuric acid (1.85 ml) for 30 min. The reaction mixture was then extracted with water. Evaporation and chromatography (ethyl acetate/heptanes 1:5) gave 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (4.2 g, 85%). Step 5 [2-(4′,6′-difluorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-difluorophenyl)pyrazole]2 (0.15 g, 0.12 mmol), 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (70 mg, 0.3 mmol) and 0.2 g of K2CO3 were refluxed under an nitrogen atmosphere in 2-ethoxyethanol for 18 h. After cooling to room temperature, water was added and a white precipitate was filtered and washed with water. The crude product was chromatographed on a silicon column with dichloromethane/methanol (9:1 v/v) as the mobile phase (110 mg, 60%).

1. extractionThe reaction mixture was then extracted with water
2. customEvaporation and chromatography (ethyl acetate/heptanes 1:5)

ORD record

ord-3cd2e12b66604484bccc29399bdc8bb7

Source dataset

uspto-grants-2009_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07473477B2