Acetic Anhydride → N-(2,5-dimethylpyrazol-3-yl)acetamide

Temperature

25 °C

A suspension of 2,5-dimethylpyrazol-3-amine (1 g, 9.00 mmol), potassium acetate (0.971 g, 9.90 mmol) and acetic anhydride (1.002 mL, 9.00 mmol) in EtOAc (25 mL) was stirred at 25° C. overnight. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford N-(2,5-dimethylpyrazol-3-yl)acetamide (1.400 g, 102%) as a pale yellow oil. Mass spectrum: MH+ 154 Sodium hydride (0.385 g, 9.14 mmol) was added to N-(2,5-dimethylpyrazol-3-yl)acetamide (1.4 g, 9.14 mmol) dissolved in THF (20 mL) under nitrogen. The resulting light suspension was stirred at 35° C. for 30 minutes then 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1.338 g, 4.35 mmol) was added. DMF (2 mL) was added and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL). Lithium hydroxide hydrate (0.548 g, 13.06 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc and water, the phases were separated and the organic phase washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (40 g) eluting with 0 to 50% EtOAc in DCM. After collection of the fractions and evaporation of the solvents, the resulting solid was triturated in petroleum ether, collected by filtration, washed with petroleum ether and dried to a constant weight to afford N-(2,5-dimethylpyrazol-3-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (900 mg, 54.1%) as an off-white solid.

1. additionSilica gel was added
2. concentrationthe mixture was concentrated
3. customThe crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM
4. customThe solvent was evaporated to dryness

ORD record

ord-f374e5441ee847738e47f38843b22da9

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08569298B2