Sodium hydride → 4-[3-Methyl-4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester

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Reaction Steps

Sodium hydride (60% dispersion in mineral oil; 7 mg, 0.18 mmol) was added to a solution of 2,4,5-trifluorophenol (18 mg, 0.12 mmol) in dimethylformamide (1 mL) and the mixture was stirred at room temperature for 15 min. A solution of 4-(4-chloro-3-methyl-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid isopropyl ester (Intermediate 21; 40 mg, 0.12 mmol) in dimethylformamide (1 mL) was added, and the reaction mixture was heated at 100° C. for 2 h. Saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (3×25 mL). The organic layer was washed with water (3 times) and brine, dried (sodium sulfate), filtered, evaporated and purified on a flash silica column (20 mm×3″) eluting with 25-33% ethyl acetate/hexanes to give 4-[3-methyl-4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (37 mg, 70%) as a white foam. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.3 Hz), 1.93-2.02 (m, 4H), 2.62 (s, 3H), 2.96-3.09 (m, 2H), 3.32 (s, 3H), 4.04-4.12 (m, 2H), 4.74-4.83 (m, 1H), 4.89-4.96 (m, 1H), 7.81-7.90 (m, 2H), 8.48 (s, 1H). Mass spectrum (ES) MH+=450.

Provenance & Evidence