Toluene → 4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester

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Reaction Steps

A solution of 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 59; 400 mg, 0.84 mmol) in a mixture of trifluoroacetic acid (3 mL) and dichloromethane (7 mL) was stirred at room temperature for 45 min. The solvents were evaporated and the residue was co-evaporated three times with dichloromethane, dried under high vacuum, and then diluted with 1M aqueous sodium carbonate solution. The mixture was extracted twice with dichloromethane and twice with 10% methanol/chloroform. The combined organic layers were dried (sodium sulfate) and evaporated. A solution of the residue in tetrahydrofuran (6 mL) and triethylamine (0.23 mL, 1.65 mmol) was cooled to −20° C. under nitrogen and a solution of isopropyl chloroformate in toluene (1 M; 0.8 mL, 0.8 mmol) was added. The mixture was stirred at −10° C. to −20° C. for 45 min, then allowed to reach room temperature, and then filtered through a Millipore filter. The filter was washed with tetrahydrofuran and ethyl acetate and the combined filtrate and washings were evaporated. The crude material was purified on a flash silica column (30 mm×4″) eluting with 75-83% ethyl acetate/hexanes to give 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (235 mg, 61%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.3 Hz), 1.92-2.04 (m, 4H), 2.98-3.12 (m, 2H), 3.28-3.30 (m, methyl sulfone and water peak), 4.07-4.15 (m, 2H), 4.75-4.84 (m, 1H), 4.96-5.05 (m, 1H), 7.60-7.63 (m, 2H), 8.02-8.05 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum (ES) MH+=460.

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