Hydrochloric Acid → 4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2-fluoro-1-fluoromethyl-ethyl ester

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Reaction Conditions

Reaction Steps

Triphosgene (208 mg, 0.7 mmol) was added to a solution of 1,3-difluoro-2-propanol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 192 mg, 2 mmol) in a mixture of pyridine (2.2 mmol) and 1,2-dichloroethane (10 mL). The solution was stirred at 40° C. for 3 h and then cooled to room temperature. 1 M aqueous hydrochloric acid (2.5 mL) and water (5 mL) were added. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried (magnesium sulfate), filtered, and evaporated. 4-(4-Methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 200 mg, 0.41 mmol) and diisopropylethylamine (350 μL) were added and the mixture was stirred for 15 min and then chromatographed, eluting with 50-75% ethyl acetate/hexanes, to give 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2-fluoro-1-fluoromethyl-ethyl ester (64 mg, 32%) as a foamy solid.

Provenance & Evidence