反应详情

A 20% solution of trifluoroacetic acid in dichloromethane (12 mL) was added to a solution of 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 60; 520 mg, 1.06 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature until TLC (6% methanol/dichloromethane) showed that all of the starting material had reacted. Volatiles were evaporated. Ether (5 mL) was added, and the solvents were evaporated again. The resulting white semi-solid was held under vacuum, then triturated with ether and held under vacuum again to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine trifluoroacetate salt (479 mg, 90%) as a white powder. A portion of this material (200 mg, 0.4 mmol) was taken up in anhydrous dichloromethane (5 mL) with diisopropylethylamine (210 μL, 1.2 mmol) and the resulting suspension was cooled to about 0° C. Ethyl chloroformate (57 μL, 0.6 mmol) was added, and the reaction mixture was stirred at 0° C. for 2 min and then at room temperature for 30 min. Water (5 mL) was added, and the layers were separated. The organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, and purified on a 4 g Isco column, eluting with 0-10% methanol/dichloromethane, to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid ethyl ester (140 mg, 77%). 1H NMR (300 MHz, DMSO-d6) δ 1.19 (t, 3H, J=7.1 Hz), 1.95-2.06 (m, 4H), 3.05-3.14 (m, 2H), 4.02-4.16 (m, 4H), 4.98-5.07 (m, 1H), 7.82 (dd, 1H, J=7.1, 8.5 Hz), 7.89 (dd, 1H, J=1.8, 8.8 Hz), 8.06 (dd, 1H, J=2.0, 9.5 Hz), 8.50 (s, 1H), 8.56 (s, 1H).

1. customhad reacted
2. customVolatiles were evaporated
3. additionEther (5 mL) was added
4. customthe solvents were evaporated again
5. customtriturated with ether