反应详情

温度

40 °C

A mixture of 4-[4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 35; 66 mg, 0.15 mmol) and 4M HCl in 1,4-dioxane (10 mL) was stirred at 40° C. for 1 h. The solvent was evaporated under vacuum to provide 1-piperidin-4-yl-4-(2,4,5-trifluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride as a solid which was used directly in the next step without purification. Dichloromethane (5 mL) was added, and the mixture was cooled to about 0° C. using an ice-water bath. Isopropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 0.22 mL, 1.0 M in toluene, 0.22 mmol) was added, followed by triethylamine (0.13 mL, 0.96 mmol). The mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. Water and dichloromethane were added and the aqueous phase was extracted twice with each of the following solvents: dichloromethane, ether and hexane. The combined organic phases were evaporated and the resulting residue was purified by C18 reversed phase HPLC using a gradient of 20-100% acetonitrile/water to give 4-[4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (47 mg, 73%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 1.28 (d, 6H, J=6.2 Hz), 1.98-2.05 (m, 4H), 2.18-2.25 (m, 2H), 3.00-3.10 (m, 2H), 4.08-4.15 (m, 2H), 4.80-4.82 (m, 1H), 5.00-5.05 (m, 1H), 7.88-7.94 (m, 2H), 8.47 (s, 1H), 8.59 (s, 1H). Mass spectrum MH+=436. HRMS Calcd. For C20H21F3N5O3 (MH+): 436.1591. Found: 436.1589.

1. customThe solvent was evaporated under vacuum