2,4,5-三氟苯酚

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared by Procedure U and Scheme AK using 2,4,5-trifluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane. Prepared by Procedure U and Scheme AK

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Potassium carbonate (53 mg, 0.39 mmol) was added to a solution of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 100 mg, 0.3 mmol) and 2,4,5-trifluoro-phenol (available from Alfa Aesar, Ward Hill, Mass., USA; 57 mg, 0.39 mmol) in dimethylformamide (5 mL). The reaction mixture was heated at 100° C. in an oil bath overnight, then it was cooled to room temperature, and water and diethyl ether were added. The aqueous phase was extracted twice with diethyl ether and three times with 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 tert-butyl ester (66 mg, 50%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.95-2.06 (m, 2H), 2.18-2.34 (m, 2H), 2.90-3.06 (m, 2H), 4.26-4.38 (m, 2H), 4.90-5.02 (m, 1H), 7.09-7.21 (m, 2H), 8.16 (s, 1H), 8.49 (s, 1H). HRMS Calcd. for C21H23F3N5O3 (MH+): 450.1748. Found: 450.1745. it was cooled to room temperature The aqueous phase was extracted twice with diethyl ether and three times with hexane The combined organic phases were evaporated the resulting residue was purified by C18 reversed phase HPLC

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 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. the reaction mixture was heated at 100° C. for 2 h 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 purified on a flash silica column (20 mm×3″) eluting with 25-33% ethyl acetate/hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared by Procedure U and Scheme AK using 2,4,5-trifluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane. Prepared by Procedure U and Scheme AK

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2,4,5-Trifluorophenol (533 mg, 3.60 mmol), 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (972 mg, 3.00 mmol), TMAD (619 mg, 3.60 mmol) and polymer-bound triphenylphosphine (Fluka) (1.2 g, 3.6 mmol) were shaken in dichloromethane (10 mL) under nitrogen for about 21 h. The polymer was filtered off and washed with dichloromethane. The solvent was evaporated and the residue was dissolved in CHCl3 and washed with 1 M Na2CO3 and brine. Removal of solvent in vacuo and purification of the residue by column chromatography on silica gel using CHCl3→CHCl3/MeOH (98:2) as eluent gave 791 mg (58%) of the title compound as its N-t-BOC derivative. The N-t-BOC intermediate (700 mg, 1.54 mmol) was treated with TFA/dichloromethane/H2O (42:53:5; 4 mL) and kept at room temperature for 50 min with stirring. The solution was concentrated and the residue precipitated with MeOH/ether. This material was dissolved in 50% aqueous MeOH and passed through an anion exchange resin (Dowex-1 X8, Cl−, 4 g) eluting with 50% aqueous MeOH. Evaporation of the solvent in vacuum gave the title compound. Yield: 513 mg (85%); mp 193-195° C.; MS-EI m/z 354 (M)+; HRMS m/z calcd for C16H17F3N4O2 (M)+ 354.1304, found 354.1301. Anal. (C16H17F3N4O2.HCl) C, H, N. The polymer was filtered off washed with dichloromethane The solvent was evaporated the residue was dissolved in CHCl3 washed with 1 M Na2CO3 and brine Removal of solvent in vacuo and purification of the residue by column chromatography on silica gel