Diisopropylamine → 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of diisopropylamine (0.072 mL, 0.508 mmol) in anhydrous THF (0.5 mL) was added a 2.5 M THF solution of n-BuLi (0.203 mL, 0.508 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at the same temperature for 15 min. before being cooled to −78° C. A solution of furan-3-carboxylic acid (28.5 mg, 0.254 mmol) in anhydrous THF (1 mL) was added. The reaction mixture was stirred at −78° C. for 30 min. before a solution of 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 89B, 80 mg, 0.195 mmol) in anhydrous THF (1 mL) was added at the same temperature. The mixture was then allowed to warm to room temperature over 30 min. The reaction was quenched with water (3 mL). The mixture was concentrated and the aqueous residue was acidified with 10% aqueous citric acid solution to pH=3. The mixture was extracted with ethyl acetate (2×3 mL). The combined organic solutions were dried (sodium sulfate) and concentrated to give 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid (110 mg, 0.211 mmol, 108% yield) as green foam solid. Next, 48 mg of the solid was purified by reverse phase preparative HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) to give 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid, TFA (32 mg) as white solid. The compound had an HPLC retention time=3.42 min. (condition C); LC/MS M+1=522.2; 1H NMR (400 MHz, MeOD) δ ppm 8.14 (1H, s), 7.88 (1H, d, J=7.9 Hz), 7.54-7.63 (6H, m), 7.48-7.52 (2H, m), 7.47 (1H, d, J=7.9 Hz), 6.72 (1H, d, J=2.0 Hz), 6.56 (1H, s), 3.03 (2H, t, J=6.9 Hz), 2.89 (2H, t, J=6.9 Hz).

Provenance & Evidence