Methanol → Trifluoroacetic acid

Participants

Reaction Steps

To a stirred mixture of 3-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 122C, 40 mg, 0.093 mmol), dichloromethane (4 mL) and MeOH (1 mL) was added azetidine-3-carboxylic acid (28.3 mg, 0.280 mmol) at room temperature followed by DBU (0.028 mL, 0.187 mmol). The reaction mixture was stirred at room temperature for 5 min. before sodium triacetoxyborohydride (59.4 mg, 0.280 mmol) was added in one lot. The mixture was stirred at room temperature overnight. More sodium triacetoxyborohydride (30 mg) was added and the mixture was stirred at room temperature for 4 hr. The mixture was concentrated and dissolved in methanol and dichloromethane. Purification using reverse phase 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), concentration and lyophilization gave 1-((3-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (51 mg, 0.079 mmol, 84% yield) as a white solid. The compound had an HPLC retention time=2.77 min. (condition C); LC/MS M+1=513.9; 1H NMR (400 MHz, MeOD) δ ppm 8.49 (1H, s), 8.18 (1H, s), 8.02 (1H, d, J=7.7 Hz), 7.89-7.93 (2H, m), 7.52 (1H, s), 7.49 (1H, d, J=7.7 Hz), 4.46 (2H, s), 4.31-4.42 (4H, m), 3.70 (1H, quin, J=8.3 Hz), 3.09 (2H, t, J=6.9 Hz), 2.93 (2H, t, J=7.0 Hz).

Provenance & Evidence