Acetic Acid → Trifluoroacetic acid

Participants

Reaction Conditions

Reaction Steps

A mixture of 3-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 118E, 20 mg, 0.047 mmol), 1,2-dichloroethane (0.4 mL), MeOH (0.4 mL), azetidine-3-carboxylic acid (14.26 mg, 0.141 mmol) and acetic acid (0.016 mL, 0.282 mmol) was heated at 50° C. (oil bath temp.) for 1 h under nitrogen. The mixture was cooled to room temperature and sodium triacetoxyborohydride (29.9 mg, 0.141 mmol) was added in one lot. The contents were stirred at room temperature for 3 hr. The mixture was concentrated and dissolved in methanol (1.8 mL) and dichloromethane (0.2 mL). 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-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (16 mg, 0.025 mmol, 52.3% yield) as a white solid. The compound had an HPLC retention time=3.77 min. (condition C); LC/MS M+1=511.2; 1H NMR (400 MHz, MeOD) δ ppm 7.99-8.05 (3H, m), 7.78 (1H, d, J=8.6 Hz), 7.51 (1H, d, J=1.1 Hz), 7.47 (1H, dd, J=7.9, 1.8 Hz), 4.46 (2H, s), 4.33-4.38 (4H, m), 3.63-3.74 (1H, m), 3.09-3.15 (4H, m), 3.00 (1H, t, J=11.7 Hz), 1.77-1.96 (5H, m), 1.54-1.67 (2H, m, J=12.0, 12.0, 11.9, 2.1 Hz), 1.35-1.53 (3H, m).

Provenance & Evidence