Methanol → Trifluoroacetic acid

Participants

Reaction Conditions

Reaction Steps

To 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 17C, 0.22 g, 0.548 mmol) in dichloroethane (2 mL) and methanol (2.000 mL) were sequentially added azetidine-3-carboxylic acid (0.066 g, 0.658 mmol) and 8 drops of AcOH at room temperature. The contents were heated at 80° C. for 75 minutes. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (0.041 g, 0.658 mmol) was added in one lot. The contents were stirred at room temperature for 30 minutes. The reaction mixture was concentrated, dissolved in acetonitrile (1.5 mL), and subjected to prep. HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were concentrated and freeze dried to yield 1-((3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (0.135 g, 0.225 mmol, 41.0% yield) as a tan solid. The compound had an HPLC retention time=3.01 min (condition C); LC/MS M+1=487.2; 1H NMR (500 MHz, MeOD) δ ppm 8.01 (1H, d, J=7.8 Hz), 7.55 (1H, d, J=8.6 Hz), 7.50 (1H, s), 7.48 (1H, dd, J=8.0, 1.7 Hz), 7.36 (1H, d, J=2.5 Hz), 7.31 (1H, dd, J=8.6, 2.5 Hz), 4.79 (1H, spt, J=6.1 Hz), 4.46 (2H, s), 4.32-4.41 (4H, m), 3.71 (1H, quin, J=8.3 Hz), 3.04 (2H, t, J=7.1 Hz), 2.77 (2H, t, J=7.2 Hz), 1.39 (6H, d, J=6.1 Hz).

Provenance & Evidence