Methanol → Trifluoroacetic acid

Participants

Reaction Conditions

Reaction Steps

To 3-(4-isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 23D, 0.3 g, 0.751 mmol) in dichloroethane (2 mL) and methanol (2 mL) was added azetidine-3-carboxylic acid (0.091 g, 0.901 mmol) followed by 8 drops of AcOH. The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride was added in one lot. The contents were stirred at room temperature for 30 min., concentrated, dissolved in acetonitrile (1.5 mL) and subjected to prep. HPLC purification 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). Fractions corresponding to the product were collected and concentrated. The oily residue was freeze dried to yield 1-((3-(4-isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (0.146 g, 0.244 mmol, 32.5% yield) as a tan solid. The compound had an HPLC retention time=3.55 min. (condition C); LC/MS M+1=485.4. 1H NMR (500 MHz, MeOD) δ ppm 7.83-7.94 (m, 3H) 7.50 (d, J=8.32 Hz, 1H) 7.38 (s, 1H) 7.34 (dd, J=8.05, 1.66 Hz, 1H) 4.33 (s, 2H) 4.18-4.28 (m, 3H) 3.58 (qd, J=8.37, 8.18 Hz, 1H) 3.15 (1H, hidden under CD3OD peak) 2.96-3.01 (m, 4H) 2.62 (d, J=6.94 Hz, 2H) 1.85-1.94 (m, 1H) 0.84 (d, J=6.66 Hz, 6H).

Provenance & Evidence