1,1-Dichloroethane → Hydrochloric Acid

Participants

Reaction Conditions

Reaction Steps

To 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 14C, 0.06 g, 0.149 mmol) in methanol (2 mL) and dichloroethane (2 mL) was added azetidine-3-carboxylic acid (0.018 g, 0.179 mmol) followed by 5 drops of acetic acid. The contents were heated at 70° C. for 1 h. The reaction mixture was then cooled to room temperature and sodium cyanoborohydride (0.011 g, 0.179 mmol) was added in one portion at room temperature. The turbid reaction mixture became clear after 15 min. at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting white solid was partitioned between dichloromethane (20 mL) and water (10 mL). The cloudy dichloromethane layer was separated, washed with brine (2×10 mL), dried over sodium sulfate and concentrated. To the resulting semi-solid was added methanol (3 mL) and the contents were triturated and filtered. The solid was combined with the filtrate and subjected to prep. HPLC. Fractions corresponding to the product were collected and concentrated. To the solid was added acetonitrile (2 ml) and 2 mL of 6N hydrochloric acid (aq). The contents were heated at 70° C. for 30 min. The reaction mixture was concentrated, azeotroped with THF (2×2 mL) and freeze dried using acetonitrile (0.5 mL) and water (1 mL) to yield 1-((3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, hydrochloric acid (0.017 g, 0.027 mmol, 18% yield) as a pale yellow solid. LC/MS M+1=487.1; 1H NMR (400 MHz, MeOD) δ ppm 7.95-8.03 (3H, m), 7.45-7.58 (2H, m), 7.39 (1H, d, J=8.8 Hz), 4.31-4.53 (6H, m), 3.67-3.79 (1H, m), 3.04-3.15 (4H, m), 1.40 (6H, d, J=6.2 Hz).

Provenance & Evidence