Triethylamine → Tert-butyl 1-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate

Participants

Reaction Steps

To a cloudy solution of 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6C, 550 mg, 1.157 mmol) and tert-butyl azetidine-3-carboxylate acetic acid (377 mg, 1.736 mmol) in anhydrous DMF (12 mL) was added triethylamine (0.645 mL, 4.63 mmol) dropwise at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 hr before being concentrated. The solid residue was partitioned between dichloromethane (2 mL) and saturated aqueous sodium bicarbonate solution (6 mL). The aqueous layer was extracted with dichloromethane (2×2 mL). The combined dichloromethane solutions were dried over sodium sulfate, concentrated and purified by silica gel chromatography (20 to 75% ethyl acetate in heptane) to afford tert-butyl 1-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate (520 mg, 0.943 mmol, 81% yield) as a solid. To the solid was added TFA (3 mL) and the mixture stirred at room temperature for 70 min before being concentrated. Dichloromethane (15 mL) was added and the mixture concentrated again. The residue was mixed with water (4 ml) and neutralized to pH=5 with an aqueous sodium acetate solution. The resulting solid was filtered and washed with water (3×1 mL). To the solid was added methanol (1 mL) and water (0.5 mL), the contents were sonicated, and filtered. To the solid was added acetonitrile (0.5 mL) and water (6 mL). Lyophilization gave 1-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid (420 mg, 0.805 mmol, 69.6% yield) as a white solid. The compound had an HPLC retention time=3.25 min. (condition C). LC/MS M+1=496.2. 1H NMR (400 MHz, MeOD+CDCl3) δ ppm 8.06 (1H, d, J=7.9 Hz), 7.77 (2H, d, J=7.3 Hz), 7.59-7.71 (3H, m), 7.51 (1H, s), 7.48 (1H, d, J=7.7 Hz), 4.42 (2H, s), 4.25-4.34 (4H, m), 3.55-3.65 (1H, m), 3.14 (4H, s).

Provenance & Evidence