Acetic Acid → 1-((3-(3-Phenyl-4-(trifluoromethyl)isothiazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid

Participants

Reaction Steps

To a clear solution of 3-(3-phenyl-4-(trifluoromethyl)isothiazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 103F, 40 mg, 0.094 mmol) in THF (3 mL) were sequentially added NMO (50% in water, 0.029 mL, 0.141 mmol) and osmium tetroxide (4% in water, 0.023 mL, 3.77 μmol) at room temperature. The solution was vigorously stirred at room temperature for 3 hr before additional NMO (0.05 mL) and osmium tetroxide (0.05 mL) was added. The mixture was stirred at room temperature overnight. Sodium periodate (28.2 mg, 0.132 mmol) in water (0.5 mL) was added. The mixture was stirred at room temperature under nitrogen for 0.5 h. The mixture was mixed with water (2 mL) and concentrated. The solid was filtered, washed with water (3×1 mL) and dried. The solid was mixed with MeOH (1 mL), 1,2-dichloroethane (1 mL), azetidine-3-carboxylic acid (19.06 mg, 0.188 mmol) and acetic acid (0.032 mL, 0.565 mmol). The reaction mixture was heated at 60° C. (oil bath temp.) for 1.5 h under nitrogen and then cooled to room temperature. Sodium cyanoborohydride (11.84 mg, 0.188 mmol) was added in one lot. The mixture was stirred at room temperature till the reaction was complete. The mixture was concentrated. The residue was dissolved in MeOH with some dichloromethane and TFA. 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, neutralization with aqueous NaOAc, filtration gave a white solid. The solid was triturated with a mixture of methanol and ethyl acetate to give 1-((3-(3-phenyl-4-(trifluoromethyl)isothiazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid (14 mg, 0.026 mmol, 27.9% yield) as a white solid. The compound had an HPLC retention time=3.19 min. (condition C); LC/MS M+1=512.0. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.84 (1H, d, J=7.8 Hz), 7.60-7.65 (2H, m), 7.53-7.58 (3H, m), 7.35 (1H, s), 7.32 (1H, d, J=7.8 Hz), 3.59 (2H, s), 3.42 (2H, s), 3.16-3.25 (3H, m), 3.02 (2H, t, J=6.9 Hz), 2.93 (2H, t, J=6.9 Hz).

Provenance & Evidence