Potassium Carbonate → 6-(4-{[3-(2,6-Dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}phenyl)-2-naphthoic acid

Participants

Reaction Steps

To solution of methyl 6-(4-hydroxyphenyl)-2-naphthoate (55 mg, 0.20 mmol) in DMF (1.0 mL) was added K2CO3 (68 mg, 0.49 mmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole (91 mg, 0.30 mmol) and the mixture was stirred at ambient temperature for 12 hr. Additional 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole (50 mg, 0.16 mmol) and K2CO3 (68 mg, 0.49 mmol) in DMF (0.5 mL) was added and the mixture stirred at 70° C. for 3 hr. The solution was diluted with 50 mL EtOAc then washed with three 25 mL portions of H2O followed by 25 mL of brine then dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (12 g of silica gel eluting with 0-40% EtOAc in hexanes over 45 minutes.) Product fractions were pooled and concentrated. To this residue was added EtOH (2.5 mL), THF (1.0 mL), H2O (0.5 mL) and NaOH (35 mg, 0.84 mmol) and the solution was stirred at 60° C. for 12 hr. The solution was concentrated to ˜⅓ volume then added dropwise to 1.0 N HCl (6 mL, aq.) The resulting solids were collected by suction filtration, washed with H2O and dried to give the title compound as an off-white solid (42 mg, 94%.) 1H NMR (DMSO-d6): δ 13.0 (broad s, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 8.12 (d, J=9 Hz, 1H), 8.01 (d, J=9 Hz, 1H), 7.95 (d, J=9 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.69 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.59-7.51 (m, 1H), 6.91 (d, J=8 Hz, 2H), 4.87 (s, 2 H), 3.45 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 532 (M+H)+.

Provenance & Evidence