Cesium carbonate → 3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-4-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid

Participants

Reaction Steps

A solution of 3-[4-(3-bromo-4-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.1 g, 0.27 mmol), 4-chloro-2-phenoxy-phenol (60 mg, 0.27 mmol), copper(I) chloride (13 mg, 0.13 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.01 mL, 0.07 mmol), and cesium carbonate (105 mg, 0.32 mmol) in NMP (3 mL) is heated to 120° C. The reaction is stirred overnight and cooled to rt. The reaction is then quenched with 1N aqueous HCl and extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude ester intermediate. The intermediate is treated with 5N NaOH (0.4 mL, 2.2 mmol) in MeOH (5 mL) and heated to reflux. The reaction is stirred at reflux for 2 hours and then cooled. The reaction is quenched with 1N aqueous HCl to obtain pH=4. The aqueous layer is extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude product. The crude is purified by prep HPLC to afford 15 mg (11%) of desired product.

Provenance & Evidence