A stirred slurry of tert-butyl 4-(2-hydroxy-5-iodobenzoyl)piperazine-1-carboxylate (7.06 g, 16.33 mmol) and potassium hydroxide (30% aqueous, 120 mL) in 2-propanol (200 mL) at 50° C. was treated with chlorodifluoromethane by bubbling a stream of the gaseous reagent through the stirring reaction mixture for 6 min. The reaction mixture was placed in a Parr high pressure reaction vessel, heated at 80° C. for 16 h and then cooled to ambient temperature. The resulting solution was concentrated to remove 2-propanol and the aqueous portion was extracted with ethyl acetate (3×200 mL). The organic portions were dried (Na2SO4) and concentrated. The residue was purified by reverse phase HPLC to give 5.55 g of tert-butyl 4-(2-(difluoromethoxy)-5-iodobenzoyl)piperazine-1-carboxylate as a white solid.
