Toluene → 5-Bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid

Participants

Reaction Conditions

Reaction Steps

A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser, solids addition system and temperature probe was charged with 2,5-dibromobenzoic acid (2685 g, 9.6 mol) and copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) and EtOAc (20 mL) were then added to the reactor, followed by 2-methoxy-4-fluorophenol (1500 g, 10.6 mol). With vigorous stirring cesium carbonate (6258 g, 19.2 mol) was added to the mixture in portions. The mixture was heated to 90° C. for 4 hours. The mixture was cooled to 35° C. and water (15 L) was added. After 15 minutes of stirring the phases were sping and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the mixture, followed by 6 M HCl (5.6 L) keeping the internal temperature below 30° C. The layers were separated and the organics were dried over MgSO4. Filtration through a pad of celite and concentration provided a solid that was reslurried in 915 mL of EtOAc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. The solids were dried to provide 2560 g of 5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a cream colored solid.

Provenance & Evidence