To a clean, dry 100-gallon reactor with stirring under nitrogen add N-methyl pyrrolidinone (83.4 L), sodium acetate (2.706 kg, 32.98 mol), 3-[2-(2-bromo-5-fluoro-phenoxymethyl)-phenyl]-acrylic acid ethyl ester (9.256 kg, 21.99 mol) and tetrabutylammonium bromide (7.088 kg, 21.99). Initiate stirring and de-gas the reaction mixture under full vacuum for 30 min, purging with nitrogen. Allow the reactor to return to ambient pressure under nitrogen and repeat the degassing procedure. Add palladium (II) acetate (167 g, 2% weight) to the reaction mixture. Heat the reaction to between 100° C. and 125° C., stirring for a minimum of 3 to 5 h. Add ethyl acetate (100 L) and stir 30 min. Add water (100 L) and stir 30 min. Discontinue stirring and allow the layers to separate for a minimum of one hour. Collect the organic layer and extract the aqueous layer with ethyl acetate (50 L, then 25 L). Combine the organic portions and wash with water (40 L), a 20% aqueous sodium chloride solution (2×20 L), stirring for a minimum of 30 min each and allowing at least 30 min for layer separation. Dry the organic solution with magnesium sulfate (8.0 kg) and add activated carbon (2.0 kg) and silica gel 60 (2.0 kg), stirring for a minimum of one hour. Filter to remove the solids. Concentrate the filtrate to dryness under vacuum at <35° C. Add methanol (20 L) to the solid residue and heat the mixture to a clear solution at 50-60° C. Add heptane (40 L) and cool to between 20° C. and 25° C. Continue to further cool the reaction mixture to −10° C. over a minimum of 3 h. Stir at −10° C. for a minimum of 12 h. Filter to collect the resulting solid product, washing with a mixture of heptane:methanol, (75:25) (2×20 L). Dry the solids under vacuum at <40° C. to a constant weight to obtain the title compound (3.7 kg, 64%).
