General procedure for the synthesis of 2-methoxy-4-chloro-5-fluoropyrimidine from 2-methoxy-5-fluorouracil: 14.4 g of 2-methoxy-5-fluorouracil (compound IV) was dissolved in 29 mL of toluene and 15.2 g of triethylamine was added as a base. The reaction mixture was heated to 50-80 °C and 18.4 g of trichlorophosphorus was slowly added dropwise. After the dropwise addition, the temperature was maintained and the reaction was continued with stirring for 5-7 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched by addition of water. The organic and aqueous phases were separated and the organic phase was collected. The organic phase was concentrated under reduced pressure to remove the solvent to afford 15.4 g of 2-methoxy-4-chloro-5-fluoropyrimidine (Compound III, straw-colored liquid) in 95.0% molar yield and 95.8% HPLC purity.
