2749-11-3

141-78-6

94695-48-4

109-94-4

106939-34-8

Step 1: 2.6 g of sodium hydride (60% dispersed in mineral oil), 50 mL of anhydrous toluene and 8.8 g of ethyl acetate were added sequentially to a dry reaction flask. It was stirred under nitrogen protection until an off-white suspension was formed. Subsequently, 8.8 g of ethyl formate was added slowly and the reaction was stirred at room temperature until complete. Upon completion of the reaction, the mixture was filtered under reduced pressure, the filter cake was collected and washed with anhydrous ether, followed by vacuum drying to give a white solid formyl ethyl acetate sodium salt. Step 2: In another dry reaction flask, 50 mL of anhydrous toluene, 5.5 g of sodium salt of methylacetate and 1.5 g of ZIF-67 ZnCoZIF catalyst were added and mixed well with stirring at room temperature. 7.7 g of 2,3,4,5-tetrafluorobenzoyl chloride was added dropwise slowly, and after the reaction was complete, 3.2 g of S-(+)-2-aminopropanol was added slowly and the reaction was heated to reflux temperature. After the reaction was completed, it was cooled to room temperature, an aqueous layer was added, the aqueous phase was extracted with toluene three times, the organic layers were combined, and the toluene was removed by distillation under reduced pressure to obtain the preliminary product. Step 3: The preliminary product obtained in step 2 was slowly added dropwise to 30 mL of anhydrous DMF solution containing 5.8 g of potassium fluoride, stirred and heated to reflux temperature for azeotropic dehydration. After completion of the reaction, DMF was removed by evaporation under reduced pressure and the residue was washed with water to neutrality to give a brown-yellow viscous solid. After vacuum drying, the intermediate (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester was obtained.