Hydrochloric Acid → Methyl 5-(2-ethoxy-1,1-difluoro-2-oxoethyl)pyrazine-2-carboxylate

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To the mixture of zinc powder (46.0 g, 0.703 mol) and triglyme (352 mL) was added TMSBr (9.12 mL, 0.070 mol) under nitrogen, and the mixture was stirred at 70° C. for 1.5 h. After the mixture was cooled to room temperature, ethyl bromodifluoroacetate (108.6 mL, 0.847 mol) was added while keeping the internal temperature at 18 to 31° C., and the mixture was stirred at 20° C. for 30 min and then cooled to 10° C. After a DMA solution of methyl 5-bromopyrazine-2-carboxylate (II, gross 914 g, net 72.7 g, 0.335 mol) was added to the mixture and rinsed the vessel with DMA (166 mL), the mixture was warmed to 20° C. Copper bromide (CuBr, 100.9 g, 0.703 mol) was added in fifth portions over 1 h, followed by stirring the mixture for 30 min. The reaction mixture was transferred into a pre-cooled (10° C.) mixture of an aqueous sodium chloride solution (10%, 705 g), hydrochloric acid (5 M, 705 mL) and toluene (1409 mL), and the resulting mixture was vigorously stirred. After phase separation, the organic layer was washed twice with aqueous sodium chloride solution (5.7%, 705 g and 2.9%, 705 g) to afford 1378 g of a toluene solution of the title compound (III). Compound (III) was obtained as a mixture of four derivatives of methyl and ethyl esters, and directly used as 100% yield to the next step.

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