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

Temperature

70 °C

To a mixture of zinc powder (4.58 g, 0.070 mol) and triglyme (35 mL) was added TMSBr (0.91 mL, 0.007 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 (10.8 mL, 0.084 mol) was added while maintaining the internal temperature at 22 to 27° C., and the mixture was stirred at 20° C. for 30 min and then cooled to 0° C. After addition of the solution of methyl 5-bromopyrazine-2-carboxylate (II, 7.23 g, 0.033 mol) in DMA (106 mL) to the mixture, the resulting mixture was warmed to 20° C. Copper bromide (CuBr, 10.0 g, 0.070 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 (ice bath) mixture of an aqueous sodium chloride solution (6.3%, 111 g), concentrated hydrochloric acid (29.4 mL) and toluene (140 mL), and the resulting mixture was vigorously stirred. The organic layer was separated and washed twice with aqueous sodium chloride solutions (5.7%, 70 g and 2.9%, 70 g) to afford 136 g of a toluene solution of methyl 5-(2-ethoxy-1,1-difluoro-2-oxoethyl)pyrazine-2-carboxylate (III).

1. temperatureAfter the mixture was cooled to room temperature
2. temperaturewhile maintaining the internal temperature at 22 to 27° C.
3. stirringthe mixture was stirred at 20° C. for 30 min
4. temperaturecooled to 0° C
5. temperaturethe resulting mixture was warmed to 20° C
6. stirringby stirring the mixture for 30 min
7. temperaturea pre-cooled
8. stirringthe resulting mixture was vigorously stirred
9. customThe organic layer was separated
10. washwashed twice with aqueous sodium chloride solutions (5.7%, 70 g and 2.9%, 70 g)

ORD record

ord-5dd01851ab7c4caebcf8bfdbabc724e0

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09227942B2