反应详情

温度

70 °C

To a solution of ethyl 2,5-difluoro-4-methylbenzoate (Preparation 12, 450 mg, 2.25 mmol) in dichloroethane (10 mL) was added N-bromosuccinimide (520 mg, 2.92 mmol) followed by benzoyl peroxide (54 mg, 0.025 mmol). The reaction was heated at 70° C. for 5 hours then benzoyl peroxide (54 mg, 0.025 mmol) followed by N-bromosuccinimide were added. The reaction was heated at 70° C. for 3 days, then an aqueous solution of sodium thiosulfate (10 mL) and water (30 mL) were added. The organic phase was extracted with dichloromethane (3×20 mL) and the combined organic phases were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a light yellow oil. The oil was dissolved in ethyl acetate (7 mL) and N,N-diisopropylethylamine (0.39 mL, 2.25 mmol) was added. The solution was cooled to 0° C. in an ice bath and diethyl phosphate (2.25 mmol, 0.22 mL) was added dropwise. The reaction was stirred at 0° C. for 2 hours before the addition of an aqueous solution of hydrochloric acid (2M, 3 mL). The organic phase was extracted with ethyl acetate (3×10 mL), and the combined organic phases were washed with brine (20 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude compound was purified by silica gel column chromatography eluting with heptane:ethyl acetate (gradient from 98:2 to 80:20) to afford the title compound as a colourless oil (455 mg, 75%).

1. additionwere added
2. temperatureThe reaction was heated at 70° C. for 3 days
3. extractionThe organic phase was extracted with dichloromethane (3×20 mL)
4. washthe combined organic phases were washed with brine (20 mL)
5. dry with materialdried over magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customto afford a light yellow oil
9. temperatureThe solution was cooled to 0° C. in an ice bath
10. extractionThe organic phase was extracted with ethyl acetate (3×10 mL)
11. washthe combined organic phases were washed with brine (20 mL)
12. dry with materialdried over magnesium sulfate
13. filtrationfiltered
14. customthe solvent removed in vacuo
15. customThe crude compound was purified by silica gel column chromatography
16. washeluting with heptane