反应详情

温度

70 °C

To a solution of ethyl 2,5-difluoro-4-methylbenzoate (Preparation 18, 4.674 g, 23.35 mmol) in 1,2-dichloroethane (70 mL) were added N-bromosuccinimide (4.57 g, 25.68 mmol) and benzoyl peroxide (56 mg, 0.23 mmol) and the mixture was heated to 70° C. for 2 days. The reaction mixture was allowed to cool, quenched with saturated aqueous sodium thiosulfate (20 mL) and diluted with water (50 mL). The organic layer was separated and the aqueous layer extracted with DCM (2×80 mL). The combined organics were washed with saturated aqueous sodium hydrogen carbonate, followed by brine, then filtered through a phase separator and concentrated in vacuo. The resulting yellow oil was redissolved in EtOAc (70 mL), and N,N-diisopropylethylamine (4.04 mL, 23.35 mmol) was added. The mixture was cooled to 0° C., and diethyl phosphate (2.29 mL, 23.35 mmol) was added. After stirring at 0° C. for 90 minutes, LCMS indicated complete conversion of the dibromomethyl impurity to the desired mono-bromomethyl product. The reaction was quenched at 0° C. with water (70 mL), followed by aqueous hydrochloric acid (2N, 10 mL). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to yield a yellow residue. The residue was purified by silica gel chromatography eluting with 0 to 3% EtOAc in heptane to afford the title compound as a clear oil (5.78 g, 89%):

1. temperatureto cool
2. customquenched with saturated aqueous sodium thiosulfate (20 mL)
3. additiondiluted with water (50 mL)
4. customThe organic layer was separated
5. extractionthe aqueous layer extracted with DCM (2×80 mL)
6. washThe combined organics were washed with saturated aqueous sodium hydrogen carbonate
7. filtrationfiltered through a phase separator
8. concentrationconcentrated in vacuo
9. dissolutionThe resulting yellow oil was redissolved in EtOAc (70 mL)
10. temperatureThe mixture was cooled to 0° C.
11. customThe reaction was quenched at 0° C. with water (70 mL)
12. customThe organic layer was separated
13. washwashed with brine (100 mL)
14. dry with materialdried over sodium sulfate
15. concentrationconcentrated in vacuo
16. customto yield a yellow residue
17. customThe residue was purified by silica gel chromatography
18. washeluting with 0 to 3% EtOAc in heptane