反应详情

温度

5 °C

To a stirred solution of 4-bromo-2-hydroxymethyl-N-(2,2,2-trifluoro-ethyl)-benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at a rate to keep the temperature of the reaction mixture under 10° C., After complete addition, approximately 45 minutes the reaction was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time the reaction mixture was re-cooled to 5° C. and a solution of bis(dimethyl amino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was completed. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure. Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether gave product as a white powder 2.81 g (88% yield). NMR (DMSO 400 MHz) 4.36-4.43 (2H, m, alk), 4.62 (2H, s, alk), 7.68-7.74 (2H, m, ar) and 7.93 (H, s, ar). F19 NMR (DMSO 400 Mhz) −69.03. ES+296

1. customunder 10° C.
2. additionAfter complete addition, approximately 45 minutes the reaction
3. waitat room temperature for 60 minutes
4. temperaturethe reaction was heated
5. temperatureat reflux for 72 hours once the addition
6. customthe reaction mixture was carefully quenched with water
7. extractionThe aqueous layer was extracted with ethyl acetate (3×100 ml)
8. dry with materialdried over Magnesium sulfate powder
9. filtrationfiltered
10. concentrationconcentrated under reduced pressure
11. customPurification by column chromatography
12. washeluting with 25% ethyl acetate 75% petroleum ether