反应详情

To a mixture of N-[(2,4-Difluoro-phenyl)-(toluene-4-sulfonyl)-methyl]-formamide (2.07 g, 6.36 mmol) and THF (15 mL) is added phosphorous oxychloride (POCl3)(1.19 mL, 12.7 mmol) over a period of 5 minutes, and the resulting mixture stirred at room temperature for 10 minutes. The reaction is then cooled to 4° C. using an ice/water bath and 2,6-lutidine (4.45 mL, 38.2 mmol) is added over 30 minutes, maintaining the temperature less than 12° C. The cooling bath is removed and the mixture stirred at room temperature for 18 hours. The reaction mixture is poured into a stirred, ice water cooled, solution of ice and saturated aqueous NaHCO3. The mixture is extracted with ethyl acetate (2×). The combined organic extracts are washed with 1N aqueous hydrochloric acid, saturated aqueous NaHCO3, brine and dried (MgSO4). The solvents are removed in vacuo, and isopropanol (18.0 mL) added to the residual brownish solid. The resulting slurry is stirred at room temperature for 2 hours, then water (9.0 mL) is added and the slurry stirred for an additional 30 minutes at room temperature. The slurry is filtered, the cake washed with 2:1 isopropanol-water (2×) and dried in a vacuum-oven (30° C.) for 48 hours. The title compound may be obtained as a tan solid (1.33 g, 68%).

1. temperatureThe reaction is then cooled to 4° C.
2. temperaturemaintaining the temperature less than 12° C
3. customThe cooling bath is removed
4. stirringthe mixture stirred at room temperature for 18 hours
5. additionThe reaction mixture is poured into a stirred, ice water
6. temperaturecooled
7. extractionThe mixture is extracted with ethyl acetate (2×)
8. washThe combined organic extracts are washed with 1N aqueous hydrochloric acid, saturated aqueous NaHCO3, brine
9. dry with materialdried (MgSO4)
10. customThe solvents are removed in vacuo, and isopropanol (18.0 mL)
11. additionadded to the residual brownish solid
12. stirringThe resulting slurry is stirred at room temperature for 2 hours
13. additionwater (9.0 mL) is added
14. stirringthe slurry stirred for an additional 30 minutes at room temperature
15. filtrationThe slurry is filtered
16. washthe cake washed with 2:1 isopropanol-water (2×)
17. customdried in a vacuum-oven (30° C.) for 48 hours