反应详情

Diethyl cyanomethylphosphonate (1.95 mL, 11.8 mmol) was added drop-wise to a cooled (ice bath) solution of 1.0 M potassium tert-butoxide in THF (11.8 mL, 11.8 mmol) which was diluted with tetrahydrofuran (12 mL). The bath was removed and the reaction was warmed to room temperature, and stirred for 90 min. The reaction solution was cooled with an ice bath again. The above prepared solution was then added over 12 min to a cooled (ice-bath) solution of 2,5-difluoro-4-(3-oxoazetidin-1-yl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (4.00 g, 12.4 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred for 30 min. The ice bath was removed, and the reaction was stirred at room temperature overnight, then quenched by the addition of 20% brine (75 mL) and ethyl acetate (75 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0% to 30%) to yield the desired product (2.6 g). 1H NMR (400 MHz, DMSO-d6) δ 8.59-8.37 (m, 1H), 7.33 (dd, J=12.5, 6.4 Hz, 1H), 6.59 (dd, J=12.0, 7.4 Hz, 1H), 5.88 (m, 1H), 4.94-4.75 (m, 4H), 4.76 (m, 1H), 1.31 (d, J=7.1 Hz, 3H) ppm. LCMS cacld. for C15H13F5N3O (M+1)+: m/z=346.1. Found: 346.1.

1. customThe bath was removed
2. temperatureThe reaction solution was cooled with an ice bath again
3. customThe above prepared solution
4. additionwas then added over 12 min to
5. stirringThe reaction mixture was stirred for 30 min
6. customThe ice bath was removed
7. stirringthe reaction was stirred at room temperature overnight
8. customquenched by the addition of 20% brine (75 mL) and ethyl acetate (75 mL)
9. customThe organic layer was separated
10. extractionThe aqueous layer was extracted with ethyl acetate (50 mL)
11. dry with materialThe combined organic layers were dried over MgSO4
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customThe residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0% to 30%)