反应详情

温度

-30 °C

To a solution of 6-(2-oxo-piperidin-1-yl)-perhydro-1,4-oxazepine-4-carboxylic acid tert-butyl ester 38.5 (0.31 g, 1.0 mmol) in THF (10 mL) at −78° C. was added dropwise 2.0 M LDA in heptane/THF/ethylbenzene (0.7 mL, 1.5 mmol) under nitrogen. The solution was allowed to warm to −30° C. for 1 h and then recooled to −78° C. prior to the dropwise addition of PhSO2Cl (0.15 mL, 1.1 mmol). The reaction was allowed to slowly warm to 10° C. and then quenched upon the addition NaHCO3 and extracted with EtOAc. The organic phase was washed with NaHCO3, brine and dried (MgSO4), filtered and concentrated in vacuo to afford a solid. The chloro intermediate was dissolved in THF (8.4 mL) and added to a suspension of 3-chloro-5-fluoro-phenylamine (0.15 g, 1.04 mmol) and sodium hydride (60% in mineral oil, 80 mg, 2.1 mmol) in THF (16 mL). The reaction mixture was heated to reflux for 90 minutes, cooled to room temperature, placed and quenched with MeOH, water, NaHCO3 and EtOAc. The organics phase was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford an oil. The oil was purified by silica gel chromatography (gradient MeOH/DCM) to afford the desired product (204 mg, 59%). LCMS, m/z 386.1 [M-tBu]+.

1. customrecooled to −78° C.
2. temperatureto slowly warm to 10° C.
3. customquenched upon the addition NaHCO3
4. extractionextracted with EtOAc
5. washThe organic phase was washed with NaHCO3, brine
6. dry with materialdried (MgSO4)
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. customto afford a solid
10. temperatureThe reaction mixture was heated
11. temperatureto reflux for 90 minutes
12. temperaturecooled to room temperature
13. customquenched with MeOH, water, NaHCO3 and EtOAc
14. customThe organics phase was separated
15. washwashed with brine
16. dry with materialdried (MgSO4)
17. filtrationfiltered
18. concentrationconcentrated in vacuo
19. customto afford an oil
20. customThe oil was purified by silica gel chromatography (gradient MeOH/DCM)