反应详情

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (2.108 g, 7.63 mmol) in anhydrous dimethylformamide (15 mL) was added BOP (4.05 g, 9.15 mmol) and the resulting mixture was stirred at room temperature under nitrogen for 5 minutes. Diisopropyl ethyl amine (2.66 mL, 15.26 mmol) was then added followed by a solution of tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (1.665 g, 7.63 mmol) in 20 mL of dichloromethane. The resulting solution was stirred at room temperature under nitrogen for 2 hours then concentrated under vacuum and the residue partitioned between ethyl acetate and water. The aqueous layer was washed twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified via silica gel flash chromatography (Isco Combiflash apparatus—120 g silica gel, 80 mL/min, 254 nM, 0% to 100% EtOAc/hexane over 6 column volumes then 100% EtOAc for 9 column volumes; title compound eluted at 100% EtOAc). Fractions containing pure title compound were collected and concentrated in vacuo to give a tan solid. Fractions containing impure product were also collected and repurified by HPLC (30×100 mm Sunfire column, 5 microns, 35 mL/min, 10% to 100% CH3CN+0.1% TFA/water+0.1% TFA over 15 min.; title compound eluted at 70% CH3CN+0.1% TEA). Fractions containing pure product were combined and concentrated in vacuo. The resulting aqueous residue was then extracted with ethyl acetate. The organic layer was collected and dried over magnesium sulfate. Concentration in vacuo gave a white solid which was combined with the material isolated from silica gel chromatography to afford the title compound.

1. stirringThe resulting solution was stirred at room temperature under nitrogen for 2 hours
2. concentrationthen concentrated under vacuum
3. customthe residue partitioned between ethyl acetate and water
4. washThe aqueous layer was washed twice with ethyl acetate
5. washThe organic layer was washed with brine
6. dry with materialdried over sodium sulfate
7. concentrationconcentrated under vacuum
8. customThe residue was purified via silica gel flash chromatography (Isco Combiflash apparatus—120 g silica gel, 80 mL/min, 254 nM, 0% to 100% EtOAc/hexane over 6 column volumes
9. washtitle compound eluted at 100% EtOAc)
10. additionFractions containing pure title compound
11. customwere collected
12. concentrationconcentrated in vacuo
13. customto give a tan solid
14. additionFractions containing impure product
15. customwere also collected
16. customrepurified by HPLC (30×100 mm Sunfire column, 5 microns, 35 mL/min, 10% to 100% CH3CN+0.1% TFA/water+0.1% TFA over 15 min.; title compound eluted at 70% CH3CN+0.1% TEA)
17. additionFractions containing pure product
18. concentrationconcentrated in vacuo
19. extractionThe resulting aqueous residue was then extracted with ethyl acetate
20. customThe organic layer was collected
21. dry with materialdried over magnesium sulfate
22. concentrationConcentration in vacuo
23. customgave a white solid which
24. customisolated from silica gel chromatography