反应详情

To a 0° C. solution of (116.9 g, 401.2 mmol) material from Step B in DCM (800 mL) was added 200 mL of TFA dropwise over 15 minutes. After removing the cooling bath, the mixture was stirred for about 2.5 hours and then concentrated to dryness. The residue was dissolved in 500 mL of DCM and saturated aqueous sodium bicarbonate is slowly added until the mixture was slightly basic. The organic portion was separated and the aqueous portion is extracted two times with DCM. The combined organic portions were dried (Na2SO4) and concentrated to dryness. The residue was dissolved in 800 mL of DCM and DIPEA (57.0 g, 441.4 mmol) was added. To the mixture was added di-tert-butyl dicarbonate (96.3 g, 441.4 mmol) in five portions over 45 minutes and then stirred at r.t. for 16 hours. The mixture was washed with 10% aqueous sodium bisulfate, and the organic portion was separated and the aqueous portion is extracted two times with DCM. The combined organic extracts were dried ((Na2SO4) and concentrated to dryness. The resulting residue was dissolved in a small amount of DCM and filtered through 7 inch silica gel in a 2L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent was concentrated to dryness and the enantiomers were separated by chiral chromatography. The first eluting isomer was labeled as isomer #1 and the second eluting is labeled as isomer #2, which afforded about 52.6 g (45%) of the final compound (isomer 2). EIS-MS 292 [M+1].

1. customAfter removing the cooling bath
2. concentrationconcentrated to dryness
3. dissolutionThe residue was dissolved in 500 mL of DCM
4. additionsaturated aqueous sodium bicarbonate is slowly added until the mixture
5. customThe organic portion was separated
6. extractionthe aqueous portion is extracted two times with DCM
7. dry with materialThe combined organic portions were dried (Na2SO4)
8. concentrationconcentrated to dryness
9. dissolutionThe residue was dissolved in 800 mL of DCM
10. stirringstirred at r.t. for 16 hours
11. washThe mixture was washed with 10% aqueous sodium bisulfate
12. customthe organic portion was separated
13. extractionthe aqueous portion is extracted two times with DCM
14. dry with materialThe combined organic extracts were dried ((Na2SO4)
15. concentrationconcentrated to dryness
16. dissolutionThe resulting residue was dissolved in a small amount of DCM
17. filtrationfiltered through 7 inch silica gel in a 2L sintered glass funnel
18. washeluting with 25% EtOAc/hexanes
19. concentrationThe eluent was concentrated to dryness
20. customthe enantiomers were separated by chiral chromatography
21. washthe second eluting