反应详情

To a 0° C. solution of (116.9 g, 401.2 mmol) material from Step B in DCM (800 mL) is added 200 mL of TFA dropwise over 15 minutes. After removing the cooling bath, the mixture is stirred for about 2.5 hours and then concentrated to dryness. The residue is dissolved in 500 mL of DCM and saturated aqueous sodium bicarbonate is slowly added until the mixture is slightly basic. The organic portion is separated and the aqueous portion is extracted two times with DCM. The combined organic portions are dried (Na2SO4) and concentrated to dryness. The residue is dissolved in 800 mL of DCM and DIPEA (57.0 g, 441.4 mmol) is added. To the mixture is added di-tert-butyl dicarbonate (96.3 g, 441.4 mmol) in five portions over 45 minutes and then stirred at room temperature for 16 h. The mixture is washed with 10% aqueous sodium bisulfate, and the organic portion is separated and the aqueous portion is extracted two times with DCM. The combined organic extracts are dried ((Na2SO4) and concentrated to dryness. The resulting residue is dissolved in a small amount of DCM and filtered through 7 inch silica gel in a 2 L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent is concentrated to dryness and the enantiomers are separated by chiral chromatography. The first eluting isomer is labeled as isomer #1 and the second eluting is labeled as isomer #2, which affords 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 is dissolved in 500 mL of DCM
4. additionsaturated aqueous sodium bicarbonate is slowly added until the mixture
5. customThe organic portion is separated
6. extractionthe aqueous portion is extracted two times with DCM
7. dry with materialThe combined organic portions are dried (Na2SO4)
8. concentrationconcentrated to dryness
9. dissolutionThe residue is dissolved in 800 mL of DCM
10. stirringstirred at room temperature for 16 h
11. washThe mixture is washed with 10% aqueous sodium bisulfate
12. customthe organic portion is separated
13. extractionthe aqueous portion is extracted two times with DCM
14. dry with materialThe combined organic extracts are dried ((Na2SO4)
15. concentrationconcentrated to dryness
16. dissolutionThe resulting residue is dissolved in a small amount of DCM
17. filtrationfiltered through 7 inch silica gel in a 2 L sintered glass funnel
18. washeluting with 25% EtOAc/hexanes
19. concentrationThe eluent is concentrated to dryness
20. customthe enantiomers are separated by chiral chromatography
21. washthe second eluting