反应详情

To a stirred mixture of methyl 2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-ethylbutanoate from Step B (475 mg, 1.59 mmol) and glycine ethyl ester hydrochloride (332 mg, 2.38 mmol) in MeOH (5 mL) were added titanium(IV) isopropoxide (1.16 mL, 3.97 mmol) and AcOH (0.273 mL, 4.76 mmol). The resulting mixture was stirred at ambient temperature for 15 min, then NaCNBH3 (150 mg, 2.38 mmol) was added. The stirred reaction mixture was heated at 50° C. for 18 h, then at 70° C. for 24 h, and allowed to cool. The mixture was quenched with saturated aqueous NaHCO3 and then extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the racemic product. The enantiomers were separated by HPLC, using a Chiralcel OD column and eluting with hexane:EtOH-60:40. The first major peak to elute was methyl [(6S)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetate and the second major peak to elute was methyl [(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetate, the title compound. MS: m/z=341 (M+1).

1. customThe stirred reaction mixture
2. temperaturewas heated at 50° C. for 18 h
3. waitat 70° C. for 24 h
4. temperatureto cool
5. customThe mixture was quenched with saturated aqueous NaHCO3
6. extractionextracted with EtOAc (2×30 mL)
7. dry with materialThe combined organic extracts were dried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customThe crude product was purified by HPLC
11. washeluting with a gradient of H2O
12. extractionextracted with EtOAc
13. dry with materialThe organic extracts were dried over Na2SO4
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customto give the racemic product
17. customThe enantiomers were separated by HPLC
18. washeluting with hexane
19. washThe first major peak to elute
20. washthe second major peak to elute