反应详情

To a stirred mixture of methyl 1-[(2-oxo-2-phenylethyl)amino]cyclopentanecarboxylate from Step A (1.10 g, 2.67 mmol) and glycine ethyl ester hydrochloride (881 mg, 6.31 mmol) in EtOH (10 mL) was added AcOH (0.72 mL, 12.6 mmol). The resulting mixture was stirred at ambient temperature for 5 min, then NaCNBH3 (397 mg, 6.31 mmol) was added. The reaction mixture was heated to 70° C. for 3 h then allowed to cool. The reaction mixture was quenched with saturated aqueous NaHCO3 and then extracted with EtOAc (3×50 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 ethyl [(8S)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate and the second major peak to elute was ethyl [(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate, the title compound. MS: m/z=317 (M+1).

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