Acetic Acid → Ethyl [(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate

HRID 1866673Notes

Reaction equation

HRID 1866673 reaction equation
O=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]1([C:10]([O:12]C)=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH2:26])[CH3:22].CC(O)=O.[BH3-]C#N.[Na+]>CCO>[O:12]=[C:10]1[C:5]2([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][C@@H:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:26]1[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:27]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 2723640Glycine ethyl ester, hydrochlorideHCID 5003444Sodium cyanoborohydrideHCID 66973058HCID 66973058, compound

Product 1

HCID 86616397Ethyl [(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-e18e5d669cef41f18a4be0c759ba3faf
Source dataset
uspto-grants-2009_12
Patent number
US07629338B2

Reaction notes

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