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

HRID 1866673노트

반응식

HRID 1866673 반응식
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]

참가 물질

6

반응물 4

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

생성물 1

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

시약·촉매·용매 1

HCID 702Ethanol용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-e18e5d669cef41f18a4be0c759ba3faf
출처 데이터셋
uspto-grants-2009_12
특허 번호
US07629338B2

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