Acetic Acid → (3R)-3-(3,5-Difluorophenyl)-3-methyl-1,4-diazaspiro[5,5]undecan-5-one

HRID 1615796Notes

Reaction equation

HRID 1615796 reaction equation
[NH2:1][C:2]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)([CH3:15])[CH2:3][NH:4][C:5]1([C:11](OC)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CC(O)=O.C([O-])(O)=O.[Na+]>>[F:23][C:18]1[CH:17]=[C:16]([C@@:2]2([CH3:15])[NH:1][C:11](=[O:12])[C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[NH:4][CH2:3]2)[CH:21]=[C:20]([F:22])[CH:19]=1

Participants

4

Reactant 3

HCID 176Acetic AcidHCID 516892Sodium BicarbonateHCID 66864381Methyl 1-{[2-amino-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylate

Product 1

HCID 58118683(3R)-3-(3,5-Difluorophenyl)-3-methyl-1,4-diazaspiro[5,5]undecan-5-one

Procedure

A solution of methyl 1-{[2-amino-2-(3,5-difluorophenyl)propyl]amino}cyclohexane carboxylate from Step F (205 mg, 0.628 mmol), and AcOH (0.36 mL, 6.28 mmol) in xylenes (5 mL) was heated at 80° C. for 3 h, allowed to cool, then poured into saturated aqueous NaHCO3 (5 mL). The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH—100:0 to 92:8, to give the racemic product. The enantiomers were separated by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH—40:60:0.1. The first major peak to elute was (3R)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one, the title compound, and the second major peak to elute was (3S)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one. MS: m/z=295 (M+1).

Workup

  1. temperatureto cool
  2. extractionThe resulting mixture was extracted with EtOAc (2×10 mL)
  3. dry with materialThe combined organic extracts were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified by silica gel chromatography
  7. washeluting with a gradient of EtOAc
  8. customMeOH—100:0 to 92:8, to give the racemic product
  9. customThe enantiomers were separated by HPLC
  10. washeluting with hexane
  11. washThe first major peak to elute
  12. washthe title compound, and the second major peak to elute

Sources & evidence

ORD record
ord-2348223799824bb8ab2a7967e3a2703b
Source dataset
uspto-grants-2014_07
Patent number
US08765759B2

Reaction notes

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