Citric Acid → 2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic acid

HRID 1048214Notes

Reaction equation

HRID 1048214 reaction equation
C([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:31][CH3:32])[CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:5]1=[O:33])C=C.C(#N)C.I([O-])(=O)(=O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC[O:58][C:59]([CH3:61])=[O:60]>O.O.[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C@@H:24]([CH2:31][CH3:32])[CH:25]([OH:30])[C:26]([F:27])([F:28])[F:29])[C:5](=[O:33])[C@@H:4]([CH2:61][C:59]([OH:58])=[O:60])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1

Participants

9

Reactant 5

HCID 311Citric AcidHCID 6342AcetonitrileHCID 8857Ethyl AcetateHCID 23667635Sodium periodateHCID 58573560(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-2-one

Product 1

HCID 585733892-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic acid

Reagents, catalysts & solvents 3

HCID 6093376Ruthenium trichloride hydrateCatalystHCID 962WaterSolventHCID 5943Carbon TetrachlorideSolvent

Procedure

To a rapidly stirring solution of 6.3 mg (0.013 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-2-one (Example 19, Step B, the diastereomer not used for Example 19 Step B)) (6.30 mg, 0.013 mmol) in a mixture of water (108 μL), acetonitrile (71.9 μL), and CCl4 (71.9 gt) was added sodium periodate (10.7 mg, 0.050 mmol), followed by ruthenium(III) chloride hydrate (0.284 mg, 1.26 μmol). After being stirred vigorously for 18 h, the reaction was acidified (10% citric acid) and diluted (EtOAc). The reaction mixture was filtered through Celite® (J.T. Baker, Phillipsberg, N.J., J.T. Baker, Phillipsberg, N.J., diatomaceous earth). The filtrate was extracted (2×EtOAc). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 45 to 70% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided the title compound as a white solid.

Workup

  1. filtrationThe reaction mixture was filtered through Celite® (J.T. Baker, Phillipsberg, N.J., J.T. Baker, Phillipsberg, N.J., diatomaceous earth)
  2. extractionThe filtrate was extracted (2×EtOAc)
  3. washThe combined organic layers were washed with sat. NaCl solution
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationthe filtrate was concentrated under reduced pressure
  7. customPurification
  8. washby reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 45 to 70% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution)

Sources & evidence

ORD record
ord-f580cfcdb2794916bbfe3137d7086fe3
Source dataset
uspto-grants-2013_10
Patent number
US08569341B2

Reaction notes

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