Citric Acid → [(3r,5r,6s)-1-[(2s)-1-Tert-Butoxy-1-Oxobutan-2-Yl]-5-(3-Chlorophenyl)-6-(4-Chlorophenyl)-2-Oxopiperidin-3-Yl]acetic Acid

HRID 931889Notes

Reaction equation

HRID 931889 reaction equation
C([C@@H]1C[C@H](C2C=CC=C(Cl)C=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]([CH2:32][CH3:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])C1=O)C=C.[C:35](#N)[CH3:36].I([O-])(=O)(=O)=O.[Na+].[C:44]([OH:56])(=[O:55])[CH2:45][C:46]([CH2:51][C:52](O)=O)([C:48]([OH:50])=O)O>O.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:28]([O:27][C:25](=[O:26])[C@@H:24]([N:6]1[C@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C@@H:52]([C:36]2[CH:35]=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH2:51][C@H:46]([CH2:45][C:44]([OH:56])=[O:55])[C:48]1=[O:50])[CH2:32][CH3:33])([CH3:29])([CH3:30])[CH3:31]

Participants

9

Reactant 4

HCID 311Citric AcidHCID 6342AcetonitrileHCID 23667635Sodium periodateHCID 68000542HCID 68000542, compound

Product 1

HCID 56591324[(3r,5r,6s)-1-[(2s)-1-Tert-Butoxy-1-Oxobutan-2-Yl]-5-(3-Chlorophenyl)-6-(4-Chlorophenyl)-2-Oxopiperidin-3-Yl]acetic Acid

Reagents, catalysts & solvents 4

HCID 6093376Ruthenium trichloride hydrateCatalystHCID 962WaterSolventHCID 5943Carbon TetrachlorideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a rapidly stirring solution of 842 mg (1.67 mmol) of tert-butyl (2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl) butanoate (Example 1, Step G) in a mixture of 7 mL of water, 5 mL of acetonitrile and 5 mL of CCl4 was added sodium periodate (1.43 g, 6.70 mmol), followed by ruthenium(III) chloride hydrate (37.8 mg, 0.168 mmol). After being stirred vigorously for 18 h, the reaction was acidified (10% citric acid) and diluted with EtOAc. The reaction mixture was filtered through celite and the filtrate was extracted with EtOAc. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 60 to 80% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) to give the title compound as a white solid.

Workup

  1. filtrationThe reaction mixture was filtered through celite
  2. extractionthe filtrate was extracted with 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. customThe residue was purified by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 60 to 80% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution)

Sources & evidence

ORD record
ord-398b5474435d492e8dea38c243721dec
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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