Acetic Acid → tert-Butyl [5-(4-chlorophenyl)-6-methyl-2-oxopiperidin-3-yl]carbamate

HRID 406549Notes

Reaction equation

HRID 406549 reaction equation
[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16](=O)[CH3:17])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.C([BH3-])#[N:36].[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CO.O.C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:15]2[CH:16]([CH3:17])[NH:36][C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14]2)=[CH:20][CH:21]=1

Participants

10

Reactant 6

HCID 176Acetic AcidHCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 517165Ammonium AcetateHCID 5003444Sodium cyanoborohydrideHCID 68747752Methyl 2-[(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-5-oxohexanoate

Product 1

HCID 86665200tert-Butyl [5-(4-chlorophenyl)-6-methyl-2-oxopiperidin-3-yl]carbamate

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 887MethanolSolventHCID 962WaterSolvent2×

Conditions

Temperature
60 °C

Procedure

To a solution of methyl 2-[(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-5-oxohexanoate (21.6 g, 58.4 mmol) in methanol (200 mL) were added ammonium acetate (45.0 g, 584 mmol), acetic acid (50.2 mL, 876 mmol), and sodium cyanoborohydride (5.51 g, 87.7 mmol). The mixture was heated at 60° C. for a total of 4 h. The mixture was then allowed to cool to ambient temperature and sodium bicarbonate and water were added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Ethanol (240 mL) and potassium carbonate (40.4 g, 292 mmol) were added. The mixture was stirred 1.5 h at 60° C. to effect epimerization to the desired epimer. Water was added followed by extraction with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol with 0.1% ammonium hydroxide) gave the title compound as a mixture of isomers. MS: m/z=361.2 (M+Na).

Workup

  1. temperatureto cool to ambient temperature
  2. extractionThe mixture was extracted with ethyl acetate (3×)
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. extractionfollowed by extraction with ethyl acetate (3×)
  8. washThe combined organic extracts were washed with brine
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customPurification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol with 0.1% ammonium hydroxide)

Sources & evidence

ORD record
ord-86537d32283f4789add33f51d0078b0b
Source dataset
uspto-grants-2014_06
Patent number
US08754096B2

Reaction notes

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