Acetic Acid → tert-Butyl 4-hydroxy-[1,4'-bipiperidine]-1'-carboxylate

HRID 1178751Notes

Reaction equation

HRID 1178751 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 176Acetic AcidHCID 79341Piperidin-4-olHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate

Product 1

HCID 9835508tert-Butyl 4-hydroxy-[1,4'-bipiperidine]-1'-carboxylateYield 74%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

1-tert-Butoxycarbonyl-4-piperidone (55 g, 0.276 mol, 1.15 eq) and 4-hydroxypiperidine (24.3 g, 0.24 mol, 1 eq) were stirred at room temperature in ethanol (160 ml) and acetic acid (16 ml) for 25 minutes. To the solution was added 2.4 g of 5% palladium on carbon type 87L Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3.5 bar at room temperature for 72 hours. The catalyst was filtered off and the mixture partitioned between water (320 ml) and iso-propyl acetate (360 ml). The aqueous was collected, and washed twice further with iso-propyl acetate (2×360 ml). The aqueous was then basified (10M aqueous sodium hydroxide, 25 ml) and the aqueous washed twice with MTBE (2×194 ml). Solvent (194 ml) was removed by distillation under vacuum (−0.7 bar, 65° C. oil bath). THF (777 ml) was added and the solution again concentrated by removal of solvent (777 ml, −0.7 bar, 65° C. oil bath). THF (485 ml) was added to the solution and solvent (485 ml) removed by vacuum distillation (−0.7 bar, 70° C.). Half of the solution was evaporated at this point to give 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester as an off-white solid (25.31 g, 74% yield; 99.6% purity HPLC area %).

Workup

  1. filtrationThe catalyst was filtered off
  2. customthe mixture partitioned between water (320 ml) and iso-propyl acetate (360 ml)
  3. customThe aqueous was collected
  4. washwashed twice further with iso-propyl acetate (2×360 ml)
  5. washthe aqueous washed twice with MTBE (2×194 ml)
  6. customSolvent (194 ml) was removed by distillation under vacuum (−0.7 bar, 65° C. oil bath)
  7. additionTHF (777 ml) was added
  8. concentrationthe solution again concentrated by removal of solvent (777 ml, −0.7 bar, 65° C. oil bath)
  9. additionTHF (485 ml) was added to the solution and solvent (485 ml)
  10. customremoved by vacuum distillation (−0.7 bar, 70° C.)
  11. customHalf of the solution was evaporated at this point

Sources & evidence

ORD record
ord-4e15c7b55aa846c0894a7d569a5adf37
Source dataset
uspto-grants-2007_10
Patent number
US07276609B2

Reaction notes

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