tert-Butyl 4-cyano-4-isopropylpiperidine-1-carboxylate → Tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate

HRID 2093601Notes

Reaction equation

HRID 2093601 reaction equation
[C:1]([C:3]1([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]>[OH-].[NH4+].C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:5][CH2:4]1

Participants

5

Reactant 1

HCID 68787901tert-Butyl 4-cyano-4-isopropylpiperidine-1-carboxylate

Product 1

HCID 68726676Tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylateYield 52.4%

Reagents, catalysts & solvents 3

HCID 935NickelCatalystHCID 702EthanolSolventHCID 14923Ammonium HydroxideSolvent

Procedure

To a solution of tert-butyl 4-cyano-4-isopropylpiperidine-1-carboxylate (90 mg, 0.357 mmol) in ammonium hydroxide (2 ml) and ethanol (4 ml) was added Raney nickel (100 mg, 1.167 mmol). The mixture was flushed with nitrogen, then flushed with hydrogen and stirred overnight under a hydrogen balloon, at which point LC/MS analysis showed the desired product. The mixture was filtered through a plug of Celite, washing liberally with methanol, and then concentrated to a small volume and partitioned between 20 ml of 1 N sodium hydroxide and 25 ml of ethyl acetate. The aqueous phase was extracted with 2×20 ml of ethyl acetate, and then the combined organics were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 50% methanol in dichloromethane over 10 column volumes to provide tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg). The title compound was then prepared from tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg) and 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (57 mg, INTERMEDIATE 2) as described in EXAMPLE 35. Mass spectrum (ESI) 545.3 (M+1). 1H NMR (500 MHz, CDCl3): 8.33 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 6.14 (br t, J=6.0 Hz, 1H), 3.63 (m, 4H), 3.47 (septet, J=7.0 Hz, 1H), 3.33 (br t, J=10.5 Hz, 2H), 1.83 (septet, J=7.0 Hz, 1H), 1.54-1.66 (m, 4H), 1.46 (d, J=7.0 Hz, 6H), 1.45 (s, 9H), 0.99 (d, J=7.0 Hz, 6H).

Workup

  1. customThe mixture was flushed with nitrogen
  2. customflushed with hydrogen
  3. filtrationThe mixture was filtered through a plug of Celite
  4. washwashing liberally with methanol
  5. concentrationconcentrated to a small volume
  6. custompartitioned between 20 ml of 1 N sodium hydroxide and 25 ml of ethyl acetate
  7. extractionThe aqueous phase was extracted with 2×20 ml of ethyl acetate
  8. washthe combined organics were washed with brine
  9. dry with materialdried (sodium sulfate)
  10. concentrationconcentrated
  11. customThe residue was purified by flash chromatography on a Biotage Horizon, 25M column
  12. washeluting with 1 column volume of 100% dichloromethane

Sources & evidence

ORD record
ord-708dbf4853e549859d552b4bab6cd246
Source dataset
uspto-grants-2013_05
Patent number
US08445480B2

Reaction notes

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