Water → Tert-Butyl 4-{2-[(1S)-1-(Acetylamino)Ethyl]-4-Chlorophenyl}Piperidine-1-Carboxylate

HRID 2415557Notes

Reaction equation

HRID 2415557 reaction equation
[C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@H:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:7].C(N(CC)CC)C.O>ClCCl>[C:1]([NH:5][C@H:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]1)[CH3:7])(=[O:3])[CH3:2]

Participants

6

Reactant 4

HCID 962WaterHCID 6367Acetyl chlorideHCID 8471TriethylamineHCID 68518377Tert-Butyl 4-{2-[(1S)-1-Aminoethyl]-4-Chlorophenyl]Piperidine-1-Carboxylate

Product 1

HCID 11668043Tert-Butyl 4-{2-[(1S)-1-(Acetylamino)Ethyl]-4-Chlorophenyl}Piperidine-1-CarboxylateYield 96.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Acetyl chloride (1.71 mL, 24.0 mmol) was added to a solution of crude tert-butyl 4-{2-[(1S)-1-aminoethyl]-4-chlorophenyl}piperidine-1-carboxylate (3-7) (5.42 g of ˜70% pure material, 11.2 mmol) and triethylamine (6.69 mL, 48.0 mmol) in dichloromethane at approximately 0° C. After 2 h, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 35 to 50% ethyl acetate/hexanes as eluent) provided tert-butyl 4-{2-[(1S)-1-(acetylamino)ethyl]-4-chlorophenyl}piperidine-1-carboxylate (3-8) as a pale yellow foam (4.1 g). If desired, traces of the minor R-enantiomer could be removed using preparative chiral high pressure liquid chromatography on CHIRALPAK AD Phase, (7.5% ethano/heptanes as eluent) to give in order of elution: R-enantiomer as a colorless solid followed by the S-enantiomer as a colorless solid.

Workup

  1. extractionextracted three times with ethyl acetate
  2. washThe combined organic extracts were washed with brine
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. customPurification of the crude residue by flash chromatography on silica gel (gradient elution; 35 to 50% ethyl acetate/hexanes as eluent)

Sources & evidence

ORD record
ord-9e27475635f240bfa6158d208f924b5b
Source dataset
uspto-grants-2004_11
Patent number
US06818658B2

Reaction notes

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