Ethyl Acetate → t-Butyl 4-[(3S)-4-Benzyl-3-methylpiperazin-1-yl]-4-methylpiperidine-1-carboxylate

HRID 2244915Notes

Reaction equation

HRID 2244915 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([C:27]#N)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)=O.C(#N)C.C[Mg]Br.C(OCC)(=O)C>O1CCCC1.CO.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([CH3:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 59017280t-Butyl 4-[(3S)-4-Benzyl-3-methylpiperazin-1-yl]-4-cyanopiperidine-1-carboxylateHCID 86587134Acetonitrile dry ice2×HCID 178418573HCID 178418573, compound

Product 1

HCID 59017283t-Butyl 4-[(3S)-4-Benzyl-3-methylpiperazin-1-yl]-4-methylpiperidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of tert-butyl 4-[(3S)-4-benzyl-3-methylpiperazin-1-yl]-4-cyanopiperidine-1-carboxylate (242 g, 0.605 mol) in tetrahydrofuran (1.5 L) in a 5 L flask was cooled down to −40° C. using dry ice/acetonitrile. Methylmagnesium bromide (3.0 M in tetrahydrofuran, 800 mL) was slowly added. After the addition, the reaction mixture was slowly warmed up to room temperature and stirred overnight. After cooling down to −40° C. using dry ice/acetonitrile, celite (200 g), and then ethyl acetate (500 mL) were carefully added. After the addition, the mixture was stirred for 4 hours while the temperature slowly rose to room temperature. The reaction mixture was cooled back down to −40° C. again, and water (200 mL), and then methanol (1.5 L) were added. After being stirred at room temperature overnight, the mixture was filtered through a thin layer of sand. The cake was taken back into a 5 L flask and stirred with methanol (2 L) for 5 hours. Insoluble solid was filtered off. The combined filtrates were concentrated to dryness. Methylene chloride (3.5 L) was added.

Workup

  1. additionAfter the addition
  2. temperatureAfter cooling down to −40° C.
  3. additionAfter the addition
  4. stirringthe mixture was stirred for 4 hours while the temperature
  5. customslowly rose to room temperature
  6. temperatureThe reaction mixture was cooled back down to −40° C. again
  7. stirringAfter being stirred at room temperature overnight
  8. filtrationthe mixture was filtered through a thin layer of sand
  9. customThe cake was taken back into a 5 L flask
  10. stirringstirred with methanol (2 L) for 5 hours
  11. filtrationInsoluble solid was filtered off
  12. concentrationThe combined filtrates were concentrated to dryness
  13. additionMethylene chloride (3.5 L) was added

Sources & evidence

ORD record
ord-ccdc05599d554985840aad3094eb7917
Source dataset
uspto-grants-2010_03
Patent number
US07678798B2

Reaction notes

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