2-Piperidone → 1-(3-Chloro-4-fluorobenzyl)piperidin-2-one

HRID 1817324Notes

Reaction equation

HRID 1817324 reaction equation
[C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14]Br>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14][N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7]

Participants

5

Reactant 3

HCID 126652-PiperidoneHCID 24758Sodium hydrideHCID 27575424-(Bromomethyl)-2-chloro-1-fluorobenzene

Product 1

HCID 669976831-(3-Chloro-4-fluorobenzyl)piperidin-2-one

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent2×

Conditions

Temperature
0 °C

Procedure

Valerolactam (153.3 g, 1.54 mol) was dissolved in NMP (3.5 L) and cooled to 0° C. NaH (67.7 g, 1.69 mol, 60% dispersion in oil) was added in portions over 5 minutes keeping the temperature at 0° C. The reaction was stirred for 30 minutes, and 3-chloro-4-fluorobenzylbromide (345.5 g, 1.54 mol) dissolved in 200 mL NMP was added over 30 minutes, again keeping the internal temperature at 0° C. The reaction was aged for 1 hour at 0° C., and allowed to warm to room temperature overnight. LCMS showed the reaction complete. The reaction mixture was quenched with 5 L distilled H2O, extracted with 3 portions of CH2Cl2 (2 L, 1 L, 1 L) and the organic layers combined and washed with three 4 L portions of water. The organic layer was concentrated and was found to contain NMP. The residual oil was dissolved in EtOAc (4 L), and extracted with three 2 L portions of water. The organic layer was concentrated to give the product that solidified upon standing.

Workup

  1. customat 0° C
  2. additionwas added over 30 minutes
  3. customat 0° C
  4. waitThe reaction was aged for 1 hour at 0° C.
  5. temperatureto warm to room temperature overnight
  6. customThe reaction mixture was quenched with 5 L
  7. distillationdistilled H2O
  8. extractionextracted with 3 portions of CH2Cl2 (2 L, 1 L, 1 L)
  9. washwashed with three 4 L portions of water
  10. concentrationThe organic layer was concentrated
  11. dissolutionThe residual oil was dissolved in EtOAc (4 L)
  12. extractionextracted with three 2 L portions of water
  13. concentrationThe organic layer was concentrated
  14. customto give the product that

Sources & evidence

ORD record
ord-cbdda365d198445081464a8a5464edfe
Source dataset
uspto-grants-2009_10
Patent number
US07598264B2

Reaction notes

Loading…