N-Methylacetamide → N-[(4-Fluorophenyl)methyl]-N-methylacetamide

HRID 1373205Notes

Reaction equation

HRID 1373205 reaction equation
[CH3:1][NH:2][C:3](=[O:5])[CH3:4].[H-].[Na+].[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[NH4+].[Cl-]>C1COCC1.C(#N)C.CCCCCCC.C(OCC)(=O)C.O>[CH3:1][N:2]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([F:8])=[CH:10][CH:11]=1)[C:3](=[O:5])[CH3:4]

Participants

10

Reactant 4

HCID 6582N-Methylacetamide2×HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 680214-Fluorobenzyl bromide2×

Product 1

HCID 21947447N-[(4-Fluorophenyl)methyl]-N-methylacetamideYield 97%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 8900HeptaneSolvent

Procedure

Slowly add a solution of 375 g (5.13 mol, 112 equiv) of N-methylacetamide in THF (1.76 L) to 224 g (5.55 mol, 1.2 equiv) of sodium hydride (60% dispersion in mineral oil) as a slurry in THF (8.75 L). After 30 minutes when 25% of the solution has been added, add 875 g (4.63 mole, 1 equiv) of 4-fluorobenzylbromide and the remaining N-methylacetamide and 4-fluorobenzylbromide solutions concurrently over the next 3 h. Use a water bath to maintain the temperature below 40° C. Stir the resulting mixture overnight and pour into a mixture of 20% NH4Cl (2.5 L), water (6.5 L), and ethyl acetate (9 L). Separate the layers and back-extract the aqueous layer with ethyl acetate (4.5 L, then 2 L). Combine the organic layers and wash with water (4 L) and then brine (7 L). Dry the organic layer (Na2SO4) and remove the solvent to afford a residue. Dissolve the residue in acetonitrile (7 L) and heptane (1.75 L). Separate the layers and wash the acetonitrile layer again with heptane (1.75 L). Combine the heptane layers and back-extract with acetonitrile (0.5 L). Combine the acetonitrile layers and evaporate to afford 0.814 kg of N-methyl-N-(4-fluorobenzyl)acetamide.

Workup

  1. customconcurrently over the next 3 h
  2. temperatureto maintain the temperature below 40° C
  3. customSeparate the layers
  4. extractionback-extract the aqueous layer with ethyl acetate (4.5 L
  5. washCombine the organic layers and wash with water (4 L)
  6. dry with materialDry the organic layer (Na2SO4)
  7. customremove the solvent
  8. customto afford a residue
  9. customSeparate the layers
  10. washwash the acetonitrile layer again with heptane (1.75 L)
  11. extractionCombine the heptane layers and back-extract with acetonitrile (0.5 L)
  12. customCombine the acetonitrile layers and evaporate

Sources & evidence

ORD record
ord-78709266d9504178aac3f6a9d6304c37
Source dataset
uspto-grants-2007_01
Patent number
US07160922B2

Reaction notes

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