Hydrochloric Acid → 1-Bromo-4-cyano-3-fluoro-5-(4-ethyl-benzyl)-benzene

HRID 1359919Notes

Reaction equation

HRID 1359919 reaction equation
CC([O-])(C)C.[K+].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](OCC)=O)=[CH:11][CH:10]=1)[CH3:8].[Br:21][C:22]1[CH:27]=C(F)[C:25]([C:29]#[N:30])=[C:24]([F:31])[CH:23]=1.Cl>CN1C(=O)CCC1>[Br:21][C:22]1[CH:27]=[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:7][CH3:8])=[CH:14][CH:13]=2)[C:25]([C:29]#[N:30])=[C:24]([F:31])[CH:23]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 27569164-Bromo-2,6-difluorobenzonitrileHCID 23665647Potassium tert-butoxideHCID 53419404Ethyl 2-(4-ethylphenyl)acetate

Product 1

HCID 592382301-Bromo-4-cyano-3-fluoro-5-(4-ethyl-benzyl)-benzene

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent2×

Conditions

Temperature
10 °C

Procedure

KOtBu (6.7 g) is added to a flask charged with a stir bar and dry NMP (30 mL) and chilled to −10° C. under argon atmosphere. A solution of ethyl (4-ethyl-phenyl)-acetate (5.6 g) and 1-bromo-4-cyano-3,5-difluoro-benzene (6.4 g) in NMP (20 mL) is added at such a rate that the solution temperature maintains below 10° C. After stirring for 1 hour at 10° C., the solution is neutralized with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and the solvent is evaporated. The residue is dissolved in THF (20 mL) and treated with 1M aqueous NaOH solution (80 mL). After stirring overnight at room temperature, the solution is acidified with 4 M HCl solution and extracted with ethyl acetate. The organic extracts are combined and dried (Na2SO4) and the solvent is evaporated. The residue is dissolved in DMF (25 mL) and K2CO3 (5.5 g) is added. The resulting mixture is stirred at 100° C. for 1 h. After cooling to room temperature, the mixture is neutralized with 1 M aqueous hydrochloric acid and the resultant mixture is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and the solvent is evaporated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0->1:1).

Workup

  1. additioncharged with a stir bar
  2. custommaintains below 10° C
  3. extractionextracted with ethyl acetate
  4. dry with materialThe combined extracts are dried (Na2SO4)
  5. customthe solvent is evaporated
  6. dissolutionThe residue is dissolved in THF (20 mL)
  7. additiontreated with 1M aqueous NaOH solution (80 mL)
  8. stirringAfter stirring overnight at room temperature
  9. extractionextracted with ethyl acetate
  10. dry with materialdried (Na2SO4)
  11. customthe solvent is evaporated
  12. dissolutionThe residue is dissolved in DMF (25 mL)
  13. additionK2CO3 (5.5 g) is added
  14. stirringThe resulting mixture is stirred at 100° C. for 1 h
  15. temperatureAfter cooling to room temperature
  16. extractionthe resultant mixture is extracted with ethyl acetate
  17. dry with materialThe combined organic extracts are dried (MgSO4)
  18. customthe solvent is evaporated
  19. customThe residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0->1:1)

Sources & evidence

ORD record
ord-33c3a6ca76ba4da5871d59e2772b397e
Source dataset
uspto-grants-2011_02
Patent number
US07879806B2

Reaction notes

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