Potassium Carbonate → 4-Cyclopropyl-2-fluoro-6-methylbenzamide

HRID 2069706Notes

Reaction equation

HRID 2069706 reaction equation
Br[C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+]>C1(C)C=CC=CC=1.O.CCCCCCC.C(OCC)(=O)C>[CH:13]1([C:2]2[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:12])[CH:3]=2)[CH2:15][CH2:14]1

Participants

10

Reactant 5

HCID 11430Potassium CarbonateHCID 14923Ammonium HydroxideHCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 594737734-Bromo-2-fluoro-6-methylbenzamide

Product 1

HCID 594738034-Cyclopropyl-2-fluoro-6-methylbenzamide

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent2×HCID 8900HeptaneSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 4-bromo-2-fluoro-6-methylbenzamide (10 g), cyclopropylboronic acid (4.87 g, 1.25 eq), tricyclohexylphosphine (725 mg, 0.06 eq), tris (dibenzyllideneacetone)dipalladium(0) chloroform adduct (446 mg, 0.01 eq) and potassium carbonate (17.9 g, 3 eq) in toluene (100 ml) and water (10 ml) was stirred under reflux in an inert (nitrogen) environment for about 24 h. The reaction mixture was then cooled to about 60° C. and treated with 10% aqueous ammonium hydroxide (60 ml) and then with ethyl acetate (60 ml). Layers were separated, the organic phase was washed with brine and filtered to remove particulate material. The extract was concentrated under reduced pressure to about 30 ml to obtain a slurry. This was diluted with heptane (80 ml) and ethyl acetate (20 ml) and then heated to reflux to dissolve all solids. The resulting solution cooled slowly to room temperature to allow the product to crystallize out. The precipitated product was isolated by filtration, washed with ethyl acetate-heptane (1:1) mixture (60 ml), dried under vacuum at about 60° C. to obtain 6.85 g (82.3% isolated yield) of product.

Workup

  1. temperatureunder reflux in an inert (nitrogen) environment for about 24 h
  2. customLayers were separated
  3. washthe organic phase was washed with brine
  4. filtrationfiltered
  5. customto remove particulate material
  6. concentrationThe extract was concentrated under reduced pressure to about 30 ml
  7. customto obtain a slurry
  8. temperatureheated
  9. temperatureto reflux
  10. dissolutionto dissolve all solids
  11. temperatureThe resulting solution cooled slowly to room temperature
  12. customto crystallize out
  13. customThe precipitated product was isolated by filtration
  14. washwashed with ethyl acetate-heptane (1:1) mixture (60 ml)
  15. customdried under vacuum at about 60° C.
  16. customto obtain
  17. custom6.85 g (82.3% isolated yield) of product

Sources & evidence

ORD record
ord-9276121b66e54034929eb19fed8b47ed
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

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