Lithium Hydroxide → 3-ethyl-4-fluorobenzoic acid

HRID 1786011Notes

Reaction equation

HRID 1786011 reaction equation
[CH2:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[C:6]([O:8]C)=[O:7])[CH3:2].[OH-].[Li+]>[Pd].CO.CO.O1CCCC1.O>[F:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2]

Participants

6

Reactant 2

HCID 3939Lithium HydroxideHCID 24971961HCID 24971961, compound

Product 1

HCID 113896193-ethyl-4-fluorobenzoic acid

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 21892291Methanol tetrahydrofuran waterSolvent

Procedure

(4-fluoro-3-ethylbenzoyl chloride was prepared in 5 steps from 3-bromo-4-fluorobenzoic acid. 3-bromo-4-fluorobenzoic acid was converted to methyl 3-bromo-4-fluorobenzoate by treatment with trimethylsilyl diazomethane (1.5 equivalents) in benzene/methanol (4/1) at room temperature. Subsequent reaction with tributyl(vinyl) tin (1.2 equivalents) in DMF in the presence of catalytic dichlororbis(triphenylphosphine)palladium(II) (0.1 equivalents) at 80° C. under an argon atmosphere, followed by aqueous work up and standard chromatography (10% ethyl acetate/hexanes), yielded methyl 4-fluoro-3-vinylbenzoate. Hydrogenation of the vinyl group by treatment of this material with palladium on carbon (10% palladium on carbon, 10% by mass) in methanol under an hydrogen atmosphere then afforded methyl 3-ethyl-4-fluorobenzoate. This material was dissolved in methanol/tetrahydrofuran/water (2/1/1) then lithium hydroxide (5.0 equivalents) was added and reaction mixture stirred at room temperature for 2 hours. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-fluoro-3-ethylbenzoic acid. This material was directly converted to 4-fluoro-3-ethylbenzoyl chloride by treatment with thionyl chloride (2.2 equivalents) in dichloromethane at room temperature for 2 hours followed by removal of the volatiles in vaccuo). The rest of the procedures were followed as indicated in general procedure B to afford N-(4-chlorophenyl)-N-[(2S,4R)-1-(3-ethyl-4-fluorobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide.

Workup

  1. customreaction mixture
  2. concentrationThe mixture was concentrated
  3. extractionextracted with ethyl acetate
  4. washThe organic layer was washed with brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-90e2427c2c1f47b09894c70bbe445f5b
Source dataset
uspto-grants-2009_03
Patent number
US07504508B2

Reaction notes

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