Acetic Acid → 6-(Benzyloxy)pyridine-3-carboxylic acid

HRID 1885504Notes

Reaction equation

HRID 1885504 reaction equation
[H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1.C(O)(=O)C>CN(C=O)C.O>[CH2:3]([O:10][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 244Benzyl AlcoholHCID 24758Sodium hydrideHCID 792226-Chloronicotinic acid

Product 1

HCID 2772386-(Benzyloxy)pyridine-3-carboxylic acidYield 88%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent3×

Conditions

Temperature
0 °C

Procedure

Oil-free NaH (1.9 g,~5 eq.) was suspended in DMF (30 ml) and the suspension was cooled in an ice bath. Benzyl alcohol (8.6 ml, ~5.2 eq.) was added slowly to the suspension via syringe. The resulting reaction mixture was stirred at 0° C. for 20 min., after which it was transferred to a precooled (0° C.) solution of 6-chloronicotinic acid (2.5 g, 15.9 mmol) in DMF (30 ml). Additional DMF (20 ml) was added to the reaction mixture to facilitate stirring. The reaction mixture was refluxed for 2 hours. Aqueous acetic acid 5% (by volume) was added to the cooled reaction mixture, and the resultant acidic mixture was extracted (3x) with ethyl acetate. The organic layers were combined, washed with brine and the solvent was removed to give a yellow liquid, from which a white solid was obtained after addition of water. Recrystallization from acetone/water gave 6-benzyloxynicotinic acid (4, Scheme I, 88% yield) as colorless needles.

Workup

  1. temperaturethe suspension was cooled in an ice bath
  2. customThe resulting reaction mixture
  3. stirringto facilitate stirring
  4. temperatureThe reaction mixture was refluxed for 2 hours
  5. extractionthe resultant acidic mixture was extracted (3x) with ethyl acetate
  6. washwashed with brine
  7. customthe solvent was removed
  8. customto give a yellow liquid
  9. customfrom which a white solid was obtained
  10. customRecrystallization from acetone/water

Sources & evidence

ORD record
ord-41135c3d9afb49bd9dab359d801a2384
Source dataset
uspto-grants-1992_09
Patent number
US05145601

Reaction notes

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