Acetic Acid → Naproxen

HRID 1599190Notes

Reaction equation

HRID 1599190 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.[N+]1([O-:23])C=CC=CC=1.C(O)(=O)C.C(OO)(=O)C>C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:23])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 6585Peracetic AcidHCID 12753Pyridine N-OxideHCID 1183081032305-59-2

Product 1

HCID 156391NaproxenYield 80.3%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent3×

Procedure

To a stirred solution of 2.00 g (9.3 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde in ethyl acetate (10 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 0.89 g (9.3 mmol) of pyridine N-oxide and 0.56 g (9.3 mmol) of acetic acid. To this solution was then added slowly dropwise 5.8 mL (14.0 mmol) of a 20.4 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 15 minutes). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 4 hours. The reaction solution was transferred into a separatory funnel, was diluted with ethyl acetate (15 mL), and was washed with a 0.1N aqueous solution of sodium thiosulfate (Na2S2 O3, 25 mL). The ethyl acetate layer was further washed with water (10 mL), and the combined water washes were back-extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were extracted with two portions of a 5% aqueous solution of potassium hydroxide (KOH, 65 mL then 25 mL). The combined KOH solutions of potassium naproxenate were acidified to pH=1 with a 5% aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet-ice bath, and then was vacuum filtered through a #1 Whatman filter. The filter cake was washed with cold water (20 mL) and the white solid thus obtained was dried in a vacuum oven 18 hours at 55° C. (25 mm Hg), giving 1.72 g (80.0%) of naproxen.

Workup

  1. customdid not exceed 10° C.
  2. custom(ca. 15 minutes)
  3. customreturned to 2° C.
  4. temperaturethe reaction was maintained at this temperature for an additional 4 hours
  5. customThe reaction solution was transferred into a separatory funnel
  6. washwas washed with a 0.1N aqueous solution of sodium thiosulfate (Na2S2 O3, 25 mL)
  7. washThe ethyl acetate layer was further washed with water (10 mL)
  8. extractionthe combined water washes were back-extracted with ethyl acetate (10 mL)
  9. extractionThe combined ethyl acetate layers were extracted with two portions of a 5% aqueous solution of potassium hydroxide (KOH, 65 mL
  10. customprecipitating the naproxen acid
  11. temperatureThe mixture was cooled in a wet-ice bath
  12. filtrationfiltered through a #1 Whatman
  13. filtrationfilter
  14. washThe filter cake was washed with cold water (20 mL)
  15. customthe white solid thus obtained
  16. customwas dried in a vacuum oven 18 hours at 55° C. (25 mm Hg)

Sources & evidence

ORD record
ord-8a7ab6778dfe4149a1032908e3f5ceb8
Source dataset
uspto-grants-1998_04
Patent number
US05739385

Reaction notes

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