Acetic Acid → Naproxen

HRID 1599187Notes

Reaction equation

HRID 1599187 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.C(O)(=[O:19])C.CC1C=CC=C(C)N=1.C(OO)(=O)C>C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:19])=[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 79372,6-LutidineHCID 1183081032305-59-2

Product 1

HCID 156391NaproxenYield 88.5%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent3×

Procedure

To a stirred solution of 16.67 g (77.8 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde (naproxen aldehyde) in ethyl acetate (78 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 4.67 g (77.8 mmol) of glacial acetic acid and 8.33 g (77.8 mmol) of 2,6-dimethylpyridine (2,6-lutidine). To this solution was then added slowly dropwise 8.87 g (116.7 mmol) of a 23.7 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. 1 hour). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 3.5 hours. Conversion of aldehyde at this time was ca. 99%, as monitored by GC (DB-1 column). The cold reaction solution was then transferred into a separatory funnel, was diluted with ethyl acetate (300 mL), and was washed with a 5% aqueous solution of sodium thiosulfate (Na2S2 O3, 100 mL). The ethyl acetate layer was further washed with two portions of water (110 mL each), and the combined water washes were back-extracted with ethyl acetate (100 mL). The combined ethyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 110 mL each). The combined NaOH solutions of sodium naproxenate were acidified to pH=1 with a 10% 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 #4 Whatman filter. The white solid thus obtained was dried in a vacuum oven overnight at 45° C. (25 mm Hg), giving 15.85 g (88.5%) of naproxen. HPLC analysis of this material (Chiracel OD-H column) indicated an `S` acid content of 99.2%, the same as the starting aldehyde as measured following KMnO4 oxidation.

Workup

  1. customdid not exceed 10° C.
  2. custom(ca. 1 hour)
  3. customreturned to 2° C.
  4. temperaturethe reaction was maintained at this temperature for an additional 3.5 hours
  5. customThe cold reaction solution was then transferred into a separatory funnel
  6. washwas washed with a 5% aqueous solution of sodium thiosulfate (Na2S2 O3, 100 mL)
  7. washThe ethyl acetate layer was further washed with two portions of water (110 mL each)
  8. extractionthe combined water washes were back-extracted with ethyl acetate (100 mL)
  9. extractionThe combined ethyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 110 mL each)
  10. customprecipitating the naproxen acid
  11. temperatureThe mixture was cooled in a wet-ice bath
  12. filtrationfiltered through a #4 Whatman
  13. filtrationfilter
  14. customThe white solid thus obtained
  15. customwas dried in a vacuum oven overnight at 45° C. (25 mm Hg)

Sources & evidence

ORD record
ord-53f07947e65b4de1a6045f1f9fe09c2c
Source dataset
uspto-grants-1998_04
Patent number
US05739385

Reaction notes

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