Acetic Acid → Naproxen

Participants

Reaction Steps

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.

Provenance & Evidence