Acetic Acid → Ibuprofen, (+-)-

Participants

Reaction Steps

To a stirred solution of 109 g (573 mmol) of 2-(4-isobutylphenyl)-propionaldehyde (ibuprofen aldehyde) in ethyl acetate (5 12 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 34.4 g (573 mmol) of glacial acetic acid and 61.4 g (573 mmol) of 2,6-dimethyl pyridine (2,6-lutidine). To this solution was then added slowly dropwise 276 mL (859 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 7° C. (ca. 1 h 40 min). After the initial exotherm, the temperature returned to 2° C,, and the reaction was maintained at this temperature for an additional 2 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 (650 mL), and was washed with a 7% aqueous solution of sodium thiosulfate (Na2S2O3, 500 mL). The ethyl acetate layer was further washed with two portions of water (750 mL each), and the combined water washes were back-extracted with ethyl acetate (300 mL). The combined ethyl acetate layers were extracted with three portions of a 5% aqueous solution of sodium hydroxide (NaOH, 750 mL twice, then 500 mL). The combined NaOH solutions were acidified to pH=1 with a 10% aqueous solution of hydrochloric acid. The resulting solution was extracted with three portions of dichloromethane (500 mL twice, then 300 mL), and the extract was dried over anhydrous Na2SO4. The extract was filtered and concentrated in vacuo to give 109 g (92.2%) of ibuprofen as an off-white solid. HPLC analysis of this material indicated an `S` acid content of 83%, the same as the starting aldehyde as measured following KMnO4 oxidation.

Provenance & Evidence