Sulfuric Acid → Ibuprofen methyl ester

Participants

Reaction Conditions

Reaction Steps

Oven-dried iodobenzene diacetate (86.4 grams(g), 0.25 mol), which experience has shown is essentially free of water, was added with stirring to p-isobutylpropiophenone (47.5 g, 0.25 mol) at room temperature (about 22°-25° C.), which temperature was maintained throughout the procedure of this example unless indicated otherwise. To the resulting mixture was added water (approximately 15.8 g, 0.88 mol) with stirring to provide a mixture containing a known amount of water. To the resulting aqueous mixture were added sequentially, with stirring, acetic anhydride (75 ml, 0.88 mol) and, dropwise, concentrated sulfuric acid (about 96% H2SO4, 0.14 ml, 3 mmol). The resulting mixture was stirred 2 hours to ensure substantially complete reaction of the anhydride with the water and then cooled to 0° C. Trimethylorthoformate (24.6 ml, 0.225 mol) was then added with stirring, followed by dropwise addition, with stirring, of concentrated sulfuric acid (about 96% H2SO4 2.5 ml, 0.05 mol) over 30 minutes. The ensuing reaction mixture was stirred an additional 2 hours at 0° C. to 20° C. The resulting ibuprofen-methyl-ester-forming reaction was quenched by adding 50 ml deionized water. HPLC (high performance liquid chromatography) analysis of the resulting reaction product comparing to an external standard, demonstrated 75% yield of ibuprofen methylester. The mixture obtained can be separated into an aqueous phase and an organic phase, followed by isolation of purified ibuprofen methyl ester from the organic phase by column chromatography or distillation. Alternatively, the crude ester can be hydrolyzed by treating with 50% aqueous sodium hydroxide, followed by extraction of the resulting aqueous phase with heptane. Acidification of the aqueous phase and recrystallation of the solid precipitate yields high-purity ibuprofen.

Provenance & Evidence