Alkylation of the sodium salt of diclofenac (I) with benzyl bromoacetate (II) in hot DMF yielded the (arylacetoxy)acetate (III). Subsequent hydrogenolysis of the benzyl ester of (III) in the presence of Pd/C gave the title carboxylic acid. Alternatively, the benzyl ester group of (III) was cleaved by means of the combination of chlorotrimethylsilane and sodium iodide. This method of selective ester hydrolysis with in situ generated iodotrimethylsilane was also applied to the corresponding methyl (IV) and tert-butyl (V) esters. In a related procedure, tert-butyl ester (V) was prepared by alkylation of diclofenac (VI) with tert-butyl bromoacetate (VII) in the presence of tertiary amines. Selective cleavage of the tert-butyl ester group of (V) was then performed by treatment with either trifluoroacetic or formic acid.
Aceclofenac was prepared by selective hydrolysis of other labile ester precursors. Alkylation of diclofenac sodium (I) with tetrahydropyranyl chloroacetate (IX), prepared by protection of chloroacetic acid (VIII) with dihydropyran, furnished the tetrahydropyranyl ester of aceclofenac (X), which was then deprotected by treatment with HCl. Similarly, the preparation of aceclofenac was reported by acidic hydrolysis of the analogous tetrahydrofuranyl ester (XI).