The precursor 2,2-dimethyl-(2-naphthyl)acetic acid (IV) was prepared as follows. 2-Naphthylacetic acid (I) was converted to the benzyl ester (II) by treatment with benzyl bromide and DBU. Dimethylation of the sodium enolate of (II) with iodomethane furnished (III). Removal of the benzyl ester group of (III) was then achieved by hydrogenolysis in the presence of Pd/C.
Ethyl phenylacetate (V) was dimethylated upon treatment with iodomethane and sodium bis(trimethylsilyl)amide, yielding (VI). Iodination of (VI) was carried out by means of iodine and sodium iodate in acidic medium, and the resulting iodo ester (VII) was subsequently hydrolyzed with KOH to the carboxylic acid (VIII). This was converted to the tert-butyl ester (X) via conversion to the corresponding acid chloride (IX) with oxalyl chloride, followed by treatment with potassium tert-butoxide. Palladium-catalyzed Heck coupling of aryl iodide (X) with N-Boc-dehydroalanine benzyl ester (XI) furnished the aminocinnamic acid derivative (XII). Then, catalytic hydrogenation of the olefin double bond of (XII) with simultaneous benzyl ester cleavage provided the protected racemic amino acid intermediate (XIII).
Alkylation of 4-methyl-3-nitro-2-pyridone (XIV) with p-methoxybenzyl chloride (XV) gave the N-benzylpyridone (XVI). The nitro group of (XVI) was then reduced to amine (XVII) by catalytic hydrogenation over Pd/C. Coupling of the intermediate amino acid derivative (XIII) with the aminopyridone (XVII) provided amide (XVIII). Selective cleavage of the N-Boc group of (XVIII) in the presence of the tert-butyl ester was achieved by treatment with HCl in dioxan. The resultant amine (XIX) was then coupled with 2,2-dimethyl-(2-naphthyl)acetic acid (IV) to furnish amide (XX). Finally, the title (S)-carboxylic acid was obtained by tert-butyl ester cleavage with trifluoroacetic acid followed by separation of the racemic mixture by means of chiral HPLC.