Aniline → Ethyl 6-acetyl-1,4-dihydro-4-oxoquinoline-3-carboxylate

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Reaction Steps

Scheme 2 below shows an illustrative chemical pathway for the synthesis of the compounds described above in Table 2. The 1,4-dihydro-6-acetyl-4-oxoquinoline-3-carboxylic acid ethyl ester 8 was prepared according to Koga et al., Journal of Medicinal Chemistry 23:1358-1363, 1980, by reacting the appropriate aniline with diethyl ethoxymethylenemalonate followed by thermal cyclization of the malonate derivative obtained. Alkylation of compound 8 with 4-fluorophenylmethylbromide in alkaline medium led to derivative 9 that was condensed with diethyl oxalate in presence of the sodium ethoxide to afford 4-[3-carboxyethyl-1,4-dihydro-1-(4-fluorophenyl)methyl-4-oxoquinolin-6-yl]-2,4-dioxobutanoic acid, ethyl ester 10 (RDS 1606). Alkaline hydrolysis of the latter compound to provide 4-[3-carboxyethyl-1,4-dihydro-1-(4-fluorophenyl)methyl-4-oxoquinolin-6-yl]-2,4-dioxobutanoic acid 11 (RDS 1607) was carried out with aqueous 1N sodium hydroxide at room temperature, while hydrolysis of the quinolinecarboxylate ester 9 to afford corresponding acid 12 required 20% aqueous sodium hydroxide (Scheme 2).

Provenance & Evidence