Studies on pyridonecarboxylic acids. V. A practical synthesis of ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, a key intermediate for the new tricyclic quinolone, prulifloxacin (NM441) and versatile new syntheses of the 2-thioquinoline skeleton

A practical synthesis of ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate (9), the key intermediate for 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid(2), NM441, was developed. The crucial points of this synthetic route are the chlorination of ethyl 4-acetoxy-2-(ethylthio)-6,7-difluoroquinoline-3-carboxylate (12) and the subsequent deacetylation of the resulting 2-(1-chloroethyl)thio compound 13 followed by the intramolecular cyclization reaction. Versatile new syntheses of 2-thioquinoline skeleton were also developed. The first route includes the intramolecular cyclization of the N,S-acetal 22 which was prepared from 2,4,5-trifluorobenzoic acid in three steps. The second one contains the regioselective attack of lithium enolate of ethyl acetate to the novel 2-(methylthio)-4H-[3,1]benzothiazine-4-one 29 at the 4-position followed by the intramolecular cyclization of the resulting beta-ketoester 30.