STUDIES ON PYRIDONECARBOXYLIC ACIDS - V - A PRACTICAL SYNTHESIS OF ETHYL XO-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 oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3- carboxylate (9), the key intermediate for -oxo-4H-[1,3]thiazeto[3,2-a] quinoline-3-carboxylic acid(2), NM441, was developed. The crucial poin ts of this synthetic route are the chlorination of ethyl -2-(ethylthio )-6,7-difluoroquinoline-3-carboxylate (12) and the subsequent deacetyl ation of the resulting 2-(1-chloroethyl)thio compound 13 followed by t he intramolecular cyclization reaction. Versatile new syntheses of 2-t hioquinoline skeleton were also developed. The first route includes th e intramolecular cyclization of the N,S-acetal 22 which was prepared f rom 2,4,5-trifluorobenzoic acid in three steps. The second one contain s 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-keto ester 30.