Practical Synthesis and Molecular Structure of a Potent Broad-Spectrum Antibacterial Isothiazoloquinolone

We report the synthesis of the new 2-sulfonylquinolone ethyl 1-cyclopropyl-6,7-difluoro-2-methanesulfonyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate ( 5 ). Sulfone 5 is a key intermediate used in the optimized synthesis of the isothiazoloquinolone 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9 H -isothiazolo[5,4- b ]quinoline-3,4-dione ( 1 ), a potent broad-spectrum antibacterial agent that is effective against clinically important resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA). Our synthetic method is free of chromatographic purification and amenable to large-scale synthesis. The molecular structures of 1, 9-cyclopropyl-6,7-difluoro-8-methoxy-9 H -isothiazolo[5,4- b ]quinoline-3,4-dione ( 4 ), 5, and ethyl 2-cyclopropylamino-6,7-difluoro-8-methoxy-4-oxo-4 H -thiochromene-3-carboxylate ( 10 ) were established unambiguously using multinuclear NMR spectroscopy and X-ray crystallography.