Practical Synthesis and Molecular Structure of a Potent Broad-Spectrum Antibacterial Isothiazoloquinolone
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Abstract
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)-9H-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-9H-isothiazolo[5,4-b]quinoline-3,4-dione (4), 5, and ethyl 2-cyclopropylamino-6,7-difluoro-8-methoxy-4-oxo-4H-thiochromene-3-carboxylate (10) were established unambiguously using multinuclear NMR spectroscopy and X-ray crystallography.