Synthesis and Antibacterial Activities of Optically Active Ofloxacin and Its Fluoromethyl Derivative

• Published in: Chemical & pharmaceutical bulletin Vol. 35; no. 5; pp. 1896 - 1902
• Main Authors: ATARASHI, SHOHGO, YOKOHAMA, SHUICHI, YAMAZAKI, KEN-ICHI, SAKANO, KATSU-ICHI, IMAMURA, MASAZUMI, HAYAKAWA, ISAO
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1987; Maruzen; Japan Science and Technology Agency
• Subjects: 7, 8-difluoro-2, 3-dihydro-3-methyl-4H-P, 4] benzoxazine; absolute configuration; Anti-Infective Agents; antibacterial activity; Bacteria - drug effects; Chemical Phenomena; Chemistry; Condensed matter: structure, mechanical and thermal properties; DL-8280; DNA gyrase; Exact sciences and technology; Fluoroquinolones; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Microbial Sensitivity Tests; N-p-toluenesulfonyl-L-proline; ofloxacin; Ofloxacin - analogs & derivatives; optically active ofloxacin; Organic chemistry; Organic compounds; Oxazines - chemical synthesis; Oxazines - pharmacology; Physics; Preparations and properties; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; X-ray analysis; Molecular structure; Tricyclic compound; Experimental study; X ray diffraction; Biological activity; Enantiomer; Absolute configuration; Aromatic compound; Antibacterial agent; NMR spectrum; Organic compounds; Oxygen nitrogen heterocycle; Crystalline structure
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.35.1896

Two optically active (100% enantiomeric excess) isomers (13a and 13b) of ofloxacin (1) [(±) -ofloxacin; DL-8280; (±) -9-fluoro-2, 3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid] and their fluoromethyl derivatives (14a and 14b) were prepared via their optically active intermediates resolved by use of high-performance liquid chromatography (HPLC). The isomers (13a and 13b) were also obtained efficiently by an alternative route via separation of the diastereoisomers (18, 19) prepared in the reaction of benzoxazine (17) with L-prolinyl chloride. The (-) -isomers of 1 and its fluoromethyl derivative (2) were approximately twice as active as the corresponding racemates, while the (+) -isomers were considerably less active than the racemates. The absolute configuration at the C3 position in the oxazine ring in a series of (-) -compounds (b) was confirmed by X-ray analysis of the hydrochloride of the (-) -benzoxazine derivative (15b) to be S.