Озеноксацин

Ozenoxacin is a novel, nonfluorinated quinolone antibiotic discovered by Toyama Chemical Co. Ltd. and developed by Maruho Co. Ltd. Ozenoxacin was approved by the PMDA of Japan in September 2015 for the treatment of acne and skin infections. Ozenoxacin shows potent antibacterial activity against anaerobic and aerobic, gram-positive and -negative bacteria, especially those implicated in superficial skin infections such as S. aureus, Staphylococcus epidermidis, and Propionibacterium acnes. The mechanism of action of ozenoxacin involves the drug’s affinity for DNA gyrase and DNA topoisomerase IV and upon binding triggers bacterial apoptosis.

Ozenoxacin is a non-fluorinated topical quinolone. It exhibits antimicrobial activity against?propionibacteria and staphylococci. Ozenoxacin can be used to treat acne and superficial skin infections.

A U.S. patent filed by co-workers at Toyama describes the only publicly disclosed synthetic approach to this drug.12 The drug?ˉs assembly hinges upon a key Stille coupling between a quinolonyl bromide and a stannylpyridine. Buchwald-Hartwig coupling of commercially available 2,6- dibromotoluene (22) and cyclopropylamine (23) gave Ncyclopropyl- 3-bromo-2-methylaniline 24 in 84% yield , and this step was followed by reaction with diethyl ethoxymethylenemalonate (25) and subsequent cyclization under acidic conditions to secure bromoquinoline 26 in 43% yield over the two-step sequence. Stille coupling of 27 with bromoquinoline 26 resulted in pyridyl quinoline adduct 28 in 80% yield. Saponification of ester 28 followed by acidic removal of the N-acetyl group delivered the active pharmaceutical ingredient ozenoxacin (III) in 75% yield.
The preparation of key stannane 27, which is not commercially available and began with the conversion of commercially available 5-bromo-2- chloro-3-methylpyridine (30) to aminopyridine derivative 31 upon treatment with aqueous methylamine at elevated temperature in a sealed vessel. The resulting aminopyridine was subjected to acetic anhydride in pyridine, resulting in acetamide 32 in good yield, and this coupling was followed by a modest-yielding palladium-catalyzed installation of the stannyl group to deliver subunit 27.