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Usage

Uses

Used in Pharmaceutical Industry:
3-Quinolinecarboxylic acid, 8-cyano-1-cyclopropyl-6-fluoro-7-[(4aS,7aS)-hexahydropyrrolo[3,4-b]-1,4-oxazin-6(2H)-yl]-1,4-dihydro-4-oxois used as an antimicrobial agent for the treatment of acute otitis externa, commonly known as swimmer's ear. The application reason is its increased antibacterial activity at pH 5-6, which is the typical pH level of the ear canal, and its high selectivity for bacterial type II topoisomerases, making it effective against a wide range of bacterial infections, including those caused by Pseudomonas aeruginosa and Staphylococcus aureus.
Used in Research and Development:
In addition to its clinical use, 3-Quinolinecarboxylic acid, 8-cyano-1-cyclopropyl-6-fluoro-7-[(4aS,7aS)-hexahydropyrrolo[3,4-b]-1,4-oxazin-6(2H)-yl]-1,4-dihydro-4-oxois also utilized in research and development for the preparation of naphthyridonecarboxylic acid derivatives. These derivatives are potential drugs for the therapy of Helicobacter pylori infections and associated gastroduodenal illnesses. The application reason is the compound's ability to target and inhibit bacterial topoisomerases, which play a crucial role in bacterial DNA replication, transcription, repair, and recombination, thus providing a promising avenue for the development of new antibiotics and therapeutic agents.

Biochem/physiol Actions

Finafloxacin is a fluoroquinolone antibiotic approved by the FDA in 2014 for treating swimmer′s ear. Its mechanism of action involves the inhibition of bacterial type II topoisomerase enzymes, DNA gyrase and topoisomerase IV

Synthesis

Synthesis of finafloxacin has been reported on kilogram scale starting from 5-fluoro-1,3-xylene (104). Catalytic chlorination through the use of FeCl3 in 1,2-dichloroethane (DCE) was followed by a photochemical chlorination at elevated temperatures to generate the polychlorinated intermediate 105 in 45% yield over two steps. The polychlorinated system 105 was then hydrolyzed with concentrated sulfuric acid to arrive at 3-formylbenzoic acid 106. Conversion of the formyl group to nitrile and the acid to the acid chloride was achieved in two steps, via condensation of the aldehyde with hydroxylamine hydrochloride in the presence of 45% NaOH and subsequent treatment with refluxing thionyl chloride to afford 107 in 62% yield for the two steps. Acid chloride 107 was converted to quinolone 109 through the following 4-step sequence, which was conducted without isolation of intermediates—107 was first coupled with ethyl 3-dimethylamino- acrylate 108 in DCM in the presence of DIPEA followed by condensation with cyclopropylamine in the presence of acetic acid. This was followed by treatment with potassium carbonate in warm NMP and, upon acidification, ethyl ester 109 was furnished in a remarkable 90% yield over the sequence. Acidic hydrolysis of ester 109 generated acid 110, which underwent coupling with pyrrolo-oxazine 111 in the presence of triethylamine (TEA) and warm acetonitrile to provide finafloxacin (XIV) in 90% yield from 109. The synthesis of pyrrolo-oxazine fragment 111 commenced with (Z)-butene-1,4-diol (112).120 Mesylation of this diol followed by reaction with tosylamide under phase transfer conditions afforded dihydropyrrole 113. Epoxidation of the olefin using 3-chloroperoxybenzoic acid (m-CPBA) to give 114, followed by subjection to ethanolamine affected an epoxide ring opening to give rise to the trans aminoalcohol rac-115. Tosylation and cyclization upon treatment with methanolic sodium hydroxide gave the bis-toluenesulfonamide 116, which was resolved at this point to >99% ee by chiral chromatography to arrive at the desired (S,S)-enantiomer. Removal of the tosyl protecting groups within 116 using hydrobromic acid in glacial acetic acid preceded treatment with KOH to finally furnish pyrrolo-oxazine 111.