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-oxo-

Description

Finafloxacin, an antimicrobial agent of the 8-cyano subclass of fluoroquinolones, was approved by the US FDA in December 2014 for treatment of acute otitis externa, commonly known as swimmer’s ear, caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus. Finafloxacin was developed by MerLion Pharmaceuticals in partnership with Bayer Health Care Pharmaceuticals, and the drug was licensed by Mer- Lion to Alcon (a division of Novartis) for development and commercialization for ear infections in North America. In contrast to other marketed fluoroquinolones, which display reduced activity in slightly acidic environments, finafloxacin exhibits increased antibacterial activity at pH 5–6, with minimum inhibitory concentration values that are 4- to 8-fold lower than at neutral pH. It is highly selective for bacterial type II topoisomerases, which are involved in bacterial DNA replication, transcription, repair, and recombination, and has broad spectrum antibacterial activity against Gram-positive and Gram-negative strains, including ciprofloxacin-resistant strains.

Uses

Used for the preparation of naphthyridonecarboxylic acid derivatives as drugs for therapy of Helicobacter pylori infections and associated gastroduodenal illnesses.

Definition

ChEBI: A quinolone that is 4-oxo-1,4-dihydroquinoline-3-carboxylic acid which is substituted at positions 1, 6, 7 and 8 by cyclopropyl, fluoro, hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl and cyano groups respectively; an antibiotic used for treatment of acute otitis externa (swimmer's ear) caused by the bacteria Pseudomonas aeruginosa and Staphylococcus aureus.

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?a107 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.