Ofloxacin synthesis

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

Before an asymmetric synthesis appeared of levofloxacin (1, (—)-ofloxacin), (—)- ofloxacin was isolated via optical, enzymatic, and crystallization resolution of the racemic ofloxacin (17) Drugs Future, 1992 Hayakawa et al., 1986, 1991). For instance, tricyclic core 52 was converted to ( + )-3,5-dinitrobenzoyl derivative 54 in 75% yield (Scheme 4.5). The enantiomers were then separated via high-performance liquid chromatography (HPLC) with a SUMIPAX OA-4200 column to deliver optically pure benzoyl esters 55a and 55b (Drugs Future, 1992 Hayakawa et al., 1986, 1991). 

W]ith the development of synthesis methods via stereoselection and improvement in the analytical methods of optical isomers in the recent years, many came to believe that only one of the enantiomers is the important substance and that the other one is, if bluntly said, an almost impure substance. Influenced by ideas like these, we decided to focus on the antibacterial activity of the two [ofloxacin] enantiomers, resulting in the apphcation of optical resolution. 

Atarashi S, et al. Synthesis and antibacterial activities of optically active ofloxacin and its fluoromethyl derivative. Chem. Pharm. Bull. (Tokyo), 1987, 35, 1896-1902. 

Later steps in the synthesis of ofloxacin were discussed in Chapter 23. 

For examples of quinolone antibiotics we can choose ofloxacin, whose synthesis is discussed in detail in Chapter 23, and rosoxacin whose synthesis is discussed overleaf. Both molecules contain the... 

The quinolone class of drugs were discovered in the 1960s when Lesher et al. isolated nalidixic acid as a by-product of chloroquine synthesis (2). More than a thousand quinolones and analogs have since been synthesized and evaluated in an attempt to reduce toxicity and increase antimicrobial potency. The attachment of a fluorine to C-6 and a piperazine or methylpiperazine to C-7 has led to more active agents such as norfloxacin, ciprofloxacin, ofloxacin and lomefloxacin (3). 

Many enantiomerically pure compounds can be made by a variety of strategies. Several conceivable strategies for the synthesis of the quinolone antibiotic ofloxacin 45 are shown below. The molecule contains only one chiral centre and this may be introduced as a fragment from the chiral pool 47 or by the resolution of a key intermediate 44 or indeed the final product.4 A synthesis developed5 for the preparation of racemic ofloxacin which incorporates racemic aminoalcohol ( )-47, could in principle... 

Quinolone antibiotics such as ofloxacin 200 are totally different from P-lactams, tetracyclines and so on and work in a different way. They offer some hope that resistance may be slow to appear. They all contain the quinolone core a benzene ring fused to a y-pyridone. Most have various amine substituents and ofloxacin has a fluorine atom. Disconnection of the enamine reveals a benzene ring with a series of heteroatom substituents (N, N, O, F) and the one fluorine suggests that a series of nucleophilic substitutions might provide a synthesis. 

Ofloxacin interferes with microbial DNA synthesis. It is indicated in the treatment of acnte bacterial exacerbations of chronic bronchitis, commnnity acquired pneumonia, uncomplicated skin and skin structure infections, acute uncomplicated urethral and cervical gonorrhea, nongonococcal urethritis, cervicitis, acute pelvic inflammatory disease, uncomplicated cystitis, complicated urinary tract infections (UTI), and prostatitis cdiV eAhy Escherichia coli. Ophthalmic use for treatment of conjunctivitis and corneal ulcer infections caused by susceptible organisms otic use for treatment of otitis externa, chronic suppurative otitis media in patients with perforated tympanic membranes, and acute otitis media in pediatric patients with tympanostomy tubes. 

The gyrase inhibitor ofloxacin (F, cf p 335) is medicinally used as an antibiotic. Its synthesis is accomplished from l,2,3-trifluoro-4-nitrobenzene (X) utilizing the following sequence of transformations ... 

Chemists from Daiichi-Seiyaku were interested in furo(2,3-g)quinoline derivatives fused with piperidine or 1,4-oxazine rings. In 1984 they reported the first synthesis of ofloxacin [8, 9]. 

Sahoo S, SasmalA, NandaR, PhaniAR,NayakPL. Synthesis of chitosan-polycaprolactone blends for control delivery of ofloxacin drng. Carbohydr Polym 2010 79 106. 

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