Norfloxacin synthesis

Norfloxacin (41), the substance which triggered this avalanche of activity, has recently been introduced into clinical practice in the United States. Its synthesis parallels closely that of its N-methyl analogue, pefloxacin, except that the nucleophilic aromatic displacement reaction of 32 is carried out with mono-N-carboethoxypiperazine instead and the final step encompasses deblocking of this carbamoyl ester moiety [8]. 

Yang M and Santerre JP. Utihzation of quinolone drugs as monomers Characterization of the synthesis reaction products for poly(norfloxacin diisocyanatododecane polycaprolactone). Biomacromolecules, 2001, 2, 134-141. 

S. Gac, J. Coudane, M. Boustta, M. Domurado, and M. Vert, Synthesis, characterization and in vivo behavior of a norfloxacin-poly(L-lysine citramide imide) conjugate bearing mannosyl residues, J. Drug Targeting, 1 (2000) 393 -06. 

The synthesis and antibacterial properties of norfloxacin (2a) were described in 1980 [65]. In this key paper in the evolution of quinolone antibacterial agents, a series of 6,7,8-polysubstituted-l-ethyl-l,4-dihydro-4-oxoquinoline-3-carb-oxylic acids (13) was synthesized, employing previously developed quantitative structure-activity relationships (QSAR) for the corresponding 6-, 7- and 8-monosubstituted derivatives versus Escherichia coli. The QSAR analysis... 

Norfloxacin Norfloxacin, l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolincarboxylic acid (33.2.18), is the first representative of a series of fluorinated qninolones as well as the first drug of the quinolone derivatives used in medicine that contains a piperazine snbstituent. The method of synthesis is basically the same as that suggested for synthesizing nalidixic and oxolinic acids. 

Quinolones (bacteriostatic inhibit DNA gyrase) e.g., ciprofloxacin, cinoxacin, enoxacin, norfloxacin Rifampin (bactericidal blocks mRNA synthesis in bacteria, inhibits RNA polymerase)... 

For example this concept was applied to the synthesis of novel (acyloxyalkoxy) carbonyl bioreversible moieties for primary as well as secondary amines functions in drugs as illustrated with the case of a prodrug from the antibacterial Norfloxacin in scheme 135 (Ref. 194). 

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). 

The palladium-catalyzed amination reaction is developed for the preparation of fluoroanilines from fluorohaloarenes (82 - 98 % yields) and the synthesis of fluoroquinolone antibaeterials including Norfloxacin (58 — 75 % yields). For both sets of substrates, the fluoro-substituent remains intact, thus, the chemoselectivity is quantitative. 

Currently there is considerable interest in fluoroquinolone antibacterials as these pharmaceuticals are used for the treatment of infections resulting from exposure to Bacillus anthracis (anthrax). In particular, Ciprofloxacin is specifically recommended however, utilization of other fluoroquinolones such as Levaquin and Te-quin is imder investigation. The first fluoroquinolone to establish clinical usage was Norfloxacin (1). This pharmaceutical also serves as an excellent example of the typical synthesis of fluoroquinolones which are almost invariably prepared via nucleophilic addition (SwAr) of an amine to a fluorochloroquinolone (2) as the final step (Scheme 1 However, it is known that this step may produce 10 - 25 % of an undesrred fluoro-substituted byproduct (3). ... 

The synthesis of fluoroquinoline antibacterials almost invariably involves substitution of the chlorofluoroquinolone with an amine as the final step (Scheme 1). Thus, the above model studies indicate excellent potential for the palladium-catalyzed amination reaction to succeed. However, initial attempts to couple the chlorofluoroquinolone derivative 2 with piperazine using the Pd2dba3/binap catalyst system and NaOtBu in toluene solvent resulted only in the recovery of unreacted starting material. Changing to more polar solvents (DMSO, DMF) or the addition of iodide salts (in an attempt to generate the iodo derivative) had no effect. It was believed that the insolubility of the carboxylic acid 2 played a role in its failure to react and that the ethyl ester would be a more productive substrate. Conveniently, the ethyl ester of 2 is an intermediate in the standard synthesis of Norfloxacin, thus, the synthesis of 13 was readily accomplished (eq 2). ... 

Catalytic synthesis of l-ethyl>6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-quinoline-3-carboxylic acid ethyl ester (Norfloxacin ethyl ester) (15a). To a dry 15 mL recovery flask equipped with a reflux condenser was added 13 (150 mg, 0.5 mmole), (R)-binap (10 mg, 0.017 mmole), cesium carbonate (360 mg, 0.950 mmole), piperazine (215 mg, 2.5 mmole), Pd2(dba)3 (10 mg, 0.010 mmole), and 1.5 mL of DMF. The reaction vessel was purged with nitrogen and heated to reflux. After three hours, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography on a 500 micron silica gel preparative plate with an elution mixture of chloroform methanol water ammonia (80 20 2 0.2) to give 101 mg of 15a as an off-white solid in 58% yield and, separately, 29 mg of 17 as a light brown solid in 22% yield. Using this procedure, the yield of 15a... 

Norfloxacin is a fluoroquinolone that interferes with microbial DNA synthesis. It is indicated as an oral treatment of urinary tract infections (UTIs) caused by susceptible organisms treatment of sexually transmitted diseases (STDs) caused by Neisseria gonorrhoeae ocular solution for treatment of superficial ocular infections due to strains of susceptible organisms and prostatitis caused by E. coli. 

Di Abietes urinary tract infection was treated with norfloxacin, a fluo-rinated member of the quinolone family. This group of drugs inhibits bacterial DNA gyrase, a topoisomerase that unwinds the closed circular bacterial DNA helix ahead of the replication fork, and thus inhibits bacterial DNA synthesis. Because eukaryotic cells have linear DNA and do not contain DNA gyrase, they are not affected by quinolones. 

The first synthesis reported were for N-1 ethyl, vinyl or fluoroethyl derivatives [3-6]. Figure 3 describes the synthesis of Norfloxacin starting from 3-chloro-4-fluoroaniline 2. 

Synthesis and antimicrobial activity of 3-formyl analogs of norfloxacin, ciprofloxacin, and pefloxacin have been reported [93]. These studies have shown definitive evidence that the 3-formyl analogs of quinolones function as prodrugs and are oxidized in vivo to carboxylic acids. The higher bioavailability of formyl derivatives may be due to a change in physical and chemical properties by the lack of their amphoteric nature, compared to the parent zwitterionic compounds. 

Fang KC, Chen YL, Sheu JY, Wang TC, Tzeng CC (2000) Synthesis, antibacterial, and cytotoxic evaluation of certain 7-substituted norfloxacin derivatives. J Med Chem 43 3809-3812... 

E. Roseeuw, V. Coessens, A.-M. Balazuc, M. Lagranderie, P. Chavarot, A. Pessina, M.G. Neri, E. Schacht, G. Marchal, and D. Domurado, Synthesis, degradation, and antimicrobial properties of targeted macromolecular prodrugs of norfloxacin, Antimicrob. Agents Chemother, 47 (11), 3435-3441, 2003. 

A lot of studies have been directed to the synthesis of fluoroquinolones, bearing a variety of piperazinyl substituents, since this part of quinolone molecule is of significant importance. Indeed, some representatives of 6-fluoroquinolones bearing at C(7) piperazine (norfloxacin, ciprofloxacin), 4-methylpiperazine (pefloxacin), 3-methylpiperazin (lomefloxacin, temafloxacin) proved to possess a much broader range of antibacterial activity, than those without the piperazine moiety, such as nalidixic and oxolinic acids. 

Pandeya S, Srirama D, Nathb G, DeClercqc E (2000) Synthesis, antibacterial, antifungal and anti-HIV activities of norfloxacin mannich bases. Eur J Med Chem 35 249-255... 

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