Ciprofloxacin synthesis

Hay, A. M., Hobbs-Dewitt, S., MacDonald, A. A., Ramage, R. Use of tetrabenzo[aic,g,f]fluorene as an anchor group for the solid/solution phase synthesis of the quinolone antibacterial, ciprofloxacin. Synthesis, 1979-1985 (1999). 

An illustration of a modified Wallach fluorination is the synthesis of 2 4 di chloro-5-fluorotoluene, an intermediate in the preparation of the fluoroquinolone antibacterial ciprofloxacin This was prepared in 69% overall yield by heating W(2,4-dichloro-5-methylphenyl) N, N dimethyltriazene in anhydrous hydrogen fluoride [44] (equation 11)... 

There are several methods of preparation of antibacterial quinolones, drugs widely used in the therapy of various bacterial diseases. The most general method is based on the nucleophilic cyclization of 2-halobenzoyl derivatives 402, leading to the key intermediates 403. The methodology is exemplified in Scheme 63 by the synthesis of a broad-spectrum drug ciprofloxacin... 

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

The Bayer synthesis of ciprofloxacin (1) patented in 1981 utilized 2,4-dichloro-5-fluorobenzoyl chloride (15) as the starting material. With the aide of magnesium ethoxide, condensation of acid chloride 15 and diethyl malonate assembled ketone 16, which was subsequently decarboxylated using tosylic acid to form ethyl 2,4-dichloro-5-fluorobenzoylacetate (17) in 82% yield in two steps from 15. A Dieckman-like condensation of 17 with ethyl orthoformate was carried out in refluxing acetic anhydride... 

Scheme 4. The Edinburgh solid/solution phase organic synthesis of ciprofloxacin (1).

It acts by inhibiting RNA synthesis, bacteria being sensitive to this effect at much lower concentrations than mammalian cells it is particularly effective against mycobacteria that lie semidormant within cells. Rifampicin has a wide range of antimicrobial activity. Other uses include leprosy, severe Legionnaires disease (with erythromycin or ciprofloxacin), the chemoprophylaxis of meningococcal meningitis, and severe staphylococcal infection (with flucloxacillin or vancomycin). 

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). 

Answer A- Microbial resistance to fluoroquinolones is increasing, and some strains of Streptococcus pneumoniae are now resistant to ciprofloxacin. The mechanism can involve changes in the structure of topoisomerase IV, one of the targets of fluoroquinolones, which inhibit nucleic acid synthesis. Pneumococcal resistance to penicillins is also increasing via changes in penicillin-binding proteins (PBPs). The other mechanisms listed underlie microbial resistance to other antibiotics as follows sulfonamides (choice B), macrolides (choice C), extended-spectrum penicillins (choice D), and beta-lactams (choice E). 

A related strategy was suggested in which one of the reactants is attached via a linker to tetrabenzo[a,c,g,i]fluorene (Tbf). The reaction product can now be purified by taking advantage of the high affinity of Tbf to charcoal in polar solvents (mixture of DCM and methanol). Desorption can be affected with non polar solvents such as toluene [144]. The method was exemplified by the synthesis of a quinolone carboxylic acid derivative (ciprofloxacin). 

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). ... 

Ciprofloxacin is a fluoroquinolone antibiotic that interferes with microbial DNA synthesis. It is indicated in the treatment of infections of the lower respiratory tract, skin and skin structure, bones and joints, urinary tract gonorrhea, chancroid, and infectious diarrhea caused by susceptible strains of specific organisms typhoid fever uncomplicated cervical and urethral gonorrhea women with acute uncomplicated cystitis acute sinusitis nosocomial pneumonia chronic bacterial prostatitis complicated intra-abdominal infections reduction of incidence or progression of inhalational anthrax following exposure to aerosolized Bacillus anthracis. Cipro IV Used for empirical therapy for febrile neutropenic patients. 

The first quinolone, nalidixic acid, was isolated as a byproduct of the synthesis of chloroquine. It has been available for the treatment of urinary tract infections for many years. The introduction of fluorinated 4-quinolones, such as ciprofloxacin (Cipro), moxifloxacin (Avelox), and gatifloxacin (Tequin) represents a particularly important therapeutic advance because these agents have broad antimicrobial activity and are effective after oral administration for the treatment of a wide variety of infectious diseases. Relatively few side effects appear to accompany the use of these fluoroquinolones, and microbial resistance to their action does not develop rapidly. Rare and potentially fatal side effects, however, have resulted in the withdrawal from the market of temafloxacin (immune hemolytic anemia), trovafloxacin... 

Ciprofloxacin interferes with microbial DNA synthesis. Hydrocortisone depresses formation, release, and activity... 

The first quinolone, nalidixic acid, was isolated as a byproduct of the synthesis of chloroquine. It has been available for the treatment of urinary tract infections for many years. The introduction of fluorinated 4-quinolones, such as ciprofloxacin (Cipro), moxifloxacin (Avelox), and gatifloxacin (Tequin), represents a particularly important... 

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