Nitrofurans synthesis

A number of 5-nitro-2-furaldehyde derivatives, called nitrofurans, are used in the treatment and/or prophylaxis of microbial infections, primarily in the urinary tract. Recent evidence suggests that the reduction of the 5-nitro group to the nitro anion results in bacterial toxicity. Intermediate metabolites modify various bacterial macromolecules that affect a variety of biochemical processes (e.g., DNA and RNA synthesis, protein synthesis) this observation may explain the lack of resistance development to these drugs. Evidence also indicates that the nitro anion undergoes recycling with the production of superoxide and other toxic oxygen compounds. It is presumed that the nitrofurans are selectively toxic to microbial cells because in humans, the slower reduction by mammalian cells prevents high serum concentrations. 

Both 2- and 3-nitrofurans with additional substituents on the available positions of the furan ring have been synthesized by cyclization procedures. The nitro-containing reagents are of type 1 or 2. No type 3 reagent seems to have been used for the synthesis of nitrofurans or condensed nitrofurans. 

Wohl s synthesis now appears to be the second best route to a stable precursor which can be hydrolyzed to malealdehyde. Ranking third is a process described by Marquis in which furane is nitrated in acetic anhydride at a low temperature to give a noncrystalline unstable product which yields 2-nitrofurane on treatment with pyridine. J. R. Johnson presented arguments for regarding the labile intermediate as the product of 1,4-addition of acetyl nitrate (7), and hence presumably convertible into malealdehyde. 

All the evidence reviewed above points to an interesting possibility that the primary action of metronidazole and nitrofurans in T. vaginalis may be the inhibition of synthesis of proteins. Whether reduction of the nitro group is the prerequisite for this activity remains to be seen. 

The synthesis of nitrofuran and nitroimidazole drugs will be discussed in Chapter 17. In this chapter the synthesis of only those nitroaryls will be described, which are of sigirificance in the chemotherapy of helminthiasis. 

The key intermediate for the synthesis of various nitrofuran drugs is 5-nitro-furfural (45, isolated as diacetate), which is obtained by careful nitration of furfural (44) with a nitric acid-acetic anhydride mixture at low temperatures [30]. Reaction of 45 with various nucleophiles gives nitrofuran drugs of the general formula 46. 

Furans continue to be useful synthons for pyridazine syntheses. A detailed investigation of the reaction between ethyl 2-methoxy-2-methyl-3-oxofuran-4-carboxylate (47) and hydrazines revealed that, depending upon reaction conditions, compound 49, a mixture of 48 and 49 or, in addition to these, also 50, is obtained.172,173 Similarly, ethyl 5-nitrofuran-3-carboxylate and hydrazine yield a pyridazine, probably by addition, ring opening of the furan, and recyclization [Eq. (12)].174 Another synthesis involves electrolytic methoxylation of a furan derivative and subsequent treatment with hydrazine.175... 

For example, the original scarlet red colour changes to yellow on heating for 30 minutes at 120° and the chemical structure of the compound changes considerably (see p. 338). The bacteriostatic activity of the yellow solution against dysentery bacillus is about 250 times greater than that of panazone. This observation has prompted the synthesis of other di-(nitrofuran) derivatives, some of which are listed in Table 6.8. 

Inhibition of nucleic acid synthesis or function (nitroimidazoles, nitrofurans, quinolones, fluoroquinolones)... 

Inhibitors of bacterial DNA synthesis These can have a broad spectrum of activity, have a low molecular weight (about 250) and require withdrawal periods. Nitrofurans and quinoxaline-M-oxides fall into this category of antibiotics. 

The synthesis, antimicrobial activity, and biodeterioration resistance of cellulose 5-nitrofuran derivatives and furan derivatives of model saccharides have been studied, and the relationship between their biological properties and chemical structures was discussed. ... 

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