2-Methyl-5-nitroimidazole Tinidazole

X-ray studies were also performed for bis(l,2,3,5-tetramethyl-4-nitropyrazolium salt [105], l-methyl-4(5)-nitro-5(4)-styrylimidazole [82], I -(/V-morpholino )-4-nitroimidazole [83], 1-sodium salt of 4-[2-[(l-methyl-5-nitro-2-imidazolyl)thio] ethoxy]-benzoic acid [106], l-methyl-4-nitro-5-chloroimidazole [107], omidazole [81], megazole [108], l-methyl-2-nitro-5-vinylimidazole [42], l-[2-(ethylsulfonyl) ethyl]-2-methyl-5-nitroimidazole (tinidazole) and one of the basic tinidazole metabolites - ammonium salt of l-[2-(ethylsulfonyl)ethyl]-4, 5-dihydro-2-methyl-4-nitroimidazole-5on [109], morpholino nitroimidazole derivatives [110, 111], l-(2-bromoethyl)-2-methyl-5-nitroimidazole [112], l-(4-chlorophenacyl)-2-methyl-... 

Tinidazole Tinidazole, l-2-(ethylsnlfonyl)ethyl-2-methyl-5-nitroimidazole (37.2.12), is also made from 2-methyl-5-nitroimidazole (37.2.9), which npon being reacted with 2-ethoxysnlfonyl-p-tolnenesnlfonate (37.2.11) transformed into the desired tinidazole. 

Fig-1 Metronidazole, l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, and side chains in positions 1 and 2 of related compounds tinidazole and ornidazole. Metronidazole and tinidazole are approved by the FDA for treatment of trichomoniasis, and ornidazole is used for this purpose outside the USA. Both tinidazole and ornidazole have been used with variable success in attempts to cure metronidazole-resistant infections... 

In spite of extensive investigations into the electrophilic substitution of imidazoles, no rational explanation has yet been found for certain features of the reaction [78], The nitration of imidazoles takes place exclusively at position 4 or 5. In reaction with the sulfuric-nitric acid mixture imidazole itself forms the 4(5)-nitro derivative [79-85], A large number of papers have been devoted to the production of 2-methyl-4(5)-nitroimidazole by the nitration of 2-methylimidazole [79, 82, 86-94], This is due to the fact that 2-methyl-4(5)-nitroimidazole is an important intermediate product in the synthesis of highly effective medical products (metronidazole, tinidazole, dimetridazole, etc.). 

Jokipii L, Jokipii AM. Comparative evaluation of the 2-methyl-5-nitroimidazole compounds dimetridazole, metronidazole, secnidazole, ornidazole, tinidazole, carnidazole, and panidazole against Bacteroides fragilis and other bacteria of the Bacteroids fragilis group. Antimicrob Agents chemother 1985 28(4) 561. ... 

The key intermediate for preparing various l-substituted-2-methyl-5-nitroimi-dazole drugs like metronidazole (22), tinidazole (24), ornidazole (25) etc. is 2-methyl-5-nitroimidazole (55), which is conveniently prepared by nitration of 2-methylimida-zole (54) [45]. Nucleophilic reaction with various substrates in presence of acids... 

Earlier attempts to prepare one of the two possible isomers had employed the facile-base-catalyzed rearrangement of the readily available [l-(2-alkyl(or aryl)sulfonyl)ethyl]-2-methyl-5-nitroimidazole which is made as one isomer from 2-methyl-4-nitroimidazole and ethylvinylsulfone <89JCS(P1)1352, 90JOC3702). Such base-catalyzed migrations in tinidazole (58) and analogous compounds seem to be specific for compounds with an A(-alkyl- or A(-aryl-ethylsulfone group which is eliminated as alkyl(or aryl)vinylsulfone followed by re-alkylation of the more reactive annular nitrogen. When 2-methyl-... 

The most commonly reported nitroimidazoles in the literature include dimetridazole (DMZ), metronidazole (MNZ), ronidazole (RNZ), and ipronidazole (IPZ) (Fig. 7.7). More recently, additional members of this class such as carnidazole (CNZ), ornidazole (ONZ), tinidazole (TNZ), and ternidazole (TRZ) have also been incorporated into analytical methods. Extensive studies on the metabolism of nitroimidazoles in poultry, beef, swine, and fish have shown that the hydroxy metabolites of the parent compounds, formed by oxidation of the side-chain in the C2 position of the imidazole ring, are of additional concern. These compounds have been shown to have toxicity equal to that of their parent forms and are often rapidly formed by metabolism within the animal. Studies in both poultry and rainbow trout have shown that the distribution of parents to metabolites is analyte- and species-specific. As a result, it has been suggested that it is imperative that a residue control program considers both the parent and the metabolites. The metabolites indicated in the literature include MNZ-OH, IPZ-OH, and HMMNI (2-hydroxymethyl-l-methyl-5-nitroimidazole) as the hydroxy metabolites of MNZ, IPZ, and DMZ, respectively. HMMNI has also been identified as a metabolite of RNZ, but through a different pathway. HMMNI is not a major metabolite of RNZ, however, and is therefore not suitable on its own for use as a marker of RNZ use. 

Tinidazole is chemically l-(2-ethylsulfonyl-ethyl)-2-methyl-5-nitroimidazole (Figure 1). It is active against protozoa and anaerobic bacteria and is used like metronidazole in a range of infections [1]. The drug is reported to hydrolyze quantitatively in alkaline conditions to 2-methyl-5-nitroimidazole and under photolytic conditions, the drug yields intermediate, rearrangement, and degradation products [2]. 

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