2- Methyl-5-nitroimidazole-l-ethanol

Metronidazole Metronidazole, 2-methyl-5-nitroimidazol-l-ethanol (37.2.10), is made by nitrating 2-methylimidazole to make 2-methyl-5-nitroimidazole (37.2.9), which is then reacted with 2-chloroethanol or ethylenoxide, which is easily transformed to the desired metronidazole [49,50]. 

Synonyms. 2-Methyl-5-nitroimidazole-1-ethanol l-(2-Hydroxyethyl)-2-methyl-5-nitroimidazole l-( 3-Ethylol)-2-methyl-5-nitro-3-azapyrrole. 

Considerable interest has been reported in the radiolytic reactions of radiosensitiz-ing nitroimidazoles such ns Metronidazole, 2-methyl-5-nitro-l//-imidazole-1-ethanol (52). Again loss of the nitro function as nitrite appears to be one of the principal events. The formation of nitrite from /-irradiation of the Ni(II) complex of the imidazole 52 arises by hydroxy radical attack to form the radical anion. This either eliminates nitrite or undergoes a four-electron reduction to a hydroxylamino derivative68,69. 

The drug most commonly used to treat Trichomonas vaginalis and some entamoebal infections, l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole [Flagyl, (3)] can also produce an aversion to ethanol in patients. It has now been shown that while (3) will displace the nicotinamide moiety of NAD+ or NADP+ in the presence of pyridine transglycosidase to produce new nucleotides, there is no reaction between (3) and NADH. It is not, however, believed that the toxicity towards anaerobic organisms is due to the new adenosine pyrophosphates derived from (3). 

An unexpected reaction occurs when 2-alkyl-4(5)-nitroimidazoles (27 R = alkyl) are reduced in protic solvents [92JCS(P1)2779]. Catalytic hydrogenation of 2-methyl-4(5)-nitroimidazole (27 R = Me) in a solution of acetic anhydride and acetic acid gave 4,4 -diacetamido-2,2 -dimethyl-5,5 -diimidazole (32 yield 10%) in addition to the expected 4-acetamido-l-acetyl-2-methylimidazole (28%). Similarly, reduction of the 2-alkyl-4(5)-nitroimidazoles (27 R = Me, Et, iPr) in ethanol solution in the presence of diethyl ethoxymethylenemalonate [EMME (135)] gives predominantly the 5,5 -diimidazole adducts (33). The formation of these products (33) is believed to involve an electrophilic addition of the starting material (27) to the electron-rich aminoimidazoles (25) [92JCS(P1)2779]. Interestingly, replacement of ethanol by dioxane suppressed diimidazole formation. 

A mixture of l,5-dimethyl-2-nitroimidazole and benzaldehyde in ethanolic KOH stirred 22.5 hrs. at room temp, under Ng l-methyl-2-nitro- -phenyl-5-imidazole-ethanol (Y 59%) added at room temp, to a stirred mixture of coned. H2SO4 and acetic acid, heated 20 min. at 110 in an oil bath l-methyl-2-nitro-5-styryl-imidazole (Y 86%). - This 2-stage process gives a better yield than direct condensation to the styryl deriv. G. Asato and G. Berkelhammer, J. Med. Chem. 15,1086 (1972). 

---