4 -5-nitroimidazole

Imidazole (15.0 g, 0.22 mol) is added slowly to concentrated nitric acid (30 ml, d 1.42) maintained at 0-5°C in an ice bath. Concentrated sulfuric acid (25 ml) is then added slowly to the solution with continuous stirring. The nitrating mixture is then heated at 100°C (2h), before cooling and pouring into ice-water to precipitate a solid. Ihis is filtered, washed with water until the filtrate is non-acidic, dried and recrystallized from ethanol to give off-white needles (16.2 g, 65%), m.p. 3.07- 308 C. 

Diazo coupling in N-unsubstituted imidazoles occurs with equal case at either C-2 or C-4(5) (or both) in reactions which have been shown to involve reaction of the imidazole anion with the diazonium ion [10]. lire intensely coloured azo dyes which are formed have long been used for identification of imidazoles, especially in qualitative chromatography [7]. The azo groups can be reduced to amino or hydrazine groups, providing a useful alternative approach, especially to 2-aminoimidazoles (see Section 8.3), 

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Chloro-l-methyl-4-nitroimidazole (204) was also used as a heterocyclic component in the Turpin reaction. Intermediate 205 was formed under mild conditions and its cyclization was achieved by heating with ethanolic dimethylamine in a sealed tube to give a blue-colored substance, which was attributed structure 206 (Scheme 32) (52JCS784). 

The mtrodncdon of a formyl or acyl group can be achieved by transformadon of VNS products. Hydrolysis ofthchloromethylnitroarenes, VNS products betweenheteroaromadcnitro compoimds and chloroform, is amethodof choice for the preparadon of heterocyclic Mdehydes, as shown in Eq. 9.41, in which 4-nitroimida2oleis converted into 5-formyl-4-nitroimidazole. ... 

Chemical Name 6-[(1-methyl-4-nitroimidazol-5-yl)thio] purine... 

Crystallization from water results in N- -ethylmorpholino-(5)-nitroimidazole (melting point 110°Cto 111°C) from mother liquors N- 3-ethylmorpholino-(4)-nitroimidazole (malting point 104°Cto 106°C) is obtained. 

A solution of a mixture of 1 -(2-acetoxypropy I)-2-methyl-4-nitroimidazole and of 1 -(2-acetoxy-propyl)-2-methyl-6-nitroimidazole (18.6 g) (prepared as described above) in 4N hydrochloric acid (186 cc) is heated at 90°Cfor90 minutes. The cooled solution is treated with ammonium hydroxide (d = 09 100 cc), saturated with sodium chloride, and then extracted with ethyl acetate (total 650 cc). The combined organic extracts are washed with a saturated aqueous... 

Comparing reaction times and yields for the condensing agents 1-triisopro-pylbenzenesulfonyl-4-nitroimidazole, mesitylenesulfonyl-3-nitro-1,2,4-triazole, 1 -triiso-propylbenzenesulfonyl-3-nitro-1,2,4-triazole, and 8-quinolinesulfonyl-3-nitro-1,2,4-triazole, the latter showed the highest yield and shortest reaction time. A fully protected 2, 5 -trinucleotide diphosphate was also successfully synthesized by means of a mixture of 8-quinolinesulfonyl chloride and 3 -nitro-1,2,4-triazole,[ 1421... 

Three approaches to the synthesis of 4-amino-5-unsubstituted imidazoles (71) have been described and are summarized in Scheme 7. These are (a) reduction of 4-nitroimidazoles (72) (b) hydrolysis of carbamates and amides (73) (c) cyclization of nitrile derivatives (74). 

The use of hydrazine hydrate in anhydrous methanol with 5% palladium on charcoal under an inert atmosphere gave excellent results for the reduction of l-benzyl-4-nitroimidazole (72 R1 = CH2Ph, R2 = H) with compound (71 R1 = CH2Ph, R2 = H) being isolated as its hydrochloride salt (96%) (74JMC1168). 

Catalytic hydrogenation of methanolic solutions of the 4-nitroimidazoles (72 R1 = D-glucopyranosyl, D-arabinopyranosyl, D-xylopyranosyl R2 = H) using platinum oxide as catalyst gave the corresponding 4-aminoimidazole nucleosides (71 R1 = D-glucopyranosyl, D-arabinopyra-nosyl, D-xylopyranosyl R2 = H) (yields 16, 33, and 25%, respectively), which were apparently isolated as the free bases but no mention of the stability of these compounds was made (72LA67). 

The hypoxia-targeting potential of 99mTc(CO)3 core labelled with 2-nitro and 4-nitroimidazoles has been studied. Phosphate coupled metronidazole gave fast clearout from major organs but high accumulation in bone. There is no tumor uptake study to date or... 

Two tautomeric equilibria have been considered for substituted imidazoles, that between 2-imidazolone 3 and its 2-hydroxyimidazole tautomer 4 [268] and also that between the 1H and 3H tautomers of 4-nitroimidazole, 6 and 5, respectively [269, 270], Karelson et al. used the D02 model with a spherical cavity of 2.5 A radius and found 2-imidazolone to be better solvated than its tautomer by 7.7 kcal/mol at the AMI level. [The asterisk in D02 indicates that the reaction field... 

Using the same theoretical model, Karelson et al. [269] and later Rzepa et al. [270] examined 4-nitroimidazole. The latter work corrected incomplete geometry optimizations present in the former study. In this instance, AMI predicts 5 to be 1.4 kcal/mol lower in relative energy than 6. However, the D02 model predicts the aqueous solvation free energies to be -25.3 and -7.1 kcal/mol for 6 and 5, respectively, rendering 6 considerably lower in energy than 5 in solution, which agrees with the experimental situation. 

It is clear in both of these studies that the small cavity size (which fails to entirely contain all of the atoms given standard van der Waals radii) causes electrostatic solvation free energies to be seriously overestimated — the difference in the 4-nitroimidazole system seems much too large to be physically reasonable. This overestimation would be still more severe were a correct DO model to have been used (i.e., one which accounted self-consistently for the full solute polarization using eq 30). Nevertheless, the D02 results may be considered qualitatively useful, to the extent that they identify trends in tautomer electrostatic solvation free energies. 

The TV-protected nitrosoimidazole carbonitrile 42 - which can easily be obtained from the commercially available 4-nitroimidazole in 4 reaction steps - was treated with phenyl methylcarbazate 43 to give a substituted triazenyli-midazole 44. The cyano group of this compound was first hydrolyzed to an amide function to produce 45, and then irradiation yielded the end product 9a in high yield (79%). 

In an attempt to understand further the carcinogenicity of azathioprine, recent work in the authors laboratory has concentrated on the photodegradation of two compounds associated with the drug. l-Methyl-4-nitro-5-thioimid-azole is a metabolite and 5-hydroxy- l-methyl-4-nitroimidazole a hydrolysis product. Both gave, on irradiation at wavelengths greater than 300 nm, 1-methylparabanic acid (248) [152], The primary metabolites of azathioprine had previously been shown to be more potent than the parent drug as photosensitizers. Both 6-mercaptopurine and these imidazoles may play roles in its neoplastic action [151]. 

The solvent effects on the relative stabilities of 4-nitroimidazole and 5-nitroimidazole exhibit interesting patterns81. In the excited state the 5-nitro isomer is more stable than the 4-nitro isomer in aprotic solvents, while the stability order is reversed in the ground state. 

Whereas several l-aryl-4-nitroimidazoles are found to be good sensitizers for superoxide ion formations85 (Type I photooxidation), only l-phenyl-2-methyl-4-nitroimidazole 140 is a photosensitizer for singlet oxygen, i.e. by energy transfer of type II photooxidation (equation 70). 

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