L- -2-methyl-5-nitroimidazole

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). 

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]. 

Azathioprine Azathioprine, 6-[(l-methyl-4-nitroimidazol-5-yl)thio]purine (31.2.1), is synthesized by heteroarylation of the sulfhydrile group of 6-mercaptopurine (30.1.2.9) with 5-chloro-l-methyl-4-nitroimidazol in the presence of sodium acetate as a weak base [13]. 

Attempted reduction of l-methyl-4-nitroimidazole with tin(II) chloride and hydrochloric acid produced some 4-chlorinated product as a result of... 

N1 - PURINE, 6-([Pg.183]

Chemical Name 6-[(l-Methyl-4-nitroimidazol-5-yl)thio]purine... 

The m-nitrobenzyl chloride analogue 2-(chloromethyl)-l-methyl-4-nitroimidazole reacts with the 2-nitropropane anions by the S l mechanism under phase-transfer conditions. A base-promoted nitrous acid elimination from the C-alkylated product gives alkenylimidazole derivatives84. 

The observation of ESR signals of nitroazoles radical anions during ESR monitoring and the appearance of blue color in the reactions of substrates with 1,1,1-trim-ethylhydrozinium iodide or 4-amino-1,2,4-triazole in f-BuOK/DMSO or MeONa/ DMSO suggests that the reaction includes a one-electron transfer stage. ESR spectra of radical anions of l-methyl-4-nitropyrazole, l-methyl-4-nitroimidazole and... 

It should be noted that ESR spectra of radical anions of l-methyl-4-nitroimidazole [850, 852], l-methyl-4-nitropyrazole [850, 851], and l-methyl-5-nitrobenzimidazole... 

Fig. 3.2 ESR spectrum of l-methyl-4-nitroimidazole radical anion recorded in the reaction obtained in vicarious C-amination condition (top) simulated ESR spectrum of l-methyl-4-ni-troimidazole RA (bottom) for HFS-coupling constants (a, mT) 1.388 (IN, N02), 0.477 (1H, H-5), 0.070 (2N, N-1,3), 0.056 (1H, H-2), 0.020 (3H, N-CH3)...

The results of the tautomeric equilibrium study of 4(5)-nitroimidazole show that in the gas phase both tautomers have similar energy, but in the solution the 4-tautomer is more stable than the 5-nitro one [256, 1124], The dipole moment of 4(5)-nitroimidazole is practically the same as that of l-methyl-4-nitroimidazole (Table 3.72). 

A distinctive fragmentation feature of these compounds is that the [M-NO]+ peak intensity of l-methyl-2-nitroimidazole is much higher than that of isomeric 4- and 5-nitroimidazoles [1293], The first fragmentation stages of l-methyl-4-nitroimidazole involve INOJ abstraction which does not occur in the case of l-methyl-5-nitroimidazole (Scheme 3.56) [1293],... 

The mechanism of electron-impact-induced loss of water from the molecular ion of nitroimidazoles has been studied [1295,1307], A possible mechanism of the elimination of water from l-methyl-4-nitroimidazole-5-carboxamide [1307] is presented in Scheme 3.59 ... 

Disposition in the Body. Absorbed after oral administration and distributed throughout the body. It is readily metabolised to mercaptopurine, which is the major active metabolite, and to l-methyl-4-nitro-5-(5-glutathionyl)imidazole other metabolites include l-methyl-4-nitroimidazole, l-methyl-4-nitro-5-thioimi-dazole, and 6-thiouric acid mercaptopurine is further metabolised to its ribonucleotide, thioinosinic acid, which is the active moiety. About 50% of a dose is excreted in the urine in 24 hours, mainly as thiouric acid and other metabolites with about 10% consisting of unchanged drug about 12% of a dose is eliminated in the faeces in 48 hours. 

METHYLNITROIMIDAZOLYLMERCAPTOPURINE 6-(T-METHYL-4 -NITRO-5 -IMIDAZOLYL)-MERCAPTO-PURINE 6-(METHYL-p-NITRO-5-IMIDAZOLYL)-THIOPURINE 6-(l-METHYL-p-NITRO-5-IMIDAZOL-YL)-THIOPURINE 6-((l-METHYL-4-NITROIMIDAZOL-5-YL)THIO)PURINE 6-(l-METHYL-4-NITROIMIDAZ-OL-5-YLTHIO)PURINE 6-((l-METHYL-4-NITRO-lH-IMDAZOL-5-YL)THIO)-lH-PURINE NCI-C03474 NSC-39084 RORASUL... 

In the electrochemical reduction of 5-bromo-l-methyl-4-nitroimidazole some cleavage of the C—Br bond is evident giving rise to the debrominated product (79JGU1877). Imidazole itself is not reducible cathodically in aqueous media, but electrons have been attached to imidazole and histidine in aqueous solution the rate of oxidation depends on pH. Protonated or quaternized imidazoles form the neutral conjugate acids of the true anion radical, and a number of anion radicals have been made from nitroimidazoles under various radiolytic conditions (79AHC(25)205). The electrochemical reduction of 2-cyanobenzimidazole 3-oxide gives sequentially 2-cyanobenzimidazole and 2-aminomethylbenzimidazole (80ZC263). 

As a rule of thumb one ean assume that reactions which are carried out in basic media involve the anion (5), which A -alkylates to give mainly the 1,4 isomer (6) if R is bulky or electron-withdrawing. In free base alkylations the tautomeric mixture (3) (4) reacts. An electron-withdrawing substituent (R) will ensure that much of the reaction will be with the major tautomer (3) even if that tautomer is the less reactive. The product mixture formed will have mainly 1,5 regiochemistry (7), e.g. 4(5)-nitroimidazole methylated in basic medium gives mainly l-methyl-4-nitroimidazole in neutral media l-methyl-5-nitroimidazole forms almost exclusively. Sterically demanding groups, however, favour the 1,4 isomer. Table 7.1.1 lists some other examples. 

Another way to study tautomerism is through pATa measurements. A comparison of the basic pATa values for 4(5)-nitroimidazole with those of l-methyl-4- (29) and l-methyl-5-nitroimidazole (30) leads one to the conclusion that the 4-nitro tautomer (28) predominates (Scheme 13) in fact the 4-nitro 5-nitro ratio has been computed as about 400 1. In this experiment the methylated compounds serve as fixed models in which the nitro substituent is fixed in each of the two possible orientations. The influence of the methyl group can be shown to be small by comparison of the pATa values for imidazole ( 7.0) and 1-methyl-imidazole (—7.1), and hence l-methyl-4-nitroimidazole resembles the major tautomer. 

The mass spectrum of l-methyl-4-nitroimidazole-5-carboxylic acid amide shows the elimination of water by an electron impact as distinct from the usual thermal process. In l,4,5-trimethylimidazole-2-carboxylic acid the principal loss is that of CO2. Subsequent loss of O, OH, and HCN was also observed (Schofield etal., p. 173). Ferguson and Schofield (pp. 172,173) have reported considerable data for imidazole JV-oxides. Thus 1-methoxy-... 

G73>. Similarly l-methyl-4-nitroimidazole chelates with Ru" through an annular nitrogen and a nitro oxygen <88CJC117>. Silver complexes of 4-nitroimidazole are similar <92CJC943>. 

Oxidative dimerization of the lithium derivatives of 1-substituted 4,5-dicyanoimidazoles give (71) <91JA6178>. Chromium trioxide in acetic acid converts 5-chloro-l-methyl-4-nitroimidazole into the... 

It is prepared by treating 6-mercaptopurine with 5-chloro-l-methyl-4-nitroimidazole. 

Azathioprine 3A1 p. 102) is the 5 -(l-methyl-4-nitroimidazol-5-yl) derivative of 6-mercaptopurine which it slowly releases in the body. It is much used as an immunosuppressant to prevent rejection of organ grafts, particularly those of the kidney (Elion, 1967 Elion and Hitchings, 1975). The 2-amino derivative of 6-mercaptopurine, known as thioguanine, is used to a smaller extent in cancer therapy and as an immunosuppressant. 

---