2- Nitroimidazole, preparation

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... 

While nitrofurans are often prepared as antibacterial agents, nitroimidazole forms the basis for an extensive class of agents used in the treatment of infections by the protozoans. Unlike bacterial infections, protozoal infections are seldom life-threatening. The physical discomfort occasioned by such infections is, however, of sufficient importance to provide a useful therapeutic place for antiprotozoal agents. A particularly common set of such conditions are parasitic infections of the genitalia caused by Trichomonas vaginalis. These disorders are called trichomoniasis. 

The introduction of a formyl or acyl group can be achieved by transformation of VNS products. Hydrolysis of dichloromethylnitroarenes, VNS products between heteroaromatic nitro compounds and chloroform, is a method of choice for the preparation of heterocyclic aldehydes, as shown in Eq. 9.41, in which 4-nitroimidazole is converted into 5-formyl-4-nitroimidazole.69... 

A basic ionic liquid, l-methyl-3-butylimidazolium hydroxide ([bmIm]OH) and l-butyl-3-methyl-methylimidazolium tetrafluoroborate ([bmim]BF4), has been introduced as a catalyst and reaction medium for the Markovnikov addition of imidazoles 116 to vinyl esters 115 under mild conditions to give imidazoesters 117 <06JOC3991 06TL1555>. A series of (nitroimidazolyl)succinic esters and diacids were prepared from the Michael-type addition of the nitroimidazole to the a,P-unsaturated ester <06S3859>. 

Hunter and Nelson (41 Mil) attempted the preparation of 4(5)-aminoimidazole (25 R = H) from its acetyl derivative (28 R = H, R1 = Me), which they obtained by reduction of 4(5)-nitroimidazole (27 R = H) with tin(II) chloride in acetic anhydride. The authors noted that hydrolysis of compound (28 R = H, R = Me) with aqueous acids resulted in fission of the imidazole ring and formation of acetic acid, formic acid, ammonia, and glycine. Base hydrolysis gave similar results (41 Mil), although a trace of 4(5)-aminoimidazole (25 R = H) was detected. 

The instability of 5-aminoimidazoles (96) has led to in situ acylation being used to obtain stable compounds and using this approach several derivatives have been prepared. For example, a solution of the appropriate 5-nitroimidazole (97) in ethyl acetate was reduced with Raney nickel, and the resulting solution of 5-aminoimidazole (96) then treated with an acid chloride to give the amides (118 R1 = Me, R2 = S02Me, COPh, R3 = alkyl, aryl, hetaryl) (25-45%) [82IJC(B)1087],... 

The direct nitration of imidazole with acidic reagents is difficult due to facile nitrogen protonation (pA aH 7). Nitration of imidazoles proceeds in the 4- and 5-positions with the amidine 2-position being quite inert. Imidazole can be directly nitrated to 4,5-dinitroimidazole but no further. 2,4,5-Trinitroimidazole (TNI) can be prepared from the successive nitration of 2-nitroimidazole the latter synthesized from the diazotization of 2-aminoimidazole in the presence of excess sodium nitrite and a copper salt. The nitrative cleavage of polyiodoimidazoles also provides a route to polynitroimidazoles. " ... 

Dinitroimidazole (2,4-DNI) (15) is readily prepared from the nitration of 2-nitroimidazole. "" 2,4-DNI exhibits moderate performance and is regarded as a shock insensitive explosive. The relatively low cost and facile synthesis makes 2,4-DNI a realistic... 

As noted above, nitrofurans and nitroimidazoles have proven useful moieties for the preparation of antibacterial and antiprotozoal agents. It is thus of note that nitrothiazoles have also been used successfully in the preparation of antiparasitic agents. Condensation of 6-nitro-2-aminothiazole (194, available from nitration of aminothiazole) with ethylisocyanate yields the antiprotozoal agent... 

The reagent is prepared by reaction of p-nitrobenzenesulfonyl chloride with 4-nitroimidazole (triethylamine). ... 

Despite many attempts it has not been possible to oxidize 2-substituted 1,2,3-triazoles 382 to the corresponding 1-oxides 326. Peracetic acid, 3-chloroperbenzoic acid, dichloropermaleic acid, trifluoroperacetic acid, peroxydisulfuric acid, and f-pentyl hydrogen peroxide in the presence of molybdenum pentachloride all failed to oxidize 382 (1981JCS(P1)503). Alkylation of 1-hydroxytriazoles 443 invariantly produced the isomeric 3-substituted 1,2,3-triazole 1-oxides 448 (see Scheme 132). However, the 2-substituted 1,2,3-triazole 1-oxides 326 can be prepared by oxidative cyclization of 2-hydroxyiminohydrazones (1,2-hydrazonooximes, a-hydrazonooximes) 345 or by cyclization of azoxyoximes 169. Additional methods of more limited scope are reaction of nitroisoxazoles 353 with aryl-diazonium ion and base, and reaction of nitroimidazoles 355 with hydroxy-amine- or amine-induced rearrangement of nitro-substituted furoxanes 357. 

Similarly, the partitioning of nitroimidazoles into octanol-water, log Poet and into four liposome preparations with different lipid composition, log KM, was determined and regression equations were derived to explain the observed variation in the pharmacokinetic parameters of these drugs [85]. The log fCM ranged from 1.5 to 0.5 and was at least two- to threefold greater than log Poct (Table 4.24). In addition, the hydrophobic substituent constants of functional groups in various partitioning systems... 

The same authors also reported on the correlation found between the radiosensi-tizing effects of five nitroimidazoles in either murine EMT-6 or Chinese hamster V79 tumor cell cultures and log Poet. or log Km. For all five partition coefficients, no significant correlation was observed for EMT-6 cells. However, highly significant correlations were obtained for V79 cells with all four log KM values, including those in liposome preparations with cholesterol added. No significant correlation was obtained with log Poet, (log Km i to log Km iv r= 0.92, 0.95, 0.947, 0.937) (log Poct r = 0.588). 

A similar procedure can be applied to the synthesis of a series of 5-nitroimidazoles83 with antibacterial properties.The S l reaction of various l-alkyl-2-chloromethyl-5-nitroimidazoles (23) with heterocyclic nitronate anions prepared from 3-nitrolactams, under phase transfer catalysis, afforded trisubstituted olefins (equation 33). 

The A-nitroimidazolcs are stable for a time even in the presence of water, but treatment with concentrated sulfuric acid cleaves the N-nitro group, and strong base opens the ring. Much of the interest in such compounds is related to their multistep complex substitution reactions in which sequential nucleophilic addition of arylamines, ring opening, ring closure, nitroamide elimination, and rearomatization gives l-aryl-4-nitroimidazoles, e.g., 840 839. This method can also be used to prepare isotopically labeled imidazoles when labeled amino acids are used as the amine. 

The introduction of a substituent at position 1 of the imidazole ring hinders nitration, and most nitro-A-methylimidazoles have been prepared by the /V-methylation of the corresponding nitroimidazoles. Thus, of the two possible nitration products only l-methyl-2-(4-nitro-2-imidazolyl)imidazole is formed by the action of one equivalent of nitric acid on l-methyl-2-(2-imidazolyl)imidazole [133] (Scheme 14). 

Recently a large number of papers have been devoted to the preparation of nitro-pyrazoles [377-380], nitroimidazoles [381-388], nitroisoxazoles [389-391], nitrothiazoles [392], nitrotriazoles [393-396], and nitrobenzazoles [397-399] due... 

In view of the importance of 2-nitroimidazoles as antibiotics e.g. 2-nitroimidazoIe azomycin ) and the problems involved in their synthesis (usually via the 2-aminoimidazole) it seemed worthwhile to attempt to prepare these compounds by thermal rearrangement of the (V-nitro compounds (by analogy with the well-known reactions of 1-nitro-pyrazoles and -indazoles) (Chapter 4.04). Thus, when 1,4-dinitroimidazole (16) is heated at 140 °C in chlorobenzene, benzonitrile or anisole there is conversion into 2,4- and 4,5-dinitroimidazoles, but considerable denitration can also occur, giving 4-nitroimidazole (Scheme 6). 2-Methyl-l,4-dinitroimidazole rearranges smoothly to 2-methyl-4,5-dinitroimidazole, but 5-methyl-l,4-dinitroimidazole appears to denitrate in preference to any other reaction. Further study of these reactions is indicated. 

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