A New Method for Preparing 4(5)-Nitroimidazolecarboxylic Acid
Abstract Generated abstract
This paper describes a more economical preparation of 4(5)-nitroimidazolecarboxylic acid, an intermediate relevant to syntheses of xanthine and related purine derivatives. The authors review earlier routes with limited yields, then present a procedure starting from 4(5)-hydroxymethylimidazole obtained from inverted sugar, using a mixed nitric and sulfuric acid nitrating system under carefully controlled temperature conditions. The method affords the nitro acid in about 70 to 72% of theoretical yield, substantially above the yields reported for prior procedures, and the product is characterized by melting point, solubility behavior, nitrogen analysis, and conversion to the methyl ester and amide.
Full Text
A New Method for Preparing 4(5)-Nitroimidazolecarboxylic Acid
L. P. Kulev, A. M. Rozhkov
4(5)-Nitroimidazolecarboxylic acid
\[ \begin{array}{c} \mathrm{HC}\!\begin{array}{c} /\,\mathrm{NH}-\mathrm{C}-\mathrm{NO_2}\\[-2pt] \backslash\,\mathrm{N}-\mathrm{C}-\mathrm{COOH} \end{array} \end{array} \]
was first obtained by Windaus and Opitz [1] from 4(5)-($\beta$-hydroxyethyl)-imidazole by heating it with a tenfold amount of 25-percent nitric acid.
Later, Fargher and Pyman [2] attempted to find a more accessible method for preparing 4(5)-nitroimidazolecarboxylic acid, pursuing the aim of carrying out the transition through aminoimidazolecarboxylic acid to the synthesis of purine derivatives. The authors treated 4(5)-imidazolecarboxylic acid, 4(5)-imidazoledicarboxylic acid, 4(5)-($\beta$-aminoethyl-imidazole), and 4(5)-cyanomethylimidazole with nitric acid, but in none of these cases did they obtain positive results.
Only in 1923 did Windaus and Langenbeck [3] succeed in finding a comparatively convenient method for preparing 4(5)-nitroimidazolecarboxylic acid from methylimidazole, which in turn was obtained from grape sugar and then subjected to nitration with fuming nitric acid under heating. The resulting 4(5)-nitromethylimidazole was then condensed with benzaldehyde, forming 4(5)-nitrostyrylimidazole, which, upon oxidation with potassium permanganate, gave 4(5)-nitroimidazolecarboxylic acid.
\[ \begin{array}{ccc} \mathrm{HC}\!\begin{array}{c} /\,\mathrm{NH}-\mathrm{C}-\mathrm{NO_2}\\[-2pt] \backslash\,\mathrm{N}-\mathrm{C}-\mathrm{CH_3} \end{array} & \xrightarrow{\ \mathrm{C_6H_5CHO}\ } & \mathrm{HC}\!\begin{array}{c} /\,\mathrm{NH}-\mathrm{C}-\mathrm{NO_2}\\[-2pt] \backslash\,\mathrm{N}-\mathrm{C}-\mathrm{CH{=}CH}-\mathrm{C_6H_5} \end{array} \xrightarrow{\ \mathrm{KMnO_4}\ } \\[16pt] & \longrightarrow & \mathrm{HC}\!\begin{array}{c} /\,\mathrm{NH}-\mathrm{C}-\mathrm{NO_2}\\[-2pt] \backslash\,\mathrm{N}-\mathrm{C}-\mathrm{COOH} \end{array} \end{array} \]
Certain changes introduced by Olbrook, Gulland, and Story [4] into the procedure of Windaus and Langenbeck made it possible to increase somewhat the yield of nitroimidazolecarboxylic acid; however, even in this case it did not exceed 23–24% of the theoretical amount.
The search for a more economical method for preparing this acid is of considerable interest, since it can be used ...
also forms the basis for the synthesis of one of the important purine derivatives—xanthine, as evidenced by the following scheme [4]:
\[ \begin{gathered} \text{4(5)-nitroimidazolecarboxylic acid} \xrightarrow{\mathrm{CH_3OH}} \text{methyl 4(5)-nitroimidazolecarboxylate} \xrightarrow{\mathrm{H_2}} \text{methyl 4(5)-aminoimidazolecarboxylate} \xrightarrow{\mathrm{KCNO}} \\ \text{ureido derivative} \xrightarrow{\mathrm{NaOH}} \text{imidazolecarboxylic acid derivative} \xrightarrow{\mathrm{HCl}} \text{xanthine} \end{gathered} \]
The conversion of xanthine into other purine derivatives, for example caffeine and theobromine, has long been known and is readily accomplished with the aid of ordinary methylating agents. According to Bredereck [5], when dimethyl sulfate acts on xanthine under definite temperature conditions and at a definite pH of the medium, the yield of caffeine reaches 90%, and the yield of theobromine is 68% of theory. This circumstance assumes special significance because the steadily increasing demand for these valuable medicinal substances compels the search for new routes to their synthesis, among which the route via nitroimidazolecarboxylic acid may prove readily accessible and economically advantageous.
The method that we have developed [6] for preparing nitroimidazolecarboxylic acid from oxymethylimidazole deserves attention in this respect.
Experimental Part
The starting product for the preparation of 4(5)-nitroimidazolecarboxylic acid—4(5)-oxymethylimidazole
\[ \begin{array}{c} \mathrm{/NH{-}CH}\\ \mathrm{HC \quad \|}\\ \mathrm{\backslash N{-}C{-}CH_2OH} \end{array} \]
was obtained by the method of L. Kulev and A. Onishchuk [7] from inverted sugar. To destroy the copper complex, instead of hydrogen sulfide it proved more convenient to use sodium sulfide in the form of its 20% aqueous solution, added until copper sulfide had completely precipitated. All other conditions for obtaining 4(5)-oxymethylimidazole were observed according to the authors’ procedure.
Into a three-necked flask fitted with a thermometer and a mechanical stirrer are poured 150 ml of fuming nitric acid (specific gravity 1.50), and to it, with stirring, 160 ml of concentrated sulfuric acid (specific gravity 1.84) are gradually added. Into the cooled nitrating mixture, 50 g of the hydrochloride of oxymethylimidazole are introduced in small portions over 35–40 min. To avoid strong heating and intensive evolution of nitrogen oxides, the flask is cooled with water, ensuring that the temperature of the mixture does not exceed 25–30°. The flask is placed in a thermostat and heated first at 39–40° for four hours, and then at 42–43° for 8 hours.
Strict observance of the temperature regime indicated here is obligatory, since otherwise (at a higher \(t^\circ\)) the reaction may proceed toward the formation of imidazolecarboxylic acid, which, as our experiments have shown, no longer passes into the nitro acid, despite prolonged heating with the nitrating mixture.
The contents of the flask are poured into a porcelain dish with 15 ml of distilled water; the dish is covered with a watch glass and placed on a boiling water bath. During the first 2–3 hours the reaction is accompanied by vigorous evolution of nitrogen oxides; thereafter it proceeds calmly and is complete after 5–6 hours. This point corresponds to the cessation of evolution of brown vapors and decolorization of the solution.
The watch glass is removed and heating is continued for some time longer, until the solution has been evaporated to approximately one third of its initial volume. The reaction mixture is cooled, poured into a beaker with water (total volume of liquid about 1.5 liters), and mixed thoroughly. Nitroimidazolecarboxylic acid separates in the form of colorless fine needles or flat prisms. The crystals are filtered off, washed 3–4 times with ice water (100 ml for each operation), thoroughly pressed out, and dried in a vacuum desiccator.
The yield of product is 42 g, or 71.5% of theory.
Nitroimidazolecarboxylic acid melts at 307–308° with decomposition. It dissolves readily in hot water and alcohol (on heating), and very readily in aqueous alkali solutions. It is insoluble in cold water, ether, benzene, carbon tetrachloride, and acetone. It dissolves in mineral acids, but does not form salts with them. Thus, for example, from solutions in concentrated sulfuric acid the nitro acid is precipitated unchanged by water. It also gives no complex compounds with picric and chloroplatinic acids, which distinguishes it from other imidazole derivatives.
Analysis of the substance obtained for nitrogen by the modified Kjeldahl method gave the following results:
0.2181 g substance — 41.5 ml 0.1 N H₂SO₄; 0.2290 g substance — 43.0 ml 0.1 N H₂SO₄. Found % N: 26.65 and 26.61. Calculated % N: 26.75.
For identification of 4(5)-nitroimidazolecarboxylic acid, its esterification was carried out in order to obtain the methyl ester by the method of Windáus and Langenbeck.
1 g of the substance obtained is introduced into a flask fitted with a reflux condenser, 19 g of absolute methyl alcohol saturated with dry hydrogen chloride is added, and the mixture is heated for 1 hour on a water bath. The contents of the flask are transferred to a porcelain dish and evaporated until crystals appear. After recrystallization from hot water the substance melts at 212–213°, which corresponds to the data of Windáus and Olsbruk for the methyl ester of 4(5)-nitroimidazolecarboxylic acid.
Analysis of the methyl ester for nitrogen
0.2447 g substance — 39.5 ml 0.1 N H₂SO₄; 0.2088 g substance — 36.5 ml 0.1 N H₂SO₄. Found % N: 24.62 and 24.49. Calculated % N: 24.56.
By the method of Windáus, the amide of 4(5)-nitroimidazolecarboxylic acid was also obtained by the action on it of phosphorus pentachloride, followed by treatment of the acid chloride with ammonia.
The acid amide consists of almost colorless long needles with m.p. 291°.
Analysis of the amide for nitrogen
0.1939 g substance — 49.5 ml 0.1 N H₂SO₄; 0.2054 g substance — 52.5 ml 0.1 N H₂SO₄. Found % N: 35.76 and 35.80. Calculated % N: 35.89.
Conclusions
- A new method has been developed for obtaining 4(5)-nitroimidazolecarboxylic acid from 4(5)-hydroxymethylimidazole by treating it with a nitrating mixture under specified temperature conditions.
The yield of the nitro acid by this method reaches 70%–72% of theory.
Literature
- Windaus, Opitz, Ber., 44, 1724, 1911.
- Fargher, Pyman, J. Chem. Soc., 115, 219, 1919.
- Windaus, Langenbeck, Ber., 56, 683, 1923.
- Allsebrook, Gulland, Story, J. Chem. Soc., 232, 1942.
- Bredereck, Schuh, Martin, Ber., 83, 201, 1950.
- Inventor’s certificate No. 102033, 10/XII—1955.
- Kulev L. P. and Onishchuk A. E., Proceedings of the Chemical-Metallurgical Institute of the West Siberian Branch of the USSR Academy of Sciences, issue 1, 77, 1949.