Synthesis of Some Derivatives of 4(5)-Nitro- and 4(5)-Aminoimidazole-5-(4)-carboxylic Acid

R. N. Gireva, N. S. Dobychina

(Presented by Professor B. V. Tronov, Doctor of Chemical Sciences)

Derivatives of 4(5)-nitro- and 4(5)-aminoimidazole-5(4)-carboxylic acid have hitherto been little studied. The literature describes the methyl ester of 4(5)-nitro- and 4(5)-aminoimidazole-5(4)-carboxylic acid [1, 2, 3]. A series of esters of nitroimidazolecarboxylic acid was obtained by L. P. Kulev and A. M. Rozhkov [4].

Amides of nitro- and aminoimidazolecarboxylic acid were described by Windhaus and Langenbeck [2]. It was of interest to obtain other derivatives of these acids.

The present work describes the synthesis of several esters (I) and ureides (II) of 4(5)-nitro- and 4(5)-aminoimidazole-5(4)-carboxylic acid:

\[ \begin{array}{c} \begin{array}{c} \mathrm{N{-}C{-}NO_2\,(NH_2)}\\ \mathrm{\ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \Vert}\\ \end{array}\\[-0.5em] \mathrm{HC}\!\begin{array}{c} \diagup \\[-0.3em] \diagdown \end{array} \begin{array}{c} \\[-1.2em] \mathrm{NH{-}C{-}COOR} \end{array} \end{array} \qquad \mathrm{I} \]

\[ \begin{array}{c} \begin{array}{c} \mathrm{N{-}C{-}NO_2\,(NH_2)}\\ \mathrm{\ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \Vert}\\ \end{array}\\[-0.5em] \mathrm{HC}\!\begin{array}{c} \diagup \\[-0.3em] \diagdown \end{array} \begin{array}{c} \\[-1.2em] \mathrm{NH{-}C{-}CONH{-}CONH_2} \end{array} \end{array} \qquad \mathrm{II} \]

Nitroimidazolecarboxylic acid was obtained from technical oxymethylimidazole sulfate by the method proposed by one of us jointly with L. P. Kulev [5], and also by a somewhat modified procedure using, instead of the usual nitrating mixture with fuming nitric acid, a mixture with potassium nitrate, which made it possible to increase slightly the yield of the nitro acid. The benzyl ester of nitroimidazolecarboxylic acid was obtained by esterification of benzyl alcohol in the presence of benzenesulfonic acid as catalyst. The diethylaminoethyl ester of nitroimidazolecarboxylic acid was obtained in concentrated sulfuric acid medium by one of the methods for preparing novocaine [6]. To obtain the dimethylaminoethyl, p-diphenyl, and ureide derivatives of nitroimidazolecarboxylic acid, the acid chloride of the latter was used. In this case the p-diphenyl ester of nitroimidazolecarboxylic acid was obtained by two methods: by heating a mixture of p-hydroxydiphenyl, acid chloride, and saturated aqueous potassium hydroxide solution in carbon tetrachloride medium, and in absolute alcohol medium (with anhydrous potassium hydroxide). The latter method gave the better results.

The reduction of nitroimidazolecarboxylic acid derivatives was carried out with cast-iron turnings in electrolyte solution and with hydrogen in the presence of Raney nickel.

Experimental Part

4(5)-Nitroimidazole-5(4)-carboxylic acid (I)

196 g of potassium nitrate is dissolved, with vigorous stirring, in 270 ml of concentrated sulfuric acid (sp. gr. 1.84), heated to 32°. To this mixture, at a temperature of 39°, technical 4(5)-oxymethylimidazole sulfate, carefully dried to constant weight in vacuo and obtained from 180 g of sugar [5], is added in small portions with continuous stirring. If the reaction mass thickens, about 50 ml more of concentrated sulfuric acid should be added. After all the oxymethylimidazole has dissolved, the reaction mass is gradually heated in a thermostat to 45–47° and nitration is conducted at this temperature for 6 hours. After 12–16 hours, the contents of the flask are transferred to a porcelain dish, the flask is rinsed with 150 ml of water, this solution is added to the main mass, the dish is covered with a watch glass, and it is heated on a boiling water bath for 3–4 hours until the evolution of nitrogen oxides ceases. To complete the reaction, a further 10–15 ml of nitric acid of sp. gr. 1.4 is added to the heated reaction mass and heating is continued for 30–60 minutes. If no further evolution of nitrogen oxides occurs, the reaction mass is cooled, the precipitated inorganic salts are filtered off, and the filtrate is poured into 1000 ml of water. The water-diluted filtrate is neutralized with crystalline soda to a weakly acidic reaction. Almost immediately, crystals of nitroimidazolecarboxylic acid begin to precipitate. For more complete separation of the latter, the mixture is left to stand for several hours. The acid is then filtered off, washed with a small amount of ice water, and dried at 50–60°; m.p. 298–300°. Yield 30–31 g (93.9–97.0%). After recrystallization from hot water, m.p. 303–305°.

Acid chloride of 4(5)-nitroimidazole-5(4)-carboxylic acid (II)

14.3 g of nitroimidazolecarboxylic acid is ground in a dry porcelain mortar (under a hood) with 19 g of phosphorus pentachloride. The reaction begins almost at once: the mixture cakes into a bright-yellow mass which, on further grinding, again hardens, turning into a light-yellow powder. The latter is transferred to an open round-bottom flask and heated on an oil bath at 120–130° until the evolution of phosphorus oxychloride and hydrogen chloride ceases, which requires 3–4 hours. To accelerate the reaction, the reaction mass should be stirred from time to time. The nitroimidazolecarboxylic acid chloride thus obtained is a light-yellow powder which begins to decompose above 240°. Yield 14.3 g (90%).

p-Diphenyl ether of 4(5)-nitroimidazole-5(4)-carboxylic acid (III)

1. A mixture of 3.0 g of p-oxyphenide, 1.0 g of caustic potash dissolved in the smallest possible amount of water, 3.3 g of nitroimidazolecarboxylic acid chloride, and 30–40 ml of carbon tetrachloride is heated in a round-bottom flask equipped with a reflux condenser and a stirrer at 65–70° until the light-yellow precipitate of the acid chloride disappears, which requires about 5 hours.

After cooling, the reaction mixture is filtered, and the precipitate is washed first with carbon tetrachloride and then treated with hot alcohol to dissolve the p-diphenyl ether. From alcohol, on cooling, 4.2 g of the ether separates as yellowish crystals, m.p. 212–214°.

After recrystallization from hot alcohol, 3.4 g (52%) of the pure ester is obtained, m.p. 232–233°.

1. A mixture of 2.4 g of p-oxydiphenyl, 0.78 g of caustic potassium, and 2.64 g of the hydrochloride of nitroimidazolecarboxylic acid hydrazide in absolute ethyl alcohol is heated to 75–80° with stirring for 3 hours. After filtration and partial distillation of the alcohol, the ester separates in an amount of 1.78 g, m.p. 216–218°. The pure ester recrystallized from hot alcohol (1.53 g, yield 63%) consists of almost colorless square plates, m.p. 232–233°. It is poorly soluble in ordinary organic solvents. It dissolves in boiling alcohol and acetone. It is insoluble in water.

Found, %: nitrogen 13.70. Calculated, %: nitrogen 13.59.

Benzyl ester of 4(5)-nitroimidazole-5(4)-carboxylic acid (IV)

A mixture of 2.25 g of the potassium salt of benzenesulfonic acid, 1.17 g of sulfuric acid (sp. gr. 1.84), and 2 g of nitroimidazolecarboxylic acid is thoroughly stirred until a homogeneous mass is formed; 20 ml of freshly distilled benzyl alcohol¹ is slowly added to it, and it is heated in a flask with a reflux condenser on a boiling water bath for 8 hours. After separation of the lower aqueous-acid layer, carbon tetrachloride (about 350 ml) is added to the alcoholic solution of the ester (upper layer) until formation of the white precipitate ceases, and the mixture is left for 24 hours.

2.7 g of ester is obtained, m.p. 198°; yield of the product recrystallized from hot alcohol, 2.4 g (76.43%), m.p. 200–201°.

Benzyl ester of 4(5)-aminoimidazole-5(4)-carboxylic acid (V)

2 g of the benzyl ester of nitroimidazolecarboxylic acid is thoroughly mixed with an excess of zinc dust. Into the mixture, with stirring, 24 ml of glacial acetic acid is slowly introduced. The mass acquires a dark violet color; it is filtered, and the precipitate on the filter is washed with 10 ml of glacial acetic acid, which is added to the main filtrate. The latter is boiled with a small amount of animal charcoal and filtered. From the filtrate, by addition of a saturated aqueous solution of picric acid, a greenish-yellow picrate of the benzyl ester of aminoimidazolecarboxylic acid is precipitated. The yellow picrate recrystallized from hot water, in an amount of 1.35 g (yield 37.4%), has m.p. 189–190°.

Found, %: nitrogen 18.65. Calculated, %: nitrogen 18.83.

The picrate of the benzyl ester of aminoimidazolecarboxylic acid is converted into the hydrochloride by the action of hydrochloric acid. 1.5 g of the picrate, 10 ml of distilled water, 2 ml of hydrochloric acid (sp. gr. 1.19), and 10 ml of benzene are heated in a flask with a reflux condenser on a water bath with stirring until the picrate is completely dissolved and the picric acid passes into the benzene layer. The benzene is separated, and the aqueous-acid layer is treated 3–4 more times with benzene for more complete removal of the picric acid. The last traces of it are removed by heating with a small amount of animal charcoal. The mixture is filtered. The filtrate is evaporated in vacuo. Yield of hydrochloride, 0.27 g (38.6%). Sulfur-yellow crystals, m.p. 165°.

It is readily soluble in water, alcohol, and acetone. It is readily diazotized; the diazo compound, when combined with ammoniacal resorcinol solution, forms a dark-bordeaux azo dye.

Dimethylaminoethyl ester of 4(5)-nitroimidazole-5(4)-carboxylic acid (VI)

A mixture of 7 g of the acid chloride of nitroimidazolecarboxylic acid with 9 ml of freshly distilled dimethylaminoethanol is heated in a flask with a reflux condenser on an oil bath at 120–125° for 2 hours. The resinous reaction mass is washed with carbon tetrachloride to remove the remaining dimethylaminoethanol and treated with 70–80 ml of alcohol acidified with 2–3 ml of hydrochloric acid (sp. gr. 1.19). Formation of a dirty-yellow crystalline precipitate with m.p. 210–212° begins at once. After several recrystallizations from acidified alcohol, white crystals with a pearlescent luster of the ester hydrochloride are obtained, melting at 224–225°. It is very readily soluble in water and is easily hydrolyzed. It is poorly soluble in alcohol and insoluble in ordinary organic solvents. With picric acid it forms a yellow picrate.

Found, %: N 21.23. Calculated, %: N 21.17.

Dimethylaminoethyl ester of 4(5)-aminoimidazole-5(4)-carboxylic acid (VII)

4.5 g of the dimethylaminoethyl ester of nitroimidazolecarboxylic acid, 110 ml of alcohol, 5.5 ml of hydrochloric acid (sp. gr. 1.19), and about 1.2 g of Raney catalyst are placed in a round-bottom flask fitted with a reflux condenser, a tube for passing hydrogen, and a stirrer lowered to the bottom.

Hydrogen is passed through the boiling mixture, with stirring, for 2.5 hours. A small amount of water and a saturated aqueous solution of picric acid are added to the red-brown reaction mass. A dark-green precipitate of the dipicrate of the amino acid ester separates. Recrystallized from water with charcoal, the bright-yellow crystalline dipicrate melts at 234°.

Found, %: N 21.45. Calculated, %: N 21.34.

The ester dipicrate is converted by the action of hydrochloric acid into the hydrochloride—white fine crystals, m.p. 240–241°. It is readily soluble in water and alcohol.

Diethylaminoethyl ester of 4(5)-nitroimidazole-5(4)-carboxylic acid (VIII)

1. Preparation of diethylaminoethanol sulfate. A mixture of 4.2 ml of freshly distilled diethylaminoethanol and 10 ml of sulfuric acid solution (1:3) is evaporated on a water bath to the consistency of syrup and kept for 24 hours in a desiccator over sulfuric acid.

2. Preparation of the ester. To a mixture of 5 g of nitroimidazolecarboxylic acid and 12 g of sulfuric acid (sp. gr. 1.84), heated to 130° on an oil bath, the syrupy yellowish sulfate salt of diethylaminoethanol is slowly added with constant stirring. Heating at 130–135° is continued for 10 hours. The thick dark-brown liquid is poured into ice water. Almost immediately a yellowish precipitate begins to separate from the solution, consisting of contaminated nitroimidazolecarboxylic acid. It is filtered off (2.17 g, m.p. 294–296°); the filtrate is treated with saturated aqueous barium chloride solution until precipitation of barium sulfate is complete (there must be no excess barium chloride). The barium sulfate is filtered off, washed thoroughly with water acidified with hydrochloric acid. The filtrate and wash waters are distilled under vacuum at 25–30°. The residue—a syrupy yellow liquid—is poured into a crystallizer. Very rapidly a further amount of pure nitroimidazolecarboxylic...

acid (1.5 g), and then white crystals of the ester gradually begin to separate from the mother liquor; these are filtered off as they form (total amount 1.5 g), m.p. 110–135°. After several recrystallizations from hydrochloric acid acidified with hydrochloric acid, grayish-white lustrous plates are obtained, m.p. 193–194°. Very readily soluble in water, less soluble in alcohol, readily hydrolyzed. Insoluble in other organic solvents.

Found, %: nitrogen 18.91. Calculated, %: nitrogen 19.14.

The ester hydrochloride in aqueous solution forms, with a saturated aqueous solution of picric acid, a greenish-yellow crystalline picrate, m.p. 165–167°.

Found, %: nitrogen 20.08. Calculated, %: nitrogen 20.20.

Ureide of 4(5)-nitroimidazole-5(4)-carboxylic acid (IX)

A thoroughly prepared mixture of 4 g of the acid chloride of nitroimidazolecarboxylic acid and 4 g of urea dried to constant weight is heated in a flask with a reflux condenser on an oil bath at 145°. After 10–15 minutes from the beginning of heating, the entire reaction mass turns into a dark-brown liquid and a vigorous reaction begins, accompanied by evolution of hydrogen chloride. After 7 hours the dark-brown melt is treated 3–4 times with water (100 ml portions) with heating; a considerable portion of the melt passes into solution, and it is filtered hot. On cooling, light-brown crystals separate slowly from the combined filtrates, in an amount of 2.4 g (yield 53%), m.p. 270–272° (with decomposition).

After recrystallization from boiling water with animal charcoal, the light-yellow lustrous crystals of the ureide melt at 275–276° (with decomposition). Sparingly soluble in cold water, soluble in hot water and in alcohol.

Found, %: nitrogen 35.21. Calculated, %: nitrogen 35.17.

Ureide of 4(5)-aminoimidazole-5(4)-carboxylic acid (X)

5 g of degreased cast-iron filings are boiled for 10 minutes with dilute hydrochloric acid solution (35 ml of water and 0.5 ml of hydrochloric acid, sp. gr. 1.19). Into the resulting electrolyte solution, with vigorous stirring and heating on a boiling water bath, 2 g of the ureide of nitroimidazolecarboxylic acid is gradually introduced. The reduction is carried out for 1 hour. The hot dark-burgundy solution is filtered from the sludge. The sludge is treated 3–4 times with acidified water, with heating and vigorous stirring for 15–20 minutes. The filtrate and wash waters are decolorized by boiling with animal charcoal. On cooling, white lustrous needles of the ureide hydrochloride separate, m.p. 272° (with decomposition). After recrystallization from hot water, m.p. 283° (with decomposition). Yield 0.71 g (34.5%). Soluble in hot water and alcohol.

Found, %: nitrogen 34.36. Calculated, %: 34.06.

References

1. K. Hofmann, The Chemistry of Heterocyclic Compounds, part 1, Imidazole and Its Derivatives. New York, 180, 1953.

2. A. Windaus and Langenbeck, Ber. 56, 683, 1923.

3. Cook A. H., Davis A. C., Sir Jau Heilbron and G. H. Thomas, J. Chem. Soc., 1071, 1949.

4. L. P. Kulev and A. M. Rozhkov, ZhOKh 27, 1389, 1957.

5. L. P. Kulev and R. N. Gireva, ZhPKh 30, 118, 1957.

6. A. M. Berkengheim, Practical Manual on Synthetic Medicinal and Fragrant Substances and Photographic Materials, Moscow—Leningrad, 67, 1942.

7. V. I. Isagulyants, Synthetic Fragrant Substances, Yerevan, 187, 1947.

1. Benzyl alcohol was obtained from benzaldehyde and formaldehyde by the method of Davidson and Bogert, simplified by Smolyanyinova and Gurevich [7]. ↩