Hydrochlorides and picrates of some esters of 4(5)-aminoimidazole-5(4)-carboxylic acid
Abstract Generated abstract
This paper reports the preparation and characterization of several esters of 4(5)-aminoimidazole-5(4)-carboxylic acid, compounds of interest as intermediates for medicinally relevant substances such as caffeine and theobromine. Nitro ester precursors were reduced mainly with cast-iron filings in electrolyte solution, while the imidazolylmethyl derivative required ferrous sulfate in ammoniacal medium, and the resulting amino esters were isolated or characterized as hydrochlorides and picrates. The study describes methyl, ethyl, isopropyl, isoamyl, and imidazolylmethyl derivatives, gives melting points, solubility behavior, yields, and analytical data, and concludes that the amino esters, unlike the corresponding nitro esters, readily form salts with strong mineral acids and complexes with picric acid.
Full Text
Hydrochlorides and Picrates of Certain Esters of 4(5)-Aminoimidazole-5(4)-carboxylic Acid
L. P. Kulev, V. R. Koroleva
Esters of 4(5)-aminoimidazole-5(4)-carboxylic acid deserve attention as starting materials in the synthesis of valuable medicinal substances, for example, caffeine and theobromine. In addition, they may also be of independent interest, since the imidazole ring in a number of cases accounts for the high physiological activity of compounds.
Of the esters of 4(5)-aminoimidazole-5(4)-carboxylic acid, only the methyl and ethyl esters have been described in the literature [1]. The first was obtained by catalytic reduction of methyl 4(5)-nitroimidazole-5(4)-carboxylate [2]. The second was obtained by condensation of ethyl aminocyanoacetate with formamidine hydrochloride [3]. The hydrochloride and picrate are known only for the methyl ester.
In order to determine the influence of the amino group on the properties of the compounds, we carried out the synthesis of several other esters of 4(5)-aminoimidazole-5(4)-carboxylic acid, their hydrochlorides and picrates.
4(5)-Nitroimidazole-5(4)-carboxylic acid was obtained by the anhydrous method from 4(5)-oxymethylimidazole [4].
The synthesis of the starting nitro esters, including the isopropyl ester obtained by us, was carried out by the methods described previously [5].
With the exception of the imidazolylmethyl ester of 4(5)-nitroimidazole-5(4)-carboxylic acid, which could be reduced only with ferrous sulfate in an ammoniacal medium, the reduction of all the other nitro esters was carried out with the aid of cast-iron filings in the presence of an electrolyte.
All the esters described here are diacid bases, giving salts with hydrochloric acid and complex compounds with picric acid of compositions 1:1 and 1:2. The hydrochlorides have the appearance of white crystalline substances, readily soluble in water and alcohol, except for the imidazolylmethyl ester hydrochloride, which is poorly soluble in alcohol.
Experimental Part
Methyl ester of 4(5)-aminoimidazole-5(4)-carboxylic acid (I)
7.5 g of cast-iron filings degreased with soda are boiled for 10 min with a hydrochloric acid solution (1.5 ml, d = 1.19) to obtain an electrolyte solution. With vigorous stirring, 3 g of methyl 4(5)-nitroimidazole-5(4)-carboxylate are added. The reduction is carried out in a thermostat at 45–47° for 2.5 hours.
The reaction mass is filtered off, the precipitate is washed several times with acidified water, and a saturated solution of picric acid is added to the filtrate. The amino ester picrate precipitates in the form of small yellow needles with m.p. 230° (from hot water). Yield 4.72 g (73%).
The amino ester hydrochloride is obtained by treating the picrate with hydrochloric acid. Colorless needles, readily soluble in water and alcohol.
Ethyl ester (II)
Obtained analogously to (I). To improve the solubility of the nitro ester, reduction is carried out in an aqueous-alcoholic medium (2:1). Picrate—yellow needles fused together, m.p. 191–192° (from hot water). Yield 73.5%. Hydrochloride—white needles, m.p. 190–191°; readily soluble in water, alcohol, warm ethyl acetate; almost insoluble in ether, benzene, and carbon tetrachloride.
From the hydrochloride the base was obtained, identical with that described in [3].
Isopropyl ester of 4(5)-nitroimidazole-5(4)-carboxylic acid (III)
To 60 ml of absolute isopropyl alcohol containing 1.5 ml of sulfuric acid ($d = 1.84$), 5 g of 4(5)-nitroimidazole-5(4)-carboxylic acid is added. The mixture is heated on a boiling water bath for two hours, then evaporated to a small volume.
Colorless shiny plates with m.p. 206–207° (from boiling water). Yield 2.54 g (38%). Insoluble in cold water, cold ether, benzene, chloroform. Readily soluble in alcohol, acetone, and ethyl acetate. Dissolves in dilute alkalis with the solution becoming yellow. Does not form salts with mineral acids or complex compounds with picric acid.
Isopropyl ester of 4(5)-aminoimidazole-5(4)-carboxylic acid (IV)
Reduction of the nitro ester is carried out analogously to (II). Picrate—yellow plates with m.p. 173–173.5° (from boiling water). Yield 80%.
The amino ester hydrochloride crystallizes with great difficulty from alcohol and water. It gradually darkens in air. Hygroscopic. Readily soluble in water, alcohol, acetone, ethyl acetate, and chloroform. Poorly soluble in ether, benzene, and carbon tetrachloride.
Isoamyl ester (V)
Obtained analogously to (II) in an aqueous-alcoholic medium (1:1). Picrate—small yellow needles, m.p. 152° (from hot water). Yield 75%.
The amino ester hydrochloride crystallizes with difficulty from water and alcohol. On heating, the aqueous and alcoholic solutions darken. Hygroscopic. Poorly soluble in ether, benzene, and carbon tetrachloride. Readily soluble in water, alcohol, ethyl acetate, acetone, and chloroform.
Imidazolylmethyl ester (VI)
To a solution of 11 g of ferrous sulfate in 10 ml of water is added a hot solution of 1 g of the imidazolylmethyl ester of 4(5)-nitroimidazole-5(4)-carboxylic acid in 10 ml of water. With constant stirring, 12 ml of 25% aqueous ammonia solution is added until a persistent ammoniacal odor is obtained.
The reaction mixture is placed on a boiling water bath, heated for 5 min, and filtered hot. Filtration is carried out into a receiver containing a small amount of dilute hydrochloric acid, since the free base of the amino ester is very unstable and is readily resinified in air.
The picrate—yellow needles with m.p. 267–268° (from hot water). Yield 2.14 g (71.3%).
The hydrochloride—thin white needles; m.p. 360–361°. Readily soluble in water, somewhat less soluble in hot alcohol. Poorly soluble in cold alcohol, almost insoluble in ether, chloroform, acetone, carbon tetrachloride, and ethyl acetate. It sublimes readily on heating.
The results of analysis of the isopropyl ester of 4(5)-nitroimidazole-5(4)-carboxylic acid and of the hydrochlorides and picrates of 4(5)-aminoimidazole-5(4)-carboxylic acid are given in the table.
Table
| Ester No. | Formulas of compounds | Found, (%) | Calculated, (%) |
|---|---|---|---|
| II | $\mathrm{C_6H_9O_2N_3\cdot 2HCl}$ | 18.85; 18.77 | 18.42 |
| II | $\mathrm{C_6H_9O_2N_3\cdot C_6H_3O_7N_3}$ | 22.12; 21.65 | 21.87 |
| III | $\mathrm{C_7H_{10}O_4N_3}$ | 21.02; 20.98 | 21.10 |
| IV | $\mathrm{C_7H_{11}O_2N_3\cdot 2HCl}$ | 17.73; 17.11 | 17.35 |
| IV | $\mathrm{C_7H_{11}O_2N_3\cdot C_6H_3O_7N_3}$ | 20.90; 20.85 | 21.11 |
| V | $\mathrm{C_9H_{15}O_2N_3\cdot 2HCl}$ | 15.77; 15.65 | 15.55 |
| V | $\mathrm{C_9H_{15}O_2N_3\cdot C_6H_3O_7N_3}$ | 19.89; 19.31 | 19.72 |
| VI | $\mathrm{C_8H_9O_2N_3\cdot 2HCl}$ | 24.77; 24.82 | 25.00 |
| VI | $\mathrm{C_8H_9O_2N_3\cdot 2C_6H_3O_7N_3}$ | 23.00; 22.96 | 23.16 |
Conclusions
-
The methyl, ethyl, isopropyl, and isoamyl esters of 4(5)-aminoimidazole-5(4)-carboxylic acid, and their hydrochlorides and picrates, have been obtained.
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It has been established that, in contrast to the corresponding esters of 4(5)-nitroimidazole-5(4)-carboxylic acid, these esters readily form salts with strong mineral acids and with picric acid.
LITERATURE
- K. Hofmann, The Chemistry of Heterocyclic Compounds, part I, Imidazole and Its Derivatives, New York, p. 180, 1953.
- A. Windaus and W. Langenbeck, Ber. 56, 683, 1923.
- A. H. Cook, A. C. Dabis, Sir Jan Heilbron and G. H. Thomas, J. Chem. Soc., 1071, 1949.
- L. P. Kulev and R. N. Gireva. ZhPKh 30, 118, 1957.
- L. P. Kulev and A. M. Rozhkov. ZhOKh 27, 1389, 1957.