DEVELOPMENT OF THE SYNTHESIS OF 3,5-DINITROBENZOIC ACID ANTIPYRILAMIDE

G. M. STEPNOVA, E. V. SHMIDT, N. F. MATVEEVA

(Presented by the scientific-methodological seminar of the Chemical-Technological Faculty)

The 3,5-dinitrobenzoic acid antipyrilamide synthesized by us, not described in the literature, showed in a pharmacological experiment high anti-inflammatory and antipyretic activity and low toxicity. The presence of these properties in this compound makes it promising for future use in medical practice.

The aim of the present work was to find a convenient method for obtaining this antipyrilamide and to develop the optimal conditions for its synthesis.

Two methods of obtaining the preparation were tested:

1. Acylation of 4-aminoantipyrine with free 3,5-dinitrobenzoic acid in an indifferent solvent medium in the presence of a chlorinating agent.

2. Acylation of 4-aminoantipyrine with 3,5-dinitrobenzoic acid acid chloride.

The first method has the advantage that it eliminates the stage of obtaining the acid chloride. As the medium in our work we used benzene and m-xylene, and as the condensing agent—phosphorus trichloride. The acylation of 4-aminoantipyrine with 3,5-dinitrobenzoic acid acid chloride was carried out both by the method described by Françen and in the presence of hydrogen chloride acceptors—an excess of 4-aminoantipyrine and potash.

Experimental Part

1. Acylation of 4-aminoantipyrine with 3,5-dinitrobenzoic acid.

0.05 gram-mole of 3,5-dinitrobenzoic acid is suspended in 25 ml of dehydrated benzene (m-xylene), placed in a round-bottom flask equipped with a stirrer, dropping funnel, and reflux condenser, and heated on an oil bath equipped with a temperature regulator to a temperature of 50°. A hot solution of 0.05 gram-mole of 4-aminoantipyrine in 25 ml of the same solvent is rapidly added to the reaction flask; dissolution of the 3,5-dinitrobenzoic acid is observed, and the reaction mass becomes homogeneous. At 60–70°, 2 ml of phosphorus trichloride is added dropwise from the dropping funnel over 20 minutes, and with stirring the mixture is heated for a specified

for a certain time at a specified temperature. Evolution of hydrogen chloride and precipitation of the reaction product are observed. The solvent is decanted, the solid reaction mass is freed of solvent, treated with a 10% solution of sodium carbonate, filtered, washed with water, dried, and the product yield is determined.

The results of experiments on the acylation of 4-aminoantipyrine with 3,5-dinitrobenzoic acid are presented in Figs. 1 and 2.

It is seen from Fig. 1 that higher product yields are obtained in vigorously boiling solvents—in benzene at 100°, and in xylene at 140°. Lowering the bath temperature has a negative effect on the yields. It is seen from Fig. 2 that the time factor does not play a substantial role in this reaction.

Fig. 1. Dependence of the yield of 3,5-dinitrobenzoic acid antipyrilamide on reaction time: I—in benzene at 100° (bath); II—in xylene at 140° (bath).

Fig. 2. Dependence of the yield of 3,5-dinitrobenzoic acid antipyrilamide on temperature: I—in benzene for 3 hr, II—in xylene for 0.5 hr.

It is most rational to carry out the reaction in benzene for 3 hours, and in xylene for 0.5–1 hour. More prolonged heating of the reaction mass in benzene does not increase the yields, while in xylene it leads to their decrease and to deterioration of the product quality owing to partial resinification.

1. Acylation of 4-aminoantipyrine with 3,5-dinitrobenzoic acid acid chloride:

a) Equimolecular amounts (0.05 g-mole each) of 3,5-dinitrobenzoic acid chloride, obtained by the interaction of 3,5-dinitrobenzoic acid with phosphorus pentachloride, and 4-aminoantipyrine in 50 ml of benzene are heated on an oil bath in a flask equipped with a reflux condenser and a stirrer at 100° for 2 hours. The reaction mass is worked up analogously to that described above. Yield 88–90%. Carrying out the reaction in a ratio of 0.1 g-mole of 4-aminoantipyrine to 0.05 g-mole of 3,5-dinitrobenzoic acid led to a yield of 93.5%;

b) To a solution of 0.05 g-mole of 4-aminoantipyrine in 30 ml of benzene, first 11 ml of a 50% solution of potash are added, and then, carefully with stirring, a suspension of 0.05 g-mole of 3,5-dinitrobenzoyl chloride in 30 ml of benzene. Evolution of carbon dioxide and warming of the reaction mass are observed. The mixture is heated on a water bath for 20–30 minutes. The reaction product, in the form of a yellow precipitate, is concentrated in the benzene layer. Yield 95–97%.

Purification of the reaction product was carried out by threefold recrystallization from 3–4 parts methanol and 1 part glacial acetic acid.

acid. 3,5-Dinitrobenzoic acid antipyrilamide is a yellow crystalline substance with a bitter taste, melting point 247–248°, insoluble in water, ether, and acetone, sparingly soluble in benzene and xylene, readily soluble in glacial acetic acid and chloroform, and soluble in hot methanol and ethanol.

Found, %: N 17.63, 17.58, \(\mathrm{C}_{18}\mathrm{H}_{15}\mathrm{O}_{6}\mathrm{N}_{5}\).

Calculated, %: N 17.63.

Conclusions

1. The optimal conditions for the acylation of 4-aminoantipyrine with 3,5-dinitrobenzoic acid in aromatic solvents in the presence of phosphorus trichloride have been determined (dependence of the yield on time and temperature).

2. A convenient method has been tested for the acylation of 4-aminoantipyrine with 3,5-dinitrobenzoic acid chloride in the presence of potassium hydroxide; it does not require prolonged heating and gives a high yield of the product.

Literature

1. N. N. Vorozhtsov. Fundamentals of the Synthesis of Intermediates and Dyes. Goskhimizdat, 555, 1955.

2. Franzen. B, 42, 2465, 1909.