CONDENSATION OF ANTIPYRINE WITH SOME OXYGEN-CONTAINING COMPOUNDS OF THE AROMATIC SERIES

F. Z. GORFINKEL

A number of medicinal and dye substances belong to the group of substituted pyrazolones. Of great interest is a derivative of 1-phenyl-3-methyl-5-pyrazolone, obtained by methylation of the latter with methyl iodide, methyl bromide, or dimethyl sulfate—antipyrine, which is a valuable antipyretic substance, as well as an analytical reagent for Cd, Bi, Pb, and other elements [5]. Antipyrine—1-phenyl-2,3-dimethylpyrazolone-5—was obtained in 1884 by Knorr [8] by condensation of acetoacetic ester with phenylhydrazine.

During this reaction, 1-phenyl-3-methylpyrazolone-5 was synthesized, which was at first taken to be a derivative of partially hydrogenated quinoline. Since quinoline derivatives possess valuable pharmacological properties, the substance obtained was tested from this point of view. It turned out that 1-phenyl-3-methylpyrazolone-5 possesses antipyretic properties. To increase solubility, 1-phenyl-3-methylpyrazolone was methylated with CH₃I.

In the course of methylation, the valuable medicinal preparation antipyrine was obtained. Antipyrine can also be prepared from acetoacetic ester and phenylmethylhydrazine, with the elimination of a molecule of water and alcohol, but this method has not found broad technical application. Soviet researchers Klebanskii and Lemke [4] developed a very effective method for obtaining antipyrine by condensation of phenylhydrazine with acetoacetic ester in toluene solution, with a yield of 1-phenyl-3-methylpyrazolone of 95%.

The 1-phenyl-3-methylpyrazolone obtained was methylated to antipyrine. Whereas previous researchers used CH₃Br as the methylating substance, which requires special apparatus, Klebanskii and Lemke used di-

methyl sulfate, which made it possible to increase the yield of antipyrine to 85%, since in the presence of dimethyl sulfate, of the three tautomeric forms in which 1-phenyl-3-methylpyrazolone reacts, form II predominates.

\[ \begin{array}{ccc} \text{I} & \rightleftarrows & \text{II} \rightleftarrows \text{III} \end{array} \]

\[ \begin{array}{c} \text{tautomeric forms of 1-phenyl-3-methylpyrazolone} \end{array} \]

After antipyrine had been obtained, an enormous number of its derivatives were synthesized, many of which are valuable medicinal substances, for example pyramidon, dioxypyramidon [2], and also valuable analytical reagents [1,6] and dyes [7].

Antipyrine derivatives may be divided into several groups.

I. Addition products with antipyrine:

a) substances of acidic character, owing to the basic properties of antipyrine;

b) salts;

c) those formed through cleavage of the double bond between the 3–4 positions.

II. Substitution products: a) owing to the activity of the (4)-hydrogen; b) oxygen in the \( \mathrm{C=O} \) group.

III. Condensation products of antipyrine owing to the activity of the (4)-hydrogen, etc.

The condensation products of antipyrine with salicylic acid—salipyrine, with aspirin—acetosalipyrine, etc., are of great interest.

The aim of the present work was the synthesis of new antipyrine derivatives—products of the condensation of antipyrine with certain oxygen-containing compounds of the aromatic series.

Experimental Part

We synthesized products of the condensation of antipyrine with benzoic acid, sulfosalicylic acid, and ortho- and para-oxybenzaldehydes.

Condensation of Antipyrine with Benzoic Acid

Equimolecular amounts of antipyrine (m.p. 113°) and benzoic acid (m.p. 121°), previously ground and mixed with one another, were fused in a test tube on a water bath. Antipyrine was taken in an amount of 0.2 g, benzoic acid 0.13 g. On heating on the water bath, at a temperature of 75–85° the mixture melted and acquired a yellowish tint, then began to solidify in the air. The benzoic acid did not sublime in this process. The melt was dissolved in a small amount of ether. After seeding and rubbing the walls of the test tube with a glass rod, a white crystalline precipitate separated.

The substance was filtered off and dried in a vacuum desiccator over \( \mathrm{H_2SO_4} \).

Properties of Benzopyrine

The substance has m.p. 65–66°. It is soluble at 17–20° in ether, alcohol, benzene, and in water on heating. Its aqueous solution is po-

shows an acid reaction to litmus. A quantitative determination of nitrogen by Kjeldahl was carried out.

Theoretically calculated: 9.003%.

Found: 8.45%.

We believe that the obtained substance—benzopyrine—is a product of the condensation of antipyrine with benzoic acid, similar to salipyrine.

An attempt made by us to obtain benzopyrine by mixing ethereal solutions of benzoic acid and antipyrine gave no positive results.

Yield: 0.248 g, in %—75.

Table of syntheses of benzopyrine

Condensation of antipyrine with sulfosalicylic acid

Solutions of 0.432 g of antipyrine (2 moles of antipyrine per 1 mole of sulfosalicylic acid) in 1.5 ml of water and 0.252 g of sulfosalicylic acid, m.p. 220°, in 1 ml of water were mixed. An emulsion formed immediately, then an oil separated. The lower oily layer was separated, washed with ether, and dried in a vacuum desiccator. After several days crystallization of the oil began. The crystals had the form of needles with m.p. 98°. The substance is readily soluble in water, alcohol, and ether; in benzene the substance dissolves poorly.

Determination of the molecular weight of the obtained sulfosalipyrine

From literature data it is known that solutions of salipyrine can be titrated, like salicylic acid, with phenolphthalein.

We determined the molecular weight of sulfosalipyrine by titrating it with phenolphthalein.

0.1190 g of substance — 4 ml of 0.103 N NaOH
0.1450 g » — 4.7 » 0.103 N NaOH
0.1600 g » — 5.2 » 0.103 N NaOH.

The molecular weight of sulfosalipyrine was calculated as 594.6. Found: 583.0. \(C_{29}H_{30}N_{4}O_{5}S\).

![structural formula]

The yield of sulfosalipyrine is 70% of theory.

Condensation of antipyrine with salicylaldehyde

1 g of antipyrine was dissolved with heating on a water bath at a temperature of 75–80° in 0.322 g of salicylaldehyde (2 molecules of antipyrine per 1 mole of salicylaldehyde). To the solution 2 ml of HCl of specific gravity 1.18 was added. At this point the liquid acquired a red-orange color. After addition of 10 ml of water the coloration disappeared; a light oil separated from the solution, which crystallized when rubbed with a rod. The substance was filtered off and dried in a vacuum desiccator over sulfuric acid. It should be noted that part of the condensate dissolves in the HCl solution. The melting point of the obtained substance in a sealed capillary is 115–116°. The substance is soluble in alcohol, hydrochloric acid, and concentrated sulfuric acid with an orange-red coloration, which disappears upon dilution. The substance obtained is insoluble in ether and benzene.

Determination of the molecular weight of the obtained dichlorohydrate of 4,4-diantipyryl-o-hydroxyphenylmethane

The dichlorohydrate of 4,4-diantipyryl-o-hydroxyphenylmethane was decomposed in a beaker with hot water, then titrated with NaOH in the presence of phenolphthalein.

Calculated molecular weight — 553.4.
Found ” ” — 556.9.

We believe that we have synthesized the following compound:

![structural formula]

dihydrochloride of 4,4-diantipyril o-hydroxyphenylmethane. The yield of the dihydrochloride was 67% of theory.

Synthesis of the free base of 4,4-diantipyril o-hydroxyphenylmethane

4.02 g of antipyrine were heated until dissolution with 1.294 g of salicylaldehyde. Then 8 ml of HCl, sp. gr. 1.18, were added. The liquid acquired an orange-red color. After addition of 40 ml of water the color disappeared, and the oil that separated crystallized. The crystalline mass obtained was filtered off and hydrolyzed in a beaker of hot water; the solution was then brought to neutral reaction. The white powder of the base obtained was filtered on a suction funnel with a double filter and washed. After drying in a drying oven at a temperature of 110°, the weight of the substance obtained was 4.17 g.

The substance has m.p. 182–183°. It is soluble in HCl and dissolves well in pyridine. It is insoluble in water, alcohol, ether, benzene, and toluene. Nitrogen in 4,4-diantipyril-o-hydroxyphenylmethane was determined by Kjeldahl:

\[ \begin{aligned} &0.1154\ \text{g of substance} \qquad 9.4\ \text{ml }0.0964\ \text{N }H_2SO_4,\\ &0.2302\ \text{g } \qquad\qquad\quad 18.2\ \text{ml }0.0964\ \text{N }H_2SO_4. \end{aligned} \]

Found — 11%; calculated 11.65%.

We believe that we isolated the free base of 4,4-diantipyril-o-hydroxyphenylmethane.

The yield of the free base was 73.5% of theory.

Condensation of antipyrine with para-hydroxybenzaldehyde

2 grams of previously finely ground antipyrine were mixed with finely ground para-hydroxybenzaldehyde (m.p. 116°), 0.644 g. To the mixture was added 3 ml of conc. HCl, sp. gr. 1.17. After addition of HCl, a yellow-orange coloration appeared immediately, which disappeared after the addition of 20 ml of water. An oil separated, which quickly crystallized when rubbed with a glass rod. The precipitate obtained was filtered off and dried in a vacuum desiccator. The melting point of the substance obtained was 186–187°. The substance does not dissolve in benzene or ether; it dissolves on heating in water and alcohol.

Determination of the molecular weight

of the dihydrochloride of 4,4-diantipyril-para-hydroxyphenylmethane

\[ \begin{aligned} &0.1550\ \text{g of substance} \qquad 6.7\ \text{ml }0.084\ \text{N NaOH}\\ &0.1656\ \text{g } \qquad\qquad\quad 7.15\ \text{ml }0.084\ \text{N NaOH} \end{aligned} \]

Calculated molecular weight 553.4.

Found 556.2.

Conclusions

1. A procedure has been developed for the condensation of antipyrine with benzoic acid, sulfosalicylic acid, and ortho- and para-hydroxybenzaldehydes.

2. New products of the condensation of antipyrine with benzoic acid, sulfosalicylic acid, and ortho- and para-hydroxybenzaldehydes have been obtained: benzopyrine, sulfosalipyrine, the hydrochloride of 4,4′-diantipyril-o-hydroxyphenylmethane, the free base of 4,4′-diantipyril-o-hydroxyphenylmethane, and the hydrochloride of 4,4′-diantipyril-p-hydroxyphenylmethane.

Literature

1. Doklady Akademii Nauk SSSR, series LXXIII, No. 6, 1950.
2. ZhOKh, issue 3, 479, 1950.
3. Pavlov. Course of Organic Chemistry, Gostekhkhimizdat, issue 1948.
4. Journal of Applied Chemistry, issue 2, 1935.
5. Ch. Zbl., vol. 4, p. 934, 1935.
6. Scientific Notes of Molotov State University, vol. VI, issue 3, 17—21, 1951.
7. ZhOKh, issue X, p. 172, 1947.
8. Annalen der Chemie, vol. 238, p. 147, 1887.