Synthesis of N-Alkylantipyrylamides of Toluic and Hydroxybenzoic Acids
Abstract Generated abstract
This paper reports the synthesis of five previously undescribed N-methylantipyrylamides derived from toluic and hydroxybenzoic acids as part of a continuing investigation of substituent effects on the pharmacological activity of substituted benzoic acid antipyrylamides. Toluic acid derivatives were prepared by acylating 4-methylaminoantipyrine with the corresponding toluic acid chlorides in benzene in the presence of aqueous potassium hydroxide, while hydroxybenzoic acid derivatives were obtained via acetoxybenzoyl chlorides followed by saponification. The products were purified by recrystallization and characterized by melting points, yields, and elemental analysis. The work expands a series of compounds considered of interest for potential anti-inflammatory, antipyretic, and analgesic activity.
Full Text
SYNTHESIS OF N-ALKYLANTIPYRYLAMIDES OF TOLUIC AND HYDROXYBENZOIC ACIDS
G. M. STEPNOVA, L. A. SHABROVA, N. S. POCHEKUNINA
(Presented by the scientific-methodological seminar of the Faculty of Chemical Technology)
We have previously obtained a series of N-alkylantipyrylamides of substituted benzoic acids [1, 2]. The substituents in these compounds were Cl, Br, NH₂, NO₂, NHCOCH₃ in the o-, m-, and p-positions, and OH and OCOCH₃ in the ortho position of the benzene ring.
Physiological tests carried out at the Tomsk Medical Institute under the direction of Professor A. S. Saratnikov, at the Novokuznetsk Scientific Research Chemical-Pharmaceutical Institute under the direction of Candidate of Medical Sciences A. P. Gilev, and at the Institute of Pharmacology and Chemotherapy of the Academy of Medical Sciences of the USSR under the direction of Candidate of Medical Sciences M. Yu. Ladinskaya showed that the synthesized compounds exhibit anti-inflammatory, antipyretic, and analgesic activity, and made it possible to draw several interesting conclusions concerning the relationship between pharmacological activity and the structure of this series of compounds [3].
Thus, the tests showed that the nature and position of the substituent in the acid nucleus have a major influence on anti-inflammatory and antipyretic activity.
In this connection, we continued our investigations into the influence of various substituents on physiological activity. The task was set to synthesize methylantipyrylamides of other hydroxybenzoic and toluic acids.
There are indications in the literature that hydroxybenzoic and toluic acids themselves possess anti-inflammatory action [4, 5].
N-Methylantipyrylamides of toluic acids were synthesized by us according to a previously developed procedure [6], by acylation of 4-methylaminoantipyrine with the acid chlorides of toluic acids in benzene medium in the presence of an aqueous potassium hydroxide solution. They were purified by recrystallization from alcohol, benzene, or their mixture.
Toluic acids were obtained by oxidation of the corresponding xylenes with dilute nitric acid according to a known procedure [7, 8]. The acid chlorides of toluic acids were obtained by reaction of the acids with thionyl chloride by the described method [9]. They were purified by distillation under vacuum.
An attempt to obtain the acid chlorides of m- and p-hydroxybenzoic acids by ordinary methods did not lead to the desired result. Therefore, we obtained the acid chlorides of acetoxybenzoic acids, used them to acylate 4-methylaminoantipyrine, and then saponified the acetyl group to the hydroxyl group without isolating the acetoxybenzoyl derivatives of 4-methylaminoantipyrine. The acetoxybenzoic acids were obtained by acetylation
oxybenzoic acids with acetic anhydride according to a known procedure. 4-Methylaminoantipyrine was used purified according to the procedure proposed by us earlier [2].
Experimental Part
4-(4′-Hydroxybenzoyl)-methylaminoantipyrine. Into a two-necked flask equipped with a stirrer are placed 10 g of acid chloride, 20 ml of benzene, and 11 g of 4-methylaminoantipyrine in 20 ml of benzene; then a 50% aqueous solution of potash is slowly added in portions, the mixture is heated to boiling, and the aqueous-organic layer is decanted from the viscous mass. After treatment of the viscous mass with aqueous alcohol with heating, colorless crystals of 4-(4-hydroxybenzoyl)-methylaminoantipyrine are obtained, m.p. 230–231°C, yield 52%. % C_calc 68.22, % C_found 67.7, % H_calc 5.7, % H_found 5.94, % N_calc 12.44, % N_found 12.04.
4-(3′-Hydroxybenzoyl)-methylaminoantipyrine. The synthesis is carried out analogously from 13.4 g of 4-methylaminoantipyrine, 12.25 g of acid chloride, and 6.45 g of potash. After completion of the reaction two layers are obtained—aqueous and benzene. The benzene layer is separated in a separatory funnel. After removal of the benzene from it, an oil is obtained, which is treated with an aqueous-alcoholic solution of alkali. The precipitated crystals are filtered off and dried.
M.p. 190–200°C. After recrystallization from aqueous alcohol—colorless crystals with m.p. 212–213°C. Yield 54%, % C_calc 67.7, % C_found 67.37, % H_calc 5.7, % H_found 5.8, % N_calc 12.44, % N_found 12.55.
4-(2′-Toluyl)-methylaminoantipyrine
Obtained analogously from 10 g of 4-methylaminoantipyrine, 7 g of acid chloride, and 5.2 g of potash. From the benzene layer an oil is formed, which is treated with a weak HCl solution, after which the pH (of the benzene layer) is brought to 7 with a soda solution. The precipitated crystals are filtered off and dried. M.p. 73–74°. Yield 7.88 g, 51.2%. Upon recrystallization from alcohol, colorless crystals are obtained, readily soluble in benzene, with m.p. 102–103°C. % C_calc 71.64, % C_found 72.03, % H_calc 6.27, % H_found 6.38.
4-(3′-Toluyl)-methylaminoantipyrine
The reaction is carried out analogously. Yield 78.8%. After recrystallization from benzene, m.p. 150–151°C. % C_calc 71.64, % C_found 71.93, % H_calc 6.27, % H_found 6.51.
4-(4-Toluyl)-methylaminoantipyrine
The reaction is carried out analogously. Yield 73%; recrystallized from benzene (1:10). M.p. 165–166°C. % C_calc = 71.64; % H_calc = 6.27; % N_calc = 12.54; % C_found = 71.34; % H_found = 6.28; % N_found = 12.94.
Conclusions
Five alkylantipyrilamides not described in the literature, with potential anti-inflammatory activity, have been synthesized.
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