4-Aminotolipyrine—an Intermediate for the Synthesis of Potential Anti-Inflammatory Agents

G. M. Stepnova, P. F. Tabinskaya, I. G. Fedkova

(Presented by the scientific seminar of the Department of Chemical Technology)

Previously we synthesized and studied acyl derivatives of 4-aminoantipyrine and N-alkylaminoantipyrines (1, 2, 3, 4, 5, 6). In pharmacological testing, some of them showed high antipyretic, analgesic, and anti-inflammatory activity. As is known, the introduction of a methyl group into a drug molecule is very often accompanied by a decrease in toxicity and an increase in physiological activity. In view of this, it was of interest to obtain 4-aminotolipyrine and subsequently use it for the synthesis of acyl derivatives with possible anti-inflammatory activity. 4-Aminotolipyrine was obtained by us analogously to 4-aminoantipyrine (7). The proposed procedure is simpler and less laborious than the procedure for obtaining 4-aminotolipyrine described in the literature (8, 9, 10, 11, 12).

Experimental Part

Tolylhydrazine hydrochloride. 54 g of 4-toluidine are dissolved in 100 ml of concentrated hydrochloric acid diluted with an equal volume of water and diazotized with 38 g of sodium nitrite dissolved in 100 ml of water. After completion of diazotization, the diazonium salt solution is added to a solution of a sulfite–bisulfite mixture (120 ml of a 40% sodium bisulfite solution and 200 g of sodium sulfite in 1 l of water) heated to 24°C. Cold reduction is carried out for two hours, and then hot reduction for 1.5 h at 80°C. To the reaction mixture cooled to 50°C, 100 ml of concentrated hydrochloric acid are added, and hydrolysis is carried out under boiling for 1.5 h. The reaction mixture is then heated for another 10–15 min with activated charcoal. It is filtered; upon cooling of the filtrate, colorless crystals precipitate, with mp 195–198°C (with decomp.). Yield 95%.

1-(4′-Tolyl)-3-methyl-5-pyrazolone. 47 g of tolylhydrazine hydrochloride in 400 ml of water are neutralized with 12 g of sodium hydroxide in 50 ml of water with stirring for 30 min at 37°C. 38 ml of acetoacetic ester are added and the mixture is kept for 1 h at the same temperature; it is then heated to 60°C and kept for another 1 h. On cooling, the 4-tolylhydrazone of acetoacetic ester separates; it is filtered off and cyclized in a medium of 10% aqueous sodium bisulfite solution (300 ml) for 1 h under boiling.

tion. The product is washed with ether. Almost colorless crystals, mp 140–141°C. Yield 70%.

Tolipyrine benzenesulfonate. 30 g of 1-(4′-tolyl)-3-methyl-5-pyrazolone is heated to 160°C in an oil bath in a round-bottomed flask with a stirrer. 30 ml of methyl benzenesulfonate is added and the mixture is kept for 45 min. The reaction mixture is cooled to 100°C and poured into 100 ml of water. The white crystalline powder is filtered off and washed with water. Yield 72%. Mp 136–137°C.

Nitrosotolipyrine. 50 g of benzenesulfonic acid tolipyrine is suspended in water at 0°C; with stirring, 9 g of sodium nitrite in 100 ml of water is added dropwise over two hours. The crystalline emerald-green product is filtered off. Yield 96%. Mp 220°C (decomp.).

4-Aminotolipyrine hydrochloride. 21 g of 4-nitrosotolipyrine is dissolved in 70 ml of glacial acetic acid and 100 ml of ethyl alcohol, and 130 ml of water is added. With stirring, zinc dust is introduced in small portions until the solution becomes pale yellow. The reaction mixture is filtered into a solution of 11 g of benzaldehyde and 20 ml of ethyl alcohol, cooled with ice; the precipitate that separates is filtered off, washed with alcohol and hot water, and then shaken in a separatory funnel with a mixture of benzene and hydrochloric acid. From the hydrochloric acid layer, the remaining benzaldehyde is distilled off with steam, and then the solution is evaporated to dryness on a water bath. 4-Aminotolipyrine hydrochloride is recrystallized from dry benzene and absolute alcohol (10:1). Slightly cream-colored crystals, mp 235–236°C. Yield 95%.

Conclusions

A method has been developed for the synthesis of 4-aminotolipyrine, an intermediate for the synthesis of potential anti-inflammatory agents.

References

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2. L. P. Kulev, G. M. Stepnova. Synthesis and study of acyl derivatives of a series of pyrazolone compounds. Izv. SO AN SSSR, No. 5, 73 (1960).

3. L. M. Semikolennyi, A. B. Solov’eva, G. M. Stepnova, V. Kh. Taksidi, E. V. Shmidt. Development of a method for obtaining 4-(4-aminobenzoyl)-aminoantipyrine. Zhurn. VKHO im. D. I. Mendeleeva, 7, no. 6, 704 (1963).

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