Study of the Acylation of 4-Alkylaminoantipyrine
Abstract Generated abstract
This study examines improved conditions for acylating 4-alkylaminoantipyrines, compounds of interest because some acyl derivatives show anti-inflammatory and antipyretic activity. Using the formation of 4-(4′-nitrobenzoyl)-methylaminoantipyrine from 4-methylaminoantipyrine and p-nitrobenzoyl chloride as a model, the authors varied solvent, temperature, acid chloride amount, and alkaline agent in a two-phase organic and aqueous alkaline system. The results indicate that near-quantitative yields can be obtained without absolute solvents or anhydrous reagents, with benzene giving the purest product and a molar amount of acid chloride sufficient. Under optimized conditions the target compound was isolated in about 96 to 97% yield, and the method was reported to give acyl derivatives of 4-methylaminoantipyrine and 4-ethylaminoantipyrine in yields above 90%.
Full Text
STUDY OF THE ACYLATION OF 4-ALKYLAMINOANTIPYRINE
L. A. SHABROVA, G. M. STEPANOVA, V. I. KOVALEVA
(Submitted by the scientific-methodological seminar of the Faculty of Chemical Technology)
Acyl derivatives of 4-alkylaminoantipyrine are of great interest, since some of them possess high physiological activity [1, 2, 3]. We have obtained a series of acyl derivatives of 4-methyl-[4] and 4-ethylaminoantipyrine.
Pharmacological tests showed that they exhibit anti-inflammatory and antipyretic action.
The literature describes the acylation of 4-alkylaminoantipyrine with acids and their acid halides, anhydrides, and esters. Acylation with acids is carried out in the presence of the dehydrating agent $P_2O_5$ [5], and with acid halides in an excess of the starting alkylaminoantipyrine [6] or with the use of organic and inorganic bases [1, 2, 3].
In all methods described in the literature, absolute solvents and anhydrous reagents are used. The yield of acyl derivatives in this case does not exceed 30–60%.
The aim of the present work was to study the conditions under which a high yield of acyl derivatives of 4-alkylaminoantipyrine is achieved, using 4-(4′-nitrobenzoyl)-methylaminoantipyrine as an example.
The acylation of 4-methylaminoantipyrine was carried out with p-nitrobenzoyl chloride in an organic solvent in the presence of an aqueous solution of an alkaline agent. The influence on the yield of 4-(4′-nitrobenzoyl)-methylaminoantipyrine of the reaction temperature, the solvent, the amount of p-nitrobenzoyl chloride, and the nature and amount of the alkaline agent was studied.
The results of the experiments are given in Table 1.
The experimental results show that the reaction proceeds almost with quantitative yield in the given solvents, but it should be noted that the purest product is obtained when acylation is carried out in benzene. To achieve a high yield, a molar amount of p-nitrobenzoyl chloride is sufficient; the amount of potash in this case may be reduced to 0.6–0.7 mole. The use of a 14% solution of soda as the alkaline agent almost does not reduce the yield of the product. The reaction temperature has little effect on the yield of the acyl derivative, since under these conditions the acid chloride evidently does not have time to undergo saponification. The starting 4-methylaminoantipyrine was purified by washing an acidic solution with chloroform, followed by precipitation with alkali.
Table 1
| No. | Amount of 4-methylaminoantipyrine, g | Amount of acid chloride, g | Amount of acid chloride, mol | Solvent | Alkaline agent | Amount of alkaline agent, g | Amount of alkaline agent, mol | Reaction temperature | Yield of reaction product, g | Yield of reaction product, % | Melting point of reaction product, °C |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 10 | 4,25 | 0,5 | benzene | — | — | — | 40 | 11,73 | 46,4 | 152–154 |
| 2 | 10 | 8,07 | 0,95 | chloroform | K₂CO₃ | 6,4 | 1 | 40 | 15,39 | 90,4 | 137–142 |
| 3 | 10 | 8,5 | 1 | chloroform | K₂CO₃ | 6,4 | 1 | 40 | 16,20 | 96 | 137–142 |
| 4 | 10 | 8,92 | 1,05 | —″— | K₂CO₃ | 6,4 | 1 | 40 | 16,01 | 94,5 | 139–142 |
| 5 | 10 | 9,35 | 1,1 | —″— | K₂CO₃ | 6,4 | 1 | 40 | 16,2 | 96 | 137–142 |
| 6 | 10 | 8,5 | 1 | —″— | K₂CO₃ | 6,4 | 1 | 20 | 16,34 | 96,6 | 137–142 |
| 7 | 10 | 8,5 | 1 | —″— | K₂CO₃ | 6,4 | 1 | 30 | 16,12 | 95,7 | 137–142 |
| 8 | 10 | 8,5 | 1 | —″— | K₂CO₃ | 6,4 | 1 | 50 | 16,00 | 95,0 | 137–142 |
| 9 | 10 | 8,5 | 1 | —″— | K₂CO₃ | 6,4 | 1 | 60 | 16,03 | 95,2 | 137–142 |
| 10 | 10 | 8,5 | 1 | benzene | K₂CO₃ | 6,4 | 1 | 40 | 16,43 | 97,5 | 154–155 |
| 11 | 10 | 8,5 | 1 | CCl₄ | K₂CO₃ | 6,4 | 1 | 40 | 16,60 | 98,0 | 150–152 |
| 12 | 10 | 8,5 | 1 | benzene | K₂CO₃ | 5,75 | 0,9 | 40 | 15,35 | 91,1 | 153 |
| 13 | 10 | 8,5 | 1 | benzene | K₂CO₃ | 5,12 | 0,8 | 40 | 15,88 | 94,1 | 153 |
| 14 | 10 | 8,5 | 1 | benzene | K₂CO₃ | 4,48 | 0,7 | 40 | 16,1 | 95,5 | 153 |
| 15 | 10 | 8,5 | 1 | benzene | K₂CO₃ | 3,82 | 0,6 | 40 | 16,18 | 96 | 153 |
| 16 | 10 | 8,5 | 1 | —″— | K₂CO₃ | 3,20 | 0,5 | 40 | 16,46 | 97,7 | 151–152 |
| 17 | 10 | 8,5 | 1 | —″— | Na₂CO₃ | 4,88 | 1 | 40 | 15,62 | 93 | 153 |
| 18 | 10 | 8,5 | 1 | benzene | NaOH | 1,84 | 1 | 40 | 16,10 | 95,5 | 154 |
Experimental Part
Starting reagents. 4-Methylaminoantipyrine is a by-product in the manufacture of analgin. It is obtained as a brown oil that crystallizes on standing; on storage it is rapidly oxidized. To obtain pure 4-methylaminoantipyrine, we proposed the following method for purifying the technical product.
100 g of technical 4-methylaminoantipyrine was dissolved in 125 ml of water with gradual addition of hydrochloric acid to pH 3.5–4. The resulting solution of methylaminoantipyrine hydrochloride was shaken in a separatory funnel with 75 ml of chloroform (2–3 times), the chloroform was separated, and 4-methylaminoantipyrine was carefully precipitated from the hydrochloric acid solution with caustic potash (to pH 7). The 4-methylaminoantipyrine was obtained as colorless crystals with a melting point of 80–81°C; the yield was 95% of the amount present in the starting product. According to the literature, 4-methylaminoantipyrine melts at 61–63°C [7].
p-Nitrobenzoyl chloride, potash, soda, and solvents were of “pure” grade.
4-(4′-Nitrobenzoyl)-methylaminoantipyrine. Into a flask equipped with a reflux condenser, dropping funnel, thermometer, and stirrer was placed a solution of 10 g of 4-methylaminoantipyrine in 20 ml of benzene and 6 ml of a 50% solution of potash. From the dropping funnel, over 10 minutes, a solution of 8.5 g of p-nitrobenzoyl chloride in 20 ml of benzene was added. The temperature of the reaction mixture rose spontaneously to 40°C. At this temperature the mixture was allowed to stand for 15 min; then 20 ml of water was added to the flask, the benzene layer was separated, and on cooling 16.4 g of 4-(4′-nitrobenzoyl)-methylaminoantipyrine precipitated from it (97% of theory), with m.p. 155–156°C. After recrystallization from benzene or from glacial acetic acid, m.p. 156°C.
Conclusions
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The influence of the reaction conditions on the yield of 4-(4′-nitrobenzoyl)-methylaminoantipyrine was investigated.
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It was shown that, under optimal conditions, 4-(4′-nitrobenzoyl)-methylaminoantipyrine can be obtained in 96–97% yield of theory.
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By the developed method, acyl derivatives of 4-methyl(ethyl)aminoantipyrine can be obtained in yields above 90%.
REFERENCES
- GDR Patent 8453, 5.11.54.
- Japanese Patent 2318, 11.4.59.
- FRG Patent 897407, 19.11.53.
- L. A. Shabrova, G. M. Stepnova. Zhurn. VKhO, 9(2), 240, (1964).
- J. Pharmac. Soc. Japan., 76, 10, 1180–1186, (1956).
- Japanese Patent 6296, 4.02.54.
- A. Skita, F. Keil und W. Stuhmer. Berichte, 75, 1646, (1942).