Synthesis and Study of Antipyrilamides of Fatty and Halogen-Substituted Fatty Acids
Abstract Generated abstract
A series of antipyrilamides of lower fatty and halogen-substituted fatty acids was prepared to examine relationships among acyl structure, solubility, and possible physiological activity. The compounds were synthesized mainly by acylating 4-aminoantipyrine with free acids in benzene in the presence of phosphorus trichloride, and their melting points, elemental analyses, and solubilities in water, benzene, and carbon tetrachloride were determined. Twelve antipyrilamides were obtained, seven reportedly new, with technical yields around 90 percent. The study found that increasing hydrocarbon chain length or halogen substitution decreased water solubility and increased lipid-solubility coefficients, supporting the authors’ suggestion that lipid solubility may contribute to activity trends in this compound series.
Full Text
SYNTHESIS AND STUDY OF ANTIPYRYLAMIDES OF FATTY AND HALOGEN-SUBSTITUTED FATTY ACIDS
E. V. Shmidt, G. M. Stepnova, S. G. Medvedeva
(Presented by the scientific seminar of the departments and laboratories of organic synthesis, KhTI)
Several antipyrylamides of lower fatty and halogen-substituted fatty acids have been described in the literature [1, 2, 3, 4]. Antipyrylamide of isovaleric acid was at one time used in Germany as a low-toxicity antifever agent [3].
Comparative pharmacological tests of some of these compounds showed that, as the hydrocarbon chain of the acyl residue increases, their anti-inflammatory, antipyretic, and analgesic activity increases [5].
In order to further study the relationship between structure, properties, and physiological activity, and to identify potential anti-inflammatory agents, new representatives of this series of compounds of the general formula were synthesized:
\[ \begin{array}{c} \text{[[structural formula of an antipyrine ring bearing } \mathrm{-NH-C(=O)-R} \text{]]} \end{array} \qquad \begin{array}{l} \text{where } R = \\[2pt] \mathrm{C_4H_9;\ C_5H_{11};\ C_6H_{13};} \\[2pt] \mathrm{C_9H_{19};\ C_{15}H_{31};} \\[2pt] \mathrm{CHCl_2;\ CCl_3,} \end{array} \]
Antipyrylamides were obtained by the acylation reaction of 4-aminoantipyrine with free fatty and halogen-substituted fatty acids in an inert solvent medium in the presence of phosphorus trichloride.
By the same method, the antipyrylamides of monochloroacetic, propionic, butyric, and isovaleric acids described in the literature were obtained.
Antipyrylamide of acetic acid was obtained by acetylating 4-aminoantipyrine with acetyl chloride in benzene solution in the presence of a concentrated solution of potassium carbonate.
The compounds obtained are colorless crystalline substances, readily soluble in alcohols and insoluble in ether and heptane.
Their characteristics are given in Table 1.
The solubility of medicinal substances in water, fats, and lipids of the organism plays a major role in their fate in the organism. Lipid solubility is customarily characterized by the distribution coefficient of medicinal substances between organic solvents immiscible with water and water.
Table 1
| No. | \(R\) | m.p., °C | Gross formula | %N found | %N calculated | %C found | %C calculated | %H found | %H calculated |
|---|---|---|---|---|---|---|---|---|---|
| 1 | *) \(\mathrm{CH_3}\) | 198–200 | \(\mathrm{C_{13}H_{15}O_2N_3}\) | 16.87 | 17.14 | ||||
| 2 | \(\mathrm{C_4H_9}\) | 174–175 | \(\mathrm{C_{16}H_{21}O_2N_3}\) | 14.63 | 14.97 | 67.03 | 66.55 | 7.35 | 7.31 |
| 3 | \(\mathrm{C_5H_{11}}\) | 175–176 | \(\mathrm{C_{17}H_{23}O_2N_3}\) | 13.94 | 13.95 | 68.16 | 67.77 | 7.79 | 7.64 |
| 4 | \(\mathrm{C_6H_{13}}\) | 175 | \(\mathrm{C_{18}H_{25}O_2N_3}\) | 13.81 | 13.33 | 68.97 | 68.54 | 7.83 | 7.94 |
| 5 | \(\mathrm{C_9H_{19}}\) | 159–160 | \(\mathrm{C_{21}H_{31}O_2N_3}\) | 11.70 | 11.76 | 71.19 | 70.51 | 8.79 | 8.67 |
| 6 | \(\mathrm{C_{15}H_{31}}\) | 140–141 | \(\mathrm{C_{27}H_{43}O_2N_3}\) | 9.46 | 9.14 | 73.80 | 73.46 | 9.65 | 9.75 |
| 7 | *) \(\mathrm{CH_2Cl}\) | 188–190 | \(\mathrm{C_{13}H_{14}O_2N_3Cl}\) | 15.45 | 15.02 | ||||
| 8 | \(\mathrm{CHCl_2}\) | 239 | \(\mathrm{C_{13}H_{13}O_2N_3Cl_2}\) | 13.35 | 13.37 | 49.30 | 49.68 | 4.26 | 4.14 |
| 9 | \(\mathrm{CCl_3}\) | 230–231 | \(\mathrm{C_{13}H_{12}O_2N_3Cl_3}\) | 12.20 | 12.05 | 44.30 | 44.70 | 3.58 | 3.44 |
* Preparations described in the literature [1, 2].
In order to elucidate the relationship between the physiological activity of the synthesized antipyrilamides of fatty and halogen-substituted fatty acids and their solubility, their solubility was determined in water, benzene, and carbon tetrachloride at 19–20°C.
Table 2
| No. | \(R\) | Solubility in g/100 ml solution at 19–20°C: water | Solubility in g/100 ml solution at 19–20°C: benzene | Solubility in g/100 ml solution at 19–20°C: \(\mathrm{CCl_4}\) | \(K\), benzene/water | \(K\), \(\mathrm{CCl_4}\)/water | Activity: anti-inflammatory | Activity: antipyretic | Activity: analgesic |
|---|---|---|---|---|---|---|---|---|---|
| 1 | \(\mathrm{CH_3}\) | 10.8 | 0.082 | 0.012 | 0.007 | 0.0011 | |||
| 2 | \(\mathrm{C_2H_5}\) | 3.15 | 0.126 | 0.02 | 0.04 | 0.0063 | 0.66 | 1.12 | 0.47 |
| 3 | \(\mathrm{C_3H_7}\) | 1.60 | 0.267 | 0.05 | 0.17 | 0.03 | 0.82 | 0.96 | 0.60 |
| 4 | \(\mathrm{C_4H_9}\) | 0.97 | 0.258 | 0.206 | 0.269 | 0.216 | |||
| 5 | iso-\(\mathrm{C_4H_9}\) | 1.00 | 0.622 | 0.622 | 1.1 | 0.96 | 0.80 | ||
| 6 | \(\mathrm{C_5H_{11}}\) | 0.30 | 2.50 | 0.268 | 8.50 | 0.90 | |||
| 7 | \(\mathrm{C_6H_{13}}\) | 0.112 | 4.76 | 0.214 | 42.50 | 1.9 | |||
| 8 | \(\mathrm{C_9H_{19}}\) | 0.0035 | 5.83 | 1.57 | 16.70 | 450 | |||
| 9 | \(\mathrm{CH_2Cl}\) | 0.84 | 0.08 | 0.095 | |||||
| 10 | \(\mathrm{CHCl_2}\) | 0.029 | 0.031 | 1.09 | |||||
| 11 | \(\mathrm{CCl_3}\) | 0.0084 | 0.039 | 4.64 |
Note: Anti-inflammatory activity is given relative to the anti-inflammatory activity of butadione, taken as unity; analgesic activity is relative to that of antipyrine. Antipyretic activity indicates the excess over the normal temperature of a febrile rabbit one hour after administration of the preparation. \(K\) is the coefficient characterizing lipid solubility.
The determination of solubility was carried out by the Meyer method [6].
The lipid solubility of the compounds obtained was characterized by the ratio of the solubilities of the compounds in organic solvents to their solubilities in water at the same temperature.
The results of these determinations are given in Table 2.
As can be seen from Table 2, with an increase in the length of the hydrocarbon radical in the acyl residue, solubility in water decreases, while solubility in organic solvents and lipid solubility increase.
With an increase in the number of halogens in the acetyl radical, solubility in water decreases, while lipid solubility increases.
Since, with growth of the hydrocarbon chain of the acyl radical, physiological activity also increases at the same time, it may be assumed that lipid solubility plays a certain role in the behavior of this group of substances in the living organism.
Experimental Part
Antipyrilamides of Fatty and Halogen-Substituted Fatty Acids
1. In a round-bottom flask equipped with a reflux condenser, stirrer, and dropping funnel, equimolecular amounts of 4-aminoantipyrine and the fatty acid are placed; a fivefold amount of anhydrous benzene is added, and the mixture is heated on an oil bath. To this solution at 60–70° over 15 minutes, a solution of 1/3 gram-mole of phosphorus trichloride in a small volume of benzene is added dropwise. In this process the formation of a cream-colored precipitate is observed, which after 15–20 minutes dissolves completely, and the reaction proceeds in a homogeneous medium. The reaction is carried out at the temperature of boiling benzene for 2–3 hours. During the entire process, hydrogen chloride is vigorously evolved. After cooling, the benzene solution is treated with a 10% solution of soda. The reaction product precipitates. It is filtered off, washed with water, dried, and recrystallized 2–3 times from ethanol or isopropyl alcohol.
The yields of technical antipyrilamides are 90–93%.
When 4-aminoantipyrine is acylated with halogen-substituted fatty acids, before the addition of phosphorus trichloride an exothermic interaction of 4-aminoantipyrine with these acids takes place, with formation of salts.
In the case of acylation of 4-aminoantipyrine with trichloroacetic acid, the suspension of 4-aminoantipyrine trichloroacetate, insoluble in benzene, is acylated. Its conversion into the antipyrilamide occurs with vigorous evolution of hydrogen chloride.
After completion of the acylation reaction, the antipyrilamides of the higher fatty acids precipitate upon cooling of the benzene solution. They are filtered off from the benzene solution, dried, treated successively with a 10% solution of soda and hot water, and recrystallized from ethanol.
Antipyrilamide of Acetic Acid
II. 0.1 gram-mole of 4-aminoantipyrine is dissolved in 75 ml of benzene; a solution of 14 g of potash in 15 ml of water is added, and, with stirring, a solution of 0.1 gram-mole of acetyl chloride in benzene is added dropwise.
In this process, strong heating is observed, with evolution of carbon dioxide gas and precipitation of acetic acid antipyrilamide in the form of a cream-colored precipitate.
color. The mixture is heated for 10–15 minutes in a hot water bath, cooled, and 10 ml of water is added to dissolve the potassium chloride. It is filtered, washed with ether, and dried. Recrystallized from ethanol.
The yield of the technical product is 90%.
Conclusions
- Twelve antipyrilamides of fatty and halogen-substituted fatty acids were synthesized, 7 of which have not been described in the literature.
- The solubility of these compounds in water and in several organic solvents immiscible with water was determined.
- It has been suggested that the physiological activity in this series of compounds is associated with their lipid solubility.
Literature
- Z. Knorr, F. Stolz. A. 293, 58, 1896.
- Knoll. C., 1346, 1910 II.
- B. Zorn, F. Schmidt. Pharmazie, 7, 12, 396, 1957.
- L. P. Kulev, G. M. Stepnova. Izv. Sib. Otd. AN SSSR, No. 5, 73, 1960.
- T. P. Prishchep. Pharmacology and Toxicology, 1, 55, 1962.
- K. N. Meyer, H. Hemmi. Biochemische Zeitschrift, 277, 1–2, 40, 1935.