ACYL DERIVATIVES OF 1-PHENYL-2,3-DIMETHYL-4-HYDROXYACETYLAMINO-5-PYRAZOLONE

E. V. Shmidt, G. M. Stepnova, Z. M. Murav’eva

(Submitted by the scientific-methodological seminar of the Chemical-Technological Faculty)

A structural component of glucocorticoids—cortisone, prednisolone, dexamethasone—which possess strong anti-inflammatory action, is a free or acetylated oxyacetyl group at the 17th carbon atom.

There is evidence that when such a group is introduced into molecules of quinoline and pyrazolone derivatives, their anti-inflammatory properties are enhanced [1, 2, 3].

Among the antipyramidamides of fatty and aromatic acids previously synthesized by us, some showed high anti-inflammatory and antipyretic activity in animal experiments [4—11].

It was of interest to introduce into the oxy group of 4-oxyacetylaminoantipyrine the residues of those acids whose antipyramidamides proved to be the most active.

The synthesis of these compounds of the general formula

\[ \begin{gathered} \text{H}_3\text{C}-\text{C}\;\boxed{\phantom{\rule{1.1em}{2.0em}}}\;\text{C}-\text{NH}-\text{C}-\text{CH}_2-\text{O}-\text{C}-\text{R} \\ \phantom{\text{H}_3\text{C}-\text{C}}\qquad\qquad\quad\;\;\;\;\;\;\;\;\;\;\;\;\;\; \| \qquad\qquad\quad \| \\ \phantom{\text{H}_3\text{C}-\text{C}}\qquad\qquad\quad\;\;\;\;\;\;\;\;\;\;\;\;\;\; \text{O} \qquad\qquad\;\; \text{O} \\ \text{H}_3\text{C}-\text{N}\;\boxed{\phantom{\rule{1.1em}{2.0em}}}\;\text{C}=\text{O} \\ \phantom{\text{H}_3\text{C}-\text{N}}\qquad\;\;\;\;\;\text{N}-\text{C}_6\text{H}_5 \end{gathered} \]
where

\[ \begin{aligned} R &= n-\text{C}_6\text{H}_4-\text{NO}_2 && \text{(II)}\\ &= m-\text{C}_6\text{H}_3-(\text{NO}_2)_2 && \text{(III)}\\ &= (\text{CH}_2)_{16}-\text{CH}_3 && \text{(IV)} \end{aligned} \]

was carried out by the interaction of 4-bromoacetylaminoantipyrine [1] with dry sodium salts of carboxylic acids in absolute alcohol; 4-(4′-aminobenzoyl)-oxyacetylaminoantipyrine [V] was obtained by reduction of the corresponding nitro derivative.

Preliminary pharmacological tests, carried out at the Tomsk Medical Institute by T. P. Pritsep, showed that compounds III and IV cause a significant decrease in capillary permeability in the inflammatory focus.

Experimental Part

1-Phenyl-2,3-dimethyl-4-bromoacetylamino-5-pyrazolone [1]

In a round-bottom flask equipped with a condenser, stirrer, and dropping funnel, 14.0 g of monobromoacetic acid is dissolved in 30 ml of benzene, heated to 50° in an oil bath, 7.0 ml of thionyl chloride is added dropwise, and the mixture is boiled until the evolution of hydrogen chloride and sulfurous gas ceases.

Then a hot solution of 20.3 g of 4-aminoantipyrine in 50 ml of benzene and 11 g of potassium carbonate is added. The mixture is boiled for 2 h; then the benzene is distilled off, the solid reaction mass is treated with water and recrystallized from isopropyl alcohol. The product obtained has a melting point of 189–191°, which is somewhat lower than that described for it in the literature [3].

1-Phenyl-2,3-dimethyl-4-(4′-nitrobenzoyl)-oxyacetylamino-5-pyrazolone [II].

In a round-bottom flask equipped with a reflux condenser and stirrer, 12.0 g of I and 7.0 g of sodium p-nitrobenzoate are placed, 100 ml of absolute alcohol is added, and the mixture is boiled for 15 h with continuous stirring. It is cooled; the solid mass is filtered off, dried, and treated with water on heating, filtered, and washed until bromide ions disappear.

The residue has a melting point of 241–242°; recrystallization from chlorobenzene does not change it. It is a colorless crystalline substance with a greenish tint, insoluble in water, alkali solutions, alcohol, ether, acetone, benzene, and chloroform.

Found, %: C = 58.47; H = 4.26; N = 13.59. C₂₀H₁₈O₆N₄.
Calculated, %: C = 58.33; H = 4.39; N = 13.66.

1-Phenyl-2,3-dimethyl-4-(3′,5′-dinitrobenzoyl)-oxyacetylamino-5-pyrazolone (III).

Obtained analogously to II from 10.0 g of I and 7.2 g of sodium 3,5-dinitrobenzoate.

Recrystallized from chlorobenzene or dioxane. It is a finely crystalline yellow substance with a melting point of 229–230°C. In solubility it is analogous to the preceding compound.

Found, %: C = 52.33; H = 4.10; N = 15.05. C₂₀H₁₇O₈N₅.
Calculated, %: C = 52.74; H = 3.73; N = 15.38.

1-Phenyl-2,3-dimethyl-4-stearoyloxyacetylamino-5-pyrazolone (IV).

Obtained analogously to II from 7.7 g of sodium stearate and 8.1 g of I. The substance is purified by recrystallization from ethanol. It is a colorless, lustrous crystalline powder with a melting point of 102–104°. It is considerably more soluble in organic solvents than the preceding compounds.

Found, %: C = 70.90; H = 9.29; N = 8.44. C₃₁H₄₉O₄N₃.
Calculated, %: C = 70.58; H = 9.30; N = 7.97.

1-Phenyl-2,3-dimethyl-4-(4′-aminobenzoyl)-oxyacetylamino-5-pyrazolone (V). In a round-bottom flask equipped with a stirrer, 70 ml of dilute hydrochloric acid (1 : 1) is placed, and, in portions with vigorous stirring, a finely ground mixture of 5 g of 4-(4′-nitrobenzoyl)-oxyacetylaminoantipyrine and 5 g of zinc dust is introduced.

Gradually the precipitate of the nitro product dissolves. It is filtered off from the residues of zinc dust. The filtrate, containing the hydrochloride salt of the amine, is slowly poured, with stirring, into a saturated aqueous solution of sodium acetate. A cream-colored precipitate separates. Melting point 132–133°. On recrystallization from alcohol and drying at 60–70°, the melting point does not change. On drying at 100° to constant weight, the melting point is 220–221°. A colorless crystalline substance, insoluble in water, soluble in acids and in alcohol on heating.

Found, %: C = 62.85; H = 5.23; N = 14.67. $\mathrm{C}_{20}\mathrm{H}_{20}\mathrm{O}_{4}\mathrm{N}_{4}$.

Calculated, %: C = 63.16; H = 5.26; N = 14.73.

Conclusions

1. Four acyl derivatives of 4-hydroxyacetylaminoantipyrine not described in the literature have been synthesized.

REFERENCES

1. B. Zorn, A. Mankel, Arch. exper. Path. u. Pharmakol., 223, 362 (1954).
2. B. Zorn, F. Schmidt, Arch. exper. Path. u. Pharmakol., 298, 140 (1954).
3. B. Zorn, F. Schmidt, Pharmazie, 12, 7, 396, 1957.
4. L. P. Kulev, G. M. Stepnova, Izv. TPI, 92, 56 (1960).
5. L. P. Kulev, G. M. Stepnova, Ibid., 102, 98 (1959).
6. T. P. Prishchep, Farmak. i toksikologiya, 1, 55 (1962).
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11. G. M. Stepnova, E. V. Shmidt, N. F. Matveeva. Izv. TPI, 151, 76, 1966.