Synthesis of Some Acyl Derivatives of Oxymethyl-(antipyryl-4)-ketone
Abstract Generated abstract
This work reports the synthesis of acyl derivatives of hydroxymethyl-(4-antipyryl) ketone as part of a study on structure and anti-inflammatory properties in substituted pyrazolones. The compounds were designed to combine an antipyrine fragment, an acylated oxyacetyl group related to corticosteroid structures, and acyl residues associated with anti-inflammatory activity. Bromomethyl-(4-antipyryl) ketone was prepared from antipyrine and then reacted with sodium salts of selected carboxylic acids in boiling absolute ethanol to replace bromine with carboxylate residues. Ten crystalline derivatives were obtained and characterized by melting point, empirical formula, nitrogen analysis, and solubility behavior, with nine reported as previously undescribed.
Full Text
SYNTHESIS OF SOME ACYL DERIVATIVES OF HYDROXYMETHYL-(4-ANTIPYRYL) KETONE
E. V. SHMIDT, N. A. NEKRASOVA
(Presented by the Scientific-Methodological Seminar of the Faculty of Chemical Technology)
The present work is a continuation of investigations being carried out at the Faculty of Chemical Technology to reveal the relationship between structure and anti-inflammatory properties in a series of substituted pyrazolones [1–3].
The prerequisite for the synthesis of acyl derivatives of hydroxymethyl-(antipyryl-4)-ketone was the fact that the oxyacetyl group, in free or acetylated form, is an important structural fragment of corticosteroid hormones—substances with powerful anti-inflammatory action. It is known that when this group is introduced into the molecules of simpler organic substances, anti-inflammatory properties appear in them or are enhanced [4, 5].
In the compounds synthesized by us, the acylated oxyacetyl group is located in the molecule of the physiologically active antipyrine, while the acyl groups are acid residues that possess anti-inflammatory properties to one degree or another. The concentration of three active principles in one molecule gives us reason to expect that the acyl derivatives of hydroxymethyl-(antipyryl-4)-ketone will exhibit good anti-inflammatory activity, the difference in which will depend on the nature of the acyl residue.
The acyl derivatives of hydroxymethyl-(antipyryl-4)-ketone were synthesized by the reaction of nucleophilic substitution of bromine in the molecule of bromomethyl-(antipyryl-4)-ketone by the carboxylate residues of the corresponding carboxylic acids [5]. The reaction was carried out in boiling absolute ethanol for 12 hours. Sodium salts of carboxylic acids were used as the nucleophilic reagents.
Bromomethyl-(antipyryl-4)-ketone was obtained by electrophilic substitution of hydrogen in the 4-position of antipyrine by the bromoacetyl group, in 28–30% yield, according to the procedure described for obtaining chloromethyl-(antipyryl-4)-ketone [6].
The acyl derivatives of hydroxymethyl-(antipyryl-4)-ketone are crystalline substances, insoluble in water and ether, soluble on heating in alcohols and aromatic hydrocarbons. Exceptions are the p-nitrobenzoyl and 3,5-dinitrobenzoyl derivatives of hydroxymethyl-(antipyryl-4)-ketone, which are insoluble in alcohols, as well as p-aminobenzoyl-hydroxymethyl-(antipyryl-4)-ketone, which is insoluble in most organic solvents.
The characteristics of the compounds obtained are given in Table 1.
Table 1
| No. | Name | \(T_{\mathrm{m}}\), °C | \(N\), calculated, % | Empirical formula | \(N\), found, % |
|---|---|---|---|---|---|
| 1 | Benzoyloxymethyl-(antipyryl-4)-ketone | 161—162 (toluene) | 8,0 | \(C_{19}H_{18}O_3N_2\) | 8,25 |
| 2 | \(p\)-Nitrobenzoyloxymethyl-(antipyryl-4)-ketone | 226—227 (chlorobenzene) | 10,63 | \(C_{19}H_{17}O_5N_3\) | 10,67 |
| 3 | \(p\)-Oxybenzoyloxymethyl-(antipyryl-4)-ketone | 242—243 (1-propanol) | 7,65 | \(C_{19}H_{18}O_4N_2\) | 7,61 |
| 4 | \(p\)-Bromobenzoyloxymethyl-(antipyryl-4)-ketone | 198—199 (toluene) | 6,52 | \(C_{19}H_{17}O_3N_2Br\) | 6,83 |
| 5 | \(p\)-Toluoyloxymethyl-(antipyryl-4)-ketone | 188—189 (2-propanol) | 7,69 | \(C_{20}H_{20}O_3N_2\) | 7,53 |
| 6 | \(p\)-Methoxybenzoyloxymethyl-(antipyryl-4)-ketone | 178—179 (2-propanol) | 7,36 | \(C_{20}H_{20}O_4N_2\) | 7,70 |
| 7 | \(p\)-Aminobenzoyloxymethyl-(antipyryl-4)-ketone | 268—269 (dimethylformamide) | 11,50 | \(C_{19}H_{19}O_3N_3\) | 11,73 |
| 8 | 3,5-Dinitrobenzoyloxymethyl-(antipyryl-4)-ketone | 236—237 (chlorobenzene) | 12,72 | \(C_{19}H_{16}O_7N_4\) | 12,57 |
| 9* | \(o\)-Oxybenzoyloxymethyl-(antipyryl-4)-ketone | 196—197 (ethanol) | 7,65 | \(C_{19}H_{18}O_4N_2\) | 7,62 |
| 10 | Stearoyloxymethyl-(antipyryl-4)-ketone | 83—84 (ethanol) | 5,46 | \(C_{30}H_{48}O_3N_2\) | 5,88 |
* The compound was described in the literature [5].
Experimental Part
Benzoyloxymethyl-(antipyryl-4)-ketone
Into a round-bottom flask equipped with a stirrer, a reflux condenser with a calcium chloride tube, are charged 8.0 g (0.025 g/mole) of bromomethyl-(antipyryl-4)-ketone, 3.73 g (0.025 g/mole) of sodium benzoate, and 60 ml of absolute ethanol. The mixture is boiled with stirring for 12 h. It is filtered from sodium bromide, and benzoyloxymethyl-(antipyryl-4)-ketone is precipitated from the filtrate with water. The product is purified by recrystallization from toluene.
By an analogous procedure \(p\)-oxybenzoyl-, \(p\)-methoxybenzoyl-, and stearoyloxymethyl-(antipyryl-4)-ketones are obtained. In obtaining the remaining compounds, owing to their lower solubility in ethanol, the method of isolating them from the reaction medium was changed. After 12 h of boiling, the reaction mass is cooled, the precipitate is filtered off and thoroughly washed with hot water until a negative reaction for bromide ions is obtained, and then recrystallized from a suitable solvent.
Conclusions
Ten acyl derivatives of oxymethyl-(antipyryl-4)-ketone have been synthesized, 9 of which have not been described in the literature.
LITERATURE
- G. M. Stepnova, E. V. Shmidt. Zhurn. VKHO im. D. I. Mendeleeva. 10, No. 3, 358 (1965).
- A. S. Saratnikov, G. M. Stepnova, E. V. Shmidt et al. Izv. Sib. otd. AN SSSR. Seriya biol.-med. 12, No. 3, 84 (1965).
- G. M. Stepnova, E. V. Shmidt. Trudy I konfer. Tomskogo otdeleniya VKHO im. D. I. Mendeleeva, Tomsk, 85 (1969).
- B. Zorn, A. Mankel. Arch. exper. Path. und Pharmakol. 223, 362 (1954).
- B. Zorn, F. Schmidt. Arch. exper. Path. und Pharmakol. 298, 140 (1954).
- H. P. Kaufmann. Ber, 75, No. 10, 1237 (1942).