Synthesis of N-Propylantipyrilamides
Abstract Generated abstract
This paper reports the synthesis of acyl derivatives of 4-propylaminoantipyrine as potential antiphlogistic agents and as analogues of previously studied methyl and ethyl aminoantipyrine derivatives. 4-Propylaminoantipyrine was prepared by catalytic hydrogenation of the Schiff base from aminoantipyrine and propionaldehyde using Raney nickel, then acylated with substituted benzoyl chlorides in benzene in the presence of aqueous potassium hydroxide. Nine previously undescribed N-propylantipyrilamides were obtained, including nitro, chloro, hydroxy, and amino benzoyl derivatives, with melting points, yields, empirical formulas, and nitrogen analyses reported. Aminoacyl derivatives were prepared by zinc and hydrochloric acid reduction of the corresponding nitro compounds, providing materials for further evaluation of how the propyl substituent affects physiological activity.
Full Text
SYNTHESIS OF N-PROPYLANTIPYRILAMIDES
L. A. SHABROVA, G. M. STEPENOVA
(Presented by the scientific seminar of the departments and laboratories of organic synthesis of the CTF)
In order to search for new antiphlogistic agents, earlier [1, 2] we obtained acyl derivatives of 4-methyl- and 4-ethylaminoantipyrine. Physiological tests of the synthesized compounds, carried out at the Tomsk Medical Institute under the direction of Professor A. S. Saratikov and at the Novokuznetsk NIKhFI under the direction of Candidate of Medical Sciences A. P. Gilev, showed that the substances exhibit anti-inflammatory, antipyretic, and analgesic activity, with some of them surpassing amidopyrine and butadione in activity.
It was of interest to obtain and study, as antiphlogistic agents, acyl derivatives of 4-propylaminoantipyrine in order to clarify the influence of the nature of the alkyl group on physiological activity. We obtained 9 derivatives of 4-propylaminoantipyrine not described in the literature—
Table 1
| Chemical name | m.p., °C | Yield, % | Empirical formula | Found, % \(N\) | Calculated, % \(N\) |
|---|---|---|---|---|---|
| 4-benzoylpropylaminoantipyrine | 162 | 86.0 | \(C_{19}H_{23}N_3O_2\) | 12.14 | 12.03 |
| 4-(4′-nitrobenzoyl)-propylaminoantipyrine | 145 | 76.6 | \(C_{21}H_{22}N_4O_4\) | 14.12 | 14.21 |
| 4-(3′-nitrobenzoyl)-propylaminoantipyrine | 151 | 90.0 | \(C_{21}H_{22}N_4O_4\) | 14.17 | 14.21 |
| 4-(2′-nitrobenzoyl)-propylaminoantipyrine | 123 | 71.0 | \(C_{21}H_{22}N_4O_4\) | 14.57 | 14.21 |
| 4-(4′-chlorobenzoyl)-propylaminoantipyrine | 150 | 80.0 | \(C_{21}H_{22}N_3O_2Cl\) | 10.81 | 10.95 |
| 4-(2′-oxybenzoyl)-propylaminoantipyrine | 140 | 80.0 | \(C_{21}H_{23}N_3O_3\) | 11.55 | 11.54 |
| 4-(4′-aminobenzoyl)-propylaminoantipyrine | 228 | 86.0 | \(C_{21}H_{24}N_4O_2\) | 15.65 | 15.38 |
| 4-(3′-aminobenzoyl)-propylaminoantipyrine | 167 | 82.0 | \(C_{21}H_{24}N_4O_2\) | 15.68 | 15.38 |
| 4-(2′-aminobenzoyl)-propylaminoantipyrine | 181 | 81.0 | \(C_{21}H_{24}N_4O_2\) | 15.45 | 15.38 |
pyrine acylated with substituted benzoic acids. Acylation was carried out in benzene with the acid chlorides of the acids in the presence of an aqueous potassium hydroxide solution. The N-propylantipyrilamides were isolated from the benzene solution after cooling and purified by recrystallization from alcohol or benzene to a constant melting point. Aminoacyl derivatives of 4-propylaminoantipyrine were obtained by reducing the nitroacyl derivatives with zinc dust in dilute hydrochloric acid. Isolation from the hydrochloric acid solution was carried out with sodium acetate or bicarbonate, after which the products were recrystallized from alcohol or water.
The characteristics of the obtained N-propylantipyrilamides are given in Table 1. 4-Propylaminoantipyrine was obtained by us by catalytic reduction of the Schiff base of aminoantipyrine with propionaldehyde by the method proposed by Skita and Keil [3]. Raney Ni was used by us as the hydrogenation catalyst. Propionaldehyde was synthesized by oxidation of propyl alcohol according to the known procedure [4].
Experimental Part
Synthesis of 4-propylaminoantipyrine. 40 g of 4-aminoantipyrine and 12 g of propionaldehyde are dissolved in 350 ml of 80% ethyl alcohol; the solution is placed in a rotating autoclave with a capacity of 0.5 l, and 20 g of catalyst (Raney Ni) is introduced. Hydrogenation is carried out at room temperature at an initial pressure of 25 atm. After 1.5 h the hydrogenation is stopped, the pressure having fallen to 10–12 atm. After completion of the hydrogenation, the catalyst is filtered off and the alcohol is distilled off. The residue after removal of the alcohol is acidified to pH 4–4.5, and 10 ml of benzaldehyde is added. The resulting benzylidene base of unreacted 4-aminoantipyrine is filtered off, and from the filtrate, after removal of excess benzaldehyde, 4-propylaminoantipyrine is liberated with alkali as an oil, which rapidly crystallizes. Yield 39 g, 90%. The content of pure 4-propylaminoantipyrine in this product is 84%. Melting point 63–65°C. The obtained 4-propylaminoantipyrine was used for acylation without further purification.
Acylation of 4-propylaminoantipyrine. Into a three-necked flask equipped with a stirrer, a dropping funnel, and a reflux condenser are placed a solution of 0.1 M propylaminoantipyrine in 50 ml of benzene, and, with stirring, a solution of 0.1 M of the corresponding acid chloride in 50 ml of benzene is added. The reaction mixture thereby warms slightly, and its color becomes red. Then, from the dropping funnel, with vigorous stirring, 0.1 M of a 50% potassium hydroxide solution is added gradually. The reaction mixture foams. After completion of the addition of the potassium hydroxide, 20 ml of water is added and the mixture is boiled for 15 min. After this the benzene solution is separated; on standing, the product crystallizes from it.
Reduction of nitroacyl derivatives of 4-propylaminoantipyrine. 10 g of finely ground powder of the nitroacyl derivative of 4-propylaminoantipyrine and 7 g of zinc dust are placed in a three-necked flask equipped with a stirrer, thermometer, and dropping funnel, and 50 ml of water is added. The mass is mixed well, and through the dropping funnel, with vigorous stirring, 30 ml of concentrated hydrochloric acid is added gradually over 10 min. During this time the reaction mixture warms to 50–60°C. After all the hydrochloric acid has been added, the mixture is stirred for another 15 min until the solution is completely decolorized, and the reduction is considered complete.
The excess zinc dust is filtered off, and the amine is precipitated from the filtrate with sodium acetate or sodium bicarbonate. The amine crystals that separate are filtered off, washed with water until the wash waters contain no Cl ion, dried, and recrystallized from alcohol.
REFERENCES
- L. A. Shabrova, G. M. Stepnova. Zhurn. VKhO, 9 (2), 240 (1964).
- L. A. Shabrova, G. M. Stepnova. Chemistry of Heterocyclic Compounds, in press.
- A. Skita, F. Keil, W. Stuhmer, Berichte, 75, 1696 (1942).
- G. V. Golodnikov. Practical Course in Organic Synthesis, 97, (1957).