Acylation of Barbiturates with Acid Chlorides of Substituted Benzoic Acids
Abstract Generated abstract
This study reports the synthesis of new N-acyl derivatives of barbital, phenobarbital, and barbamyl as part of a search for barbiturate compounds with potential anticonvulsant activity and to examine the effect of substituents in the acyl residue. The barbiturates were acylated with acid chlorides of ortho-bromo-, para-bromo-, and para-nitrobenzoic acids in the presence of pyridine, followed by purification and characterization. Six crystalline derivatives were obtained, with analytical data, melting points, yields, ultraviolet maxima, and infrared carbonyl and NH absorption bands reported. Unlike earlier acylations with benzoic and para-chlorobenzoic acid chlorides, these reactions produced little or no diacylated products under comparable conditions, and the compounds were submitted for pharmacological testing.
Full Text
ACYLATION OF BARBITURATES WITH ACID CHLORIDES OF SUBSTITUTED BENZOIC ACIDS
A. A. SHESTEROVA, G. S. SAVEL'EVA, A. G. PECHENKIN
(Presented by the Scientific-Methodological Seminar of the Chemical-Technological Faculty)
Previously [1, 2, 3] we obtained \(N\)-benzoyl derivatives of 5,5-phenylalkyl- and 5,5-ethylalkylbarbituric acids. As pharmacological tests showed, all of them possess anticonvulsant activity to one degree or another. In order to search for new anticonvulsants and to clarify the influence of substituents located in the acyl residue on anticonvulsant activity, we synthesized acyl derivatives of barbital, phenobarbital, and barbamyl containing bromine in the acyl residue (ortho and para positions) and a nitro group (para position). All the compounds described are white crystalline substances, insoluble in water and petroleum ether; they dissolve on heating in benzene, ethyl and isopropyl alcohols, acetone, and carbon tetrachloride. Most of them dissolve without heating in chloroform.
The acylation of the indicated barbiturates was carried out with acid chlorides of ortho-bromo-, para-bromo-, and para-nitrobenzoic acids in the presence of pyridine.
It is interesting to note that, in the acylation of barbiturates with the acid chlorides of benzoic [2] and parachlorobenzoic acids [3], along with monoacyl derivatives, diacyl derivatives are obtained (up to 15%). Under the same conditions, when acylating with the acid chlorides of ortho-bromo-, para-bromo-, and para-nitrobenzoic acids, as well as when acylating with the acid chlorides of ortho- and meta-nitrobenzoic acids [3], diacyl derivatives are almost not formed. Data from analysis, UV and IR spectra of the compounds obtained are given in Table 1.
Fig. 1
Experimental part
0.1 mole of barbiturate, 0.1 mole of acid chloride, and 0.1 mole of pyridine are placed in a three-necked flask equipped with a reflux condenser and stirrer, heated in an oil bath at \(125\text{–}135^\circ\mathrm{C}\) for 2–6 h. Then the reaction mass is dissolved, with heating, in 40–50 ml of benzene. The precipitate that separates after cooling is dried, washed
Table 1
| Name | \(R_1\) | \(R_2\) | \(x\) | Melting point, °C | Yield of purified, % | Recrystallization solvent | Analysis for nitrogen, found, % | Analysis for nitrogen, calculated, % | \(\lambda_{\max}\), \(m\mu\) | Frequencies of valence vibrations, CO | Frequencies of valence vibrations, NH |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1. 5,5-Diethyl-1/3/-para-bromobenzoylbarbituric acid | \(C_2H_5\) | \(C_2H_5\) | Br | 138–140 | 18 | Petroleum ether: benzene 3:2 | 7,62 | 7,24 | 266 | 1700, 1710, 1730, 1770 |
3050 3140 |
| 2. 5,5-Diethyl-1/3/-ortho-bromobenzoylbarbituric acid | \(C_2H_5\) | \(C_2H_5\) | Br | 134–136 | 32,7 | Carbon tetrachloride | 7,62 | 7,80 | 252 | 1667, 1698, 1720, 1759 |
3212 |
| 3. 5,5-Phenylethyl-1/3/-para-bromobenzoylbarbituric acid | \(C_2H_5\) | \(C_6H_5\) | Br | 200–202 | 13,2 | Dichloroethane | 6,70 | 7,28 | 265 | 1695, 1715, 1745, 1775 |
3068 3220 |
| 4. 5,5-Phenylethyl-1/3/-ortho-bromobenzoylbarbituric acid | \(C_2H_5\) | \(C_6H_5\) | Br | 144–145 | 6,0 | Carbon tetrachloride | 6,70 | 6,70 | 252 | ||
| *5. 5,5-Phenylethyl-1/3/-paranitrobenzoylbarbituric acid | \(C_2H_5\) | \(C_6H_5\) | \(NO_2\) | 162–164 | 26,5 | Chloroform | 11,04 | 11,54 | 264 | 1667, 1705, 1766 |
3095 3158 |
| 6. 5,5-Ethylisoamyl-1/3/-ortho-bromobenzoylbarbituric acid | \(C_2H_5\) | iso-\(C_5H_{11}\) | Br | 130–132 | 6 | Ethyl | 6,84 | 7,00 | 252 | 1675, 1690, 1705, 1766 |
3058 |
* Obtained [4] with m.p. 161–162.
with acidified water, dried, and recrystallized to a constant melting point. The solvents for recrystallization are indicated in Table 1. Owing to the difficulty of purifying compounds 2 and 4 (Table 1), before recrystallization they were twice passed, in the form of a chloroform solution, through a column packed with aluminum oxide.
Conclusions
Six \(N\)-acyl derivatives of barbiturates containing bromine in the acyl residue (ortho and para positions) and a nitro group (para position) have been obtained and submitted for pharmacological testing.
References
- L. P. Kulev, A. A. Shesterova. ZhOKh, 31, issue 4, 1378, 1961.
- L. P. Kulev, A. A. Shesterova. Proceedings of the First Scientific Conference of the Tomsk Branch of the All-Union Chemical Society named after D. I. Mendeleev. Tomsk State University Press, Tomsk, 1969.
- A. A. Shesterova, S. D. Yaroslavtseva, A. G. Pechenkin. Izv. TPI, vol. 214.
- Bojarski Iacek, Kahl Wladislaw, Roszn. chem., 1964, 38, No. 10, 1493—1497.