Bulletin
of the Tomsk Order of the October Revolution
and Order of the Red Banner of Labor
S. M. Kirov Polytechnic Institute

Volume 214 1977

SYNTHESIS OF BENZYLACYL DERIVATIVES OF DIAMIDES OF CERTAIN DICARBOXYLIC ACIDS

A. G. PECHENKIN, V. P. PYPKINA, V. A. BAZHINA

(Presented by the scientific-methodological seminar of the organic departments of the Faculty of Chemical Technology)

It is known [1, 3] that certain linear derivatives of urea of the type
$C_6H_5CH_2NHCONHAc$ (I), possessing anticonvulsant action, have low toxicity, which favorably distinguishes them from related cyclic urea compounds. Experiments studying the action of fragments of the urea molecule that theoretically may be formed during their chemical transformations in the organism [6] led to the discovery that amides also are of definite value.

In order to determine the influence of the urea fragment on anticonvulsant activity in compounds of type I, we synthesized a series of analogous derivatives of diamides of malonic, succinic, and oxalic acids of the general formula:

\[ C_6H_5CH_2NHCO(CH_2)_xCONHAc,\quad \text{where } x=0,1,2. \]

The synthesis of these compounds was carried out from the amides of the corresponding acids, followed by their acylation with monobenzylamidomalonic acid in the presence of phosphorus trichloride.

It should be noted that acylation of acid amides of normal structure proceeds with higher yields than acylation of amides of iso-structure acids. All synthesized preparations possess low anticonvulsant action. Thus, replacement of the urea fragment in compounds of type I by diamides of oxalic, malonic, or succinic acids leads to a decrease in anticonvulsant activity.

Experimental Part

1. Monobenzylamide of malonic acid [2, 7]

Into a three-necked flask equipped with a condenser and stirrer are charged 10 g of malonic acid, 10 g of benzylamine, and 20 ml of dry xylene. The reaction mass is heated at 105°C for 1.5 hours. Upon cooling, a white precipitate forms; it is washed with ether to remove benzylamine, dried, and recrystallized from ethanol.

m.p. 117–118°C, yield—44%

\[ N_{\mathrm{B}}=7.25\% \qquad N_{\mathrm{H}}=7.57\% \qquad C_{10}H_{11}NO_3 \]

2. N-benzyl-N¹-isovaleryldiamide of malonic acid

Into a three-necked flask equipped with a stirrer, condenser, and dropping funnel are charged 2.2 g of isovaleric acid amide, 4.2 g of monobenzylamide of malonic acid, and 50 ml of dry xylene; the mixture is heated to 70°C, and 1 ml of phosphorus trichloride is added dropwise over 20 minutes. The temperature is then raised until HCl appears (test with ammonia). At a temperature of 120°C the mixture is heated for 4 hours. A precipitate of phosphorous acid forms in the reaction mixture. The xylene layer is decanted into an evaporating dish. After evaporation of the xylene, a yellow precipitate separates; it is dried and recrystallized from ethanol.

Under analogous conditions, acylation of the amides of valeric, butyric, isobutyric, and benzoic acids is carried out; the characteristics of the acylation products are given in Table 1.

Table 1

General formula: $C_6H_5CH_2NHCOCH_2CONHAc$

3. Monobenzylamide of succinic acid

Into a three-necked flask with a condenser and stirrer are charged 60 g of succinic acid, 55 ml of benzylamine, and 150 ml of dry xylene; the mixture is heated in an oil bath at 110°C for 1 hour. Upon cooling, a white precipitate separates; it is washed with ether to remove benzylamine, dried, and recrystallized from ethanol.

m.p. 129—131°C, yield — 65%

\[ N_{\mathrm{c}}=6.76\% \qquad N_{\mathrm{f}}=6.36\% \qquad C_{11}H_{13}NO_3 \]

4. N-benzyl-N¹-benzoyldiamide of succinic acid

Into a three-necked flask with a stirrer, condenser, and dropping funnel are charged 6 g of benzoic acid amide, 10 g of monobenzylamide of succinic acid, and 100 ml of dry xylene; the mixture is heated at 150—160°C, and 1.4 ml of phosphorus trichloride is slowly added from the dropping funnel. The reaction is carried out for 3 hours. The xylene solution is then decanted, and after evaporation of the xylene a yellow precipitate of the product remains, which is recrystallized from alcohol.

m.p. 98—99°C, yield — 75%

\[ N_{\mathrm{c}}=9.03\% \qquad N_{\mathrm{f}}=8.93\%. \qquad C_{18}H_{18}N_2O_3 \]

5. N,N¹-benzylisovaleryloxamide

Into a three-necked flask equipped with a condenser, stirrer, and dropping funnel are charged 10 g of benzyloxamide; 90 ml of benzene and 6.5 ml of isovaleric acid are added. The mixture is heated at re-

with stirring on an oil bath to 75°C, and phosphorus trichloride is added dropwise in an amount of 2.8 ml. The synthesis is continued at a temperature of 90–95°C. The product is filtered off and recrystallized from alcohol.

Under analogous conditions, acylation of other amides was carried out; the characteristics of the acylation products are given in Table 2.

Table 2

General formula: $\mathrm{C_6H_5CH_2NHCOCONHCOR}$

Conclusions

1. N-benzyl-N$^1$-acyl derivatives of diamides of oxalic, malonic, and succinic acids, not described in the literature, have been synthesized.

2. The synthesized compounds possess low anticonvulsant activity.

Literature

1. R. Barlow. Introduction to Chemical Pharmacology. Izdatinlit, 1959, 105–107.
2. J. E. Toman, L. S. Goodman, Phisiol. Rev. 28, 409, (1948).
3. M. D. Mashkovskii. First supplement to the 1959 edition, “Meditsina,” 1964, 31–34.
4. L. P. Kulev, A. A. Shesterova. ZhOKh, 31, 1379, (1961).
5. L. P. Kulev, G. M. Stepanova, V. G. Stolyarchuk, O. N. Nechaeva. ZhOKh, 30, 1385, (1960).
6. G. Dyson, P. May. Chemistry of Synthetic Medicinal Substances. Moscow, 1964, 285.
7. N. S. Dobychina. Synthesis and Study of N,N$^1$-Substituted Ureas. Dissertation, 1966, Tomsk.