Some Acyl Derivatives of 1-Benzylsemicarbazide

A. G. Pechenkin, I. G. Fedkova, Z. M. Murav’eva

(Presented by the Scientific-Methodological Seminar of the Organic Departments of KhTF)

The barbiturates, oxazolidine-2,4-diones, and hydantoins currently used as active anticonvulsant agents contain in their molecule the grouping

\[ R-\overset{\ |}{\mathrm{C}}-\overset{\ |}{\underset{\mathrm{O}}{\mathrm{C}}}-\overset{\ |}{\mathrm{N}}-, \]

which should be regarded as responsible for their anticonvulsant activity [1].

For the manifestation of anticonvulsant activity, it is specifically the benzamide portion of the molecule (chloracon) that is important [2].

N. K. Kochetkov and N. V. Dudykina found that replacement of the benzyl residue in chloracon by other groupings completely removes the anticonvulsant activity [3].

On the basis of works [4, 5], it may be assumed that the presence of the hydrazine grouping determines the anticonvulsant activity of arylhydrazides of diaryl- and dialkylglycolic acids.

A whole series of hydrazine derivatives has been obtained [6—11] that act on the central nervous system and are used in psychotherapy. As a result of a number of works [12—14], it was found that introduction of an acyl residue into the molecule of barbiturates or other urea derivatives significantly increases the anticonvulsant activity of the starting compounds.

It was of interest to obtain acyl derivatives of benzylsemicarbazide of the general formula:

\[ \mathrm{C_6H_5CH_2NH-NH-C(=O)NH-R}, \]

where \(R\) is acyl, in which the benzyl radical is combined with the hydrazine grouping, and to study their biological activity. Acylation was carried out with acid chlorides.

Six acyl derivatives of 1-benzylsemicarbazide, not described in the literature, were obtained and submitted for testing for biological activity.

Experimental Part

1-Benzylsemicarbazide—the intermediate for the synthesis of acyl derivatives of semicarbazide—was obtained by us according to the procedure described in the literature [15, 16].

1. 1-Benzyl-4-acetylsemicarbazide.

Into a three-necked flask equipped with a condenser and a stirrer are charged 5 g of 1-benzylsemicarbazide and 100 ml of dry xylene. The mixture is heated to 70°C, and 4 ml of acetyl chloride is added from a dropping funnel. The reaction mixture is heated to 110°C and kept for approximately 2 hours, cooled, and filtered. The white, dense powder is recrystallized from ethanol.

\[ T_{\mathrm{m.p.}} = 204\text{--}205^\circ\mathrm{C}. \qquad \text{Yield } 70\% \]

\[ N_{\mathrm{calc}} = 21.35 \qquad N_{\mathrm{found}} = 20.88 \]

The remaining five compounds were obtained analogously.

II. 1-Benzyl-4-propionylsemicarbazide.
Obtained from 5 g of 1-benzylsemicarbazide, 3 ml of propionyl chloride, and 100 ml of dry xylene.

White powder, recrystallized from ethanol.

\[ T_{\mathrm{m.p.}} = 193\text{--}194^\circ\mathrm{C}. \qquad \text{Yield } 70\% \]

\[ C_{\mathrm{calc}} = 59.75 \qquad C_{\mathrm{found}} = 60.15 \]

\[ H_{\mathrm{calc}} = 6.79 \qquad H_{\mathrm{found}} = 7.1 \]

\[ N_{\mathrm{calc}} = 19.02 \qquad N_{\mathrm{found}} = 19.05 \]

III. 1-Benzyl-4-butyrylsemicarbazide.
Obtained from 5 g of 1-benzylsemicarbazide, 3.2 ml of butyryl chloride, and 100 ml of dry xylene.

White powder, recrystallized from ethanol.

\[ T_{\mathrm{m.p.}} = 194\text{--}195.5^\circ\mathrm{C}. \qquad \text{Yield } 73.3\% \]

\[ N_{\mathrm{calc}} = 17.87 \qquad N_{\mathrm{found}} = 17.89 \]

\[ H_{\mathrm{calc}} = 7.21 \qquad H_{\mathrm{found}} = 7.52 \]

\[ C_{\mathrm{calc}} = 61.28 \qquad C_{\mathrm{found}} = 61.51 \]

IV. 1-Benzyl-4-isobutyrylsemicarbazide.
Obtained from 5 g of 1-benzylsemicarbazide, 3.2 ml of isobutyryl chloride, and 100 ml of dry xylene.

White powder, recrystallized from ethanol.

\[ T_{\mathrm{m.p.}} = 222\text{--}223^\circ\mathrm{C}. \qquad \text{Yield } 69\% \]

\[ N_{\mathrm{calc}} = 17.87 \qquad N_{\mathrm{found}} = 17.76 \]

V. 1-Benzyl-4-valerylsemicarbazide.
Obtained from 20 g of 1-benzylsemicarbazide, 14.6 g of valeryl chloride, and 300 ml of dry xylene.

White powder, recrystallized from ethanol.

\[ T_{\mathrm{m.p.}} = 195\text{--}196^\circ\mathrm{C}. \qquad \text{Yield } 73.4\% \]

\[ N_{\mathrm{calc}} = 16.86 \qquad N_{\mathrm{found}} = 17.31 \]

VI. 1-Benzyl-4-isovalerylsemicarbazide.
Obtained from 20 g of 1-benzylsemicarbazide, 14.6 ml of isovaleryl chloride, and 300 ml of dry xylene.

White powder, recrystallized from ethanol.

\[ T_{\mathrm{m.p.}} = 201\text{--}202^\circ\mathrm{C}. \qquad \text{Yield } 75.2\% \]

\[ N_{\mathrm{calc}} = 16.86 \qquad N_{\mathrm{found}} = 17.27 \]

Literature

1. I. S. Berdinskii, V. E. Kolla, Z. G. Zubova. Substituted hydrazides of oxycarbonic acids. Scientific Notes of Perm State University, 2, 1963.
2. S. Kushner, B. Cassel, I. H. Morton, I. H. Williams, J. Org. Chem., 16, 8, 1823 (1951).

1. N. K. Kochetkov, N. V. Dudykina. Some \(N\)-substituted β-chloropropionamides, ZhOKh, 27, 1899, 1957.

2. V. E. Kolla, Z. G. Zubova. Pharmacology and Toxicology, 3, 287, 1964. “Anticonvulsant action of arylhydrazides of substituted glycolic acids.”

3. V. E. Kolla. Chemical structure, anticonvulsant activity, and toxic action of arylhydrazides of substituted glycolic acids. Proceedings of the Natural-Science Institute at Perm State University named after A. M. Gorky, 14, 7, 1964.

4. Swiss patent, 377842, RZhKh, 1966, 12N243P.

5. English patent, 869575, RZhKh, 1962, 8J314.

6. English patent, 981460, RZhKh, 1962, 15N248P.

7. U.S. patent, 3129259, RZhKh, 1966, 15N236P.

8. Swiss patent, 377840, RZhKh, 1966, 9N245P.

9. Australian patent, 247366, RZhKh, 1966, 16N250P.

10. L. P. Kulev, G. M. Stepnova, V. G. Stolyarchuk, O. N. Nechaeva. Acyl derivatives of barbituric acid. ZhOKh, 30 (KhSP).

11. L. P. Kulev, A. A. Shesterova. Acyl derivatives of barbiturates, hexamidine, and diphenylhydantoin. ZhOKh, 27, 1399, 1957.

12. N. S. Dobychina. Synthesis and study of \(N\)-, \(N^1\)-substituted ureas. Dissertation, Tomsk, 1966.

13. A. von Baeyer, Ber., 27, 1918 (1894).

14. Kessler, Rupe, Ber., 45, 26, “1-Benzilsemicarbazide.”