METHOD FOR ACYLATION OF \(N\)-ALKYLUREAS

N. S. DOBYCHINA, A. G. PECHENKIN, L. G. TIGNIBIDINA

(Presented by the scientific-methodological seminar of the Chemical-Technological Faculty)

Among \(N,N'\)-alkylacyl derivatives of ureas, valuable physiologically active substances have been found. For obtaining the indicated urea derivatives, three methods are known from the literature:

1. By the Hofmann reaction from acid amides [1]. By this method it is possible to obtain only such \(N,N'\)-derivatives of urea in which the alkyl contains one carbon atom fewer in the chain than the acyl residue, for example ethylpropionylurea, \(\mathrm{C_2H_5HNCONHCOCH_2CH_3}\). Therefore the use of this method is limited.

2. The reaction of acid amides with isocyanates [2]. The yields of \(N,N'\)-alkylacylureas in this case reach 89%. However, carrying out the synthesis is hindered by the fact that the starting materials are substances of low availability. In addition, isocyanates possess high toxicity.

3. Acylation of \(N\)-alkylureas with various acid derivatives in the presence of certain catalysts:

a) with acid chlorides, with yields of acyl derivatives from 26 to 78% [3, 4];

b) with acid chlorides in the presence of potash [5], pyridine [6, 7], and phenazone [6];

c) with acid esters; the monosodium salts of \(N\)-alkylureas are acylated [8].

A common shortcoming of the methods indicated in item 3 is that, for the acylation of urea derivatives, it is necessary specially to prepare pure acid chlorides or esters of the corresponding carboxylic acids, which makes the preparation of \(N,N'\)-alkylacyl derivatives of ureas more expensive and more complicated. In addition, work with pyridine, if it is not a component of the final products, is always undesirable because of its high toxicity.

We have developed a simpler, economical, and convenient method for obtaining \(N,N'\)-alkylacylureas, consisting in the fact that the acylation of \(N\)-alkylureas is carried out in one stage with carboxylic acids in the presence of phosphorus trichloride in an inert solvent medium.

\[ 3\,\mathrm{RHNCONH_2} + 3\,\mathrm{HOOCR_1} + \mathrm{PCl_3} \rightarrow 3\,\mathrm{RHNCONHCOR_1} + \mathrm{H_3PO_3} + 3\,\mathrm{HCl}. \]

In this case, the \(N,N'\)-alkylacylureas synthesized by our method are obtained, as a rule, in higher yields and in purer form than the products obtained by acylating \(N\)-alkylureas with acid chlorides [9].

Acylation procedure

Into a three-necked round-bottom flask equipped with a mechanical stirrer, a reflux condenser, and a dropping funnel are placed 1 mole of alkylurea and 2 moles of carboxylic acid; dry benzene or xylene is added in an amount of 300 ml for each 100 g of alkylurea. The flask with its contents is placed in an oil bath, which is heated to 75°. From the dropping funnel, at this temperature, phosphorus trichloride (in a molar ratio to the acid of 1 : 1) is added dropwise over the course of 1 hour. The bath temperature is then raised to 90–100°C and maintained for 12 hours. After completion of the reaction (monitored by the evolution of hydrogen chloride), the mass is decanted from the precipitated phosphorous acid, the solvent is evaporated or distilled off in vacuo, and the precipitate (a dry white substance)

Table 1

\[ \mathrm{RHNCONHCOR_1} \]

*) Acylation was carried out at 110°.
**) Acylation was carried out at 120°.

is washed with a small amount of alcohol. After treatment with alcohol and washing with 10% sodium hydroxide solution, the product is recrystallized 2–3 times from a water–alcohol mixture (1 : 2), using 3 ml of the mixture per 1 g of product.

Comparative data on the acylation of alkylureas with acid chlorides and with acids in the presence of phosphorus trichloride are given in Table 1.

Using the synthesis of 14 compounds as an example, the applicability of the method for acylating alkylureas with carboxylic acids in the presence of phosphorus trichloride has been demonstrated.

REFERENCES

1. Hofman, Ber., 14, 2725; 15, 758, 769.

2. P. F. Wiley, J. Am. Chem. Soc., 71, 310—311 (1949); C. A. 1949, 6162.

3. S. R. Safir, H. Dalalian, W. Fanchawе, K. Cyr, R. Williams, S. Upham, L. Goldman, S. Kuschner. J. Am. Chem. Soc., 77, No. 18, 4840—4841 (1955); Ref. Zh. Khim. 1956, 28930.

4. E. Borowski, J. Konope. Przem. Chem., 11, 635—636 (1955); Ref. Zh. Khim. 1956, No. 19, 61488.

5. Macuo Josyhary, J. Pharmac. Soc. Japan, 83, No. 5, 480—487 (1963); Ref. Zh. Khim. 1964, 7 Zh 168.

6. J. H. Beasley, V. Petrow, O. Stepanson, Y. Pharmacy and Pharmac., 13, No. 11, 694—697 (1961).

7. R. Duschinski, U. S. 42 522 Sept. 30 (1952); C. A. 1953, 8775.

8. A. Stempel, Y. Lolauskas, J. A. Aschliman, J. Organic Chem., 20, No. 4, 416 (1955).

9. L. P. Kulev, N. S. Dobychina. Zhurn. VKhO, 8, No. 6, 701 (1963).