SU289596A1 - METHOD OF OBTAINING CYCLIC DIAMODOESTERPHOSPHORIC ACID - Google Patents

Description

This invention relates to a process for the preparation of new cyclic phosphoric acid diamido esters of the general formula

SNGCN C1 N-CHj

Hg CH SNg-N-CH, R O-CHa

where Xi is chlorine or hydroxyl; R is hydrogen, methyl, p-chloroethyl or R-Oxythyl group.

The synthesized compounds have a cytostatic effect. And they can be used in medicine and veterinary medicine.

The proposed method for the preparation of phosphoric acid cyclic diamido esters is based on methods known from the literature and consists in the fact that compounds of the general formula

X-CH2-CH, -SH1

house of cyclic amphodophosphoric phosphoric acid

CHgCHgCi

, 2.2

N - CH ..

CH.

sn;

where X is a halogen atom, preferably chlorine.

The reaction is carried out in the presence of chlorine chloride acceptors, which can be used to use known compounds of the basic type, such as alkali metal carbonates and bicarbonates, tertiary amines, for example, triethylamine. pyridine. These compounds are administered in an amount of at least

I mole

The reaction is carried out in an environment of an inert organic solvent, for example, chloroform, methylene chloride, benzene, ether, dioxane, at room temperature or at an elevated temperature.

Example 1. N, N, N-tpi- (2-chloroethyl) -N, O-propylene ether phosphoric acid. 42.6 g of M, K-bms- (2-chloroethyl) -amine is dissolved in 150 ml of methylene dichloride and, with perchloroethyl-K, 0-propylene efluoride of phosphoric monochloride, in 65. methyl chloride or methylene chloride. The mixture is heated to boiling for an hour “immediately after that it is evaporated in a vacuum. The residue is treated with 350 ml of abs. ether, and the precipitated precipitate of the N, N-6uc- (2-chloroethyl) -amine hydrochloric acid salt is separated. The ether solution is washed with dilute hydrochloric acid and then with a solution of acidic sodium carbonate. After drying the washed solution, ether is distilled off over sodium sulfate and the oily residue is thoroughly dried. The latter is dissolved in a tenfold volume of abs. ether, filtered on coal and again evaporated. The residue obtained is dissolved in 40 ml of abs. ether and crystallized to initiate crystallization after cooling to -5 ° C. The crystals which separated out after 24 hours were filtered and dried in vacuo.

The output of 24.3 g (50.1% of theory). T. pl. 51 - 52 ° C.

Example 2. 1, K-bms- (2-chloroethyl), Opropylene ether phosphoric acid.

In a solution containing 218 g (1 mol) of N- (2-chloroethyl) -M, 0-propylene ether of phosphoric acid monochlorohydride in QQQ ml of methylene chloride, 127.6 g (1.2 mol) of N- (1) hydrochloric acid salt are suspended. 2-chloroethyl) amine and, with stirring, 212 g of triethylamine are added dropwise. At the same time, the reaction mixture is brought to a boil. After adding the total amount of triethylamine, the mixture is heated at reflux temperature, e, for 2 hours. Then the mass is cooled and the separated sulphate of triethylamine is filtered off. The filtrate is washed successively with 60 ml of dilute hydrochloric acid (pH 3), twice with 60 ml of water, dilute soda solution, and two more times with water. The resulting solution is dried over sodium sulfate and then methylene chloride is distilled off under normal pressure. The oily residue is dried in vacuo and immediately after that extracted with 500 ml of abs. the ether. The oily extract after the introduction of the seed is subjected to crystallization in the refrigerator. The crystals precipitated for 1 hour are filtered off, washed with a small amount of cold ether and dried at room temperature under vacuum.

Output 185 g (71% of theory). T. pl. 39-4GS.

Example 3. M-methyl-K N-b "c- (2-chloroethyl) -Y, 0-tsropyleneetherdia, mid phosphoric acid.

In a suspension of 21.8 g N-chloroethyl-N, O-propylene ether monohydride of phosphoric acid and 14.3 g of the N-methyl-N- (2-chloroethyl) -amine hydrochloric acid salt in 100 ml of methylene chloride is added dropwise at by stirring 22.2 g of triethylamine. The reaction mass is heated for 3 hours at a temperature determined by the boiling point of the solvent, and after cooling, the liberated triethylamine hydrochloride salt is filtered off. The filtrate is washed with dilute hydrochloric acid, diluted with brine and then with water. The solution of the product in methylene chloride is dried over sulfuric acid, sodium hydroxide, and then evaporated in an iBakum. 10 Output 13 g (47.2% of theory).

The product is a colorless oil; 1.5038.

Example 4. N, N-6uc- (2-chloroethyl) -N- (25 hydroxyethyl) - N, 0 - propylene enofirmonic phosphoric acid.

To a solution of 8.0 g of the hydrochloric acid salt of N- (2-chloroethyl) -H- (2-hydroxyethyl) -amine and 10.1 g of triethylamine in 50 ml of chloroform are added dropwise over 45 minutes and at a temperature of 28 ° C the solution 10.9 g of N- (2-chloroethyl) M, 0-propylene ether of monochlorohydrin of phosphoric acid in 50 ml of chloroform. The solution is stirred for 2 hours at room temperature.

5 and immediately after this for 2 hours at a temperature of 40 ° C. During the night, the hydrochloride salt was isolated with triethylamine, 1 and the solution was filtered and the solution was evaporated in vacuo. The resulting oily product is extracted for several hours in the Soxhlet abs. ether and the ether extract evaporated in vacuo. The newly obtained oily liquid is again extracted in an extractor for liquid substances and again

5 evaporated. The resulting oily product is mixed with a small amount of ABO.E and filtered on a filter with a glass porous plate of G 4. A slightly yellowish soluble in water and having an average viscosity oily product are obtained, which is subjected to further drying under high vacuum for several hours.

Yield 6.5 g (42.6% of theory) p 1.5073.

5 Example 5. M- (2-g. Hydroxyethyl) -K- (2-chloroethyl) -M, O-propylene etherodiamide phosphoric acid.

43.6 g of N- (2-chloroethyl) -N, O-propylene ether of phosphoric acid monochloride is dissolved in 200 ml of methylene chloride and added with stirring to a solution: PO. Solution of 15 g of N-methylaminoethanol and 20, 2 g of triethylamine in 40 ml of methylene chloride. In this case, the reaction mass is heated to the boiling point of methylene chloride. After adding the total amount, the hours boil for another 2 hours. Then the mass is cooled and the separated triethylamine hydrochloride salt is filtered off. Solution

the product in methylene chloride is washed three times with 50 ml of water. After drying the methylene chloride and the bottom phase over sodium sulfate, the solvent is evaporated to dryness in vacuo. The result is a colorless oil. Exit 42 g (81.8% of theory), p 1,5006.

Example 6. N- (2-hydroxyethyl) -N- (2chloroethyl) -K, O-propylene ether phosphoric acid.

To a solution of 16.8 g of ethanol-inin and 27.8 g of triethylamine in 150 ml of methylene chloride, a solution of 54.5 g of M- (2-chloroethyl) -M, 0-propylene ether and phosphoric acid monochloride hydride are added dropwise with stirring 150 liters of methylene chloride. At the same time, the reaction mass is heated to the boiling point of methylene chloride. After adding the total amount, the mixture is boiled for another 3 hours. Then the mass is cooled and filtered CHrCHj-N-P

R 0 SNg

There are precipitated hydrochloride salt of triethylamine. The solution of the product is washed in methylene chloride-successively with a small amount of dilute hydrochloric acid and two times with a small amount of water. After drying the methylene chloride phase over sodium sulfate, the solution is evaporated in vacuo. The result is a colorless oily product. Yield 42.5 g (69.9% of theory), ng 1.5050.

The table shows the results of pharmacological tests of the compounds obtained in examples I and 2.

CHcCHgCl I / N - CHE

 N, N, -6uc-p - chloroethylamino-KO-propylenetherdnampd literature). DS50 (4) was determined on rats affected by Yoshida ascid caused by sarcoma with a four day distribution of the total dose. The treatment started on the day of vaccination. The observation was carried out for 90 days. DL50 (1) was determined on the same rats with a single use of the drug. The observation time is 14 days. The compound of Example I is distinguished by a good chemotherapeutic effect in the treatment of mice resistant to the usual chemotherapy of sarcoma 37 and Ehrlich carcinoma. Substance A is ineffective against such tumors or acts only in subtoxic doses. The compound of Example 2 is characterized by the fact that, in the case of mortality, the accumulation of toxic biologically active components is insignificant. Thus, for substance A, the value of DL50 (4) is 140 mg / kg and is lower than the value of DL50 (1), while for Compound studied in Example 2, the value of DL50 (4) is 190 mg / kg and clearly exceeds the value of DL50 (I). Mala toxic cumulative matter with prolonged use of the drug .. phosphoric acid (It is known from In addition, the compound of example 2 is distinguished by good solubility in water and is a new type of compounds exhibiting cytostatic effect, in which both 2- The chloroethyl groups are not located on one nitrogen atom, as in compounds like nitrogen mustard, but are located on two different nitrogen atoms in the above-mentioned acid amides. Finally, the proposed compounds are characterized by a high stability In aqueous solutions. In a bicarbonate buffer solution (pH 7.5) at a temperature of 37.5 ° C for 10 days, they split only a Vg fraction from the amount of chlorine ions that are cleaved from known substances. The results are shown below. equ1 mol chloride ions, the substance is split for

P ip d e m invention

The method of producing cyclic phosphoric diamido esters of the general formula

CHaCHgCl N-CHg X, - CHg-CI g N-CHg

R O-SNG

where Xi is chloro: p or hydroxyl; R is hydrogen, a methyl, p-chlorostile or p-hydroxyethyl group, characterized in that the compound of the general formula:

Xg-SNg-SNg-F R

where R and Xi - has the above value, is reacted with cyclic amidospir phosphoric acid halide of general formula

CH gQHgCl N - CHg

O - CH,

where X is an atom of halogen, preferably chlorine, in the presence of acceptors of hydrogen chloride in the medium of an inert solvent.