SU359811A1 - Method of producing halogen aminocarboxy derivatives - Google Patents

Description

The invention relates to a method for producing halogenamine carboxylic compounds of the steroid series, which have pharmacological action and can be used as products for further syntheses.

It is known that chlorine esters when interacting with ammonia or amines give carbamic acid esters.

The transformation of the steroid esters of chlorogolic acid and their reactions with amines to the "synal N-substituted halogenamine carboxylic compounds" has not been described.

The proposed method for the preparation of halogen aminocarboxypropanode of the steroid series

I-C-X O

I ii

-C-O-C-NHR, I

where С-С is part of the steroid skeleton;

X is a halogen atom,

R is an alkyl aryl, arylalkyl, cyclohexyl group, an unsubstituted or substituted amino group, or an acid residue, is that the corresponding chlorogel suspension ether is reacted with LH-active compounds in an organic solvent medium

the presence of acid binding agents with the release of the target product by known techniques. Chloroic acid esters are obtained from cis or granous halohydrins of the steroidal series by reaction with phosgene in an inert solvent, preferably benzene, by adding a basic catalyst. The reaction with the active compound is carried out in an appropriate solvent.

with the addition of an acid bonding agent that does not react with chlorotic acid ester, for example a tertiary amine. Ethanol, tetrahydrofuran or acetone, for example, is used as a solvent, and amines, hydrazine or substituted hydrazine, amide, amino acids or their carboxyl derivatives are used as NH-active compounds. If a strong base is added in an appropriate amount, then

NH-active compounds can be used in the form of their most frequently occurring salts. According to the proposed method, chloroic acid ester, not purified from excess phosgene or containing it, can be used.

th solution of phosgene (250zhg phosgene per ml.). After cooling to 0 ° C, 0.2 ml of triethylamine dissolved in 1.3-1.5 ml of benzene was slowly added to the reaction mixture. The reaction mixture is left to stand overnight at room temperature, then filtered and evaporated in vacuo. The resulting oily, slowly crystallizing substance is used in further syntheses without further purification.

T., pl. 116-119 ° C.

Example 2. 16a-Bromo-17 p - cyclohexyl-1 inocarbox "estra -1,3,5 (10) - triene-3-methyl ether.

The chlorobolic acid ester prepared according to example 1 of 500 IU of Sha-bromo-3-methoxyester1, 3.5 (10) -triene-17 p-ol is dissolved in 20-25 ml of acetone and treated with 1 ml of cyclohexylamine under ice-cooling. After standing for 1 hour in an ice tank, the reaction mixture is poured into water and the separated product is filtered off with suction. Crystallization can be carried out from methanol.

T. pl. 155-158 ° C.

Example 3. 17p-Ethylaminocarboxy-16abromestra-1, 3.5 (10) -triene-3-methyl ester.

The chloroic acid ester prepared according to example 1 from 500 mg of 16a-bromo-3-methoxyester1, 3.5 (10) -trien-17p-ol is dissolved in 20-25 ml of acetone and treated with ice-cooling with 2 ml of ethylamine. After standing for 1 hour in a water bath, the reaction mixture was poured into water and extracted with benzene.

After drying the benzene solution and evaporating the benzene, an oil which crystallizes from methanol is obtained.

T. pl. 175-178 ° C.

Example 4. 17R-Benzylaminocarbokoi-16abromestra-1, 3.5 (10) -triene-3-methyl ether.

The chlorobolic acid ester prepared according to example 1 from 500 mg of 16a-bromo-3-methoxyestra-1, 3.5 (10) -trien-17p-ol is dissolved in 20-25 ml of acetone and treated with ice-cooling with 1 ml of benzylamine . After standing for 1 hour in an ice bath, the reaction mixture is poured and extracted with benzene. After drying the benzene solution and evaporating the benzene, an oil is obtained; the oil, iKOTqpoie | Cry, is crystallized from methanol.

T. pl. 160.5-163 ° C.

Example 5. 17p - Anilinocarboxy - Abramestra-1, 3.5 (10) -triene-3-methyl ether.

Chlorogolic acid ester, prepared from 500 mg of 16a-bromo-3-methoxyestra-1,3,5 (10) triene-17p-ol, is dissolved in 20-25 ml of acetone and treated with 1 ml of aniline while cooling with ice. After standing for 1 hour in an ice bath, the mixture was poured into water and extracted with benzene. After drying the benzene solution and evaporating the benzene, an oil is obtained which crystallizes from a mixture of benzene and petroleum ether.

Example 6 17p-Anilinecarboxy-16p-chlorostra-1, 3.5 (10) -triene-3-methyl ether.

Chlorogolic acid ester prepared from 500 mg of 16p-chloro-3-methoxyestra-1,3,5 (10) -trien-17p-ol is dissolved in 20-25 ml of acetone and treated with ice-cooling with 1 ml of aniline. After standing for 1 hour in an ice bath, the mixture is poured into water and extracted with benzene. After drying the benzene solution and evaporation of the benzene in vacuo, a colorless chromatographically pure amorphous product is obtained.

Example 7. 16a-Bromo-17p-hydrazincarboxyestra-1, 3.5 (10) -triene-3-methyl ether.

Chlorogolic acid ester obtained from 500 mg of 16a-bromo-3-methoxyestra-1,3,5 (10) -trien-17p-ol is dissolved in a mixture of 15 ml of absolute alcohol and 5 ml of absolute tetrahydrofuran and treated with ice cooling 0 , 6 ml of 98% hydrazine hydrate. After standing for 1 hour in an ice bath, the mixture is poured into an aqueous solution of sodium chloride and the precipitated product is sucked off. Purification is carried out by chromatography on silica gel, and the basic impurities are then eluted with a mixture of benzene and ether (10: 1) and then the desired product is mixed with a mixture of benzene and methanol (10: 1). Crystallization from a mixture of methanol and water.

T. pl. 146-149 ° C.

Example 8. 16a-Bromo-17p-isoprolylidenehydrazincarbocoiestra - 1,3,5 (10) -triene-3-methyl ester.

Chlorogolic acid ester, prepared from 500 mg of 16a-bromo-3-methoxyestra-1,3,5 (10) triene-17p-ol, is dissolved in 20 ml of acetone and treated with ice-cooling with 0.6 ml of 98% hydrazine hydrate . After a hundred to

for 1 hour in an ice bath, the reaction mixture is poured into water or into an aqueous solution of sodium chloride and the separated product is filtered off with suction. Purification is carried out by silica gel chromatography, with a mixture of benzene and

acetone (85: 1), the main impurities are eluted, and then a small amount of impurities is then eluted with a mixture of benzene and acetone (40: 1), and then the desired product. The crystallization is carried out from a mixture of acetone and water.

T. pl. 153-156 ° C.

Example 9. 16a-Bromo-17p-S, M-dimethyl-Drazincarboxyestra-1, 3.5 (10) is triene-3-methyl ester. Chloroic acid ester obtained by

Example 1, out of 500 mg of 16a-bromo-3-methoxy-estra1, 3,5 (10) -trien-17p-ol, is dissolved in a mixture of 15 ml of absolute ethanol and 5 g of absolute tetrahydrofuran and treated with ice-cooling with 1 ml of N-dimethylhydrazine. Then 0.1 ml of triethylamine is added. After pouring the mixture into water and for some time, the product is sucked off. Purification is carried out by chromatography on silica gel with a mixture of benzoate and ether (10: 1). At the same time, first the necessary product. Crystallization is carried out from a mixture of methanol and water.

T. pl. 179-182 ° C.

Example 10. 17p-Carbatoxymethylaminecarboxy-16a-bromotera-1,3,5 (10) -triene-3-methyl ether.

Chloroic acid ester, prepared from 500 mg of 16a-bromo-3-methocystera-1,3,5 (10) triene-17p-ol, is dissolved in 20 ml of acetone. To the resulting solution, 700 mg of glycocoyl ethyl ether hydrochloride is added with good stirring and cooling, 0.8 ml of triethylamine in 5 l of acetone is added dropwise. After 2 hours, the reaction mixture is poured into water and the resulting emulsion is extracted with ether. After drying the ether solution and evaporation of the ether, a slowly crystallizing oil is obtained which is recrystallized from methanol.

T. pl. 155-158 ° C.

Example 11. 17p-Acetamidecarbox "-16abroestra-1, 3.5 (10) -triene-3-methyl ether.

Chlorogolic acid ester, obtained from 500 mg of 16a-bromo-1,3,5 (10) -triei-17p-ol, is dissolved in 20 ml of acetone and treated with 200 mg of acetamide. Then 0.5 ml of triethylamine is added, after which the mixture is stirred at room temperature for 3 hours and poured into water. After removing the ether and drying the ether solution, the ether is evaporated. The obtained semi-solid product is purified by chromatography on silica gel (Eluentbenzene). T. pl. 117-120 ° C (petroleum ether).

Subject invention

1. Method for preparing halogenamine carboxy derivatives of the steroid series of the formula

I-C-X O

I ii

-C-O-C-NH-R,

where C-C is part of the steroid skeleton,

X is a halogen atom,

R-alkyl, aryl, arylalkyl or cyclohexyl group, an unsubstituted amino group or acid residue, characterized in that the corresponding chloroic acid ester is reacted with NH-active compounds in an organic solvent medium in the presence of an acid-binding agent, such as tertiary amines, to isolate Target product known techniques.

2. A method according to claim 1, characterized in that the salts with the addition of a sufficiently strong base are used as the NH-active compounds.