SU450405A3 - The method of obtaining 17-ethynyl estriol - Google Patents

Description

(54) METHOD OF OBTAINING 17a-ETHYNYL ELASTRIOLS

one

This invention relates to a new process for the preparation of 17a-ethynyl-estriols or their 3-o-alkyl or 3-o-cycloalkyl derivatives having valuable properties.

A method of preparing 16a, 17p-dioxy17a-ethynyl estriol is known, which consists in that the mixture of 16a, 171p-dioxy-17cc-ethynyl- and 1 dev, 17a-dioxy-17p-ethynyl-estriol, obtained by ethynylating the corresponding 16a-acetate of estrone, is subjected to fractional crystallization.

However, fractional crystallization is a time-consuming, inconvenient method for separating a mixture of compounds, and the use of this method does not allow sufficiently complete separation of the mixture of isomers of 17a-ethinyl estriol.

The aim of the proposed method is to eliminate the indicated disadvantages and simplify the process.

Describes a process for the preparation of 17a-ethinyl estriols of formula I

HE

 -- --he-

where R is hydrogen, Ci-Cz-alkyl or Cs-Sb-cycloalkyl, meaning that a mixture of isomers having formulas I and II

ten

.-xi xr

g lj n

II G1 g

2Q where R has the meaning given above,

subjected to reaction with acetone in the presence of acid and get the acetonide of formula III

25

III

where R has the above value,

which is separated from the target compound and the latter is either isolated or, if desired, a compound of formula II, where R is hydrogen, is reacted as a metal salt of 17a-ethynyl estriol with the C3-Cb-cycloalkyl halide derivative in dimethylformamide and gives the Cs-Ce-cycloalkyl ether Formula I, wherein iR is a Cs-Ce-cycloalkyl group, which is isolated by known techniques.

This mixture of 17c-ethinyl estriols is obtained by ethynylation of 16a-acetoxyestrone. The proposed method allows fairly simply and effectively separating this mixture of isomers and isolating the target 17a-ethynyl-17p-hydroxyisomer.

The method of separating 17a-ethynyl estriol from 17p-ethinylestr-1,3,5 (10) -triene-3.16a, 17-triol (its 17p-ethynyl-17a-hydroxy-isomer) consists in forming the acetonide of the last of these compounds, and separating the acetonide from unreacted 16a, 17p-dioxo compounds using chromatography or fractional crystallization or another suitable method. The above process is applicable not only to compounds having a free phenolic group at the 3-position of the estriol molecule, but also to compounds that have a lower alkyl or cycloalkyl ether group at the 3-position.

17a-ethynyl estriol can be converted to its corresponding 3-cyclopentyl ether by reacting with a halo-derivative of cyclopentyl in the presence of sodium methoxide, thallium ethoxide or the like.

When conducting the reaction, the triol is dissolved in methanol and treated with excess amount of freshly prepared sodium methoxide. A solution of the triol in methanol can also be treated with thallium ethylate, or it can be used with other reactive monovalent alcohols, such as potassium, lithium, rubidium, or cesium. After the formation of the triol metal salt, it is recovered as a solid by evaporation of the solvents and suspension in benzene. The resulting suspension is added to a large volume of dimethylformamide, or the salt is suspended, or the salt is dissolved directly in dimethylformamide. The halide derivative of Cs-Ce-cycloalkyl is then added to the suspension, preferably in dimethylformamide with heating under reflux, preferably under a nitrogen atmosphere. The target cycloalkyl ester, formed as a result of the above reaction, is recovered by a known method.

Example 1 ZM of ethyl magnesium bromide reagent Grignara in tetrahydrofuran medium prepared by the standard method is filtered through glass wool and gradually added to 700 ml of tetrahydrofuran previously saturated with acetylene at 0 ° C. During the addition of ethyl magnesium bromide, the reaction mixture is cooled to 0 ° C and acetylene is slowly bubbled through the solution. As a result of the reaction, 1.75 mol of ethinyl magnesium bromide is obtained in a medium of 1300 ml of tetrahydrofuran. Thereafter, a solution containing 10 g of 16a-hydroxyestrone diacetate in 250 ml of tetrahydrofuran is added dropwise to the solution of ethinyl magnesium bromide. The reaction mixture is heated under reflux for 24 hours under a nitrogen atmosphere, then cooled to 0 ° C. About 750 ml of a saturated ammonium chloride solution are added carefully, then an equal volume of water. The organic layer is extracted with ethyl acetate, the extract is separated and washed successively with water and 5% saturated sodium chloride solution. The solution is dried and the solvents are evaporated in vacuo. The resulting residue is triturated with approximately 1 L of boiling hexane and the hexane extract is discarded. The insoluble residue is dissolved in about 1500 ml of acetone, to which 5 ml of a 70% aqueous solution of perchloric acid is added. The solution is transferred to a flask, the contents of which are stirred with a magnetic blender at

ambient temperature for 12 hours. Solid sodium bicarbonate is then added in an excess amount and the mixture is filtered. The filtrate is concentrated to a volume of 250 ml and diluted with an equal volume of ethyl acetate. The ethyl acetate layer is washed successively with water and a saturated aqueous solution of sodium chloride, and then dried. The volatile constituents are removed by evaporation in vacuo. The resulting residue is suspended in chloroform and chromatographed over 500 g of the adsorbent "Florisil", which is washed out with 3000 ml of chloroform, followed by vacuuming of the chloroform in vacuo to give an orange

oily product. The oil is dissolved in a mixture of ether and hexane, which serves as a solvent. Crystals of 17 (3-ethynyl estra 1, 3.5 (10) -triene-3.16a, 17a - triol - 16.17-acetonide, having a melting point of about 208-21 ° C are obtained. Additional chromatography of 1000 ml of ether gives a fraction containing both 17a-ethinyl estriol and 17 | p-isomer, as evidenced by the determination by the method of thin layer chromatography.

1 liter of methanol gives a dark brown solid after evaporation of the solvent, showing only a single spot when examined by thin layer chromatography. Solid washed

chloroform and filtered. 5 g of 17CC-etynilstriol are obtained in the form of a slightly reddish-brown powdery solid, melting at 243-245 ° C. Recrystallization of the solid from the mixture

ethyl acetate with hexane gives light reddish-brown crystals of 17a-ethinyl estriol, melting upon decomposition at 245 ° C.

Example 2 11.3 g of 17a-ethynyl estriol, prepared as above, are dissolved in 500 ml of methanol. A 50% molar excess of freshly prepared sodium methoxide in methanol is added. The resulting solution is concentrated in vacuo to a solid, which is the sodium salt of 17a-ethynyl estriol. The solid is dissolved by heating in 500 ml of dimethylformamide. 50 ml of cyclopentyl bromide is added and the mixture is heated at reflux temperature under nitrogen for 4 hours. The reaction mixture is cooled and then diluted with 1 L of ethyl acetate and 1 L of water. The resulting organic layer is washed three times with water, then with a saturated solution of sodium chloride and dried. After evaporation of the solvent in vacuo, a solid residue is obtained, which is suspended in chloroform and chromatographed on approximately 100 g of phlorisil. Washout with chloroform after evaporation of the solvent gives a brownish solid residue, after recrystallization of which from a mixture of ethyl ether and hexane, about 7.7 g of 17-ethynyl estriol 3-cyclopentyl ether is obtained, melting at 162-165 ° C.

Example 3. 2.1 g of 17a-ethynyl estriol is dissolved in 100 ml of absolute ethanol and a solution containing about 0.6 ml of ethyl acetate in 100 ml of benzene is added dropwise while moving. Stirring is continued for 10 minutes, after which the solvents are removed by evaporation in vacuo. The residue consisting of the thallium salt of 17a-ethinyl estriol is suspended in 100 ml of dimethylformamide. 10 ml of cyclopentyl bromide is added and the mixture is heated at 90-95 ° C for 4 hours under nitrogen atmosphere. 17a-Ethynyl estriol 3-cyclopentyl ether, prepared in this way, is isolated and purified as indicated in Example 2.

Subject invention

The method of obtaining the 17a-ethinyl estriols of formula I

With CR

--HE

where R means hydrogen, Ci-Cz-lkili or

Sa-sa-cycloalkyl, characterized in that

that, in order to simplify the process, a mixture of isomers having formulas I and AND

Uh -o Csch

I; -one

.one

R. with

Csch

AND

where R has the above meaning, is subjected to reaction with acetone in the presence of acid and get the acetonide of formula 111

cn

111

where R has the above meaning, which is separated from the target compound; the latter is either isolated or, if desired, a compound of formula I, where R is hydrogen, is reacted in the form of the metal salt 17: a-ethinyl estriol with the halo-Cs-Sb-cycloalkyl in the medium dimethylformamide, and a Cs-Ce-cycloalkyl ester of the formula I is obtained, where R is a Cs-Sb-cycloalkyl group, which is isolated by known techniques.