DE1199263B - Process for the preparation of 17- (2-alkenyl) -bzw. 17- (2-alkynyl) -oestra-1, 3, 5 (10) -triene-3, 17beta-diols and their esters - Google Patents

Description

Process for the preparation of 17- (2-alkenyl) -bzw. 17- (2-AEdnyl) -östra-1,3,5 (10) -triene-3,17ß-diols and their esters. 17a - (2 - alkynyl) - estra - 1,3,5 (10) - triene - 3,17fl - diols and their esters of the general formula wherein X and Y are hydrogen or. is an alkanoyl radical having 1 to 6 carbon atoms and R is a 2-alkenyl or 2-alkynyl radical having 3 to 6 carbon atoms.

Examples of the alkanoyl radicals represented by X and Y are Formyl, acetyl, propionyl, butyryl, valeryl, caproyl and their branched chain Isomers- The 2-alkenyl radicals represented by R are e.g. B. the 2-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl radical and their branched-chain isomers, while the 2-alkynyl radicals z. B. the 2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl radical and their branched chain Are isomers.

Starting materials for the preparation of the compounds of the general formula (1) are the 17-keto compounds of the general formula in which Y 'denotes hydrogen or an alkanoyl or 2-tetrahydropyranyl radical. By reacting these starting materials with an organometallic reagent of Rorinel RZ, in which R is the same as above and Z is -Mg-halogen or -Zn-halogen or Z can also be lithium when R is a 2-alkenyl radical, and subsequent hydrolysis the organometallic addition group and hydrolysis of the optionally present 2-tetrahydropyranyl group of the intermediate product obtained gives the compounds of the general formula (1) in which X is hydrogen and R and Y are the same as above. In an alternative procedure, the corresponding 3-monoesters and 3,17-diesters are obtained by reacting the compounds of the general formula (1) in which X is hydrogen and R and Y have the same meaning as above with at least 1 equivalent of a corresponding acylating agent of the general formula (1). Selective deacylation of these 3,17-diesters gives the corresponding 17-monoesters of the formula (1).

Another process for the preparation of the 2-alkenyl compounds of the general formula (1) relates to the reaction of a corresponding 2-alkynyl compound with a reducing agent which reduces an alkynyl group to an alkenyl group.

All measures carried out according to the procedure are known per se.

For use in the process described above, the preferred organometallic reagents are alkenyl magnesium halides, e.g. Allyl magnesium bromide, 1- (2-methyl-2-propenyl) magnesium chloride, etc., and alkynyl magnesium halides and alkynyl zinc halides, e.g. propargyl magnesium bromide and propargyl magnesium bromide. Other valuable organometallic reagents are the 2-alkenyllithium compounds. z. B. allyllithium, and the 2-alk, enylzinc halides. z. B. Allyl zinc bromide. If an excess of the organometallic reagent R-Mg-halogen or 2-alkenyl lithium is used as starting materials of the general formula (11) in the reaction with the 3-monoesters, the addition to the keto group! accompanied by hydrolysis of the 3-alkanoyloxy group to a hydroxy group. Under mild conditions, any 3-alkanoyloxy group present in the starting material is retained during the reaction with the excess R-Zn-halogen.

The organometallic addition group of the intermediate from the Treatment with an organometallic reagent is done with an acidic reagent, such as Ammonium chloride or dilute mineral acid, e.g. B. hydrochloric or sulfuric acid, hydrolyzed. The ether group at hand. namely the 2-tetrahydropyranyl radical of the intermediate can be hydrolyzed simultaneously with the organometallic addition group. if the acidic reagent is a dilute mineral acid, or below mild conditions can be treated with a mineral acid.

The 3-monoester products of the general formula (I) can be prepared by reacting the corresponding 3.17i -, '- diols with at most 1 equivalent of a corresponding acylating agent. For this purpose, a corresponding alkanoic anhydride is preferred as the acylating agent, e.g. B. acetic anhydride. or alkanoic acid halide, e.g. B. acetyl chloride, soft in the presence of an acid-binding agent, e.g. B. pyridine can be used. The selective acylation in the 3-position using an alkanoic acid anhydride or an alkanoic acid halide is achieved under mild conditions, e.g. B. at room temperature. The 3-monoformates can be prepared by using formic acid or a mixed formic acid-acetic acid anhydride as the acylating agent. Another possibility is to produce the 3-monoester products directly by reacting the 3-Hydroöstra-1,3,5 (I0) -trien-17-one-3-monoesters as starting materials with R-Zn-halogen, since the 3- A1-kanoyloxy group can be obtained during the reaction.

The 3,17-diester products of the formula (I) can be prepared by reacting the corresponding 3,17fl-diols of the general formula (1) with at least 2 equivalents of a suitable acylating agent. Preferred acylating agents are the isopropenyl alkanoates, which are used in the presence of an acidic catalyst, e.g. B. isopropenyl acetate in the presence of p-toluenesulfonic acid. Other valuable acylating agents are alkanoic anhydrides and alkanoic acid halides, which are soft in the presence of an acid-binding agent, e.g. Pyridine used w - Earth. The 3,17-diesters can be prepared by using an alkanoic anhydride or an alkanoic acid halide as acylating agent and carrying out the reaction at reflux temperature. Another possibility is to convert the 3-Monoester of formula (1) with an acylating agent suitable for the production of 3,17-diester is-The 17-Monoester can be obtained by selective deacylation of the 3,17-diester produce. Selective deacylation can be achieved in a number of ways, e.g. By hydrolysis with alkali, alcoholysis with a lower molecular weight alcohol in the presence of alkoxide ions, or by treatment with an alkali metal aluminum hydride under selective conditions.

A suitable reducing agent for the process to be used 2-alkynyl compounds is hydrogen in the presence of a hydrogenation catalyst, z. B. a noble metal such as platinum or palladium or Raney # nickel. More suitable Reducing agents are the alkali metal aluminum hydrides, e.g. B. lithium aluminum hydride, and diborane.

The compounds of the present invention exhibit valuable pharmacological properties Properties. You are e.g. B. hormonal agents. The 2-alkenyl compounds lead a progestational proliferation of the uterine epithelium. They also show 2-Alkenyl compounds an advantageous combination of both progestational as well as estrogenic properties, as evidenced by their ability to affect the decidua Cause changes in the uterine lining. Except for their hormonal properties the 2-alkynyl compounds are valuable as intermediates for the production the corresponding 2-alkenyl compounds.

The estrogenic effect of the products of the process combined with a progestational effect is surprising, since structurally very closely related compounds, such as 17a-vinyloestra- 1,3,5 ( 10) -triene-3,17fl-diol and 17a-ethynyloestra-1, 3,5 (10) -triene-3,17p-diol, only have estrogenic effects. It makes the compounds obtainable according to the invention valuable for the treatment of menstrual disorders in which their use leads to better and safer results than the application of compounds with only an estrogenic or progestational effect.

In the following examples the temperatures are given in degrees Celsius, and the amounts of the materials are - unless otherwise stated - in parts by weight. Example 1 To a slurry of 50 parts of magnesium in 133 parts of tetrahydrofuran is added dropwise with stirring a solution of 23.5 parts of allyl chloride in 89 parts of tetrahydrofuran. A solution of 27 parts of 3-hydroxy-estra-1,3, 5 (10) - trien - 17 - one in 666 parts of tetrahydrofuran, which contains a further 126.9 parts of allyl chloride, then becomes spontaneous over a period of about 3 hours added to the refluxing mixture. The reflux is continued for about a further 2 hours, after which the reaction mixture is cooled and a solution of 125 parts of ammonium chloride in 5M parts of water is added with stirring. The two layers are separated and the aqueous phase is extracted with ether. This extract is combined with the original organic layer, then washed with water, dried over anhydrous magnesium sulfate and freed from the solvent under reduced pressure. Crystallization of the oily residue from ethyl acetate gives 17a-Aelöstra-1,3,5 (10) -triene- 3.17p-diol, which forms a solvate with 0.25 molar equivalents of ethyl acetate and melts at about 110 to 112 ', [a] #, = + 154'. The same product is obtained by using an equivalent amount of allyl lithium in place of the allyl magnesium chloride. Example 2 A mixture of 2.5 parts of 17a-allylo-1,3,5 (10) -triene-3,17fl-diol, 2.5 parts of acetic anhydride and 15 parts of pyridine is stored for about 4 hours at room temperature, then it is slowly poured in a mixture of ice and water. The gummy product which separates is isolated by decantation, then triturated with an ice-water mixture to give the crystalline product, which is filtered off, washed with water and recrystallized from aqueous acetone, so that needle-like crystals of 17a-allylo-moiety 1,3,5 (10) -triene-3,17fl-diol-3-acetate are formed, which melt at about 126 to 128 '; Ultraviolet maxima are observed at 268 and 275 millimicions, with molecular extinction coefficients of 730 and 725, respectively. The same product is obtained by using an equivalent amount of acetyl chloride instead of acetic anhydride.

Example 3 A solution of 7.4 parts of 3-chloro-2-methyl-1-propene in 35 parts of anhydrous ether is added to a slurry of 7.3 parts of magnesium in 70 parts of anhydrous ether under nitrogen. A solution of 13.5 parts of 3 - Hydroxyestra - 1,3, 5 (I0) -trien-17-on and IOTeilen 3-chloro-2-methyl-1-propene in 355 parts of tetrahydrofuran is then added dropwise with stirring at such a rate added that the reflux is maintained. The reflux is continued for a further 2 hours and the reaction mixture is cooled and then treated with an excess of aqueous ammonium chloride. The mixture obtained is filtered and the filter cake is washed with tetrahydrofuran. The organic solids are distilled off under reduced pressure and the residue obtained is dissolved in benzene. This solution is chromatographed using a silica gel column and the column is washed out with benzene and then with benzene with increasing additions of ethyl acetate. The 5% ethyl acetate in the benzene eluate are evaporated to dryness and the resulting residue is recrystallized from aqueous methanol, so that 17a- (2-methallyl) -estra-1,3,5 (10) -triene-3,17ß-diol is formed, which is at about 164 to 165 ' melts. It is also characterized by an ultraviolet maximum at about 280.5 millimicrons with a molecular extinction coefficient of about 2300 . The same product is obtained by using an equivalent amount of 3-hydroxyestra-1,3,5 (10) -trien-17-one-3-acetate instead of 3-hydroxyestra-1,3,5 (10) -triene-17 -on.

Example 4 By reacting 2.6 parts of 17a- (2-methallyl) -estra-1,3,5 (10) -triene-3,17β-diol with 2.5 parts of acetic anhydride and 15 parts of pyridine according to the procedure of the example 2, 17a- (2-methallyl) -estra-1,3,5 (10) -triene-3,17β-diol-3-acetate is obtained. Recrystallization from acetone-heptane gives platelets of the pure material which melt at about 120 to 12 l '. Ultraviolet peaks are observed at about 268 to 275 millimicrons with molecular extinction coefficients of about 785 and 748, respectively. The same product is obtained by using an equivalent amount of acetyl chloride in place of the acetic anhydride.

Example 5 A mixture of I part 17a-allyloestra-1,3,5 (10) -triene-3,17fl-diol, 20 parts isopropenyl acetate and 0.15 part p-toluenesulfonic acid monohydrate is heated gently for about 7 hours so that the acetone formed distills off can. After cooling, ether is added to this reaction mixture and the organic solution is washed successively with water, aqueous sodium bicarbonate and water. then dried over anhydrous potassium carbonate which contains decolorizing charcoal. The resulting solution is freed from the solvent under reduced pressure, so that 17a-allyloestra-1.3,5 (10) -triene-3.17 # -diol-3,17-diacetate is formed, which melts at about 120 to 121 '.

If 1.04 parts of 17a- (2-methallyl) -estra-1,3,5 (10) -triene-3,17fl-diol are used in the process described above, 17a- (2-methallyl) -estra- 1,3,5 (10) -triene-3,17fl-diol-3,17-diacetate, which melts at about 109 to 111 #.

EXAMPLE 6 0.5 part of p-toluoisulphonic acid is added to a solution of 100 parts of 3-hydroxyestra-1,3,5 (10) -trien-17-one in 500 parts of dry benzene and 40 parts of dihydropyran. The resulting mixture is allowed to stand for 1 hour at room temperature and then shaken out four times with 300 parts each of saturated aqueous sodium bicarbonate and twice with 300 parts of salt solution each time. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is taken up in 300 parts of ethanol and the resulting solution is cooled. The resulting precipitate is filtered off, and 3-hydroxyestra-1,3,5 (10) -trien-17-one-3- (2-tetrahydropyranyl) ether is obtained. Using an equivalent amount of this ether in the procedure of Example 3 gives 17a- (2-methallyl) -estra-1,3,5 (10) -triene-3,17fl-diol-3- (2-tetrahydropyranyl) ether . A mixture of 10 parts of 17a- (2-methallyl) -estr-1,3,5 (I0) -triene - 3,17fl - diol - 3 - (2 - tetrahydropyranyl) - ether, 100 parts of methanol and 0.5 parts of Hydrochloric acid is refluxed for 2 minutes and then diluted with 100 parts of water. On cooling to room temperature, a precipitate is formed, which is filtered off and recrystallized from aqueous ethanol, 17a- (2-methallyl) -estra-1,3,5 (10) -triene-3,17fl-diol, which is formed with the product of Example 3 is identical.

Example 7 A mixture of 27 parts of 3-hydroxyestra-1,3,5 (10) -trien-17-one, 33 parts of zinc and 700 parts of tetrahydrofuran is refluxed with stirring. To this solution, 60 parts of 3-bromo-1-propyne are gradually added while the mixture is gently refluxed; then refluxing is continued for a further 11/2 hours. The reaction mixture is cooled and decanted from the zinc into a solution of 163 parts of concentrated hydrochloric acid and 2000 parts of water. The resulting mixture is extracted with chloroform and the chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in a mixture of 150 parts of ethanol and 52 parts of acetic acid. The mixture is then refluxed with 7.5 parts of trimethylaminoacetohydrazide hydrochloride for about 112 hours. The solution is cooled and poured into a mixture of ice and water, a dark brown precipitate separating out. This is purified by chromatography by adsorption on silica gel in a column and then washed out with benzene, which contains increasing amounts of ethyl acetate. The desired product is recrystallized from a mixture of acetone and heptane. pure 17a- (2-propynyl) -estra-1,3,5 (10) -triene-3,17β-diol is obtained which melts at about 162 to 165 '.

Example 8 A mixture of 54 parts of 17a- (2-propynyl) -estra-1,3,5 (10) -triene-3,17fl-diol, 1500 parts of dioxane, 1000 parts of pyridine and 30 parts of a catalyst composed of 5% palladium on calcium carbonate is shaken in a hydrogen atmosphere until about 1 molar equivalent of hydrogen is consumed. At this point the hydrogenation is stopped and the catalyst is filtered off. The filtrate is concentrated in vacuo to about 500 parts, diluted with 3000 parts of ether and washed with dilute aqueous hydrochloric acid until Congo red indicates an acidic reaction as an indicator. The solution is successively with water. 5% sodium carbonate solution, washed again with water and with saturated aqueous sodium chloride solution. The ether solution is dried over sodium sulfate, concentrated on a steam bath to about 500 parts and diluted with 8000 parts of petroleum ether. After about 16 hours at 00 the product is filtered off, dried and recrystallized from a mixture of ethyl acetate and petroleum ether. Recrystallization from ethyl acetate gives 17α-allyloestra-1,3,5 (10) -triene-3,17β-diol, which is identical to the product described in Example 1.

Example 9 Using an equivalent amount of 17a- (2-propynyl) -estra-1,3,5 (10) -triene-3,17fl-diol-3-acetate and 17a- (2-propynyl) -estra-1 , 3,5 (10) -triene-3,17fl-diol-3,17-diacetate in the process of Example 18 gives the corresponding 17a-allyl derivatives.

Claims (1)

Claim: Process for the production of 17- (2-alkenyl) -bzw. 17- (2-alkynyl) -estra-1,3.5 (10) -triene-3,17ß-diols and their esters of the general formula in which X and Y is hydrogen or an alkanoyl group having 1 to 6 carbon atoms and R is a 2-alkenyl or 2-alkynyl radical containing 3 to 6 carbon atoms, d a d u rch gc -kenn characterized in that by conventional methods a) a compound of the general formula in which Y 'is hydrogen or an alkanoyl or 2-tetrahydropyranyl radical, is reacted with an organometallic reagent of the formula RZ, where R has the same meaning as above and Z is -Mg-halogen or -Zn-halogen or can also be lithium , if R is a 2-alkenyl radical, then hydrolyzed the organometallic addition group and any 2-tetrahydropyranyl ether group present in the intermediate product, or b) a compound of the general formula (1) in which X is hydrogen and R and Y have the same meaning as above , reacts with at least 1 equivalent of a corresponding acylating agent and optionally hydrolyzes the 3-position acyloxy group in the 3,17-diacylates obtained, or e) a compound of the general formula wherein X and Y have the same meaning as above and R 'is a 2-alkynyl radical, brings into contact with a reducing agent which reduces the alkynyl group to an alkenyl group.