DE1010964B - Process for the preparation of 4-estren-3, 17-diols and their esters - Google Patents

Description

Process for the production of 4-estrene-3, 17-diols and their esters The invention relates to a process for the production of certain highly active, synthetic agents which influence the metabolism, in particular 4-estrene-3, 17-diol, its in 17 -Position substituted derivatives and their esters, The compounds according to the invention can be represented by the following formula « in which R and R 'denote hydrogen, the benzoyl radical or acyl radicals of aliphatic carboxylic acids having 1 to 8 carbon atoms. A can either be a hydrogen atom or a lower saturated or unsaturated aliphatic hydrocarbon radical.

In the structural formula above, R and R 'can be hydrogen, den Benzoyl radical and acyl radicals mean derived from aliphatic carboxylic acids are such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl; Cyclopentanoacetyl, Cyclopentanopropionyl or cyclohexanoacetyl radicals and the like. The radical A can be hydrogen or a lower alkyl radical such as a methyl or ethyl radical, straight-chain or branched propyl and butyl radicals, an alkenyl radical, e.g. B. a vinyl, allyl or butenyl radical and alkynyl radicals, e.g. B. an ethynyl, propynyl, butynyl radical or the like.

The compounds of the structural formula above can be used in a simple manner Way by reducing the corresponding 3-keto - '#' compounds. The reduction can be carried out with reagents that select the keto group reduce without the unsaturated bond between the carbon atoms in 4- and 5 position to attack. A typical example is the Meerwein-Ponndorf-Verley reaction be applied. Furthermore, alkali metal aluminum hydrides and are particularly favorable Bonhydrides such as lithium aluminum hydride and sodium borohydride.

The 4-estrene-3 substituted in the 17-position by an alkyl group, 17-diols can be obtained by hydrogenation of 17a-substitution products of 4-estren-3, 17-diols are produced in which the a-position substituent consists of an unsaturated aliphatic hydrocarbon radical. Such residues can be ethylene or Acetylene bonds contain and include, for example, ethynyl, propynyl and Butynyl and vinyl, propenyl, allyl radicals and their higher homologues. As an an example 17a-ethynyl-4-oestren-3, 17-diol is used to carry out such a hydrogenation in solution or suspension in a hydrogen atmosphere in the presence of a suitable one Catalyst, for example a noble metal catalyst, such as palladium on charcoal, shaken. The compound is gradually via 17a-vinyl-4-oestren-3, 17-diol reduced to 17 ethyl-4-oestren-3, 17-diol. Under the conditions described the hydrogenation of the double bond in the core is a relatively minor one Side reaction. An advantageous and equivalent modification of this method for Production of 17-ethyl-4-oestren-3, 17-diol is the catalytic reduction of 17a-vinyl-4-oestrene-3, 17-diol.

The reduction of a 3-position keto group and the hydrogenation of a 17 unsaturated hydrocarbon radicals are known measures. Their application leads to the special starting materials used according to the invention however, substances that are particularly valuable for medicine and veterinary medicine are used in only low androgenic effects, excellent progestational and anabolic metabolism possess promoting effectiveness.

Suitable starting materials for the preparation of 17a-alkenyl and - '# Alkynyl derivatives of 4-estren-3, 17-diol are 17a-substitution products of 19-nortestosterone, in which the 17a-position substituent is an unsaturated is an aliphatic hydrocarbon radical. You can easily search for different Processes are produced in which acetylene, acetylene homologs or organometallic Compounds become attached to a 17-ketosteroid. For example, 17a-ethynyl-19-nortestosterone by the addition of acetylene 3-methoxy-2,5 (10) -oestradien-17-one and then acid catalyzed hydrolysis and isomerization of the obtained Product. The addition of allyl magnesium bromide to 3-methoxy-2, 5 (10) -oestradien-17-one and subsequent acidic hydrolysis and isomerization gives 17-allyl-19-nortestosterone. These 19-nortestosterone derivatives can then be used selectively in 3-position, e.g. B. with alkali metal aluminum hydride or borohydride or after Meerwein-Ponndorf-Verley reaction with formation of the 17a-substitution product of 4-Oestren-3,17-diols are reduced.

The 3,17-diesters of the invention are prepared from the 3,17-diols in a conventional manner Procedure received. The 3-position oxy group can be selectively obtained using 1 Molar equivalents of acyl halide or anhydride are esterified; this procedure is particularly applicable to the derivatives substituted in the 17-position. 17 monoester are made by reducing the corresponding ester of 19-nortestosterone or its 17a-substituted derivatives with sodium borohydride or an equivalent reagent obtain; the esterification of the 3-position oxy group of the monoester obtained results Diesters substituted by two different acyl groups.

The following examples illustrate the process according to the invention. Example 1 A solution of 7.2 parts of 19-nortesterone in 700 parts of ether is under Stirring a suspension of 6 parts of lithium aluminum hydride in 210 parts of ether added. The mixture is heated to 35 ° for 45 minutes while stirring; after that will an amount of acetone added to decompose the excess lithium aluminum hydride sufficient. Then water is added, the organic layer is separated off and washed first with water and then with saturated sodium chloride solution. After this Dry over anhydrous sodium sulfate and filter, the solvent is im Vacuum removed. The residue is dissolved in a 10% solution of ethyl acetate in benzene applied to a chromatographic column containing 760 parts of silica gel. The column is then filled with benzene and 5-, 10- and 15% solutions of ethyl acetate washed in benzene. Elute with a 20% solution of ethyl acetate in benzene and repeatedly recrystallizing the residue from a mixture of ethyl acetate and cyclohexane gives 4-estrene-3, 17-diol, which melts at about 202-204 °. The infrared absorption spectrum shows a broad band at 3.0 and a band at 6.05 #t. It is evidently the 4-oestren-3a, 17ß-diol.

A mixture of 1 part of 4-estren-3, 17-diol, 10 parts of benzoic anhydride and 1 part of finely powdered potassium benzoate is stirred for 24 hours at room temperature, then cooled with ice and left to stand for a further 3 hours at room temperature. Of the The resulting precipitate is filtered off, washed with water and successively extracted recrystallized aqueous ethanol and cyclohexane. The 3,17-dibenzoyloxy-4-oestrene obtained shows infrared maxima. at 5.8 and 6.1 #t.

Example 2 A solution of 14.4 parts of 19-nortestosterone in 400 parts Methanol and 50 parts of ethyl acetate become a solution of 10 parts of sodium borohydride added in 200 parts of methanol. The mixture is about 1 hour at room temperature kept and first with 30 parts of water and then with one to reduce the pH to 6 treated with sufficient amounts of acetic acid. The reaction mixture is concentrated to about 50 parts on a steam bath in a stream of nitrogen. After this Dilute with 600 parts of water, the precipitate is filtered off and washed with water washed. Chromatography on silica gel as in the previous example gives 4-Oestren-3,17-diol having the same physical properties as those in the above Example product received. Example 3 A mixture of 35 parts of 19-nortestosterone propionate, 100 parts of methanol and 10 parts of ethyl acetate are 20 parts of sodium hydride in 50 Parts of methanol were added. After stirring for 1 hour at room temperature, 6 parts Water is added and the pH is lowered to 6 by adding acetic acid. The mixture is reduced to one third by concentration on a steam bath in a stream of nitrogen of its original volume, and this remainder is poured onto it with water Diluted twice its volume. The precipitate is filtered off with water washed and following the procedure of Example 1 over a column of silica gel chromatographed.

Elution with a 15% solution of ethyl acetate in benzene gives the 17-propionoxy-4-oestren-3-ol. The infrared absorption shows maxima at 2.9 and 5.8 #t. Example 4 50 parts of ethyl acetate and 10 parts of sodium borohydride in 200 parts of methanol are added to a mixture of 22 parts of 19-nortestosterone β-cyclopentanopropionate in 1000 parts of methanol. The mixture is stirred for 10 minutes at 20 ° and then treated with 30 parts of water and an amount of glacial acetic acid sufficient to reduce the pH to about 6. The mixture is concentrated to 300 parts by concentration on the steam bath in a nitrogen atmosphere and then diluted with two times its volume of water. A precipitate forms, which is filtered off and washed with water. Recrystallization from ethyl acetate and cyclohexanone gives 17- (β-cyclopentanopropionoxy) -4-oestren-3-ol, which can be further purified by chromatography on silica gel. The product shows infrared maxima at 3.0, 5.8 and 6.05 @ ,. It has the following structural formula: EXAMPLE 5 2 parts of sodium borohydride in 12 parts of methanol are added to a solution of 2 parts of 17α-ethyl-19-nortestosterone, which can be prepared by the process specified in US Pat. No. 2,721,871, in 25 parts of methanol. The mixture is kept at room temperature for 60 minutes and then slowly acidified with acetic acid. The mixture is diluted with 150 parts of water and cooled to 0 °. The resulting precipitate is filtered off, washed with water and recrystallized from aqueous methanol using charcoal to decolorize. In this way, 17a-ethyl-4-oestren-3, 17-diol is obtained. It appears that this product contains predominantly the 3 [beta], 17 [beta] isomer and that there is a small admixture of the 3a epimer. The product melts on a melt block at around 80 °, partially solidifies again and melts again at 125 °. The above material shows no specific absorption in the ultraviolet range between 220 and 360 mp ..

A solution of one part of 17a-ethyl-4-oestren-3, 17-diol in 4 parts of propionic anhydride and 4 parts of pyridine is heated on a steam bath in a nitrogen atmosphere for 1 hour and then treated with ice. The solid precipitate is collected on a filter and successively recrystallized from aqueous methanol and petroleum ether. The 17a-ethyl-3-propionoxy-4-oestren-17-ol obtained in this way melts at about 87 to 88.5 ° and shows infrared maxima at 2.79; 5.82; 6.87; 8.40; 9.25 and 9.92 A mixture of 253 parts of 17a-ethyl-4-oestren-3, 17-diol, 852 parts of succinic anhydride and 2000 parts of pyridine is heated on a steam bath for 90 minutes and then treated with ice. After 30 minutes the precipitate is filtered off, washed with water and recrystallized first from aqueous methanol and then from a mixture of ethyl acetate, cyclohexane and petroleum ether. The 3-hemisuccinate of 17a-ethyl-4-oestren-3, 17-diol, which is obtained in this way, melts at about 168 to 170 °. Example 6 A solution of 28 parts of 17a-propyl-19-nortestosterone, prepared e.g. B. according to the method given in US Pat. No. 2,721,871 , in 200 parts of methanol, a solution of 17.5 parts of sodium borohydride in 120 parts of methanol is added. The mixture is kept at room temperature for 45 minutes and then treated with 5 parts of water and 15 parts of acetic acid. The reaction mixture is diluted with water and then cooled. The precipitate is filtered off and recrystallized from aqueous methanol. The mixture of 17a-propyl-4-oestren-3ß, 17ß-diol and 17a-propyl-3a, 17ß-diol obtained in this way shows infrared maxima at 2.9 and 6.0 #t. EXAMPLE 7 7.2 parts of 19-nortestosterone in 700 parts of ether are added to a suspension of 6 parts of lithium aluminum hydride in 2100 parts of ether. The mixture is stirred while heating on a steam bath for 45 minutes; then the unreacted lithium aluminum hydride is decomposed by adding acetone. The mixture is diluted with water, the organic layer is separated and washed successively with water and saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the ethereal solution is evaporated under vacuum; the residue is dissolved in benzene and applied to a chromatographic column which contained 760 parts of silica gel. The column is developed with benzene and then successively with 5- and 10% solutions of ethyl acetate in benzene. Further elution with a 15% solution of ethyl acetate in benzene and the concentration of the eluate results in a residue which is recrystallized from acetone and water, ethyl acetate and petroleum ether and again from acetone and water and a 4- Oestren-3, 17-diol gives. This compound is apparently the 4-oestren-3ß, 17ß-diol. It shows infrared maxima at 2.91; 6.0; 6.90; 8.26; 8.78; 9.36; 9.61, 11.21, 11.43 and 11.62 p, and no ultraviolet absorption spectrum between 220 and 360 m # t.

The further development of the column with a 20% solution of Ethyl acetate in benzene and concentrating the eluate gives a relatively smaller one Amount of a compound which is believed to be the 3 a-epimer of the above 4-oestren-3, Represents 17-diol. Successive recrystallizations from aqueous methanol and then from ethyl acetate and cyclohexane give one melting at about 202-204 ° Product. The infrared absorption spectrum shows maxima at 3.0; 6.05; 7.01; 7.23; 7.42; 7.84; 8.80; 9.19; 9.46; 10.05; 11.06 and 11.64 A mixture of 10 parts of 4-oestren-3, 17-diol (which melts at about 169 to 172 °), 50 parts acetic anhydride, 100 Parts of glacial acetic acid and 2 parts of sodium acetate are kept at room temperature for 2 hours, then treated with ice and left for two more hours. The precipitation is filtered off and washed with water. By recrystallization from aqueous Methanol and then from cyclohexane are obtained 3, 17-diacetoxy-4-oestren, the melts at about 135 to 137.5 °. Example 8 A mixture of 3 parts of 17a-ethynyl-19-nortestosterone, made by the process disclosed in U.S. Patent No. 2,702,811 3 parts of sodium borohydride and 160 parts of methanol is used for 20 minutes Kept room temperature; then 10 parts of water are added. The mixture will then acidified with acetic acid and slowly diluted with water. After cooling A precipitate forms, which is successively composed of aqueous methanol and then from a mixture of ethyl acetate and petroleum ether to form the at about 149 to 17a-ethynyl-4-oestren-3, 17-diol which melts at 150 ° is recrystallized. The infrared absorption spectrum this compound shows maxima at 2.89; 3.08; 6.03; 6.92 and 7.12 by a mixture of 11 parts of 50% palladium on charcoal in 2000 parts of dioxane is 1 hour a hydrogen stream is formed. Then 87 parts of 17a-ethynyl-4-oestren-3, 17-diol in 1500 parts of dioxane is added and the mixture is hydrogenated to 2 molar equivalents Hydrogen has been absorbed. The catalyst is filtered off and the solvent is evaporated under vacuum. The crystalline residue is in 2700 parts of benzene dissolved and then given to a chromatographic column, the 5000 parts of silica gel contained. The column is filled with benzene and then with 5 and 10% solutions of Ethyl acetate developed in benzene. Obtained by eluting with a 15% solution the 17a-ethyl-4-oestren-3, 17-diol, which has the same physical properties has like the product of Example 7.

You can also use a mixture of 10.8 parts of 17a-ethynyl-4-oestren-3, 17-diol, 300 parts of dioxane, 1000 parts of pyridine and 6 parts of one made from 5% palladium on calcium carbonate existing catalyst in a hydrogen atmosphere Shake until about 1 molar equivalent of hydrogen has been used. Then it will be the hydrogenation is interrupted and the catalyst is filtered off. The filtrate will concentrated under vacuum to about 100 parts, diluted with 600 parts of ether and washed with 1N hydrochloric acid until a sample with congo red indicates an acidic reaction. The solution is successively with water, with 5% sodium bicarbonate solution, washed again with water and with saturated sodium chloride solution. The ether phase is dried over sodium sulfate, concentrated to about 100 parts on a steam bath and diluted with 150 parts of petroleum ether. After 12 hours of storage at 0 ° the 17-vinyl-4-oestren-3, 17-diol obtained in this way is filtered off and dried and recrystallized from a mixture of ethyl acetate and petroleum ether. The infrared absorption spectrum shows maxima at 2.9 and 6.0 [j ,.

A mixture of 5 parts of 17a-vinyl-4-oestren-3, 17adiol, 40 parts Dioxane and 1.5 parts of 5% palladium on charcoal is in a hydrogen atmosphere shaken until about 1 molar equivalent of hydrogen has been consumed. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure Evaporated to dryness. Repeated recrystallization of the residue from methanol gives 17-ethyl-4-oestren-3, 17-diol, which has a double melting point at about 80 and 130 °. Example 9 A solution of 1 part of 17a-ethyl-19-nortestosterone 120 parts of absolute 2-propanol are mixed with 11 parts of freshly distilled aluminum isopropylate treated and then slowly distilled until the distillate no longer contained acetone. The remaining 2-propanol is distilled off, and the residue is under Stir poured into 200 parts of cold water. The mixture is extracted with ether. This extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The backlog will be like in the example? recrystallized and also gives 17-ethyl-4-oestren-3, 17-diol, which has the same properties has like the product of Example 7.

The use of 17a-methyl-19-nortestosterone in place of the above 17 a-ethyl compound used gives 17-methyl-4-oestren-3, 17-diol. The infrared absorption spectrum this compound shows maxima at 2.92; 6.03; 6.9; 7.3 and 8.7 #t.

Example 10 A solution of 35 parts of sodium borohydride in 250 parts Methanol is a solution of 56 parts of 17α-allyl-19-nortestosterone in 400 parts Methanol added. The mixture is kept at room temperature for 30 minutes, with Diluted 10 parts of water and weakly acidified with acetic acid. With further dilution with water and cooling, a precipitate forms, which is filtered off and repeated recrystallized from aqueous methanol and a mixture of acetone and petroleum ether will. A double melting point indicates the presence of two epimeric forms of the 17a-Allyl-4-oestren-3, 17-diols. The infrared spectrum shows maxima at 2.9 and 6.0 & ..

A mixture of 1 part of 17a-allyl-4-oestren-3, 17-diol, which according to the above process was obtained, 10 parts of methanol and 2.5 parts of one from 5 ° j, Palladium on calcium carbonate catalyst is made in a hydrogen atmosphere shaken until 1 molar equivalent of hydrogen has been consumed. The catalyst is filtered off, and the residue obtained after concentrating the filtrate is repeatedly recrystallized from methanol and gives 17a-propyl-4-oestren-3, 17-diol, which has the same physical properties as the product of the example 6th

Example 11 A solution of 10 parts of 17a-vinyl-4-oestren-3, 17-diol 40 parts of propionic anhydride and 40 parts of pyridine are added under nitrogen Heated for minutes on a steam bath and then treated with ice. The resulting Precipitate of 17a-vinyl-4-oestren-3, 17-diol-3-propionate is filtered off and recrystallized successively from aqueous methanol and petroleum ether.

With a mixture of 1 part activated carbon containing 5% palladium, and 200 parts of dioxane, hydrogen is passed for 1 hour. Then you give 1G parts 17a-vinyl-4-oestren-3, 17-diol-3-propionate in dioxane solution. The resulting mixture is shaken until about 1 molar equivalent of hydrogen is absorbed. The catalyst is then filtered off and the filtrate under reduced pressure Pressure evaporated to dryness. By successive recrystallization aqueous methanol and petroleum ether give 17α-ethyl-4-oestren-3, 17-diol-3-propionate with a melting point of about 87 to 88 °.

The same compound can also be obtained by using 17a-ethynyl-4-oestren-3, Esterified 17-diol and hydrogenated the ester obtained until 2 molar equivalents Hydrogen are absorbed.

Claims (3)

PATENT CLAIMS: 1. Process for the preparation of 4-estrene-3,17 -diols and their esters of the general formula in which R and R 'are hydrogen, the benzoyl radical or acyl radicals. aliphatic carboxylic acids having 1 to 8 carbon atoms and A is hydrogen or a lower aliphatic, saturated or unsaturated hydrocarbon radical, characterized in that one in a compound of the general formula in which R 'and A have the meaning given above, the 3-position keto group is reduced in a known manner with a reducing agent which does not attack the nuclear double bond, then, if A is an unsaturated hydrocarbon radical, this optionally with a reagent which does not attack the nuclear double bond in a known manner hydrogenated and optionally one or both hydroxyl groups esterified in a manner which is also known. 2. The method according to claim 1, characterized in that that the reduction of the keto group with a hydride of the formula (alkali metal) X H4, in which X is an element of III. Group of the periodic table with an atomic number means less than 24, in particular with sodium borohydride or lithium aluminum hydride, or according to the method of Meerwein-Ponndorf. 3. The method according to claim 1 and 2, characterized in that 19-nortestosterone, 19-nortestosterone - ß - cyclopentyl propionate, 17 a - methyl, 17a-ethyl, 17a-propyl, 17a-vinyl, 17a-allyl or 17a-ethynyl-19-nortestosterone used as a starting material. Considered References: Danish Patent No. 74 977; U.S. Patent No. 2,666 769, 2 691028; Journ. Amer. Chem. Soc., Vol. 76, p. 4482 (1954); Angew. Chemistry, Vol. 53, P.266 (1940).