DE1182229B - Process for the preparation of 7-methyl steroids - Google Patents

Description

Process for the production of 7-methyl steroids The invention relates to a process for the production of 7-methyl steroids of the general formula in which P is hydrogen or the methyl group, M is hydrogen, an alkyl, alkenyl or alkynyl group, Y is hydrogen or the acyl radical of a lower carboxylic acid, X is hydrogen or a fluorine atom and Z = H2; H, a-OH; H, ß-OH or H, α-acyloxy, where, if P is hydrogen, the 1 (2) position is saturated and, if P is a methyl group, the 1 (2) position can be saturated or unsaturated, and P and M only represent a methyl group at the same time when the 1 (2) position is saturated.

The process according to the invention consists in that, in a manner known per se, a 6-dehydro compound of the general formula in which P, Y and Z have the meaning given above and R is hydrogen or an alkyl group, in the presence of an agent promoting the 1,6-addition reaction with a methylmagnesium halide, the 7-methyl compound of the general formula obtained is reacted in which P, Y, Z and R have the meaning given above, a) optionally microbiologically hydroxylated in the 11-position or a 17β-position acyloxy group obtained in this compound is hydrolyzed and optionally the 11-hydroxy compound obtained (Z = H, OH) or the compound unsubstituted in the 11-position (Z = H2), in which Y and R are hydrogen, oxidizes to the corresponding 7-methyl-3,17-diketo or 7-methyl-3,11,17-triketo compound converted into the 3-enamine, which converts the 3-enamine with an alkyl, alkenyl or alkynyl magnesium halide, an alkyl or alkenyl lithium or an alkali derivative of an alkyne to the 3-enamine of the 17-alkylated, alkenylated or alkynylated 7a-methyl steroid, from this the 3-position enamine group is removed hydrolytically, the compound thus obtained is optionally converted into a 17-acyloxy derivative and, if M is an alkynyl radical, this is optionally catalytically hydrogenated to an alkyl group, or b) if P is a e is a methyl group and M is an alkyl radical or hydrogen and Y and Z have the meanings given above, the 1 (2) position is dehydrogenated. if Z in the starting material is H, β-OH, optionally the 9 (11) position is dehydrated, the 9 (11) double bond is added to the hypohalous acid, the 9α-halogen-11β-hydroxy compound obtained with a weak base in the The corresponding 9β, 11β-oxido compound is transferred, the 9β, 11β-oxido compound is treated with hydrogen fluoride, the 9α-fluoro-11 @ -hydroxy compound obtained is optionally oxidized with chromic acid to give the 11-ketone and, if appropriate, the mixture of 7a- and 7β-methyl epimers is carried out Treatment with chloranil separates.

The 7-methyl-19-nortestosterone and 7-Methyltestosterone as well as the 1-Dehydro-7-methyltestosterone possess elevated levels of androgens and anabolic, furthermore antiestrogenic, gonadotropin-inhibiting and progestational ones as well as the central nervous system calming properties, being the ratio of anabolic to androgenic effects especially with 7-methyl-19-nortestosterones is cheap.

So the 7a, 17a-dimethyl-19-nortestosterone has 22 times the anabolic and only the 5.7-fold androgenic effect of 17a-methyl-19-nortestosterone. The relationship from anabolic to androgenic effect is 3.9 for him, for 17a-methyl-19-nortestosterone n u t 1.0. It is the most effective anabolic agent ever studied.

7f, -Methyl-] 7a-ethyl-19-nortestosterone is 22 times more anabolic Effect of 17a-ethyl-19-nortestosterone, and 7a-methyl-17a-ethinyl-19-nortestosterone is 40 to 60 times more effective than gonadotropin-inhibiting effects 17a-athinyl-19-nortestosterone.

The 17β-cyclopentylpropionic acid ester and the 17β-phenylpropionic acid ester of 7a-methyl-19-nortestosterone have the same duration of action 13 or 12 times anabolic, 5 times myotropic and more than 5 or 5 times anadrogenic Effect of testosterone-17ß-cyclopentylpropionate. The excellent one is also surprising Effect of 7 (<- methyl-19-nortestosterone and its 17-acetate when administered orally, which is rare in steroid compounds without alkyl substituents in the 17-position.

The 17-acetate of 7a-methyl-19-nortestosterone is due to its pronounced, but only relatively short-lasting androgenic effect in the Suppression of tumors is important.

The methylation of the 7a position also leads to testosterones to an increase in the myotropic and androgenic effects. The 7a-17a-dimethyltestosterone shows 13 times myotropic, about 6 times anabolic when administered orally and the 3-fold androgenic effect of 17a-methyl-testosterone. It is with humans effective even in small doses. The ratio of anabolic to androgenic effects is 1.9 for him, only 1.0 for 17a-methyltestosterone. 1-dehydro-7a, 17a-dimethyltestosterone is 1.6 times as effective as 1-dehydro in terms of its gonadotropin-inhibiting effect - 17a - methyl - testosterone, and 7a - methyl-17a-äthinyl-testosteron sets at oral administration reduced fertility by more than 2.5 times that of 17a-athinyltestosterone.

The 7a-methyl-19-nortestosterone are also valuable starting materials for the production of 7a-methylestrone and 7a-methylestradiol, the increased anti-gonadotropin, anti-fertility and anti-cholesterol Show blood-lowering effect. It is obtained by treating 7a-methyl-19-nortestosterone with dehydrating microorganisms and subsequent hydrogenation.

For therapeutic use, the process products are listed under Use of the usual solid and liquid carriers in which they are dissolved, dispersed or can be suspended, in administration forms which can be administered orally and parenterally transferred, z. B. in tablets, powders, capsules, pills, solutions, emulsions, Suspensions, syrups and elixirs, if possible a certain unit per unit Amount of steroid included. The 17a-alkyl compounds are preferably used orally, because they have a particularly beneficial effect in this form of administration.

To carry out the process according to the invention, this is used as the starting material used 6-dehydro-testosterone or 6-dehydro-19-nortestosterone with an excess a methyl Grignard reagent, such as methyl magnesium iodide or bromide, in the presence of copper (I) chloride or another suitable, in Grignard Reactions, K h a -r a s c h and R e i n m u t h, Prentice Hall, Inc. Publishers (1954), p. 219, implemented catalyst described. However, CuCl is preferred. The implementation can be used in various inert solvents, e.g. B. in benzene, toluene, ethylene glycol dimethyl ether, Ether, tetrahydrofuran or mixtures of these solvents. The reaction temperature can be between -40 ° C and the boiling point of the reaction mixture lie. In general, a temperature between 0 and 60 ° C. is preferred. There one Oxygen function in the 17-position and, to a limited extent, also a hydroxyl group in the 11 position reacts with the Grignard reagent is to ensure a complete implementation more than one molar equivalent of Grignard compound used. A ratio of at least 5 moles of Grignard compound is preferably used Mole steroid. The best yields are achieved with methyl magnesium bromide.

Is in the received 7-methyl-19-nortestosterone or 7-methyl: testosterone Y is hydrogen, the hydroxyl group in the 17-position can be used in a conventional manner, e.g. B. by treatment with a suitable acid anhydride or acid halide in the presence a tertiary base such as pyridine, acylated.

According to reaction path a) of the process according to the invention, the 7a-methyl-19-nortestosterone obtained is then optionally hydroxylated in the 11-position. To this end, it is subjected to the action of a microorganism of the genus Mucorales, Aspergillus, Penicillium or Streptomyces which introduces a hydroxyl group in the 11 a position according to the processes described in U.S. Patents 2,602,769, 2 649 400, 2 649 401 and 2 649 402 or a microorganism hydroxylating the lß-position, e.g. B. of the genus Cunninghamella blakesleeana, Curvularia lunata or Trichothecium roseum. The introduction of a hydroxyl group in the position is z. Example 22 of U.S. Patent No. 2,602,769.

If Y represents an acyloxy group, this becomes during the microbiological Hydroxylation generally removed. It must therefore, if so desired are subsequently reintroduced. In this case, an optionally in 11 a-position hydroxyl group present are acylated.

To obtain compounds in which Z is a keto group, oxidized one the corresponding 11a- or 1 l ß-hydroxy compound in a known manner with chromic acid or sodium or potassium dichromate, with one at the same time optionally in the 17-position existing hydroxyl group is oxidized to the keto group if the 17a-position is not is substituted.

An oxidation of the 17-position hydroxyl group without impairment To reach a 11a or 11a hydroxyl group, one oxidizes to O p p e n a u e r, e.g. B. using aluminum tert-butoxide and acetone or Cyclohexanone in the presence of an anhydrous organic solvent such as toluene, Benzene, petroleum ether or dioxane.

The 17-keto compounds are then treated, if appropriate in the presence of an acidic catalyst, with a suitable secondary cyclic amine, e.g. B. pyrrolidine, piperidine, a C-alkyl-substituted pyrrolidine or piperidine, such as 2,4-dimethyl-pyrrolidine, 3-propyl-piperidine, 2-methyl-pyrrolidine, 3,4-dimethyl-pyrrolidine, 3-ethylpyrrolidine, 3-isopropyl pyrrolidine, 3,3-dimethylpyrrolidine or with other pyrrolidines and piperidines substituted by lower alkyl groups, in order to obtain the corresponding 3-enamine. Pyrrolidine is preferred. Advantageously, the amine is used in excess and the reaction is carried out with heating in the presence of a suitable solvent, e.g. B. a lower alcohol such as methanol or ethanol. The 3-enamine generally separates out after the reaction mixture has been concentrated and cooled.

It is then replaced in the 17-position by an alkyl, alkenyl or alkynyl radical substituted. The 3-enamine is used for this in the presence of a solvent, such as Dimethyl ether, tetrahydrofuran or benzene, with an alkyl, alkenyl or alkynyl magnesium halide around. The Grignard reagent is preferably used in an excess of about 10 moles per Moles of enamine used. The 17-alkyl-, 17-alkenyl- or 17-alkynyl-3-enamine obtained is generally not isolated, but in situ by treatment with an aqueous one Solution of a base such as sodium hydroxide or potassium hydroxide, hydrolyzed. Before the excess of the Grignard reagent with water, ammonium chloride solution or the like. decomposed.

A suitable alkylating agent or alkenylating agent can also be used Alkyl or alkenyl lithium compound can be used. This implementation becomes expedient in an inert solvent such as ether, benzene or toluene using an excess of lithium compound of preferably at least 1.5 mol per Molar compound to be alkylated carried out. Usually one works at room temperature, however, can also use elevated temperatures up to the boiling point of the solvent.

The 17a-alkynyl compounds can also by reaction with a Alkali metal derivative, e.g. B. the sodium or potassium derivative of a corresponding Alkyne can be obtained. It is preferably carried out in the presence of an inert one Solvent, such as dimethylformamide or dimethyl sulfoxide. The so produced 17-Alkynyl-3-enamines are also generally not isolated, but usually hydrolyzed in situ as indicated above.

The 17-alkenyl and 17-alkynyl compounds can then, optionally after acylation of free hydroxyl groups in the presence of a suitable hydrogenation catalyst, such as palladium-carbon, can be hydrogenated to the corresponding 17-alkyl compounds.

When treating 6-dehydro-17a-ethyl-testosterone (US Pat. No. 2,739,974) with a methyl Grignard reagent in the presence of an agent which promotes 1,6-addition, e.g. B. copper (I) chloride, according to the method described above, 7a-methyl-17a-ethyl-testosterone is obtained.

This compound can also be obtained by using 7a-methyl testosterone with chromic acid or sodium or potassium dichromate to form 7a-methyl-androstene-3,17-dione oxidized, this converted into a 3-enamine, the 7a-methyl-androstene-3,17-dione-3-enamine with an ethyl Grignard reagent and the 3-enamine of 7a-methyl obtained = 17a-ethyl-testosterone hydrolyzed in situ without isolation.

An alternative production method consists in the implementation of 7a-methyl-androstene-3,17-dione-3-enamine with an alkali metal compound of an alkyne, e.g. B. sodium or potassium acetylide, Hydrolysis of the 7a-methyl-17a-ethinyl-testosterone-3-enamine obtained without isolation and hydrogenation of the 7a-methyl-17a-ethinyl-testosterone formed to 7a-methyl-17a-ethyl-testosterone.

The δ-dehydro-19-nortestosterone acetate which can be used as starting material in the process according to the invention obtained by reacting 19-nortestosterone with acetic anhydride and acetyl chloride in pyridine solution, subsequent bread ration of the 3,17ß-diacetoxy-19-nor obtained äs, ä-androstadiens and elimination of hydrogen bromide from the 6-bromo-19-nortestosterone-17-acetate formed (See British Patent 833 183).

A 17-alkyl-19-nbrtestosterone is used instead of 19-nortestosterone and corresponding acid anhydrides and acid chlorides, 17-alkyl-6-dehydro-19-nortestosterone-17-acylate is obtained. The free 17-hydroxy compounds can in a conventional manner, for. B. by treating with a base such as sodium or potassium hydroxide in aqueous or aqueous-alcoholic Solution.

After reaction path b) of the process according to the invention, the 7-methyltestosterone obtained by reaction with a methyl Grignard compound in 1-dehydro-7-methyl-testosterone transferred. This can be done in a known manner, for. B. be purified by recrystallization or chromatography. Contains the raw 1-dehydro compound still has substantial amounts of starting material, so this can separated by conversion into the 3-enamine, e.g. B. by cooking for several hours in benzene in the presence of a secondary cyclic alkyleneamine such as pyrrolidine. The 1-dehydro compound does not form an enamine under these conditions. The mixture -from 1-dehydro compound and 3-enamine can by treating with dilute mineral acid, in which the 3-enamine dissolves, are separated. The 1-dehydro compound can optionally can still be purified by recrystallization.

If the d1-7-methyl-testosterone contains a hydroxyl group in the 11 position, so it is converted into the corresponding 7-methyl-d1,9 (11) -dehydro-testosterone by known methods, if necessary converted. It is in z. B. methylene chloride, tert-butyl alcohol, dioxane, tert-amyl alcohol or acetone solution to the 9 (11) double bond hypohalogenous Acid deposited. Instead of free hypohalous acid, it is advantageous to use an N-halo amide or imide, from which the hypohalogenous is formed in the presence of a mineral acid Forms acid in situ. Suitable N-halogenamides or imides are, for. B. N-chloroacetamide, N-bromoacetamide, N-bromosuccinimide, N-chlorosuccinimide and N-iodosuccinimide. As a mineral acid one generally uses dilute perchloric acid or dilute sulfuric acid. The reaction is usually carried out between 0 and 30 ° C, but can also at higher or lower temperatures. The hypohalous acid releasing The reagent is generally used in equimolar amounts or in a slight excess used by about 25%. A large excess can be used, but is not desired, as it can lead to an attack at other locations on the molecule. The reaction time is generally from 4 to 5 minutes to 1 hour. After completion the reaction is the excess hypohalous acid by adding sodium sulfite or other sulfites or bisulfites destroyed. The obtained A 1-7-M ethyl - 9a - halogen -11ß - hydroxy - testosterone is made by adding water and extraction the reaction mixture with an organic solvent such as methylene chloride, Chloroform, benzene, toluene, ether, ethyl acetate or hexane hydrocarbons, the are known under the trade name "Skellysolve B", or by filtering isolated. If necessary, it can be purified by recrystallization or chromatography will.

By treating the 9a-halo-IIß-hydroxy compounds with a weak base, e.g. B. potassium acetate, sodium bicarbonate, or a sodium acylate, such as sodium acetate in an organic solvent such as methanol, ethanol, isopropanol, Dioxane, tert-butyl alcohol or tetrahydrofuran, the 9β, 11β-oxido compound is obtained. If the starting material contains an acyloxy group in the 17 position, it is preferably used Sodium or potassium acetate to cause simultaneous hydrolysis of the acyloxy group avoid. The reaction is advantageously carried out with heating. The response time is usually between 3 and 12 hours. One can also use a methanolic solution the 9a-halogen-11ß-hydroxy compound with an aqueous base, such as sodium hydroxide solution, potassium hydroxide solution, Stir barite liquor or the like. The base is slowly stirring only added in such an amount that the reaction mixture against phenolphthalein about Reacts alkaline for 1/2 minute. The 1-dehydro-7-methyl-9ß, 11ß-oxidotestosterone obtainable in this way is separated in the usual way from the reaction mixture, for. B. by adding Water and filtering off the precipitate or by extraction with a with water immiscible solvents, e.g. B. ether, hexane hydrocarbons, pentane hydrocarbons, Benzene, ethyl acetate, chloroform, methylene chloride or carbon tetrachloride. then can be purified by recrystallization or chromatography.

41-7-methyl-9a-fluoro-Ilß-hydroxytestosterone is obtained from d1-7-methyl-9ß, 1ß-oxido-testosterone by reaction with 48% aqueous hydrofluoric acid in a solvent. Suitable solvents are methylene chloride, ethylene dichloride, chloroform or carbon tetrachloride. Methylene chloride and carbon tetrachloride are preferred. The reaction is advantageously carried out in the presence of an acid catalyst, such as perchloric acid, toluenesulfonic acid or sulfuric acid. The reaction temperature is preferably between 20 and 30 ° C. and the reaction time between 1 and 24 hours. Instead of aqueous hydrofluoric acid, it is also possible to use hydrogen fluoride gas in the form of a cooled solution in alcohol-free chloroform or methylene chloride, which advantageously contains tetrahydrofuran. In this case, the cold in a polyethylene bottle contained solution of 9SS, 11 beta-oxido compound in chloroform, methylene chloride or carbon tetrachloride with a cold solution of hydrogen fluoride in chloroform, methylene chloride or carbon tetrachloride is mixed. The closed bottle is kept at low temperatures for 1 to 24 hours, e.g. B. at -40 to + 10 ° C, preferably -25 to 0 ° C, held. After the reaction has ended, the reaction mixture is neutralized with an aqueous base such as sodium bicarbonate, sodium carbonate, potassium carbonate or bicarbonate or dilute sodium or potassium hydroxide solution and the resulting dl-7-methyl-9a-fluoro-11β-hydroxy-testosterone or its Esters obtained from the reaction mixture in a known manner, e.g. B. by extraction with a water-immiscible organic solvent such as ether, ethyl acetate, hexane hydrocarbons, chloroform, carbon tetrachloride or methylene chloride. The raw product can be prepared in a conventional manner, e.g. B. by recrystallization or chromatography, can be purified.

The corresponding d 1- 7 - methyl - 9a- halogen-11-keto-testosterone is obtained in a known manner by oxidation with chromic acid in an organic Solvents, e.g. B. acetic acid, acetic acid + benzene or dilute mineral acid and methyl chloride. If available, 17-permanent Acyloxy groups with an alkali metal base in a dilute aqueous-alcoholic solution or hydrotysed with dilute mineral acid.

The pure 7-stereoisomers are obtained by fractional crystallization or by chromatography about activated charcoal and treating the adsorbed isomer mixture with chloranil, which attacks only the 7ß-isomer, while the 7a-isomer remains unchanged, and separation of the 7a-isomer from the from the 7β-isomers formed 6-dehydro compound. The reaction with the chloranil 6-dehydro-7-methyl compound formed can be obtained by selective hydrogenation, e.g. B. with Palladium-carbon (S h e p h e r d and co-workers, Journ. Chem. Soc., 77, p. 1212 [1955]), can be converted back into the 7ß-methyl compound.

The 6-dehydro-testosterone required for process route b) can reaction of testosterone with chloranil (see US Pat. No. 2,739,974) or by reacting a suitable 3ß-hydroxy-5-androstene with aluminum-tert: butylate and p-quinone are produced. The 3ß-hydroxy-5-androstene are obtained by reducing a testosterone 3-enol ester with sodium borohydride.

The following examples explain the process according to the invention. For the preparation of the starting compounds, in the context of the present invention Protection not desired. Example 1 a) 7a-methyl-19-nortestosterone acetate 30 ml of tetrahydrofuran (obtained by percolating technical grade tetrahydrofuran with an acid from neutral aluminum oxide, discarding the first 15 ml of the percolate) were in an ice bath and cooled with stirring and under nitrogen with 25 ml of a 3 molar Methyl magnesium bromide solution and 0.4 g copper (I) bromide were added. This mixture was a solution of 3 g of 6-dehydro-19-nortestosterone-17-acetate and with stirring small amounts of CuBr in 50 ml of tetrahydrofuran purified as above were added.

The mixture was stirred with cooling for a further 10 minutes and then poured into a nitrogen-purged mixture of hydrochloric acid diluted with ice, saturated with sodium chloride, and ether. The ether layer was separated and washed successively with sodium chloride solution, dilute sodium hydroxide solution and sodium chloride solution. The ether extracts were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was dissolved in 5 ml of pyridine + 5 ml of acetic anhydride. After standing for 18 hours at room temperature, ice and water were poured in and the product was extracted with ether. The extract was washed with dilute acid, dilute sodium hydroxide solution and water, dried and evaporated. The residue was dissolved in methylene chloride and the solution was chromatographed over synthetic magnesium silicate, known under the trade name "Florisil". The acid was eluted with hexane hydrocarbons containing increasing amounts of acetone. The fractions in which 7α-methyl-19-nortestosterone-17-acetate was determined on the basis of an infrared analysis were combined and evaporated to dryness. The oily residue was dissolved in Acefon and chromatographed on an acetone-soaked column made of 20 g of diatomaceous earth (known under the trade name "Celite") and 10 g of activated carbon (known under the trade name "Darco"). The column was eluted with acetone. The first 750 ml were evaporated to dryness. The residue from 7a-methyl-19-nortestosterone-17-acetate was recrystallized from methanol. 1 g of crystalline material was obtained; M.p. = 111 to 114 ° C; [a] 0 = 48 ° (chloroform). The UV spectrum (in ethanol) pointed at 240 mg. (e = 17,350) has a maximum.

Analysis for C2, Hw0z: Calculated ... C 76.32, H 9.15; Found ... C 76.28, H 9.44.

b) 7a-methyl-19-nortestosterone A solution of 3 g of 7a-methyl-19-nortestosterone-17-acetate in 40 ml of a 5% solution of potassium carbonate in 800% aqueous methanol was refluxed under nitrogen for 2 hours. The mixture was made with ether extracted, the ether extract washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was triturated with ether. The remaining crystalline solid consisted of 7a-methyl-19-nortestosterone; F. = 140 to 145.5 ° C. An analysis sample (made from a mixture of acetone and hexane hydrocarbons recrystallized) melted at 145 to 146 ° C; [a]. = 55 ° (chloroform). The UV spectrum (in ethanol) had a maximum at _241 mg (E = 17,150).

Analysis for C1eHaa0z: Calculated ... C 79.12, H 9.78; Found ... C 79.13, H 10.19. c) 7a-Methyl-19-norandrosten-3,17-dione A solution of 1.4 g of 7a-methyl-19-nortestosterone in 15 ml of pyridine was added to a suspension of 1.4 g of chromium trioxide in 15 ml of pyridine with stirring and cooling. After the addition was complete, the mixture was stirred at room temperature (about 20 ° C.) for 20 hours, then diluted with a mixture of equal parts of benzene and ether and filtered through a layer of diatomaceous earth ("Celite"). The filter layer was washed well with a mixture of ether and benzene (1: I), then with water and again with the solvent mixture. The filtrate and the organic layer of the washing liquid were combined and washed several times with water. The washing water was extracted again with ether + benzene (1: 1). The combined organic layers were dried and evaporated to dryness. The residue was triturated with ether. The remaining solid was filtered off. 1.4 g of crystalline 7a-methyl-19-norandrostene-3,17-dione were obtained; M.p. = 195 to 198 ° C. An analytical sample obtained by recrystallization from acetone melted at 201 to 204 ° C. The UV absorption spectrum (in ethanol) showed a maximum at 239.5 mg. (c = 17,000).

Analysis for C1sHw02: Calculated ... C 79.69, H 9.15; found ... C 79.66, H 8.87.

d) 7a-Methyl-19-norandrostene-3,17-dione-3-pyrrolidyl-enamine One drop of pyrrolidine was added to a solution of 10 mg of 7a-methyl-19-norandrostene-3,17-dione in low-boiling methanol. The resulting solution was concentrated and cooled. The precipitated crystalline solid was filtered off, washed with a little methanol and dried. It consisted of 7a-methyl-19-norandrostene-3,17-dione-3-pyrrolidyl-enamine; F. = 151 to 160 ° C. The UV spectrum (in ether) showed a maximum at 282 m # t (F = 23 450). The IR spectrum (in mineral oil) showed maxima at 1735, 16.35, 1 600, 1200, 1 1 80, 1155 and 1035 cm- '.

e) 7a-methyl-17a-äthinyl-19-nortestosteron 1 m (a 20 weight percent Suspension of sodium acetylide in xylene was centrifuged. The deposited solid was taken up in 6m1 of freshly distilled dimethyl sulfoxide. This mixture was the 3-pyrrofidyl-enamine obtained from 0.5 g of 7a-methyl-19-norandrosten-3,17-dione was added. It was then kept under nitrogen for 5 hours, followed by the excess sodium acetylide destroyed by the dropwise addition of water. By adding about 2m1 of water and 5 ml of methanol gave a clear solution which was heated on the steam bath for 1 hour and then extracted with ether. The ether extracts would be treated with dilute hydrochloric acid, Washed dilute soda solution and water, dried over magnesium sulfate, filtered and concentrated to dryness. The residue was washed with a mixture of ether and hexane hydrocarbons triturated and recrystallized twice from acetone @ hexane hydrocarbons. Man received 0.161 g of 7a-methyl-17a-ethinyl-19-nortestosterone. M.p. = 197 to 199.5 ° C. That UV spectrum (in ethanol) possessed at 240.5 m &. a maximum. The IR spectrum (in Mineral oil) showed maxima at 3390, 3240, 2100, 1663 and 1623 cm- '. Analysis for C2iH28O.a: Calc ::; . . . C 80.72, H 9.03; felt. ° @ -. . . . C 80.44, H 9.05. 1) 7a-methyl-17a-ethinyl-19-nortestosterone-17-acetate A mixture of 1 g of 7a-methyl-I7a-äthinyl-19-nortestosteron, 20m1 acetic anhydride and 1 ml of pyridine was heated to 140 ° C. for 1 hour under nitrogen and with stirring. After cooling to room temperature, 100 ml of water were added to the mixture and stirred for 2 hours. The precipitated solid was filtered off. He passed from a mixture of 7a-methyl-17a-äthinyl-19-nortestosterone-17-acetate and the 3,17-diacetate of the corresponding 3-enol. The latter connection was made by refluxing for 1 hour with 100 ml of methanol which concentrated 2 ml Hydrochloric acid contained, hydrolyzed. The reaction mixture was then diluted with water and extracted with ether. The ether extract was dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in methylene chloride and taken over synthetic magnesium silicate chromatographed. The column was filled with hexane hydrocarbons, containing increasing amounts of acetone, eluted. Those containing the desired product Fractions (determined by paper chromatography) were evaporated to dryness. The 7a-methyl-17a-ethinyl-19-nortestosterone-17-acetate obtained was obtained from aqueous Recrystallized methanol; F. = 160 to 162 ° C.

g) 17a-ethyl-7a-methyl-19-nortestosterone A suspension of 30 mg 1 o / o palladium-carbon in 20 ml of dioxane (purified according to Fieser, Methods of Organic Chemistry, 2nd edition, p. 368) was saturated with hydrogen at normal pressure. Then 100 mg of 7a-methyl-17a-ethinyl-19-nortestosterone were added and the mixture hydrogenated at normal pressure until 2 equivalents of hydrogen were consumed. The reaction mixture was filtered through diatomaceous earth ("Celite") and the filtrate was evaporated to dryness. The residue was combined with the residue from a 50 mg batch in methylene chloride dissolved and over 50 g of synthetic magnesium silicate soaked with hexane hydrocarbons chromatographed. The column was filled with hexane hydrocarbons, the increasing amounts Contained acetone, eluted. The fractions containing the desired product (by IR analysis determined) were combined and evaporated to dryness. The residue was recrystallized twice from a mixture of hexane hydrocarbons and ether and gave crystalline 17a-ethyl-7a-methyl-19-nortestosterone. F. = 138 to 139 ° C. The UV spectrum (in ethanol) showed a maximum at 241 mt. (e = 17,000).

Analysis for C21H3202: Calculated ... C 79.69, H 10.19; Found ... C 79.43, H 10.23. Example 2 7a, 17a-dimethyl-19-nortestosterone To a solution of 2.75 g of 7a-methyl-19-norandrosten-3,17-dione-3-pyrrolidyl-enamine in 70 ml of tetrahydrofuran were added rapidly with stirring and under nitrogen to 25 ml of a 3 molar solution of methylmagnesium bromide in diethyl ether. The resulting mixture was distilled until the temperature of the vapors reached 55 ° C. The mixture was then refluxed for about 4 hours. An ice-cold ammonium chloride solution and then 130 ml of methanol and 25 ml of 50% sodium hydroxide solution were then carefully added with stirring. The mixture was stirred for several hours at 40 ° C. under nitrogen and then concentrated to about one third of its volume under reduced pressure. It was then diluted with water and extracted with ether. The extract was washed with water, dilute hydrochloric acid, dilute sodium carbonate solution and water, dried over sodium sulfate, filtered and concentrated to dryness. The residue was dissolved in methylene chloride and chromatographed over 100 g of synthetic magnesium silicate. The column was eluted with hexane hydrocarbons containing increasing amounts of acetone. Those fractions which, on the basis of an IR analysis, did not contain any 17-carbonyl compound were combined and evaporated to dryness. The residue was recrystallized from a mixture of acetone and hexane hydrocarbons. 7a, 17a-dimethyl-19-nortestosterone were obtained; F. = 180 to 183 ° C. [a]. = 33 ° (chloroform). Example3 7a-methyl-testosterone a) Following the procedure of Example 1, a) 7a-methyl-testosterone was produced from testosterone.

b) 7a-methyl-androstene-3,17-dione To a solution of 20g sodium dichromate dihydrate in 200 ml of acetic acid were stirred and cooled by means of a water bath 20 g 7a-methyltestosterone given. After standing for several hours, the reaction mixture became poured in about 11 water. The deposited precipitate was filtered off with Water washed and dried. The product (18.7 g; m.p. 186-191 ° C) was recrystallized from a mixture of acetone and hexane hydrocarbons to give 15.6 g of crystalline 7a-methyl-androstene-3,17-dione. M.p. = 194 to 196 ° C; [a] "= 196 ° (Chloroform). The UV spectrum (in ethanol) showed a maximum at 241 m # x (e = 17 250).

Analysis for C2oH2802: Calculated ... C 79.95; H 9.39; Found ... C 79.8-1, H 9.33.

c) 7a-methyl-androstene-3,17-dione-3-pyrrolidylenamine 15.6g 7a-methyl-androstene-3,17-dione were dissolved in the smallest possible amount of boiling methanol. Passing through of nitrogen, 10 ml of pyrrolidine were added. After cooling, the precipitated one became Solid filtered off, washed with methanol and ether and about 15 minutes at 60 ° C dried. The 3-pyrrolidyleneamine of 7a-methyl-androstene-3,17-dione was obtained as a crystalline solid. M.p. = 199-205 ° C (decomposition); [a], = 190 ° (pyridine). The UV spectrum (in ether) had a maximum at 282 m # t (e = 29,900).

Analysis for C? AH35N0: Calculated ... C 81.53, H 9.98, N 3.95; Found ... C 81.57, H 9.76, N 3.77. d) 7a-methyl-17a-äthinyl-testosteron 25 ml of a suspension of sodium acetylide (0.2 g / ml) in xylene were centrifuged. The sodium acetylide thus separated was suspended in 160 ml of freshly distilled dimethyl sulfoxide, and a suspension of the above enamine in 100 ml of dimethyl sulfoxide was added. After stirring for 3 hours under nitrogen, 30 ml of water and 50 ml of methanol were added. The mixture was then heated to 50 to 60 ° C. for 1 hour, stirred at room temperature overnight, diluted with water and extracted three times with 100 ml of methylene chloride each time. The combined extracts were washed with dilute hydrochloric acid and water and evaporated to dryness to give 2 g of product. The aqueous washing liquids were combined and made alkaline with sodium hydroxide solution. This solution was extracted again with methylene chloride. The combined extracts were washed with dilute hydrochloric acid, dilute sodium carbonate solution and water, dried over sodium sulfate, filtered and concentrated to dryness. The residue (3.9 g) was dissolved with the aforementioned 2 g in acetone and treated with a mixture of activated charcoal ("Darco"), diatomaceous earth ("Celite") and synthetic magnesium silicate. It was then filtered and the filtrate was evaporated to dryness. The residue was recrystallized from acetone-hexane hydrocarbons, 3.9 g of crystalline 7a-methyl-17a-ethinyl-testosterone with a melting point of 190 to 192.5 ° C. being obtained. An analytically pure sample with a melting point of 191 to 193 ° C. was obtained from ethyl acetate; [a] o = 41 ° (chloroform). The UV spectrum (in ethanol) showed a maximum at 242 m # L (e = 16,550).

Analysis for C22Hw02: Calculated ... C 80.93, H 9.26; found ... C 80.86, H 9.33.

e) 7a-methyl-17a-ethyl-testosterori A suspension of 0.2 g of 1% strength Palladium-carbon catalyst in 40m1 of dioxane was treated with hydrogen at normal pressure saturated. 1 g of 7a-methyl-17a-ethinyl-testosterone was added to the suspension. Then in the presence of hydrogen until the theoretical amount of hydrogen was absorbed shaken. The filtered solution was evaporated to dryness under reduced pressure. The residue was made from a mixture of ether, methylene chloride and hexane hydrocarbons recrystallized. 0.8 g of 7a-methyl-17a-ethyl-testosterone was obtained in the form of a crystalline solid. M.p. = 140.5 to 143 ° C. UV maximum (in ethanol) at 242 mt, (e = 16,350).

Analysis for C22H3402: Calculated ... C 79.95, H 10.37; Found ... C 80.15, H 10.39. Example 4 a) 7a, 17-dimethyl-testosterone To a mixture of 0.4 g of copper (1) chloride, 20 ml of 4 molar methyl magnesium bromide in ether and 60 ml of distilled tetrahydrofuran, a mixture of 2.0 g 6-dehydro-17-methyl-testosterone, 60 ml distilled tetrahydrofuran and 0.2 g copper (1) chloride are added. After removing the ice bath, stirring was continued for a further 4 hours. Ice and water were then carefully added, the solution acidified with 3N hydrochloric acid and extracted several times with ether. The combined ether extracts were washed with a sodium chloride solution and then with sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and applied to a column of 75 g of synthetic magnesium silicate soaked with hexane hydrocarbons. The column was eluted with 250 ml of hexane hydrocarbons, 0.51 hexane hydrocarbons containing 2% acetone, 21 hexane hydrocarbons containing 4% acetone and 3.51 hexane hydrocarbons containing 6% acetone. First four fractions of 250 ml each and then fractions of 150 ml each were collected. The residues from fractions 8 to 16 were combined and chromatographed again over 125 g of synthetic magnesium silicate. The column was run with hexane hydrocarbons containing 60% acetone. The eluate was collected in fractions of 150 ml each. Fractions 18 to 29 were combined and dissolved in acetone, decolorized with charcoal and recrystallized from acetone. 1 g of a crystalline mixture of the 7-epimers of 7,17-dimethyl-testosterone was obtained; M.p. = 120 to 140 ° C; @m X, OH = 243 mt .; am = 13,775. [a], = 55 ° (chloroform).

Analysis for C21H3202: Calculated ... C 79.69, H 10.19; found . . . C 79.18, H 10.07.

The 7-epimers were prepared according to the method described in Example 5 separated. The 7a, 17-dimethyl-testosterone melts at 163 to 165 ° C, the ß-epimer at 127 to 129 ° C.

b) 1-Dehydro-7a, 17a-dimethyl-testosterone A mixture of 8.0 g 7a, 17a-dimethyl-testosterone, 8.0 g of mercury, 6.5 ml of glacial acetic acid, 5.0 g of selenium dioxide and 300 ml of tert-butyl alcohol was refluxed for 4 hours under nitrogen and with constant stirring. To Addition of a further 2.0 g of selenium dioxide and heating for a total of 7 hours was the result The reaction mixture was concentrated to about 200 ml under a rapid stream of nitrogen. After diluting with a mixture of methylene chloride and ether, the solution became three times with fresh ammonium sulfide solution, twice with dilute ammonia and twice washed with water. The solution was then dried, filtered and brought to dryness evaporated. The gummy residue was dissolved in methylene chloride and poured onto a Column of 200 g of synthetic magnesium silicate with hexane hydrocarbons was soaked. The column was filled with hexane hydrocarbons, the increasing amounts Contained acetone, eluted. Those fractions that are based on a paper chromatographic Analysis 1-dehydro-7a, 17a-dimethyl-testosterone contained, were pooled and taken out recrystallized from a mixture of acetone and hexane hydrocarbons; F. = 153 up to 156 ° C; [a] "= -6 ° (chloroform). Max n011 = 243.5 m # L; a M = 15,500.

Analysis for C21H30O2: Calculated ... C 80.2-1, H 9.62; found ... C 80.29, H 9.76. Example a) 7,17-Dimethyl-11ß-hydroxy-testosterone 100 ml of a 3 molar methylmagnesium bromide solution in ether were added to a mixture of 1.6 g of CuCl in 240 ml of purified tetrahydrofuran. A solution of 8.0 g of 6-dehydro-Iβ-hydroxy-17-methyl-testosterone and 0.8 g of partially dissolved CuCl in 300 ml of tetrahydrofuran was added to this solution under nitrogen and with stirring and cooling with ice-salt. After 15 minutes the reaction mixture was poured into a mixture of ether, dilute hydrochloric acid and ice and saturated with sodium chloride. The ethereal layer was separated off, washed with sodium chloride solution, then with sodium hydroxide solution saturated with sodium chloride solution and again with sodium chloride solution and dried over magnesium sulfate. The dry solution, after being filtered, was evaporated to dryness. The residue was dissolved in methylene chloride and chromatographed over 250 g of synthetic magnesium silicate. The column was eluted with 250 ml each of the following solvents: three times with methylene chloride, twice with methylene chloride + 2% acetone, nine times with methylene chloride + 4% acetone, twice with methylene chloride + 10% acetone, three times with methylene chloride + 50% acetone, once with Acetone.

The fractions 10 to 20 eluted with methylene chloride and 4 to 10% acetone were combined and freed from the solvent. The residue was dissolved in hot methanol and filtered. After removal of the solvent, the residue was triturated with a mixture of acetone and hexane hydrocarbons. 3.2 g of a crystalline mixture of the 7-epimers of 7,17-dimethyl-11ß-hydroxy-testosterone were obtained. M.p. = 218 to 224 ° C (after softening); A mä'4eH = 243 mN .; am = 15,175; [a], = 102 ° (chloroform). Analysis for C21H3203: Calculated ... C 75.86, H 9.70; found ... C 75.56 H 9.57.

The pure 7β-Epimere.wurde by six recrystallizations of the Epimer mixture obtained from acetone-methanol; M.p. = 242 to 246 ° C; @ max'cH = 245.5 m # t; am = 15,175; [a], = 105 ° (chloroform).

Analysis for C21H3203: Calculated. . . C 75.86, H 9.70; Found ... C 75.59, H 10.04. To obtain the 7a-epimer, 0.5 g of the epimer mixture in 50 ml of tert-butyl alcohol was refluxed with 0.5 g of chloranil under nitrogen for 21/2 hours. The reaction mixture was then concentrated under a rapid stream of nitrogen and then diluted with methylene chloride. The solution was washed with dilute sodium hydroxide solution and water, dried, filtered and freed from the solvent. The residue with absorption maxima A m8 sc1 at 245 and 291 m # t was combined with that from a second identical experiment and chromatographed over 100 g of magnesium silicate. The column was eluted with 250 ml each of the following solvents: twice with hexane hydrocarbons, twice with hexane hydrocarbons + 4% acetone, twice with hexane hydrocarbons + 8% acetone, twice with hexane hydrocarbons + 12% acetone, twice with hexane hydrocarbons + 14% acetone, twice with hexane hydrocarbons + 160 % Acetone, twice with hexane hydrocarbons and 180% acetone, twice with hexane hydrocarbons + 20% acetone, twice with hexane hydrocarbons + 24% acetone, twice with hexane hydrocarbons + 280% acetone and twice with acetone. The residues of the fractions eluted with hexane hydrocarbons and 18% acetone were combined. After recrystallization from acetone, they gave 100 mg of 7a, 17a-dimethyl-I lß-hydroxytestosterone. M.p. = 242 to 244 ° C (decomposition); A m $ H4OH - 295.5 m # t; am = 23250; [a]. = 310 ° (chloroform).

Analysis for C21 Hao03: Calculated ... C 76.32, H 9.15; found ... C 76.49, H 9.53. The residues of the fractions obtained with hexane hydrocarbons and 16 and 18 °,! O acetone were combined and chromatographed (1: 1) over a column of activated carbon, known under the trade name "Darco", and diatomaceous earth, known under the trade name "Celite" . The column was eluted in the following manner: nine times with 100 ml of methanol each time, five times with 100 ml of a mixture of methanol and acetone (1: 1) each time, seven times with 50 ml of a mixture of methanol and acetone (1: 1) each, seven times with 50 ml of a mixture of methanol and acetone (1: 2), three times with 50 ml of acetone each time and four times with 50 ml of a mixture of acetone and methylene chloride (1: 4) each time. Fractions 12 to 20 were combined and freed from the solvent. After recrystallization from acetone, the residue gave 60 mg of the 7α-epimer of 7,17α-dimethyl-11β-hydroxytestosterone. F. = 225 to 230 ° C (after previous softening), # ', 1,' x "'= 243 m # t; am = 15 825. Analysis for C21H3203: Calculated ... C 75.86, H 9, 70; found ... C 75.65, H 9.96.7 ", 17a-dimethyl-lla-hydroxy-testosterone is obtained by 11a-hydroxylation of 7a, 17a-dimethyltestosterone according to the method of US Pat. No. 2,602 769. The 7a, 17a-dimethyl-1la-hydroxytestosterone melts at 230 to 234.5 ° C; [a], = 81 ° (chloroform); im @ ° H = 243 m # t. B) 7a, 17a-dimethyl -9 (11) -dehydro-testosterone By dehydrating the 7a, 17a-dimethyl-11β (or 11a) -hydroxy-testosterone obtained according to a), 7a, 17a-dimethyl-9 (11) -dehydro-testosterone was obtained; F. = 172 to 176 ° C; ACMOH = 240 m @ .; a M = 16,800.

The 11 ß-hydroxy compound was dehydrated as follows: A two-phase mixture of 2.5 g of 7a, 17a-dimethyl-11 ß-hydroxy-testosterone, 250 ml of benzene, 200 ml of ether, 100 ml of concentrated hydrochloric acid and 100 ml of water was used heated under reflux for 18 hours with vigorous stirring. After cooling, the layers were separated. The aqueous phase was extracted three times with 75 ml of ether each time. The ether extracts were combined with the benzene-ether phase, washed with dilute, aqueous potassium carbonate solution and water, dried over sodium sulfate and filtered. The solvent was then removed and the residue was recrystallized from a mixture of methylene chloride and hexane hydrocarbons. c) 7a, 17a-dimethyl-9a-bromo-llß-hydroxytestosterone A solution of 2 g of 7a, 17a-dimethyl-9 (11) -dehydro-testosterone in 100 ml of acetone was cooled to 15 ° C and treated with 2 g of N- Bromacetamide dissolved in 50 ml of water treated. At a bath temperature of 12 ° C. , 10 ml of 0.8 n-perchloric acid were added. After 5 minutes a further 10 ml and after a further 10 minutes a further 20 ml of 0.8 n-perchloric acid were added. After a total reaction time of 20 minutes, a saturated sodium sulfite solution was slowly added with stirring. The mixture was then diluted with 200 ml of water. The deposited product was filtered off and redissolved. The solution was washed with water, dried over sodium sulfate and freed from the solvent. 7a, 17a-dimethyl-9a-bromo-11β-hydroxy-testosterone were obtained.

d) 7a, 17a-dimethyl-9ß, 11ß-oxido-testosterone A mixture of 7a, 17a-dimethyl-9a-bromo-11ß-hydroxy-testosterone, Potassium acetate and tert-butyl alcohol were heated on the water bath for 1 hour and then poured into ice water. The precipitate thus precipitated out was filtered off and recrystallized. Essentially pure 7,17-dimethyl-9ß, 11ß-oxido-testosterone was obtained.

e) 7a, 17a-dimethyl-9a-fluor-llß-hydroxy-testosterone A cooled Solution of 1.13 g of 7a, 17a-dimethyl-9ß, lß-oxido-testosterone in 20m1 of non-alcoholic Chloroform was cooled to alcohol-free chloroform, in which 3 minutes hydrogen fluoride had been initiated, given. The mixture was in a polyethylene bottle 4 Hours at -15 ° C and then in excess. saturated sodium bicarbonate solution poured. The aqueous layer was separated and extracted three times with chloroform. The chloroform layer and the extracts were washed with water over sodium sulfate dried and concentrated. The residue was over 100 g of anhydrous synthetic Magnesium silicate and chromatographed with 20: I to 9: 1 mixtures of hexane hydrocarbons and acetone eluted. The 9a-fluoro-7a, 17a-dimethyl-11 obtained after evaporation of the solvent ß-hydroxy-testosterone melted with decomposition at 242 to 252 ° C.

Claims (2)

Claims: 1. Process for the production of 7-methyl steroids of the general formula in which P is hydrogen or the methyl group, M is hydrogen, an alkyl, alkenyl or alkynyl group, Y is hydrogen or the acyl radical of a lower carboxylic acid, X is hydrogen or a fluorine atom and Z is H2, keto oxygen, H, a-OH; H, β-OH or H, α-acyloxy, where, if P is hydrogen, the 1 (2) position is saturated and, if P is a methyl group, the 1 (2) position can be saturated or unsaturated and P and M only represent a methyl group at the same time when the 1 (2) position is saturated, characterized in that a 6-dehydro compound of the general formula is obtained in a manner known per se in which P, Y and Z have the meanings given above and R is hydrogen or an alkyl group, in the presence of an agent promoting the 1,6-addition reaction with a methylmagnesium halide, the resulting 7-methyl compound of the general formula in which P, Y, Z and R have the meaning given above, a) optionally microbiologically hydroxylated in the 11-position or a 17β-acyloxy group contained in this compound is hydrolyzed and optionally the 11-hydroxy compound obtained (Z = H, OH) or the compound unsubstituted in the 11 position (Z = H2) in which Y and R are hydrogen, oxidized to the corresponding 7-methyl-3,17-diketo or 7-methyl-3,11,17-triketo compound, these in converts the 3-enamine, which converts the 3-enamine with an alkyl, alkenyl or alkynyl magnesium halide, an alkyl or alkenyl lithium or an alkali derivative of an alkyne to the 3-enamine of the 17-alkylated, alkenylated or alkynylated 7a-methyl steroid the 3-position enamine group is removed hydrolytically from this, the compound thus obtained is optionally converted into a 17-acyloxy derivative and, if M is an alkynyl radical, this is optionally catalytically hydrogenated to an alkyl group, or b) if P is a methylg r group, M is an alkyl radical or hydrogen and Y and Z have the meaning given above, the 1 (2) position is dehydrogenated, if Z is H, β-OH in the starting material, optionally the 9 (11) position is dehydrated, to the 9 (11) double bond under halogen acid, the 9α-halogen-11β-hydroxy compound obtained is converted into the corresponding 9β, 11β-oxido compound with a weak base, the 9β, 11β-oxido compound treated with hydrogen fluoride, optionally the 9a obtained -Fluoro-Ilß-hydroxy compound is oxidized with chromic acid to give the corresponding 11-ketone and, if necessary, the mixture of 7a- and 7ß-methyl-epimers is separated by treatment with chloranil. 2. The method according to claim 1, characterized in that one a 6-dehydro-19-nortestosterone-17-acylate was used as the starting material. Into consideration Drawn Papers U.S. Patent No. 2,838,534; Journ. At the. Chem. Sc., 81, pp. 408 ff. (1959); Journ. Org. Chem., 24, p. 121 ff. (1959).