DE1112738B - Process for the production of 4-methyl-17 ª ‡ -alkyl steroids of the androstane series - Google Patents

Description

Process for the production of 4-methyl-17a- @ alkyl steroids of the androstane series The present invention relates to a process for the production of 4-methyl-17ca-alkyl steroids of the androstane series of the general formula in which there can be a double bond in the 1 (2) position and / or 4 (5) position, R is an alkyl radical with 1 to 6 carbon atoms and R ,. = H, α- or β-0 is H or keto oxygen.

The 4-methyl-17oc-alkylandrostanes which can be prepared according to the invention have progestational, antiestrogenic, steroid potentiating, regulating the central nervous system and gonadotropin formation inhibitory activity. They also cause a Relaxation of the uterus and control the water and mineral balance. Of special Benefit is their favorable ratio of anabolic to androgenic effectiveness.

The 4,17a-dimethyl-llß-oxytestosterone z. B. possesses when administered orally 61 "/, the anabolic and only 8.60 /, the androgenic effectiveness of methyltestosterone, so that the ratio of anabolic to androgenic potency is 7: 1. at parenteral administration has the 4,17ca-dimethyl-1lß-oxytestosterone 20% anabolic efficacy of testosterone propionate and no detectable androgenic Properties. The 4ß, 17a-Dimethyl-1lß, 17ß-dioxyandrostan-3-one possesses with oral Administration 25% of the anabolic potency of methyltestosterone and none detectable androgenic effectiveness.

The ratio of anabolic to androgenic effectiveness is at 4,17a-dimethyl-11ß-oxytestosterone and 4ß, 17oc-dimethyl-11ß, 17ß-dioxyandrostan-3-one thus much cheaper than with methyltestosterone and testosterone propionate. Therefore, if the androgenic side effect limits the therapeutic application, it becomes with 4,17cc-dimethyl-1ß-oxytestosterone and 4ß, 17ca-dimethyl-11ß, 17ß-dioxyandrostan-3-one A decidedly greater anabolic effect is achieved with the same androgenic effect than with methyltestosterone or testosterone propionate. This is especially true in pediatrics and Geriatrics Matters, where marked androgenic effects are contraindicated.

Because of their anabolic effect, those which can be produced according to the invention can be found Compounds to promote nitrogen metabolism, weight gain, the Restoring muscle strength and improving well-being in the weakened Patient application. Here comes the fact that they are also given orally are effective, benefit. Their ability to increase erythrocyte production makes they are especially valuable in anemic conditions. Because their application is fast Causes weight gain, they are also suitable as supplementary feed.

The compounds according to the invention can be used for their administration dispersed, dissolved or suspended in solid or liquid carrier materials will. The solid preparations can, preferably in unit doses, in the form of tablets, capsules, pills or the like. Be brought.

To carry out the process according to the invention, a 3-enemine is used an 11-oxy- or 1-1-keto-17ß-oxy-17a-alkyl-4-androsten-3-one (11-oxy- or 11-keto-17a-alkyltestosterone) with a cyclic secondary amine with a methyl halide for corresponding 3-enamine of 11-oxy- or 11-keto-17ß-oxy-4-methyl-17oc-alkyl-4-androsten-3-one implemented. The 11,17-dioxy-4-methyl-17a-alkyl-4-androsten-3-one obtained after hydrolytic removal of the enamine group can subsequently with an oxidizing agent such as chromic acid or the like. To the corresponding 11-keto compound are oxidized.

The catalytic reduction of these compounds, e.g. B. in the present of palladium on charcoal or the like, gives 11,17ß-dioxy-4-methyl-17a-androstan-3-one or 17β-Oxy-4-methyl-17rx-alkylandrostane-3,11-dione. Those made in this way 4ß-Methylepimeren can with a hydrogen halide, a mineral acid or a Base can be converted into the corresponding 4x-methylepimers.

The introduction of a 1 (2) double bond in the 4-androstene derivatives can in a microbiological way with Septomyxa affinis according to the US patent 2602769 described method or be done chemically by means of selenium dioxide.

The starting materials for the process according to the invention can include 17a-alkyl-11-ketotestosterone and 11-oxyandrostene-3,17-dione by the method of U.S. Patent 2735854 in combination with the method of U.S. Pat. No. 2,781,342.

The used as starting material for the process according to the invention 3-enamine is dissolved in an inert, dry organic solvent such as ethanol, Methanol, isopropanol, butanol, ethyl acetate, chlorinated hydrocarbons, etc., with a Excess methyl halide methylated.

A preferred method is to treat the dry 3-enamine with an excess of methyl iodide in dry methanol with heating on the reflux condenser until the reaction has ended. After completion of the reflux treatment the excess methyl iodide is distilled off.

The 3-enamines of 4-methyl-17x-alkyl-11,17ß-dioxy-4-androsten-3-one prepared in this way and 4-methyl-17oc-alkyl-17ß-oxy-4-androstene-3,11-dione can be mixed with water, aqueous Acid or base or alkanol-water mixtures with removal of the 3-enamine group and reformation of the d 4-3-keto group are hydrolyzed.

A preferred method of hydrolyzing the 3-enamine group is in treatment with a methanol-water solution containing 1 to 3% sodium hydroxide contains. The solution is refluxed for 2 hours and then by distillation concentrated under normal pressure to remove most of the methanol. then is diluted with water and with ether, methylene chloride, benzene, toluene, hexane or od. Like. Extracted. The combined solvent extracts are dried, and that Solvent is distilled off.

The 4-alkyl derivatives thus obtained can by customary processes, z. B. by recrystallization or chromatographically, be purified.

The 4-alkyl-11ß- and 4-alkyl-11cx-oxysteroids prepared in this way can by known methods, for. B. in acetic acid solution with molar amounts or a slight excess of chromium trioxide or with a haloamide or haloimide an acid, such as N-bromoacetamide, N-chlorosuccinimide or N-bromosuccinimide, which is found in pyiidine, Dioxane or other suitable solvents is dissolved, to the corresponding 11-keto compound are oxidized. After the oxidation is complete, the chromium trioxide is added of methyl alcohol, ethyl alcohol and the like and the N-bromoacetamide, N-bromosuccinimide and other N-haloacylamides and imides destroyed by adding a bisulfide. The 4-alkyl-II-ketosteroids obtained are prepared by conventional methods, for. B. by Felling with water or extraction with water-immiscible solvents, such as methylene chloride, ether, benzene, toluene, hexane and the like, and then distilling off of the solvent won. They can subsequently be chromatographed by recrystallization or cleaned by both methods.

By hydrogenation of the 4 (5) double bond in the presence of a Hydrogenation catalyst, such as palladium on charcoal, barium sulfate, zinc oxide, calcium carbonate, Mercury salts and the like or mixtures of these catalysts, with palladium on If charcoal is preferred, the corresponding saturated androstanes are obtained. The reaction is usually carried out in a solvent, especially in alkanols, Hexane, acetone, methyl ethyl ketone, dioxane, acetic acid or similar organic solvents. Of these, tert-butyl alcohol and 95% ethanol are preferred. The catalyst can be saturated with hydrogen before the introduction of the 4-methyl-d-4-steroid. It is preferred to bring the steroid and catalyst before introducing the hydrogen in a solvent together.

It is not necessary that the hydrogenation be carried out under pressure will. When a hydrogen pressure is applied, a pressure of 0.70 to about 1.75 will be achieved kg / cm2 preferred. Generally, a pressure of from about 0.07 to about 7.05 kg / cm 'or be applied more. The temperature can be about 0 to 100.degree. Room temperature leads to satisfactory results. The hydrogenation is carried out until about 1 molar equivalent of hydrogen is absorbed. The catalyst is then filtered off and recovering the hydrogenated product by conventional separation or extraction processes. The hydrogenated product can be chromatographed or by recrystallization from normally organic solvents or mixtures thereof used to separate steroids getting cleaned.

The obtained 4ß-Methylepimeren can by treatment at 0 ° C or slightly higher temperatures in an organic solvent such as chloroform, Methylene chloride, ether and the like, in the presence of a proton donating agent, such as alcohols, organic acids and the like, with a hydrogen halide, e.g. B. gaseous Hydrogen chloride, or an ethanolic solution of aqueous hydrochloric acid in the 4a-methyl epimers are converted. The mixture should be used during the addition of the acid kept at temperatures below room temperature, preferably at about 0 ° C will. The reaction mixture can then with dilute alkali solution and subsequently washed with water, dried and evaporated under reduced pressure. The crude 4x-methyl products obtained in this way from the reaction mixture can be purified by recrystallization.

The epimerization can also be done with an alkali, z. B. by treating the in an organic solvent such as methanol, located 4β-epimers with sodium hydroxide and potassium hydroxide solutions.

The following example explains the process according to the invention: Heated for hours. The solution was concentrated to about 175 cc by distilling off the excess methyl iodide. Then 30 cc of 10% sodium hydroxide solution were added. The alkaline solution was refluxed for 2 hours. Most of the methanol was then distilled off and the solution was thus concentrated to about 50 cc. After adding 100 cc of water, the reaction mixture was extracted three times with 100 cc of methylene chloride each time. The combined extracts were washed with water, dried over sodium sulfate and concentrated, whereupon 8.1 g of syrup were obtained. The syrup was dissolved in 70 cc of methylene chloride and diluted with 105 cc of hexane hydrocarbons, a precipitate formed which was filtered off. The mother liquor was chromatographed on 160 g of synthetic magnesium silicate and mixtures of acetone and Hexankohlenwasserstoffen (fractions of 180 cc) as follows washed: fractions 1 to 21 7: 39-acetone Hexankohlenwasserstoffe 22 to 50 10: 90-acetone Hexankohlenwasserstoffe Fractions 35 to 44 showed ultraviolet absorption maxima between 249 and 252 m # t. They were combined and 1 g of 4,17a-dimethyl-llß-oxytestosterone was obtained from them. Recrystallization from acetone gave 0.62 g of an analytical sample which melted at 219 to 221 ° C. and had an optical rotation of ocv = 120 ° (in chloroform). The ultraviolet absorption was Am, 6 ° x = 253 m &; am 15325. Analysis for C2, H3203 # Calculated. . . . . . . . . . . . . . . C = 75.86, H = 9.70; found . . . . . . . . . . . . . . . C = 75.90, H = 9.39. b) A solution of 0.5 g of 4,17oc-dimethyl-1β-oxytestosterone, 0.15 g of chromium trioxide, 10 cc of glacial acetic acid and 0.5 cc of water was stirred and kept at room temperature for 8 hours. The excess oxidizing agent was then destroyed by adding methanol, the mixture was poured into 50 cc of ice water, the precipitated precipitate was collected on a filter and recrystallized three times from ethyl acetate and hexane hydrocarbons. 4,17a-dimethyl-11-ketotestosterone was obtained as a slightly colored crystalline substance.

c) A mixture of 0.5 g of the 4,17a-dimethyl-llß-oxytestosterone obtained according to a), 55 ccm of tert-butyl alcohol and 100 mg of 5% palladium on charcoal was at a pressure of 1.11 kg / cm2 hydrogenated in a Parr hydrogenation plant. After 45 minutes, no more hydrogen was taken up. The reaction mixture was filtered through a diatomaceous earth filter to remove the catalyst and the filtrate was concentrated by distillation to a syrup which was dissolved in ether, filtered and concentrated. 0.17 g of crystalline 4β, 17oc-dimethyl-11β, 17β-dioxyandrostan-3-one with a melting point of 200 to 201 ° C. were obtained. Recrystallization from methylene chloride-hexane hydrocarbons gave 0.10 g of a slightly colored solid substance with a melting point of 200 to 201 ° C. and an optical rotation of [a) v = 7 ° (chloroform).

Analysis for C2, H3403: Calculated ............... C = 75.40, H = 10.25; found . . . . . . . . . . . . . . . C = 74.62, H = 10.08, 74.47, 10.10.

The 11-position hydroxyl group of the compound obtained can be used below are oxidized to the keto group by the method described under b).

d) A mixture of 0.5 g of the 4,17a-dimethyl-11-ketotestosterone obtained according to b), 55 ccmtert.-Butyl alcohol and 100 mg 5% palladium on charcoal was at a Pressure of about 1.05 kg / cm2 hydrogenated in a hydrogenation plant according to Pfarr. After 45 hours no more hydrogen was taken up. The reaction mixture was used for removal of the catalyst filtered through a diatomaceous earth filter. The filtrate was through Distillation concentrated to a syrup, which was dissolved in ether, filtered and concentrated became. The 4β, 17a-dimethyl-17β-oxyandrostane-3,11-dione was obtained by recrystallization Purified from methylene chloride-hexane hydrocarbons.

e) A solution of 1.63 g of the 4β, 17α-dimethyl-11β, 17β-dioxyandrostan-3-one obtained according to c) and 1.65 cc of absolute ethanol in 165 cc of chloroform was 1/2 hour to -5 to Maintained -10 ° C while passing hydrogen chloride gas through the solution. The reaction mixture was then poured into 300 cc of ice and saturated aqueous sodium bicarbonate. the organic layer was separated with aqueous sodium bicarbonate and then with Washed with water and dried over anhydrous sodium sulfate. The solution obtained was chromatographed on synthetic magnesium silicate. After washing out with acetone and hexane hydrocarbons and recrystallization from methylene chloride-hexane hydrocarbons 4a, 17ca-dimethyl-lß, 17ß-dioxyandrostan-3-one were obtained.

f) A mixture of 1 g of the 4,17a-dimethyl-11ß-oxytestosterone obtained according to a), 50ccmt.buty1-alcohol, 0.5 cc of glacial acetic acid and 0.4 g of selenium dioxide was refluxed for 24 hours. Additional (0.4 g) selenium dioxide was then added and the reflux condenser continued for 24 hours. The reaction mixture was concentrated in vacuo to about 14 cc and extracted with ethyl acetate. The ethyl acetate extract was washed with a cold, dilute, aqueous ammonium hydroxide solution, then with a cold, freshly prepared aqueous ammonium sulfide solution and again with aqueous ammonium hydroxide solution, water and finally with dilute acid. Then the extract was dried over sodium sulfate, filtered and evaporated to dryness. 0.55 g of residue from crude 1-dehydro-4,17a-dimethyl-11ß-oxytestosterone was obtained. The residue was dissolved in methylene chloride, adsorbed on 35 g of synthetic magnesium silicate and washed out with 35 cc fractions of 100% acetone in hexane hydrocarbons. Fractions 17 to 26 inclusive were combined and 0.29 g of 1-dehydro-4,17a-dimethyl-11ß-oxytestosterone were obtained from them. Recrystallization from acetone-hexane hydrocarbons gave 227 mg of 1-dehydro-4,17oc-dimethylllß-oxytestosterone with a melting point of 209 to 211 ° C and an optical rotation [a] D = 51 ' (chloroform) and infrared maxima in mineral oil of 1600, 1615, 3350 and 3440 cm- '.

The above procedure can also be used with others, one in the 11-position Carry out oxygen-containing 17a-alkyltestosterones.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of 4-methyl-17a-alkyl steroids of the androstane series of the general formula in which there can be a double bond in the 1 (2) position and / or 4 (5) position, R is an alkyl radical with 1 to 6 carbon atoms and R ,. = H, α- or ß-OH or keto oxygen, characterized in that a 3-enamine of the general formula in which R and R, have the meaning given above and n = 1 or 2, reacts with a methyl halide, hydrolyzes the 4-methyl-3-enamine obtained, optionally in a manner known per se, the 11-position hydroxyl group of the 4- Methyl-17oc-alkyl-11,17ß-dioxy-4-androstan-3-one is oxidized to the keto group, optionally the 4 (5) double bond is hydrogenated and the 4ß-methyl group is epimerized or optionally the 1 (2) position des 11-oxy (or keto) -4-methyl-17a-alkyl-17ß-oxy-4-androsten-3-one chemically or microbiologically dehydrated. 2. The method according to claim 1, characterized in that that the starting material is a 3-enamine of 17cx-methyl-11ß, 17ß-dioxy-4-androsten-3-one used.