DE1443619B - 7 alpha-methyl-4-esters unsubstituted in the 3-position and processes for their preparation - Google Patents

Description

(II)

- R,

(H)

wherein R, a free or esterified hydroxy group and R _{2 is} a hydrogen atom or an aliphatic carbon radical having 1 to 3 carbon atoms or R ₁ and R ₂ together represent an oxo group and R _{3 is} a thioketal group or a hydrogen atom together with an esterified hydroxyl group, the radical R ₃ eliminated, a 17 \ -unsubstituted 17 /? - hydroxy compound possibly obtained by saponification is oxidized to the 17-oxo compound and any 17-oxo compound obtained with a metal derivative of a lower saturated or unsaturated aliphatic hydrocarbon to the corresponding 17A-alkyl-17/9-hydroxy compound implements.

The present invention relates to 7'i-methyl-4-oestrenes unsubstituted in the 3-position, of the general types Formula I.

R,

(D

35 where R _{1 is} a free or esterified hydroxy group and R _{2 is} a hydrogen atom or an aliphatic hydrocarbon radical having 1 to 3 carbon atoms or R, and R ₁ together is an oxo group and R _{3 is} a thioketal group or a hydrogen atom together with an esterified hydroxy group, the remainder R _{3 is} eliminated and that any 17-unsubstituted 17 /? -Hydroxy compound obtained by saponification is oxidized to the 17-oxo compound and any 17-oxo compound obtained with a metal derivative of a lower saturated or unsaturated aliphatic hydrocarbon to the corresponding 17 \ - Reacts alkyl-17 / f-hydroxy compound.

A thioketal group R ₃ is e.g. B. one that arises when an oxo group is reacted with a lower aliphatic mercaptan or thioglycol, such as methyl, ethyl or propyl mercaptan or ethylene, 1,2-propylene or 1,3-propylene-dithiol. If R _{3 stands} for a hydrogen atom together with an esterified hydroxyl group, examples of the latter are those which, upon esterification with lower aliphatic carboxylic acids, e.g. B. acetic, trifluoroacetic, trimethyl acetic, propionic or caproic acid. develop.

The elimination of the above-mentioned sulfur-containing groups can be advantageous with either Nickel catalysts, such as Raney nickel, in one

⁶ S organic solvents, e.g. B. an alcohol or ether such as methanol, ethanol, tetrahydrofuran, dioxane, glycol dimethyl ether or a polyglycol ether, or with an alkali or alkaline earth metal.

like lithium, sodium. Potassium or calcium, in liquid ammonia and / or a lower aliphatic Amine, such as diethylamine or ethylenediamine. possibly in the presence of the latter ethers, respectively. An esterified allylic hydroxyl group in the 3-position can by known methods, for. B. hydrogenolytic. for example through the mild action of complex light metal hydrides such as lithium aluminum hydride, or by catalytically excited hydrogen. Palladium catalysts are particularly suitable as catalysts for this purpose, such as palladium on calcium or strontium carbonate. An esterified hydroxyl group can also analogous to the method given above, e.g. B. with lithium in ethyl or diet hyhmin, split off will.

If, after the elimination of the substituent R _{: 1,} a 7wjnsubsiluierte 17 / f-hydroxy compound is obtained, this is treated with an oxidizing agent, e.g. 13. a compound of hexavalent chromium, such as chromium trioxide. oxidized to the 17-oxo compound. The optionally obtained 17-oxo bond can be converted into 17-substituted n / i-hydroxy compounds by reaction with a metal derivative, in particular a Grignard compound or an alkali metal, such as lithium or sodium derivative, of a lower aliphatic hydrocarbon.

The invention also relates to those embodiments of the process, in which one of one obtainable as intermediates at some stage Connection runs out and performs the missing steps or the procedure at any stage terminates, or in which a starting material is formed under the reaction conditions.

The compounds of formula II used as starting materials can, for. B. from dun corresponding 7-unsubstituted I '- ⁶ -3-oxo-estradienes are produced. Treatment with methyl magnesium iodide in the presence of copper (I) chloride or copper (II) acetate and subsequent hydrolysis gives I '-3-oxo-7 \ -methyl-oestrenes. These can either be converted into the thioketals with the abovementioned mercaptuns or thioglycols or by reduction, for example with lithium aluminum hydride or sodium borohydride. can be converted into the corresponding 3-hydroxy compounds. The latter can be esterified using known methods.

The new estrenes of Formula 1 can be used as remedies, e.g. B. in the form of pharmaceutical preparations. Find use, which they in a mixture with a suitable for enteral or parenteral administration pharmaceutical organic or inorganic, solid or liquid carrier material. For the Formation of the same are those substances in question that do not react with the new compounds, such as. B. Water, gelatin. Lactose, starch, stearyl alcohol. Magnesium stearai. Talc, vegetable oils. Benzyl alcohol. Rubber, propylene glycol, polyalkylene glycols. Cholesterol or other known excipients. The pharmaceutical preparations can, for. B. as tablets. Dragees, capsules or in liquid form in the form of solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances. like preservation, stabilization. Wetting or emulsifying agents, solubilizers or salts to change the osmotic Pressure or buffer. They can also contain other therapeutically valuable substances. The pharmaceutical Preparations are obtained by conventional methods and contain the active ingredient, e.g. B. in a Amount from 0.1 to 50 percent by weight or from 0.1 to 100 mg per single dose.

The new compounds can also be used in veterinary medicine, for example in one of the above forms or in the form of feed or additives for animal feed. Here z. B. the usual extenders and thinners or feed used.

The invention is described in more detail in the following examples. The temperatures are in degrees Celsius specified; the specific rotations were determined with chloroform solutions.

example 1

A solution of 10 g of P-3,3-ethylenedithio-7-methyl-17 / i-acetoxy-oestrene in absolute tetrahydrofuran is added dropwise to 300 ml of liquid ammonia at -40 ° ^{C. while stirring.} Then 7 g of sodium are added in portions. The blue solution is stirred for 15 minutes, whereupon the excess of sodium is destroyed by alcohol and most of the ammonia is evaporated off at room temperature. A mixture of ether and methylene chloride (5: 1!) Is added to the residue, whereupon it is washed successively with water, dilute hydrochloric acid, 2N sodium hydroxide solution and water Chromatography on 250 g of aluminum oxide (activity II) chromatographies, giving the I '-7-v-methyl-17 / hydroxy-oestrene. After dissolving from ether, pentane melts at 132.5 to 133'. [Λ] ι 40.5 (r ■ - 1.01).

3.2 g of l'-7'-methyl-17 / hydroxy-esters are dissolved in 120 ml of acetone and 4 ml of an 8n-chromium (VI) oxide solution in dilute sulfuric acid are added at 0 ° while stirring. After stirring for 1 minute at the same temperature, the reaction mixture is poured into 400 ml of ice water, extracted with ether and the ethereal solutions are washed successively with water, saturated sodium hydrogen carbonate solution and water. The residue of the dried and, with the addition of benzene, evaporated ethereal solutions in a water jet vacuum is purified by chromatography on 100 g of aluminum oxide (activity II). The i ^ -v-methyl-H-oxoestrene is obtained. It melts at 153.5 to 155.5 ° after dissolving from ether -pentane, h] g> - '\ 2V (c 0.962).

To a methylmagnesium cooled to 10 °

bromide solution, prepared by introducing methyl bromide into a suspension of 30 g of magnesium and

400 ml of ether, you give 30 ^{g of 1} -7'v-methyl-17-oxo-

estern with rinsing with 300 ml ether. After one and a half hours of refluxing in the The reaction mixture is slowly cooled with an ice-cooking mixture under a stream of nitrogen with 750 ml of saturated ammonium chloride solution and then with 750 ml of water. After adding more ether and separation of the aqueous layer, this is extracted twice more with ether. the essential solutions are washed with water.

dried and evaporated in a water jet vacuum with the addition of benzene. The residue, which contains the crude l ¹ -7 \, 17A-dimethyl-17 /? - hydroxy-oestrene, is purified by chromatography on 1.8 kg

Alumina (activity II); M.p. 122 to 122.5 ° (from aqueous methanol), [\] f - + 18.2 ° (r - 0.961).

Example 2

To 9.5 g of magnesium and 40 ml of ether, 4.5 g of freshly distilled allylbroinide are slowly added in a stream of nitrogen with stirring in 15 ml. Add ether in drops. 15 minutes after the end of the reaction, the Grignard solution is pressed with nitrogen through a glass wool fuser, rinsing three times with 10 ml of ether each time, into a new flask filled with nitrogen. With stirring, can now be 3 g 1 ⁴ -7V-methyl-17-oxoöstren dropwise in 12 ml of benzene, and rinsed with 5 ml ether. After stirring for three hours at room temperature, 30 ml of saturated ammonium chloride solution are slowly added dropwise while cooling with an ice-sodium chloride mixture. The aqueous phase is extracted twice with benzene, whereupon the organic phases are washed with water, dried and vacuum evaporated in a water jet. Chromatography of the residue on '-'O- Ahiminiumoxide (activity II) gives the I'-yv-methyl-n ^ allyl-n / I-hydroxy-estrogen. after - ^% dissolving once from methanol at 50 to 53 schmilzi. Yield 2.45g. [\]? - 4 24.5 (c - 0.832)

Example 3

A mixture of 3.1 g of l'-7A-methyl-17-oxoestrogen, 20 ml of toluene and 280 ml of ether is saturated with acetylene gas at 0. Then leave between -10 and 0 ^; 60 ml of a 1.8 N solution of sodium t-amylate in tert-amyl alcohol - toluene (1: 3.42) are added dropwise within 20 minutes and acetylene gas is then passed ^{through at 0 to 3 r} for a further 15 hours. The reaction mixture is then poured onto 400 ml of 20% ammonium chloride solution at 5 °. After thorough shaking, the aqueous layer is separated off. It is extracted with ether and the organic solutions are washed with ice-cold ammonium chloride solution solutions to 100g of aluminum oxide (activity II) chromatography, wherein the 1 -7 ^4> -methyl-l7 \ is obtained -äthinyi-L7P-hydroxy-estrene It melts by reprecipitation from aqueous methanol at 87 ° to 88 ° (c.. - 0.981).

Example 4

14.3 matography is purified on aluminum oxide; F. 177 to 178 °. Mf - + 83.5 ° (r - 0.955).

Example 5

12 g I ⁴ -3-oxo-7 * -methyl-17 are / Miydroxy-estrene / left standing hours at room temperature with stirring with 360 ml of ether, 40 ml and 40 ml Dithioäthylenglykol Boririfluoridätherat vermischi and 3. ¹ The cooled solution is rinsed with 600 ml of ice-cold methylene chloride ether (1: 2) on 1 liter of ice-cold 2N sodium hydroxide solution, whereupon it is shaken well and undissolved flakes are removed by filtration. The aqueous phase is extracted twice with 1 liter of ice-cold methylene chloride-ether (1: 4) each time. After washing the organic solutions twice with 500 ml each of ice-cold 2N sodium hydroxide solution and with water, these are dried and evaporated in a water-jet vacuum. After redissolving the residue from methylene chloride ether, 13.03 g of l'-3.3-ethylenedithio-7-methyl-17 /? -Hydroxy-oestrene with a melting point of 212 to 213 ° ^{C. are obtained} . [v) f ■■ = - 91.3 ° (r - 0.977). Chromatography of the mother liquor on 60 g of aluminum oxide (activity II) yields a further 530 mg of dithioctalum. By acetylation with pyridine - - acetic anhydride there is obtained the l ⁴ described in Example 4 -3,3-Äthylendithio-7A-mcthyl-17 / facetoxy-estrene.

13.02 g I'-3.3-ethylenedithio-7 \ -methyl-17 / hydroxy-estrogen are added to 400 ml of liquid ammonia while stirring at -50 " in 180 ml of absolute tetrahydrofuran while rinsing with 20 ml of tetrahydrofuran. The dithioketal falls in fine crystalline form Shape. Now 4.7 g of sodium are added within 10 minutes at a temperature of about 45 ' small pieces, whereby the dithioketal goes back into solution and the reaction solution finally colors deep blue. 3 minutes later this is mixed with 20 ml of alcohol, and after decolorization is left the Evaporate ammonia. The residue is mixed with 500 ml of water and the mixture with once 1 liter of methylene chloride - ether (1: 5) and extracted twice with 500 ml of ether. The organic solutions it is washed with 500 ml of 2N sodium hydroxide solution and then with water, dried and evaporated in a water-jet vacuum a By dissolving from ether - pentane 9.76 g of I'-7A-methyl-17 / -mivdroxy estrogen are obtained. which is identical to the product described in Example 1.

That used as the starting material in Example 1 I '- 3.3- ethylenedithio-7 \ -methyl-17 /? - acetoxy - estrogen can be made as follows:

A mixture of 30 g of ⁴ -3-oxo-7 \ -methyl-17 ^ -acetoxy-oestrene and 900 ml of absolute ether is stirred with 100 ml of ethylenedithioglycol and 10On. ¹ Ikirlritluoridätherat added. After 20 hours, the mixture is poured into 2.5 liters of ice-cold 2N soda solution while stirring and cooling, rinsing with ether. The outer phase is extracted again with ether, and the organic phases are then extracted with ice-cold 2N sodium hydroxide solution and water. The residue of the dried and with the addition of benzene evaporated in a water jet vacuum consists of the crude I "-3,3-ethylenedithio-7 \ -methyl-17 // - acetoxy-estrogen, which by chromium

Example 6

A mixture of 6 g of ¹ -3-oxo-7 \, 17 \ -dimethyl-17 / i-hydroxy-esters, 180 ml of ether, 20 ml of dithioethylene glycol and 20 ml of boron trifluoride etherate is left to stand for 50 minutes at room temperature. Pour on it; they are stirred and cooled to 500 ml of ice-cold 2N sodium hydroxide solution and rinsed with an ice-cold mixture of 220 ml of ether and 100 ml of methylene chloride. The organic phase is washed twice with 250 ml of ice-cold 2N sodium hydroxide solution and with water, whereupon the aqueous solutions are subsequently extracted twice with 500 ml of ice-cold methylene chloride ether (1: 4) each time. The residue of the dried and evaporated organic solutions, after redissolving from methylene chloride-ether, gives 6.4 gl ¹ -3,3-ethylenediophio-7 \ .l7 \ -dimethvl-17 /?

157 \ [a]? - + 61 ° (r - 0.399). From the mother liquor another 350 mg of the same compound can be obtained.

A solution of 6.54 g of 1 ¹ -3,3-ethylenedithio-7 \ .17 \ -dimethyl-17 /? - hydroxy-oestrene in 90 ml of absolute tetrahydrofuran is added to 200 ml of liquid ammonia while rinsing with 10 ml of tetrahydrofuran. At -50 to 45 ^N the mixture is stirred within 12 minutes with 2.4 g of sodium and 5 minutes later with 10 ml of alcohol. After the ammonia has evaporated and 250 ml of water have been added to the residue, it is extracted three times with 500 ml of ether. The ethereal solutions are washed with 250 ml of 1 η sodium hydroxide solution and with water, dried and evaporated in vacuo. By redissolving the residue twice from aqueous methanol, 3.1 g of 1'-7A, 17 \ -dimethyl-17/3-hydroxy-oestrene, which is identical to the compound described in Example 3, are obtained.

Example 7

To the 10 g of ethyl bromide and magnesium Grignard compound prepared in 400 ml of ether are added 10 g of 1 ⁴ λ -7-methyl-17-oxo-estrene, and the solution is left for one hour boil. The reaction mixture is then slowly mixed with 200 ml of saturated ammonium chloride solution and then with 200 ml of water, while cooling with an ice-methanol mixture. After the aqueous phase has been extracted twice with ether, the organic solutions are washed twice with water. dries and steams them. The residue is chromatographed on 300 g of aluminum oxide (activity H), 3.6 g of the starting material being used from the fractions eluted with a benzene-petroleum ether (1: 9) mixture by dissolving from a methylene chloride-pentane mixture '-7A-methyl-17-oxoestrous recovered. The fractions obtained with benzene-petroleum ether (1: 4) and (3: 7) mixture, after redissolving in methanol, give 4.5 gl ⁴ -7 \ -Methyl-17 - \ .- ethyl-17 /? - hydroxy-oestrene, which melts fuzzy between about 50 and 62 °. [- »]? ■ 16 ^C (c l.OoSi. 1 R absorption bands at 2.75 and 2.87 μ and two other sharp and intense bands at 7.21 and 10.25 μ (in methylene chloride).

Example 8

3 g of l'-3-Oxo-7> -methyl-17 /) - acetoxy-acetoxy dissolved in 150 ml of methanol, 800 mg of sodium borohydride were added to the solution and the mixture was at room temperature for 1 hour touched. The reaction mixture is then neutralized with acetic acid and evaporated after adding a little water in a water jet vacuum. The residue is taken up in ether, the solution washed with water, dried and evaporated. The crude I'-3-hydroxy-7 \ -methyl-17β-acetoxy-oestrene obtained in this way (2.9 g, IR absorption bands at 2.78, 5.77, 8.10 and 9.74 μ) is then dissolved in 50 ml of pyridine, the solution at

> 50 mixed with 2 g of tosyl chloride and left to stand for 18 hours at f> to 10 ^r . The reaction mixture is diluted with ether then there was added under ice-cooling with dilute hydrochloric acid, it is washed in succession with sodium bicarbonate solution and water, the organic phase is dried and evaporated ^{e 'n} · ^Man ehält so 3.1g 1 ⁴ -3-tosyloxy-7 \ - methyl-17 / i-acetoxy-oestrene.

1 g of the tosylate obtained is dissolved in 50 ml of tetrahydrofuran, the solution with stirring to a

* 5 suspension of 500 mg of lithium aluminum hydride in 100 ml of tetrahydrofuran added dropwise. After 30 minutes of heating to 60, the cooled solution is carefully mixed in succession with a mixture of 1 ml of ethyl acetate and 10 ml of tetrahydrofuran, 1 ml of water in 10 ml of tetrahydrofuran and then with 10 g of anhydrous sodium sulfate and filtered. The filtrate is evaporated in a water jet vacuum and the residue is chromatographed on aluminum oxide (activity II). This gives 350 mg of 1 -7 ⁴ \ -methyl-17 / i-hydroxy-estrene. which is identical to the product obtained according to Example 1.

^{If you reduce the 1 1} -5-oxo-7 \ .17 \ -dimethyl-17 ^ -hydroxy-oestrene instead of 1 ¹ -3-oxo-7 \ -methyl-17 / i-acetoxy-oester, one obtains the l ⁴ -3.17 / j-di-

4 "hydroxy-7 \, 17> -dimethyl-oestrene. This is called Acetic anhydride in Pyndine into the corresponding 3-Acetai transferred and reacted with excess sodium in ammonia. According to the example 6 The specified work-up gives the P-7 \, 17-v-Diniethyi-'up-hydroxy-ostreri. that with rter in the example 1 and 6 described connection is identical.

209548/510

Claims (2)

Patent claims:
1. 7a-Methy] -4-oestrene of the general formula CH, wherein R _{1 represents} a free hydroxyl group and R _{2 represents} an aliphatic hydrocarbon radical having 1 to 3 carbon atoms. 2. Process for the preparation of in 3-position unsubstituted 7a-methyl-4-oestrenes of the general Formula I. (D wherein R _{1 represents} a free hydroxyl group and R _{2 represents} an aliphatic hydrocarbon radical having 1 to 3 carbon atoms, and processes for their preparation. The aliphatic hydrocarbon radicals with 1 to 3 carbon atoms are methyl, ethyl, propyl or isopropyl, vinyl, allyl, ethynyl or propynyl radicals in question. The new methyl estrenes have valuable pharmacological properties Properties. They show a particularly high anabolic-androgen quotient on the test animal, a high oral effectiveness and a long duration of action and are therefore the appropriate Clearly superior to 3-oxo compounds. They are also characterized by a pronounced blood cholesterol-lowering effect Effect. In the case of compounds which have a lower alkynyl radical in the 17 \ position, a gestagenic and antigonadotropic effect is determined. They can therefore be used as anabolic steroids, antihypercholestenemics. Progestin and Ovulaiion inhibiting agents find use. They are too suitable as intermediate products for the manufacture of medicinal products. The new compounds are obtained when in a manner known per se in a compound of the general formula II wherein R _{1 represents} a free hydroxyl group and R _{2 represents} an aliphatic hydrocarbon radical having 1 to 3 carbon atoms, characterized in that in a manner known per se in a compound of the general formula II -R ₂