DE2832603A1 - 7-Organo:sulphonyl-1,3,5-oestratriene derivs. - useful as intermediates for oestrogen(s) and ovulation inhibitors - Google Patents

Abstract

Oestratriene derivs. of formula (I) are new: (where R1 and R2 are lower alkyl; X is protected CHOH; R3 is alkyl or opt. substd. aryl; R4 is H or Me; Z is H or OR1). Cpds. (I) are useful as intermediates for oestratriene derivs. of formula (II) which are intermediates for prepg. oestrogenic agents and ovulation inhibitors.

Description

The invention relates to those characterized in the claims

Objects.

The 7-methyl-1,3,5 (10) -estratrienes of the general formula I are new Compounds used as intermediates for the preparation of pharmacologically active Steroids can be used.

The preparation of the new compounds according to the invention Process and the further reaction to the pharmacologically active compounds takes place in such good yields and so few reaction steps that in an unexpected way an economical production of these important compounds is made possible.

Lower alkyl groups R1 and R2 should be alkyl groups with 1-4 C atoms are understood, such as methyl, ethyl, propyl, isopropyl, Butyl, methyl and ethyl groups being preferred.

If R3 is a lower or middle alkyl group, are in particular middle alkyl groups, for example with 4-8 carbon atoms in the alkyl radical, are suitable. Particularly the hexyl radical is appropriate.

However, lower alkyl groups with 1-4 carbon atoms can also be used in the alkyl radical.

If R3 is an optionally substituted aryl radical before, the phenyl radical is to be regarded as preferred. The phenyl radical can also be added be substituted, preferably by a methyl group.

As a protecting group in the functionally protected hydroxymethylene group X, ester and ether groups come into question, as they are for the experimental one Chemists are familiar.

In the context of the method according to the invention are in particular in alkaline and weakly acidic reaction medium resistant protective groups can be used. So are preferably suitable protective groups ether residues. Alkoxymethylene groups are preferred with 1 to 4 carbon atoms suitable as protective groups, for example: the methoxy, ethoxy, propyloxy, butyloxy or isopropyloxy radical, the tert. Butyloxy is preferred.

Mixed acetals such as, for example, are also suitable Tetrahydropyranyl ether or ethoxyethyl ether.

If Y is a ketalized carbonyl group, then suitable ones come Residues of lower alkylenedioxymethylene groups with 1 to 6 carbon atoms in the alkylene radical into consideration, such as B. 1,2-Äthglendioxymethylene, 1,3-propylenedioxymethylene, 2,3-butylenedioxymethylene, 2 ', 2'-dimethyl-1', 3'-propylenedioxymethylene, 2, 4-pentylenedioxymethylene or 1,2-phenylenedioxymethylene, 1,2-ethylenedioxymethylene is to be regarded as preferred.

The cyclization of the starting compounds carried out in reaction step a) of the general formula II is carried out according to methods known per se, for example in Presence of acidic catalysts. Suitable catalysts for the cyclization are strongly dissociating carboxylic acids, phenols, mineral acids, sutonic acids or Lewis acids. Trifluoroacetic acid or mineral acids such as, for example, are particularly suitable Sulfuric acid, phosphoric acid, perchloric acid.

The cyclization is usually carried out in an organic solvent such as in alcohols, ethers, ketones, hydrocarbons, chlorinated Hydrocarbons, etc.

carried out and can at temperatures between -40 ° C to 80 ° C, preferably at -25 ° C to -10 ° C.

Of course, the 7RS sulfonyl isomer mixture of the general Formula II before the cyclization using the usual methods such as chromatography and / or separated into the antipodes by recrystallization.

Both antipodes can be in 7-position to the corresponding ones without isomerization Compounds of the general formula III are cyclized.

If the isomers are only separated after the cyclization, by adding a strong base such as lithium alkyl (e.g. Li-methyl, Li-butyl), lithium diisopropylamide or alkali hydrides (e.g. Li-, Na-, K-Ehydrid) the anion of the 7'-sulfonyl-oestra-1,3,5 (10), - 9 (11) tetraene is formed that with water or acids such as acetic acid, practically quantitative isomerized to the 7β-sulfonyl-oestra-1,3,5 (10), 9 (11) -tetraenen.

A separation of the isomer mixture is of course also possible of the general formula III by the customary methods such as, for example, chromatography or recrystallization possible before the further reaction.

The hydrogenation of the compounds carried out in reaction step b) of the general formula III takes place catalytically.

The catalysts include heavy metal catalysts, preferably those of the 8th subgroup, such as palladium, optionally on supports such as calcium carbonate, activated charcoal or barium sulfate burns, or Raney nickel in question.

The hydrogenation can be carried out both at room temperature and at lower or at an elevated temperature.

A reaction temperature is preferred for carrying out the reaction selected from 0 ° C to 50 ° C.

The hydrogenation can be carried out either under normal pressure or at elevated pressure Printing can be carried out. The hydrogenation is preferably carried out under a hydrogen pressure from 1-80 atmospheres.

In the hydrogenation, 7β-sulfonylöstra-1,3,5 (10) -trienes are obtained in very good yields obtained in the presence of a strong base (preferably with bases like side 6, paragraph 2) deprotonated and largely to 7-sulfonyl-oestra-1,3,5 (10) -triene when acidified are isomerized.

The subsequent methylation in the 7-position followed according to the usual Methods, for example with methyl iodide, and can without prior isomerization the hydrogenation products are made. The reaction is expediently carried out in such a way that the hydrogenation product deprotonates and methylates in a one-pot reaction will.

7B-methyl-7a-sulfonyl-1,3,5 (10) -estratrienes of the general type are isolated Formula I in very good yields.

The methylation can take place at low temperatures (from about -700C) as well as at elevated temperatures (up to about + 500C), but preferably at -200C to be carried out to room temperature.

Suitable solvents for the methylation are polar, aprotic ones organic solvents such as hexamethylphosphoric acid triamide, dimethyl sulfoxide, Dimethylformamide and others or ethers (e.g. tetrahydrofuran, dimethoxyethane, diethyl ether i.a.) or hydrocarbons such as toluene or benzene.

Of course, it is also possible to use the general First methylate formula III and then hydrogenate it. The methylation can then be carried out as described above. For example, by being in the present of lithium alkyl (e.g. Li-methyl, Liiutyl), lithium diisopropylamide or alkali hydrides (e.g. Li, Na, E hydride) the anion is formed, which methylates with methyl iodide will.

The 7'-methyl-7β-sulfonyl-oestra-1,3,5 (10), q (II) -tetraene obtained in this way are selectively hydrogenated by the customary processes described above to give the 7'-methyl-7ß-sulfonyl compounds of the general formula I.

To convert the new compounds of the general formula I into the compounds of the general formula V where R1, R2 and X have the above meaning, the sulfonyl group is split off electrochemically or chemically.

If the sulfonyl group is split off according to chemical working methods, the compound I is in a protic or aprotic organic solvent or mixtures thereof (dissolved as completely as possible) with one known per se Desulfurization reagent or combinations thereof reduced.

Preferred reducing agents are, for example, alkali metal amalgams such as lithium, sodium or potassium amalgam. When using these reducing agents the reaction is preferably carried out in protic polar solvents such as alcohols (expediently methanol, ethanol or isopropanol) carried out. For the purpose of solubility improvement non-polar solvents such as hydrocarbons can be added to the reaction mixture (e.g. toluene), etc., can be added.

The reaction is carried out at room temperature to the boiling point Reaction mixture, preferably carried out at 60-1000C.

Solutions of alkali metals are also very suitable reducing agents (Lithium, sodium, potassium) in ammonia or a lower alkylamine (e.g. methylamine, Ethylamine) at -700C to room temperature. The implementation is most expedient under normal pressure; However, it can also be used under increased pressure, e.g. under partial pressure of the solvent used.

The combination of an aluminum hydride is also used as a reducing agent (e.g. lithium aluminum hydride or diisobutyl aluminum hydride) as a reducing agent and Raney nickel as a desulphurisation reagent. The reduction takes place in one polar aprotic solvent, preferably hexamethylphosphoric triamide, optionally with the addition of triphenylphosphine, at room temperature up to 1000C, preferably 500-600C, the subsequent desulfurization is carried out in protic or aprotic solvents such as alcohols (especially methanol or ethanol), Ketones (e.g. acetone, methyl ethyl ketone, etc.) or hydrocarbons (e.g. toluene, Benzene and the like) at room temperature to 80 ° C, preferably at 400700 °, if necessary in the presence of hydrogen.

The electrochemical reduction is carried out in an undivided cell. The cathode consists of metals with high hydrogen overvoltage e.g. Hg, Pb, Cd or also amalgamated carrier material such as preferably Cu or Au. The anode material is not critical for the reaction and only has to be stable under the reaction conditions be; graphite and platinum-coated titanium are preferably used. As a solvent come to the expert known protic solvent in question, such as preferably water, lower alcohols (especially methanol, ethanol), amines (Ammonia, hydrazines, methyl-, ethylamine, etc.) and their mixtures. As an auxiliary solvent ether (e.g. TIEF, dioxane) or ester (e.g.

Ethyl acetate) can be added. The usual alkali metal salts are used and alkaline earth salts. Halide, perchlorate, BF4, PF6, aryl sulfonates can be used as anions i.a.

can be applied. The preferred current density is 10 3 to 10 -1 Amp./qm2. A parallel H2 development is necessary for the desired reaction to insignificant.

The conversion of the compounds of general formula V into pharmacological effective compounds, in particular with estrogenic and ovulation-inhibiting effects takes place according to methods known per se.

For example, the functionally protected 17β-hydroxymethylene group X converted into a free Hydroxytnethylengruppe and then to the 17-Eeto compound oxidized. Then the 1,3-dieter can - as is known - to a 7α-methyl- # 1,3,5, (10) -estratrien-17-one-1,3-diacetate are converted, its production and further processing in the German patent specification 1 593 509 is described.

The preparation of the new starting compounds of the general formula II takes place according to the methods known to the person skilled in the art.

For example, after protection of the 5-eeto group by etalization 1ß-tert-butoxy-7ass-methyl-4- (phenylsulfonylmethyl) -3a, 4,5,6,7,7a-hexahydroindan-5-one alkylate according to the usual methods with 3,5-disubstituted benzyl bromides. Man receives the isomer mixture of the general formula II, from which the well crystalline 7S compound can be easily separated, for example by crystallization.

Preparation of the new starting compounds 5,5-ethylenedioxy-1ß-tert-butoxy-7ass-methyl-4- (2- (3,5-dimethoxyphenyl ) -l RS -phenylsulfonyl-ethyl) -perhydroindene a) lß-tert-butoxy-7ass-methyl-5,5-ethylenedioxy-4- (phenylsulfonylmethyl) 0.2 ml of concentrated sulfuric acid, 5.65 g of β-tert-butoxy-7ass-methyl-4- (phenylsulfonylmethyl) -3a, 4,5,6,7,7a-hexahydroindane-5-o are dissolved in 50 ml of dioxane 10 ml ethylene glycol and 5 ml orthoformic acid ester. One leaves at room temperature Stand for 24 hours, then draws off most of the solvent in a vacuum and takes it off in ether. After shaking with saturated NaHC03 solution and water is over Na2S04 dried, filtered and evaporated. The residue is dissolved in methylene chloride dissolved and after addition of hexane, 4.75 g (75% of theory) are isolated, melting point: 130-1320C, i'D 90 (1% in CHCl3).

b) 1-bromomethyl-3,5-dimethoxybenzene 7.3 g of 3,5-dimethoxybenzyl alcohol (43 mmol) are dissolved in 130 ml of absolute ether with 2.4 ml of phosphorus tribromide (25 mmol) were added and the mixture was refluxed for 2.5 hours. Then you give on ice separates the ether phase, washes them with saturated sodium bicarbonate solution and sodium chloride solution, dried with sodium sulfate, filtered and distilled the solvent is removed in vacuo, yield after crystallization from pentane: 7.93 g (79% of theory), melting point: 72-75 ° G.

c) In the solution of 17.0 g of 5,5-xthylenedioxy-lß-tert-butoxy-7ass-methyl-4- (phenylsulfonylmethyl) perhydroindene (40 mmol) in 80 ml of tetrahydrofuran are added 5.6 ml of diisopropylamine and the mixture is cooled -700C. Then 24 ml of about 2N butyllithium solution in hexane (about 50 mmol) added and stirred at 2000 for 30 minutes. After cooling to -700C, it is alkylated by adding a solution of 10.2 g of 3,5-dimethoxybenzyl bromide (44 mmol) in 120 ml of tetrahydrofuran. The mixture is slowly warmed to -20 ° C and remains Stand at this temperature overnight. Then you add 8 ml of glacial acetic acid, it draws The solvent is removed in vacuo and the residue is taken up in chloroform.

After shaking with 1N sodium hydroxide solution, 1N hydrochloric acid and saturated Sodium bicarbonate solution is dried with sodium sulfate, filtered and distilled the solvent in a vacuum. The crude yield is 29.9 g and exists according to thin layer chromatography mainly from a mixture of the two isomers.

Example 1 17β-tert-Butoxy-1,3-dimethoxy-7 "-phenylsulfonyl-oestra-1,3,5 (10), 9 (11) -tetraene 15.5 g of 5,5-ethylenedioxy-lβ-tert-butoxy-7ass-methyl-4- (2- (3,5-dimethoxyphenyl) -lRS-phenylsulfonylethyl) perhydroindene are dissolved concentrated in 150 ml of acetone, cools to -200C and slowly drops with stirring O ml Sulfuric acid 10 added. It is not stirred for minutes at this temperature and then poured into a saturated sodium bicarbonate solution. Shake three times Chloroform, the organic phase is dried with sodium sulfate, filtered and distilled the solvent in a vacuum. The crude yield is 14.6 g. After chromatography on 1.5 kg of silica gel with a gasoline / ethyl acetate gradient (99: 1 to 0: 100) is obtained one 9.28 g of a mixture, from which 4.74 by crystallization from diisopropyl ether g of 17β-tert-butoxy-1,3-dimethoxy-7α-phenylsulfonyl-oestra-1,3,5 (10), 9 (11) -tetraene can be obtained. (Yield: 35). Melting point: 119-1210C t7D = -70.5 ° C (1% in chloroform).

Example 2 17β-tert -Butoxy-1,3-dimethoxy-7β-phenylsulfonyl-1,3,5 (10), 9 (11) -estratetraene 17.1 g of crystalline 5,5-ethylenedioxy-1β-tert-butoxy-7ass-methyl-4- (2- (3,5-dimethoxyphenyl) -lS-phenylsulfonylethyl) perhydroindene are dissolved in 360 ml of anhydrous toluene (Melting point 140-141 ° C, «2D = + 19 ° C), 12 ml of trifluoroacetic anhydride and 3.5 ml of trifluoroacetic acid. The mixture is stirred for 30 minutes at room temperature, partitioned between Water and ether, the ether phase washes acid-free with saturated bicarbonate solution and after drying and evaporation, a residue is obtained which consists of diisopropyl ether crystallized, 13.9 g of 17β-tert-butoxy-1,3-dimethoxy-7β-phenylsulfonyl-1,3,5 (10), 9 (11) -estratetraene supplies.

Melting point: 155-1590C, [α] D = t63 ° C (1 °, b in chloroform).

Example 3 2.04 g of crystalline 7a-phenylsulfonyl compound is used in 20 ml of absolute tetrahydrofuran dissolved. 0.56 ml of diisopropylamine are added and cools down to -70 ° C.

Then 2.4 ml of about 2N butyllithium are added and 15 minutes at -70 ° C stirred. At this temperature adds 1 ml of glacial acetic acid is added, draws off most of the solvent in vacuo and takes up in chloroform. After shaking with 1N sodium hydroxide solution, 1N hydrochloric acid and saturated sodium bicarbonate solution is dried with sodium sulfate, filtered and evaporated, leaving a residue of 2.08 g remain. After crystallization from ether, 1.31 g (65.56) of 17β-tert-butoxy-1,3-dimethoxy-7β-phenylsulfonyl-oestra-1,3,5 (10), 9 (11) -t are obtained received etraen. Melting point: 160-163 ° C., Example 4 17β-tert-butoxy-1,3-dimethoxy-7β-phenylsulfonyl-oestra-1 1315C10) -triene 1.28 g of 17β-tert-butoxy-1,3-dimethoxy-7B-phenylsulfonylestra-1,3,5 (10), 9 (11) -tetraene are dissolved in 50 ml benzene and 50 ml ethanol, with 650 mg palladium / carbon (1056) hydrogenated at room temperature. After 2 hours a further 325 mg of catalyst are added. After a total of 3 hours, the uptake of hydrogen has ended and the mixture is filtered and concentrated and recrystallizes from diisopropyl ether, yield: 1.01 g (790 / o), melting point 165-166 ° C Z- «JD = 12.80C (1% in chloroform).

3 e 1 s p 1 e 1 5 17B-tert-butoxy-1,3-dimethoxy-7 "-phenylsulfonyl-oestra-1,3,5 (10) -triene 0.1 ml of diisopropylamine and 0.5 ml of 2N butyllithium (hexane) are dissolved in 1 ml of absolute Tetrahydrofuran with ice cooling, cools to -50 ° C and gives about 200 mg of 17β-tert-butoxy-1,3-dimethoxy-7β-phenylsulfonyl-1,3,5 (10) -triene dissolved in 4 ml of tetrahydrofuran added. After 30 minutes at -20.degree. C., the mixture is cooled to 700.degree and acidified with glacial acetic acid. It is taken up in chloroform, shaken with 1N sodium hydroxide solution, 1 N hydrochloric acid and concentrated bicarbonate solution, the organic phase dries with sodium sulfate, filtered and evaporated in vacuo. Ether becomes 70 mg of the Title compound isolated. Yield about 35%.

Melting point: 217-221 ° C (ether) r «D = + 30.4 ° C (1% in chloroform).

Example 6 17β-tert -Butoxy-1,3-dimethoxy-7a-methyl-7β-phenylsulfonyl-oestra-1,3,5 (10), 9 (11) -tetraene 3.06 g of 17β-tert-butoxy-1,3-dimethoxy-7-phenylsulfonyl-oestra-1,3,5 (10), 9 (11) -tetraene The mixture of isomers is dissolved in 20 ml of absolute tetrahydrofuran, and 0.84 ml of diisopropylamine is added added and cools down to -700C. 3.7 ml of about 2N butyllithium solution are then added (in hexane) and stir at 200 ° C. for 1 hour. After cooling to -700C, 2 ml Methyl iodide in 10 ml of tetrahydrofuran is added, the solution is slowly dissolved Warm up to 200C and keep at this temperature overnight.

It is acidified with a little glacial acetic acid, evaporated and taken with chloroform and shaken one after the other with 1N sodium hydroxide solution, 1N hydrochloric acid and saturated Bicarbonate solution. The solution is dried with sodium sulfate and evaporated in vacuo and the residue recrystallized from diisopropyl ether, yield: 2.35 g (75 56), Melting point: 167-1680C rt7D = f790C (1 56 in chloroform).

Example 7 17β-tert-Butoxy-1,3-dimethoxy-7a-methyl-7β-phenylsulfonylöstra-1 13 15 (l0) -triene 7.92 g of 17β-tert-butoxy-1,3-dimethoxy-7α-methyl-7B-phenylsulfonyl-oestra-1,3,5 (10), 9 (11) - tetraene in 1.61 ethanol with 4.0 g palladium / carbon (10%) in 2 hours at room temperature. It gets off the catalyst and crystallizes.

filtered off and evaporated to 400 ml, yield 6.56 g (83% of theory), Melting point: 176-1800C Ä7D = t112 ° C for example 8 (1 56 in chloroform).

17β-tert-Butoxy-1,3-dimethoxy-7β-methyl-7a-phenylsulfonylestra-1,3,5 (10) -triene From 4 ml of diisopropylamine and 10 ml of about 2N butyl and 15 ml of tetrahydrofuran lithium solution (Hexane) / one prepares a solution of lithium diisopropylamide, which one at -50 ° C with the solution of 3.0 g of 17β-tert-butoxy-1,3-dimethoxy-7β-phenylsulfonyl-oestra-1,3p (10) -triene in 40 ml tetrahydrofuran and after 15 minutes standing at room temperature with 11 ml methyl iodide offset.

The mixture is stirred for one hour at room temperature, acidified with glacial acetic acid and the solvent is distilled off in vacuo. The residue is dissolved in chloroform and one after the other with 1N sodium hydroxide solution, 1N hydrochloric acid and saturated sodium bicarbonate solution washed. After drying with sodium sulfate and filtration, the distillation is carried out Solvent from and receives 3.6 mg of crude product, which crystallizes out Ether / diisopropyl ether 2.4 g of the title compound provides.

Melting point: 185-1890C ragD- + 42 ° C (1% in chloroform).

Example 9 17β-tert -Butoxy-1,3-dimethoxy-7α-methyl-1,3,5 (10) -estratriene 133 mg of 17β-tert-butoxy-1,3-dimethoxy-7β-methyl-7α-phenylsulfonyl-1,3,5 (10) -estratriene are dissolved in 20 ml of methanol, are 150 mg of disodium hydrogen phosphate and 3.6 g of 656 sodium amalgam and heated under reflux for 2 hours.

The precipitate is then separated off and the solution is largely concentrated and distributed between chloroform and water.

The organic phase is washed neutral and dried with sodium sulfate and evaporated. The crude yield of 108 mg is recrystallized from methanol and 60 mg of the title compound are obtained, melting point: 135-136 ° C fiaD = tl26 ° C (0.5% in chloroform).

B e 1 portion 1 10 105 mg of 17β-tert-butoxy-1,3-dimethoxy-7β-methyl-7rphenylsulfonyl-1,3,5 (10) -estratriene are in 60 ml of methanol in the presence of 2 g of lithium perchlorate and 2 ml of hydrazine hydrate (80%) in an undivided cell between a mercury cathode and a graphite anode electrolyzed at 0.25 amps. When the reaction is complete, the electrolyte becomes evaporated, the residue is mixed with water and filtered. The colorless residue turns off Recrystallized methanol and 62 mg of the compound of Example 9 are obtained.

Melting point: 135-136 ° C, fia7D = t 12,500 (0.5% in chloroform).

For example 11 95 mg of 17β-tert-butoxy-1,3-dimethoxy-7α-methyl-7β-phenylsuZonyl-1,3,5 (10) -estratriene are in 100 ml of ethanol in the presence of 2.5 g of sodium p-toluenesulfonate and 10 ml of 25% NH40H solution in an undivided cell between an amalgamated Gold cathode and a graphite anode electrolyzed at 0.25 amps.

When the reaction has ended, the electrolyte is evaporated and the residue is evaporated mixed with water and filtered.

The colorless residue is recrystallized from methanol and one receives 50 mg of the compound of Example 9.

EXAMPLE 12 66 mg of 17β-tert-butoxy-7a-methyl-7β-phenyl are dissolved sulfonyl-1,3,5 (10) -estratriene in 1.5 ml of methanol and 0.5 ml of toluene, gives 600 mg Add 6% sodium amalgam in three portions within an hour and heat with stirring to 500C, the mercury is separated off, the solvent is evaporated, takes up in chloroform and shakes with 1N hydrochloric acid and saturated bicarbonate solution the end. After drying, it is evaporated and the residue crystallized, the Compound of Example 9 is obtained.

For example, 1 13 128 mg of 17β-tert-butoxy-7a-methyl-7β-phenylsulfonyl-1,3,5 (10) -estratriene it is heated in 3 ml of hexamethylphosphoric triamide with 130 mg of triphenylphosphine and 80 mg lithium aluminum hydride for three hours at 50 ° C under nitrogen.

Then it is diluted with ether, carefully decomposed with water and repeated several times extracted with ether. After drying and evaporation, the residue becomes 112 mg taken up in 10 ml of ethanol and hydrogenated with Raney nickel for three hours at 60.degree. After filtering off and evaporation, 80 mg remain, which crystallizes from methanol 42 mg of the compound of Example 9 yield.

3 e i s p i e 1 14 Pour into 30 ml of dried ammonia at 700C the solution of 66 mg of 17β-tert-butoxy-7β-methyl-7a-phenylsulfonyl-1,3,5 (10) -estratriene in 5 ml of tetrahydrofuran, 0.05 ml of tert-butanol and 20 mg of lithium. After 15 minutes Stirring at -70 ° C., ammonium chloride is added until it is discolored, and the ammonia is evaporated and acidified with 2N acetic acid. Partition between chloroform and saturated Bicarbonate solution and receives 53 mg from the organic phase, which after crystallization give the compound of Example 9.

3 e i s p i e 1 15 a) starting compound 5,5-ethylenedioxy-1β-tert-butoxy-7ass-me ethyl -4- C 23 -methoxyphenyl) -l -phenyl sulfonyl-ethyl) -perh; ydroinden To the solution of 4.25 g of 5,5-ethylenedioxy-1β-tert-butoxy 7ass-methy1-4- (phenylsulfonylmethyl) perhydroindene (10 mmol) in 30 ml of THF are added at -70 ° C. 6.5 ml of 15% strength butyllithium solution in hexane and then stir for 30 minutes at 200C.

The solution of 2.5 g of 3-methoxybenzyl bromide in 30 ml is then added TUF and let the mixture stand at this temperature overnight. One acidifies with acetic acid, taken up in chloroform and shaken with saturated bicarbonate solution the end. After the organic phase has dried and the solvent has been stripped off, it remains 7.3 g of crude product that after chromatography 5.2 g of the title compound supplies as a mixture of isomers.

b) 17β-tert-Butoxy-3-methoxy-7β-phenylsulfonyl-1,3,5 (10), 9, (11) -estratetraene The mixture of isomers described above is dissolved in 50 ml of ethanol and 0.5 ml is added concentrated sulfuric acid added. It is left to stand overnight at room temperature, then adds bicarbonate and largely distills off the solvent. Of the The residue is partitioned between water and chloroform, and the organic solution is dried and narrowed. After chromatography on silica gel, 2.9 g of the desired ones are obtained Compound which crystallizes from ethyl acetate / diisopropyl ether. Melting point 143-144 ° C, [α] D = + 73 ° C (0.5% in chloroform).

For example, 1 16 17β-tert-butoxy-3-methoxy-72-phenylsulfonyl-1,3,5 (10) -estratriene 1.0 g of estratetraene from Example 15 b) is dissolved in 100 ml of acetone and hydrogenated Normal pressure and room temperature with 200 mg palladium / carbonate (10%). After 4 hours it is filtered, the solvent is distilled off and crystallized from diisopropyl ether, Yield 0.75 g, melting point 149-155 ° C., aD = 50 ° C. (0.5% in dioxane).

For example, 1 17 17β-tert-butoxy-3-methoxy-7-methyl-7-phenylsulfonyl-1,3,5 (10) -estratriene 482 mg of 17β-tert-butoxy-5-methoxy-7R-phenylsulfonyl-1,3,5 (10 |) -estratriene are dissolved in 10 ml of tetrahydrofuran, cools to -70 ° C and treated with 1 ml of butyllithium solution in hexane.

The mixture is allowed to come to room temperature and 1 ml of methyl iodide is added. After stirring for 3 hours, the mixture is acidified with acetic acid and the solvent is distilled partly off, taken up in chloroform and shaken with saturated bicarbonate solution the end. After drying and distilling off the solvent, the desired one is obtained Compound as an oily mixture of isomers.

For example 1 18 3-methoxy-7a-methyl-11 3, 5C10) -estratrien-17β-ol The product obtained in Example 17 is dissolved in 10 ml of methanol and added in portions a total of 1 g of potassium amalgam. The mixture is refluxed at 60 ° C. for 2 hours and separated then from the mercury and the solvent largely evaporates. The residue is taken up in chloroform and treated with 2N hydrochloric acid and saturated bicarbonate solution shaken out. After drying and evaporation, the residue is taken up in ethanol and heated to 700C for one hour with a few drops of concentrated sulfuric acid.

The solvent is largely withdrawn and taken again chloroform and shakes out with 2N sodium hydroxide solution and water. After drying, evaporation and Crystallization gives 3-methoxy-7α-methyl-1,3,5 (10) -estratrien-17β-ol, Melting point 129-130 ° C, [α] D = + 66 ° C (0.5 56 in chloroform).

Claims (3)

Process for the production of 7-methyl-estrogens Patent claims 1.) Process for the production of 7-methyl-estrogens of the general formula I. wherein R1 and R2 are lower alkyl groups, X is a functionally protected hydroxymethylene group, R3 is a lower or middle alkyl group or an optionally substituted aryl group and Z is a hydrogen atom or an OR1 group, characterized in that a) a compound of the general formula II in which R1, R2, R3, Z and X have the above meanings and Y represents a free or ketalized carbonyl group, cyclizes, b) the compound of the general formula III obtained wherein Z R1, R2, R3, / and X have the above meaning hydrogenated and methylated in any order. 2.) Compounds of the general formula IV wherein 111, 112, R3, Z and X have the above meaning and R4 is a hydrogen atom or a methyl group and represents a double or single bond. 3.) Use of the compounds of the general formula I for the preparation of compounds of the general formula V where R1, 112, Z and X are as defined above.