DE2035879A1 - New compounds in the steroid series and processes for their production - Google Patents

Description

Wh

qAMr.07 Aß Dr.W.Schc'XDip'.lng.P.WHih. SANDOZ AG. u _Djpl . _{| ng G.} oornrAerg Case 6OO-6316 Basel or. V. Sc! - .. ei - '. ^ 3rzik

Dr. P. Weinhold, Dr. D. GucM 5FrOnWMM;, Gr. Eschwh «*« fc ·

The present invention relates to compounds of formula I wherein R ₁ is hydrogen or an alkyl group having 1 or 2 carbon atoms, and to processes for the preparation de- ven.

According to the invention, compounds of the formula I ■ arrive by either

a) Compounds of the formula II in which R has the above meaning. and Rp is an alkyl group having 1-4 carbon atoms means subjected to a rearrangement with the aid of an aqueous acid or

b) Compounds of the formula III, in which R. has the above meaning, or subjects to a rearrangement

c) Compounds of the formula IV, wherein R _{1 has the} above meaning, is subjected to an oxidation or

d) Compounds of the formula V, in which R _{1 has the} above meaning and the ring A has the structures expressed by the formulas 1) or 11), are subjected to oxidation under acidic conditions.

The method specified under a) can, for example, such as as described below:

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Compounds of formula II are * conveniently dissolved in a water-miscible solvent, for example in a lower alcohol such as methanol Exposure to a strongly acidic aqueous medium, especially § the aqueous solution of a strong acid at a pH of four Less than 3, preferably between 1 and 2 and at Temperatures between 0 ° and 100 ° C, preferably between Subjected to acid hydrolysis at 20 ° and 70 ° C and thus rearranged. Instead of the strongly acidic aqueous medium However, a weaker acidic aqueous medium with a pH value between 3 and 4 can also be used, however, a longer exposure time, for example more than 3 hours, is necessary here. To make a Strongly acidic mediums have sulfuric acid, p-toluenesulfonic acid, hydrochloric acid or oxalic acid and for the production a weaker acidic medium, the oxalic acid or acetic acid proved to be suitable «case for implementation the rearrangement using an organic acid which is suitable as a solvent, the reaction should expediently be carried out in an excess of the same.

The procedure specified in section b) can be carried out as described below

Compounds of formula III are among those in section a) specified reaction conditions rearranged with the exception that here the presence of water is not

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is essential. Instead of the acidic media described in section a), a basic medium, for example consisting of an aqueous solution, an alkali metal hydroxide such as sodium or potassium hydroxide in a concentration between 0.01N and about 2N can also be used for the rearrangement of compounds of the formula III will. The basic rearrangement is expediently carried out in an inert organic, preferably water-miscible, solvent such as dioxane, methanol or ethanol. The reaction temperature should be between 20 ° and 120 ° C, but preferably at the boiling temperature of the reaction mixture, which can Reaktiorisdauer between a ³ Z ² I and 6 hours expediently. ·

The procedure specified in section c) can be carried out as described below:

The oxidation of compounds of the formula IV can take place under Use of conventional oxidation methods for the conversion of sec. Alcohols in ketones, for example, using an oxidation method known under the name "Oppenauer Oxidation". This is that one Compounds of the formula IV in an inert organic

and solvents, for example acetone / benzene or toluene, treated with aluminum tert-butoxide at the boiling point. Another method is that you compounds of the formula IV in an inert organic solvent • For example, benzene at boiling point with silver carbonate treated. Another method is that

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man compounds of formula IV in an inert organic Solvent, for example pyridine, acetone or dimethylformamide, at temperatures between 0 ° and treated with chromium trioxide at 30 ° C. The oxidation with the aid of chromium trioxide can optionally be carried out in the presence an acid, for example a mineral acid such as sulfuric acid or an organic acid such as acetic acid be performed. This organic acid can replace the solvent in excess.

The procedure given in section d) can be carried out as described in _{7 below:}

The oxidation of compounds of the formula V, in which the ring A has the structure of the formula 1), and which are referred to below as compounds of the formula Va, should be carried out in the presence of water with the aid of chromium trioxide as the oxidizing agent. It is advisable to use a strongly acidic aqueous reaction medium with a pH of less than 3, preferably between 1 and 2. This can be replaced by a weaker acidic aqueous reaction medium with a pH of 3 to k . The acids necessary for the production of these acidic media are given in section a).

The oxidation can be carried out in an inert organic solvent, for example acetone, pyridine or dimethylformamide, at temperatures between 0 ° and 50 ° C, preferably between 20 ° and 30 ° C.

The oxidation of compounds of the formula V, wherein the Ring A has the structure of the formula ii) and the

*)
'where R ₁ and R _{2 have the} above meanings

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*) hereinafter referred to as compounds of the formula Vb can be carried out either in the presence of water or without water with the aid of chromium trioxide as the oxidizing agent. It is advantageous here to use the reaction medium described for the oxidation of compounds of the formula Va, although the presence of water is not necessary. The reaction temperature should be ⁰ ° and 50 ° C preferably between 20 ° and 3O ⁰ C in the present case between O.

The compounds of the formula .1 thus obtained can be known catfish are isolated and cleaned.

The starting compounds used in process a) Compounds of the formula II can be obtained by oxidation of the ITβ-Cl'-hydroxyethyl) group of compounds of the formula Va be obtained. The oxidation of these compounds the formula Va is carried out using the in section c) described method, but with the exclusion of an acid.

The in the procedure of section b) as an exit connection 20 ' fertilize compounds of formula III used can from compounds of the formula II duroh exposure to a weaker acidic reaction medium can be obtained. The weakly acidic reaction medium is described in section a). The reaction time is preferably less than 3 hours.

. The compounds of the formula III thus obtained can then to be isolated.

¹ wherein R _{1 has the} above meaning

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The compounds of the formula IV used as starting compounds in section c) can be obtained by compounds of formula Va with the aid of an aqueous acid using that described in section a) Procedure.

The compounds of the formula Vb used as starting compounds in section d) can be obtained by compounds of the formula Va under less acidic conditions for preferably less than 3 hours Hydrolyzed using the method described in section a). .

The compounds of the formula Va used as starting compounds in section d) can be obtained by reducing the aromatic ring of compounds of the formula VI in which R 1 and R _{2 have the} above meanings.

The reduction of compounds of the formula VI can be carried out with the aid of the so-called Blrch reduction method. For this purpose, a mixture consisting of compounds of the formula VI, liquid ammonia and a promoter donor, for example a lower alcohol, such as tert. Butanol or ethanol mixed with a light metal, for example sodium, potassium or lithium. In this reduction, ammonia is used as the reaction medium and the temperature and pressure must be adjusted so that ammonia remains in a liquid state. The temperature reduction is expediently carried out between -70 ° and + 30 ° C., but preferably at the boiling point of ammonia. If desired, the reduction can also be done in counter

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wait for an inert organic solvent, for example a cyclic ether such as tetrahydrofuran to be carried out ..- The reduction is expediently carried out at atmospheric pressure.

Compounds of the formula VI can be obtained by adding compounds of the formula VII in which R 1 and R 1 above Have meaning hydrated.

The hydration of compounds of the formula VII can, for example, be carried out in such a way that these first in an inert organic solvent, for example Tetrahydrofuran at temperatures between 10 ° and 50 ° C, preferably between 20 ° and J0 ° C, with Treated borane, and then the reaction product under basic conditions, for example in the presence an alkali metal hydroxide, for example sodium hydroxide, for example at temperatures between -10 ° and + 15 ° preferably between 0 ° and 5 ° C treated with hydrogen peroxide. The reaction is conveniently carried out without isolation of the intermediately formed reaction product of compounds of the formula VlI carried out with borane * The borane can either be pure or dissolved in an inert organic solvent, for example tetrahydrofuran, be used.

The compounds of formula VII can be obtained by introducing the ethylidene group into compounds of the formula VIII in which R 1 and R p have the above meaning.

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The introduction of the ethylidene group is twofold carried out using the Wittig reaction. Here, compounds of the formula VIII with a triarylethylphosphonium ylide, for example triphenylethylphosphonium ylide implemented, 'which one in situ by the action of a triaryl-ethyl-phosphoniumlialidsz. B. Triphenyl-ethyl-phoGphoniumJodj.ds on a strong base, for example Sodium methyl sul finyl methide in an inert. Solvent, for example dimethyl sulfoxide, ™ 10 The introduction of the ethylidene group is expedient at temperatures between 50 ° and 120 ° C, preferably between 60 ° and 100 ° C.

Compounds of the formula VIII can be obtained by compounds of the formula IX in which R and R have the above meaning own, in position 17 subject to a split of the Ketal Biririung.

The splitting of the ketal bond in position.1? of connections of the formula IX can be carried out in a manner known per se. For example, you can do this for this Use the procedure described in section a), where splitting under strongly acidic conditions is preferred.

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Compounds of formula IX can be prepared by removing the carbonyl group in position 11 of the compounds of the formula X in which R, and Rp have the above meaning, reduced.

The reduction of the carbonyl group in position 11 of the compounds of the formula X can, for example, under. Using the Wolff-Klshner reduction process can be carried out. For this purpose, compounds of the formula X are heated with, hydrazine or a mixture of hydrazine dihydrochloride and hydrazine hydrate in a water-miscible solvent with a boiling point of at least 210 ° C., for example di- or triethylene glycol, to a temperature of, for example, 130 ° C. The hydrazone formed is ansehliessend by continuous heating to boiling temperature and distilling off water in the presence of an alkali metal hydroxide, for example potassium or sodium hydroxide, converted into compounds of formula \ IX.

The compounds of the formula X can be obtained by adding compounds of the formula XI, in which R ₁ and R _{2 have the} above meaning, with compounds of the formula XIV, in which Z represents the acidic radical of a mineral acid or an organic! Sulphonic acid, with the exception of the remainder of the hydrogen fluoride satire, is reacted in the presence of a strong base.

For the above reaction, compounds of the formula XIV which can be used are, for example, methyl chloride, methyl bromide, methyljo- • did, methylarylsulfonates, for example methyl paratoluene • sulfonates, and methyl alkylsulfonates, for example methyl methanesulfonate.

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In the above reaction, compounds of the formula XV can be used as strong bases, in which M for an alkali metal, e.g. sodium or potassium, and A for hydrogen. Alkoxy with 1-6 carbon atoms or a -NHp or -CHp ~ SOp-CH, group stands.

The reaction of compounds of the formula XI with compounds of the formula XIV is conveniently carried out in an inert gas atmosphere, for example a nitrogen atom, and in an inert organic one Solvent, for example tert. Butanol or dimethy lsulf oxide. Instead of the solvent however, a 10-200-fold excess of compounds of the formula XIV can occur, provided these compounds of formula XIV are liquid. A preferred compound of Formula XIV is methyl iodide and a preferred one Compound of the formula XV potassium tert-butoxide The reaction can take place at temperatures between -10 ° and + 60 ° C be performed. However, the reaction mixture is preferably first cooled with ice and then let the temperature rise to * room temperature.

The compounds of the formulas XIV and XVI used as starting compounds in the above process are known or can be prepared from known starting compounds in a manner known per se » ^x

. The compounds of formula XI can be prepared ^ by adding the H-Hydro3ty «group of compounds of the formula

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XII, in which R _{1 and R 2 have the} above meanings, is oxidized to a carbonyl group.

The oxidation of the II-hydroxy group of compounds of the formula XII can, for example, using the methods described by Pfitzner and Moffatt, J. Am. Chem. Soc. 8 £, pages 5661 and 5670 (1965) using dimethyl sulfoxide, dicyclohexylcarbodiimide and a proton source and an anhydrous phosphoric acid or dichloroacetic acid. The reaction is conveniently carried out in an inert organic solvent, for example an aromatic hydrocarbon such as benzene, at temperatures between 15 ° and 35 ° C., preferably between 20 ° and 3> 0 ° C. The oxidation of the 11-hydrox.y group of compounds of the However, formula XII can also be carried out using the Jones reagent (J. Chem. Soc. 19 * 16 , 39 and Reagents for Organic Synthesis, Fieser and. Fieser, page 1 ^ 2).

Compounds of the formula XII can be obtained by one the phenolic hydroxyl group of compounds of the Formula XIII, in which -R, has the above meaning, is etherified.

The etherification of the phenolic hydroxyl group of compounds of the formula XIII can, for example, with the aid of an alkylating agent, for example alkyl iodide with 1-4 carbon atoms can be carried out. The implementation is expediently carried out in a basic reaction • medium for example in the presence of anhydrous potassium carbonate in an inert organic solvent, for example in a lower alcohol such as methanol.

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The reaction temperature should be between 6θ ° and 100 ° C. Preferably the reaction is, however, at the boiling temperature of the reaction mixture carried out _β If the solvent used is an alcohol *, it is expedient that die'Alkylgruppe of the alcohol and the alkyl group of Alkylierungsraittels about once bees. ".

The compounds of the formula XIII used as starting compounds in the above process are known or can be based on known starting compounds confessed. Way to be made.

The compounds of the formula I prepared according to the invention have extremely advantageous pharmacodynamic properties Properties; which are particularly evident in express a progestational effect. This progesta " The so-called Clauberg test shows the tional effect by observing the change in the uterus b @ i still immature female white rabbits, Di © Verbin "fertilize formula I can therefore be used in fertility" used to control and regulate menstruation «,

To be administered daily amount of compounds of formula I is between 0 _s l to 30 mg "This amount is preferably mg in smaller doses between 0 ^, 05 and 15 twice a day or in sustained release form administered =, the daily amount to be administered independently of the Body weight0

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For the above use, the connections of the Formula I alone or together with a suitable estrogen,

which is used, for example, in an amount of 0.1 mg. The estrogen can either be with the compounds of the formula I mixed and administered in this way or, on the other hand, the estrogen can initially only be used in the first Part of the menstrual cycle and then in the later days of the Cyelus together with compounds of the formula I administered.

For the above use, the compounds of the formula I be administered together with a pharmaceutically acceptable carrier and other additives. The administration can either orally in the form of tablets, capsules, elixirs, suspensions or solutions or parenterally in the form of injection solutions, Suspensions or emulsions take place.

An example tablet composition for oral Administration can consist of the following components, for example:

0.5 part of 17β-acetyl-9a-methylestra-4-en-3-one, 2 parts Tragacanth, 89 parts of lactose, 5 parts of corn starch, 3 parts Talc and 0.5 part magnesium stearate.

In the following examples, the temperatures are given in degrees Celsius, and room temperature corresponds to one Temperature of 25 ° C, unless otherwise stated.

The compounds of the formulas Va, VIII and X are valuable intermediate compounds for the preparation of compounds of the formula I.

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C-- H

- H

CH

I.
CHOH

CH

- .15-

ii)

VI

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ORIGINAL INSPECTED

6oo-6; ji6

VII VIII

IX

ine

5 sts

600-

XI

XII

HO

XIII

CH ^ -Z XIV

M-A XV

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Va

CHOH

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Example 1; 17ß-Aoet yl- ^ g ~ methylöstra "4-en"; ^ - »on

A mixture consisting of 15 g of 17 ~ ethylenedioxyestra-1, 3,5 (10) -triene-3, 11ß-diol, 30 g of anhydrous potassium carbonate, 75 ml of methanol and 60 ml of methyl iodide is refluxed with stirring for 3 hours . The mixture is then cooled and diluted by adding 200 ml of water. The methanol and methyl iodide are removed by distillation under reduced pressure and the aqueous residue is extracted twice with methylene chloride. The combined organic extracts are washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After removing the solvent, a residue is obtained which is recrystallized from diethyl ether. The 17-ethylenedioxy-11ß-hydroxy-3-methoxyestra-1 _J 3i5 (10) -triene obtained in this way melts between 125.degree. And 126.degree.

To a stirred solution of 5 * 13 g of 17-ethylenedioxy-11β-hydroxy-3-methoxyestra-1,3,5 (10) -triene in a mixture of 25 ml of dimethyl sulfoxide and 25 ml of benzene, 3 ml Pyridine and 9.3 g of N / N-dicyclohexylcarbodiimide added. This mixture is then cooled and 1.5 ml of chloroacetic acid are added. The mixture is at room temperature stirred for 1 1/2 hours. After that, the mixture by dropwise addition of 50 ml of diethyl ether and a solution of A g of oxalic acid in 10 ml of methanol.

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The suspension obtained is stirred for 40 minutes at room temperature and then filtered base piltrate is evaporated to dryness and the residue obtained is partitioned between methylene chloride and a 10% aqueous sodium bicarbonate solution. The organic phase is separated off, washed with water and dried over sodium sulfate. It is then evaporated to dryness under reduced pressure. The residue is chromatographed on a silica gel column / using chloroform, ■ to which various proportions of methanol have been added., Is used as the eluent. The fractions obtained by eluting with chloroform, which contains 3 % methanol, are combined and evaporated to dryness ο The residue obtained is recrystallized from hexane / diethyl ether (lsi) . The thus obtained

IT-ethylenedioxy-J-methoxyestra-liJiSClOj-trien-II-one. melts between 122 ° and 123 ° C ₀

trien-ll ~ on

To a stirred solution, cooled in an ice bath, of 10 * 5 g of 17-ethylenedioxy "> = methoxyestra = 1.3 * 5 (10) = triene-11" on in 300 ml of methyl iodide are added in a nitrogen atmosphere for 10 minutes 120 ml of a 1.1 molar solution of tert Kaliwn "- butoxide in tert _o - Buty" added to alcohol is then exposed to the temperature rise to room temperature and the mixture is stirred for 18 hours *. Connection =. Send the mixture is poured into 500 ml of water and extracted 2 times with methylene chloride, the combined organic

/ 20?

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Extracts are washed with water and over sodium sulfate dried. After removing the solvent, an oil is obtained which is recrystallized from diethyl ether. So he Holding 17-ethylenedioxy-3 ~ methoxy-9a-methylöstra-l, 3.5 (lO) -trlen-ll-one melts between 142 ° and 1 ^ 5 ° C.

trien

A mixture consisting of 53 ^ mg ^ -Aethylendioxy - ^ - methoxy-9a-methylostra-l, 3,5 (10) -trien-ll-one, 1 g hydrazine dihydrochloride, 5 g hydrazine hydrate and 35 g triethylene glycol is heated to a temperature of 130 ° C and at this temperature held for 2 Y2 hours. Thereafter 1.8 g potassium hydroxide are added in beads and the Temperature increased to 210 ° C. This temperature is during Maintained 2 y2 hours using a mixture of hydrazine and water slowly distilled off. The reaction mixture is then cooled and diluted with water, with a precipitate arises, which is filtered off. The precipitate is dissolved in methylene chloride and the organic solution dried over sodium sulfate. After removing the solvent a residue is obtained from hexane / diethyl ether is recrystallized. The 17-ethylenedioxy-3-methoxy-9a-methylÖstra-1,3,5 (10) -triene obtained melts at 115 ° C.

To a warm solution of 220 mg IY

thoxy-9a-methylestra-1,3j5 (10) -triene in 5 nil methanol . 1 ml of a 2N hydrochloric acid was added and the mixture was heated to boiling under reflux for 5 minutes. After that, will

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cooled and the crystals which have precipitated out are filtered off. The crystalline residue is washed with a small amount of diethyl ether ,, The thus obtained 3 ~ methoxy-9a-methylöstra l _i, 5 _s 5 (l0) -triene-17 on "melts between - I90 ⁰ and 192 ⁰ C.

To a solution of sodium methylsulfinylraethide, prepared by the action of 2.4 g of sodium hydride on 45 ml of dimethyl sulfoxide, a solution of 22.4 g of ethyl triphenylphosphonium iodide in 90 ral of dimethyl sulfoxide is quickly added at room temperature. 4 g of 3-methoxy = 9a-methylöstra-> l _i) 3 _J , 5 (10) - are added to the resulting deep red mixture. trien-17-one was added and the mixture was kept at 60 ° C. for 18 hours. Then it is poured onto ice (200 g), the mixture is extracted with petroleum ether and the petroleum ether solution is filtered through 13 g of aluminum oxide (grade I). After evaporation of the solution one obtains the 17-ethylidene-I-rnetho · = · xy-9c £ -methyl6stra-1,3,5 (10) -triene «

ii °.) - trien

2.55 of a 1 molar commercial solution of borane in tetrahydrofuran is added to a solution of 500 mg of 17% ethylidene ~ 3 ~ methoxy ~ 9ffiHi! Ethyl oestra "1, 3j, 5 (10)" triene in 30% tetrahydrofuran. Thereafter, the mixture is for 90 _s utes stirred at room temperature with 6.1 ml of a 10 aqueous sodium hydroxide solution are added, then on-send dropwise 2,5.ml a 30 $ strength Wasserstoffper oxide solution was added at 0 ° C. After standing 1½ hours at 0 ° C

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100 ml of water are added and the mixture is extracted with diethyl ether. After drying over sodium sulphate, the ethereal solution is evaporated and so the ^ ß- ^ l-HydrQ xyäthyl ^ -methoxy-ga-niethylöstra-l ^ SilO ^ tr ^ obtained.

serve

To a solution of 3 * 6 5 (10) -triene in a boiling mixture (-3 consisting of 100 ml of liquid Ammonia, 50 ml of tetrahydrofuran and 20 ml of tertiary butanol are added in small portions, 0.8 g of lithium, and the resulting mixture is kept for 3 hours at ~ 3 ° C. Then 30 ml of methanol are carefully added and the ammonia is allowed to evaporate 200 ml of an ice-cold 0.5 molar aqueous sodium hydroxide solution are added and the mixture is extracted with diethyl ether.

2.5 (10) diene. '

To a mixture of 260 mg of chromium trioxide in 10 ml of pyridine, 302 mg of 17β- (l ^f -hydroxyethyl) »3-methoxy-9a-methylestra-2,5 (10) -diene are added and the mixture is kept at 25 ° C. for 18 hours held. Then ice is added to the mixture and extracted with benzene. The benzene solutions are passed through a short column containing 10 g of alumina

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(Degree Ι-ϊϊ) contains * filtered and the filtrates to dryness evaporated. After recrystallization from acetone / hexane (lsi), the pure 17β-acetyl-3 ° methoxy-9a-niethylöstra » 2.5 (10) -diene.

A solution of 1 g of 17β-acetyl-3-methoxy-9a-raethylöstra » 2.5 (10) -diene in 8O ml of methanol is mixed with a solution of 1 g of oxalic acid mixed in 20 ml of water and. the mixture obtained was then kept at 50 ° C. for 30 minutes the mixture is evaporated to about 20 ml in vacuo and poured in ice water. The precipitate formed will filtered off, washed with water until a neutral reaction and dried., After recrystallization from acetone / hexane (lsi) one obtains the 17ß-acetyl-9ßHnethylöstra-5 (10) ~ en -> - one,

A solution of 1 g of 17β-acetyl 9a-methylb'stra = 5 (10) -en ->"one in 80 ml of methanol is heated to 40 ° C. together with 5 ml of 5N hydrochloric acid. After 30 minutes, ice water and 1 g of sodium acetate was added and the precipitate formed is filtered off ,, This is washed and dried and ^ anschlies "transmitted from methylene dichloride / diethyl ether recrystallized ₀ the obtained 17.beta." acetyl "9a ^{c =} R ^l ßthylöstra'-4-eii '= 3 ^a> o ^ melts between 151 ⁰ and 155 ° C ₄

Example 2: 17β ° acetyl-9g "methylQstra ° ^i! L ° -eii ° _i 3 ° -pn

A solution of 1 g of 17β-acetyl ° 9a-methylestra »5 (10) -en-3-one in 10 ml of ethanol is mixed with 10 ml of a» 0.1 M aqueous potassium hydroxide solution and the mixture obtained

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heated to boiling under reflux for 1 hour. Thereafter the mixture is poured into water and the precipitate formed is filtered off. This will be up to neutral reaction washed with water and then dried. After recrystallization with methylene chloride / 17ß-Aeetyl-9a-methylöstra-4-en-3 is obtained in diethyl ether on from the melting point 151 ° to 155 ° C. -

Example 3; 17β "acetyl-9" -fnethylestra-4-en-3-one

Using that described in section k) of Example 1 Method, however, when replacing the 17β-acetyl-9a-methylöstra-5 (10) -en-3-one used there by approx. ■ equivalent proportions of that obtained in accordance with section i) of example 1 17β-Acetyl-3-methoxy-9a-methylestra-2,5 (10) -diene one arrives at 17β-acetyl-9a-methylestra-4-en-3-one from Melting point 151 ° to 155 ° C. ·

Example 4; 17β-acetyl-9ct- methylestra- ⁱ l-en-3-one

Using the method described in section k) of the example, but replacing the 17β-acetyl-9a-methylö'stra-5 (10) -en-3-one used there by approx. ^{Equiv. proportions of the 17β- (1 f} -hydroxyethyl) -3-methoxy-9oc-methylöstra-2,5 (10) -diene obtained according to section h) of Example 1 lead to 17β- (1'-hydroxyethyl) -9amethylöstra -4-en-3-one.

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Using the method described in section i) of Example 1, but replacing the 17β- (l ^f -hydroxyethyl) "3 ^c3 fflethoxy" 9a-me.thyl "oestra-2,5 (10) -diene used there by approx "Equivalent equivalents of 17β- (l ^! -Hydroxyethyl) -9a" niethylöstra-4-en-3-one are obtained sum iyß-acetyl-9-ffiethylöstra "4" en "3-one with a melting point of 151 ° to 155 ° ° C.

Example 5s 17 [deg.] Acetyl-9g-methyldstra-4-en-3-one

2, 7 g of chromium trioxide were added with cooling, and 50 ml of dimethylformamide containing 2 ml of concentrated sulfuric acid were further added to the mixture obtained. The dark red mixture obtained is left to stand for 2 hours at room temperature and then shaken out with a mixture of water and diethyl ether. The ethereal phase is separated, washed with "a saturated aqueous Matriumblearbonatlösung ge ° and anschllessend dried over sodium sulfate," After evaporation of the ethereal solution gives the 17ß "Aeetyl ™ 9a-methylöstra-4-en -> = Qki _i, which according Umkristal »Lization from diethyl ether / methylene chloride (5s1) between 151 ° and 155 ° C melts.

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Example 6; 17ß-acetyl-13-ethyl-9a-methylg; ona-4-en-3-one

serve

When replacing the 17-Aethyiendioxyöstra-l _Ä 5.5 (10) -triene-3, llß-diol used in section a) of Example 1 by approx. equivalent proportions of 1> -Aethyl-17-äthylendioxygona-1,3,5 (10) -triene-j5, 11ß-diol and using the method described in sections a) to i) of the example, 17ß-acetyl is obtained -13-ethyl-3-methoxy-9a-methylgona-2,5 (10) -diene.

b)

When replacing the one described in section k) of Example 1 17ß-acetyl-9a-methylöstra-5 (10) -en-3-one by approx. equivalent proportions of 17β-acetyl-1; I-ethyl-9a-niethylgona-2,5 (10) -diene using the procedure described in this section, the 17ß-acetyl-

Example 7t. 173-acetyl-9a-methylestra-4-en-3-one

Using the in section a) of the example described procedure, but when using approx. equal proportions of ethanol and ethyl iodide instead the methanol and methyl iodide described there the 17-ethylenedioxy-3-ethoxy-llß-hydroxyÖstra-l, 3, 5 (10) -trien, which is made using the methods described in Sections

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b) to i) of the method described in Example 1 is converted into the 17β «aetyl-5» ethoxy-9a »methylöstra-2 _J , 5 (10) -diene *

b)

When replacing the 17β ~ acetyl ~ 9a-methylestra-5 (10) ~ en ~ 3- * one described in section k) of Example 1 by approx. equivalent proportions of 17β-acetyl = 3 ~ ethoxy-9a-methylöstra ~ 2 _J , 5 (10) - = diene are obtained using the process described there to 17β-acetyl-9cx-methylöstra-4 = en-3-one from Melting point 151 ° to 155 ° C.

Example 8 s

Using the method described in Example 5 * but replacing the 17β- (1 ^l -hydroxyethyl) -9s-methylöstra-4-ene ° 5 ^ra on used there by approximately equivalent proportions of 17 ° "(l ⁸ ° -hydroxyethyl) -5 ° methO '»xy-9a-methylestra-2 _ji 5 (10) -diene one arrives at 17β ~ ace ~ W tyl-9a-methylestra-4» en-3-one with a melting point of 151 ° to 155 ° C.

20th

When replacing the in section a) of the example. benenen 17-ethylenedioxyÖ8tra »1.3« 5 (10) through approx. equivalent units before lendioxygona-l _J, 3 _ff 5 (10) -triene "3s> LLSs ^t" diol and ranter

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Application of the sections a) to i) of example 1 method described, one arrives at 17β ~ acetyl-r5-propyl-9a ~ methylgona-2,5 (10) -diene. ■

Using the be in section k) of Example 1 written procedure, but with replacement of the 17ß-acetyl-9a-methylöstra-5 (10) -en-5-one used there approx. equivalent proportions of 17β-acetyl-13-propyl-9amethylgona-2,5 (10) -diene one arrives at 17ß-acetyl-l> propyl ^ a-methylgona - ^ - en-jJ-one.

Example IQi 173-Aoetyl-9a-methylestra-4-en- "5-p n

Using the method described in section j) of Example 1, but replacing the 17β-acetyl-3-methoxy-9a-methylestra-2,5 (10) -diene used there by approx. equivalent proportions of 17ß- (l'-hydroxyethyl) -3-methoxy-9a-methylöstra-2,5 (l0) -diene (obtained using { '■ h of the section) of Example 1 described procedure) to get to the 17ß - (l ^l -hydroxyethyl) -9a-methyl8stra-5 (10) -en-5-one.

Using the method described in Example 5, but replacing the 17β- (1 ^f -hydroxyethyl) -9tt-niethylÖ8tra-4-en-3-one used there by approx. equivalent proportions of 17ß- (l ^l -Hydroxyäthyl) -9a-methylöstra-5 (10) -en-3-one to get to the 17-acetyl-9a-methylöstra-4 of melting point 151 ° to 155 ° C.

1 & 9SQ8 / 2Q79

* L.; '"I> *" - ■' - · ■ ■

Claims (10)

- 30 - 600-6516 Claims Process for the preparation of compounds of the formula I, in which R, represents hydrogen or an alkyl group with 1 - or 2 carbon atoms, characterized in that that one either a) Compounds of the formula II, in which R _{1 has the} above meaning and R _{2 is} an alkyl group having 1-4 carbon atoms, is subjected to a rearrangement with the aid of an aqueous acid or b) Compounds of the formula III in which R, as defined above, is subjected to a rearrangement or c) Compounds of the formula IV in which R ^ has the above meaning possesses, is subject to oxidation or d) Compounds of the formula Y ₁ , in which R., has the above meaning and the ring A has the structures expressed by the formulas i) or ii), are subjected to oxidation under acidic conditions. 2. A process for the preparation of compounds of the formula Va, in which R, stands for hydrogen or an "alkyl group with 1 or 2 carbon atoms and R _g © means an alkyl group with 1-4 carbon atoms" known by the fact that the aromatic ring of Compounds of the formula VI, in which R, and Rp have the above meaning, reduced »- 10Sit8 / 2G * · _Λ - Ji - 600-6 ^ 16 3 · Process for the preparation of compounds of the formula VIII in which R 1 is hydrogen or an alkyl group having 1 or 2 carbon atoms and Rp is an alkyl group having 1-4 carbon atoms, characterized in that compounds of the formula IX in which R ₁ and R 'have the above meaning, subject to a cleavage of the ketal bond in position 17. 4, Process for the preparation of compounds of the formula X, where R, represents hydrogen or an alkyl group with 1 or 2 carbon atoms and Rg is an alkyl group with 1-4 carbon atoms, characterized in that compounds of the formula XI, wherein R, and Rp have the above meaning with compounds of Formula XIV, wherein Z is the acidic radical of a mineral acid or an organic sulfonic acid with the exception of the The remainder of the hydrofluoric acid is in the presence a strong base. 109008 / 20TS - 22 - 600-6516 5. Compounds of the formula I in which R 1 represents hydrogen or an alkyl group having 1 or 2 carbon atoms stands. 6. Compounds of the formula Va, in which FL stands for hydrogen or an alkyl group with 1 or 2 carbon atoms and Rp is an alkyl group having 1-4 carbon atoms means. 7. Compounds of the formula VIII in which R 1 is hydrogen or an alkyl group having 1 or 2 carbon atoms and Rp is an alkyl group having 1-4 carbon atoms. 8. Compounds of the formula X in which R. is hydrogen or an alkyl group having 1 or 2 carbon atoms and R _{2 is} an alkyl group having 1-4 carbon atoms. . .. 9. Therapeutic composition characterized by the content of compounds of the formula I, wherein R. for Is hydrogen or an alkyl group having 1 or 2 carbon atoms. 3700 / sT / sE 10 9808/2079