DE2152378A1 - New organic compounds and processes for their production - Google Patents

Description

Sandoz AG. ' Case 600-6438

Jj3.se j.

New organic compounds and processes for their

Manufacturing

The invention relates to compounds of the formula I,

OH

^R l ^ - CH = C = CH ₂

RON
where R is hydrogen or an alkanoyl group with 2-4 carbon atoms and R is a straight-chain alkyl group with 1-5 carbon atoms and either X and Y together are a second CC bond and Rp is hydrogen or X is a β-hydrogen atom, Y is oc-hydrogen atom or an oc-methyl group and Rp denotes hydrogen or a methyl group, with the proviso that - if Y stands for an α-methyl group - Rp denotes hydrogen, as well as processes for their preparation.

The inventive preparation of compounds of Formula I is characterized in that you have either

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a) to compounds of the formula la,

HON

Yes

wherein R ₁ . R, X and Y have the above meaning, arrives,

- ^λ 2

by using compounds of the formula II,.

OH H ₂ . ^R - "

II

- CH = C = CH ₂

wherein R 1, R 1, X and Y have the above meaning, with hydroxylamine or one of its acid addition salts or. :.

b) to compounds of the formula Ib,

OH

R ¹ ON

CH = C = CR ₂

Ib

in which R- ,, R ₂ , X and Y have the above meaning and R ^{1 stands} for an alkanoyl group having 2-4 carbon atoms, elongated by reacting compounds of the formula Ia with an aliphatic acylating agent.

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The reaction given under a) of compounds of the formula II. With hydroxylamine or one of its acid addition salts is expediently under anhydrous conditions, preferably in an "inert organic" Solvent, for example a lower alcohol such as methanol or ethanol carried out. The reaction temperature should preferably be lower than the boiling point of the reaction medium, with moderate temperatures 'Room temperature, for example, are preferable. The hydroxylamine reagent can be prepared in situ or separately are, for example, by reacting a hydroxylamine salt, for example the hydrochloride with a base such as sodium acetate, sodium hydroxide or pyridine. If for the preparation of the hydroxylamine reagent Pyridine is used, an excess of the same can be the solvent for the subsequent Form reaction with compounds of formula II. Preferably, the hydroxylamine reagent is the salt of a weak acid, "especially the hydroxylamine acetate, used because in the reaction with compounds of the formula II an overly acidic reaction medium, d. i. pH 3 or including, because of the acid sensitivity of the 17ß-propadienyl radical should be avoided ";

The acylation of compounds of the formula Ia indicated in the process of section b) is expediently carried out with the aid of an aliphatic acylating agent capable of forming an alkanoyl group with 2-4 carbon atoms introduce, for example with the help of aliphatic acids with 2-4 carbon atoms or their acid anhydrides. The reaction is preferably carried out in the presence

of acid-binding agents and at moderate temperatures, f

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for example between -10 ° and + 50 ° C, in particular carried out at room temperature. As a reaction medium an inert organic solvent is suitable, but this can be achieved by an excess of the acylating agent be replaced if the acylating agent is liquid under the reaction conditions.

A mixture of acetic anhydride and pyridine is preferably suitable for introducing the acetyl group. The acylation according to the invention should be strongly acidic F 10. Acylating agents are avoided if possible, since the 17cc propadienyl residue. under strongly acidic conditions could be attacked.

The compounds of the formula I thus obtained can be isolated and purified in a manner known per se.

The compounds of the formula I can also be used in the form of their Syn- and anti-isomers occur. These are obtained by using the mixtures of these obtained by the above process Isomers in a manner known per se, for example by. Separates chromatography. The syn and anti isomeric forms of compounds of the formula I as well as their form according to the invention mixtures obtained and the process for their preparation are an object of the present invention.

Some of the compounds of the formula II used as starting compounds are known. Unknown compounds of the Formula II, which are summarized below under the formula Ha, are prepared as described below will.

To compounds of the formula Ha,

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C CH = C = CII

Ha

where R, has the above meaning and either R « ^{1 is} a methyl group and R ^, ^{1 is} hydrogen, or Rp ^{1 is} hydrogen and R- ^{1 is} a methyl group, can be obtained by using compounds of the formula III,

III

and R 'have the above meaning, the reactions indicated below under 1) to 4)

where R- ,, Rp

subject.

Implementation 1): Compounds of the formula III are mixed with compounds of the formula IV,

IV

wherein P is an active metal or the halide of an active metal, for example an alkali metal such as lithium, sodium or potassium, aluminum or zinc or a group -MgBr or -MgI, and either R ^ and are the same or different and each is an alkyl group with 1-J> carbon atoms or R ₂ . and R_ together with the nitrogen atom form a pyrrolidino, piperidino or homopiperidino ring, reacted and that

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Reaction product then to compounds of the formula V, * "·

wherein R ,, Rp ¹ , R, ¹ , R ^, and. Rp. Have the above meaning, hydrolyzed.

Implementation 2): Compounds of formula V are through implementation with compounds of formula VI

R ₆ -X VI

wherein R / - denotes an alkyl group with 1-j carbon atoms and X for the anionic part of a mineral acid with the exception of the fluoride ion or the anionic part an alkyl sulfonic acid or an aromatic sulfonic acid stands, quaternized., where one leads to compounds of formula VIII,

^0H Θ \ Π

3I ₀ -NR ₁ - Χ * ^v

VIII

where R ,, R "', RI ¹ , R ^, Rc-, Rg and X have the above meaning.

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Implementation 3): Compounds of the formula VIII are mixed with a hydride equilibrium consisting of compounds of the formula X,

Y ^ W ₁ -MH "X

where Y is an alkali metal or an alkaline earth metal, for example lithium, sodium, potassium, calcium or magnesium, and M is aluminum, gallium or boron, and VL, \ L · and VL, are identical or different and are each hydrogen, an A. Alkyl or alkoxy groups each having a maximum of 6 carbon atoms or an alkoxyalkoxy group in which the alkyl and alkylene groups each have up to 6 carbon atoms and with compounds of the formula XI, '

W, l 4

W-M-H 5

XI

wherein M has the above meaning and \ L · and W _{r are} identical or different and each represent hydrogen or an alkyl group having 1-6 carbon atoms, treated in an aprotic organic medium which is not detrimental to the reaction, resulting in compounds of Fon; »el XII,

where R

CH = C = CH,

XII

'and R' have the above meaning.

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Implementation 4): - Compounds of formula XII are in one weakly acidic medium in compounds of formula XIII,

XIII

in which R 1, R 1 and R 4 have the above meaning, converted.

Implementation 5): Compounds of the formula XIII become ver ~ compounds of the formula Ha rearranged.

The above under l) reaction of compounds of the formula III with compounds of the formula IV is preferably carried out in an anhydrous organic medium at temperatures between - ~ J> 0 ° and + 100 ° C, preferably between -20 ° and + 50 ° C, carried out and the subsequent hydrolysis of the reaction product, for example using water or an aqueous salt or base solution 'such as an aqueous ammonium chloride solution or an aqueous sodium chloride solution, carried out. In this reaction, the compounds of formula IV preferably used are N, N-dimethylamino-2-propynyl lithium, which is conveniently prepared in situ, for example by dissolving lithium in ethylenediamine and adding Ν, Ν-bimethylamino-2-propyne.

The realization medium used in the above procedure hangs in particular from the "organometallic" reagent used. For example, if P stands for

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-MgBr, -MgI or Li, a medium consisting of a cyclic or an acyclic ether, for example diethyl ether or tetrahydrofuran and, - if P sodium means - a medium, for example a mixture of liquid ammonia and diethyl ether, a mixture of ethylenediamine and tetrahydrofuran, a mixture of dioxane and fyridine or ". dioxane or pyridine can »If as a compound of the formula IV N, N-dimethylamino-2-propynyl lithium is used and this is prepared in situ in ethylenediamine, so can ethylenediamine can be used as another solvent in the above reaction.

The quaternization of connections specified under 2) of the formula V is expediently carried out in an inert organic solvents, such as acetone, at temperatures between -20 ° and + 30 ° C, with neither that Solvent nor temperature are critical. In the compounds of the formula VI used, the anionic Remainder, for example a chloride, bromide, iodide. Methanesulfonate or p-toluenesulfonate, with iodide being preferred. The preferred compound of Formula VI is methyl iodide.

In the implementation indicated under 3) are preferred Hydride ion sources lithium aluminum hydride, lithium borohydride, sodium dihydro-bis (2-methoxyethoxy) aluminate, lithium gallium hydride, Magnesium aluminum hydride, lithium diisobutylmethyl aluminum hydride, Lithium trimethoxy aluminum hydride, diethyl aluminum hydride and diborane. In this procedure are used as aprotic solvents in particular cyclic and acyclic ethers such as diethyl ether, tetrahydrofuran ^ O drofuran or dioxane and aromatic solvents such as benzene, Toluene, pyridine or a mixture of the solvents mentioned. The reaction is conveniently carried out at temperatures between -40 ° and + 120 ° C, for example at boiling point

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temperature of the reaction mixture carried out. However, it is advantageous to use a temperature between -10 ° and + 50 ° C, since, although faster reactions are achieved at higher temperatures, the reaction at a lower temperature gives purer reaction product. If desired, the reaction can be carried out in an inert gas atmosphere, for example in a nitrogen atmosphere, and it is advantageous to keep the reaction mixture free from moisture. In this reaction, preference is given to using compounds of the formula VIII in which R ₂ , R ₁ - and R ^ are each methyl.

The reaction indicated under 4) is under, weakly acidic Conditions for example in a medium with a pH of 3-4 for a relatively short time, for example performed less than 3 hours. Organic acids are used to produce the weakly acidic medium, such as oxalic acid or acetic acid and, as solvents, either inert, water-miscible organic Solvents such as lower alcohols, for example methanol or, if the acids used, under the reaction conditions are liquid and suitable as a solvent, an excess of these acids. The implementation is expedient carried out at temperatures between 0 ° and 100 ° C, preferably between 15 ° and 50 ° C.

The rearrangement of compounds of the formula indicated under 5) XIII is carried out under basic or acidic conditions in the presence or absence of water.

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The rearrangement under basic conditions is expediently carried out in an inert organic solvent, e.g. B. dioxane, methanol or ethanol and at temperatures between 20 ° and 120 ° C, preferably between 20 ° and . 30 ° C or at the boiling point of the reaction mixture. The reaction time can be between 1/4 hour and 6 hours. Maintains aqueous basic conditions with the aid of aqueous sodium or potassium hydroxide solutions Conveniently in a concentration of 0.01 N to 2 N. Non-aqueous basic conditions are maintained one expediently when using alkali metal alkoxide, for example sodium methoxide.

The rearrangement under acidic conditions is expediently carried out in a strongly acidic medium, for example at a pH of 3 or below, in particular between 1 and 2, using, for example, oxalic acid, p-toluenesulfonic acid or a mineral acid such as hydrochloric acid. However, rearrangement may also, and this is preferably _F under weakly acidic conditions take place, which will be described in connection with the indicated below 4) implementation.

However, the procedures in Sections 4) and 5) can also although not preferred, summarized and compounds of the formula XII of an aqueous-acidic hydrolytic solution Be subjected to rearrangement. This rearrangement can take place under strongly acidic conditions that go hand in hand can be described with the rearrangement given under 5).

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The compounds of the formula prepared according to the invention I are characterized by extremely favorable pharmacodynamic Properties and can therefore be used as a remedy. In particular, the compounds have the formula I a strong progestational effect, as shown, for example, the results of the well-known Clauberg tests (described in Endocrinology. £ r5> 464 (1958)) taken from v / ground. The connections of the example 1 also has an estrogenic effect. The compounds of the formula I can therefore be used in fertility control for regulating menstruation and for regulating of the oestrus, for example, be used in domestic animals.

In addition to the above The compounds of the formula I have a progestational effect which interrupts fluctuations Effect. -

The amount of compounds to be administered daily Formula I for fertility control and for regulating menstruation and oestrus should be between 0.015 and 10 mg, this amount either in a single dose or in multiple doses between 0.007 and 5 mg twice is administered daily or in sustained release form.

The amount of compounds of the formula I to be administered daily to interrupt a pregnancy should be between 1 and 20 mg administered between 1 and 6 days during the luteal phase of the reproductive cycle should be.

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For the above application, the compounds of the formula I can be mixed with pharmaceutically acceptable carriers Additives mixed and either orally in the form of tablets, capsules, elixirs, suspensions or solutions or parenterally in the form of injection solutions or suspensions.

A representative composition suitable for oral administration is a capsule made using the following components are produced in a known manner:

Components -Weight (mg)

17cr-Propadienylöstra-4-en-17β-5

ol-3-one oxide m

Inert solid diluents 245

15 (starch, lactose, kaolin)

Tablets and capsules suitable for oral administration for fertility control contain the The components mentioned below. The manufacture of these Tablets and capsules are made in a manner known per se:

Components:

17oc'-Propadienylestr, α-4-en-17βo1-3-one oxime

25 tragacanth lactose

Cornstarch talc

Magnesium stearate
■. 500 mg 300 mg

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( (mg A Not Capsules Tablets 0.5 ο, - 10 299.5 247 - 25th 2, , 5 5

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Sterile suspensions for injection and liquid suspensions suitable for oral administration which contain the The ingredients listed below are manufactured under known conditions. These suspensions become fertility control-once administered daily:

Components Weight (mg) 0.2 liquid sus - 47.5 - sterile inject 1.25 pensions for upon need tion suspension 0.4 oral Verabr. upon need nen 5 0.5 4.5 17a-Propad.ienylöstra-4-
en-17β-ol-3-one oxime 12.5 1.0 Sodium carboxymethyl
cellulose ■ 0.01 - 5 Methyl cellulose - - 2500 Polyvinyl pyrrolidone - - upon need Lecithin upon need
to 5 ml Benzyl alcohol - Magnesium aluminum siltcat - Gourmet fabrics Dyes - Methyl paraben upon need Propyl paraben upon need
to 1 ml Polysorbate 80 (ex. Tween
80) Sorbitol solution 70 % Buffering agents water

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The following Examples 1-7 (Example 8 describes the preparation of an intermediate compound) illustrate the invention. All temperatures are given in degrees Celsius and the room temperature is between 20 ^e and J0 ° C. '

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Example 1: 17g-Propadienylöstra-4-en-17β-or -3-one

A solution of 5 g of 17a-propadienylöstra-4-en-17ß-ol-3-one in 42 ml of absolute ethanol is mixed with a solution of the acetic acid addition salt of hydroxylamine (prepared from 5.32 g of hydroxylamine hydrochloride and 11.3% of sodium acetate trihydrate in 42 ml of absolute ethanol, the resulting precipitate being filtered off) mixed. The mixture thus obtained is kept at room temperature for half an hour. It is then diluted k 10 with water and the precipitate which has separated out is filtered off. This consists of 17oc-Propadienylöstra-4-en-17ß-ol-3 ~ one oxime with a melting point of 101-164 °.

Example 2: 17a-Propadienylöstra-4 _J 9 (10) -dien-17β-ol- ^) - one oxime

A solution of 5 g of 17a-propadienylöstra-4,9 (10) _dien-17ß-ol-j5-one in 42 ml of absolute ethanol is mixed with a solution of the hydroxylamine-acetic acid salt (prepared according to the method described in Example 1) . The resulting mixture is left to stand at room temperature for 1/2 hour. It is then diluted with water and the precipitate formed is filtered off. This consists of 17a-propadienylöstra-4 _J 9 (10) -dien-17ß-ol -> - one oxime with a melting point of 9> 119 ° C.

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Example ~ 5: 13-Aethyl-17ß-p ropadien ylp; ona - 4-en-

Using the procedure described in Example 1, however, if the 17 "-propadienylöstra-4-en-17β-ol-3- ° n used there is replaced by approx. equivalents Portions of ljJ-ethyl- ^ cc-prbpadienylgona - ^ - en-17ß-ol-3-one 13-ethyl = 17α-propadienylgona-4-en-17β-ol-3-one is obtained oxime.

Example h: llß-Methyl-lTa -prop adienylöstra - ^ - en-17ß-ol-3 ~ one

a) 3-Methoxy-ll3-methyl-17a-N, N-dimethylaminopropinyl estra-

1.8 g of lithium are added in small portions to 120 ml of ethylenediamine with stirring at a temperature between 50 ° and 60 ° under a nitrogen atmosphere. After the addition is complete, the blue solution obtained is heated to 75 ° -85 ° for 11/2 hours, a pale yellow reaction mixture being obtained. The mixture is cooled to 10 ° and 20 g of N, N-dimethylamino-2-propyne are added dropwise over 5 minutes. The mixture is then stirred at room temperature for 1 hour and then a solution of 2.6 g of 3-methoxy-11ß-methylöstra-2,5 (10) -diene-17-bn in 0 ml of tetrahydrofuran is added. The mixture is stirred at room temperature for k hours and after cooling in an ice / water mixture under a nitrogen atmosphere with 100 ml of brine and then with 250 ral diethyl

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ether shifted. The two phases are separated and the aqueous phase is extracted repeatedly with benzene. The organic phases are combined and washed with brine. After drying over sodium sulfate, the solvents are evaporated and the residue is recrystallized from diethyl ether. The resulting J-methoxy-LLSs-methyl-17cc-N, N - dimethylaminopropinylöstra ~ 2,5 (lO) -diene-17.beta.-ol melts ^ό between 170 ° and 175th

b) 3-methoxy-11ß-methyl-17a-N, N-dimethylaminoproginyl- ¹⁰

A solution of 2.5 g of I-methoxy ~ LLSs-methyl-17a-N, N ~ dimethylaminopropinylöstra-2 _J 5- (l0) -diene-17.beta.-ol in 60 ml acetone is added 15 nil of methyl iodide. The solution is at 5 ° · during. Left to stand for 18 hours, a crystalline precipitate being formed. This is filtered off and recrystallized from acetone. The 5-methoxyllß-methyl-17cc-N, l · I-dlmethyiaminopropinylöstra-2 _! .5 (10) -dien-17ß-ol-methiodide melts between 255 ° and 260 ° (with decomposition).

c) ^

To a suspension of 3.1 g of 3-methoxy-11ß-methyl-17a-N, N-dimethylaminopropinylestra-2,5 (10) -dien-17ß-ol-inethiodid in 100 ml of anhydrous tetrahydrofuran is added with ice cooling J ml of a 70 ■ $> solution of sodium

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di-4nethoxyäthoxy) -aluminium hydride in benzene, which with ' 10 ml of tetrahydrofuran is diluted. The reaction mixture left to stand until it has reached room temperature and then stirred for 2 hours. Complete solution occurs here. Then v / ater is added to. to decompose the excess of the hydride. put / and the tetrahydrofuran is untar reduced Pressure removed. The aqueous residue is extracted with methylene chloride and the organic phase over Dried sodium sulfate. After removing the solvent, the residue is crystallized from diethyl ether / hexane (1: 2) um, whereby the 3-methoxy-11ß-methyl-17a-propadienylestra-2,5 (10) -dieri-17ß-ol of m.p. 155 ° is obtained. ..

d) llß-Methyl-3.7a-p £ opaäienylöstra-4 ~ enr «17g-ol-3-one- To a solution of 800 mg of I-methoxy-11β-methyl- * 17 «~ propadienylestra-2,5 (10) -dien-17β-ol in 10 ml of methanol 5 drops of concentrated hydrochloric acid are added and the mixture is left at room temperature for 1/2 Standing hour. The mixture is then diluted with ice / water and an aqueous saturated sodium bicarbonate solution added carefully until the mixture no longer shows an acidic reaction. Then the solution is made with diethyl ether extracted and the organic phase, after separation, dried over sodium sulfate. After evaporation of the solvent a residue is obtained which is recrystallized from diethyl ether / hexane (1: 2) llß-Methyl-17a-propadienylöstra-4-en-17ß-ol-3-oh melts between 137 ° and 139 °.

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e)

oxime

Using the method described in Example 1, however, replacing the 17oc-propadienylöstra-4-en-17β-ol-3-one used there by approximately equivalent proportions of 11ß-methyl-17a-propadienylösträ-4-en-17ß "Ol-3-one one arrives at 11β-methyl-17oc ~ propadiepylöstra-4-en-17β ~ ol-3-one oxime.

Example 5: N-acetoxy- 17 (x-propadienylö'str a-4 "en-17β-. ΣΙ-3-οη oxime

A solution of 3 g of 17a ~ propadienylöstra-4-en-17ß-ol-3-one oxime (manufactured in _

Example 1) 'in 30 ml of pyridine is mixed with 10 ml of acetic anhydride and the erhaJtene mixture at room temperature for 1 hour, allowed to stand * After vrird with "ice / water diluted and never _formed:' dersehlag filtered It consists of N-Ac.etoxy. .-17apropädienylöstra.-4 ~ en-17β-ol-3-oh oxime.

Example 6: N-acetoxy-17g-propadienylöstra-4 _> 9 (10 ') -dien-17β-ol-3-one oxime

Using the procedure described in Example 5 However, when replacing the 17oc-propadienylöstra-4-en-17ß-ol-3-one used there oxime by equivalent proportions of

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17α-Propadienylöstra-4,900) ~ diene-17β-oil-3-one oxime one arrives at N-acetoxy-17α-propadienylöstra-4 _J 9 (10) -dien-17β-ol -> - one

Example 7 ?, 9a> methyl-17a- propadlenylöstra ~ 4 ~ en 17β-ol -3-one

a) 9a-jMethylöstra-2,5 (10) ~ diene »3, J / ^ ß-diol - ^ - methyl ether

A solution of 6 g of 9a-methylestrone rftethyl ether in 90 ml

ι- - Tetrahydrofuran and 90 ml of 1-butanol v; ird to 200 ml

added to boiling liquid ammonia. Then 2.8 g of lithium are added in several portions over the course of 10 minutes and the blue solution obtained is stirred while boiling for 6 hours. The ammonia is then allowed to escape overnight and 50 ml of methanol and then 100 - ¹ ^ l of a saturated aqueous sodium chloride solution and 200 ml of benzene are added to the residue. The 2 phases formed are separated and the organic phase with a saturated aqueous sodium chloride solution and then washed with 200 ml of benzene. The 2 phases formed are separated and the organic phase is washed with a saturated aqueous sodium chloride solution. The organic phase is then dried over anhydrous sodium sulfate and evaporated. The residue is recrystallized from methanol. The 9α-methylestra-2,5 (10) -diene-3,17β-diol-3-methyl ether thus obtained melts between 116 ° and 120 °.

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b) 3-

A device also consists of 5 g of 90> methylestra-2,5 (10) -diene-3,17ß-diol-3-methyl ether and 4.5 g of aluminum isopropoxide in 45 ml of benzene and 45 ml of 2-butanone heated to boiling for 22 hours with stirring,

using a water trap. It is then cooled and the reaction mixture is added to 100 ml of a 2N aqueous sodium hydroxide solution and this is obtained. Then 50 ml of benzene were added to the equipment. The organic layer is separated, washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. After the solvent has been removed, a residue is obtained which is recrystallized from diethyl ether / ilexane (1: 1). The J-methoxy-9a-methylöstra-2 _i 5 (10) -dien-17-one thus obtained melts between 155 ° and 158 °.

c) 17a-N, N-dimethylaminopropinyl-9 ^ -methylöstra ~ 2 _J 5 (10) -

-3,17β-diol-3-methyl ether

2.2 g of lithium are used in small portions in a nitrogen atmosphere and added with stirring to 150 ml ^ ethylenediamine at a temperature between 50 ° and 60 °. After completion the addition, the blue solution obtained is heated to 75 ° bjs 85 ° for 1 to 1 1/2 hours, with a pale yellow reaction mixture is obtained. This is cooled to 10 ° and treated with 24 g of N, N-dimethylamitio-2-propyne added for 5 minutes. After that, at room

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temperature for 1 hour and a solution of 3.2 g of 3-methoxy ~ 9a ~ tnethylÖstra-2 _i 5 (LO) -dien-17-one in 40 ml of tetrahydrofuran was added. The resulting mixture is stirred at room temperature for 16 hours. It is then cooled down. (Ice / water) - and in a nitrogen atmosphere, 200 ml of a saturated aqueous sodium chloride solution and then 300 ml of benzene are added. The two layers are separated and the aqueous layer is extracted 3 times with benzene. The organic phases are combined and washed with a saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent is removed. The residue obtained as residue 17a-IM, N-Diinethylaminopropinyl-9a-methylÖstra-2 _i 5 (10) -diene-3,17ß-diol-3-methylether is an oil which is used for the subsequent implementation.

d)

diene-3,17ß-di-3-methyl ether-nieth3odide

To a solution of 3.8 g 17a-N _i H-Dimethylaminopropinyl-9a-methylöstra-2 _J 5 (lO) -diene-3,17i3-diol-3-methyl ether in 90 ml of acetone was added to 30 ^m l of methyl iodide. The resulting solution is left to stand at 5 ° for 18 hours, a precipitate being formed. This is filtered off and recrystallized from methanol / acetone (1: 5). The 17α-NjN-dimethylaminopropynyl-9α-methylestra-2,5 (10) -diene-3,17β-diol-3-methyl ether methiodide thus obtained melts at 240 ° to 2 ° -3 ° (with decomposition).

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e) 9a-methyl-17a-propadienylestra-2,5 (10) -diene-5 _{; J} 17ßdiol-3-methyl ether

To a suspension of 3.3 g of 17oc ~ N, N-dimethylaminopropinyl-9a-methylöstra-2, 5 (10) ~ dieri-3,17ß-diol-3-methyl ether methiodide 100 ml of anhydrous tetrahydrofuran are added to 10 ml of a 70% solution of sodium di. (methoxyathoxy) aluminum hydride in benzene with 25 ml of tetrahydrofuran is diluted, too. The reaction mixture is left to stand until it has reached room temperature.

and then stir it for 2 hours, resulting in a complete solution. Then it becomes water added to decompose the excess of the hydride, and the tetrahydrofuran is evaporated off under reduced pressure. The aqueous residue is extracted with methylene chloride and the methylene chloride solution is then extracted dried over anhydrous sodium sulfate. After removal of the solvent, the 9oc-methyl-17ocpropadienylöptra-2 is obtained, 5OO) -diene-3,17ß-diol-3-methyl ether as an oil that is sufficiently pure for the following Implementation. '

f) 9a ~ methyl-17a-propadlenylestra-4-en-17β-ol ~ 3-one

To a solution of 600 mg of 9 ° i-methyl-17oc-propadienylestra-2,5 (10) -diene-3,17ß-diol-3-methyl ether 5 drops of concentrated hydrochloric acid are added to 10 ml of methanol to and, lets the mixture stand at room temperature for - 1/2 hour. Then you dilute with ice / Water and adds a saturated aqueous solution of Na-

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trium bicarbonate slowly until the solution is not acidic Reaction shows more. Then it is extracted with diethyl ether and the ethereal solution over anhydrous Dried sodium sulfate. After removing the solvent, a residue is obtained which consists of diethyl ether is recrystallized. This gives 9α-methyl-17α-propadlenylöstra-4 »en-17β-ol-3 · one.

g) 9a ~ methyl-17a-propadienylestra-4-en-17p «ol» 3-one ^ ox3m

Using the Yev described in Example 1, however, when replacing the 17 «-propadienylöstra-4-en-17ß-ol-3-one used there by equivalent proportions of 9α- · methyl-17oc · -prΰpadienylöstra ~ ⁱ ^ -en- 17ßol-J-one obtained the 9 ^a -M ^et hyl "l-7a-'Propadienylöstra ~ 4-en-3-one oxime 17ßol-.

¹ ^ example 8; 9a-Metbyl-17a> propadi enylöstra- ^J * -en-17ß ~

a) 9a-Methyl-lYa-propadienylöstra-5 (10) -en-17ß-ol-3-one

A solution of 12 g of 9a-methyl-17a ~ propadienylöstra-2,5 (10) -dien-3,17ß-diol-3-methyl ether (obtained in the process of section e) of Example 7) in 80 ml of glacial acetic acid and 20 ml of water for 3 hours at room temperature ditched. The reaction equipment is then poured onto ice and the mixture is added by adding neutralized with a 1 N aqueous sodium hydroxide solution, whereby a precipitate is formed. The precipitate is with Extracted methylene chloride. The methylene chloride extract

CONSTRUCTION ORIGINAL 209852/1090

- 26 -, ■ 600-6458

is washed with water, dried over anhydrous sodium sulfate and the solvent evaporated in vacuo. The residue (1: 1) consists of Dläthyiäther / hexane, and in this case the 9 ^{a-methyl-17a-propadienylöstra} - 5 (l0) - en-17ßol-3-one, mp 129-151 ° received..

b) 9cc- ^ ethyl-17a-propadienylestra-4-en-17β-ol-2 ~ ^one

17 g of 9a-methyl-17a-propadienylöstra-5 (10) -en-17ß-ol-3-one are introduced into a solution of 1.7 g of sodium methoxide in 170 ml of dry methanol. The Geraisch is stirred for ₃ until it is clear. Solution is formed and this is then left to stand for 1 1/2 hours. Some crystals fall out. The solvent is then partially evaporated in vacuo, the 9a-methyl-17a-propadienylöstra h -en-17ß-ol-5-one crystallizing out.

Example 9 t Separation of the isomers

9i £ -Methyl-17 <£ -propadienylöstra-4 --- en-17β-ol-3-Qn - oxime (obtained by the method of section g) of Example 7) is separated into its isomeric porms using silica gel plates , whereby a mixture of ethyl acetate and benzene (1: 9) is used as the mobile phase. The isomeric forms can be isolated as raschär and slower moving bands of which U are given "V. Spectra (in methanol) below:

\ = 242, E 1 io 1 cm = 530 and

'»Max ■

■ = 244, E 1 io 1 cm = 443

Max

The IR spectrum (in chloroform) of the mixture and of the individual isomers shows a weak absorption at 1630 cm and thus shows the presence of a 3-0xim-

In the presence of a 3-0xo group, the absorption in this area would be greater.

209852/1090

Claims (2)

6OO-6V58 Patent claims: Vorve for the production of connections of the Formula I, R. k CH = C = CH .. where R is hydrogen or an alkanoyl group with 2-4 carbon atoms and P is a straight-chain alkyl group with 1-5 carbon atoms and either X and Y together are a second CC bond and R _{2 is} hydrogen or X is a β-hydrogen atom, Y is an α-hydrogen atom or an α-methyl group and R _? Hydrogen or a methyl group mean with the proviso that - if Y stands for an α-methyl group - Rp means hydrogen, characterized in that either . a) to compounds of the formula Ia, ..OH HON Yes wherein R ,, R ₂ , X- and Y have the above meaning, obtained by compounds of the formula II, 600-64 ^ 8 OH .. CH = C-CH ₂ II where R ,, Rp, X and Y have the above meaning, with hydroxylamine or one of its acid addition salts or b) to compounds of the formula Ib, Oh h Ib R ¹ ON Ή Η where R., R _? , X and Y have the above meaning and R ^{1 stands} for an alkanoyl group with 2-4 carbon atoms, is obtained by reacting compounds of the formula la with an aliphatic alkylating agent. - ^r - ■ 2GS852 / 1Q90 , SAD ORIGINAL - 29 - 600-64 ^ 8 Germany 2. Compounds of the formula I in which R is hydrogen or an alkanoyl group having 2-4 carbon atoms and R, a straight chain alkyl group with l-> Mean carbon atoms, and either X and Y together form a second C-C bond mean, and Rp stands for hydrogen, or X a β-hydrogen atom, Y an α-hydrogen atom or a α-methyl group and Rp hydrogen or a methyl group mean with the proviso that - if Y is an α-methyl group stands - R ^ means hydrogen. J. Medicinal products characterized by the content of compounds of the formula I. ORIGINAL 209852/1090