NO163068B - BUILDING CONSTRUCTION. - Google Patents

Abstract

In order to reduce weight, but also to provide a strong and weather-protected building construction built up of prismatic space modules (10), gutter-shaped connecting elements (24a-d) are welded to adjacent, outwardly facing frame beams in the space modules (10) so that they are joined to a monolithic unit. At least two lifting beams (26) are welded to vertical joining elements (24a) at each gable side of the building structure, and vertical and horizontal reinforcing beams (27, 28) are welded in at exposed nodes.

Description

Method of preparation of therapeutic

active l-hydroxy-17a-alkynyl-jzSstradiols or

ethers or esters thereof.

The present invention relates to a process for the production of therapeutically active 1-hydroxy-17a-alkynyl-dstradiols with the general formula:

where and R 2 , which.may.be.the.same or different, are hydrogen,

methyl,.tetrahydropyranyl or acyl, and R^ is hydrogen, chlorine or a saturated or unsaturated aliphatic group with 1 or 2 carbon atoms, by which method one in a manner known per se in 1-hydroxy-ostrone, optionally after prior etherification of the 1,3-dihydroxy group, transfers the -keto group in the 17-' position by means of an alkynylmagnesium halide with the formula R^C=CMgBr or a corresponding alkali metal alkynylide to a 17p-hydroxy-17oc-alkynyl group, and depending on the ultimately desired ' meaning of R-^ and B.^ then in any order, optionally hydrolytically cleaves, esterifies or etherifies free or etherified hydroxy groups. As acyl groups, the residues of e.g. acetic acid, propionic acid, hydroxypropionic acid, p-chloropropionic acid, cyclopentylpropionic acid, caproic acid, onantic acid, benzoic acid, mono- and dichloroacetic acid, trimethylacetic acid, succinic acid etc. into account.

With a view to the pharmaceutical use of the process products, preferably methyl, ethyl and tetrahydropyranyl residues are suitable as ether residues.

The new compounds are produced by methods known per se.

For alkynylation, e.g. alkyne, chloroalkyne or dialkyne and an alkali metal, preferably in the presence of a tertiary alcohol or in the presence of ammonia, possibly at elevated pressure, act on the 17-ketone in a suitable solvent. Chloralkyne or dialkyne is preferably formed during the reaction of halogenated alkenes or halogenated alkynes with alkali.

Instead of alkali metal alkynylide, alkynylmagnesium halide can also be used.

Suitable solvents are e.g. ether, such as diethyl ether, tetrahydrofuran and dioxane or hydrocarbons, such as benzene and toluene. As tertiary alcohols, e.g. tert-butyl and tert-amyl alcohol in speech.

As 1-hydroxy-bstrone is not a very stable compound, it may be appropriate to proceed from such compounds in which the hydroxy group in the 1- and 3-position is etherified. When these ether residues are only to be introduced as temporary protecting groups, it is advantageous to ether with dihydropyran, as this ether residue is easily cleavable in the 17-position after ', performed alkynylation as is known.

Free or liberated hydroxyl groups can then be changed by possible partial esterification and/or etherification and possible partial cleavage of the first introduced groups or by transesterification. ,

The selective acylation in the 1- and 3-position preferably takes place with pyridine acid anhydride at room temperature. Alkylating compounds such as diazomethane and dialkyl sulphate are used for etherification in the 1- and 3-position.

For esterification of the 17p-hydroxy group in the 1,3-diesters and 1,3-diethers obtained, e.g. acetic anhydride in the presence of strong acids such as p-toluenesulfonic acid, or pyridine/acid anhydride in the heat, affect the steroid. The latter methods can also be used to immediately transfer the free trihydroxy compounds to the triacyl-ate. The 1- and 3-OH groups can be released from the triacylates by gentle partial saponification.

1,3-diester and 1,3-diether can be converted with dihydropyran in the presence of a strong acid, such as p-toluenesulfonic acid, into the corresponding 17-tetrahydropyranyl ethers. The etherification of the 17-OH group in the produced 1,3-diethers with an alkyl residue is preferably carried out with alkyl halides in liquid ammonia. Both of the latter methods make it possible to etherify all three OH groups in the trihydroxy compound in a single work operation.

From 1,3-diacyl-17-tetrahydropyranyl derivatives, the 1- and 3-OH groups can be set free by alkaline saponification.

If one wants to arrive at 1,3,1,78-trihydroxy compounds whose 17-0H group is alkylated or acylated, it is particularly advantageous to etherify the 1-hydroxy-sterone with dihydropyran, after the alkynylation and introduce the desired alkyl or acyl residue into the obtained 176-OH group and then selectively cleave the tetrahydropyranyl groups from the 1,3-position. Afterwards, the 1,3-dihydroxy compounds obtained can be etherified or esterified as desired.

The process products have valuable therapeutic properties. They excel.eg. by surprising estrogen and ovulation-inhibiting activity. The compounds can be applied orally or subcutaneously. The many times superior effect of the process compounds in the ovulation inhibition test and in the Allen-Doisy test is shown in the following table by means of 1-hydroxy-17cc-ethynyl-oestradiol (1), the corresponding 1,3-diacetate (II) and l-hydroxy-17a-butadiynyl-pstradiol-1,3-diacetate (III) in comparison with the known estrogens IV and V.

For therapeutic use, the new estradiol derivatives are worked up with the additives, carriers and taste corrections common in galenic pharmacy by methods known per se to the usual pharmaceutical forms. For oral application, in particular tablets, dragées, capsules, pills, suspensions or solutions come into question, and for parenteral application particularly oily solutions, such as e.g. Sesame oil or castor oil solutions, which may also additionally contain another fat thinner, such as e.g. benzyl benzoate or benzyl alcohol. The concentration of the active substance in the medicines formulated in this way is of course also dependent on the form of application, thus tablets contain approx. 2O-r and oily solutions for intramuscular injection per ml approx. 50y working connection.

The indication area for the medicine based on the compounds produced according to the invention is disorders for which a treatment with estrogen, possibly in combination with progestogenically active compounds, is indicated. Examples include menopause and its sequelae, mammary carcinoma after menopause, prostate carcinoma, peripheral blood flow disorders, amenorrhoea in combination with e.g. norethisterone acetate are the process compounds

also suitable for bringing the ovary to rest.

The following examples will illustrate the procedure.

Example 1

a) From 30 g of magnesium shavings and 91.<*>+ ml of ethyl bromide, a Grignard solution is prepared in ^•00 ml of tetrahydrofuran from which

1-2 hour introduction of acetylene gives the acetylenemagnesium bromide compound. A solution of 7 g of 1-hydroxyestrone in 150 ml of tetrahydrofuran is added dropwise to the suspension and this mixture is stirred for 20 hours at 70°C under argon, after cooling the reaction mixture is split with saturated, aqueous ammonium chloride solution, the organic phase is separated and the aqueous phase is extracted several times with ether. The combined organic phases are washed with saturated sodium chloride solution and filtered over sodium sulfate. The residue remaining after evaporation of the solvent is chromatographed over silica gel and 1-hydroxy-17a-ethynyl estradiol is eluted with benzene/acetic acid ester. The raw product is dissolved in acetic acid ester, filtered over charcoal and recrystallized from acetic acid ester/hexane.

You get 2 g of 1-hydroxy-17a-ethynyl estradiol with m.p. 189-190 - 191°C.

UV: 6207 <=> 38AOO

g286 <=>2,160

b) 2 g of 1-hydroxy-17a-ethynyl estradiol' are dissolved in 15 ml of pyridine and 5 ml of acetic anhydride. This reaction mixture is allowed to stand for 15 hours

at room temperature and then poured into 10 times the amount of ice water. The precipitate that has formed is suctioned off, washed with water, filtered and recrystallized from isopropyl ether with methylene chloride. Moon receives 2 g of 1-hydroxy-17a-ethynyl estradiol-1,3-diacetate with m.p. 197-198-199°C.

UV: £20? = 18,900

€ 266 k12'' c) Dissolve 2.5 g of l-hydroxy-17a-ethynyl estradiol-l,3-diacetate in 30 ml of acetic anhydride and add little by little while cooling

and convert 1.9 g of p-toluenesulfonic acid into 18 ml of acetic anhydride. After a reaction time of 5 hours, it is poured into ice water and the separated tri-acetate is filtered off after stirring for 1 hour, washed neutrally and filtered. 2.6 g of 1-hydroxy-17a-ethynyl estradiol triacetate is obtained.

d) A mixture of 3 g of 1-hydroxy-17q-ethynyl-1,3-diacetate in 15 ml of pyridine and 10 ml of acetic anhydride is heated for 10 hours in an oil bath

(150°C bath temperature) under nitrogen. After cooling to room temperature, the batch is poured into ice water, where it is stirred for 1 hour and then the precipitate is filtered off, washed with water and dried. 2.8 g of 1-hydroxy-17a-ethynyl estradiol triacetate is obtained.

uv: e20? <=><18>.500

£?66 'flO

Example 2

3 g of 1-hydroxy-17a-ethynyl estradiol is acetylated, as in Example le) or ld) described, to 1-hydroxy-17o-ethynyl estradiol triacetate.

UV: £ 2Q7 = 18,500,

^266 = 'J+10

Example 3

a) To a solution of 2 g of 1-hydroxy-17a-ethynyl estradiol in 150 ml of ether, add an ethereal diazomethane solution until the yellow

color of diazomethane remains. The solvent is then distilled off in a vacuum, leaving 1-hydroxy-17a-ethynyl estradiol-1,3-dimethyl ether.

b) 1 g of 1-hydroxy-17'oc-ethynyl-estradiol is dissolved in 100 ml of aqueous potassium chloride, which contains 2 molar equivalents of K0H, and added under

decoupling 2 molar equivalents of dimethylsulphate. After 1 hour, the precipitated dimethyl ether is extracted with ether, the organic phases are washed with water and dried. After evaporation of the solvent, 1-hydroxy-17a-ethynyl estradiol-1,3-dimethyl ether is obtained.

UV: £2Q5 <=> 38,200

^-28»+ = 2,060 c) lg 1-hydroxy-17a-ethynylbstradiol-1,3-dimethyl ether is esterified analogously to Example lc) or ld) to 1-hydroxy-17oc-ethynylbstradiol-1,3-dimethylether -17B-acetate. ~.

UV: e2Q5 = 38,100

£2Q]+ = 2,050

Example h

1 approx...100 ml of liquid ammonia is added at -80° to -60°C after adding a trace of ferric nitrate to 0.13^ g of sodium in small pieces. After the blue color disappears, 1.8 g of 1-hydroxy-17a-ethynyl estradiol-1,3-dimethyl ether in 50 ml of tetrahydrofuran are added dropwise over the course of 10 minutes and the mixture is stirred for 1 to 2 hours. 1 g of methyl iodide in 10 ml of tetrahydrofuran is then added and stirred for another 3 hours. The mixture is then poured onto ice, neutralized with acetic acid to the neutral point and extracted with methylene chloride. The organic phases are washed with water and filtered over sodium sulfate. After evaporation of the solvent, 1-hydroxy-17oc-ethynyloestradiol-1,3,176-trimethylether is obtained as a residue.

UV:t205 = 38,300

€28? = 2.0<l>f0

Example 5

550 mg of l-hydroxy-17a-ethynyloestradiol forethres as described

in Example h, using 0.13 g of sodium and 1 g of methyl iodide to 1-hydroxy-17α-ethynyl estradiol trimethyl ether.

uv<:£>205<-=> 38..300

e2Q5 = 2. 0k0

Example 6

2 g of 1-hydroxy-17α-ethynyloestradiol-1,3,17β-triacetate are suspended in 100 ml of methanol. A solution of 1 g of potassium carbonate in 10 ml of distilled water is added to this suspension while stirring at room temperature. After 1.5 hours, the reaction mixture is slightly acidified, added while stirring to ice water, the precipitate is suctioned off after some time and washed neutrally. 1.2 g of 1-hydroxy-17oc-ethynyl estradiol-17B-acetate is obtained.

UV:6206 = 38.500

<8>287 = 2' 15°

Example 7

To 550 ml of lithium shavings in 200 ml of absolute ether, add 5.7 g of methyl iodide in 100 ml of absolute ether. After brief heating, cool to 0°C and 20 g of transdichloroethylene in 50 ml of absolute ether are added over the course of 30 minutes under nitrogen. The dressing bath is removed and stirred for 1.5 hours at room temperature. To this solution of lithium-chloro-acetylene is added 1.5 g of 1-hydroxy-bsterone dissolved in 300 ml of absolute toluene over the course of 30 minutes. The mixture is heated with stirring for 1.5 hours and then cooled to -60°C. At this temperature, the reaction mixture is split with 2.5 g of ammonium chloride in saturated aqueous solution. After heating to room temperature, extract with ether, filter over sodium sulphate and distill off the solvent. One obtains 1-hydroxy-17oc-chlorethynyl-bstradiol.

UV: c 2 O 6 = 38,300

^285 = 2,200

Example 8

For about. 300 ml of liquid ammonia is introduced at -80 to -60°C

after adding a trace of ferric nitrate 1.3?8 g of sodium in small pieces. After the blue color has disappeared, 2^.6 g of 1,<*>+-dichlorobutyne-(2) are added dropwise. After the addition is complete, 5 g of 1-hydroxybsterone dissolved in absolute tetrahydrofuran is added, and it is allowed to react for 2 hours with stirring at -*+0°C. The reaction mixture is decomposed with saturated aqueous ammonium chloride solution, the ammonia is allowed to evaporate on standing and the compound is extracted with methylene chloride. The extract is washed with water, filtered over sodium sulphate and freed from solvent. One obtains 1-hydroxy-17oc-butadiynyl-bstradiol.

UV: £206 = 38,300

6285 = 2,200

Example 9

1.2 g of 1-hydroxy-17oc-ethynyl estradiol-17B-acetate is etherified as described in Example 3a)5 with an ethereal diazomethane solution. 1-hydroxy-17a-ethynyl-bstradiol-1,3-dimethylether-17b-acetate is obtained.

UV: €20? <=> 38,100

t28k = 2-050

Example 10

1.8 g of 1-hydroxy-17a-chloroethynyl-bstradiol is acetylated as described in Example 1b) to 1-hydroxy-17oc-chlorethynyl-bstradiol-1,3-diacetate with m.p. 225 - 227°C (hexane/acetone)..

UV: f 206 <=>22•600

*266 - <h0>°

Example 11'

1 g of 1-hydroxy-17a-butadiynyl-bstradiol is acetylated as described in Example 1b)., to 1-hydroxy-17a-butadiynyl-bstradiol-1,3-diacetate 'with-m.p. 181+°C (hexane/acetone).

UV: f 206 = 19,200

£253 = <h>9<h>

f286 = W

<£>305<=><1>55

Example 12

The solutions of 1.06 g of 1-hydroxy-17α-ethynyl-bstradiol-1,3-diacetate in 70 ml of benzene and of 10 mg of p-toluenesulfonic acid in 20 ml of benzene are both evaporated to half volume, cooled, combined and added to 1 ml dihydropyran. This mixture is stirred for 1 hour at room temperature, then shaken with ice-cold sodium bicarbonate solution and washed neutrally with water. After drying, removal of the solvent and recrystallization from hexane, 1-hydroxy-17oc-ethynyl-oestradiol-17B-tetrahydropyranyl ether-1,3-diacetate with m.p. 13^ - 135°C

UV: £207 = 16,800

^266 <=> 39^

Example 13

a) Dissolve 2 g of 1-hydroxy-estrone in 70 ml of absolute benzene. The solution is evaporated by distillation to 50 ml. 20 mg of p-toluenesulfonic acid

is dissolved in 30 ml of benzene and this solution is evaporated to 15 ml. Both solutions are combined after cooling. Add h ml of freshly distilled dihydropyran to the mixture and stir for 2 hours at room temperature. It is then diluted with ether, the organic phases are washed one after the other with sodium bicarbonate solution and water, filtered and freed from solvent. One thus obtains 1-hydroxy-bstron-1,3-ditetrahydropyranyl ether.

uv: e205 = 38,500

Z2Qk = 2.100

b) From 15 g of magnesium shavings and 1+5.7 ml of ethyl bromide, a Grignard solution is prepared in ^00 ml of absolute tetrahydrofuran, in which acetylene

is introduced for 1 - 2 hours. A solution of 5.5 g of 1-hydroxy-bstron-1,3-di-tetrahydropyranyl ether in 100 ml of absolute tetrahydrofuran is added dropwise to this suspension of the ethylene magnesium bromide compound and this mixture is stirred for 20 hours at 70°C under argon. After cooling, a saturated, aqueous ammonium chloride solution is added to the reaction mixture, the organic phase is separated and the aqueous phase is extracted a few times with ether. The combined organic phases are washed with saturated sodium chloride solution and filtered over sodium sulfate. After evaporation of the solvent, 1-hydroxy-17a-ethynyl-bstradiol-1,3-di-tetrahydropyranyl ether is obtained.

UV: £20? <=> 38,500

e28lf = 2,100 c) To 1.1 g of lithium shavings in ^00 ml of absolute ether, 11.0 g of methyl iodide in 200 ml of absolute ether is added dropwise. After brief heating, it is cooled to 0°C and under nitrogen, 0 g of transdichloroethylene in 100 ml of absolute ether is added over the course of 30 minutes. The Kjble bath is removed and the reaction mixture is stirred at room temperature for 1.5 hours. To this solution of lithium-chloroacetylene, 1.6 g of 1-hydroxybstron-1,3-di-tetrahydropyranyl ether dissolved in 150 ml of absolute toluene is added over the course of 30 minutes. The mixture is heated for 1.5 hours with stirring and then cooled to -60°C. At this temperature, 5 g of ammonium chloride in saturated aqueous solution is added to the reaction mixture. After heating to room temperature, extract with ether, the extract is passed over sodium sulphate and the solvent

is removed. One obtains 1-hydroxy-17a-chloroethynyl estradiol-1,3-di-tetrahydropyranyl ether.

UV: £206 = 38,300

e285 = 2,200

d) In approx. 150 ml of liquid ammonia is introduced at -80 to -60°C after adding a trace of ferric nitrate 6.9 g of sodium in small pieces. After the blue color has disappeared, 12.3 g of 1,^-dichlorobutyne-(2) are added dropwise. After the end of the addition, k.2 g of 1-hydroxy-bstron-1,3-di-tetrahydropyranyl ether dissolved in absolute tetrahydrofuran is added, and it is allowed to react with stirring for 2 hours at

-<1>+0°C. The reaction solution is decomposed with saturated, aqueous ammonium chloride solution, the ammonia evaporates on standing and compound

the iron is extracted with methylene chloride. The extract is washed with water, filtered over sodium sulphate and freed from the solvent. One obtains 1-hydroxy-17a-butadiynyloestradiol-1,3-di-tetrahydropyranyl ether.

UV: <t>2Q6 <=> 38,300 <£>2gi = 5,300

<£>285=2. oho <e>230 <=>7,800

e297 = 5-370

Example lh

For about. 100 ml of liquid ammonia is introduced at -80 to -60°C

after adding a trace of ferric nitrate 0.13*+ g of sodium in small pieces. After the blue color has disappeared, 2.5 g of 1-hydroxy-17a-ethynyl-estradiol-1,3-di-tetrahydropyranyl ether are added dropwise in 50 ml. absolute tetrahydrofuran over 10 minutes and the mixture is stirred for 1 to 2 hours. Then add 1 g of methyl iodide in 10 ml

absolute tetrahydrofuran and there is stirred for a further 3 hours. The reaction mixture is then poured onto ice, neutralized with acetic acid and extracted with methylene chloride. The organic phase is washed with water and filtered over sodium sulphate. After evaporation of the solvent, 1-hydroxy-17a-ethynyl estradiol-1,3-di-tetrahydropyranyl-176-methyl ether is obtained.

UV: <e>20? <=> 38,300

e285 = 2. <0>h0

Example 15

1 g of 1-hydroxy-17β-ethynyl estradiol-1,3-di-tetrahydropyranyl ether-17β-methyl ether is heated with 1 g of oxalic acid and 1 ml of water in 50 ml of ethanol for 5 minutes under reflux. It is then cooled, the reaction mixture is poured into ice water and the precipitate is filtered off, washed and dried. One thus obtains 1-hydroxy-17a-ethynyl estradiol-17B-methyl ether.

UV: <£>207 <=>38,500

£286 = 2,160

Example 16

1 g of 1-hydroxy-17a-ethynyl estradiol-17B-methylether is dissolved in 5 ml of pyridine and 5 ml of acetic anhydride under cooling. The reaction mixture is allowed to stand for 15 hours at room temperature and is then poured into the 10-fold amount of ice water. • The deposited precipitate is suctioned off, washed with water and - tbrres. : One obtains 1-hydroxy-17a-ethynyl estradiol-178-methylether-1,3-diacetate.

UV: t20? =18,800

e266 = klQ

Example 17

An ethereal diazomethane solution is added to a solution of 1.5 g of 1-hydroxy-17a-ethynyl estradiol-17B-methylether in 150 ml of ether until the yellow color of diazomethane remains. The solvent is then distilled off in vacuum and 1-hydroxy-17a-ethynyl-1,3517B-trimethylether is obtained.

UV: 620^ = 38,200

e285 = 2.050

Example 18

A mixture of 3 g of 1-hydroxy-17a-ethynyl estradiol-1,3-di-tetrahydropyranyl ether, 15 ml of pyridine and 10 ml of acetic anhydride is heated for 10 hours in an oil bath (150°C bath temperature) under nitrogen. After cooling to room temperature, the batch is poured into ice water, where it is stirred for 1 hour and then the sediment is filtered off, washed with water and dried. One obtains 1-hydroxy-17oc-ethynyl estradiol-1,3-di-tetrahydropyranyl ether-176-acetate.

UV: f20^ = 38.^00

e28lf = 2,100

Example 19-

1.5 g of 1-hydroxy-17a-ethynyl estradiol-1,3-di-tetrahydropyranyl ether-17B-acetate is hydrolyzed as described in Example 15, to L-hydroxy-17a-ethynyl-b estradiol-17B-acetate.

UV: e2Q? = 38,500

e286 = 2,150

Example 20

2 g of 1-hydroxy-17a-ethynyl estradiol-17B-acetate is acetylated as be written in Example 16, to 1-hydroxy-17α-ethynyl estradiol-1,3,17B-triacetate.

UV: £2Q7.= 18,700

^266 V A<20>

Example 21

1.5 g of 1-hydroxy-17a-ethynyl estradiol-1,3-di-tetrahydropyranyl ether is hydrolyzed as described in Example 15, to 1-hydroxy-17a-ethynyl estradiol. After recrystallization from acetic acid ester and hexane, the compound melts at 189 - 191°C.

UV: 6207 = 38AOO

£286 = 2,160

Example 22

From 3.65 g of magnesium shavings and 16.3 g of ethyl bromide, i

150 ml of absolute tetrahydrofuran a Grignard solution, in which 8 g of propyne dissolved in 60 ml of absolute tetrahydrofuran are added dropwise. The temperature is kept at -60°C. As soon as gas evolution has ceased, add 6.8 g of 1-hydroxy-ostrone-1,3-di-tetrahydropyranyl ether dissolved in 100 ml of absolute tetrahydrofuran, and heat under nitrogen and exclusion of moisture for 20 hours at 70°C. The processing is carried out as described in Example 13b). One thus obtains 1-hydroxy-17a-propynyl-bstradiol-1,3-di-tetrahydropyranyl ether.

UV: e2Qk = 38,300

&285 = 2' 105

Example 2. 3

To a solution of 351 g of 1-hydroxy-17a-ethynyl-6estradiol in 25 ml of absolute pyridine, 6.0 ml of palmitic acid chloride <p>g is added, which is stirred under nitrogen for *+8 hours at room temperature. The reaction mixture is then poured into water while stirring and the precipitate is filtered off. One takes. into ether, wash the ether extract neutrally with water, dry and evaporate. The residue is purified by chromatography over silica gel. 3.95 g of 1-hydroxy-17a-ethynyl-oestradiol-1,3-dipalmitate is obtained as a yellowish oil.

Example 2h

To a solution of 1.25 g of 1-hydroxy-17ct-ethynyl-6estradiol

in 10 ml of pyridine, 3.8 ml of onanoic anhydride are added under nitrogen and stirred for 8 hours at room temperature. Then, over the course of 2 hours, 5 ml of water is added while stirring at h5°C and stirring continues at this temperature for 3 hours. The solution is extracted with ether and the ethereal solution is successively washed ice-cold with 2N sulfuric acid, water, 5% soda ash solution and then washed neutrally with water, filtered and evaporated. The residue is purified by chromatography over silica gel and 1.9 g of 1-hydroxy-17a-ethynyl-estradiol-1,3-dionaritate is obtained as a colorless oil.

Claims (1)

Procedure for the production of therapeutically active 1-hydroxy-17a-alkynyl-6estradiols or ethers or esters thereof with the general formula: where R^ and R^, which may be the same or different, are hydrogen, methyl, tetrahydropyranyl or acyl, and R^ is hydrogen, chlorine or a saturated or unsaturated aliphatic group with 1 or 2 carbon atoms, characterized in that on i and for himself known manner in 1-hydroxy-bstrone, optionally after prior etherification of the 1,3-dihydroxy groups, transfers the keto group in the 17-position with the help of an alkynylmagnesium halide with the formula R^C=CMgBr or a corresponding alkali metal alkynylide to a 17B-hydroxy-17a -alkynyl group, and depending on the ultimately desired meaning of R-^ and R2 then in any order optionally hydrolytically cleaves, esterifies or etherifies free or etherified hydroxyl groups.