DE2207421B2 - acylates, processes for their production and medicaments containing them - Google Patents

Description

wherein R ^{1 is} a lower alkyl radical, R ^{2 is} a hydrogen atom or an acyl radical, R 'is a hydrogen atom or a substituted or unsubstituted, saturated or unsaturated lower alkyl radical, X is an oxygen atom or the grouping is a hydrogen atom, OR ⁴ , in which R ^{4 is} a hydrogen atom or a Represents acyl radical.

2. ^ jS-Hydroxy-IS-methyl-lSa.iea-methylen-4-oestren-3-one.

3. 17 _i 3-Hydroxy-18-methyl-17a: -äthinyl-15 <\ ;, 16 "- methylen-4-estren-3-one.

4. 17 /? - Hydroxy-17 "-äthinyl-15", 16a-methylen-4-estren-3-one.

5. 17j3-acetoxy-18-methyl-15 ", 16" -methylene-4-estren-3-one.

6. 170-Acetoxy-15 ", 16! X-Niethylen-4-Oestren-3-one.

7. 17 / 3- Acetoxy-18-methy 1-17 * -äthiny I-15 <x, 16 «- methylene-4-estren-3-one.

8. Medicines based on the compounds according to claims 1 to 7.

9. Process for the preparation of 15a, 16 «-methylene-4-estren-17 / J-ols of the general formula I.

O-R ²

(D

wherein R ^{1 is} a lower alkyl radical, R ^{2 is} a hydrogen atom or an acyl radical, R ^{3 is} a hydrogen atom or a substituted or unsubstituted, saturated or unsaturated lower alkyl radical, X is an oxygen atom or the grouping 11, OR ⁴ , in which R ^{4 is} a hydrogen atom or a Represents acyl radical, denoted by the fact that a 15 ", 16" -methylene-17-oxo-5 (6) - or 5 (IO) -östren of the general formula II

in which R ^{1 has} the meaning given above. The invention relates to 15Ä, 16'-methylene-4-oestrene-17jS-oIe of the general formula I according to Claim 1. Lower alkyl radicals R ¹ are alkyl radicals having 1 to 5 carbon atoms. Preferred alkyl radicals are the methyl and ethyl groups.
The acyl radicals R ² and R ⁴ are physiologically acceptable

Jt inert acid residues in question, which differ from acids derive, which are commonly used for the esterification of steroid alcohols. These include, among others. the organic carboxylic acids with 1 to 18 carbon atoms, those of the aliphatic, aiicyclic, aromatic

j (! see or belong to heterocyclic series and the can be saturated or unsaturated, mono- or polybasic and / or substituted, as examples of the Substituents alkyl, hydroxy, oxo or amino groups or halogen atoms may be mentioned. For this

»Also include the common inorganic acids. The acids are lower, medium and higher carboxylic acids, preferably those with up to 5 carbon atoms in question, of which, for example, formic acid, acetic acid, propionic acid, butyric acid

w acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethyl acetic acid, diethyl acetic acid, tert-butyl acetic acid, cyclopentyl acetic acid

· ») Acetic acid, cyclohexylacetic acid, mono-, di- and trichloroacetic acid, Aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid. Lactic acid, succinic acid, adipic acid, benzoic acid, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid.

■> <) Furthermore, the common inorganic acids, such as. B. sulfuric and phosphoric acid into consideration.

To the production; ' water-soluble preparations come the commonly used esters into consideration.

) ^r ) Examples include the esters of succinic acid, adipic acid, sulfuric acid and phosphoric acid, which are optionally converted into the alkali metal salts.
The lower alkyl radicals R ³ are alkyl radicals with 1

wi up to 5 carbon atoms. Example white The methyl, ethyl, butyl, vinyl, ethynyl or buladiynyl radicals may be mentioned. The ethynyl radical is preferred. The alkyl radical can also be substituted in a suitable manner, the chloroethinyl radical being preferred.

* "> Since the compounds according to the invention are used as Pharmazcutika are useful and anabolc. contain gestagen or other valuable steroid hormone components, are also medicines that contain these compounds

contain. Subject of the invention. Thus, the steroids of the formula I, in which R ^{3 has,} inter alia, the meaning hydrogen, have a strong anabolic activity. So it turns out z. B. 18-methyl-15 ", 16" -methylene-19-nor-testosterone in the usual seminal vesicle, prostate and levator ani test superior to the standard compound testosterone propionate. On the other hand, steroids of the formula I ₁ in which R ^{3 is,} inter alia, an unsaturated alkyl radical, are distinguished by a strong gestagenic activity. For example, 18-methyl-r / a-äthinyl-15 ", 16 <x-me" hylen-19-nor-testosterone proves to be significantly more effective than known progestins in the fertilization inhibition test. The higher esters are also distinguished by a protracted effectiveness.

The anabolic compounds according to the invention can be used, inter alia, for the treatment of diseases are used which are based on a protein deficiency or in which an administration of Anabolic steroids is indicated. The gestagen compounds can e.g. B. Use in contraception preparations find, where they are used as a gestagen component in combination with an estrogenic hormone component, such as B. ethinyl estradiol, or can be used as the sole active component. To the The new compounds are used for therapeutic purposes with those which are customary in galenical pharmacy Additives, carrier substances and taste corrections according to methods known per se to the common pharmaceutical forms processed. Tablets, coated tablets, Capsules, pills, suspensions or solutions in question and especially oily ones for parenteral administration Solutions such as B. sesame oil or castor solutions, which may also contain a diluent, such as B. benzyl benzoate or benzyl alcohol may contain. The concentration of the active ingredient in the sun formulated drugs depends on the form of application.

The compounds according to the invention can also be intermediates for such pharmacologically valuable Be steroids that are converted by known conversion processes, such as. B. rearrangement, hydrogenation, Dehydration, etc. can be obtained.

The present invention also relates to a process for the preparation of the 15 ″, 16α-methylene-4-estren-17/3-ols of the general formula I.

general formula II

O-R ²

wherein R ^{1 is} a lower alkyl radical, R ^{2 is} a hydrogen atom or an acyl radical, R ^{J is} a hydrogen atom or a substituted or unsubstituted, saturated or unsaturated lower alkyl radical, X is an oxygen atom or the grouping H, OR ¹¹ , in which R ^{4 is} a hydrogen atom or a Represents acyl radical, means that it is characterized in that an i5A, ioa-methyien-i7-oxo-5 (ö) or 5 (iö) -östren egg

(H)

where R ^{1 has} the meaning given above and Y is a keto group, preferably protected as a ketal, reduced by methods known per se and cleaving off the primarily introduced keto protecting group and, depending on the ultimately desired meaning of X, R and R ^4, optionally subsequently per se as is known, the 17-hydroxy group is esterified and / or the 3-keto group is reduced and in the molecule

2 (i any free hydroxyl groups present are esterified.

The 17-keto group can be reduced by hydrogenation in the presence of a conventional catalyst, which in the presence of hydrogen the reduction effected by five-membered ring ketones. Also can

_> ■> the hydrogen as a metal hydride on the 17-ketone Formula II are transferred. As hydrogen donors have: especially complex hydrides, such as z. B. sodium hydridoborate, lithium hydridoaluminate, sodium hydridotrimethoxoborate and lithium hydrido-

j (i tri-tert-butoxoaluminate proven.

The reduction can also be carried out by known methods with an organometallic compound in which the organic radical R ³ is and which is an alkyl magnesium halide, such as. B.

j5 methyl magnesium bromide or iodide, an alkenyl magnesium and / or alkenyl zinc halide, e.g. B. vinyl magnesium bromide or allyl magnesium bromide, an alkyl magnesium halide such as ethynyl magnesium bromide, Propynyl magnesium bromide or propynyl zinc bromide, or an alkali metal acetylide, such as potassium acetylide, can act. The organometallic compound used as a reducing agent can also be used in situ are formed and made to react with the 17-ketone of the formula II. So you can z. B. to Reaction with organometallic alkynyl compounds on the ketone in a suitable solvent Alkyne, chloroalkyne or alkadiyne and an alkali metal, preferably in the presence of a tert. Alcohol or act of ammonia, possibly under increased pressure.

The reduction of the 17-keto group is carried out in a preferred embodiment in the presence of, e.g. B. made as a ketal, protected 3-keto group. The ketal residues are derived from the commonly used Protection of free oxo groups from alcohols used, for example, ethylene glycol and 2,2-dimethyl-1,3-propanediol.

The reduction of the 3-keto group can be carried out by methods known to the person skilled in the art.

You can, for example, by hydrogenation in the presence of a customary catalyst in the presence of Hydrogen causes the reduction of unsaturated six-ring ketones to take place. But you can also with Metal hydrides or hydrido complex compounds

hi, for example sodium hydridoborate, Lithium hydridoaluminate, sodium hydridotrimethoxoborate and lithium hydridotri-tert.-butoxoalu-

For the subsequent esterification, the usual in steroid chemistry come to the esterification of Steroid alcohols in question. For the acylation of a hydroxyl group in the 3-position be for example the reaction with an acid anhydride in the presence of a tertiary amine at room temperature called for the esterification of a 170-hydroxyl group be for example the reaction with acid anhydrides in the presence of strong acids, such as. B. p-toluenesulfonic acid, or the reaction with an acid anhydride in the presence of a tert. Amines in the The latter methods can also be used to put the 3,17-dihydroxy steroids in to transfer the diacylate.

The cleavage of the keto protective group is after r> carried out methods known to those skilled in the art. For example, mineral acids are used for decetalization, such as B. perchloric acid, sulfuric acid or hydrochloric acid, or organic acids, such as. B. oxalic acid, in Betrachi.

The preparation of the 15 ", 16" -Methylene-17-oxo-5 (6) - or 5 (10) -estrenes of the formula II are described in the form of the ketals using Examples A and B.

A. 3,3- (2 ', 2'-Dimethyl-1', 3'-propylenedioxy) -18-methyl-15a, 16 * -methylene-5 (6) - or 5 (10) -estren-17-one

46.2 g of natural 18-methyl-19-nor-4,16-pregnadiene-3,20-diene are in 2.5 m! Benzene with 37.1 g of 2,2-dimethyl-1,3-propanediol and 2.7 g of p-toluenesulfonic acid heated under reflux with a water separator for 6 hours, jo After cooling, the reaction solution is washed with saturated sodium hydrogen carbonate solution and water and dried over sodium sulfate and evaporated to dryness in vacuo. The residue obtained in this way is chromatographed on silica gel and it is r>, recrystallized from diisopropyl ether, 28.6 g of natural 3,3 (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-19- nor-5,16- or 5 (10), 16-pregnadien-20-one of melting point 145- 155 ⁰ C.
UV: e ₂ 43 = 8530.

38.2 g natural 3,3 (2 ', 2'-dimethyl-r, 3'-propylenedioxy) -18-methyl-19-nor-5,16- or 5 (10), 16-pregnadienl! 0- one, dissolved in 229 ml tetrahydrofuran, was added to a cooled to -20 ⁰ C solution of 29.2 g potassium tert-butylate in 343 ml of dimethylformamide, 57 ml of absolute tert-butanol 4 j tem, 22.9 ml Trime'.hylphosphit while passing oxygen through it in the course of 30 minutes. Stirring is then continued for a further hour at -20 ° C. while passing oxygen through the reaction solution Dissolved methylene chloride and dried over sodium sulfate. The residue obtained after evaporation is chromatographed on silica gel and it is 5 ^% , recrystallized from diisopropyl ether / methylene chloride, 15.5 g of natural 17-hydroxy-3,3 (2 ', 2'-di-

methyl-l ', 3'-propylenedioxy) -18-methyl- 19-nor-5,15-
and 5 (10), 15-pregnadien-20-one with a melting point of 202-214 ° C. bo

14.0 g natural 17-hydroxy-3,3 (2 ', 2'-dimethylr, 3'-propylenedioxy) -18-methyl-19-nor-5,15- or 5 (10), 15-pregnadien-20-one are dissolved in 140 ml of absolute tetrahydrofuran, with 14.0 g of lithium tri-tert.-butyloxyalan ^ it offset and 1 hour at room temperature> ratiir left standing. The reaction solution is in Ice water is stirred in, mixed in with dilute sulfuric acid and extracted with methylene chloride. That The crude product obtained after drying and evaporation is chromatographed on silica gel and it becomes 13.0 g natural 17.20g-Dihvdroxy-3 ^ {2 '^' - dimethylr, 3'-propylenedioxy) -18-methyl-19-nor-5,15- and 5 (10), 15-pregnadiene, respectively.

10.4 g natural 17,20f-dihydroxy-3,3 (2 ', 2'-dimethyl-1 ', 3'-propylenedioxy) -l 8-methyl-19-nor-5,15- or 5 (10), 15-pregnadiene are mixed in with 185 ml of absolute ether and 185 ml of absolute ethylene glycol dimethyl ether 16.8 ml of methylene iodide and 20.8 g of zinc-copper were heated under reflux for 5 hours. It will then be with Diluted methylene chloride, washed with saturated ammonium chloride solution and water, over sodium sulfate dried and in a vacuum to dryness; evaporated. The residue is chromatographed on silica gel and there are 6.8 g of natural 17.20i - Dihy-

droxy-3,3 (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-15 «, 16a-methylene-19-nor-5- or 5 (10) -pregnen obtained.

9.0 g natural 17,20f-dihydroxy-3,3 (2 \ 2'-dimethyl-1 ', 3'-propylenedioxy) -18-methyl-15 «, 16a-methylene-19-nor-5- or 5 (10) -pregnen are prepared in 360 ml of methylene chloride with 27 g of pyridine-chromic acid complex ( by converting chromium (VI) oxide into pyridine and isolating the precipitated complex) added and stirred for 3 hours at room temperature. The reaction solution is filtered through a frit and the filtrate evaporated to dryness in vacuo. The residue is chromatographed on silica gel and it 3.9 g of natural 3,3- (2 ', 2'-dimethyl-1'3'-propylenedioxy) -18-methyl-15ft, 16tt-methylene-5- and 5 (10) -estren-17-one, respectively.

B. 3,3- (2 ', 2'-Dimethyl-1 \ 3'-propylenedioxy) -15Ä, 16 & -methylene-5 (6) - or 5 (10) -estren-17-one

5.0 g of 19-nor-4,16-pregnadiene-3,20-dione are refluxed in 250 ml of benzene with 4 _: 0 g of 2,2-dimethyl-13-propanediol and 300 mg of p-toluenesulfonic acid with a water separator heated. It is worked up as described in Example A. After chromatography on silica gel, 4.9 g of 3,3 (2'.2'-dimethyl-r, 3'-propylenedioxy) -19-nor-5.16- or 5 (10), 16-pregnadien-20-one are obtained .
UV: 6239 = 9200.

5.0 g of 3,3 (2 ', 2'-Dimethyl-r, 3'-propylenedioxy) -19-nor-5,16- or 5 (10), 16-pregnadien-20-one are mixed with potassium t-butoxide solution, oxygen and trimethyl phosphite reacted at -5 ° C as described in Example A and worked up. After chromatography on silica gel, recrystallized from diisopropyl ether / methylene chloride, 1.5 g of 17-hydroxy-3,3 (2 ', 2'-dimethyl-r, 3'-propylenedioxy) -19-nor-5,15- and 5 (10), 15-pregnadien-20-one with a melting point of 241-249 ° C.

44.5 g of 17-hydroxy-3,3 (2 ', 2'-dimethyl-l'3'-propylenedioxy) -19-nor-5,15- or 5 (10), 15-pregnadien-20-one are in 440 ml of absolute tetrahydrofuran with 45 g Lithium tri-tert-butoxyalanate reacted and worked up as described in Example A. After chromatography on silica gel 37.6 g 17.20 | -Dihy-

droxy-3,3 (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -19-nor-5,15- and 5 (10), 15-pregnadiene, respectively.

35.6 g 17.20 £ -dihydroxy-3,3 (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -19-nor-5.15- and 5 (10), l 5-pregnadiene in 475 ml of absolute ether and 475 ml of absolute Ethylene glycol dimethyl ether with 57.3 ml of methylene iodide and 71.2 g of zinc-copper 6.5 hours with stirring on Heated to reflux. It is worked up as described in Example A. According to Chromatography on silica gel

the 17.7 g l7.20 £ -dihydroxy-3.3 (2 ', 2'-dimethyl-r, 3'-propylenedioxy) -15ft, 16rti-niethylen-19-nor-5- or 5 (10) -pregnen obtained.

17 g 17.20 | -dihydroxy-3.3 (2 ', 2'-dimethyl-1'.3'-propylenedioxy) -15 <\, 16 <x-methylene-19-nor-5- or 5 (10) -pre- "> gnen are in 1.35 ml of methylene chloride with 51 g of pyridine-chromic acid complex Reacted for 1 hour at room temperature and worked up as described in Example A. After chromatography on silica gel, 7.4 g of 3,3 (2 ', 2'-dimethyl-l', 3'-propylenedioxy) -15 «, 16ix-methy- in len-5- or 5 (10) -östren-l 7-one obtained. A sample recrystallized from hexane melts at 173-177 ° C.

The free oxo compounds can be prepared from the ketals by known methods.

The following examples illustrate the invention without ι ^r> restricting it:

example 1

12.0g natural 3.3 (2 ', 2'-dimethyl-l', 3'-propylenedioxy) -! 8-methyl-15 ", 16" -methylene-5- or 5 (10) -öslren-17-one 12.0 g of lithium tri-tert-butoxyalanate are added in 200 ml of absolute tetrahydrofuran and stirred for 1 hour at room temperature. It is then stirred into ice water with dilute sulfuric acid acidified, extracted with methylene chloride and the methylene chloride phase washed neutral. To Drying and evaporation and chromatography on silica gel 11.5 g of natural 3,3 (2 ', 2'-dimethyl-

1 ', 3'-propylenedioxy) -18-methyl-15a, 16'-methylene-5-
or 5 (10) -östren-17 /? - ol obtained. jo

Example 2

11.5g natural 3,3 (2 ', 2'-dimethyl-r, 3'-propylenedioxy) -18-methyl-15a, 16a-methylen-5- or 5 (10) -estren-17,8-ol are refluxed in 414 ml of methanol with 8.3 g of oxalic acid in 83 ml of water for 2.5 hours. It is then stirred into ice water, the precipitate which has separated out is filtered off and dissolved in methylene chloride. The residue obtained after drying and evaporation is chromatographed on silica gel. 7.0 g of natural 17 /? - hydroxy-18-methyl-1 5λ, 1 6a-methylen-4-estren-3-one are obtained.
UV: 6240 = 16,200.

B is ρ ie 1 3 _4;

2.0 g of 3,3 (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -15a, 16 amethylene- 5- or 5 (10) -estren-17-one are dissolved in 30 ml of absolute tetrahydrofuran with 2.0 g of lithium tri-tert-butoxyalanate implemented as described in Example 1 and worked up. 1.95 g of 3,3 (2 ', 2'-dimethyl-5n r 3'-propylenedioxy) -15 ", 16" -methylene-5- or 5 (10) -estrene obtain.

Example 4

1.95 g of 3,3 (2 ', 2'-dimethyl-r, 3'-propylenedioxy) -15 «, 16ixmethylene-5- or 5 (10) -östren-17j3-ol are dissolved in 70 ml of methanol with 1, 4 g of oxalic acid in 14 ml of water are heated under reflux for 3 hours. After processing, as in the example! 1, 1.5 g of 17 ^ -hydroxy-15 ", 16" -methy- M) len-4-estren-3-one are obtained after chromatography on silica gel.
UV: 8239 = 17,500.

Example 5

900 mg of magnesium shavings are converted into ethyl magnesium bromide in 13 ml of absolute tetrat5 hydrofuran with 2.93 ml of ethyl bromide. While cooling with ice, this solution is added dropwise to 26 ml of absolute tetrahydrofuran through which acetylene is passed. A solution of 900 mg of natural 3,3 (2 ', 2'-dimethyl-1 \ 3'-propylenedioxy) -18-methyl-15 (X, 16 «-methylene-5- or 5 (10 ) -estren-17-one in 25 ml of absolute tetrahydrofuran and stirred for 3 hours at room temperature. The excess Grignard reagent is then mixed with saturated ammonium chloride solution and the aqueous phase is extracted with ether. After drying and evaporation, 910 mg of natural 3.3 ( 2 ', 2'-dime

ethyl-1 \ 3'-propylenedioxy) -18-methyl-17Ä-ethhiny! -
15a, 16a-methylen-5- and 5 (10) -östren-17j3-ol were obtained.

Example 6

900 mg raw natural 3,3 (2 ', 2'-dimethyl-r, 3'-propylenedioxy) -l 8-methyl-17a-ethinyl-15a, 1 6a-methylene-5- or 5 (10) -östren-17 /} - ol are dissolved in 10 ml of methanol heated under reflux for 45 minutes with 1.08 g of oxalic acid in 2.5 ml of water. It is then diluted with ether, washed neutral with water, dried and evaporated to dryness in vacuo. The residue will on silica gel chromatography. Recrystallized from diisopropyl ether, 500 mg of natural 17 /? - Hy-

droxy-18-methyl-17a-ethinyl-15 «, 16a-methylen-4-estren-3-one obtained from melting point 189.5-191 ° C. UV: 6240 = 17,200.

Example 7

2.0 g of Mg turnings are converted into ethynyl magnesium bromide as described in Example 5 and with 2.0 g 3,3 (2 ', 2'-Dimethyl-1', 3'-propylenedioxy) -15a, 16a-methylene-5- or 5 (10) -östren-17-one in 20 ml of absolute tetrahydrofuran and 2.5 hours at room temperature touched. After working up, 2.0 g

3,3 (2 ', 2'-Dimethyl-r, 3'-propylenedioxy) -17a-ethinyl-15a, 16a-methylene-5- or 5 (10) -östren-17 /? - ol obtained.

Example 8

2.0 g of crude 3,3 (2 ', 2'-DimethyI -!', 3'-propy! Endioxy) -17a-ethinyl-15 «, 16a-methylene-5- or 5 (10) -estrous- 2.0 g of oxalic acid in 2.2 ml of water are added to 170-ol in 20 ml of methanol and the mixture is refluxed for 2 hours. It is worked up as described in Example 6. After chromatography on silica gel, it is recrystallized from diisopropyl ether / methylene chloride. 1.2 g ^ / J-Hydroxy- ^ a-äthinyl-ISa.iea-methyien ^ - östren-3-one with a melting point of 145-146 ^C C obtained. UV: 6239 = 17,700.

Example 9

5.0 g natural
methylen-4-oestren-3-one are left to stand in 20 ml of pyridine and 10 ml of acetic anhydride for 18 hours at room temperature. It is then stirred into ice water, the precipitate which has separated out is filtered off and dissolved in methylene chloride. The methylene chloride phase is washed in succession with dilute hydrochloric acid, water, sodium hydrogen carbonate solution and water. After drying and evaporation, 5.5 g of natural 17 /? - acetoxy-18-methyl-15a, 16a-methylen-4-estren-3-one are obtained.
UV: 6240 = 17,100.

Example 10

1.0 g of 17 ^ -hydroxy-15a, l 6a-methylen-4-estren-3-one are reacted in 4 ml of pyridine with 2 ml of acetic anhydride as described in Example 9 and worked up. It

werden.umkristallisiert from Hexan.820 mg 17 / ^ - Aeetoxy-15 \ 16i \ methylene-4-estrene-3-one erhallen ⁰ C from 139.5 to 140.5 Schnielzpunki!.
UV: S ₂ J ₉ = 18,000.

Example 11

600 mg of natural 17 / j-hydroxy-18-methyl-17i \ - äthinyl-15iV, 16a-methylen-4-oestren-3-one are refluxed in 2 ml of acetic anhydride and 2 ml of pyridine for 10 hours in a stream of nitrogen. It is then stirred into ice water, the deposited precipitate is filtered off, washed with water and dried. To cleave the 3-enol acetate formed in the process, it is taken up in 30 ml of methanol and refluxed with 0.3 ml of concentrated hydrochloric acid for 15 minutes. After ice water precipitation, the precipitate is filtered off, washed with water and dried. After chromatography on silica gel, 510 mg of natural n / S-acetoxy-IS-methyl- ^ Ä-äthinyl-ISa.ie «- methylen-4-estren-3-one are obtained. A recrystallized sample from diisopropyl ether melts at 167.5 to 169.5 ⁰ C.
UV: 6240 = 17,600.

Example 12

500 mg 17 natural .beta.-hydroxy-18-methyl-15 17ääthinyl (X, 16ot-methyien-4-estrene-3-one in 2 ml of butyric anhydride and 2 mL of pyridine heated for 10 hours in a nitrogen stream at 160 ° C. It is then worked up and the 3-enol ester cleaved as described in Example 11. After chromatography on silica gel, 450 mg of natural 17 /? - butyryloxy-18-methyl- 17 acethinyl-1 5λ, 1 6a-methylene-4-oestrous obtained on 3. A sample recrystallized from pentane melts at 118-122 ⁰ C.
UV: e ₂ 40 = 16,900.

Example 13 Example 16

500 mg natural ^
ethynyl-15a, 16 <x-methylene-4-estrene-3-one in 2 ml Önanthsäureanhydrid and 2 ml of pyridine, 17 hours in a nitrogen stream at 17O ⁰ C heated. It is then worked up as described in Example 11 and the 3-enol ester is cleaved. The excess oenanthic acid is removed by steam distillation. The product obtained after ether extraction is chromatographed on silica gel, and there are 380 mg of natural 17 /? - Heptanoyloxy-18-methyl-17 "-äthinyl-15 <x, l 6" -methylene-4-oestren-3-one as Obtain oil.
UV: £ 240 = 17,000.

Example 14

400 mg of 17 ^ -hydroxy-17'-ethinyl-15o, 16iX-methylen-4-estren-3-one are reacted and worked up in 2 ml of acetic anhydride and 2 ml of pyridine as described in Example 11 Acetoxy-nÄ-äthinyl-lSÄ.iea-methylen-4-oestren-3-one obtained.
UV: 6240 = 17,100.

Example 15

150 mg mg of 17jS-butyryloxy-17'-ethinyl-15a, 16'-methylen-4-estren-3-one.
UV: 6239 = 17,400.

150 mg of 17 / f-hydroxy-17 "-äthinyl-15iX, 16" -melhylen-4-oestren-3-one are reacted in 1 ml of enanthic anhydride and 1 ml of pyridine as described in Example 11 and worked up. After chromatography on silica gel, 140 mg of 17j? -Heptanoyloxy-17a; -äthinyl-15Ä, 16 "-methylene-4-estren-3-one are obtained as an oil.
UV: 62M = 17,200.

'"Example 17

250 mg natural l7j? -Hydroxy-18-methyl-17aethinyl-15a, 16 (X-methyle: i-4-oestren-3-one are in 20 ml of absolute tetrahydrofuran with 800 mg of lithium

i) tri-ieri.-buloxy-alanai added and 1 hour at room temperature touched. It is then stirred into ice water, acidified with dilute sulfuric acid, with Extracted methylene chloride and washed the methylene chloride phase neutral. After drying and evaporation 240 mg of crude product are obtained. After recrystallization from diisopropyl ether, 140 mg natural SjS ^ jS-dihydroxy-lS-methyl- ^ a-ethinyl-15a, 16a-methylene-4-estren obtained from melting point 183 to 187 ° C.

^2j example 18

300 mg of 17JS-hydroxy-17 (X-ethinyl-15 ", 16" -methylene-4-estren-3-one are verjo in 25 ml of absolute tetrahydrofuran with 950 mg of lithium tri-tert-butoxyalanate sets and stirred for 1 hour at room temperature. It is worked up as described in Example 17. To Chromatography on silica gel is 250 mg 3jS, 17 /? - Dihydroxy-17'-ethinyl-15 & .16 & -methylene-4-esters were obtained.

^y> Example 19

300 mg of natural S / J ^ jS-dihydroxy-IS-methyl- ^ aäthinyl-15 «, 16a-methylen-4-estren are left to stand in 1 ml of pyridine with 0.5 ml of acetic anhydride for 18 hours at room temperature. It is stirred into ice water, the deposited precipitate is filtered off, washed with water and dried. It will be 320 mg natural 17 | 3-Hydroxy-3jS-acetoxy-18-methyl-17a-ethinyl-15 ", 16 <x -methylene-4-estren obtained from melting point 117 to 118.5 ° C.

Example 20

250 mg 3j3,17jS-dihydroxy-17 "-äthinyl-15", 16a-me-

ethylene-4-esters are dissolved in 1 ml of pyridine with 0.5 ml of acetic anhydride implemented and worked up as described in Example 19. There are 260 mg ^ jS-Hydroxy-SjS-acetoxy-17 <x-äthinyl-15 <x, l 6a-methylene-4-esters obtained.

Example 21

100 mg of natural 3j3,17 /? - dihydroxy-18-methy] -17aäthinyI-15a, 16a-methylene-4-esters are refluxed in 1 ml of pyridine and 1 ml of acetic anhydride for 10 hours in a stream of nitrogen. It is then stirred into ice water, the deposited precipitate is filtered off, washed with water and dried. After chromatography on silica gel, 60 mg of natural SftIT / J-diacetoxy-IS-methyl-III are obtained
methylene-4-esters obtained.

_b5 Example 22

125 mg Sft ^ jS-dihydroxy-lTa-ayc
ethylene-4-esters are dissolved in 1 ml of pyridine and 1 ml of acetic anhydride for 10 hours in a stream of nitrogen on the back

river heated. It is, as described in Example 21, worked up. After chromatography on silica gel, 70 mg of 3 / ?, 17 /? - diacetoxy-17a-ethinyl-15 ", 16" -methylene-4-esters are obtained obtain.

Example 23

200 mg of natural 17/3 acetoxy-18-methyl-17iX-äthinyl-15 «, 16 <x-methylen-4-estren-3-one are mixed with 670 mg of lithium trilert.butoxyalanate in 20 ml of absolute tetrahydrofuran and 1 Stirred for hour at room temperature. It is, as described in Example 17, worked up. After chromatography on silica gel, 160 mg of natural 3β- hydroxy-17j3-acetoxy-1,8-methyl-17'-ethinyl-15α, 16% -methylene-4-estrogen are obtained.

Example 24

150 mg ^ / S-acetoxy-Uoc-äthinyl-ISa.iea-methylen-4-estren-3-one 500 mg of lithium tri-tert-butoxyalanate are added in 15 ml of absolute tetrahydrofuran and stirred for 1 hour at room temperature. It is, as described in Example 17, worked up. After chromatography 105 mg of 3 /? - Hydroxy-17 /? - acetoxy-17 "-äthinyl-15", 16a-methylene-4-oestrene are applied to silica gel obtain.

Example 25

1.0 g natural 3,3 (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-15 ", 16" -methylene-5- or 5 (10) -östren-17-one are dissolved in 30 ml of absolute tetrahydrofuran and in a Grignard solution (made from 1 g of Mg turnings, 3.25 ml of ethyl bromide and 15 ml of absolute Tetrahydrofuran) and stirred for four hours at room temperature. Then the reaction mixture is added with saturated ammonium chloride solution, the aqueous phase is separated off and extracted with it Ether. The combined organic phases are washed with water, dried and concentrated. You get 950 mg raw natural 3,3 (2 ', 2'-dimethyl-1', 3'-

propylenedioxy) -l 8-methyl-17 "-ethyl-15", 16flt-methylene-5- or 5 (10) -estren-170-ol.

Example 26

300 mg raw natural 3,3 (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-17 "-ethyl-15 <x, 16 <x-methylene-5 or 5 ( 10) -östren-17 /? - ol are refluxed in 10 ml of methanol with 300 mg of oxalic acid in 1.5 ml of water for 45 minutes. It is, as described in Example 6, worked up. After chromatography on silica gel-3-one -methylene-4-estrene 130 mg natural 17j3-hydroxy-l8-methyl-1 7a ethyl-15a, 16 'obtained.
■ -, UV: t: _i4 o = 16,900.

Example 27

One of 185 mg lithium and 0.83 ml methyl iodide methyllithium produced in 15 ml of absolute ether

H) solution are 670 mg of trans-dichloroethylene in 3 ml given absolute ether and stirred for 1.5 hours at room temperature. About this solution of lithium chloroacetylide 500 mg of natural 3,3 (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-15 <x, 1 6a-methy-

i "> len-5- or 5 (10) -estren-17-one dissolved in 20 ml of absolute Toluene was added dropwise over the course of 15 minutes and then heated under reflux for 2.5 hours. The excess The reagent is then decomposed with ammonium chloride solution while cooling, it is diluted with ether and

2 »washed neutral with water. After evaporation 520 mg of raw natural 3,3 (2 ', 2'-dimethyl-

1 ', 3'-propylenedioxy) -18-methyl-17ot-chloroethinyl-15a, 16 <x-methylene-5- or 5 (10) -östren-17 /? - ol obtained.

,. B e i s ρ i e I 28

520 mg raw natural 3,3 (2 ', 2'-dimethyl-l', 3'-propylenedioxy) -18-methyl-17a-chloroethinyl-15ix, 16ix-methylen-5- or 5 (10) -estrous- 17 /? - ol are refluxed for 45 minutes in 20 ml of methanol with 500 mg of oxalic acid in 2.5 ml of water. It is, as described in Example 6, worked up. After chromatography on silica gel, 280 mg of natural 7β- hydroxy-18-

methyl-17A-chloroethinyl-1 5λ, 1 öa-methylen ^ -östren-3-one obtained.
UV: 6240 = 17,200.

Example 29

300mg natural 3,3 (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-17 "-äthinyl-15", 16 "-methyIen-5-

or 5 (10) -östren-17j3-ol are thiophene-free in 50 ml Benzene hydrogenated with 200 mg Lindlar catalyst until 2 equivalents of hydrogen are absorbed. The catalyst is filtered off and evaporated to dryness in vacuo. It will be 300 mg raw natural 3,3 (2 ', 2'-Dimethyl-r, 3'-propylenedioxy) -18-methyl-17 (x-ethyl-15 «, 16a-methylene-5- or 5 (10) -estren-17j3-ol.

Claims (1)

Patent claims: 1. 15 <x, 16 * -Methyien-4-oestren-17 / J-ole of the general formula 1 O-R ² R ¹ (D and Y denote a keto group, preferably protected as a ketal, reduced by methods known per se or reacted with an organometallic compound donating the organic radical R ³ and splitting off a primarily introduced keto protecting group and, depending on the ultimately desired meaning of X, R ² and R ^4, if appropriate, the 17-hydroxyl group is then esterified in a manner known per se and / or the 3-keto group is reduced and free hydroxyl groups present in the molecule are esterified.