SE426834B - SET TO MAKE 15ALFA, 16ALFA METHYLENE-4-OSTREN-17BETA OILS - Google Patents

Description

7713896-4 2 As acyl groups R2 and R4, there are physiologically acceptable acid residues which originate from acids which are usually used for the esterification of steroid alcohols. This includes e.g. Organic carboxylic acids having 1 to 18 carbon atoms, belonging to the aliphatic, alicyclic, aromatic or heterocyclic series, which may be saturated or unsaturated, mono- or polybasic and / or substituted, examples of which are alkyl, hydroxy, oxo or amino groups or halogen atoms. This also includes the usual inorganic acids.

As acids, there are lower, intermediate and higher carboxylic acids, preferably those having up to 15 carbon atoms, in question, of which, for example, ant, acetic, propionic, butyric, isobutyric, valerian, isovaleric are mentioned. -, kapron, önant-, capryl-, geranium-, kaprin-, undecyl-, laurin-, tridecyl-, myristin-, pentadecyl-, trimethyl-vinegar-, diethyl-vinegar-, tert-butyl-acetic- monochloroacetic, dichloroacetic and trichloroacetic, aminoacetic, diethylaminoacetic, piperidinoacetic, morpholinoacetic acid, lactic, succinic, adipic, benzoic, nicotinic and isonicotinic acids and furan-2-carboxylic acid.

In addition, the usual inorganic acids, e.g. sulfuric and phosphoric acid, in question.

In order to prepare water-soluble preparations, the usual esters are usually used. Examples which may be mentioned are esters of succinic acid, adipic acid, sulfuric acid and phosphoric acid, which are optionally converted into alkali metal salts.

When the compounds prepared by the method of the invention exhibit valuable steroid hormone properties, they can be used as pharmaceuticals.

Thus, steroids of formula I are distinguished by a strong progestogenic action. 18-methyl-17α-ethinyl-15u, 16u-methylene-19-nortestosterone (C) is found, for example, in fertility inhibition tests and in the usual Clauburg test superior to the known compound 18-methyl-17u-ethinyl-19-nortestosterone (D). The table below lists the results of subcutaneous administration of (C) and (D) to rabbits in the fertility inhibition test and in the Clauberg test. 7713896-4, 3 Table B f kt '- inhibition test Clauberg_test Compound' Dose (mg) Effect Dose (mg) Me Phail C 18-methyl-17d-ethinyl- -15d, 16a-methylene--19-nortestosterone 0.3 active 0.01 2.2 D 18-methyl-17d-ethinyl--19-nortestosterone 0.5 inactive 0.01 1.0 The table clearly shows the higher activity, ie the superior effect of the compounds according to the invention.

The higher esters of the compounds of the invention are further characterized by a contracted action.

The progestogenic compounds according to the invention can be used, for example, in contraceptive preparations, in which case they are used as a progestogen component in combination with an estrogen-active hormone component, e.g. ethinyl estradiol, or as the sole active component. The progestogenic compounds can, for example, also be introduced into preparations for the treatment of gynecological disorders.

The new compounds are prepared for use with the additives, carriers and taste-correcting agents customary in galenic pharmacy in a manner known per se for the usual pharmaceutical forms. For oral administration, tablets, dragees, capsules, pills, suspensions and solutions are particularly relevant, and for parenteral administration, oil solutions, for example sesame oil or castor oil solutions, are particularly relevant, which may additionally contain a diluent, e.g. benzyl benzoate or benzyl alcohol. The concentration of the active substance in the drugs thus formulated depends on the form of administration.

The compounds prepared according to the invention can also constitute intermediates for such pharmacologically valuable steroids, which are obtained by conversion methods known per se, e.g. re-storage, hydration, dehydration, etc.

The process according to the invention for the preparation of 15u, 16u-methylene-4-oestren-176-ols of the general formula I in which R1, R2, R1, X and R4 denote the same as above, is characterized in that in a manner known per se, a 15u, 16u-methylene-17-oxo-5 (6) - or 5 (10) -esters of the general formula II> II // Y react where R1 represents the same as above and Y represents a keto-group preferably protected as ketal, with an organometallic compound which gives off the residue R3, cleaves a primarily introduced protecting group and, depending on the finally desired meaning of X, R2, R3 and R, optionally thereafter on and for esterifies the 17-hydroxy group.OCh / or reduces the 3-keto group and esterifies free hydroxy groups present in the molecule.

The reaction with an organometallic compound can be carried out by known methods, the organic residue being R 3 and in which case it may be an alkylmagnesium halide, e.g. methylmagnesium bromide or iodide, an alkenylmagnesium and / or alkenylzinc halide, e.g. vinylmagnesium bromide or allylmagnesium bromide, an alkinylmagnesium halide, e.g. ethinylmagnesium bromide, propionylmagnesium bromide or propinylzinc bromide, or an alkali metal acetylide, e.g. potassium acetylide.

The organometallic compound used can also be formed in situ and reacted with the 17-ketone of formula II. Thus one sounds. for example, for reaction with organometallic alkinyl compounds an alkine, chloroalkine or alkadiene and an alkali metal act on the ketone in a suitable solvent, preferably in the presence of a tertiary alcohol or of ammonia possibly at elevated pressure.

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

The reduction of the 3-keto group can be carried out in ways known to those skilled in the art. It can be effected, for example, by hydrogenation in the presence of a conventional catalyst which, in the presence of hydrogen, results in the reduction of unsaturated sex ring ketones. However, the reduction can also be carried out with metal hydrides or hydrido complex compounds. Examples which may be mentioned are sodium borohydride, lithium aluminum hydride, sodium trimethoxyborohydride and lithium tert-butoxyaluminum hydride.

For the subsequent esterification, the procedures commonly used in steroid chemistry for the esterification of steroid alcohols come into play.

For acylation of a hydroxy group in the 3-position, mention should be made, for example, of reaction with an acid anhydride in the presence of a tertiary amine at room temperature. For esterification of a 178-hydroxy group, for example, reaction with acid anhydrides in the presence of strong acids, e.g. p-toluenesulfonic acid, or reaction with an acid anhydride in the presence of a tertiary amine in heat. The latter procedures can also be used to convert 3,17-dihydroxisteroids to diacylate.

The cleavage of the keto protecting group is carried out in a manner known to those skilled in the art. For decetalization, for example, mineral acids, e.g. perchloric acid, sulfuric acid or hydrochloric acid, or organic acids, e.g. oxalic acid, in question.

Preparation of the 15u, 16a-methylene-174mw-5 (6) - or 5 (10-estrenes of formula II used as starting compounds) is described in the form of ketals by means of Examples A and B below.

A) 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-15d, 16d-methylene--5 (6) - or 5 (10) -estrene-17- on. 46.2 g of natural 18-methyl-18-nor-4,16-pregnadiene-3,20-dione are heated in 2.5 l of the mixture with 37.1 g of 2,2-dimethyl-1,3-propanediol and 2, 7 g p- -Lutulene sulfonic acid 6 hours with water separator and reflux. The reaction solution is washed after cooling with a saturated sodium bicarbonate solution and with water, dried over sodium sulphate and evaporated in vacuo to dryness. The residue thus obtained is chromatographed on silica gel to give, after recrystallization from diisopropyl ether, 28.6 g of natural -3,3- (2 ', 2'-dimethyl-123'-propylenedioxy) -18-methyl-19- nor-5,16- resp. 5 (10) -16-pregnadien-20-one. Mp: 145-1ss ° c. uv:: 243 = 8530. 38.2 g of natural 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-19--nor-5,16- resp. (10), 16-Pregnadien-20-one dissolved in 229 ml of tetrahydrofuran is added dropwise to a solution cooled to -20 ° C of 29.2 g of potassium tert-butylate in 343 ml of dimethylformamide, 57 ml abs. tert-butanol and 22.9 ml of trimethyl phosphite with conduction of acid within 30 minutes. The mixture is then stirred for a further 1 hour at -ZOOC while passing acid. The reaction solution is then introduced into ice water slightly acidified with acetic acid. The separated precipitate is filtered off, washed well with water, dissolved in methylene chloride and dried over sodium sulphate. The residue obtained after evaporation is chromatographed on silica gel to give, after recrystallization from diisopropyl ether-methylene chloride, 15.5 g of natural 17-hydroxy-3,3- (2 ', 2'-dimethyl-1', 3'- propylenedioxy) -18-methyl-19-nor-5,15- resp. (1U, 15- -pregnadien-20-one. Mp: 202-214 ° C. 14.0 g of natural 17-hydroxy-3,3- (2 ', 2'-dimethyl-1', 3 ' -propylenedioxy) -18-methyl-19-nor-5,15- and 5 (10), 15-pregnadien-20-one are dissolved in 140 ml of absolute tetrahydrofuran and 14.0 g of lithium tri-tert are added thereto. butoxyalanate and the mixture is allowed to stand for 1 hour at room temperature.

The reaction solution is introduced into ice water, acidified with dilute sulfuric acid and extracted with methylene chloride. The crude product obtained after drying and evaporation is chromatographed on silica gel to give 13.0 g of natural 17,20-C-dihydroxy-3,3- (2 ', 2'-dimethyl--1', 3'-propylenedioxy). -18-methyl-19-nor-5,15- resp. 5 (10), 15 ~ pregnadi- en is heated in 185 ml abs. ether and 185 ml abs. ethylene glycol dimethyl ether with 16.8 ml of methylene iodide and 20.8 g of zinc copper for 5 hours at reflux. The mixture is then diluted with methylene chloride, washed with saturated ammonium chloride solution and with water, dried over sodium sulfate and evaporated in vacuo to dryness. The residue is chromatographed on silica gel to give 6.8 g of natural 17,20c-dihydroxy-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-15a , 16a-methylene-19-nor-S- resp. 5 (10) -pregnen.

To 9.0 g of natural 17,20; -dihydroxy-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-15u, 16a-methylene- 19 ~ nor ~ 5- resp. The 5 (10) impregnated in 360 ml of methylene chloride is added 27 g of pyridine-chromic acid complex (prepared by reacting chromium (VI) oxide in pyridine and isolating the separated complex) and the mixture is stirred for 3 hours at room temperature. The reaction solution is filtered through a porcelain filter and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel to give 3.9 g of natural 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-15a, 16a-methylene-5- resp. 5 (10) -estren-17-one.

B) 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -15a, 16a-methylene-5 (6) - or 5 (10) -estren-17-one. 5.0 g of 19-nor-4,16-pregnadiene-3,20-dione is heated in 250 ml of benzene with 4.0 g of 2,2-dimethyl-1,3-propanediol and 300 mg of p-toluenesulfonic acid for 2 hours. with water separator and backflow. The mixture is worked up as described in Example 1. After chromatography on silica gel, 4.9 g of 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -19-nor--5 are obtained. , 16- resp. 5 (10), 16-pregnadien-20-one. UV: e239 = 9200. 5.0 g 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -19-nor-5,16- resp. (10) A6-pregnadien-20-one is reacted with potassium tert-butylate solution, oxygen and trimethyl phosphite at -50 ° C as described in Example A and worked up in the same manner. After chromatography on silica gel and recrystallization from diisopropyl ether-methylene chloride, 1.5 g of 17-hydroxy-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -19-nor-5, 15- resp. 5 (10), 15-pregnadien-20-one. Mp: 241-249 ° C. 44.5 g of 17-hydroxy-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -19-nor- ~ 5,15 ~ resp. 5 (10), 15-pregnadien-20-one is reacted in 440 ml of abs. tetrahydrofuran with 45 g of lithium tri-tert-butoxyalanate as described in Example A and worked up in the same manner. After chromatography on silica gel, 37.6 g of 17,205-dihydroxy-3,3- (2 ', 2'-dimethyl--1', 3'-propylenedioxy) -19-nor-5,15- resp. 5 (10), 15-pregnadien. 35.6 g of 17,20β-dihydroxy-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -19--nor-5,15- resp. 5 (10), 15-pregnadiene is heated in 475 ml abs. ether and 475 m] abs. ethylene glycol dimethyl ether with 57.3 ml of methylene iodide based on 71.2 g of zinc cup no. iimmv avoid stirring with return flow.

The mixture is prepared as described in Example A. After chromatography on silica gel, 17.7 g of 17,20C-dihydroxy-3,3- - (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -15a, 16a are obtained. -methyl-19-nor-5- resp. 5 (10) -pregnen. 7713896-4 8 17 g 17,205-dihydroxy-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -15a, 16u-methylene-19-nor-5- resp. The 5 (10) impregnates are reacted in 1.35 ml of methylene chloride with 51 g of pyridine-chromic acid complex 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 are obtained. - (2 ', - 2'-dimethyl-1', 3'-propylene dioxy) -15u, 16a-methylene-5- resp. 5 (10) -estren-17-one. 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 limiting it.

Example 1 - 900 mg of magnesium turnings are reacted in 13 ml. abs. tetrahydrofuran with 2.93 ml of ethyl bromide to ethyl magnesium bromide. This solution is added dropwise upon ice-cooling to 26 ml of abs. tetrahydrofuran, through which acetylene is passed. To this ethinylmagnesium bromide solution is added a solution of 900 mg of natural 3,3- (2 ', - 2'-dimethyl-1', 3'-propylenedioxy) - -18-methyl-15a, 16a-methylene-5- resp. 5 (10) -estren-17-one in 25 ml abs. tetrahydrofuran and the mixture is stirred for 3 hours at room temperature.

To the excess grignard reaction component is then added ammonium chloride solution and the aqueous phase is extracted with ether. After drying and evaporation, 910 mg of natural 3,3- (2 '' - 2'-dimethyl-1 ', 3'-propylenedioxy) -18-methyl-17a-ethinyl-15a, 16a-methylene-5 and . s (1o) -östren-173-01.

NMR: ppm 0.86, 0.91, 0.98, 1.05, 1.06, 2.62, 3.30-3.70, 5.46 (cDc13111 - IR: cm -1 3390, 3280, 2090 , 1105, 1065 (KBr) Example 2 - 900 mg crude natural 3,3- (2 ', - 2'-dimethyl-1', 3'-propylenedioxy) '18-methyl-17u-ethinyl-15a, 16a -methylene-5- and 5 (10) -oestren-176-ol are heated in 10 ml of methanol with 1.08 g of oxalic acid in 2.5 ml of water for 45 minutes at reflux, the mixture is then diluted with ether, washed neutral with water, dried and evaporated in vacuo to dryness The residue is chromatographed on silica gel to give, after recrystallization from diisopropyl ether, 500 mg of natural 178-hydroxy-18-methyl-17α-ethinyl-15H, 16α-methylene-4-estrenic acid. 3-one, mp: 189.5-191 ° C.

UV: 6240 = 17 200. ' Example 3 2.0 g of magnesium turnings are reacted as described in Example 1 to ethinylmagnesium bromide and to this is added 2.0 g of 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) - 15d, 16u-methylene-5- resp. 5 (10) -estren-17-one in 20 ml abs. tetrahydrofuran and the mixture is stirred 2; hour at room temperature. After work-up, 2.0 g of 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -17α-ethinyl-15α, 16α-methylene-5- and 5 (10) -estren-176-ol.

NMR: ppm 0.86, 0.91, 0.98, 1.05, 1.14, 2.62, 3.30-3.70, 5.46 (IK13) IR: cm -1 3360, 3280, 2100, 1105, 1060 (KBr) Example 4 Til2.5 g1a3,3- (2 ', 2'-dimethyl-1', 3'-propylendixol) -17a-ethinyl-15a, 16a-methylene-5- resp. 5 (10) -Estrene-176-ol in 20 ml of methanol is added 2.0 g of oxalic acid in 2.2 ml of water and the mixture is heated at reflux for 2 hours. The mixture is worked up as described in Example 2. After chromatography on silica gel and recrystallization from diisopropyl ether-methylene chloride, 1.2 g of 17β-hydroxy-17α-ethinyl-15α, 16H-methylene-4-estren-3-one are obtained. Mp: 145-146 ° C.

UV: 6239 = 17,700.

Example 5 600 mg of natural 173-hydroxy-18-methyl-17d-ethinyl-15a, 16a-methylene-4-estren-3-one are heated in 2 ml of acetane anhydride and 2 ml of pyridine for 10 hours in a stream of nitrogen with reflux. The mixture is then poured into ice water. The separated precipitate is filtered off, washed with water and dried. To cleave the 3-enol acetate thus formed, the product is taken up in 30 ml of methanol and heated with 0.3 ml of conc. hydrochloric acid 15 minutes with reflux. The precipitate, after precipitation in ice water, is filtered off, washed with water and dried. After chromatography on silica gel, 510 mg of natural 17β-acetoxy-18-methyl-17α-ethinyl-15α, 16α-methylene-4-estren-3-one are obtained. Mp: 167.5-169.5 ° C (recrystallized from diisopropyl ether). UV: 2240 = 17,600.

Example 6 500 mg of natural 17S-hydroxy-18-methyl-17d-ethinyl-15a, 16d-methylene-4-estren-3-one are heated in 2 ml of butyric anhydride and 2 ml of pyridine for 10 hours in a stream of nitrogen at 160 ° C. The mixture is then worked up as described in Example 5 and the 3-enol ester is cleaved in the same manner.

After chromatography on silica gel, 450 mg of natural 176-butyryloxy-18-methyl-1H-ethinyl-15α, 16H-methylene-4-estren-3-one are obtained. vv; C240 = 16 eoo. M.p .: 118-122 ° C (recrystallized from pentane).

Example 7 500 mg of natural 17β-hydroxy-18-methyl-17α-ethinyl-15α, 16α-methylene-4-estren-3-one are heated in 2 ml of enanoic anhydride and 2 ml of pyridine for 17 hours in a stream of nitrogen at 170 ° C. The mixture is then worked up as described in Example 5 and the 3-enol ester is cleaved in the same manner. the excess island acid is removed by water vapor distillation. The product obtained after extraction with ether is chromatographed on silica gel to give 380 mg of natural 17β-heptanyloxy-18-methyl-17α-ethinyl-15α, 1Ga-methylene-4-estren-3-one as an oil. UV: s240 = 17000 Example 8 400 mg of 173-hydroxy-17α-ethinyl-15α, 16α-methylene-4-estren-3-one are reacted in 2 ml of acetane anhydride and 2 ml of pyridine as described in Example 5 and worked up in the same manner. After chromatography on silica gel, 390 mg of 176-acetoxy-17α-ethinyl-15α, 16α-methylene-4-estren--3-one are obtained. vv; 2240 = 17,100. Example 9 150 mg of 176-hydroxy-17H-ethinyl-15u, 1Gu-methylene-4-estren-3-one are reacted in 1 ml of butyric anhydride and 1 ml of pyridine as described in Example 5 and processed in the same way. After chromatography on silica gel, 130 mg of 17β-butyryloxy-17α-ethinyl-15α, 16α-methyls-4-estren-3-one are obtained. UV: s239 = 17,400.

Example 10 h 7 150 mg of 176-hydroxy-17α-ethinyl-15α, 16α-methylene-4-estren-3-one are reacted in 1 ml of enanoic anhydride and 1 ml of pyridine as described in Example 5 and worked up in the same manner. After chromatography on silica gel, 140 mg of 175-heptanoyloxy-17α-ethinyl-15u, 16u-methyl-4-estren-3-one are obtained as oil, UV: s239 = 17,200. Example 11 To 250 mg of natural 17β -hydroxy-18-methyl-17α-ethinyl-15d, 16α-methylene-4-estren-3-one in 20 ml abs. tetrahydrofuran is added 800 mg of lithium tri-tert-butoxyalanate and the mixture is stirred for 1 hour at room temperature. The slurry is then stirred into the ice bath, acidified with dilute sulfuric acid, extracted with methylene chloride and the methylene chloride phase is washed neutral. 240 mg of crude product are obtained after drying and evaporation. Men receive, after recrystallization from diisopropyl ether, 140 mg of natural 38,178-dihydroxy-18-methyl-17u-ethinyl-15u, 16a-methylene-4-esters. M.p .: 183-187OC. Example 12 To 300 mg of 178-hydroxy-17H-ethinyl-15α, 16α-methylene-4-estren-3-one in 25 ml of abs. tetrahydrofuran is added 950 mg of lithium tri-tert-butoxy-alanate and the mixture is stirred for 1 hour at room temperature. The mixture is worked up as described in Example 11. After chromatography on silica gel, 250 mg of 3β, 17β-dihydroxy-17α-ethinyl-15α, 16α-methylene-4-esters are obtained. UV: 5209 = 3800.

Example 13 - 300 mg of natural 3β, 176-dihydroxy-18-methyl-17α-ethinyl-15β, 16α-methylene-4-esters are allowed to stand in 1 ml of pyridine with 0.5 ml of acetane anhydride for 18 hours at room temperature. The mixture is stirred into ice water. The separated precipitate is filtered off, washed with water and dried. 320 mg of natural 176-hydroxy-35-acetoxy-18-methyl-17u-ethinyl-15a, 16u-methylene-4-esters are obtained. Mp: 117-118.5 ° C.

Example 1 - 250 mg of 3β, 11β-dihydroxy-17α-ethinyl-15α, 16β-methylene-4-esters are reacted in 1 ml of pyridine with 0.5 ml of acetane anhydride as described in Example 13 and worked up in the same manner. 260 mg of 17β-hydroxy-3β-acetoxy-17α-ethinyl-15α, 16α-methylene-4-esters are obtained. UV: EZO9 = 3300. ¶Éë¶ÉÉ-lÉ. 100 mg of natural 38,178-dihydroxy-18-methyl-17u-ethinyl-15a, 16a-methylene-4-esters are heated in 1 ml of pyridine and 1 ml of acetic anhydride for 10 hours in a stream of refluxed nitrogen. The mixture is then stirred into ice water. The separated precipitate is filtered off, washed with water and dried. After chromatography on silica gel, 60 mg of natural 38,17β-diacetoxy-1Emethyl-17H-ethinyl-15α, 16α-methylene-4-esters are obtained.

UV: 6209 = 3600.

Example 16 125 mg of 38,17ß-dihydroxy-17u-ethinyl-15a, 16u-methylene-4-esters are heated in 1 ml of pyridine and 1 ml of acetic anhydride for 10 hours in a stream of nitrogen at reflux. The mixture is worked up as described in Example 15. After chromatography on silica gel, 70 mg of 3β, 17β-diacetoxy-17α-ethinyl-15β, 16α-methylene-4-esters are obtained. UV: ezog ~ 3350. åë fl case To 200 mg natural 178-acetoxy-18-methyl-17u-ethinyl-15u, 16a-methylene-7713896-4 12 -4-estren-3-one in 20 ml abs. tetrahydrofuran is added 670 mg of lithium tri-tert-butoxyalanate and the mixture is stirred for 1 hour at room temperature. The mixture is worked up as described in Example 11. After chromatography on silica gel, 160 mg of natural 36--hydroxy-17β-acetoxy-18-methyl-17H-ethinyl-15d, 16α-methylene-4-esters are obtained.

UV: s = 3550. 209 Exemgel 18-* To 150 mg 176-acetoxy-17u-ethinyl-15u, 16u-methylene-4-estren-3-one in 15 ml abs. tetrahydrofuran is added 500 mg of lithium tri-tert-butoxy-alanate and the mixture is stirred for 1 hour at room temperature. The mixture is worked up as described in Example 11. After chromatography on silica gel, 105 mg of 38-hydroxy-178-acetoxy-17α-ethinyl-15H, 16α-methylene-4-esters are obtained. UV: 6209 = 3600.

Example gel 19 To a methyl lithium solution, prepared from 185 mg of lithium and 0.83 ml of methyl iodide in 15 ml of abs. ether, 670 mg of trans-dichloroethylene is added to 3 ml of abs. ether and the mixture is stirred for 1 hour at room temperature.

To this solution of lithium chloroacetylide is added dropwise 500 mg of natural 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-15a, 16a-methylene-5- and 5 (10) -estren-17-one dissolved in 20 ml abs. toluene within 15 minutes and then the mixture is heated for 2% hour with reflux. the excess reactant is then decomposed while cooling with an ammonium chloride solution. The mixture is diluted with ether and washed neutral with water. After evaporation, 520 mg of crude natural 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -18-methyl-17u-chloroethinyl are obtained. - -15a, 16a-methylene-5- resp. 5 (10) -estren-176-ol.

Example 20 520 mg of crude natural 3,3- (2 ', 2'-dimethyl-1', - 3'-propylenedioxy) -18-methyl--17α-chloroethinyl-15u, 16u-methylenew5- resp. 5 (10) -Easter-17β-ol. Is heated in 20 ml of methanol with 500 mg of oxalic acid in 2.5 ml of water for 45 minutes at reflux. The mixture is worked up as described in Example 6.

After chromatography on silica gel, 280 mg of natural 176-hydroxy-18-methyl-17α-chloroethinyl-15α, 1H-ethylene-4-estren-3-one are obtained.

UV: C240 = 17 200.

Example 21 21 mg of natural 36,178-dihydroxy-18-methyl-17α-ethinyl-1Sa, 16α-methylene-4-esters are allowed to stand at room temperature for 15 hours with 1 ml of enanthic anhydride and 0.5 ml of pyridine. After work-up 7713896-4 '13 as described in Example 13, 100 mg of natural 17β-hydroxy-3β-heptanoyloxy-18-methyl-17α-ethinyl-15α, 16α-methylene-4-esters are obtained as an oil.

UV: E210 = 3100.

Example 22 250 mg of natural 36-hydroxy-176-acetoxy-18-methyl-17α-ethinyl-15u, 16d-methylene-4-esters are allowed to stand at room temperature for 18 hours with 2.5 ml of collidine and 1.5 ml of caprylic anhydride. After work-up as described in Example 13, 180 mg of 17β-acetoxy-3β-octanoyloxy-18-methyl-17β-ethinyl-15α, 16α-methylene-4-esters are obtained as oil.

UV: 6209 = 3200 ..

Comparative examples The compounds according to the invention were tested for progestogenic activity in comparison with the corresponding 156,166-methylene compounds, which are previously known from Danish patent specification 119 429.

The survey results have been compiled in the table below. According to the Clauberg test described above, after subcutaneous application of the active substances, the secretory conversion of Endometrium to castrated rabbits was determined. The determination was made using the Mc Phail scale (grades 1-4, with 1 = no effect and 4 = complete conversion). 7713896-4 14 Clauberg-Teet s.k.

Compound 'Dose (mg) of nail 175-hydroxy-18-methyl-0,5,2,2 -17u-ethinyl-15α, 16α-methylene-0,1,1,1,1-4-estren-3-one 0.0 § 2.0 0.01 1.5 «7ß-acetoxy-13-methyl-0.1 5.2-17α-ethinyl-15a, 16a-methylene '0.05 5.0 -4-estren-3-one 0.01 1.0 17B-hydroxy-18-methyl- '0.5 2.9 -17u-ethinyl-155.16 fi-methylene-0.1 1,8 -4-estren-s-one 0.03 1 (Danish patent 119,429) 17E4nydroxy-17α-ethinyl-0.1 2,5 -151.16: -methylene-4-esters 0.03 1,2 -5-one 0.01 1.1 17§- hydroxy-1α-ethinyl-1,0 1,9 -153,163-methylene-4-estren-E-one 0,1 1,0 (Danish patent 115 585) The table shows that the 1Ba, 16u-methylene compounds according to the invention is about 10 times more effective than the known 15β, 16β-methylene compounds.

Claims (1)

A process for the preparation of 150,16a-methylene-4-estren-17β-ols of the general formula IX in which R1 represents a methyl or ethyl group, R2 represents a hydrogen atom or an acyl group having 1- 18 carbon atoms or an inorganic acid residue, R 3 represents an ethinyl or chloroethinyl group and X represents an oxygen atom or the grouping / H / ï o R 4 where R 4 represents a hydrogen atom or an acyl group having 1-18 carbon atoms or an inorganic acid residue, characterized in that converts a 15a, 16u-methylene-17-oxo-5 (6) - or 5 (10) -esters of the general formula II II in which R1 represents the same as above and Y represents a keto group preferably protected as ketal , with an organometallic compound releasing the residue R3, cleaves a primarily introduced protecting group and, depending on the final desired meaning of X, R2, R3 and R4, optionally then esterifies the 17-hydroxy group and / or reduces the 3-keto group and esterifies in the molecule corresponding f ria hydroxy groups. REQUIRED PUBLICATIONS; DK 119 429 (co7c -169/10)