DE1114487B - Process for the preparation of 6a, 6a-dichloro-6,7-methylene and 6a, 6a-dibromo-6,7-methylene compounds of í¸-3-keto steroids of the androstane and pregnane series - Google Patents

Description

Process for the production of 6a, 6a-dichloro-6,7-methylene and 6a, 6a-dibromo-6,7-methylene compounds of 44-3-keto steroids of the androstane and pregnane series. The invention relates to a process for the production of A4-3 -Ketosteroids of the androstane and pregnane series, which are substituted by a dichloro or dibromomethylene group. The structure of the new compounds obtained according to the invention has not yet been elucidated. The carbon atom of the dihalomethylene group can either be connected to the carbon atom in position 6 via a double bond (see formula) or to form a 3-membered ring with carbon atoms 6 and 7 (see formula 1I). In these formulas, X means chlorine or bromine. For the sake of clarity, the new compounds are to be named in the following according to the formula II, but with the restriction that the result of the structure elucidation changes the nomenclature of the compounds. According to the nomenclature chosen for these compounds in the description, 6 a denotes a carbon atom which is bonded to carbon atoms 6 and 7 of the steroid structure. The compounds are therefore referred to as 6 a, 6 a-dichloro and 6 a, 6 a-dibromo-6,7-methylene steroids.

The compounds prepared by the process of the invention are the 6 a, 6 a-dichloro- and 6 a, 6 a-dibromo-6,7-methylenetestosterone and -progesterone as well as derivatives of these compounds, which can carry various substituents, z. B. a hydroxyl group in position 17 or 21, which optionally esterifies both are, a keto or hydroxyl group in position 11 and a fluorine or chlorine atom in position 9. If there is a hydroxyl group in position 11 or 17, then they be a- or ß-oriented.

The compounds prepared by the process of the invention have not yet been described in the literature and show surprising physiological properties Effect as such or in the form of its derivatives.

According to the invention, an enol ether or a ketal of a .j 4-3-keto steroid is used the androstane or pregnane series reacted with a tetrahalomethane, in which the halogen is either bromine or chlorine and bromine.

If the 3-keto group is masked as an enol ether or a ketal group, so the double bond between carbon atoms 4 and 5 is in the 5 (6) position relocated. The tetrahalomethane grips the double bond between the carbon atoms 5 and 6 mainly with the formation of a 6-trihalomethyl derivative. These Connections are more or less unstable and slowly transform into the desired ones 6 a, 6 a-dihalogen derivatives. The conversion occurs faster in the presence of a Acid acceptor. In some cases it is possible to use the 6-trihalomethyl derivative to isolate from the reaction mixture.

In general, the implementation of the steroids in question proceeds with the tetrahalomethane slowly at room temperature, at least if you have the Reaction mixture to diffuse daylight suspends. The reaction will accelerated considerably with light of wavelengths between 2000 and 8000 angstroms. An ordinary lightbulb or a quartz-mercury lamp can be used for irradiation suitable size can be used.

In addition, it was found that the reaction is caused by acid acceptors, like collidine or pyridine, by organic peroxides or with the help of magnesium metal can be catalyzed in the reaction mixture.

The reaction is preferably carried out by dissolving the enol ether or Ketal of the steroid compound in the tetrahalomethane or in a mixture of the tetrahalomethane with an inert solvent of suitable boiling point, such as dioxane.

Another implementation is that the acid acceptor, d. H. the base, as a solvent or as a mixture with an inert solvent used.

In either case, the reaction is conveniently carried out by heating the mixture under reflux to boiling at temperatures between 50 and 150 ° C, optionally with irradiation of the reaction mixture or by using a the catalysts mentioned carried out.

After the reaction has ended, the mass becomes dry in vacuo evaporated. In many cases, the desired substance can be obtained by recrystallization of the residue obtained pure. In other cases it is useful to use the residue to dissolve in inert solvents, the impurities such. B. by adsorption, Chromatography, etc., and remove the desired compound from the eluate isolate.

Some of the 3-ethyl ethers of the enol compounds of the _14-3-ketosteroids have not yet been described in the literature. You can the same way how derAndrosten-4-dione-3,17-äthylenoläther-3 are produced, its representation in reports of the German Chemical Society, 71, p.1769 (1938), described is.

The process of the invention is illustrated by the following examples explained in more detail.

Example 1 Preparation of 6-tribromomethyltestosterone Al. 31.6 g of testosterone 3-ethylenol ether in 250 ml of freshly distilled 2,4,6-collidine were mixed with 66.4 g of tetrabromomethane. After standing at room temperature for 48 hours, the precipitate consisting of the addition compound of collidine hydrobromide and tetrabromomethane was filtered off.

The filtrate was poured into ice-cold dilute hydrochloric acid with stirring poured and the precipitating crystalline 6-tribromomethyltestosterone filtered off, washed with ether and with methanol and dried at room temperature. yield 45 g; Mp. 215-216 ° C (decomposition). The UV spectrum showed an absorption maximum at 238 m «(a = 12900). In the IR spectrum in chloroform there was a maximum at 1600 and 1672 c10-1.

Calculated C44.5519 / &, 1-15.05.1 / o, Br 44.47% .; found C 44.60%, H 5.19%, Br 44.32%. A.2. 3.16g testosterone-3-ethylenol ether, dissolved in propylene oxide, 3.32 g of tetrabromomethane were added and the solution was exposed to direct sunlight exposed. After a short time, crystals separated out from the solution. After 5 hours Allowing to stand at room temperature, the crystals were collected and washed with ether. Yield 1.9 g; Mp 213-216 ° C. The product was the same as that obtained above Identical product.

Bi. Preparation of 6 a, 6 a-dibromo-6,7-methylenetestosterone 5.39 g of the 6-tribromomethyltestosterone obtained according to Example 1, A in 100 ml of pyridine were heated on the steam bath for 30 minutes. After cooling, water was added and the crystalline precipitate was collected and recrystallized from ethanol. Yield 4.05g; Mp. 230 to 231 ° C. An analytical preparation, which was obtained after further recrystallization from ethanol, had a melting point of 232 to 233 ° C .; [a] ö ° = -f-210 °. @ "ax 250 10u, (f = 10 400); IR spectrum in KBr: 1578, 1607 and 1660 cm- '.

Calculated C 52.42%, H 5.72%, Br 34.88 "/ o; found C52.170 / 9, H 5.72%, Br 34.88%. Bz. Preparation of 6 a, 6 a-dibromo-6,7-methylenetestosterone acetate to a Solution of .5.7 g of the 6-tribromomethyltestosterone obtained according to Example 1, A 20 ml of acetic anhydride were added to 65 ml of dry pyridine. After standing overnight at room temperature the mixture was poured onto 500 ml of water. the Precipitated crystals were filtered off and recrystallized from ethanol. yield 5.1 g, m.p. 168-169 ° C; [a] δ = -f-180 °; IR spectrum: 1570, 1605, 1672 and 1723 c10-1.

Calculated C 52.81-1 / o, H 5.64%, Br 31.95%; found C 52.99 "/ o, H 5.78%," Br 31.98%. Example 2 Production of 6 a, 6 a-Dibromo-6,7-methylenetestosterone 9.5 g of testosterone-3-ethylenol ether, dissolved in 165 ml of chloroform, were treated with 9.6 g of tetrabromomethane. The solution was refluxed for 20 hours and during this time irradiated with a 500 W incandescent bulb (3800 ° Kelvin). The solution was then evaporated to dryness in vacuo and the residue was digested with 30 ml of ethanol; the crystals which formed were filtered off and recrystallized from ethanol. Yield 5.4 g, m.p. 229-230 ° C. A, nax 250 10N, (a = 10 400); [a] δ = + 210 ° (in chloroform).

Calculated C 52.411%, H 5.71%, Br 34.880 / "; found C 52.37" / o "H5.760 / 9, Br 34.880 / a. By refluxing the reaction mixture for 2 hours, 9.5 g of starting material were obtained received only 4.9 g of product.

Example 3 Preparation of 6 a, 6 a-Dibromo-6,7-methylenetestosterone 3.3 g of 3-ethylenedioxytestosterone were dissolved in 50 ml of chloroform and 3.3 g of tetrabromomethane solved. the The solution was refluxed for 20 hours and irradiated with a 250 W light bulb during this time. The reaction mixture was worked up in the same way as described in Example 2. yield 920 mg, m.p. 229-230 ° C. Example 4 A. Preparation of 6a, 6α-dibromo-6,7-methylenetestosterone 3.2 g of testosterone-3-ethylenol ether in 50 ml of dioxane were mixed with 3.3 g of tetrabromomethane added and 2 hours under irradiation with a 500 W lamp (3800 ° Kelvin) on Reflux heated to boiling. The solution was then evaporated to dryness in vacuo and the residue digested with 10 ml of methanol. The crystals were filtered off and recrystallized from ethanol. Yield 1.6 g, m.p. 228-230 ° C.

The procedure was repeated with the same amounts of substance, however carbon tetrachloride was used instead of dioxane. There were 920 mg of the desired Obtained dibromo compound.

B. Preparation of the 17-acetate of 6 a, 6 a-dibromo-6,7-methylenestosterone 3 g of 6 a, 6 a-dibromo-6,7-methylene testosterone, dissolved in 20 ml of anhydrous pyridine, were mixed with 10 ml of acetic anhydride and left to stand at room temperature for 24 hours. The solution was then evaporated to dryness in vacuo and the residue was recrystallized from ether-petroleum ether. Yield 2.9 g, mp 159-161 'C. [a] δ = + 194 ° (in chloroform). The same acetate was also prepared from the 3-ethylenol ether of testosterone acetate in the manner described in Example 2. Example 5 A. Preparation of 6-trichloromethyltestosterone 20 g of testosterone-3-ethylenol ether in 60 ml of dioxane and 5 ml of pyridine were mixed with 10 ml of trichlorobromomethane and left to stand at room temperature for 20 hours. After being filtered off, the filtrate was poured onto a large amount of water. The substance separated out as an oil which, after decanting with ether, crystallized. Yield 12.5 g; Mp. 212-215 ° C (decomposition). @max 242 mg (f = 12500).

Calculated C 59.19%, H 6.7011 / o, Cl 26.21%; found C 59.8711 / o, H 6.8411 / o, Cl 26.90%. B. Preparation of 6 a, 6 a-dichloro-6,7-methylentestosterone 10 g of trichloromethyl testosterone in 150 ml of pyridine were heated on the steam bath for 30 minutes. After cooling, water was added. The substance was finally caused to crystallize by rubbing the wall of the vessel with a glass rod. After recrystallization, 7.6 g of substance with a melting point of 208 ° to 210 ° C. were obtained; [a] δ = -f-264 °. 7 "iax 246 mg (F = 10400). Calculated C65.030 / 9, H 7.0819 / o, C1 19.19%; found C 65.15%, 1-17.20%, c119.23.1 / 0. EXAMPLE 6 Preparation of 6a, 6a-dichloro-6,7-methylenetestosterone 3.2 g of testosterone-3-ethylenol ether in 50 ml of chloroform and 2.6 ml of dichlorodibromomethane were refluxed for 20 hours with a 500 -W lamp (3800 ° Kelvin). The brown solution was then evaporated to dryness in vacuo on the steam bath and the fatty residue was digested with 25 ml of ether. After standing for 1 hour, the solid material was filtered off and dissolved in the smallest possible amount of methanol The solution was left to stand at 0 ° C. Crystals separated out, which were filtered off and dried. Yield 2.0 g, melting point 210 to 211 ° C.

By evaporation of the methanolic mother liquor and recrystallization the residue from ether was able to recover testosterone from melting point 150 to 152 ° C will.

Example 7 Preparation of 6a, 6a-dichloro-6,7-methylenetestosterone 3.3 g of 3-ethylenedioxytestosterone in 50 ml of trichlorobromomethane were 2 hours on Heated to reflux to the boil and irradiated with a 250 W lamp (2800 ° Kelvin). The solution was then evaporated to dryness in vacuo and the residue, as described in Example 6, worked up. Yield 2.2 g; Mp. 209 to 210 ° C. Something Testosterone could be recovered from the mother liquor.

The reaction mixture was refluxed for 20 hours instead of 2 hours heated to boiling, the yield from 3.3 g of testosterone-3-ketal was 2.4 g.

From 3.3 g of testosterone-3-ketal in 50 ml of trichlorobromomethane, at room temperature Stored for 24 hours, 470 mg of the same compound were obtained.

When the same solution is irradiated with UV light at 18 ° C for 24 hours 800 mg of the desired product were obtained. Example 8 Preparation of 6a, 6a-dichloro-6,7-methylenetestosterone 3.3 g of testosterone-3-ketal in 50 ml of trichlorobromomethane were mixed with 250 mg of benzoyl peroxide added and the mixture is heated in the dark at 100 ° C on the steam bath for 5 hours. After evaporating the reaction mixture and working up the residue, such as Described in Example 6, fell 1.1 g of the desired substance from mp 210 to 211 ° C. Example 9 Preparation of 6a, 6a-dichloro-6,7-methylenetestosterone 3.3g Testosterone-3-ketal in 50m1 trichlorobromomethane were mixed with 200 mg magnesium turnings (for Grignard reactions) and 5 hours in the dark with stirring at 100 ° C heated. The magnesium was then filtered off and the solution evaporated to dryness. The greasy residue was as described in Example 6, worked up. Yield 1.1g; Mp. 209 to 210e C.

Example 10 Preparation of 6 a, 6 a-Dibromo-6,7-methylene 17, #, - methyltestosterone 12 g of the 3-ethylenol ether of 17a-lbiethyltestosterone in 65 ml of anhydrous dioxane and 4 ml of anhydrous pyridine were mixed with 12 g of tetrabromomethane and the solution heated to boiling under reflux for 2 hours under irradiation with a 250 W lamp. After cooling, undissolved substances were filtered off and the filtrate in vacuo evaporated to dryness. The residue was dissolved in 5 ml of anhydrous ethanol and hexane are added until precipitation occurs. Yield 8 g; Mp 194-195 ° C. @ Rnac 251 mu (F = 10600).

Example 11 Preparation of 6a, 6α-Dibromo-6,7-methylene-19-nortestosterone acetate This compound was obtained analogously to the 6 a, 6 a-dibromo-6,7-methylenetestosterone, whereby according to method AI of Example 1 for the preparation of the intermediate 6-tribromomethyl derivative was worked. This was carried out in 350% yield without further purification Heat in pyridine as described in Example 1, B, to give the desired compound converted. After recrystallization from methanol, the substance had a melting point of 146 to 147 ° C; 250 mu (F = 13,900).

Calculated C 51.86%, H 5.3811 / o, Br 32.86%; found C51.930 / 9, H 5.38% -, Br 32.79%. Example 12 Preparation of 6 a, 6 a-dichloro-6,7-methylene progesterone 3.4 g of progesterone-3-ethylenol ether in 75 ml of chloroform and 2.4 g of dichlorobromomethane were refluxed for 4 hours under irradiation with a 500 W lamp (3800 ° Kelvin) heated to boiling. The solution was then evaporated to dryness in vacuo, the fatty residue dissolved in 50 ml of ether, the solution on a 10 cm long aluminum oxide column of 2 cm diameter and eluted with 500 ml of ether. The essential Solution was evaporated to dryness and the residue was recrystallized from ethanol. Yield 1.65 g; M.p. 168 to 170 ° C; 246 mu (e = I1000).

Calculated C 66.83e / 01 H 7.11%, C 117.900; 0; found C67,090 / 9, H7,210 / &, Cl 17.86%. Example 13 Preparation of 6 a, 6 a-Dichloro-6,7-methyleneprogesterone 4.0 g of progesterone-3,20-diethylene glycol ketal in 75 ml of trichlorobromomethane was taken under Irradiation with a 500 W lamp (3800 Kelvin) for 2 hours at reflux to the boil heated. The reaction mixture was then evaporated to dryness in vacuo, the residue dissolved in 100 ml of acetone; for splitting off the 20-position ketal group 10 ml of 8% sulfuric acid were added and the solution was refluxed for 1 hour Boiling heated. Most of the acetone was then distilled off, the solution diluted with 500 ml of ether, washed three times with 200 ml of water each time, with sodium sulfate dried and then evaporated to dryness. After recrystallization from methanol 450 mg of the desired substance with a melting point of 166 ° to 170 ° C. were obtained.

Example 14 Preparation of 6 a, 6 a-Dibromo-6,7-methylene progesterone 34.2 g of progesterone-3-ethylenol ether in 200 ml of anhydrous dioxane and 16.1 ml of pyridine 66.4 g of tetrabromomethane were added and the solution was kept at room temperature for 24 hours ditched.

A crystalline precipitate, which was the addition product of 1 mol of pyridine hydrobromide and 1 mol of tetrabromomethane, was filtered off and the filtrate was heated on the steam bath for 3 to 4 hours. After cooling, the precipitate, consisting mainly of pyridine hydrobromide, was filtered off, the filtrate was diluted with 500 ml of ether, carefully washed with water, dried and the solvent was then stripped off in vacuo. The residue crystallized on addition of methanol. After recrystallization from methanol, the desired product was obtained in a yield of 36%. Mp 201-202 ° C; [a] δ = r 242 °; 7 "tU,. 250 mu (, - = 9750); shoulder at 285 mu (a = 5600). The IR spectrum in chloroform showed bands at 1570, 1622, 1678 and 1700 cm- '.

Calculated C 54.56%, H 5.830 / G, Br 33.01%; found C 54.4811 / o, H. 5.821 / e, Br 32.95%. Example 15 Preparation of 6 a, 6 a-Dibromo-6,7-methylene progesterone 12 g of progesterone-3-ethylenol ether, dissolved in 300 ml of chloroform and mixed with 11.5 g of tetrabromomethane added, were 4 hours under irradiation with a 500 W lamp (3800 ° Kelvin) heated to boiling under reflux. The solution then went to dryness in vacuo evaporated, the residue taken up in 200 ml of ether, the solution on an aluminum oxide column 15 cm in length and 3 cm in diameter and eluted with 11 ether. The ether was evaporated and the residue was recrystallized from ether. yield 7.0 g; Mp. 195 to 196 ° C.

Example 16 Preparation of 6 a, 6 a-Dibromo-6,7-methylene-17a-hydroxyprogesterone 2.87g of 17a-hydroxyprogesterone-3-ethylenol ether, in 20m1 of anhydrous dioxane and 2m1 Dissolved anhydrous pyridine and mixed with 5.30 g of tetrabromomethane, 31 / z Left for hours in diffuse daylight at room temperature. The crystallized Precipitation, probably an addition compound of tetrabromomethane and pyridine hydrobromide, was filtered off and the filtrate was refluxed for 1 hour. To cooling and filtering off the essentially consisting of pyridine hydrobromide The filtrate was precipitated to an aqueous ammonium sulfate solution poured and the mixture shaken out several times with ether. The United Ether extracts were washed with aqueous ammonium sulfate solution and dried; the solvent was then removed in vacuo. The oily residue was in Dissolved 20 ml of methanol and 1.5 ml of 4N sulfuric acid and refluxed for 30 minutes Boiling heated. After cooling, the precipitated crystals were collected and washed with methanol and subsequently with ether. After two recrystallizations from acetone, the desired substance had a melting point of 230.5 to 231 ° C.

After recrystallization from ethylene glycol monomethyl ether (known under the trade name Methylcellosolve) the substance fell in a modification of the m.p. 246 to 247 ° C; [a] δ = -I-169 ° (in chloroform). @ .x 252 mg, (E = 10 250).

Calculated C 52.81%, H 5.64 "/ o, Br 31.95%; found C 52.640 / e, H 5.97 "/ o, Br 31.79%. The compound prepared in this way became 17a-acetate prepared as follows: 2.34 g of 6a, 6a-dibromo-6,7-methylene-17a-hydroxyprogesterone, in a mixture of 20 ml of glacial acetic acid and 15 ml of acetic anhydride were suspended after adding 2.30 g of p-toluenesulfonic acid, shaken for 16 hours at room temperature. The clear solution obtained was poured into 500 ml of water and the resulting solution Precipitation filtered off, washed with water and dried over phosphorus pentoxide. After recrystallization from benzene-hexane, 2.48 g (97% of theory) of the desired Compound obtained which crystallized with 1 mole of benzene. Mp 114-117 ° C; [a] δ = -f-143 ° (in chloroform); @max at 249 mw (e = 10,200), shoulder at 280 to 285 m [, (s = 6200).

Calculated C 58.0011 / o, H 5.85%, Br 25.80%; found C 58.14 / o, I -16.06,%, Br 25.72%. Example 17 Preparation of 6 a, 6 a-Dibromo-6,7-methylene-11-deoxycorticosterone acetate This compound was analogous to the 6a, 6a-dibromo-6,7-methylenetestosterone from the 3-Ethylenol ether of 11-deoxycorticosterone-21-acetate using the method A1 of Example 1 for the preparation of the intermediate 6-tribromomethyl derivative obtained, which without further purification in 45% yield by heating in pyridine, as described in Example 1, B2, was converted into the desired compound. After recrystallization from methanol, the substance had a melting point of 176 ° to 177 ° C; @., "ax 250 m [, (E = 11400).

Calculated C53.16%, H5.5811 / o, Br 29.46%; found C 52.91%, H 5.69%, Br 29.31%. Example 18 Preparation of 6 a, 6 a-Dibromo-6,7-methylendesoxycorticosterone acetate By reacting 4 g of 3-ethylenol ether of deoxycorticosterone acetate in 75m1 of chloroform with 3.3 g of tetrabromomethane and working up the reaction mixture, as described in Example 15, a residue was obtained from which the desired Substance in an amount of 1 g by recrystallization from a mixture of the same Volumes of ether and methanol was obtained. Mp. 169 to 170'F C.

Example 19 Preparation of 6a, 6a-Dibromo-6,7-methylene-17a-hydroxy-11-deoxycorticosterone-21-acetate 46 g of the 3-ethylenol ether of 17a-hydroxy-11-deoxycorticosterone-21-acetate in 200 ml of anhydrous dioxane and 20 ml of pyridine were added after adding 73 g of tetrabromomethane Left for 16 hours at room temperature. The precipitated precipitate was filtered off and the filtrate heated to boiling under reflux for 2 hours. After cooling down and filtering off another precipitate, the solution was diluted with 500 ml of ether, washed with water, dried and concentrated in vacuo. The oily residue was dissolved in hot methanol, the crystalline product filtered off after cooling. The substance became practical by recrystallization from ethylene glycol monomethyl ether Obtained pure form of mp 228-229.5 ° C; A "", 251 m # t (E = 9950); shoulder at 280 to 285 m [. (a = 5800).

Calculated C 51.63%, H 5.42%, Br 28.631%; found C51.610 /% H 5.49 "/ o, Br 28.70%. Example 20 Preparation of 6 a, 6 a-Dibromo-6,7-methylenecortisone acetate Analogous to Example 14, but using the 3-ethylenol ether of cortisone acetate, the crude product of the desired substance was obtained. It was solved by solving in cleaned with hot methanol. Upon cooling, the impurity, cortisone acetate, separated in crystal needles. By adding water to the filtrate, the desired substance fell the end. After recrystallization from ethylene glycol monomethyl ether, the substance was obtained in a yield of 551%. Mp 236-237 ° C; [a] δ = -f-256 ° (in chloroform). 2. ", ax 252 mu, (a = 9650); shoulder at 275 to 280 m # t (a = 5250). In the IR spectrum in chloroform bands appeared at 1570, 1607, 1668, 1703, 1720 and 1735 cm- '.

Calculated C 50.37%, H 9.9311 / o, Br 27.96%; found C 50.27%, H 5.12%, Br 27.96%. Example 21 Preparation of 6 a, 6, a-Dibromo-6,7-methylenecortisone acetate 60g of the 3-ethylenol ether of cortisone acetate in 300 ml of anhydrous dioxane, 60 g of tetrabromomethane and 30 ml of anhydrous pyridine were under irradiation with a 250 W lamp (2800 ° Kelvin) at reflux for 2 hours. heated to boiling. The pyridine became. added to bind the hydrogen bromide evolving during the reaction.

After cooling, the precipitation became mainly pyridine hydrobromide filtered off and the filtrate evaporated to dryness in vacuo. The residue was dissolved in ether, the ethereal solution washed with water and after drying evaporated to dryness with magnesium sulfate. Of the Residue was treated with petroleum ether to remove excess tetrabromomethane and the remaining solid, 65 g, dissolved in hot methanol. The solution was left to stand overnight, whereupon 20g of cortisone acetate crystallized out, which were filtered off. The filtrate was evaporated to dryness in vacuo and the residue dissolved in hot acetone. After the solution has cooled and filtered off another small amount of cortisone acetate was added to water. Here 19 g of the desired product precipitated out in crystalline form. The crude product showed one Mp. From 226 to 228 ° C. By recrystallization from ethyl acetate 16 g of substance with a melting point of 232 to 234 ° C. were obtained. After another recrystallization from ethyl acetate the melting point rose to 234-235 ° C.

Example 22 Preparation of 20-ethylenedioxy-6 a, 6 a-dibromo-6,7-methylenecortisone acetate 3.8g of the 3-Äthylenoläthers des 20-Äthylendioxycortisonacetats in 40 ml of anhydrous Dioxane and 2.6 g of tetrabromomethane and 0.64 ml of pyridine were irradiated for 3 hours heated to boiling with a 250 W lamp (2800 ° Kelvin) at the rear foot. The one here The precipitate formed was filtered off and the filtrate was concentrated in vacuo to give a syrup. The residue was dissolved in 100 xnl ether, the ethereal solution twice with each Washed 100 ml of water and, after drying with magnesium sulfate, evaporated to dryness. The residue was dissolved in 50 ml of benzene and on 100 g of silica gel (fineness DIN sieve 0.05 to 0.07 mm) chromatographed. Initially pure was used for elution Benzene, then a mixture of 1 part by volume of ethanol and 99 parts by volume of benzene used. The fractions of the eluate obtained with this mixture that due to analysis by paper chromatography contained the desired substance combined and the solution evaporated to dryness. The residue was washed with ether digested, whereupon the substance crystallized. Yield 1.6 g; Mp 196-200 ° C. After recrystallization from methanol, 1.1 g of product with a melting point of 210 to 211 ° C obtained. @, "@ ax in ethanol 252 m # t (e = 9900), shoulder at 275 to 280 mu (s = 5900).

Calculated ............ C 50.669 / o, H 5.249 / o; found ............. C 50.84%, H 5.450 / i).

Claims (5)

PATENT CLAIMS: 1. Process for the production of 6a, 6a-dichloro-6,7-methylene and 6a, 6 a-dibromo-6,7-methylene compounds of A ¢ -3-ketosteroids of the androstane and pregnane series, characterized in that an enol ether or a ketal the corresponding d4-3-ketosteroid compound with a tetrahalomethane where the halogen is bromine or chlorine and bromine, converts and optionally the 17-position The hydroxyl group of the compound obtained is acetylated by methods known per se. 2. The method according to claim 1, characterized in that the reaction is carried out in the presence of an acid acceptor. 3. The method according to claim 1, characterized in that that the reaction is carried out in the presence of an organic peroxide. 4: Procedure according to claim 1, characterized in that the reaction in the presence of metallic Magnesium performs. 5. The method according to claim 1, characterized in that the reaction is accelerated by irradiating with light.