DE1178848B - Process for the production of cyclic acetals of the androstane or oestrane series - Google Patents

Description

Process for the production of cyclic acetals of the androstane resp. estran series The present invention relates to a process for the production of cyclic 16,17-acetals of the androstane or * Ostran series.

The process according to the invention is illustrated by the following reaction scheme: wherein X is a halogen, e.g. B. chlorine, bromine, iodine; R stands for a lower alkanoyl radical, e.g. B. the acetyl, propionyl or butyryl radical, or for a lower alkoxythiocarbonyl radical, e.g. B. the methoxythiocarbonyl, ethoxythiocarbonyl or propoxythiocarbonyl radical; R 'is hydrogen or a lower alkyl radical, e.g. B. the methyl, ethyl, propyl or butyl radical; the phenyl radical is a lower alkylphenyl radical, e.g. B. the tolyl or xylyl radical; or a lower phenylalkyl radical, e.g. B. the benzyl or phenethyl radical; R "represents a lower alkyl, phenyl, lower alkylphenyl or lower phenylalkyl radical; if bonded, R 'and R" represent a cyclic lower alkyl radical, e.g. B. the cyclopentyl or cyclohexyl radical; and wherein the wavy line illustrates an α or β configuration.

According to the invention, cyclic acetals of the Androstan- and Ostran series are used prepared by a corresponding 16-halo-17-oxo compound with a reactive derivative of a lower thioalkanoic acid or alkyl dithiocarboxylic acid converts, optionally with intermediate protection of a 3-position oxo group, the obtained 16β-substituted thio-17-oxosteroid with an alkali metal hydride compound reduced, the obtained 16P-mercapto-17fl-oxysteroid with an aldehyde or ketone condensed in the presence of an acidic catalyst and optionally the obtained Compounds converted into the corresponding 3-oxo-4-enes by known methods.

The invention is illustrated by the preparation of a 16,17-cyclic acetal of 16fl-mereapto-17fl-oxysteroids, starting from the compound of the formula in which A stands for a free or protected α-oxymethylene, β-oxymethylene or carbonyl group, X has the meaning given above and the wavy line illustrates the α or β configuration; in which a 4 (5) or 5 (6) double bond can also be present. According to the invention is obtained from this steroid 16,17-cyclic acetal of 16ss-mercapto-1 7.beta.-oxysteroids illustrated by the general formula in which R 'and R "are as defined above. This compound is an antigonadotrophic agent.

If the inventive method is applied to a 16-halo 1 7-oxo-androstane, the conversion can be shown by the following formulas: wherein A, X, R, R 'and R "have the same meaning as mentioned above; a 4 (5) or 5 (6) double bond can be present; the hydrogen atom in the 5-position, if the double bond mentioned does not exist, has a or fl configuration.

As examples of the 16-halo-17-oxo-androstane used as starting materials the following compounds can be mentioned: 3a-oxy-16a-chloro-l '/ - oxo-5ß-androstane, -ia-Oxy-16a-bro. #, - 17-oxo-5fl-androstane, 3fl-Oxy-16a-bromo-17-oxo-5a-androstane, 3a-Oxy-16ß-bromo-17-oxo-5fl- androstane, 3P-Oxy-16 # -bromo-17-oxo-5a-androstane, 3 # -Oxy-16a-iodo-17-oxo-5a-androstane, 3fl-Oxy-] 6a-chloro-17-oxo-5 (6 ) -androstan, 3a-Oxy-16a-bromo-17-oxo-5 (6) -androsten, 3fl-Oxy-16a-bromo-17-oxo-5 (6) -androsten, 3a-Oxy-16ß-bromo-17-oxo-5 (6) -androsten, 3fl-Oxy-16fl-bromo-17-oxo-5 (6) -androsten, 3a-oxy-16fl-iodo-17-oxo-5 (6) -androstene, 3,17-dioxo-16a-chloro-5fl-androstane, 3,17-dioxo-16a-bromo-5a-androstane, 3,17-Dioxo-16a-bromo-5fl-androstane, 3,17-Dioxo-16ß-bromo-5a-androstane, 3,17-Dioxo-16 # -bromo-5ß-androstane, 3,17-Dioxo-16a-chloro-4-androstene, 3,17-Dioxo-16a-bromo-4-androstene or 3,17-Dioxo-16fl-bromo-4-androstene.

The free oxo radical in the 3-position can by the in the present Process used reactants are attacked in an undesirable manner. It is therefore advisable to protect said free oxo radical beforehand. In contrast, protection of the free oxy radical in the 3-position is unnecessary. However, the acylated compound can be more easily than the corresponding free oxy compound be generated. In such a case, the acylated compound can be used as such are subjected to the method according to the invention.

Said 16-halo-17-oxo-androstanes are known compounds and can be prepared according to a conventional method (J. F d rie et al, USA. Patents 2857403 and 2 831 872; B. E is 11 and co-workers, J. Chem. Soc., P. 800 [1958]; J. F a jk o 9 et al., Chemical Abstracts, 53, p. 4349 [1959]).

The process according to the invention essentially comprises three stages.

In the first stage z. B. a 16-halo-17-oxo-androstane II with a sulfur-containing organic acid such as a thioalkanoic acid, e.g. B. thioacetic acid, thiopropionic acid, thiobutyric acid, or an alkyldithiocarboxylic acid, z. B. methyldithiocarboxylic acid, ethyldithiocarboxylic acid, propyldithiocarboxylic acid, brought to reaction. Usually the reaction is carried out in such a way that the 16-halo-17-oxo-androstane containing an alkali metal salt of said sulfur organic acid, e.g. B. with sodium thioacetate, potassium thioacetate, potassium thiopropionate, Potassium thiobutyric acid, potassium methyl dithiocarbonate, sodium ethyl dithiocarbonate, potassium ethyl dithiocarbonate, Sodium propyldithiocarbonate, potassium propyldithiocarbonate, in a suitable medium, z. B. acetone, ether, dioxane, tetrahydrofuran, at room temperature for several Hours treated.

In the second stage, the 16-substituted thioandrostane 111 thus obtained is treated with an alkali metal hydride, e.g. B. lithium aluminum hydride, lithium borohydride, sodium borohydride, reduced. The reaction is usually carried out by treating the 16-substituted Thioandrostans 111 with said reducing agent in a suitable medium, eg. B. ether, dioxane, tetrahydrofuran, benzene. and, if necessary, with heating.

In the third stage, the 16-mercaptoandrostane IV obtained is with a carbonyl compound such as an aldehyde or ketone, e.g. B. acetaldehyde, propionaldehyde, Butyraldehyde, benzaldehyde, acetone, methyl ethyl ketone, diethyl ketone, methyl butyl ketone, Dipropyl ketone, dibutyl ketone, cyclohexanone, benzophenone, in present an acidic catalyst, e.g. B. p-toluenesulfonic acid or sulfuric acid, condensed.

Although the process according to the invention has just been illustrated from stage to stage You can do these stages one after the other without isolating the product in each Stage, which is particularly advantageous in those cases where the intermediates produced are not stable. For example, this is 16-mercaptoandrostane IV relatively unstable and should expediently the reaction in the subsequent Stage are subjected to without isolation from the reaction mixture.

Of these compounds, the A4-3-oxocyclic acetals la are useful as antigonadotrophic agents. When administered orally to a mouse of a body weight of 15 to 17 g, 40 days old, at a dose of 1 mg, z. B. 3-Oxo-16fl-mercapto-17ß-oxy-4-androstene-16,17-acetonide an antigonadotrophic activity with the inhibition ratio of 81.82 () / o, which is approximately equivalent to that previously known antigonadotrophic steroid, the 17a-ethynyl-19-nortestosterone. The other A4-3-oxo-cyclic acetals la also have similar activities. The cyclic acetals I, which are not included in the A4-3-oxo-cyclic acetals la, can easily be converted into the cyclic acetals la in the usual way.

Protection is not sought for the production of the starting materials in the context of the present invention. a) Preparation of 3,3-ethylenedioxy-16FL-bromo-17-oxo-5 (6) -androsten U3 g 3,17-dioxo-1 6ss-bromo-4-androstene (J. F a j -ko # and Employees, Chemical Abstracts, 53, p. 4349 [1959]) are combined with 200 ml of anhydrous benzene, 15 ml of ethylene glycol and 450 mg of p-toluenesulfonic acid and the resulting solution is refluxed for 16 hours. After cooling, the reaction mixture is neutralized with aqueous sodium carbonate solution and shaken with benzene. The benzene layer is washed with water and the solvent is removed under a reduced pressure. The residue obtained in this way is crystallized from ether and recrystallized from dichloromethane-acetone and yields 6.83 g of 3,3-ethylenedioxy-16β-bromo-17-oxo-5 (6) -androsten in the form of crystals with F. = 204 bis 206'C. Analysis for C21H2903Br: Calculated ... C 61.61, H 7.14, Br 19.52, found ... C 61.79, H 7.24, Br 19.75.

b) Preparation of 3,3-ethylenedioxy-16ß-ethoxythiocarbonylthio-17-oxo-5 (6) -androsten To a suspension of 917 mg 3,3-ethylenedioxy- 1 6fl-bromo- 1 7-oxo-5 (6) -andst in 20 ml of acetone, 595 mg of potassium ethyldithiocarbonate are added, after which the resulting solution is stirred for 5 hours at room temperature. After adding water to the reaction mixture, the mixture is extracted with benzene-ether (1: 1). The extract is washed with water and dried. After removing the solvent, the remainder weighing 1.077 g is dissolved in a small amount of benzene and chromatographed on 25 g of clay. The eluate of 904 mg obtained is crystallized from methanol and recrystallized from chloroform-ethanol, and 644 mg of 3,3-ethylenedioxy- 1 6fl-ethoxythiocarbonylthio- 1 7-oxo-5 (6) -androsten are obtained in the form of needles with F . = 208 to 210'C (decomposition).

[al'D " = + 1.3 '± 2' (C = 1.078 chloroform). Analysis for C241im04S2: Calculated ... C 63.96, H 1.6 1, S 14.23 - found ... C 63.64, H 7.63, S 14.1 1.

c) Preparation of 3,3-ethylenedioxy-16fl-mercapto-17fl-oxy-5 (6) -androsten A solution of 480 mg 3,3-ethylenedioxy-16fl-ethoxythiocarbonylthio-17-oxo-5 (6) -androsten in a mixture of 60 ml of tetrahydrofuran and 20 ml of anhydrous ether is added dropwise to a suspension of 20O mg of lithium aluminum hydride in 20 ml of ether and the mixture is stirred under reflux for 3 hours. After adding ice water to the reaction mixture, the organic solvent layer is washed successively with 10% hydrochloric acid, water, 10% sodium carbonate solution and finally with water and dried. After removing the solvent, the residue of 406 mg is washed with ether and gives 300 mg of 3,3-ethylenedioxy-16β-mercapto-17fl-oxy-5 (6) -androsten as crude crystals with a temperature of 207 to 211 ° C.

d) Preparation of 3-oxo-16fl-mercapto-17fl-oxy-4-androstene-16,17-acetonide 100 mg 3,3-ethylenedioxy-16fl-mercapto-17β-oxy-5 (6) -androsten are mixed with 10 mg p -Toluenesulfonic acid in 5 ml of acetone heated at reflux for 5 hours. The reaction mixture is then mixed with water and the precipitated crystals are filtered. After these crystals have been dissolved in benzene petroleum ether (1: 1) , they are chromatographed on 3 g of clay. The eluted substance is crystallized from acetone-methanol and yields 80 mg of 3-oxo-16ß-mercapto-17ß-oxy-4-androstene-16,17-acetonide in the form of leaflets with a temperature of 228 to 230.degree.

Analysis for C22H3202S: Calculated ... C 73.29, H 8.95, S 8.89; Found ... C 73.52, H 9.18, S 8.7 1. a) Production of 3,3-ethylenedioxy-16ß-bromo-17-oxo-5 (6) -androstene 3,17-dioxo-16ß-bromo-4-androstene is subjected to the ketalization according to Example 1, a) and gives 3 , 3-ethylenedioxy-16ß-bromo-17-oxo-5 (6) -androsten.

b) Preparation of 3,3-ethylenedioxy-16fl-acetylthio- 1 7-oxo-5 (6) -androsten To a suspension of 504 mg 3,3-ethylenedioxy-16β-bromo-17-oxo-5 (6) - rusting in 20 ml of acetone, 282 mg of potassium thioacetate are added, and the resulting solution is stirred for 4 hours at room temperature, that is at 10 to 25 ° C. After adding water to the reaction mixture, the precipitate is filtered, dried and crystallized from methanol, after which 412 mg of 3,3-ethylenedioxy-16p-acetylthio-17-oxo-5 (6) -androsten in the form of needles with F. = 172 bis 173'C can be obtained.

la] -D " = -6.8 '± 2' (C # 1.078 chloroform). Analysis for C23H3204S. Calculated ... C 68.28, H 7.97, S 7.93 found ... C 68 , 20, H 8.03, S 7.77.

c) Preparation of 3,3-ethylenedioxy-16β-mercapto- 1 7fl-oxy-5 (6) -androsten 352 mg of 3,3-ethylenedioxy-16β-acetylthio-17-oxo-5 (6) -androsten are with 150 mg of lithium aluminum hydride treated as in Example 1, c) and give 250 mg of 3,3-ethylenedioxy-16fl-mercapto-17fl-oxy-5 (6) -androsten.

d) Preparation of 3-oxo-16ß-mercapto-17ß-oxy-4-androstene-16,17-acetonide 250 mg of 3,3-ethylenedioxy-16ß-mercapto-17ß-oxy-5 (6) -androsten are with acetone condensed in the presence of p-toluenesulfonic acid as in Example 1, d) and yield 173 mg of 3-oxo-16ß-mercapto-17ß-oxy-4-androstene-16,17-acetonide in the form of crystals with a m.p. = 221 to 225 'C. 3,686g of 3,3-ethylenedioxy-16ß-mercapto-17ß-oxy-5 (6) -androsten, prepared as in Example 1, a), b) and c), are mixed with 120 ml of diethyl ketone and 300 mg of p-toluenesulfonic acid during Treated under reflux for 13 hours. The reaction mixture is then shaken with benzene, the benzene layer is washed with aqueous sodium carbonate and then with water and finally dried. After removing the solvent, the residue is chromatographed on alumina. The substance eluted with petroleum ether-benzene (1: 1, 1: 2) is crystallized from petroleum ether and recrystallized from methanol and yields 1.85 g of 3-oxo-16ß-mercapto-17ß-oxy-4-androstene diethyl ketone-16, 17-cyclic acetal in the form of needles with F. = 144 to 146'C.

[a12080 = + 40.00 ± 20 (C = 1.043 chloroform). Analysis for C2411wO2S: Calculated ... C 74.18, H 9.34, S 8.25; Found ... C 74.30, H 9.34, S 8.28. 2.588g of 3,3-ethylenedioxy-16ß-mercapto-17ß-oxy-5 (6) -androstene, prepared as in Example 1, a), b) and c), are mixed with a mixture of 100 ml of benzene, 120 mg p -Toluenesulfonic acid and 8 ml of benzaldehyde treated for 8 hours at reflux. The reaction mixture is then shaken with benzene, the benzene layer is washed with aqueous sodium carbonate and then with water and finally dried. After removing the solvent, the residue is chromatographed on alumina. The substance eluted with petroleum ether-benzene (2 -. 1, 1 #: 1, 1: 2) is crystallized from ether and recrystallized from acetone-methanol and yields 458 mg of 3-oxo-16P-mereapto-17β-oxy-4- Androstene-benzaldehyde-16,17-cyclic-acetal in needles with F. 171 to 173'C / 180'C.

[al "D" + 115.2 '± 2' (C = 1.170 chloroform). Analysis for C2611wO2S: calculated ... C 76.43, H 7.89, S 7.85; found ... C 76.48, H 8.04, S 8.15. 720 mg of 3,3-ethylenedioxy-16β-mercapto-17fl-oxy-5 (6) -androsten, prepared as in Example 1, a), b) and c), are mixed with 30 ml of benzene, 70 mg of p-toluenesulfonic acid and 1 ml of cyclohexanone treated under reflux for 8 hours. Thereafter, the reaction mixture is shaken with benzene, the benzene layer is washed with aqueous sodium carbonate solution and then with water and finally dried. After evaporation of the solvent, the residue is chromatographed on alumina. The substance eluted with petroleum ether-benzene (1: 1, 1: 2) is crystallized from methanol and yields 270 mg of 3-oxo-16ß-mercapto-17-oxy-4-androstene-cyclohexanone-16,17-cyclic acetal in needles with F . = 185 to 187 ° C (decomposition).

[al'D "= + 37.6 '± 2' (C = 1.123 chloroform). Analysis for C25H2602S: Calculated ... C 74.95, H 9.06, S 8.00; found ... C74, 81, H9.10, S8.09. 170 mg of 3,3-ethylenedioxy-16fl-acetylthio-17-oxo-5 (6) -androstene, prepared as in Example 2, a) and b), are reduced with 80 mg of lithium aluminum hydride as in Example 1, c). 160 mg of the reduction product are heated with 50 ml of 800 / () strength acetic acid on a water bath for 1 hour and then shaken with a mixture of water and ether. The ether layer is washed until neutral and the solvent is removed; a residue is obtained which is heated with pyridine and acetic anhydride on a water bath for 1 hour. The product obtained in this way is treated in the usual way and chromatographed on alumina. The substance eluted with petroleum ether-benzene (1: 1) and benzene is crystallized from acetone-hexane and yields 152 mg of 3-oxo-16ß-acetylthio-17ß-acetoxy-4-androsten in leaflets with a temperature of 183 to 184 ° C .

[al ID 10 = + 68.911 ± 2 " (C = 0.992 chloroform). Analysis for G3% O4S: Calculated ... C 68.28, H 7.97, S 7.93; found ... C 68 , 01, H 8.03, S 7.89 A solution consisting of 152 mg of 3-oxo-16fl-acetylthio-17fl-acetoxy-4-androstene and 200 mg of potassium carbonate in 5 ml of methanol and 1 ml of water is made up The reaction mixture is then diluted with water and shaken with chloroform. The chloroform layer is washed with water and then dried. After evaporation of the solvent, 122 mg of residue is obtained, which is chromatographed on activated magnesium silicate with benzene and benzene-ether (9: 1, 4: 1) eluted substance is crystallized from methanol-water and delivers 88 mg of 3-oxo-1 6ss-mereapto-17-oxy-4-androstene in small needles 178 F. up to 180'C.

'D "' = + 54.5 '± 2' (C = 1.155 chloroform). Analysis for C19H2sO2S: Calculated ... C 71.20, H 8.8 1, S 10.0 1, found ... C 71.55, H 9.08, S 9.9 1. 3-Oxo-16ß-mereapto-17ß-oxy-4-androstene is heated with acetone in the presence of p-toluenesulfonic acid and gives 3-oxo-16fl-mercapto- 17β-oxy-4-androstene-16,17-acetonide. 3fl - Acetoxy - 16ß - bromo - 17 - oxo - 5 (6) - androsten (B. E 11 is and coworkers, J. Chem. Soc., P. 800 [19581) is with potassium ethyl dithiocarbonate as in example 1, b) implemented and gives 3ß-acetoxy-16ß-äthoxythiocarbonylthio- 1 7-oxo-5 (6) -androsten, which is reduced with lithium aluminum hydride and after condensation with acetone in the presence of p-toluenesulfonic acid as in Example 1, c) and d) 3fl , 17β-Dioxy-16β-mereapto-5 (6) -androstene-16,17-acetonide in the form of platelets with F. = 214 to 216 ° C results.

The 3.beta. thus prepared, 17FL-dioxy-16ss-mercapto-5 (6) - 16.17 - - can acetonide in 3 - androsten-oxo 16FL-mercapto-17-oxy-4-androstene 16,17-acetonide, according a conventional oxidation process, e.g. B. with the help of Oppenauer oxidation can be converted. 3,17-Dioxo-16fl-bromo-5a-androstane (J. Fajko # et al., Chimeal Abstracts, 53, p.4349 [1959]) is subjected to the ketalization as in Example 1, a). The 3,3-ethylenedioxy-16β-bromo-17-oxo-5a-androstane thus obtained is reacted with potassium thioacetate as in Example 2, b) and gives 3,3-ethylenedioxy-16β-acetylthio-17-oxo-5a-androstane after which the latter compound is reduced with lithium aluminum hydride; after subsequent reaction with acetone in the presence of p-toluenesulfonic acid as in Example 1, c) and d) , 3-oxo-16ß-mereapto-17ß-oxy-5a-androstane-16,17-acetonide is obtained in needles with F. = 210 to 212'C. The 3-oxo-16ß-mereapto-17ß-oxy-5a-androstane-16,17-acetonide produced in this way has a sodium retention activity and an antigonadotrophic activity. To a suspension of 3,079g 3fl-acetoxy-16ss-bromo-17-oxo-5a-androstan (J. F k j o 9 and employees Chernical Abstracts, 53, p 4349 [1959]) in 50 ml of acetone are 1 , 28 g of potassium thioacetate were added and the mixture thus obtained was stirred for 3 hours at room temperature, that is at 10 to 25 ° C. After adding water, the precipitate is filtered from the reaction mixture, dried and crystallized from acetone-methanol; obtained 2.578 g of 3.beta.-acetoxy-1 6ss-acetylthio 1 7-oxo-5a-androstan in needles with mp = 145 to 147'C. Analysis for CwH, 3404S: Calculated ... C 67.94, 14 8.43, S 7.89; found . . . C 68.05, H 8.65, S 7.95.

As in Example 1, c) 3ß-acetoxy-16ß-acetylthio-17-oxo-5a-androstane is reduced with lithium aluminum hydride and the reduction product is heated with acetone in the presence of p-toluenesulfonic acid, which 3ß, 17ß-dioxy-16ß- mercapto-5a-androstane-16,17-acetonide in Forfti of prisms with F. = 196 to 198'C results.

Analysis for C22HwC # 2 $: Calculated ... C 72.47, H 9.95, S 8.80, found ... C 72.17, H 10.08, S 8.79.

3ß, 17ß - Dioxy - 16ß - mercapto - 5a - androstane-16,17-acetonide is heated with pyridine and acetic anhydride and gives 3ß-acetoxy-16ß-mercapto-17ß-OXY-5a-androstane-16,17-acetonide in leaflets with F. = 173 to 175'C.

Analysis for C24% 03S: Calculated ... C 71.13, H 9.42, S 7.89; Found ... C 71.03, H 9.66, S 8.05.

The 3β, 17β-dioxy-16β-mercapto-5α-androstane-16,17-acetonide produced above shows lipoid converting as well as antogonadotropic activity. A suspension of 624 mg of 3.beta.-acetoxy-1 6a-bromo-17-oxo-5a-androstan (J. F jk a o 9 and co-workers, Chemical Abstacts, 53, p 4349 [1959]) is dissolved in 20 ml of acetone with 260 mg of potassium thioacetate are added and the resulting mixture is stirred for 3 hours at room temperature, that is at 10 ° to 25 ° C. After adding water, the precipitate is filtered off from the reaction mixture, dried and crystallized from methanol; 541 mg of 3ß-acetoxy-16fl-acetylthio-17-oxo-5a-androstane are obtained in needles with a F. = 142 to 145 ° C.

3ß-Acetoxy-16fl-acetylthio-17-oxo-5a-androstane is treated as in Example 9 and gives 3ß, 17ß-dioxy-16fl-mercapto-5a-androstane-16,17-acetonide in prisms with F. = 196 to 198'C. a) Preparation of 3-methoxy-16β-acetylthio-17-oxo-1,3,5 (10) -estratriene A suspension consisting of 142 mg of 3-methoxy-16a-bromo-17-oxo-1,3,5 (10) -estratriene (W. S. J ohnson and coworkers, J. Am. Chem. Soc., 79; S. 2005 [1957]) and 80 mg of potassium thioacetate in 6 ml of acetone is for 31/2 hours at room temperature, that is at 10 to 25'C, stirred. After adding water, the precipitate is filtered off from the reaction mixture, dried and crystallized from methanol. The crude crystals are recrystallized from acetone-methanol (5 : 1) and give 124 mg of 3-methoxy-16β-acetylthio-17-oxo-1,3,5 (10) -estratriene in white flakes with m.p. 186 to 187 'C.

[al -D "' = + 154.9 ± 2' (chloroform). Analysis for C2, H260 # S: Calculated ... C 70.35, H 7.3 1, S 8.94; found ... C 70.34, H 7.40, S 8.94.

b) Preparation of 3-methoxy-16ß-mercapto-17ß-oxy-1,3,5 (10) -estratriene. A solution of 260 mg 3-methoxy-16fl- is added to a suspension of 110 mg of lithium aluminum hydride in 12 ml of anhydrous ether. acetylthio-17-oxo-1,3,5 (I 0) -estratriene in 30 ml of tetrahydrofuran with stirring at room temperature, that is at 10 to 25 ° C, allowed to drop in over 10 minutes. The solution thus obtained is then refluxed for 31/2 hours. After adding water to the reaction mixture, the precipitate is treated with dilute hydrochloric acid. The Atherschicht is dried over anhydrous sodium sulfate, and after completion evaporation of the ether, the residue obtained, the 3-methoxy-16ss-mercapto-1 7.beta.-oxy-1,3,5 containing (I0) -estratriene.

c) Preparation of 3-methoxy-16ß-mercapto-17fl-oxy-1,3,5 (10) -estratriene-16,17-acetonide To the residue obtained above, 20 mg of p-toluenesulfonic acid and 10 ml of acetone are added and the The resulting mixture was treated at reflux for 4 hours with the exclusion of moisture. The knocked down white needles are filtered hot. 30 ml of water are added to the filtrate and the precipitate is filtered off, which, after drying, gives 146.6 mg of crude crystals. These crude crystals were chromatographed on 7 g of clay using benzene-petroleum ether (1: 1) as the solvent. The 102.7 mg of crude 3-methoxy-1 6fl-mercapto-1 7fl-oxy-1,3,5 (10-estatriene-16,17-acetonide thus obtained are recrystallized from acetone and give 77 mg of white needles F. = 169 to 170'C.

Analysis for C22H3002S: Calculated ... C 73.70, H 8.43, S 8.94; found . . . C 74.03, H 8.57, S 8.86.

The 3-methoxy-16fl-mercapto-17β-oxy-1,3,5 (10) -estratriene-16,17-acetonide produced above shows catabolic, uterotrophic and anti-DOCA (deoxycorticosterone acetate) activities. A solution of 200 mg of 3-methoxy-16a-bromo-17-oxo-1,3,5 (10) -estratriene is treated with clay, eluted after 60 hours and yields 40 mg of 3-methoxy-16ß-bromo-17- oxo-1,3,5 (I0) -estratria.

A suspension of 24 mg of 3-methoxy-16ß-bromo-17-oxo-1,3,5 (10) -estratriene and 15 mg of potassium thioacetate in 3 ml of acetone is stored for 31/2 hours at room temperature, that is at 10 to 25 'C, stirred. After adding water to the reaction mixture, the precipitate is filtered, dried and crystallized from acetone-methanol (5 : 1) and yields 18 mg of 3-methoxy-16ß-acetylthio-17-oxo-1,3,5 (10) -estratriene in white crystals with F. = 184 to 187'C.

The 3-methoxy-16p-acetylthio-17-oxo-1,3,5 (10) -estratriene obtained above is reduced with lithium aluminum hydride, then reacted with acetone in the presence of p-toluenesulfonic acid as in Example 11, b) and c) and provides 3-methoxy-1-mercapto-6fl 17FL-oxy-1,3,5 (I0) -estratriene-16,17-acetonide.

Claims (1)

Claim: Process for the production of cyclic acetals of the androstane or ostran series, d a - characterized in that a corresponding 16-halo-17-oxo compound with a reactive derivative of a lower thioalkanoic acid or alkyl-dithiocarboxylic acid, optionally with intermediate protection of a 3 -content oxo group, the 16ß-substituted thio-17-oxosteroid obtained is reduced with an alkali metal hydride compound, the 16ß-mercapto-17ß-oxysteroid obtained is condensed with an aldehyde or ketone in the presence of an acidic catalyst and, if appropriate, the compounds obtained in the corresponding 3-oxo-4-enes transferred.