CH617443A5 - Process for the preparation of steroid carbolactones - Google Patents

Abstract

A process for preparing spironolactone of the formula <IMAGE> and similar spirolactones starts from an acetal of 3ss,17-dihydroxy-17 alpha -pregn-5-ene-21-carbaldehyde and entails the following sequence a) bromination in position 5,6 b) oxidation in position 3 c) dehydrobromination in position 5,6 to form the 4,6-dien-3-one group d) addition of thioacetic acid or another thiocarboxylic acid onto the 6,7 double bond e) ring closure in position 17 to give the spirolactone by acid treatment and oxidation, e.g. with chromic acid. The products are known aldosterone antagonists. The process gives better yields and is simpler than the methods already disclosed.

Description

The present invention relates to a process for the preparation of 3-oxo-17-pregn-4-ene-21,17-carboxylic acid lactones of the formula

/ v °

wherein R is an acylthio group, in particular a lower — acy 1- ““ thio group, primarily the acetylthio group.

The compounds are known aldosterone antagonists, such as, for example, the spironolactone, the compound of the formula I in which R represents the acetylthio group, which is commercially available under the trade name Aldacton A.

h5 Numerous processes for the preparation of these compounds have been proposed in the literature and patent literature. In general, the corresponding Pregna-4,6-diene compound of the formula

3rd

617 443

and a thiocarboxylic acid, e.g. Thioacetic acid, e.g. attached according to the procedure of German Patent 1 121 610.

For the preparation of the compound of formula (I ') e.g. the method described in Journal of the American Chem. Society, 79, pages 4808 and in US Pat. No. 2,705,712 can be used, which can be represented schematically as follows (Method A)

C = CH

OH C ^ HjMgBr

Pd + C / H

\ J / H

©

Oppenauer

The above process for the preparation of the 4,6-diene compound of the formula (I ') can be regarded as outdated today because of the unsatisfactory yields. Better variants are, for example, the process of the United States patents 3,738,983 and 3,270,008, which takes the following route (process B):

617 443

CE,? = CH R 3 »

= Alkyl

HO

'N / A

C S CH

a) CH3Mg Br b) C02

r \ U +

d) N (Et) 3

H2-Pd / CaC03 MeOH / N (Et)

HO'v / \ /

Br2

Li2C03 / LiBr DMF

Then, in German Offenlegungsschrift 2 237 143, a method for producing the spironolactone is given in accordance with the following scheme (method C):

617 443

617 443

One variant of this is claimed in German Offenlegungsschrift 2 248 834 (method D) and another in German Offenlegungsschrift 2 248 835. (Method E).

German Offenlegungsschrift 2 251 476 claims a process which does not lead via the compound (I '), and which is based on the above compounds V corresponding to 3-oxo-4,6-diene derivatives, is added to this thioacetic acid and the resulting corresponding 3-oxo-7a-acetylthio-4-ene derivatives with an intact 17β-hydroxy-17a-propionaldehyde acetal side chain in acid solution are oxidized to spinonolactone. The addition of thioacetic acid to the 6,7-double bond while preserving the substituents contained in the starting material in the 17-position is described as surprising in this patent, since cyclization in the following sense was actually to be expected in the acidic medium of thioacetic acid

0-I

0-

S-CO-CH.

OH'

-0

However, an experimental review of this process has now shown that the above-mentioned 3-oxo-4,6-dienes with 17β-hydroxy-17a-propionaldehyde acetal side chain to be used as starting materials are not known at all and also not according to Information in DOS 2 251 476 can be produced: namely the 3-oxo-4-enes with the 17β-hydroxy which are initially obtainable according to DOS 2 237 143 and 2 248 834 (cited on page 4 of DOS 251 476) -17a-propionaldehyde-acetal side chain dehydrated with chloranil (as also in US Pat. No. 3,137,690, also cited on page 4 of DOS 2 251 476 and on page 12 in the experimental section), the corresponding 4,6- Dienes, but the 4,6-dienes of the cyclic derivatives formed according to the above scheme,

where here instead of the acetylthio group, where appropriate. the ether group derived from the alcohol used as solvent is present. The method described and claimed in DOS 2 251 476 cannot therefore be carried out.

All of the above processes for the production of. Carboxylic acid lactones of formula (I) are unsatisfactory from an operational point of view. In the first published process A, reactions are used which are not very suitable for industrial implementation, such as the lengthy treatment of carbon dioxide in the second stage and the catalytic hydrogenation in the third. In addition, the yields are very low.

In process B, the yield is about 20% by weight, based on the dehydroepiandrosterone used, which is used as the starting compound for the preparation of the 17 a-ethynyl-androst-5-en-3β, 17β-diol indicated as the first stage in the diagram.

In processes C-E, the weight yields, according to the experimental part of the patent applications concerned, again based on the dehydro-epiandroste-ron used, are in the range between 10-23%.

We have now found a process for the preparation of compounds of the formula I above which gives higher yields than those of the prior art and is also simpler, more convenient and more reproducible from an operational point of view than that.

The process of the present invention for preparing the compounds of the formula I is characterized in that

that an acetal of 3ß, 17ß-dihydroxy-17a-pregn-5-en-21-carbaldehyde in basic to and with a neutral medium is treated with a brominating agent suitable for the addition of bromine to a double bond, the 3-hydroxy-5 obtained , 6-dibromo derivative with a compound of 6-valent chromium under basic to neutral conditions to the corresponding 3-oxo-steroid, the product obtained dehydrobrominated, to introduce a 7a-acylthio group with the thiocarboxylic acid corresponding to this acylthio group, and thereupon reacted thereon product obtained treated with a compound of hexavalent chromium in acid solution.

The addition of bromine to the 5,6-double bond of the starting materials mentioned can be carried out by means of a bromination agent which is capable of generally adding bromine to double bonds, it being necessary to ensure that the reaction is carried out in a basic to neutral medium. This addition can thus be carried out in a manner known per se, e.g. by using bromine in an inert neutral solvent, e.g. a halogenated hydrocarbon such as ethylene chloride or chloroform, or a lower alkyl lower alkanoic acid amide, e.g. Dimethylformamide, optionally in the presence of a buffer, such as an organic or inorganic base, or in an organic nitrogen bubble which is used in excess, such as bromine in a tertiary organic aromatic base, such as pyridine or its C-methyl homologs, such as the picolines , especially collidine. With the nitrogen bases mentioned, bromine forms intermediate perbromides or perbromides of hydrogen halide salts of the bases mentioned, e.g. the perbromides of the hydrogen bromide salts. Such perbromides can also be used advantageously for the bromination according to the process. In particular, pyridine hydrobromide perbromide is used. A small excess over the amount of bromine theoretically required for the bromination of a double bond is advantageously used.

In addition to the perbromides of the nitrogen bases mentioned or of other bases, the bromine addition products of bromine on ethers, such as in particular cyclic ethers such as dioxane, can also be used. In these cases, too, it is advantageous to add a tertiary aromatic base, such as one of the abovementioned.

The perbromides or bromine adducts are in an inert organic solvent, such as those mentioned above, but also in an ether, a ketone, a hydrocarbon, in alcohols, such as, in particular, lower aliphatic monohydric or dihydric alcohols, such as methyl or ethyl alcohol, or n-butanol, or ethylene glycol, implemented.

Bromine addition complexes other than those mentioned above can also effect the addition according to the process, e.g. the addition complex of bromine with tetramethylammonium bromide.

It is very advantageous to use pyridine hydrobromide perbromide that one in pyridine solution and at room temperature or at low or elevated temperature, e.g. between -10 ° and + 100 °, preferably between 0 ° and + 20 °.

The process-related oxidation of the 3-hydroxy-5,6-dibromo addition product obtained with a compound of the hexavalent chromium to the corresponding 3-oxo steroid, e.g. Chromium trioxide or chromic acid should take place in a basic to neutral medium. If necessary, a sufficient amount of the base previously used for the bromination, i.e. e.g. Pyridine, so that one avoids exceeding the neutral point, or one adds a pyridine chromate solution to the bromination reaction mixture obtained in the previous step.

7

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This operation is advantageous at temperatures from approx. -10 ° to approx. + 30 °.

The de-bromination of the chromic acid oxidation product which is then to be carried out according to the method can also be carried out in a manner known per se. One uses e.g. inorganic basic agents, such as lithium salts, especially lithium halides, primarily lithium bromide, in the presence of a basic salt of an alkali metal or alkaline earth metal, such as the carbonates or basic carbonates e.g. of lithium, sodium, calcium or magnesium. A dialkylamide of a lower aliphatic carboxylic acid, in particular a di-lower alkyl derivative, such as e.g. Dimethylforma-mid, at temperatures between 0 ° and approx. 180 °, advantageously at temperatures between 80 and 150 °. Nitrogen-containing bases of aromatic character, such as those mentioned above, in particular pyridine or collidine, can also be used for dehydrobromination.

After hydrogen bromide has been removed in the manner described, the reaction product is the 4,6-diene-3-one derivative containing the 17a-propionic acid aldehyde-acetal side chain. According to the process, this is now reacted with a thioalkanoic acid in a manner known per se, i.e. as is known for the compounds of formula (I '), and then treated in succession or simultaneously with an acid and a compound of hexavalent chromium.

The said addition of a thiocarboxylic acid to the 4,6-diene derivative can be carried out in a manner known per se in the sense given above, e.g. by treating the steroid with an excess of thiocarboxylic acid without solvent in the heat. However, better yields result from the reaction of the 4,6-steroid diene in a polar solvent, in particular an alcohol, primarily a lower alkanol with 1-7 C atoms, with about 1.5-3.5 mol of thiocarboxylic acid, if desired with the addition of water. The best yields are obtained at temperatures between 0 ° and approx. 120 °, e.g. if at the boiling point of the alcohols mentioned, such as methanol, ethanol, propyl alcohol, isopropyl alcohol, the butanols or pentanols, in the absence of water. implements. The most favorable is the temperature interval between

50 and 100 °. In this way, very good yielders of the desired 7a-acylthio derivative are obtained without significant formation of the 7β-isomer. Lower thioalkanoic acids with 1-7 C atoms, such as thio-5-acetic acid, thiopropic acid or thiovaleric acid, are used in particular as thiocarboxylic acids.

In the subsequent treatment with an acid and a compound of hexavalent chromium, the deacetalization of the aldehydacetane group with ring closure in the propionaldehyde side chain with the 17β-hydroxyl group and the oxidation thereof to the corresponding lactone group take place simultaneously. The oxidation can be carried out with chromium trioxide in an acidic solution, in particular a mineral acidic solution, such as in particular in sulfuric acid, hydrochloric acid or one of the phosphoric acids, or in a lower carboxylic acid, such as an alkane carboxylic acid having 1-7 C atoms, such as formic, acetic or propionic acid or one of the butyric or valeric acids, or in mixtures of these acids, it being possible to add water if appropriate. Furthermore, the reaction can optionally: <> also in organic solvents such as ketones or ethers, e.g. in acetone, dioxane or tetrahydrofuran, with or without the addition of water.

A separate treatment with one of the acids mentioned can also be carried out before the oxidation, the cyclic hemiacetal mentioned above being formed first, and the oxidation being carried out in a second stage under the conditions just mentioned.

The acetals to be used as starting materials are derived from any aliphatic, alicyclic, araliphatic-111 or mixed aliphatic-alicyclic alcohol, especially from lower alkanols with 1-7 C atoms or lower alkane diols with 1-7 C atoms. In particular, the ethylene glycol acetal of 3ß-17ß-dihydroxy-17a-pregn-5-en-21-carbaldehyde is used as the starting material.

i5 The process can be illustrated using the following example of the preparation of spironolactone, in which the theoretical yields, based on the starting material I ", are also entered. As can be seen, the total yield of spironolactone IV ', based on the starting material I", is 47% i.e.:

617 443

8th

CH I OH o

1) Pyridine perbromide

2) Chromium trioxide pyridine

3) Li2C03 + dimethylformamide

Thioacetic acid in methanol

Chromic acid 64% of theory related to compound II "

IV '

SCOCH

Spironolactone 47% of theory or on I ''

To make a comparison with previous methods, e.g. In those of the above-mentioned German published documents, the preparation of I "from dehydro-epi-androsterone according to the method used in those patent applications for the reaction of dehydro-epi-androsterone with a chloropropionaldehyde acetal, for example the ethylene acetal, in the presence of lithium must be included This takes place with a yield of approximately 60% of theory. If all the yields are converted to percentages by weight, based on dehydro-epian-drosterone, the preparation of spironolactone by the process of the present invention results as in the following Examples 2 and 4 produced a yield of approximately 41%, as shown above, however, the yields in the processes CE discussed above are approximately 10-23 percent by weight of spironolactone, based on dehydro-epi-androsterone.

The process of the present application can be carried out with an even higher yield of the desired end products, provided that the compound I "is prepared from dehydro-epi-androsterone by addition of chloropropionaldehyde-ethylene acetal / Li and if the following new and inventive variant is chosen, the , as a special embodiment of the

The process of the present invention relates to the subject matter: It was found that when the dehydro-epi-androsterone is reacted with the chloropropionaldehyde-ace-50 tal in the presence of lithium, a considerable amount of dehy-dro-epi-androsterone can be recovered if after the reaction has been carried out in a manner known per se, the reaction product is treated with steam. Both dehydro-epi-andro-55 sterone and the reaction product, e.g. the 17a- (3'-ethylene-dioxy-propyl) -androst-5-en-3ß, 17-diol by conventional purification operations such as chromatography, e.g. on aluminum oxide, and / or crystallization, separate easily. This improvement in the presentation of the starting material of the present process, e.g. Illustrated in Example 8 below, the yield can be e.g. of spironolactone increase even further.

A particular advantage of the present process is furthermore that when the starting material is reacted with M in the case of the brominating agent, in addition to the oxidation thereof and the dehydrobromination, the 4,6-dien-3-one intermediate is taken as a single compound which one easily, e.g. by pure crystallization, preserved in the pure state

9

617 443

can. In contrast, it is e.g. in the processes C-E discussed above, all of which go through the 4,6-dien-3-one stage according to formula VIII, it is difficult to obtain pure preparations of this constitution, since they are always mixtures of the alkoxy epimeric at the 21-carbon atom Connections.

One consequence of this is that cleaning in the final stage, e.g. for Spironolactone, very tedious and complex. In contrast, products of such quality are obtained in the last stages of the present process that normally a simple cleaning operation, such as e.g. the crystallization is already sufficient to obtain completely pure products.

The advantage of the present method compared to the above-mentioned method B of US Pat. Nos. 3,738,983 and 3,270,008, in addition to the advantages already mentioned with regard to the yields, is also that, in comparison, it has only a few operations which are technically simple to design .

The invention is illustrated in the following examples. The temperatures are given in degrees Celsius.

example 1

20 g of dehydro-epi-androsterone are abs in 500 ml. Tetra-hydrofuran dissolved. Then 5.2 g of lithium wire cut into small pieces are added. It is then cooled to 0 ° with an ice bath and 38 g of β-chloropropionaldehyde-ethylene-acetal in 50 ml of abs are added dropwise with stirring in an N2 atmosphere over the course of 15 minutes. Tetrahydrofuran too. The cooling is so strong (ice-salt mixture) that the reaction temperature does not exceed 10 °. The mixture is then stirred for a further 2 hours at 0 ° and overnight at room temperature (all under nitrogen). The excess lithium pieces are then separated off and the reaction solution is poured onto ice water. Then extracted with ethyl acetate and washed neutral with saturated aqueous NaCl solution. The crude product obtained after drying over Na2S04 and evaporation of the organic phase is filtered on 300 g of neutral A1203 act. II. Thereby, unreacted reagent and non-steroid-like impurities are eluted with 3 l of petroleum ether-toluene (1: 1) mixture. With CH2C12 as eluent, 19.9 g of 17a- (3'-ethylenedioxy-propyl) -androst-5-en-3ß, 17ß-diol are obtained, which melts at 181-182 ° after crystallization from acetone-petroleum ether. Yield 16.4 g (60.6% of theory). IR. 3600.3450 cnr ^ CHjClz). -NMR: 0.87, s, CH, (18); 1.02, s, CH3 (19); 3.50, m, CH (3); 3.92, m, -0CH2CH20-; 4.91, t, J = 4, CH (3 '); 5.34, m, CH (6)

(CDC13).

Example 2:

6 g of 17a- (3'-ethylenedioxy-propyl) -androst-5-en-3ß, 17ß-diol are added to 5.4 g of solid pyridinehydrobromide perbromide in 60 ml of pyridine at 0 °. Then the mixture is stirred for 3 hours at 0 ° with exclusion of moisture. 1 hour after the start of the reaction, 4.5 g of CrO 3 in 6 ml of H20 are added dropwise to 45 ml of ice-cold pyridine, the dropping rate being chosen so that the temperature in the flask does not exceed 10 °. The resulting pyridine chromate solution is then stirred at 0 ° until the parallel bromination reaction has ended. Then the pyridine chromate solution is poured into the bromination solution and the mixture is stirred for a further 3 hours at 0 ° and then additionally overnight at room temperature.

Then dilute with plenty of CHC13 and wash successively four times with saturated aqueous NaCl solution, ten times with water and again four times with saturated NaCl solution. The organic phase is then dried with Na2S04 and evaporated to dryness in vacuo.

The resulting crude oxidation product is dissolved several times in toluene for azeotropic removal of residual pyridine and evaporated to dryness in vacuo. Then dissolved in 108 ml abs. Dimethylforamide, mixed with 10.8 g each of LiBr and Li2C03 and heated with stirring in N2 atomic spheres to 100 ° in the course of 15 minutes and then left at that temperature for a further 5 hours. Afterwards, the mixture is allowed to cool, diluted with ethyl acetate and washed ten times with water and once with saturated aqueous sodium chloride solution. The phase dried over Na2S04 is then evaporated in vacuo and the resulting evaporation residue is filtered on 100 g of neutral 10 A1203 (Act. II). The apolar impurities are first eluted with 500 ml of toluene. The subsequent ethyl acetate eluates consist of 4.56 g of 17β-hydroxy-17a- (3'-ethylenedioxy-propyl) -androsta-4,6-dien-3-one, which once recrystallized from acetone-petroleum ether and melted at 132 °. After recrystallization, yield 15.44 g (74.7% of theory).

IR .: 3570.3450.1655.1620.1585 cm- '(CH2C12) .- UV .: 287 (19700) inC2H5OH. - NMR: 0.95, s, CH3 (18); 1.10, s, CH3 (19); 3.95, m, -0CH2CH20-; 4.89, t, J = 4, CH (3 '); 5.65, s, CH (4); 6.08, s (2H), CH (6) + CH (7) (CDC13). - [a] D = -6 ° (1.04 inCHCl3).

Example 3:

5 g of 17β-hydroxy-17a- (3'-ethylenedioxy-propyl) -androsta-4,6-dien-3-one are dissolved in 50 ml of metha-5 noi at room temperature. Then 7.5 ml of water and 2.5 ml of thioacetic acid are added in succession and the mixture is stirred for 3 hours at room temperature. It is poured onto ice-cold 2N aqueous NaHC03 solution, extracted with ethyl acetate and washed neutral with saturated aqueous NaCl solution. After drying (Na2S04) -w and evaporation in vacuo, 5.86 g of 7a-acetylthio-17β-hydroxy-17a- (3'-ethylenedioxy-propyl) -androst-4-en-3-one [IR. 3450 (broad 1685.1670.1620 cm "1 (CH2C12); NMR. 0.92, s, CH3 (18); 1.22, s, CH3 (19); 2.33 s, SCOCH3; 3.94, m, CH (7) + - 0CH2CH20-4.91, t, J = 4, CH (3 '); 5.68, bs, CH (4) «(CDC13)], which are directly processed further. 86 g of crude product are dissolved in 200 ml of acetone and cooled to 0 ". 10 ml of 8N Cr03 in 8N H2S04 are then added dropwise with stirring so that the temperature does not exceed 10 °. The mixture is then stirred for 45 minutes at room temperature. 411 is then added dropwise another 5 ml of the above Cr03 solution at room temperature and stirring for a further hour at room temperature, then 10 ml of methanol are added, the mixture is stirred for another 10 minutes and then diluted with ethyl acetate Sodium acetate and sodium chloride, dried over Na2S04 and evaporated to dryness in vacuo, giving 5.5 g of a crystalline tube product, from which 2.75 g of spironolactone (7a -Acetylthio-3-oxo-17a-pregn-4-en-21,17-carbolactone s «(51% of theory based on the starting material of Example 3) from Doppelsmp. 135 and 202 ° is obtained. IR. 1770.1670-1700 wide, 1620 cm-1 (CH2Cl2) .UV. 240 (19400) in C2H5OH. -NMR. 0.97, s, CH3 (18), 1.20, s, CH3 (19), 2.31, s, SCOCH3; 2.84.8 line signal, J66 = 15, J67 = 4, J46 = 2, CH (6ß): 3.97, ss m. CH (7) 5.68, d.J. = 2. CH (4) (CDC13). '

Example 4:

1.80 g of 17β-hydroxy-17a- (3'-ethylenedioxy-propyl) -andro-60 sta-4,6-dien-3-one are dissolved in 5.1 ml of boiling methanol. 1 ml of thioacetic acid is then added dropwise to the boiling solution in the course of 5 minutes and the mixture is then boiled for a further 30 minutes. It is then cooled, diluted with ethyl acetate and washed successively with aqueous solutions of NaHC03 and ft5 NaCl to the neutral point. The organic phase is then dried over Na2SO4 and evaporated in vacuo. This results in 2.09 g of crude product, which is aqueous in 80 ml of acetone at 0 ° while stirring with 4 ml of an 8 N CrO 3 solution in 8 N

617 443

10th

H2S04 can be moved. The mixture is then stirred at room temperature for 1 hour, 2 ml of the above CrO 3 solution are added and the mixture is stirred for another hour. It is then taken up in ethyl acetate, washed three times with saturated aqueous solutions of sodium acetate and NaCl, dried over Na2S04 and evaporated to dryness in vacuo. This results in 1.87 g of crude spironolactone, from which 1.25 g of pure compound are obtained by single crystallization from CH2Cl2-methanol. (Physical data as in example 3).

Example 5:

20 g of dehydro-epi-androsterone are abs in 500 ml. Tetra-hydrofuran dissolved. Then 5.2 g is cut into small pieces of bare lithium wire. Thereupon it is cooled to 0 ° with an ice bath and 38 g of β-chloropropionaldehyde-ethylene acetate in 50 ml of abs are added dropwise with stirring in N2 atomic sphere over the course of 15 minutes. Tetrahydrofuran too. The cooling is so strong that the reaction temperature does not exceed 10 °. The mixture is then stirred for a further 2'A hours at 0 ° and overnight at room temperature (all under nitrogen). The excess lithium pieces are then separated off, poured onto ice water and the excess reagent and its decomposition products are separated off by means of steam distillation. The non-volatile residue is finally extracted with methylene chloride. The resulting methylene chloride phase is washed neutral with saturated aqueous NaCl solution, dried over Na2S04 and evaporated in vacuo. The resulting crude product is filtered on 600 g of neutral A1203 of Act II. First four fractions are eluted with 1 liter of methylene chloride. Then the column is washed out with 6 fractions of methylene chloride-ethyl acetate (4: 1) mixture (1 liter each). Evaporation of the third fraction gives 3.2 g of unreacted crude dehydro-epi-androsterone, from which 2.65 g of pure substance are recovered by crystallization from i5 acetone-petroleum ether. Fractions 4-10 yield 20.1 g 17a- (3-ethylenedioxy-propyl) -androst-5-en-3ß, 17ß-diol, which melts at 181-182 ° after crystallization from methylene chloride petroleum ether (17 g; 74 % of theory, taking into account the recovered raw material).

Claims (20)

617 443 2. The method according to claim 1, characterized in that an acetal is used as the starting material, which is derived from lower alkanols or alkane diols having 1-7 C atoms. 2nd PATENT CLAIMS 1. Process for the preparation of compounds of the formula % / Y a) wherein R represents an acylthio group, characterized in that an acetal of 3ß, 17ß-dihydroxy-17a-pregn-5-en-21-carbaldehyde in basic to and with a neutral medium with a brominating agent suitable for the addition of bromine to a double bond treated, the resulting 3-hydroxy-5,6-dibromo derivative with a compound of the 6-valent chromium oxidized under basic to neutral conditions to the corresponding 3-oxo steroid, the product obtained dehydrobrominated, to introduce a 7-a-acylthio group with the thiocarboxylic acid corresponding to this acylthio group and then treating the product obtained with a compound of hexavalent chromium in acid solution. 3. The method according to claim 1, characterized in that the ethylene glycol acetal of 3ß, 17 ß-dihydroxy-17 a-pregn-5-en-21-carbaldehyde is used as the starting material. 4. The method according to claim 1, characterized in that the bromination with bromine or an ether-bromine storage product or a perbromide of a tertiary aromatic nitrogen base in a lower aliphatic chlorinated hydrocarbon, a diniederalkyl-lower alkanoic acid amide, optionally in the presence of a buffer, or in a tertiary organic aromatic base. 5. The method according to claim 4, characterized in that pyridine hydrobromide perbromide is used in pyridine and the reaction is carried out at low temperature or at room temperature. 6. The method according to claim 5, characterized in that brominated between 0 ° and + 20 °. 7. The method according to claim 1, characterized in that the 5,6-dibromo addition product is oxidized with chromium trioxide or with chromic acid in a tertiary aromatic base. 8. The method according to claim 7, characterized in that pyridine is used as the base. 9. The method according to claim 7, characterized in that one oxidizes at temperatures between -10 ° to + 30 °. 10. The method according to claim 1, characterized in that one carries out the dehydrobromination of the chromic acid oxidation product with inorganic basic agents. 11-7 carbon atoms oxidized. 11. The method according to claim 10, characterized in that lithium halides are used in the presence of a basic salt of an alkali metal or alkaline earth metal. 12. The method according to claim 10, characterized in that lithium bromide is used in the presence of lithium carbonate, and the dehydrobromination in dimethylformamide is carried out at temperatures between 80 ° and 150 °. 13. The method according to claim 1, characterized in that the product obtained by the dehydrobromination in a lower alkanol with 1-7 C atoms and at temperatures between 0 and 120 ° with about 1.5-3.5 mol of one Reacts thiocarboxylic acid. 14. The method according to claim 13, characterized in that at temperatures between 50 and 100 ° in one , anhydrous alcohol. 15. The method according to claim 13, characterized in that reacting with a lower thioalkanoic acid having 1-7 C atoms. 16. The method according to claim 15, characterized in î that you react with thioacetic acid. 17. The method according to claim 1, characterized in that a compound obtained by conversion with thioacetic acid is treated with a compound of hexavalent chromium in mineral acid solution. . 18. The method according to claim 17, characterized in that is oxidized with chromium trioxide in sulfuric acid, optionally with the addition of acetone. 19. The method according to claim 17, characterized in that with chromium trioxide in a lower carboxylic acid 20. Process for the preparation of compounds of the formula wherein R represents an acylthio group, characterized in that v; net that dehydroepiandrosterone is reacted with a chloropropionaldehyde acetal in the presence of lithium, the reaction mixture is treated with steam, unreacted dehydroepiandrosterone from the corresponding acetal of 3ß, 17ß-dihydroxy-17a-pregn-5-en-21-carba in the residue of steam distillation! separates dehyds, and the latter is implemented according to the process of claim 1.