DE2717310A1 - PROCESS FOR THE PREPARATION OF 17-ACETALS FROM 3-ALKOXYOESTRA-2,5 (10) -DIEN-17-ONES - Google Patents

Description

10

MITSUBISHI CHEMICAL INDUSTRIES LIMITED Tokyo, Japan

15th

¹¹ Process for the preparation of 17-acetals from 3-alkoxy · oestra-2,5 (10) -dien-17-ones "

Priority: April 19, 1976, Japan, No. 44 295/76 December 7, 1976, Japan, No. i46 835/76

The invention relates to a new method for the production of 17-acetals of 3-alkoxyestra-2,5 (10) -dien-17-ones by Birch reduction of the corresponding 17-acetals of 3-alkoxyestra-1,3,5- (10) -trien-17-ones. The compounds that can be produced according to the invention are valuable intermediate products for the production of steroid hormones, such as 17iX-ethynyl-19 -nox-testosteron (norethhisteron).

In the JA-AS 17 O3O / 196O is a method for production of 3-methoxyö3tra-2,5 (10) -dien-17-one-ethylene eetal by reduction of 3-methoxy5stra-1,3,5 (10) -trien-17-one-ethylene acetal with lithium or sodium, liquid ammonia and isopropanol

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described in the presence of diethyl ether. This process has the disadvantage that large amounts of diethyl ether and liquid Ammonia must be used.

It is also known Ι, Ί-dihydrosteroids, such as 3-Methoxyöstra 2,5 (10) -dien-17-one diethylacetal, by reducing the corresponding aromatic steroids, such as 3-methoxyestra-1,3 »5 (10) -trien-17-one-diethylacetaljmit Lithium or sodium, liquid ammonia and tert-butanol in the presence of tetrahydrofuran to manufacture; see J. Fried and J. A. Edwards, Organic Reactions in Steroid Chemistry, Vol. 1, pp. 25-27 and 49-50 and J. Org. Chem. 26: 3237-32-5 (1961). This Process has the disadvantage that the use of larger amounts of tert-butanol, which acts as a proton donor and as a solvent serves, the reaction rate slows down.

Impurities in the starting compounds, such as in the 17-acetals the 3-Alkoxyöstra-l, 3,5 (10) -trien-17-one and the liquid Ammonia and the solvents! Probably have one unfavorable effect on the conversion of the starting steroids into the 17-acetals of the 3-alkoxyöstra-2,5 (10) -dien-17-ones. These unfavorable Side effects can be avoided by purifying the starting compounds and solvents, but is this is uneconomical because of the overall yield of 17-acetals the 3-alkoxyestra-2,5 (10) -dien-17-one is reduced and L5-solvent losses appear.

The invention is based on the object of providing a method for _L J098U / 0881

- JT-

Preparation of 17-acetals from 3-alkoxyöstra-2,5 (10) -dien-17-ones by Birch reduction of the corresponding 17-acetals of 3-alkoxyestra-1,3 »5 (10) -trien-17-ones to create that is reliably reproducible, runs in high yield and selectivity and the disadvantage of using larger amounts of solvents such as diethyl ether, tert-butanol and liquid ammonia, avoids, This object is achieved by the invention.

The invention thus relates to a process for the preparation of 17-acetals from 3-alkoxyestra-2,5 (10) -dien ~ 17-ones of the general kind Formula I.

(D 15

in the row and row either a C,,. ~ -Alkyl radical or together a C__ ₁₀ -alkylene radical and R-, a C _1Q -alkyl radical, by reduction of 17-acetals from 3-alkoxyestra-If3,5 (10) -trien-17-ones (starting steroid) of the general formula II

O O

(ID

ΓΎ Ί

the
in which R., R_ and R, / have the above meaning, with sodium or potassium in liquid ammonia and a tertiary alcohol

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in the presence of tetrahydrofuran, dioxane or tetrahydropyran (solvent), which is characterized in that one
(a) a maximum of 90 ml (measured at the boiling point of the system) of liquid ammonia per gram of sodium or potassium;
(b) a maximum of 100 ml (measured at 15 C) of solvent per gram of sodium or potassium,

(c) sodium or potassium and

(d) the starting steroid is used in such proportions that the starting steroid is practically

^ ⁰ table is dissolved and that two liquid phases are formed, with an upper phase consisting mainly of sodium
or potassium and liquid ammonia and a colored lower phase composed mainly of solvent, liquid
Ammonia and the parent steroid,

The process according to the invention proceeds according to the following reaction scheme:

Birch reduction

(ID (D

The 17-acetal of 3-alkoxyöstra-2,5 (10) -dien-17-one of the general formula I (hereinafter referred to as ESD for short) is obtained by Birch reduction of a 17-acetal of 3-alkoxyöstra-1,3 » 5 (10) - L 109844/0881 _i

trien-17-one of the general formula II (hereinafter referred to as ETA designated).

In the general formulas I and II, the radicals R. and R- can each denote alkyl radicals having 1 to 10, preferably 1 to 5 carbon atoms, such as the methyl, ethyl, propyl or butyl group. R ₁ and R ~ together can also denote an alkylene radical having 2 to 10, preferably 2 to 5 carbon atoms, such as the ethylene, 1-methylethylene, trimethylene, tetramethylene group. Rv denotes an alkyl radical having 1 to 10, preferably 1 to 5 carbon atoms, such as the methyl, ethyl, propyl or butyl group.

Specific examples of those used in the process of the invention Parent steroids (ETA) are

3-Methoxyöstra-1,3,5 (10) -trien-17-one-ethylene acetal, 3-Äthoxyöstra-1,3,5 (10) -trien-17-one-ethylene acetal _/ 3-Methoxyöstra-1,3 , 5 (10) -trien-17-one-dimethylacetal, 3-Methoxyöstra-l, 3,5 (10) -trien-17-one-diethylacetal, 3-Äthoxyöstra-l, 3,5 (10) -triene- 17-one diethylacetal, 3-methoxyestra-1,3,5 (10) -trien-17-one-propylene acetal and 3-methoxyestra-1,3,5 (10) -trien-17-one-tetramethylene acetal.

A particularly preferred starting sterol is 3-methoxyestral, 3,5 (10) -trien-17-one-ethylene acetal.

According to the method according to the invention, the Birch reduction of ETA with sodium or potassium, preferably sodium as a re-

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reducing agent, a tertiary alcohol such as tert, butanol or tert-amyl alcohol, preferably tert-butanol as proton donor, liquid ammonia and tetrahydrofuran, dioxane or tetrahydropyran, preferably tetrahydrofuran, carried out as solvents.

Sodium or potassium are used as reducing agents. The use of potassium on an industrial scale is dangerous because of its violent reaction with water. Therefore sodium is the preferred reducing agent. The use of lithium instead of sodium or potassium is technical because of the low selectivity and the difficulty of controlling the reaction Scale associated with a higher reaction rate is not preferred.

Tert-butanol and tert-amyl alcohol are considered tertiary alcohols preferred because of the high selectivity. Tert-butanol is particularly preferred.

The low solubility of ETA in liquid ammonia requires the presence of a solvent in which ETA is soluble. in the Process according to the invention tetrahydrofuran, dioxane or tetrahydropyran are used, which easily dissolve ETA. The preferred one The solvent is tetrahydrofuran because of its low boiling point. In the process according to the invention, the combination of sodium, liquid ammonia and tetrahydrofuran gives the best results.

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Characteristic features of the process according to the invention are the amounts of sodium or potassium, liquid ammonia and solvents and ETA and their proportions. The meaning of the amounts and the proportions of the four components are as follows and explained with reference to the drawing, which shows the change in the phase state with the amounts of liquid ammonia, tetrahydrofuran and 3-methoxyestra-1,3,5 (10) -trien-17-one-ethylene acetal (hereinafter referred to as EMF for short) or sodium. In the drawing, the menu items are on the abscissa axis (x-axis)

¹ ^ gene of liquid ammonia, measured at the boiling point of the system, and the amounts of tetrahydrofuran, measured at 15 ° C., are plotted on the ordinate axis (y-axis). If the amounts of liquid ammonia and tetrahydrofuran per gram of sodium are in the area above curve A, two liquid

^ sige phases. The upper phase is colored reddish brown and consists mainly of sodium and liquid ammonia. The lower phase consists mainly of tetrahydrofuran, liquid Ammonia and emf. If the proportions of liquid ammonia and tetrahydrofuran per gram of sodium are in the range

² ^ half of curve A, a single phase with a reddish brown to deep blue color is formed.If the quantity ranges of liquid ammonia and tetrahydrofuran per gram of sodium are in the range above curve C, the lower phase consists mainly of tetrahydrofuran, liquid ammonia and EMF, and it is practically colorless. If the proportions are in the area below curve C, the lower phase is colored deep blue.

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If the lower phase is colorless and consists mainly of tetrahydrofuran, If there is liquid ammonia and EMF, the sodium is not dissolved in the lower phase. On the other hand, if the lower Phase is colored, sodium is dissolved in it.

If the amounts of liquid ammonia and tetrahydrofuran per gram of EMF are in the region above curve B, then there is EMF in the system completely resolved. If they are in the area below the curve

B, EMF is not completely resolved in the system. 10

To increase the reaction rate, it is essential that the EMF in the reaction system is practically complete solved. Provided part of the EMF is in the form of a solid is present, the reaction rate is very slow. It is crucial to further increase the rate of reaction Meaning that the sodium is dissolved in the lower phase, in which the EMF is also practically completely dissolved.

^ O If the sodium is practically not dissolved in the lower phase, in which the EMF is present, good contact between the upper and lower phases by vigorous stirring is necessary, which is technically complex. Therefore, the amounts of liquid ammonia and tetrahydrofuran per gram of sodium should be in the area below curve C, while the amounts of liquid ammonia and tetrahydrofuran per gram of EMF should be in the area above curve B.

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If the amounts of liquid ammonia and tetrahydrofuran per gram of sodium are in the area below curve A, in in many cases EMF is not completely resolved in the reaction system. This fact is explained by the small amounts used of liquid ammonia and tetrahydrofuran and the ratio from sodium to emf,

From the above it can be seen that to increase the reaction rate of the Birch reduction the ETA is present as completely dissolved as possible in the reaction system and that in the lower phase, in which the ETA is dissolved, the sodium or potassium is dissolved.

In order to make the process according to the invention economical, preferably no large amounts of liquid ammonia are used and solvents are used. The liquid ammonia is generally used in an amount of at most 90 ml, preferably at most 75 ml and in particular a maximum of 60 ml per gram of sodium or potassium is used. The amounts are measured at the boiling point of the sy-

stems measured.

The amount of solvent per gram of sodium or potassium is "generally at most 100 ml, preferably at most 75 ml and in particular a maximum of 60 ml. The quantities are measured at 15 ° C

measure up.

In a preferred embodiment of the method according to the invention, in which a combination of sodium, EMF, tetrahydro-

109844/0881

furan and liquid ammonia is used, the ratio is from sodium to EMK to tetrahydrofuran to liquid ammonia 1 g: 0.5 to 4.0 g: 25 to 100 ml: 25 to 90 ml, preferably 1 g: 1.0 to 2.5 g: 30 to 70 ml: 35 to 70 ml, with the proviso that the EMF in the reaction system is practically complete is present in dissolved form and that two liquid phases are formed, the lower phase is colored.

In the process according to the invention, at least 2 g equivalents Sodium or Potassium used per mole of ETA. The preferred amount of sodium or potassium is in the range of 3.0 to 10 grams Equivalents per mole of ETA.

The tertiary alcohol is used in such an amount that 2 equivalents of protons per mole of ETA are available. If the proportion of tertiary alcohol is increased, the solubility of sodium or potassium and the rate of Birch reduction are reduced because the sodium or potassium is quickly consumed by its reaction with the tertiary alcohol. The tertiary alcohol is therefore preferably used in such an amount that 2 to k equivalents of protons are available per mole of ETA. In general, the tertiary alcohol becomes the reaction system 30 to 120 minutes after the start of the reaction

added.
25th

To avoid side reactions that are caused by impurities in the starting compounds and the solvent, the Birch Heduktion present invention is preferably _L 09844/0881 is also in the presence of? _J

an alicyclic hydrocarbon and / or an aliphatic Hydrocarbon carried out, which may have a side chain. Examples of usable alicyclic Hydrocarbons are compounds with 5 to 15, preferably 5 to 10 carbon atoms, such as cyolopentane, cyclohexane, cycloheptane, Cyclooctane, cyclononane, cyclodecane, methylcyclopentane, methylcyclohexane and isopropylcyclohexane. The preferred alicyclics Hydrocarbons are cyclopentane, cyclohexane, cyclooctane and methylcyclohexane. Examples of usable aliphatic Hydrocarbons are compounds with 5 to 25, preferably 5 to 15 carbon atoms, such as pentane, isopentane, Hexane, 2,2-dimethylbutane, heptane, 2-methylhexane, octane, isooctane, Nonane and decane. The preferred aliphatic hydrocarbons are hexane, heptane, octane and isooctane. The alicyclic or aliphatic hydrocarbon is generally used in a Amount of 1 to 20 ml, preferably 2 to 10 ml, used per gram of ETA.

The method according to the invention is distinguished from the known Method characterized in that it makes the production of ESD reliable and reproducible on a technical scale and to a high degree Yield and selectivity made possible. Another advantage of the process is the fact that smaller amounts of

Solvent and liquid ammonia can be used. 25th

The examples illustrate the invention. Percentages mean mole percent, conversion means Hol (converted EMF minus not converted EMF) per mole converted EMF, expressed in percent.

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Selectivity means moles of 3-methoxyestra-2,5 (10) -dien-17-one-17-ethylene acetal formed (hereinafter referred to as MEE for short) per mole converted EMF, expressed as a percentage.

Example 11 A 100 ml three-necked flask fitted with an ammonia gas inlet tube, equipped with a reflux condenser cooled with dry ice and a stirrer, 1.0 g of EMK, 0.5 g Sodium and 25 ml of tetrahydrofuran charged. The EMF is brought into solution by stirring. Then 30 ml of ammonia are in the flask condensed. The temperature of the reaction mixture falls to -28 to -29 ° C. The reaction mixture then separates in two liquid phases. The reddish brown colored upper one Phase consists mainly of liquid ammonia and sodium, while the lower, deep blue colored phase consists mainly of EMF, tetrahydrofuran, liquid ammonia and a low Amount of sodium. The reaction mixture is stirred at about 200 rpm for 1 hour. A mixture of 1 ml of tetrahydrofuran is then added and 2 ml of tert-butanol were added dropwise over the course of 5 minutes. The mixture is stirred for a further 2 hours. After that is the reddish brown color of the upper phase has practically disappeared and it has become a practically homogeneous phase with deep blue color. The liquid ammonia is then placed on a water bath and then the tetrahydrofuran under reduced » Pressure distilled off at a temperature below 30 ° C. The crystalline residue obtained is in 15 al Benzene added. The benzene solution is washed with water, dried and under reduced pressure at a temperature

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evaporated below ¹ IO ^{0 C.} The residue is dried. 1.0 g of crude MEA are obtained. The gas chromatographic analysis shows a conversion of 99.7 % and a selectivity of 92.5 t.

Example 2

Example 1 is repeated with 1.0 g of EMK, 0.5 g of sodium, ¹ JO ml of tetrahydrofuran and 40 ml of liquid ammonia. 1.0 g of crude MEA are obtained. The gas chromatographic analysis shows a conversion of 99.6 % and a selectivity of 92.5%.

Example 3

Example 1 is repeated with 1.0 g of EMK, 0.5 g of sodium, 30 ml of tetrahydrofuran and 35 ml of liquid ammonia. 1.0 g of crude MEA are obtained. The gas chromatographic analysis shows a conversion of 99.9 % and a selectivity of 92.7 %

Example 4

Example 1 is repeated with 1.0 g of EMK, 0.7 g of sodium, 28 ml of tetrahydrofuran and 35 ml of liquid ammonia. 1.0 g of crude MEA are obtained. The gas chromatographic analysis shows a conversion of 99.9 % and a selectivity of 92.0 tons.

Example 5

A 500 ml three-necked flask filled with an ammonia gas

inlet tube, a stirrer and a 200 ral dropping funnel with measuring scale is equipped with 150 ml of liquid ammonia. The ammonia is L I0984A / 0881 j

-φ-

ter condensed and then added to the flask. The flask is then charged with 5.0 g of crude EMK containing impurities adversely affecting the conversion of EMF to MEE, as well as 2.5 g of sodium, 125 ml of tetrahydrofuran and 30 ml of n-octane. The mixture is stirred at 200 rpm for 1 hour. A mixture of 5 ml of tetrahydrofuran and 10 ml of tert-butanol is then added dropwise over the course of 5 minutes. The mixture is then stirred for an additional 2 hours. The ammonia are then distilled off in a water bath and then the tetrahydrofuran under reduced pressure at a temperature below 30 ^{° C.} A crystalline pesticide remains, which is extracted with 100 ml of benzene. The Benζöllösung is washed with water, dried and ^{evaporated under reduced pressure at a temperature below 40 0} C, the residue is dried. 5.0 g of crude MEA are obtained. The gas chromatographic analysis shows a conversion of 99.6 % and a selectivity of 92.3 *.

Example 6

Example 5 is repeated with 5.0 g of the crude EMK, 2.5 g of sodium, 125 ml of tetrahydrofuran, 150 ml of liquid ammonia and 15 ml of n-decane. The gas chromatographic analysis shows a conversion of 99.1 % and a selectivity of 91.6 %.

Example7

Example 5 is made with 5.0 g of the crude EMK, 2.5 g sodium, 125 ml Tetrahydrofuran, 150 ml of liquid ammonia and 10 ml of cyclohexane repeated. The yield of crude MEE is 5.0 g. the

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Gas chromatographic analysis shows a conversion of 98.8 % and a selectivity of 92.3 %

Comparative Example 1 This example explains the Birch reduction in which the EMF is not completely dissolved in the reaction system. The conversion is correspondingly reduced.

Example 1 is carried out with 1.0 g of EMK, 0.5 g of sodium, 20 ml of tetrahydrofuran and 30 ml of liquid ammonia. When the liquid ammonia is introduced, part of the lustful EMF is precipitated. The yield of crude MEA is 1 g. The gas chromatographic analysis shows a conversion of 83.2 %

and a selectivity of 93.3 %>
15th

Comparative example 2

This example explains the Birch reduction, in which EMF is not annoyed, and by extending the response time

sales are increased.
20th

Comparative example 1 is repeated, but the reaction time after the addition of tert-butanol is 8 hours. The yield of crude MEA is 1 g. The gas chromatographic analysis shows a conversion of 99.3 % and a selectivity of 93.1 %.

Comparative Example 3 Example 1 is with 1.0 g of EMK, 1.0 g of sodium, 10 ml of tetrahydro-

^L 109844/0881 ^J.

furan and 40 ml of liquid ammonia repeatedly. The reaction mixture does not separate into two liquid phases and takes on a deep brown color. This state is maintained until the reaction is terminated. The gas chromatographic analysis shows a conversion of 86, ^ % and a selectivity of 90.7 %,

Comparative ^Example 1J

Comparative Example 3 is repeated, but the reaction time is after the addition of tert, butanol 8 hours The initial yield of crude ™ MEE is 1.0 g. The gas chromatographic analysis shows a conversion of 39.3 % and a selectivity of 88.5 %.

Comparative example 5

^ In this example the EHK is solved in the lower phase, while the sodium is practically not dissolved in it. The amount of oil is increased by increasing the agitation.

A 200 ml three-necked flask equipped with an ammonia gas inlet tube, a reflux condenser cooled with dry ice and a stirrer is loaded with 1.0 g of EMK, 1.0 g of sodium, 50 ml of tetrahydrofuran and 30 ml of liquid ammonia, sends. The reaction mixture separates into two liquid phases, the upper phase taking on a reddish brown color and the lower phase being colorless. The reaction mixture is stirred at 600 rpm for about 1 hour. Then a mixture of 2 ml of tetrahydrofuran and ¹ ml of J over 5 minutes tert, butanol is added dropwise, and stirring for another 2 hours

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continued. The reddish brown color of the upper phase has then almost disappeared, while the lower phase is almost colorless. The reaction mixture is then worked up as in Example 1. 1.0 g of crude MEA are obtained. The gas chromatographic analysis shows a conversion of 97 »5 % and a selectivity of 89.3?.

Comparative example 6

This example illustrates the fact that with a lower concentration Tration of sodium in the lower phase compared to the comparative example 5 an increase in the stirring does not bring about any appreciable increase in the conversion.

Comparative example 5 is repeated with 1.0 g of EMK, 1.0 g of sodium, 60 ml of tetrahydrofuran and 20 ml of liquid ammonia. The gas chromatographic analysis shows a conversion of 89.8 % and a selectivity of 93.6 %.

Comparative Example 7 In this example, the Birch reduction is carried out with raw EMK in In the absence of a hydrocarbon carried out. A satisfactory conversion is not obtained.

Example 5 is made with 5.0 g of the crude EMK, 2.5 g sodium, 125 ml

Tetrahydrofuran and 150 ml of liquid ammonia repeated. the

Yield of crude MSE is 5.0 g. Gas chromatographic analysis shows a conversion of 95.3 % and a selectivity of 92.5 %.
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Le

Claims (1)

P ate η ta η s ρ r \\ c .h__e_ 1, ' Process' for the preparation of 17-acetals from 3-alkoxy-oestra-2,5 (10) -dien-17-ones of the general formula I (D in the R ^ and H_ either a C. «Q-Alky! residue each or together a C _? . "-Alkylene radical and!?, A C." (II) in the R., R _? and R, which have the above meaning, with sodium or potassium in liquid ammonia and a tertiary alcohol in the presence of tetrahydrofuran, dioxane or tetrahydropyran (solvent), characterized in that one (a) 90 ml or less (measured at the boiling point of the system) liquid ammonia per tra.rim "latrinm or potassium, (b) a maximum of 100 ml (^ enesr.on be !. l'j ^o C) L ") Sunc3mittel per Grar.ia sodium or potassium, "~ 7 0 Ή} A k I 0 8 8 1 ORIGINAL INSPECTED (c) sodium or potassium and a * (d) The parent steroid is used in such proportions that the parent steroid is practical in the reaction system is dissolved and two liquid phases can be formed, with an upper phase consisting mainly of sodium or potassium and liquid ammonia and a colored lower phase mainly composed of solvent, liquid ammonia and the parent steroid. ^ O 2, method according to claim 1, characterized in that one as the starting steroid 3-methoxyÖ3tra-1,3,5 (10) -trien-17-one-ethylene acetal begins. 3. The method according to claim 1 and 2, characterized in that that the solvent used is tetrahydrofuran, 4. The method according to claim 1 to 3, characterized in that that: nan as tertiary alcohol tert -butanol or tert-amyl alcohol used. 5. The method according to claim 1 to ^, characterized in that that sodium is used. 6. The method according to claim 1, characterized in that ^ at most 75 ml of liquid ammonia per gram of sodium or potassium and no more than 75 ml of solvent used per gram of sodium or potassium. L- J09844 / Q881 7 · The method according to claim 6, characterized in that a maximum of 60 ml of liquid ammonia per gram of sodium or potassium and a maximum of 60 ml of solvent per gram of sodium or Potassium uses »
5 3. The method according to claim 1, characterized in that ^ aη at least 2 g equivalents of sodium or potassium per mole of starting steroid used. 9, method according to claim 8, characterized in that one 3.0 to 10 g equivalents of sodium or potassium per mole of starting steroid used" 1O ₁ process according to claim 1, characterized in that the tertiary alcohol is used in an amount corresponding to 2 equivalents of protons per mole of starting steroid. 11. The method according to claim 10, characterized in that the tertiary alcohol is used in an amount corresponding to 2 to ¹ l equivalents of protons per mole of starting steroid, 12. The method according to claim 1, characterized in that the tertiary alcohol 30 to 120 minutes after the start of Implementation adds.
25th 13. The method according to claim 1, characterized in that the reaction in the presence of an alicyclic and / or aliphatic hydrocarbon performs. ^L 509844/0881 lh «Process according to Claim 13», characterized in that an alicyclic hydrocarbon with 5 to 15 carbon atoms and / or an aliphatic hydrocarbon with 5 to 25 carbon atoms is used. 15. The method according to claim 13 »characterized in that the alioyclic and / or aliphatic hydrocarbon used in an amount of 1 to 20 ml per gram of starting steroid 10 J098U / 0881