DD268953A1 - PROCESS FOR THE PREPARATION OF 3-ALKOXY-13BETA-ALKYL-GONA-2,5 (10) -DI-17BETA-OL-DERIVATIVES - Google Patents

Abstract

The invention relates to a novel combined process for the birch reduction of 3-alkoxy-13b-alkyl-gona-1,3,5 (10), 8-tetraene-17b-ol derivatives and 3-alkoxy-13b-alkyl-gona- 1,3,5 (10), 9 (11) -tetraene-17b-ol derivatives or of mixtures of the D8 and D9 derivatives or their racemates. By steroselective reduction of the D8 / D9 double bond, 22 is reduced to the 3-alkoxy-13b-alkyl-gona-1,3,5 (10) -triene-17b-ol derivatives using proton donor mixtures with pKa values, hereinafter referred to as partial reduction of the aromatic A-ring using proton donors with pKa values of 21 in high excess, into the 3-alkoxy-13b-alkyl-gona-2,5 (10) -diene-17b-ol derivatives become. In this process, the first reduction stage is carried out at temperatures above 40C and the second reduction stage below 42C. The isolation of the reaction products by extraction with tetrahydrofuran and Faeller or by crystallization from alcohols. With the new method, using max. 5 to 8 moles of alkali metal per mole of steroid compared to the previously known state of the art achieved by a throughput increase to 5 times a significantly improved capacity utilization and more favorable material economy.

Description

Field of application of the invention

The invention relates to a combined process for the Birch reduction of 3-alkoxy-13β-alkyl-gona-1,3,5 (10), 8-tetraene-17β-ol derivatives, 3-alkoxy-13β-alkylgona-1, 3,5 (10), 9 (11) -tetraene-17β-ol derivative 9n and mixtures of the 13β-alkyl-A ^e / A ⁹ derivatives and of racemates of the said compounds without intermediate isolation of the 3-alkoxy-13β-alkylgona 1,3,5 (10) -triene-17β-ol derivatives to the 3-alkoxy-13β-alkyl-gona-2,5 (10) -diene-17β-ol derivatives. 3-alkoxy-13β-alkyl-gona-2,5 (10) -diene-17β-ol derivatives sin ', important intermediates of steroidal total synthesis for the preparation of highly effective drugs such as nandrolone esters, norethisterone acetate, norgestrel, dienogestrel and others

-2- 268 953 Characteristic of the known technical readings

For the synthesis of 19-norsteroids by total synthesis after that of IVTorgov and others Doklady. Akauk Nauk SSSR, 135, 73-76 (1960) (Ca 55,11462 (1961)) are applied according to the well-known literature procedures according to which 3-alkoxy-13β-alkyl-gona-1,3 , 5 (10) 8-tetraene-17ß-o! -Deiivate whose A ^wi1l- isomers or their racemates preferably with lithium in liquid ammonia using ethers such as diethyl ether, dioxane and tetrahydrofuran or mixtures thereof and addition of aniline as proton donor. itor to the 3-alkoxy-13ß-alkyl-gona-1,3,5 (10) -triene-17ß-ol derivatives or their racemates and reacting these products after purification by recrystallization in a yield of 50% to 80% d (See also KK Koshoev, SNAnanchenko, IVTorgov Khim, prirod, Soedenii Akad., Nauk SSSR, 1965, 1980 to 188, CA 63, 13346 [19691, H. Smith, Brit. Pat., 1010052, CA, 64, 12757 to 12758 (1966) TBWindholz et al., Steroids 6,409 [1965] CH Kno. D. Tank, N.L. Wendler Chemistry and Ind. 1,340 [1966]

C. Rufer, E. Schroeder, H. Gibian *

Liebigs Ann Chem. 701,260 to 216 [1967] G. Qunikert et al. LiebigsAnn.Chem. 1981, 2335 to 2371).

To convert the Estradioletherderivate so shown in Norsteroide further reduction with alkali metals in liquid ammonia is required. According to the literature which has become known, processes are used according to which 3-alkoxy-13β-alkyl-gona-1,3,5 (10) -triene-17β-ol derivatives or their racemates preferably with lithium, but also with potassium or Sodium in liquid ammonia with the addition of alcohols, preferably tertiary alcohols, to the partially reduced 3-alkoxy-13ß-alkyl-gona-2,5 (10) -diene-17ß-ol derivatives or their racemates reacted. See also

A.J.Birch.S.M.MukherjiJ.Chem.Soc. 2531 (1949) A. LWilds, N.A. Nelson, J. Am.Chem.Soc. 78,5366 (1953) J.A. Hartmann et al. J.Am.Chem.Soc.78, 5662 (1956) C.H. Robinson, O. Guoj, E.P. Oliveto J. Org. Chem. 25, 2447 (1960) V.M.Rzehezinikov, S.N. Ananchenko, I.V.Torgov

Khim. prirod. Soedenenii Akad. Nauk. SSSR 19665.90 to 100 CA 63, 13342 (1965) WP 67423

The procedure described here requires a high use of materials such as ammonia and solvents, it is also particularly laborious and has the particular disadvantage that dealing with strong estrogenic steroids such as estradiol derivatives in the isolation after the 1st reduction stage, as well as the cleaning the isolated crude products and reuse in the second reduction stage is unavoidable. Furthermore, under -33 ⁰ C, the condensation of ammonia and carrying out the reaction bie temperatures requires a large amount of energy that must be applied 2 times in successive reduction stages in the described procedure.

The disadvantages of this procedure were recognized early on and also described a number of so-called. Combined process, according to which the successive reduction stages can be carried out in a one-pot process.

VM Rzeheznikov, SN Ananchenko, IVTorgov, Izv. Akad. Nauk SSSR Osdel Khim Nauk 1962, 465-470 (CA57, 15175f (1962)) describe the reduction of dl-D-homo-3-methoxy-estra-1,3,5 (10) 8-tetraene-17β-ol with lithium or potassium and lithium in liquid ammonia / tetrahydrofuran Üiethylether mixtures at -40 ° C, which after a certain reaction time _; Ethanol is added to reduce the aromatic Α-ring. The yields of dl-D-homo-3-methoxy-estra-2,5 (10) -diene-i 17ßol amount to 50 to 70% by this procedure.

For the reaction of 1 mole of steroid, this method requires about 14 mol of potassium and 182 mol of lithium and a large reaction volume which is not justifiable for industrial processes (see table). A newer process variant; by G. Quinkert et al. Liebigs Ann. Chem. 1981.2335-2371 also uses 19MoI potassium and lithium per mole 99MoI \

Steroid. Toluen is also used as the solvent in this process, which is reduced to the 1,4-dihydrotoluene under the conditions used for Birch, thus consuming additional alkali metal. The amounts of ammonia and alkali metal mentioned for this method are also not suitable for a technical process, toluene is completely unsuitable because of the Kor.bewerbreaktion proceeding hereby.

After one of C. Rufer u. a. Liebigs Ann Chem. 702.141 to 148 (1967), which, according to the author, a method of H. Smith, J. Chem. Soc. (London) 1964,4472; Tetrahedron / (London) 22, 1019 (1966); J. Med. Chem. 9,338 (1966); Brit. Pat. 1010052 (1960) (CA64, 12757 to 12758 [1966]) are essential!

Improvements are achieved by lowering the alkali metal required for de reduction to about 20 mol / mol steroid and reducing the amounts of ammonia and solvent required for the reaction. In this method, the j

1. reduction stage with the addition of aniline and at temperatures of -40 ° C. The second reduction step is carried out with the addition of ethanol at a temperature of ⁰ C -6O. Compared to the hitherto known, largely technically used procedure of the separate implementation of these reaction steps (see also WP 67423), however, this process also requires a large reaction volume, which is not responsible for the technical implementation;

too high a consumption of solvent centers and too expensive workup and isolation of the reaction product. j

The use by tea of the procedure described by C. Rufer will be followed by a combined one;

Reduction method to gaining benefits by the insufficient economics of this method nullified (see j

also table). j

The object of the invention is the treatment of an improved combined Birch reduction process, according to which 3-alkoxy-13ßalkyl-gona-1,3,5 (10) 8-tetraene-17ß-ol with a max. Consumption of 10 moles of alkali metal / mole steroid and a minimum consumption of ammonia and solvents zi · 3-alkoxy-13ß-alkyl-gona-2,5 (10idien-17ß-ol reduced and isolated in a simplified Aufarbeitungspvozeß in high yields and in high purity The process must be technologically simple and economically feasible.

Explanation of the essence of the invention

It is an object of the present invention to provide an improved ancestor for the "combined Birch reduction" of 3-alkoxy-13β-alkyl-gona-1,3,5 (10) -8-tetraene-17β-ol without intermediate isolation of the 3-alkoxy-13β-olefin. to provide alkyl-gona-1,3,5 (10) -triene-17β-ol to the 3-alkoxy-13β-alkyl-gona-2,5 (10) -diene-17β-o, after carrying out the reactions is ensured in high concentrations technologically simple and economically favorable.

According to the invention, this object is achieved in that for the preparation of 3-alkoxy-13ß-alkyl-2,5 (10) -gonadien-17ß-ol derivatives of 3-alkoxy-13ß-alkyl-gona-1,3,5 (10 ) 8-tetraen-17β-ol derivatives or 3-alkoxy-13β-alkyl-gono-1,3,5 (10) 9 (11) -tetraene-17β-ol derivatives or mixtures of Δ * - and A ⁹ Or their racemates a combined one-pot Birch reduction method is applied. It is characterized in that the reduction of Birch in a concentration ratio steroid / ammonia / tetrahydrofuran = 1: s7: s9 with the addition of proton donor mixtures with pKa values of a 22 at reaction temperatures above -40 ° C and thereby by alkali metal dosing the reduction in a low concentrations of solvated electrons are added to the 3-alkoxy-13β-alkyl-gona-1,3,5 (10) -triene-17β-ol derivatives which are subsequently subjected to intermediate isolation with the addition of a large excess of pKa proton donors £ 21 in the ratio steroid proton donor = 1: 1.8 to 3.0 and temperatures below -42 ⁰ C with a high concentration of alkali metal or solvated electrons to the 3-alkoxy-13ß-alkyl-gona-2,5 (10 ) -diene-17ß-ol derivatives or the corresponding dl derivatives are reduced and the reaction products after addition of water by extraction with tetrahydrofuran, subsequent concentration and precipitation cder by crystallization are isolated s. The proton donors required for this combined procedure for the stereoselective reduction of the Δ * or Δ'-double bond and the partial reduction of the aromatic Α-ring of the steroid molecule are so adjusted to each other in terms of the required amount and their proton activities that a complete flow of stereoselective reduction of the Δ ⁸ · or A ⁹ double bond takes place and the proton donors used for this purpose do not act as buffer substances in the partial reduction of the aromatic Α-ring inhibiting or self-consumption of reducing agents (partial reduction of aniline) affects the complete reduction of the aromatic system or prevented.

According to the procedure of the invention, these conditions by proton donors with pKa a22 such as aniline, diphenylamine or mixtures thereof with alcohols such as ethanol, propanols or butanols in the ratio 1: 0.1 to 1:10 for the stereoselective reduction of A * - and Δ ' Double-bond of the steroid best met, it is achieved by the alcohol content that the amount of aromatic amine can be kept relatively low, which has a particularly advantageous effect on the required alkali metal requirement for the subsequent reduction of the aromatic Α-ring. For the partial reduction of the aromatic Α-ring proton donors with pKa values 21 21, pure alcohols such as propanols or butanols are used in high excess, which also act as excellent solvents for the steroid and the resulting alkoxides at the lower reaction temperatures.

The temperature control is particularly important for the combined reduction process, it is with the reaction temperature above -40 ° C, preferably at -32 ⁰ C to -35 ⁰ C prevented that formed as intermediates 3-alkoxy-13ß-alkylgona-1,3 To crystallize out 5 (10) -triene-17β-ol derivatives during the reaction. In contrast, a temperature below -42 ⁰ C is required in the second reaction stage, since at these temperatures, the side reactions of the alkali metals with the alcohols used as proton donors is pushed back so far that it does not compete for the reduction process and the excess alcohol used can be effective as a solvent. The process according to the invention preferably uses sodium as alkali metal, since in the first reduction stage it is preferably metered so that only a low concentration of solvated electrons results in the reduction of the A ⁸ / A ⁸ double bonds, the amounts required for this stage of alkali metal 2.5MoVMoI steroid (theoretically 2MoI required) should not exceed. In contrast, the second reduction stage requires a high concentration of solvated electrons, which is ensured at the reaction temperatures below -42 ⁰ C by a rapid addition of 3 to β McI alkali metal per mole of steroid. This low alkali metal consumption of the total reduction process of 5 to θ mole / mole of steroid (theoretically total of 4 moles of alkali metal / mole steroid required) is surprising compared to the known literature but especially in the application of sodium in a combined reduction process and makes the optimal design of the present Procedure particularly clear.

In addition, the processing according to the invention and the isolation of the reaction products could be particularly favorable. After the completion of the reduction process, the ammonia is distilled off and by addition of water to the reaction mixture, the phase separation of the tetrahydrofuran phase and aqueous phase is achieved, the tetrahydrofuran phase separated, the aqueous phase is extracted with tetrahydrofuran and concentrated the combined tetrahydrofuran under reduced pressure. this makes possible

a) the extensive concentration with the addition of water, the reaction products are almost completely precipitated;

b) by fractional separation of the tetrahydrofuran with small amounts of alcohol, the crystallization dor reaction products of the remaining alcohol in the residue with the addition of small amounts of water.

As a result of the crystallization process, particularly pure reaction products are obtained in a yield of 85 to 93% of theory. receive.

The work-up method according to the invention has over the prior art literature of extraction with Diethyl ether or methylene chloride in view of the technical application particular advantages, since the reuse

of tetrahydrofuran by simple recovery processes that require no complex investment guaranteed

However, the known literature processes require special separation methods for diethyl ether / tetrahydrofuran or Methylene chloride / tetrahydrofuran mixtures for which special equipment is required or is the reuse of Exclude methylene chloride / tetrahydrofuran mixtures, since methylene chloride-containing tetrahydrofuran by reaction with Alkali metals can cause explosions in the implementation of Birch reduction. The advantages of the invention shown here for the individual process steps over the known methods Procedures will be used in conjunction with the low levels of ammonia and ammonia required for this new process Tetrahydrofuran particularly clearly (see table). With this new procedure, the advantages of the combined Procedure-optimal utilization of the plants, low solvent consumption, low alkali metal consumption,

simple workup and isolation of the reaction products as well as optimal energy utilization compared to all previously

become known method also economically effective, which is also clear in the increase in throughput to about Sfache (im

comparable reaction volume) compared to the previously known, most effective method of C. Rufer expressed

comes.

As 3-alkoxy-13β-alkyl-gona-1,3,5 (10) 8-tetraene-17β-ol derivatives may be used

3-methoxy-13β-methyl-gona-1,3,5 (10) -8-tetraene-17β-ol,

3-methoxy-13β-ethyl-gona-1,3,5 (10) -8-tetraene-17β-ol and as

3-alkoxy-13β-alkyl-gona-1,3,5 (10), 9 (11) -tetraene-17β-ol derivatives

3-methoxy-13ß-methyl-gona-1,3,5 (10), 9 (11) -tetraene-17-ol

3-Methoxy-13β-ethyl-gona-1,3,5 (10) 9 (11) -tetraene-17β-ol or mixtures of the 13β-methyl-A ⁸ / A ⁹ derivatives

13β-ethyl-A ^e / A »derivatives

or the racemates of said compounds are used.

Dio examples given below are intended to explain the process of the invention in more detail without it in any way

limit.

table Torgcv u. a. required amounts per mole of steroid Mol Al kalime tall per mole of steroid Quinkert u. a. 50 mi required amounts per mole of steroid • 27.5 1 - 670 κ Mol Al kalime tall per MoP steroid 9 98 • U) et · method At the age of Literature 312 g Satisfied with literature I6O ml 284 85 1 - 6.9 1 Mol steroid C + ion feedstocks 2.3 g 9.5 1 O, 5l6.g - - (B Ol tn A ⁸ _Steroid 70 inl 20.5 1 -   - 690 g t- 3 H ₅ tetrahydrofuran 150 ml - - potassium 165 1 O diethyl ether - 68 1 1.49 - toluene 500 ml - 12.5 ml - volume per ammonia - - lithium ro aniline - 14.6 1.25 g (S alcohol potassium 585 s 300 ml 17 ι Alka. !metal 4.39 54 1 - g · Cb 400 ml - σ o alcohol lithium 1.28 kg 183 Γ alkali metal 9.35 g 47.5 1 reaction 35O ml - Diethyl ether methylene chloride - - Tetraliydrofuran - acetic acid

table

method

Caller u. a. (Schering) method of investigation

Batch sizes required moles of alkali required moles of alkali

according to litera- quantities per liuietall quantities per 'metal per

door;.! ol steroid per mole -Mol steroid mol steroid

f; A _. _Λ _ -J .1

feedstocks

/ \ -Steroid 116 g 298 g Tetrahycirofuran 1.66 1 4.26 1 diethyl ether - - toluene - - ammonia 3.54 9.1 1 aniline 225 ml 576 ml alcohol Alk al metal lithium ( "Resamt)

56.2 g

144 g

20.5

g 99O ml

1,605 1

ml

Isoprop.

ml

Sodium. 46 κ

cn in

C CS

Alcohol Alkali metal

560 ml '1.44 1 isopropanol ml

sodium

g - 92 g

Diethyl ether

Metylchloride l680 ml

T etrahydrofuran

Acetic acid 337 ml

5.82

060 nl 1.0 1

15.4 1 3.3 1

3-4

cn ro

^ ⁴ S SB

(B O

σ ·> ο c

I-H ₉

et · ρ CR

K< S3

O C (B

HHA

e £

CO = n-

e + φ μ.

(P 5 O

t 3

O TJ 0)

H- ^ I 3- O

embodiments example 1

3-methoxy-13β-methyl-1,2,5 (10) -gonadiene-17β-ol

In a 6 l sulfonating flask equipped with stirrer, thermometer, dry ice condenser, dry ice cold bath, dropping funnel and Supply line for argon / ammonia gas is condensed 1.41 ammonia.

284.0 g of 13β-methyl-3-methoxy-1,3,5 (10) 8-gona-tetraene-17β-ol are dissolved in tetrahydrofuran and this solution is dissolved in 80 ml

Aniline added.

20 ml of aniline are mixed with 43 ml of isopropanol. The steroid tetrahydrofuran solution is added to the liquid with stirring

Given ammonia. At a temperature of the reaction mixture of -33 "C, 35 g of sodium become within 45 minutes

added to the reaction mixture that no or only weak blue coloration of the reaction solution takes place (lower

Electron concentration). After this, 21 ml of proton donor mixture are added followed by the remainder to reduce the A ⁸ double bond

13g sodium added in the same manner.

Subsequently, 250 ml of ammonia are condensed to the reaction mixture and added 450 ml of isopropanol. The Reaction mixture is then cooled by means of Trockeneiskältebad to -45 ⁰ C. At this temperature, 69 g of sodium in

to the reaction mixture over a period of 30 to 45 minutes, the first quantities - about 25 g - have to be added very rapidly in order to achieve the blue coloration of the reaction solution-high electron concentration immediately with the addition. The further addition of sodium should then be such that no discoloration of the reaction solution takes place in the meantime and there are always small amounts of sodium bronze present. The reaction mixture is then stirred for 1.5 hours at -45 ⁰ C, for decolorization of the reaction mixture or to destroy the excess sodium is allowed to the reaction solution at-36 ⁰ C to -33 ⁰ C to warm, there is performed for a short time, the decolorization of the reaction solution by Reaction of the sodium with the excess isopropanol. 235 g of ammonium chloride are added to the reaction mixture, then the ammonia is distilled off and water is added to the tetrahydrofuran isopropanol solution. After phase separation is the

Separated tetrahydrofuran Isopropanollösiing, the aqueous-alkaline phase twice with 250 ml of tetrahydrofuran

extracted, the tetrahydrofuran solutions combined and concentrated under vacuum as far as possible, din crystallization of the

Reduction product is carried out in the remaining isopropanol solution with the addition of small amounts of water. Yield: 90 to 98% d. Th. (Depending on the addition of water) λ Example 2

3-methoxy-13ß-tthyl-2,5 (10) -gonadien-17.beta.-ol

59g 3-Methoxy-13ß-ethyl-gona-1,3,5 (10) 8-ietraenol Werdan in 290ml of tetrahydrofuran and iu a mixture of 320ml

Ammonia and 22 ml aniline / 3 ml isobutanol. The reaction mixture is cooled to -35 ⁰ C and within 45 minutes in portions with a total of 7.5g sodium so

added that no blue reaction solution is obtained. Another 10ml addition of proton donor mix and 3.2g

Sodium takes place within another 30 minutes. Then 70ml ammonia are post-condensed, 100ml isopropanol added to the reaction mixture and the Reaction mixture adjusted to a temperature of -48 ⁰ C. At this temperature, 15g of sodium within 20 Added minutes to the reaction mixture and then stirred for a further 1 hour at -45 ⁰ C to -48 ⁰ C stirred. '- \. After this reaction time, the reaction mixture is allowed to warm to 35 ⁰ C, wherein the decolorization of the reaction solution

he follows. The reaction mixture is then mixed with 45 g of ammonium chloride, the ammonia with the addition of 10OmI

Distilled off tetrahydrofuran, the residue is treated with water and the tetrahydrofuran solution after phase separation

separated. The further work-up is carried out as described in Example 1. The crystalline isolated reaction product is washed after suction with a little isopropanol and then sucked dry.

Built-up: 87 to 95% of the total Example 3

3-methoxy-13ß-ethyl-2,5 (10) -gonadien-17.beta.-ol

A mixture of 3-methoxy-13β-ethyl-gona-1,3,5 (10) 8-tetraene-17β-ol and 3-methoxy-13β-ethyl-gona-1,3,5 (10), 9 ( 11) -tetraen-

17β-ol (29.8 g) is reacted analogously to 3-methoxy-13β-ethyl-1,2,5 (10) -gonadiene-17β-ol as described in Example 2.

Yield: 22.7 g

Example 4

dl-3-methoxy-13β-ethyl-2,5 (10) -gonadiene-17β-ol

118 g of dl-3-methoxy-17β-ethyl-gona-1,3,5 {10) 8-tetraene-17β-ol are reacted as described in Example 1.

Yield: 109.2 g

Claims (7)

1. Process for the preparation of 3-alkoxy-13β-alkyl-2,5 (10) -gonadiene-17β-ol derivatives from 3-alkoxy-13β-alkyl-gona-1,3,5 (10) -8-tetrazone -17-ol derivatives or 3-alkoxy-13β-alkyl-gond-1,3, b- (10) 9 (11) -tetraene-17β-o! Derivatives or mixtures of Δ ⁸ and A ⁹ derivatives Combined one-pot Birch reduction process, characterized in that the Birch reduction in a concentration ratio steroid / ammonia / tetrahydrofuran - 1: <7: <9 with the addition of proton donor mixtures with pKa values> 2 "at reaction temperatures above -4O ⁰ C carried thereby by alkali metal addition, the reduction at a low concentration of solvated electrons to the 3-alkoxy-13ß-alkyl-gona-1,3,5 (10) -triene-17ß-ol derivatives, which subsequently followed without intermediate isolation Addition of a high excess of proton donors with pKa values <21 in the ratio steroid / proton donor 1: 1.8 to 3.0 and temperatures maintain) -42 ⁰ C at a high concentration Alkali metal or solvated electrons to the 3-A'koxy-13ß-alkyl-gona-2,5- (10) -diene-17ß-ol derivatives reduced and the reaction products after addition of water by extraction with tetrahydrofuran, subsequent concentration and precipitation or be isolated by crystallization. 2. The method according to item 1, characterized in that correspond as proton donors with pKa values> 22 aniline, diphenylamine or mixtures thereof with alcohols such as ethanol, propanols or butanols in the ratio 1: 0.1 to 1:10, dip these conditions and are used as proton donors with pKa values ^ 2 / pure alcohols such as propanols or butanol in high excess, which are used in dt 'r 2nd reduction stage simultaneously as an additional solvent. 3. The method according to the items 1 and 2, d idurch characterized in that in the first reduction stage, the alkali metal addition is preferably carried out at temperatures of -32 ⁰ C to -35 ° C, wherein the reduction carried out at a low electron concentration and not per mole steroid more than 2.5 moles of alkali metal can be used. 4. The method according to items 1 to 3, characterized in that the second reduction stage at temperatures of -42 ⁰ C to -52 ⁰ C, preferably -45 ⁰ C performed and per mole of steroid 3 to 6MoI alkali metal while maintaining a high electron concentration be used. 5. Process according to items 1 to 4, characterized in that sodium is preferably used as alkali metal. 6. Process according to items 1 to 5, characterized in that as 3-alkoxy-13ß-alkyl-gona-1,3,5 (10), 8-tetraene-17ß-ol derivatives 3-methoxy-13β-methyl-gona-1,3,5 (10) -8-tetraene-17β-ol, 3-methoxy-13β-ethyl-gona-1,3,5 (10) -8-tetraene-17β-ol and as 3-alkoxy-13β-alkyl-gona-1,3,5 (10), 9 (11) -tetraene-17-ol derivatives 3-methoxy-13ß-methyl-gona-1,3,5 (10), 9 (11) -tetraene-17-ol-3-methoxy-13ß-ethyl-gona-1,3,5 (10), 9 (11) tetraene-17β-ol or mixtures of the 13β-methyl-A ⁸ / A ⁹ derivatives 13β-Ethyl-A ⁸ / A ⁹ derivatives or the racemates of said compounds are used. 7. The method according to items 1 to 6, characterized in that the isolation of the reaction products after abortion of the tetrahydrofuran by precipitation with water or by crystallization from alcohols.