DD289539A5 - PROCESS FOR THE PREPARATION OF 11 BETA- (4-ACETYLPHENYL) -17ALPHA-ALKOXY-METHYL-ESTRA-4,9-DIEN-3-ONES - Google Patents

Abstract

The invention relates to a process for the production of * which are of interest as potential fertility control agents for the pharmaceutical industry. In the chemical process, a 3-ketal protected * is converted into a corresponding *, which is converted into alcoholates *. The * are * stereoselectively converted to 5a, 10a epoxides, these are opened by Grignard reaction with p-substituted Arylmagnesiumbromiden to 11b-arylsubstituierten 5a-Hydroxyestrenen and hydrolyzed under acidic conditions, the 17b-hydroxyl group esterified by acylating or in a 17b Urethane is converted. {Estrane; * Antigestagens; Fertilitaetskontrolle; Drug}

Description

-2- 289 539 Field of application of the invention

The invention relates to a chemically synthetic process for the partial removal of 11β- (4-acetylphenyl) -17a-alkoxymethyl-estra-4,9-dien-3-ones of the general formula I. Such compounds are of interest to the pharmaceutical industry.

Characteristic of the known state of the art

11ß-aryl-substituted Estra Abdiene are already known. For example, 11β-aryl-17α-propynyl or 17α-ethynyl-estra-4,9-dien-3-ones are described in patent FR2497807 (EP57115), 11β- (4-dimethylaminophenyl) -17a-CH ₂ X-substituted Estra-4,9-dienes described in the patents DE3506785 (EP192598) and WO88 / 01686 and the 11ß- (4-acetylphenyl) -17amethoxy-methyl-estra-4,9-dien-3-one in the patents DE3504421 and EP190759 mentioned. For the latter compound no overall method of preparation is given, no intermediates and no biological assay results are published.

The introduction of the ^ a-CH ^ moiety takes place starting from 11β-aryl-substituted 17-ketosteroids according to the method of Hübner, Ponsold, Oettel and Freund (Arzneim. Forsch. 30, 401 (198O)) via a spiroepoxide and its cleavage, Die Herstellung The 11β-aryl-substituted 17-ketosteroids are prepared from 5a, 1 Oa-epoxy-estr-9 (11) -en-17-cotons by Grignard reaction, whereby a part of the 17-ketone reacts with it and produces mixtures which are carefully purified A series of 11-aryl-substituted Estra-4,9-dienes are antigestagenic in that they can competitively displace the natural progesterone, which is essential for maintaining pregnancy, from the receptor, without itself a gestagenic activity, due to a higher affinity for a progestagen receptor They can be used for postcoital fertility control use.

The dosage of the international standard substance RU 38486 (mifepristone ") in humans is quite high at 10 to 1000 mg per day compared to many other steroid hormones, whereby the success rate varies from 60% (in China) to approx 90% (in Europe) Since the compound also has undesirable antiglucocorticoid activity in addition to the antigestagenic activity, it is desirable to find more active compounds or compounds with improved dissociation of activity.

Object of the invention

The aim of the invention is the preparation and description of novel compounds of general formula I with improved efficacy for use as postcoital fertility inhibitors.

Explanation of the essence of the invention

The invention has for its object to provide a simple process for the preparation of 11 ß- (4-acetylphenyl) -17a-alkoxymethylestra-4,9-dien-3-ones of the general formula I, wherein

R is an alkyl radical having 1 to 6 carbon atoms,

R ^{1 represents} a hydrogen atom, an acyl radical COR ² or urethane radical CONHR ³ , R ^{2 represents} a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms and R ^{3 represents} a hydrogen atom, an alkyl radical having 1 to 4 carbon atoms or an aryl radical (with the exception of R * = H and R ² = CH ₃ ).

According to the invention, the object is achieved by reacting 3-ketalo Estra-5, (10), 9 (11) -dien-17-one with Trimethylsulfoniumhalogonid and bases in solvents to 17-spiro-1 ', 2'-oxiranes , this with alkali metal alcoholates in absolute alcohols to the 17a-alkoxymethyl-17ß-hydroxy-estra-5 (10), 9 (11) -dien reacts, these by epoxidation with H ₂ O ₂ in the 5a, 10a-epoxy-17a alkoxymethyl-estr-9 (11) -en-17β-ols, these with 1- (4-bromophenyl) -ethanone-1,1-ketals and Grignard magnesium in the presence of Cu-I salts to the 11β-aryl substituted ones 17a-alkoxymethyl-estr-9-en-5a-diols and hydrolyzed these unier acidic conditions to the 11 ß- (4-acetylphenyl) -17a-alkoxymethyl-17ß-hydroxy-estra-4,9-dien-3-ones and from the latter, the 17β-esters or 17β-urethanes of 11β- (4-acetylphenyl) -17a-alkoxymethyl-estra-4,9-dien-3-ones.

In the broad expansion of the process, the 3,3-dimethoxy-estra-5 (10), (9 (11) -dien-17-one of the formula II with trimethylsulfonium halides in the form of bromides or iodides in dimethyl sulfoxide or dimethylformamide in the presence of potassium tert-butanolate or benzene in the presence of KOH to the 3,3-dimethoxy-estra-5 (10), 9 (11) -diene-17-spiro-1 ', 2'-oxirane III reacted with sodium alcoholates reacting at the boiling point of the corresponding absolute alcohol (methanol, ethanol or propanol) to the 17a-alkoxymethyl-17β-hydroxy-estra-5 (10), 9 (11 J) of general formula IV by epoxidation with H ₂ O ₂ in presence of Hexafluoracexon or hexachloroacetone in chloroform or methylene chloride, at temperatures between O ⁰ C and 25 ⁰ C, the 5a, 10a-epoxy-17a-alkoxymethyl-estr-9 (11) -en-17-ols formed of the general formula V, those with 1- (4-bromonaphonyl) -ethanone-1,1-ethylene ketal and Grignard magnesium in diethyl ether or tetrahydrofuran in the presence of CuCl at temperature n between 0 ° C and 30 ° C to the 11 ß-aryl-substituted 17a-alkoxymethyl-estr-9-en-5a-17ß-diols of the general formula VI are reacted. By acid hydrolysis with dilute acetic acid in methanol, acetone or tetrahydrofuran, at temperatures between OX and 80 ° C or on acidic alumina, arise the 11β- (4-acetylphenyl) -17a-alkoxymethyl-estra-4,9-diene-3 -one of the general formula I, the esterification with acid anhydrides or acid chlorides having 1 to 6 carbon atoms and triethylamine or pyridine, optionally in the presence of 4- (dimethylamino) -pyridine at room temperature or their conversion to 17ß-urethanes by reaction of 17ß-alcohols with alkyl isocyanates having 1 to 4 carbon atoms or with free or substituted aryl isocyanates in the presence of triethylamine in benzene at temperatures between 20 ° C to 9O ⁰ C or by reaction of 17ß alcohols with phosgene in benzene and subsequent reaction with amines.

According to the process, the 11β (4-acetylphenyl) -17a-alkoxymethyl-estra-4,9-dienes

N-acetoxy-N-M-acetylphenyl-U-methoxymethyl-estra-.g-diene-S-on,

11β- (4-acetylphenyl) -17a-methoxymethyl-1ββ-phenylaminocarbonyloxy-estra-4,9-dien-3-one,

11β- {4-acetylphenyl) -17a-ethoxymethyl-17β-hydroxy-estra-4,9-dien-3-one,

17β-acetoxy-11β- (4-acetylphonyl) -17a-ethoxymethyl-estra-4,9-dien-3-one,

11β- (4-acetylphonyl) -17β-hydroxy-17α-propoxymethyl-estra-4,9-dlen-3-one or

- 11β- (4-acetylphenyl) -17β-propionyloxy-17a-propoxymethyl-estra-4,9-dien-3-one.

In the 11β-aryl-substituted-17α-alkoxymethyl-estra-4,9-aien-3-ones hitherto described in the literature, the introduction of the 17a-alkoxymethyl group took place after the introduction of the 11β-aryl group.

With the method according to the invention it is better with respect to the yield and a uniform reaction procedure to introduce the alkoxymethyl group first at C-17 and then to functionalize it at C-11. By esterification of the 17ß-hydroxy group to reach the esters, which are surprisingly active in the animal experiment.

As a measure of the strength of the antigestagenic effect was the animal experimentally determined abortive effect of the substances. For this purpose, female gravid rats (positive sperm detection = 1st pregnancy day) in the weight between 180g to 200g on the 5th to 8th day of pregnancy were subcutaneously suspended in peanut oil. After autopsy on the 18th

until the 20th day of pregnancy, the uteri were examined. The abortive effect was determined from the ratio of no longer gravid to inseminated animals. For the international standard substance RU38486 a 100% abortive effect was achieved according to this method with a dosage of 2: 3mg per animal over 4 days.

For the claimed compounds, a 100% abortive effect is determined at a dose of 2 mg per day over 4 days. These compounds are thus animal studies more effective than the international standard.

The inventive method is explained by the formula scheme and the embodiments.

embodiments

example 1

Preparation of 17β-substituted 11β- (4-acetylphenyl) -17a-methoxymethyl-estra-4,9-dien-3-ones

a) Preparation of 3,3-dimethoxy-estra-5 (10), 9 (11) -diene 17β-spiro-1 ', 2'-oxirane

6.3 g of 3,3-dimethoxy-estra-5 (10), 9 (11) -dien-17-one are suspended in 40 ml of DMSO and treated with 8.16 g of trimethylsulfonium iodide and 5.6 g of potassium tert. butanolate stirred at room temperature. After 2 hours, 5 mmol of trimethylsulfonium iodide and 5 mmol of potassium tert. butanolate added. After 5 hours, the mixture is poured into ice water, extracted with ethyl acetate, the organic phase is washed with aq. NH ₄ Cl solution and water, dried over Na ₂ SO ₄ and concentrated under vacuum. This gives 6.7 g of 3,3-dimethoxy-estra-5 (10), 9 (11) -diene-17β-spiro-1 ', 2'-oxirane as a yellow oil, which waxes waxy after a short time.

After washing with methanol, needles are obtained.

M.p. 94 ⁰ C to 98 ⁰ C

[a] _D = + 164- (CHCl ₃ ).

'H-NMR (CDCi)), TMS as internal standard:

ö (ppm): 0.88 (s, 3H, H-18); 2.63 to 2.90 (m, 2H, ABX system, J = 5Hz _A8, 17Q-CH ₂ OCH ₃₎ 3,23sund3,24 (s, je3H, 2x OCH _3); 5.50 (d, 1H, J = 4Hz, H-11).

b) Preparation of 3,3-dimethoxy-17a-methoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol

6,6g of 3,3-dimethoxy-estra-5 (10), 9 (11) -diene-17β-spiro-1 ', 2'-oxirane are dissolved in 60 ml abs. Dissolved methanol and heated with 20ml 3NNaOCH _{3 for} 4 hours under reflux. After addition of aq. NH ₄ Cl solution is extracted with ethyl acetate, washed neutral and dried over Na ₂ SO ₄ . The organic phase is evaporated under vacuum. There remains 6.35 g of 3,3-dimethoxy-17-methoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol as a colorless oil

[Q] ₀ = + 304 ° (CHCl ₃ )

¹ H NMR (CDCl ₃ )

δ (ppm): 0.88 (s, 3H, H-18); 2.61 (s, 1H, OH); 3.23 (s, 6H, 2χOCH ₃ ); 3.37 (s, 3H, 17a -CH ₂ OCH ₃ ); 3.15-3.51 (m, 2H, ABX system Jab = 9Hz, 17Q-CH ₂ OCH ₃ ); 5.53 (s, broad, 1H, H-11).

c) Preparation of 3,3-Dimethoxy-5a, IOa-epoxy-17a-methoxymethyl-estr-9 (11) -en-17β-ol

5.44 g of 3,3-dimethoxy-17a-methoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol are dissolved in a mixture of 25 ml of methylene chloride and 2 ml of pyridine. At 2O ⁰ C is added 2.5 ml of H ₂ O ₂ (30%) and 0.25 ml of hexachloroacetone is added, stirred for 20 hours at room temperature, aq. Na ₂ S ₂ O ₃ solution and extracted with methylene chloride, the organic phase is washed neutral, dried with Na ₂ SO ₄ and evaporated under vacuum. The tube product is purified to 250 g (alumina alkaline) with a benzene / ethyl acetate gradient. This gives 3.5 g of 3,3-dimethoxy-5a, 10a-epoxy-17a-methoxymethyl-9 (11) -en-17β-ol as a colorless oil.

(a) ₀ = + 21 "(CHCI ₃ )

¹ H NMR (CDCl ₃ )

ö (ppm): 0.88 (s, 3H, H-18), 2.62 (s, 1H, OH); 3.12-3.48 (m, 2H, ABX system J _AB = 9Hz, 17a-CH ₂ OCH ₃ ); 3.12 and 3.18 (s, each 3 H, 2x OCH ₃ ); 3.35 (s, 3H, 170 -CH ₂ OCH ₃ ); 6.03 (s, wide, 1H, H-11).

d) Preparation of 3,3-dimethoxy-17a-methoxymethyl-11β- [4- (1,1-ethylenedioxyethyl) -phenyl] -estr-9-en-5a, 17β-diol

To 607 mg of magnesium in 5ml abs. Ether is added dropwise under argon 0.2 ml of dibromoethane and then 6.075 g of 1- (4-bromophenyl) -ethanone-1,1-ethylene ketal in 30 ml abs. THF. The mixture is stirred for 2.5 hours at 5O ⁰ C and then cooled to -2O ⁰ C from. After addition of 250mg CuCl is maintained for 15 minutes at this temperature and then 3.79 g of 3,3-dimethoxy-5a, 10a-epoxy-17amethoxymethyl-9 (11) en-17ß-ol in 20ml abs. THF dropped. After 2 hours of stirring at room temperature, the approach with

aq. NH ₄ Cl solution decomposes. After extraction with ethyl acetate, the organic phase is washed neutral, dried over Na ₂ SO ₄ and evaporated under vacuum. This gives 6.4 g of a crude product containing alumina (alkaline) with a

Benzen / ethyl acetate gradient is purified. Yield: 4.03 g of 3,3-dimethoxy-17a-methoxymethyl-1-p- [4- (1,1-ethylenedioxyethyl) -phenyl] -estr-9-ene-5a, 17β-diol as colorless

Ia] ₀ = -19 "(CHCl ₃ )

¹ H NMR (CDCl ₃ )

ö (ppm): 0.44 (s, 3H, H-18); 1.64 (s, 3H, 11P-C ₉ H ₈ O ₂ -CH _3); 2.57 (s, 1H, OH); 3.22 and 3.24 2 (s, each 3H, OCH ₃ ); 3.11-3.47 (m, 2H,

ABX system J _AB = 9 Hz, 17a-CH _a OCH ₃ ); 3.30 (s, 3H, 170.-CHjOCH ₃ ); 3.74-4.03 (m, 4H, AA ', BB' System, Ethylon Ketal); 4.24d (1H, J = 6Hz, H ₇ 11); 4.65 (s, 1H, OH); 7.17-7.37 (m, 4 aromatic protons, AA ', BB' system).

e) Preparation of 11β- (4-acetylphfinyl) -17β-hydroxy-17a-methoxymethyl-estra-4,9-dien-3-one 2,16g 3,3-dimethoxy-17a-methoxymethyl-11β-I4- ( 1,1-ethylenedioxyethyl) -phenyl-estr-9-ene-5a, 17β-diol are allowed to stand in 50 ml of 70% acetic acid at room temperature, then pre-diluted with water, extracted with ether and washed neutral, dried over Na ₂ SO ₄ and evaporated under vacuum. The crude product is recrystallized from acetone / ether and again from acetone

Mp. 173 ° C to 176 ⁰ C; Ia) ₀ = + 177 "(CHCI ₃ )

¹ H-NMR (CDCl ₃₁ TMS)

ö (ppm): 0.51 (s, 3H, H-18); 2.57 (s, 3H, COCH ₃ ); 3.40 (s, 3H, OCH ₃ ); 3.14-3.62 (m, 2H, ABX system, J _AB = 10Hz, 170.-CH ₂ OCH ₃ ); 4.42 (d, 1H, J = 6.5Hz, H-11); 5.78 (s, 1H, H-4); 7.19-7.92 (m, 4 aromatic protons, AA ', BB' system). UV (EtOH): A _m "= 260nmloge = 4.23 ληι = 302nm log e = 4.29

e) Preparation of 17β-acetoxy-11β- (4-acetylphenyl) -17a-methoxymethyl-estra-4,9-dien-3-one 217mg 11β- (4-acylphenyl) -17β-hydroxy-17a-methoxymethyl-estra-4 , 9-dien-3-one are dissolved in 8 ml of acetic anhydride / pyridine (1: 1), treated with 100 mg of 4 × dimethylaminopyridine and allowed to stand at room temperature for 12 hours. After addition of water is extracted with CH ₂ Cl ₂ , the organic phase with dilute HCl, water, aq. Bicarbonate solution and washed again with water, dried over Na ₂ SO ₄ and evaporated under vacuum. The resulting oil is purified by preparative layer chromatography on silica gel PF ₂₆₄ with a Banzen / acetone mixture. 165 mg of 17β-acetoxy-11β- (4-acetylphenyl) -17a-methoxymetyl-estra-4,9-dien-3-one are obtained as a colorless foam. Ia] = ₀ + 142 "(CHCI ₃₎ ¹ H-NMR (CDCI ₃₁ TMS)

ö (ppm): 0.47 is, 3H, H-18); 1.98 (s, 3H, OCOCH _3); 2.57 (s, 3H, COCH ₃ ); 3.35 (s, 3H, OCH ₃ ); 3.79 (d, 2H, J = 4Hz, 17a-CH ₂ OCH ₃ ); 4.44 (d, 1H, J = 6Hz, H-11); 5.78 (s, 1H, H-4); 7.26-7.92m (4 aromatic protons, AA ', BB' system). Mass spectrum: m / e 476.2665 (M ⁺ ) UV (EtOH): A _1111x = 257 nm log ε = 4.15 K _1n = 299 nm log e = 4.13

e) Preparation of 11β- (4-acetylphenyl) -17a-methoxymethyl-17β-phenylaminocarbonyloxy-estra-4,9-dien-3-one 217 mg of 11β- (4-acetylphenyl) -17β-hydroxy-17α-methoxymethyl-estrone 4,9-dien-3-one are available in 20ml abs. Benzen dissolved, treated with 1 ml of triethylamine and 1 ml of phenyl isocyanate, heated under reflux for 3 hours and concentrated in vacuo. It is then boiled with chloroform, filtered off, the organic solution is concentrated and purified by preparative layer chromatography on silica gel PF ₂₅₄ '. This gives 230 mg of crude product which is recrystallized from acetone. Mp: 225 ° C to 230 ° C; IaI ₀ = + 127 "(CHCI ₃ )

¹ H-NMR (CDCl ₃ , TMS)

ö (ppm): 0.53 (s, 3H, H-18); 2.56 (s, 3 H, COCH _3); 3.37 (s, 3H, 00H ₃ ); 3.87 (d, 2H, J = 5Hz, 17a-CH ₂ OCH ₃ ); 4.45 (d, 1H, J - 5.4 Hz, H-11); 5.79 (s, 1H, H-4); 6.57 (s, 1H, NH); 7.25-7.92 (m, 9 aromatic protons). Mass spectrum: m / e434.2451 (M ⁺ -C ₆ H ₆ NCO) UV (EtOH) A _max = 243 nm log ε = 4.21 Amax = 291 nm log ε = 4.; <O

Example 2 Preparation of 17β-substituted 11β- (4 - /. Cetylphenyl) -17a-ethoxymethyl-estra-4,9-dien-3-ones

b) Preparation of 3,3-dimethoxy-17a-ethoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol3,63g 3,3-dimethoxy-estra-5 (10), 9 (11) -dien-17ß-spiro-1 ', 2'-oxirane are dissolved in 50ml abs. Dissolved ethanol and heated with 10ml NaOC ₂ H _{6 for} 5 hours under reflux. It is then diluted with NH ₄ Cl solution, extracted with ethyl acetate, the organic phases are washed neutral, dried over Na ₂ SO ₄ and evaporated in vacuo. The tube product (4.2 g) is purified by chromatography on alumina with a benzene / ethyl acetate gradient. This gives 3.6 g of 3,3-dimethoxy-7a-ethoxymethyl-estra-5 (10), 9 (11) -diene-17ß-ol as a colorless oil.

Ia] ₀ = +118 "(CHCl ₃ ).

¹ H-NMR (CDCl ₃₁ TMS)

ö (ppm): 0.88 (s, 3H, H-18); 1.19 (t, 3H, J = 7Hz, 17a-CH ₂ OCH ₂ CH ₃ ); 2.62-3.25 (m, 2H, ABX system, J _AB = 8.5Hz, 17a-CH ₂ OC ₂ H ₆ ); 3.23 (s, 6H, 2x OCH ₃ ); 3.41-3.62 (q, 2H, J = 7Hz, 17a-CH ₂ OCH ₂ CH ₃ ); 5.54 (s, broad, 1H, H-11).

c) Preparation of 3,3-dimethoxy-5a, 10a-epoxy-17a-ethoxymethyl-estfcr-9 (11) -en-17β-ol

2.76 g of 3,3-dimethoxy-i, i-ethoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol are dissolved in a mixture of 20 ml of chloroform and 1.5 ml of pyridine C. 2 ml of H ₂ O ₂ and 0.2 ml of hexachloroacetone are added and the mixture is stirred for 12 hours After addition of bisulfite solution, the mixture is extracted with chloroform, washed with aq Na ₂ CO ₃ -LOSUnQ and dried over Na ₂ SO ₄ and the The crude product is purified on a 120 g aluminum oxide (alkaline) with a benzene / ethyl acetate gradient to give 1.9 g of 3,3-dimethoxy-5a, 10a-epoxy-17a-ethoxymethyl-estr-9 (11). -en-17ß-ol as a colorless foam

Ia] ₀ ± 0 "(CHCIj)

¹ H-NMR (CDCl ₃₁ TMS)

δ (ppm): 0.88 (s, 3H, H-18); 1.18 (t, 3H, J = 6.5Hz, 17-QCH ₂ OCH ₂ CH ₃ ); 2.63-3.53 (m, 2H, ABX system, J _AB = 9.5Hz, 17aCH ₂ OC ₂ H ₆ ); 3, 12, and 3.18 (s, je ₃ H, 2 x OCH ₃ ); 3.39-3.60 (q, 2H, J = 7Hz, 17Q-CH ₂ OCH ₂ CH ₃ ); 6.03 (s, wide, 1H, H-11). Mass spectrum: m / e 3,92,2829 (M ⁺ )

d) Preparation of 3,3-dimethoxy-17a-ethoxymethyl-11β- [4- (1,1-ethylenedioxyethyl) phenyl] -estr-9-ene-5a, 17β-diol

From 607 mg of magnesium and 6.08 g of 1- (4-bromophenyl) -ethanone-1,1-ethylene ketal in THF, a Grignard solution is prepared, which is cooled to -20 ° C and treated with 250 mg CuCl. The mixture is stirred for 15 minutes at this temperature and then added dropwise 1.9 g of 3,3-dimethyl-5a, 10a-epoxy-17a-ethoxymethyl-estr-9 (11) -en-17ß-ol in 25ml abs. THF added. After 2 hours stirring at room temperature is washed with aq. Decomposed NH ₄ Cl solution, extracted with ethyl acetate, the organic phase with aq. Bicarbonate solution and water, dried over Na ₂ SO ₄ and evaporated in vacuo. The crude product (6.1 g) is purified on alumina (alkaline) with a benzene / ethyl acetate gradient. There are obtained 1.43 g of 3,3-dimethoxy-17aethoxymethyl-11β- [4- (1,1-ethylenedioxyethyl) phenyl] -estr-9-ene-5a, 17β-diol as a colorless oil, which at -5 ⁰ C freezes. [Q] ₀ = -6 ° (CHCl ₃ )

'H-NMR (CDCl ₃ , TMS)

δ (ppm): 0.45 (s, 3H, H-18); 1.22 (t, 3H, J = 7Hz, 17Q-CH ₂ OCH ₂ CH ₃ ); 1.63 (s, 3H, 11β-CaHaOj-CHj); 2.68 (s, 1H, OH); 3.21 and 3.24 (s, je3H, 2 x _OCH3); 3.14-3.58 (m, 2H, ABX systems, J _AB = 9Hz, 17Q-CH ₂ OC ₂ H ₆ ); 3.40-3.61 (q, 2H, J = 7Hz, 17Q-CH ₂ OCH ₂ CH ₃ ); 3.74-4.03 (m, 4H, AA ', BB' system, ethylene ketal); 4.17β (d, 1H, J = 6.5Hz, H-11); 4,46s (1H, OH); 7.12-7.39 (m, 4 aromatic protons, AA ', BB' system).

e) Preparation of 11β- (4-acetylphenyl) -17a-ethoxymethyl-17β-hydroxy-estra-4,9-dien-3-one

11g3,3-dimethoxy-17a-ethoxymethyl-11β- [4- (1,1-ethylenedioxy-ethyl) -phenyl) -estr-9-ene-5a, 17β-diol are dissolved in 30 ml of 70% acetic acid and at room temperature Stirred for 4 hours. After addition of dilute aq. NaOH is extracted with ethyl acetate, the organic phase is washed neutral, dried over Na ₂ SO ₄ and evaporated under ', ikuum. The yellow oil is purified by preparative layer chromatography on silica gel PF ₂ C ₄ with the mobile phase mixture benzene / acetone 9: 1. There can be 565 mg .beta.-11 (4-AcetylphenyD-17 a-ethoxymethyl-17 isolate ß-hydroxy-estra-4,9-dien-3-one, which crystallized from acetone as a shiny needles. Mp. 83 ⁰ C to 96 ⁰ C and again at 142 ° C to 145 ⁰ C. (aln = + 176 "(CHCl ₃ ) ¹ H-NMR (CDCI ₃₁ TMS)

δ (ppm): 0.51 (s, 3H, H-18); 1.23 (t, 3h, J = 7Hz, 17a-CH ₂ OCH ₂ CH ₃ ); 2.57 (s, 3H, COCH ₃ ); 2.74 (s, 1H, OH); 3.18-3.63 (m, 2H), ABX system, J _AB = 9Hz, 17a-CH ₂ OC ₂ H ₆ ); 3.44-3.65 (q, 2H, J = 7Hz, 17a-CH ₂ OCH ₂ CH ₃ ); 4.41 (d, 1H, J = 7Hz, H-11); 5.78 (s, 1H, H-4); 7.24-7.91 (m, 4 aromatic protons, AA ', BB' system)

Mass spectrum: m / e 448.2632 (M ⁺ ) UV (EtOH) A _m = 261 nm = 4.14 n = x = 301 nm = 4.15

e) Preparation of 17β-Acefoxy-11β- (4-acetylphenyl) -17u-ethoxymethyl-estra-4,9-dien-3-one 350mg of 11β- (4-acetylphenyl) -17a-ethoxymethyl-17β-hydroxy estra-4,9-dien-3-one are suspended in 10 ml of triethylamine, admixed with 3 ml of acetic anhydride and 112 mg of dimethylaminopyridine and stirred at room temperature for 12 hours. After addition of CH ₂ Cl ₂ is washed with dilute HCl and War.oer, the organic phase dried over Na ₂ SO ₄ and evaporated under vacuum. The crude product is purified by preparative layer chromatography on silica gel PF ₂₅₄ with the mobile phase mixture benzene / acetone 9: 1. With acetone / hexane, 270 mg of 17β-acetoxy-11β- (4-acetylphenyl) -17aethoxymethyl-estra-4,9-dien-3-one can be obtained as a foam, [alo = + 153 ° (CHCf ₃ ) ¹ H- NMR (CDCl ₃ , TMS)

δ (ppm): 0.50 (s, 3H, H-18); 1.20 6t, 3H, 17a-CH ₂ OCH ₂ CH ₃ ); 2.00 (s, 3H, 17Q-OCOCH ₃ ); 2.57 (s, 3H, COCH ₃ ); 3.49 (m, 2H, 17a-CH ₂ OCH ₂ CH ₃ ); 3.82 (m, 2H, 17 a -CH ₂ OC ₂ H _s ); 4.44 (d, 1H, J = 7Hz, H-11); 5.79 (s, 1H, H-4); 7.06-8.06 (m, 4 aromatic protons, AA ', BB' system).

UV (EtOH) A _011x = 257nm Löge = 4.25 λαι »χ = 300.5nm Löge = 4.2-9

Example 3

Preparation of 17β-substituted 11β- (4-acetylphenyl) -17a-propoxymethyl-estra-4,9-diene-3-oliene

b) Preparation of 3,3-dimethoxy-17a-propoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol 6,6g 3,3-dimethoxy-estra-5 (10), 9 (11 ) -diene-17β-spiro-1 ', 2'-oxirane are suspended in 30 ml of n-propanol and mixed with 15 ml of a 3 N NaOC ₃ H ₇ solution. It is heated for about 4 hours until complete reaction on the water bath, cooled and diluted with ether. The organic phase is washed neutral, dried over Na ₂ SO ₄ and evaporated under vacuum. The crude product is purified on alumina (alkaline) with a benzene / ethyl acetate gradient. This gives 6.8 g of 3,3-dimethoxy-17a-propoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol as a colorless oil, which is used directly in the next step.

c) Preparation of 3,3-dimethoxy-5a, 10a-epoxy-17a-propoxymethyl-estr-9 (11) -en-17β-ol

6.8 g of 3,3-dimethoxy-17a-propoxymethyl-e8tra-5 (10), 9 (11) -diene-17β-ol are dissolved in 30 ml of methylene chloride and 0.5 ml of pyridine and taken together with 4nil H] O ₂ and 0 , 4 ml Hexfluoracetonmonohydrat be! Room tempatur stirred for 30 hours. After addition of aq. Bisulfite solution is extracted with CH ₂ Cl ₂ , washed neutral with water, dried over Na ₂ SO ₄ and concentrated. The oil is purified on 180 g alumina (alkaline) with a benzene / ethyl acetate gradient. There are obtained 3,9f 3,3-dimethoxy-5a, 10a-epoxy-17apropoxymethyl-estr-9 (11) -en-17β-ol as a colorless oil. [Q) ₀ = + 6 "(CHCl ₃ ) ¹ H-NMR (CDCl ₃ , TMS)

δ (ppm): 0.80 (s, 3H, H-18); 0.83 (t, 3H, 17a -CH ₂ OCH ₂ CH ₂ CH ₃ ); 2.67 (s, 1H, OH); 3.04 and 3.10 (s, each 3H, 2 x OCH ₃ ); 3.04-3.44 (m, 2H, 170 -CH ₂ OC ₃ H,); 3.10-3.26 (m, 2H, 17a-CH ₂ OCH ₂ C ₂ H _B ); 5.95 (s, wide, 1H, H-11).

d) Preparation of 3,3-Dimethoxy-11β- [4- (1,1-ethylenedioxyethyl) phenyl] -17a-propoxymethyl-estr-9-ene-5a, 17β-diol To 560 mg of magnesium in 5 ml abs. Ether is added under argon 0.2 ml of dibromoethane and added dropwise with stirring 5.7 g of 1- (4-bromophenyl) -ethanone-1,1-ethylene ketal in 50ml abs. THF added. After 3 hours at 5O ⁰ C is cooled to -20 ° C, 220mg CuCl added and stirred for 15 minutes. Thereafter, 3.25 g of 3,3-dimethoxy-5a, 10a-epoxy-17a-propoxymethyl-estr-9 (11) -en-17ßol in 25 ml of THF at ^{0 0} C is stirred, stirred for 2 hours at room temperature and the mixture with aq , NH ₄ Cl solution decomposes. It is extracted with ethyl acetate, the organic phase is washed colorless and neutral, dried over Na ₂ SO ₄ and evaporated. The crude product is purified on alumina (alkaline) with a bonehyde / ethyl acetate gradient. This gives 3.8 g of 3,3-dimethoxy-11ß- [4- (1,1-ethylenedioxyethyl) phenyl-17apropoxymethyl-estr-9-en-5a, 17ß-diol as an oil, which is processed directly.

e) Preparation of 11β- (4-acetylphenyl) -17β-hydroxy-17α-propoxymethyl-estra-4,9-dien-3-one

1.7 g of 3,3-dimethoxy-11β- [4- (1,1-ethylenedioxyethyl) phenyl] -17a-ropoxymethyl-estr-9-en-5a, 17β-diol are added in 50 ml of 70% acetic acid for 4 hours Stirred room temperature, taken up in ethyl acetate and the organic phase washed neutral, dried over Na ₂ SO ₄ and evaporated in vacuo. The crude product is recrystallized from methanol. M.p. 103 "(CHCl ₃ ) ¹ H-NMR (CDCl ₃ , TMS)

δ (ppm): 0.50 (s, 3H, H-18); 0.90 (t, 3H, 17β-CH ₂ OCH ₂ CH ₂ CH ₃ ); 2.56 (s, 3H, COCH ₃ ); 4.43 (d, 1H, J = 6Hz, H-11); 5.78 (s, 1H, H-4); 7.20-7.95m (aromatic protons, AA ', BB' system)

UV (EtOH) A _m , _x = 258 nm log ε = 4.29 λ = 300 nm l = 4.32

e) Preparation of 11β- (4-acetylphenyl) -17β-propionyloxy-17α-propoxymethyl-estra-4,9-dien-3-one 232mg of 11β- (4-acetylphenyl) -17β-hydroxy-17α-propoxymethyl- Estra-4,9-dien-3-one are suspended in 8 ml of triethylamine, admixed with 3 ml of propionic anhydride and 50 mg of dimethylaminopyridine and allowed to stand at 20 ° C. for 20 hours. After addition of dilute HCl is extracted with CH ₂ Cl ₂ , washed neutral, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. The crude product is purified by preparative layer chromatography on silica gel with benzene / acetone (6: 1). ml; Ether / hexane 160mg of 11β- (4-acetylphenyl) -17β-propionyloxy-17a-propoxymethyl-estra-4,9-dien-3-one obtained as a solid foam

(a) _D = + 172 "(CHCl ₃ ) ¹ H-NMR (CDCl ₃ , TMS)

δ (ppm): 0.44 (s, 3H, H-18); 0.91 (t, 3H, 170 -CH ₂ OCH ₂ CH ₂ CH ₃ ); 1.06 (t, 17 ^ OCOCH ₂ CH ₃ ); 2.56 (s, 3H, COCH ₃ ); 3.35 (t, 2H, J = 6.5Hz, 170-CH ₂ OCH ₂ CH ₂ CH ₃ ); 3.64-3.86 (m, 2H, ABX system, 170-CH ₂ OC ₃ H ₇ ); 4.42 (d, 1H, J = 7Hz, H-11); 5.77 (s, 1H, H-4); 7.23-7.95 (m, 4 aromatic protons, ΑΑ ', ΒΒ'-system)

UV (EtOH) X _mlx = 256 nm = 4.36 am = 300 nm = 4.36

O O O O ro co X X

O =

Claims (3)

A process for the preparation of 11β- (4-acetylphenyl) -17a-alkoxymethyl-estra-4,9-dien-3-ones of general formula I in which R is an alkyl radical having 1 to 6 carbon atoms, R ^{1 represents} a hydrogen atom, an acyl radical COR ² or urethane radical CONHR ³ , R ^{2 represents} a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms and R ^{3 represents} a hydrogen atom, an alkyl radical having 1 to 4 carbon atoms or an aryl radical (except when R ¹ = H and R ² = CH3), characterized in that a) reacting 3-ketals of Estra-5, (10), 9 (11) -dien-17-one with trimethylsulfonium halide and bases in solvents to 17-Spirc-1 ', 2'-oxiranes, b) reacting these with alkali metal alkoxides in absolute alcohols to give the 17a-alkoxymethyl-17β-hydroxy-estra-5 (10), 9 (11) -dienes, c) converting them into the 5a, 10a-epoxy-17a-alkoxymethyl-estr-9 (11) -en-17β-ols by epoxidation with H ₂ O ₂ , d) these with Grignard 1- (4-bromophenyl) -ethanone-1,1-ketals and magnesium in the presence of Cu-I salts to give the 1-β-aryl substituted -alka-alkoxymethyl-esti-M-en-BaiUss diols implements as well e) hydrolyzing them under acidic conditions to the 11β- (4-acetylphenyl) -17a-alkoxymethyl-17β-hydroxyestra-4,9-dien-3-ones, and from the latter optionally hydrolyzing the 17β-esters or 17β-urethanes of 11β- (4 Acetylphenyl) -17a-alkoxymethyl-estra-4,9-dien-3-one. 2. The method according to claim 1, characterized in that in step a) as3-ketaldehestra-5, (10), 9 (11) -diene-17-on3.3-dimethoxy-estra-5 (10), (9 (11) -diene-17-onyl is reacted with trimethylsulfonium halides in the form of the bromides or iodides in dimethyl sulfoxide or dimethylformamide in the presence of potassium tert-butanolate or in benzene in the presence of KOH, in process step b) used as alkali metal alcohol dio sodium compounds at the boiling point of the alcohol, in process step c) the epoxidation with H ₂ O ₂ in the presence of hexafluoroacetone or H8xachloraceton in halogenated solvents such as chloroform or methylene chloride, at temperatures between ^{0 0} C and 25 ⁰ C performs, in process step d) Grignardization in an ether, such as diethyl ether or tetrahydrofuran, in the presence of Cu-I-salzon, as CuCl performed and as 1- (4-bromophenyl) -ethanone-1,1-ketaldas ethylene ketal at temperatures between 0 ⁰ C and 30 ⁰ C reacted . in process step e) the ester hydrolysis with acids, such as dilute acetic acid, in water-miscible solvents such as methanol, acetone or tetrahydrofuran, at temperatures between ^{0 0} C and 8O ⁰ C or on acidic carriers, such as acidic alumina, and the esterification with acid anhydrides or acid chlorides with 1 to 6 carbon atoms and bases such as triethylamine or pyridine, optionally in the presence of 4- (dimethylamino) pyridine at room temperature and the 17ß-urethanes either by reacting the 17ß alcohols with alkyl isocyanates having 1 to 4 carbon atoms or free or substituted aryl isocyanates in the presence of tertiary bases, such as triethylamine, in inert solvents, such as benzene, at temperatures between 20 ⁰ C to 90 ⁰ C or by reacting the 17ß alcohols with phosgene in inert solvents, such as benzene, and subsequent reaction with amines. 3. The method according to claim 1 and 2, characterized in that the 11 ß (4-acetylphenyl) -17aalkoxymethyl-estra-4,9-dienes 17β-acetoxy-11β- (4-acetylphenyl) -! 7a-methoxymethyl-estra-4,9-dien-3-one, 11ß- (4-acetylphenyl) -17a-methoxymethyl-17β-phenylaminocarbonyloxy-l-l-4,9-dien-3-one, 11ß- (4-acetylphenyl) -17a-ethoxymethyl-17β-hydroxy-estra-4,9-dien-3-one, 17β-acetoxy-11β- (4-acetylphenyl) -17a-ethoxymethyl-estra-4,9-dien-3-one, - 11β- (4-acetylphenyl) -17β-hydroxy-17α-propoxymethyl-estra-4,9-dien-3-one or - 11β- (4-acetylphenyl) -17β-propionyloxy-17a-propoxymethyl-estra-4,9-dien-3-one. For this 1 page formulas