DD299068A5 - PROCESS FOR PREPARING 11 BETA-ARYL SUBSITUTED 17 BETA-ALKOXY-17 ALPHA -ALKOXYMETHYL-ESTRA-4,9-DIEN-3-ONES - Google Patents

Abstract

The invention relates to a chemical-synthetic process for the preparation of 11b-aryl-substituted compounds which are of interest as potential agents for the control of fertility in the pharmaceutical industry. In the process, * with bases in the 17b-alkoxides are converted, which are reacted with alkyl halides to 17b ethers and then epoxidized selectively in the * with H2O2 to the 5a, 10a epoxides, then with p-substituted Arylmagnesiumbromiden in the presence of copper I salts are opened to 11b-aryl-substituted 5α-hydroxysteroids and converted to the 11b-aryl-substituted * under acidic conditions. {Estrane; 11b-aryl substituted * 17b-ethers; Antigestagens; Drug}

Description

For this 1 page with formula scheme

Field of application of the invention

The invention relates to a chemically synthetic process for the preparation of 11β-aryl-substituted 17β-alkoxy-17aalkoxymethyl-estra-4,9-dien-3-ones of the general formula I. Such compounds are of interest to the pharmaceutical industry.

-2- 299 068 Characteristic of the known state of the art

11β-aryl substituted Estra-4,9-diune are known. For example, 11β-aryl-17α-propynyl or 17α-ethynyl-4,9-dien-3-ones are described in the patent FR 2497 807 (EP 57115), 11β-phenyl-substituted 17α- (3-hydroxypropyl) -estra 4,9-dienes in the patent DE 3306121 (EP 116974), 11β- (4-dimethylaminophenyl) -17α- (3-hydroxypropyl) -estra-4,9-dienes having a 13G-alkyl chain in the patent DE 3321826 (US Pat. EP 129499), 11β-arylestrene-4,9-dienes having a 17a (3-hydroxypropyl-2-enyl) radical in the patent DE 3347126 (EP 147361), 11β- (4-formyl or 4-) Acetylphenyl) -stra-4,9-diones in the patent DE 3504421 (EP 190759), 11β- (4-dimethylaminophenyl) -17a-CH ₂ X-substituted estra-4,9-dienes in the patent DE 3506785 (EP 192598) and WO 88/01686. A number of 11β-aryl substituted Estra-4,9-di-compounds are antigestagenic in that, by virtue of their higher affinity for a progestin receptor, they can competitively force the natural progesterone, which is essential for the maintenance of pregnancy, from the receptor without itself a progestational activity to unfold. They can be used with regard to the use for postcoital fenility control. The dosage of the international standard substance RU 38486 (Mifepriston®) in humans is quite high with 10mg to 1000mg per day compared to many other steroid hormones. The success rate for use as a human abortion varies between 60% (in China) and about 90% (in Europe). Since the compound also has an undesirable antiglucocorticoid activity in addition to the antigestion activity, it is desirable to find more active compounds or compounds having 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 post-coital homeostasis inhibitors.

Presentation of the essence of the invention

The invention is based on the object of specifying a chemical, synthetic process for the preparation of 11β-aryl-substituted 17β-alkoxy-17α-alkoxymethyl-estra-4,9-dien-3-one-donor general formula I in which R 'is a Alkyl radical having 1 to 6 carbon atoms,

R ^{2 is} an alkyl radical having 1 to 6 carbon atoms or a CH ₂ O (S) R _r radical with R ₁ in the meaning of alkyl radicals having 1 to 4 carbon atoms and

R ^{3 is} a dimethylamine), an acetyl or ketalized acetyl group.

According to the invention, the object is achieved by reacting 17a-alkoxymothyl-17β-hydroxy-estra-5 (10), 9 (11) -diene-3-ketals by deprotonation with bases in 17β-alcohols of 17a-alkoxymethyl -estra-5 (10), 9 (11) -diene-3-ketals, which are prepared by alkylation with alkyl halides to give 17- 3-alkoxy-17a-alkoxymethyl-estra-5 (10), 9 (11) -diene-3 ketones, which selectively epoxidizes with H ₂ O ₂ to give the 5a, 10a-epoxy-17β-alkoxy-17a-alkoxymethyl-estr-9 (11) -en-3-ketals, these with arylmagnesium halides in the p-slope magnesium to a Dimethylamine- or ge ^<r hützte acetyl own, 17a-alkoxymethyl-estr-9-en-5a-ols opens to the 11 beta-aryl-17-alkoxy as well as these unte ^r ß acidic conditions to give the desired 11 aryl-substituted 17β-alkoxy-17a-alkoxymethyl-estra-4,9-dien-3-ones nydrolisiert. In the further development of the method as 17 a-alkoxymethyl-1 '/ ß-hydroxy-estra-5 (10), 9 (11) -diene-3-ketals, the 3,3-dimethyl ketals of the general formula II, as a base for the deprotonation Alkalinaphthalid and used as the organic solvent tetrahydrofuran to form the alcoholates of the general formula III. The alkylation with alkyl halides, Alkyloxyälkylhaloger.iden or Alkylthioalkylhalogenide carried out directly or in solvents, wherein the 17 ß-alkoxy-17aalkoxymethyl-estra-5 (10), 9 (11) -dione-3-ketals of the general formula IV arise. These are prepared by epoxidation with H ₂ O ₂ and kaolin acetones, in the presence of catalytic amounts of tertiary bases or with halogenated aldehydes in the presence of water-binding agents in inert solvents in the 5a, 10a-epoxy-17ß-alkoxy-17a-alkoxymethyl-estr-9 ( 11) -en-3-ketals of general formula V and these by Grignardierung in an E. - in the presence of copper-l-salts with a 1- (4-bromophenyl) -ethanone 1,1-kotalz'jden 11th ß-aryl-substituted 17ß-alkoxy-17a-alkoxyniethyl-estr-9-en-5a-ol of the general formula IV implemented. These are converted by acid hydrolysis with acids in water-miscible solvents or on acidic carriers to the 17ß-alkoxy-17a-alkoxymethyl-estra-4,9-dien-3-one of the general formula I. In the preferred embodiment of the process, 17a-alkoxymethyl-17β-hydroxy-estra-5 (10), 9 (11) -diene-3-dimethylketals of general formula II are deprotonated with sodium or lithium naphthalide in tetrahydrofuran and reacted with alkyl halides, alkyloxyalkyl halides, Alkylthioalkylhalogeniden reacted directly or in ether at temperatures> 0 ° C to the 17ß-alkoxy-17a-alkoxvrnethyl-estra-5 (10), 9 (11) -diene-3-ketals of general formula IV. The epoxidation with H ₂ O ₂ and hexachloroacetone and l-lxafluoroacetone takes place in the presence of catalytic amounts of triethylamine or pyridine, or with chloral hydrate in the presence of anhydrous primary alkali metal phosphate and alkali metal carbonate or alkali metal carbonate at temperatures> 0 ⁰ Ci; ι Mathylene chloride or chloroform, wherein the 5a, 10a-epoxy-i7ß-alkoxy-17a-alkoxymethy! -estr-9 (11) -en-3-ketals of allgerminen Formal V arise. By Grignardization in tetrahydrofuran with CuCl and 1 - (4-Br nyU-ethanone 1,1-ethylene ketal at temperatures between ^{0 0} C and 3O ⁰ C are the 11 ß-arylsi'bstituierten 17ß-alkoxy-17a alkoxymethylestr-9-en-5a-olene of the general formula IV formed by acid hydrolysis with dilute acetic acid in methanol, acetone or tetrahydrofuran at temperatures between ^{0 0} C and 8O ⁰ C or on acidic alumina in the 17 ß-alkoxy-17 aalkoxymethyl-estra-4,9-dien-3-one of the general formula I.

 In the process according to the invention, the 11β-aryl-substituted 17β-alkoxy-17α-alkoxymethyl-estra-4,9-dienes were obtained

11ß- (4-Aoetylphenyl) -17β-methoxy-17a-methoxymethyl-3stra-4,9-dien-3-one,

11β- (4-dimethylaminophenyl) -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β- (4-acetylphenyl) -17a-eioxymethyl-17β-metroxy-eRtra-4,9-dien-3-one and

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

The effective 11β-aryl substituted Estra-4,9-dien-3-ones described hitherto in the literature have a 17β-hydroxy group which is responsible for the adhesion of the steroid to the receptor via a hydrogen bond for the formation of a stable steroid receptor complex is of essential importance. It is surprising that compounds which have a 17 ß-ether function in place of a 17 ß-hydroxyl group, reveal an increased effect in animal experiments.

Direct etherification of the 17β-hydroxy group in 11β-aryl substituted estra-4,9-dien-3-ones is not possible because of side reactions of the carbonyl function. It has been found that the introduction of the 17 ß-ether grouping in a particularly favorable manner at the stage of 17a-alkoxymethyl-17 ß-hydroxy-estra-5 (10), 9 (11) -diene-3-ketals type II takes place ,

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 day of pregnancy) weighing between 180g and 200g on days 5 to 8 of pregnancy were subcutaneously suspended with the test compound in peanut oil

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 RU 38486 a 100% abortive effect was achieved according to this method with a dosage of 2 3 mg per animal over 4 days.

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

The inventive method is explained by the Foimelschema and the embodiments.

embodiments

aeispieli

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

a) 2,6g 3,3-dimethoxy-17a-methoxymethyl-estra-5 (10), 9 (11) -diene-17β-o! are dissolved in 20 ml of THF and added dropwise at 20 ° C to a solution of sodium naphthalide (prepared from 1.28 g of naphthalene and 250 mg of sodium in 50 ml of THF) to form the alkoxide.

b) To the dark green solution is added after 30 minutes at 20 ° C 5ml methyl iodide and stirred for 2 hours at this temperature, decomposed with methanol and then with water, extracted with ethyl acetate, the organic Pnase washed neutral, dried over K ₂ CO ₃ and Na ₂ SO ₄ ".and the solvent is evaporated off in vacuo, the crude product (6.7 g) is purified by column chromatography on 120 g of aluminum oxide (alkaline) with a benzene / ethyl acetate gradient, and 2.36 g of 17β-methoxy-17a are obtained. methoxymethyl-estra-5 (10), 9 (11) -diene-3,3-dimethylketal win as a colorless oil.

[a] ₀ = + 110 ° (CHCl ₃ , c = 0.45)

¹ H NMR (CDCl ₃₁ TMS):

δ (ppm): 0.87 (s, 3H, H-18); 3.22 and 3.23 (2s, je3H, 2x OCH _3); 3.28 (s, 3H, 17β-OCH ₃ ); 3.38 (s, 3H, 17a -CH ₂ OCH ₃ ); 3.25-3.68 (m, 2H, ABX system, 17Ci-CH ₂ OCH ₃ ); 5.52 (s, wide, 1H, H-11).

c) In a mixture of 15 ml of methylene chloride and 0.5 ml of pyridine are dissolved 1.88 g of 17ß-methoxy-17a-methoxymethyl-estra-5 (10), 9 (11) -diene-3,3-dimethylketal and at 2O ⁰ C. with ₂ ml of H ₂ O ₂ and 0.2 ml of hexachloroacetone. After 20 hours, aq. B'sulfite solution added and extracted with methylene chloride. It is washed neutral, dried over K ₂ CO ₃ and Na ₂ SO ₄ and the solvent is distilled off under vacuum. The crude product is purified by column chromatography on 70 g alumina (alkaline) with a benzene / ethyl acetate gradient. It is possible to isolate 1.24 g of 5a, 10a-epoxy-17β-methoxy-17-methoxymethyl-estr-9 (11) -en-3,3-dimethylketal.

Mp. 116 ° C to 119 ⁰ C (hexane)

[old, = +7 ⁰ C (CHCI ₃ )

¹ H NMR (CDCl ₃₁ TMS):

δ (ppm): 0.88 (s, 3H, H-18); 3.12 and 3.17 (2s, each 3H, 2x OCH ₃ ); 3.27 (s, 3H, 17β-OCH ₃ ); 3.35 (s, 3H, 17a -CH ₂ OCH ₃ ); 3.38 (m, 2H, ABX system, 17Q-CH ₂ OCH ₃ ); 5.99 (s, wide, H-11).

d) To 486mg of magnesium in 5ml abs. Ether is added dropwise under argon 0.15 ml of dibromoethane and then 4.95 g of 1- (4-bromophenyl) -ethanone-1,1-ethylenketal in 30 ml abs. THF. The mixture is stirred for 3 hours at 5O ⁰ C internal temperature, cooled to ^{0 0} C and adds 170mg CuCl added. After a further 20 minutes, 1.18 g of 5a, 10a-epoxy-17β-methoxy-17a-methoxymethyl-estr-9 {11) -en-3,3-dimethylketal in 20 ml of THF are added dropwise. It is ge for 2 hours at room temperature, the mixture decomposed with aq: ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed neutral, dried over Na ₂ SO ₄ and evaporated under vacuum. The crude product is purified by column chromatography on 70 g alumina (alkaline) with a benzene / ethyl acetate gradient clay. This gives 970 mg of 3,3-dimethoxy-11β- [4- (1,1-ethylenedioxyethyl) -phenyl] -11β-methoxy-17a-methoxymethyl-estr-9-en-5a-ol as a colorless oil which is obtained directly is further processed.

e) 970 mg of 3,3-dimethoxy-1 "β- [4- (1,1-ethylenedioxyethyl) -phenyl] -17β-methoxy-17a-methoxymethyl-estr-9-en-5a-ol in 20 ml of dilute acetic acid 20 After addition of water, the mixture is extracted with ethyl acetate, the organic phase is washed with dilute aqueous NaOH and water, dried over Na ₂ SO ₄ and evaporated under reduced pressure. Acetylphenyl) -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

Mp. 133 ⁰ C to 137 ⁰ C (ether) [a) _D = + 17O ⁰ C (CHCI ₃₎ 'H-NMR (CDCI ^ TMS):

δ (ppm): 0.50 (s, 3H, H-18); 2.57 (s, 3H, COCH ₃ ); 3.24 (s, 3H, 17β-OCH ₃ ); 3.40 (s, 3H, 170 -CH ₂ OCH ₃ ); 3.34-3.63 (m, 2H, ABX-systeine, 170-CH ₂ OCH ₃ ); 4.41 (d, J = 7.1 Hz, 1H, H-11); 5.78 (s, 1H, H-4); 7.23-7.90 (m, 4H, AA'BB 'system of the aromatic). UVinEtOH: X _msx = 259nmlöge = 4.27 λ ™ = 300 nm log ε = 4.33

Example 2

Preparation of 1p- (4-acetylphenyl) -17a-othoxymethyl-17P-methoxy-estra-4,9-dien-3-one

a) A sodium naphthalide solution (prepared from 250 mg of sodium and 1) is added dropwise to 1.88 g of 3,3-dimethoxy-17a-ethoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol in 30 ml of FHF. 28g naphthalene in 50ml THF) until a dark green color persists to form the alkoxide.

b) After 30 minutes at room temperature, add 4 ml of methyl iodide and stir for a further 2 hours. The approach is with aq. NH ₄ Cl-LoSUnQ decomposed, extracted with ethyl acetate. The organic phase is washed neutral, dried over K] COa and Na ₂ SO ₄ and the solvent is evaporated off under vacuum. The crude product is purified by column chromatography on alumina (alkaline) with a benzene / ethyl acetate gradient. It can be 1.56g 17a-ethoxymethyl-17ßmethoxy-estra-5 (10), 9 (11) -diene-3,3-dimethylketal win as a colorless oil, which is used directly in the next stage.

c) 1.56 g of 17a-ethoxymethyl-17β-methoxy-estra-5 (10), 9 (11) -diene-3,3-dimethylketal are dissolved in 20 ml of methylene chloride and 0.5 ml of pyridine and at 20 ° C with 3ml H ₂ O. ₂ and 0.3 ml of hexachloroacetone were added. After 20 hours, aq. Bisulfite solution added and extracted with methylene chloride, washed neutral, dried over K ₂ CO ₃ and Na ₂ SO ₄ and the solvent is distilled off under vacuum. The crude product is purified by column chromatography on 60 g of alumina (alkaline) with a benzene / ethyl acetate gradient. This gives 940 mg of 5a, 10a-epoxy-17a-ethoxymethyl-17ß-methoxy-estr-9 (11) -en-3,3-dimethylketal as a colorless oil, which is used directly in the next stage.

d) To 486 mg magnesium in 5 ml abs. Ether is added dropwise, under argon, 0.15 ml of dibromoethane and then 4.95 g of 1- (4-bromophenyl) -ethanone-1,1-ethylene ketal in 30 ml of abs. THF. The mixture is stirred for 3 hours at 5OX internal temperature, cooled to 0 ° C and added 170mg CuCl. After a further 20 minutes, 940 mg of 5a, 10a-epoxy-17a-ethoxymethyl-17β-methoxy-estr-9 (1D-ene-3,3-dimethylketal in 20 ml of THF are added dropwise, the mixture is stirred at room temperature for 2 hours, the batch is stirred with The orf mixed phase is washed neutral dried over Na ₂ SO ₄ and evaporated under vacuum.The crude product is purified by column chromatography on 60 g of alumina (alkaline) with a benzene / ethyl acetate gradient cleaned 700 mg of 3,3-dimethoxy-11β- [4- (1,1-ethylenedioxyethyl) -phenyl] -17α-ethoxymethyl-17β-methoxy-estr-9-en-5a-ol are obtained as a colorless oil, which is processed directly.

e) 700 mg of 3,3-dimethoxy-11β- [4- (1,1-ethylenedioxyethyl) -phenyl] -17α-ethoxymethyl-17β-methoxy-estr-9-en-5a-ol are dissolved in 20 ml of dilute acetic acid (70 %) stirred for 20 hours at room temperature. After addition of water is extracted with ethyl acetate, the organic phase with dilute aq. NaOH and water, dried over Na ₂ SO ₄ and evaporated under vacuum. The crude product is purified by preparative Schichtchromatographio on silica gel 60 with the mobile phase mixture benzene / acetone9: 1 (v / v). 290 mg of 11β- (4-acetylphenyl) -17a-ethoxymethyl-17β-methoxy-estra-4,9-dien-3-one are obtained.

Mp. 134 ⁰ C to 137 ^C C (acetone / ether) Ia] ₀ = + 18O ⁰ C (CHCI ₃₎ 'H-NMR (CDCI _3, TMS):

P (ppm): 0.52 (s, 3H, H-18); 1.26 (t, J = 6Hz, 3H, 17Q-CH ₂ OCH ₂ CH ₃ ); 2.56 (s, 3 H, COCH _3); 3.24 (s, 3H, 17β-OCH ₃ ); 3.54 (q, J = 7 Hz, Ί 7 0 -CH ₂ OCH ₂ CH ₃ , superimposed on the AB system of the 17 a-CH ₂ OCH ₂ CH ₃ moiety); 4.41 (d, J = 7.5 Hz, H-11); 5.77 (s, 1H, H-4); 7.24-7.80 (m, 4H, AA'BB 'system of the aromatic)

UVinEtOH: \ _m "= 258nm log e = 4.27 X _max = 300.7 nm log ε = 4.33

Example 3

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

a) To 3,9g3,3-dimethoxy-17a-propoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol in 30 ml of THF is added dropwise as long as a sodium naphthalide solution (prepared from 375 mg sodium and 1.9 g Naphthalene in 100ml THF) until a dark green color persists to form the alkoxide.

b) After stirring for 30 minutes at 20X is added dropwise to the solution 8 ml of methyl iodide slowly and stirred for a further 3 hours at room temperature. After addition of aq. NH ₄ Cl solution is extracted several times with ethyl acetate. The organic phase is washed neutral, dried over K ₂ CO ₃ and Na ₂ SO ₄ and the solvent is evaporated off under vacuum. The crude product is purified by column chromatography on 140 g alumina (alkaline) with a benzene / ethyl acetate gradient. It can be 3.56g 17ß-methoxy-17a-propoxymethyl-estra-5 (10), 9 (11) -diene-3,3-dimethylketa! win as a colorless oil, which is used directly in the next stage.

c) To 3.56 g of 17β-methoxy-17α-propoxymethyl-estra-5 (10), 9 (11) -diene-3,3-dimethylketal in 20 ml of methylene chloride are added 1 g of NaHCO ₃ , 2.5 g of NaH ₂ PO ₄ , 4 Added 5 ml H ₂ O ₂ and 1.5 g chloral hydrate. The mixture is stirred for about 3.5 hours until complete conversion at room temperature, water is added and extracted with methylene chloride. The organic phase is washed successively with aq. Bisulfite solution, K ₂ CO ₃ solution and water, dried over Na ₂ SO ₄ and evaporated in vacuo. The crude product is purified by column chromatography on 120 g alumina (alkaline) with a benzene / ethyl acetate gradient. This gives 2.45 g of 5a, 10a-epoxy-17ß-methoxy-17a-propoxymethyl-estr-9 (11) -en-3,3-dimethylketal as a colorless oil, which is used directly in the next stage.

d) To 560mg of magnesium in 5ml abs. Ether is added successively O, 2 ml of dibromoethane and 5.7 g of 1- (4-bromophenyl) -ethanone-1,1-ethylene ketal in 30 ml of abs. THF. The mixture is stirred for 3 hours at 5O ⁰ C internal temperature, cooled to ^{0 0} C and adds 220 mg of CuCl added. After a further 20 minutes, 2.45 g of 5a, 10a-epoxy-17ß-methoxy-17a-propoxymethyl-ostr-9 (11) -en-3,3-dimethylketal are added dropwise in 40 ml of THF. It is stirred for 3 hours at room temperature, decomposed with aq. NH ₄ Cl solution and extracted with ethyl acetate, it is washed colorless and neutral, dried over Mg ₂ SO ₄ and evaporated in vacuo. The crude product is purified on 100 g alumina (alkaline) with a benzene / ethyl acetate gradient. This gives 1.5 g of 3,3-dimethoxy-11β- [4- (1,1-ethylenediox '> ethyl) -phenyl] -17β-methoxy-17a-propoxymethyl-estr-9-en-5a-ol as a colorless Oil that is used directly in the next stage.

e) To 1.5 g of 3,3-dimethoxy-11β- [4- (1,1-ethylenedioxyethyl) -phenyl] -17β-methoxy-17α-propoxymethyl-estr-9-en-5a-ol are diluted in 20 ml Added acetic acid (70%) and the mixture stirred for 4 hours at room temperature. After addition of water is extracted with excess acid, the organic phase with dilute aq. NaOH and water, dried over Na ₂ SO ₄ and evaporated in vacuo. The crude product is recrystallized from ether / acetone / hexane. 790 mg of 11β- (4-acetylphenyl) -17β-methoxy-17α-propoxymethyl-estra-4,9-dien-3-one are obtained.

Mp 118 ° ^{C to} 120 ° C [α] _D = + 16O ⁰ C (CHCl ₃ ) 'H-NMR (CDCl ₃ , TMS):

δ (ppm): 0.54 (s, 3H, H-18); 0.94 (t, J = 7Hz, 3H, 170 -CH ₂ OCH ₂ CH ₂ CH ₃ ); 2.57 (s, 3H, COCH ₃ ); 3.23 (s, 3H, 17β-OCH ₃ ); 3.37 (t, J = 6.5Hz, 2H, 17Ci-CH ₂ OCH ₂ CH ₂ CH ₃ ); 3.31-3.52 (m, 2H, £ J 21 Hz, AB system of 170-CH ₂ OCH ₂ CH ₂ CH ₃ ); 4.41 (d, J = 7Hz, 1H, H-11); 5.77 (s, 1H, H-4); 7.19-7.84 (m, 4H, AA'BB 'system of the aromatic). UV in EtOH: \ _mtx = 258 nm log e = 4.29 λπ ,, χ = 301 nm log ε = 4.34

Example 4

Preparation of 11β- (4-dimethylaminophenyl) -17β-methoxy-17a-methoxymethyl-estra-4,9-dien-3-one

d) To 850mg of magnesium in 10ml abs. THF is added dropwise under argon 0.15 ml of dibromoethane and then

5 g of p-bromodimethylaniline in 15 ml abs. THF. The mixture is stirred for 3 hours at 50 ° C internal temperature, cooled to -? 0 ° C and adds 200mg CuCl added. After a further 20 minutes, 1.72 g 5a, 10a-epoxy-17β-methoxy-17a-methoxymethyl-estr-9 (11) -en-3,3-dimethyl ketal in 15 ml THF are added dropwise. The mixture is stirred for 1 hour at 10 ⁰ C to 15 ° C and then at room temperature, the approach with aq. Ammonium chloride solution decomposed and extracted with ether. The organic phase is washed neutral, dried over Na ₂ SO ₄ and evaporated under vacuum. The crude product is purified by column chromatography on 70 g of alumina (alkaline) with a benzene / ethyl acetate gradient. This gives 1.1 g of 3,3-dimethoxy-11β- (4-dimethylaminophenyl) -17β-methoxy-17a-methoxymethyl-estr-9-en-5a.-ol as a colorless oil, which is further processed directly.

e) 700 mg of 3,3-dimethoxy-11β- (4-dimethyldminophenyl) -17β-methoxy-17α-methoxymethyl-estr-9-en-5a-ol are stirred in 20 ml of dilute acetic acid for 20 hours at room temperature. After addition of water is extracted with ethyl acetate, the organic phase with dilute aq. NaOH and water, dried over Na ₂ SO ₄ and evaporated in vacuo. After repeated preparative layer chromatography on alumina (neutral) and silica gel PF ₂₆₄ , 420 mg of 11β- (4-dimethylaminophenyl) -17β-metyloxy-17a-methoxymethyl-estra-4,9-dien-3-one are obtained as a foam.

(O] = ₀ + 167 ⁰ C (CHCI ₃₎ 'H-NMR (CDCI _3, TMS):

δ (ppm): 0.59 (s, 3H, H-18); 2.95 (s, 8H, N (CH ₃ I ₂ , 3.26 (see 3H, 17β-OCH ₃ ); 3.41 (s, 3H, 17a -CH ₂ OCH ₃ ); 3.30-3.64 (m, 2H, ABX system, 17 O -CH ₂ OCH ₃ ); 4.30 (d, J = 7Hz, 1H, H-11); 5.75 (s, 1H, H-4); 6.60-7.06 (m, 4H, AA'BB'-system of the aromatic) UVinEtOH: X _mH = 261 nm delta = 4.15 λπι = 304 rim log ε = 4.16

2 * 3068

O O i O O η ro X X cc j O. ec X O L

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Claims (3)

1. A process for the preparation of 11 ß-arylsubstituiorten ^ ß-alkoxy ^ a-alkoxymethyl estiaAg-dien-3-one of the general formula I, wherein R ^{1 is} an alkyl radical having 1 to 6 carbon atoms, R ^{2 is} an alkyl radical having 1 to 6 carbon atoms or a CHaO (S) R ₁ radical having Ri in the meaning of alkyl radicals having from 1 to 4 carbon atoms and R ³ e ^! ne dimethylamine, an acetyl or ketalized acetyl group, characterized in that a) 17a-Alkoxymethyl-17β-hydroxy-estra-5 (10), 9 (11) -diene-3-ketalde by deprotonation with bases in 17β-alcoholates of 17α-alkoxymethyl-estra-5 (10), 9 (1l) -dien-3-ketenes, b) reacting them by alkylation with alkyl halides to give 17β-alkoxy-17α-alkoxymethyl-estra-5 (10), 9 (11) -diene-3-ketals, c) they are selectively epoxidized with H ₂ O ₂ zo the SaJOa-epoxy-Uß-alkoxy-l / a-alkoxymethvl-estr-gdD-en-S-ketals, d) opening them with arylmagnesium halides having a dimethylamino or a protected acetyl group in the position para to magnesium, to give the 11β-aryl-substituted 17β-alkoxy-17α-alkoxymethyl-estr-9-en-5a-olone, as well e) hydrolyzing them under acidic conditions to the desired 11β-aryl-substituted 17β-alkoxy-17α-alkoxymethyl-estra-4,9-dien-3-ones. 2. The method according to claim 1, characterized in that one in process step a) as 17a-alkoxymethyl-17β-hydroxy-estra-5 (10), 9 (11) -diene-3-ketal, the 3,3-dimethylketal of general formula II, as a base for the deprotonation of alkali naphthelide, such as sodium or lithium naphthalide, and as organic solvent uses tetrahydrofuran, in process step b) alkylation with alkyl halides, or Alkyloxyalkylhalogeniden Alkylthioalkylhalogenide directly or in solvents such as ether, C carried out at temperatures 20 ^0, in method step c) epoxidation with H ₂ O ₂ and haloacetones, such as hexachloroacetone or hexaflucracetone, in the presence of catalytic amounts of tertiary bases, such as triethylamine or pyridine, or with haloaldehydes, such as chloral hydrate, in the presence of water binding agents, such as anhydrous primary alkaline phosphate and alkali metal carbonate or alkali carbonate, at temperatures of 20 ^° C. in inert solvents, such as methylene chloride or chloroform, in process step d) the Grignardization in an ether, such as diethyl ether or tetrahydrofuran, in the presence of copper-l-salts, such as CuCl, and carried out as 1- (4-bromophenyl) -ethanone-1,1-ketal the ethylene ketal at temperatures between 0 ⁰ C and 30 ⁰ C and implemented in process step e) acid hydrolysis with acids, such as dilute acetic acid, in water ^:. "ibaren solvents, wi - methanol, acetone or tetrahydrofuran, at temperatures between 0 ⁰ C and 8O ⁰ C or on acidic carriers, such as acidic alumina, performed. 3. The method according to claim 1 and 2, characterized in that the 11 ß-aryl-substituted 17ß-alkoxy-17a-alkoxymethyl-estra-4,9-dienes 11β- (4-acetylphenyl) -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, - 11β- (4-dimethylaminophenyl) -17β-methoxy-17a-methoxymethyl-estra-4,9-dien-3-one, - 1 ¹ ß- (4-acetylphenyl) -17a-ethoxymethyl-17ß-methoxy-estra-4,9-dien-3-one and - 11ß- (4-acetylphenyl) -17ß-methoxy-17a-propoxymethyl-estra-4,9-dien-3-one produces.