DD289537A5 - PROCESS FOR THE PREPARATION OF 11 BETA-ARYL-GONA-4,9-DIENES - Google Patents

Abstract

It describes the production of * which are of interest as potential hormone antagonists for pharmaceutical research and industry. In their synthesis one starts from *, which is converted by ketal cleavage, followed by bromination / dehydrobromination and ketalization into * and by means of a base and an alkylating agent optionally alkylated at the 17-ethynyl and / or 17-oxygen function or with formaldehyde at the 17 Ethynyl group be hydroxymethylated. Subsequently, the alkylated or hydroxymethylated * are converted by epoxidation in the *, which by Grignardierung with a Arylmagnesiumhalogenid in the presence of a CuI salt initially in 11b-aryl-gon-9-en-5a-ols and by means of acid in a water-soluble organic solvent finally be converted into the target compounds. {* potential hormone antagonists; * Ketal cleavage; Bromination / dehydrobromination; ketalization; alkylation; hydroxymethylation; epoxidation; Grignardization; 11b-aryl-gon-9-en-5a-ols}

Description

methyl-gon-9-en-5a-ol,

- 11β- (4-dimethylaminophenyl) -17a -ethynyl-3,3-ethylenedioxy-17β-methoxy-13-methyl-gon-9-ene-5a-ol,

- 17a-Ethynyl-11β- [4- (2'-methyl-1 ', 3'-dioxolan-2'-yl) -phenyl] -17β-methoxy-13-methyl-gon-9-en-5a-ol .

3,3-ethylenedioxy-17α- (3'-hydroxy-1'-propynyl) -17β-methoxy-11β- [4- (2'-methyl-1 ', 3'-dioxolan-2'-yl) - phenyl] -13-methyl-gon-9-en-5a-ol,

3,3-ethylenedioxy-17α- (3'-hydroxy-1 '(Z) -propenyl) -17β-methoxy-11β- [4- (2'-methyl-1', 3'-dioxolane-2 ' yl) -phenyl-13-methyl-gon-9-en-5a-ol and

3,3-ethylenedioxy-17a (3'-hydroxypropyl) -17β-mefhoxy-11β- [4- (2'-methyl-1 ', 3'-dioxolan-2'-yl) -phenyl] -13- methyl-gon-9-en-5a-ol

manufactures

 5. The method according to claim 1 to 3, characterized in that the 11 ß-aryl-gona-4,9-dienes

- 11β- (4-dimethylaminophenyl) -17β-methoxy-17α-propynyl-13-methyl-gona-4,9-dien-3-one,

11ß- (4-acetylphenyl) -17β-msthoxy-17-propynyl-IS-methyl-gono-diene-S-on,

- 11β- (4-dimethylaminophenyl) -17β-methoxy-17α-ethynyl-13-methyl-gona-4,9-dien-3-one,

- 11β- (4-acetylphenyl) -17β-methoxy-17α-ethynyl-13-methyl-gona-4,9-dien-3-one,

11β- (4-acetylphenyl) -17α- (3'-hydroxy-1'-propynyl) -17β-methoxy-13-methyl-gona-4,9-dien-3-one,

- 11β- (4-acetylphenyl) -17α- (3'-hydroxy-1 '(Z) -propenyl) -17β-methoxy-13-methyl-gona-4,9-dien-3-one and

- 11β- (4-acetylphenyl) -17α- (3'-hydroxypropyl) -17β-methoxy-13-methyl-gona-4,9-dien-3-one.

To this 1 page Formoln

Field of application of the invention The invention relates to a process for the preparation of 11ß-aryl-gona-4,9-serve the general formula I, wherein

R, = CH ₃ OdBrC ₂ H ₆ ,

R ₂ = OCH ₃ , SCH ₃ , N (CH ₃ I ₂ , NHCH ₃ , CN, CHO, CH ₃ CO, CH ₃ CHOH, R ₃ = H, alkanoyl or alkyl having in each case 1 to 6 C atoms and R ₄ = C =CH, CsCCH ₃ , CsCCH ₂ OH, C =CCH ₂ alkakanoyl, C ₁ -C ₂ -alkylalkanoyl, CH ₂ CH ₂ CH ₂ alkanoylyl having in each case 1 to 6 C atoms, CsCCH ₂ OH and CH ₂ CH ₂ CH ₂ OH, which are of pharmacological interest due to structural features. The Field of application is thus in the pharmaceutical industry. Characteristic of the known state of the art

Methods of preparing 11β-aryl-gona-4,9-dienes having a 17a-ethynyl, 17a-propynyl, 17a-hydroxypropenyl, 17α-propargyl and 17a-hydroxypropyl group in combination with a 17β-hydroxy group are known (46th Annual Meeting of the Endocrin Society, San Francisco [Ca], June 16-18, 1982; A. Belanger, Steroids 37, [1981] 361).

The introduction of the 17a-ethynyl, 17a-propynyl and 17a-propargyl group, wherein in the latter the OH group must be protected beforehand, via the 17-keto compounds by reaction with the corresponding alkali alkynylidene. Compounds with a 17ß-Ethergruppierung instead of the OH group are flat without specifying a particular way

and claimed by examples (EP 0057115 A2,1982). Alkylation of the 17beta-OH group with 4,9-dien-3-ones by methods known per se, which is generally to be understood as a conversion into the alkoxide and addition with a modifying agent, appears to be unsuitable in the process, since experience has shown that alkylation takes place in Neighboring position to the 3-keto group can not be avoided (A. Bowers, and W. Reusch, Tetrahedron Letters, 1973, 696). The best-known member of the list of compounds listed is Ru 38486, mifepristone, which has an antiglucocorticoid and particularly strong antigestagenic activity, by virtue of which it is used for post-coital fertility control, because it has the antigestagenic effect necessary for pregnancy Progesterone is displaced from the receptor, but is itself not progestogen-active, and because of this property triggers miscarriage.As a prerequisite for a high binding to the progesterone, the presence of a 17β-OH group was considered to be an adhesion site for the receptor The steroid Hezeptorbindung should take place here via hydrogen bond via the 17ß-OH function.

Object of the invention

The aim of the invention is the preparation of 11β-aryl-gona-4,9-dienes according to a new process and the provision of new substances having a 17β-ether ring instead of a 17β-OH group for pharmaceutical research and industry in order to obtain their To use potential.

Explanation of the essence of the invention

The invention has for its object to provide a technologically easy to implement chemical synthetic method for the preparation of 11ß-aryl-gona-4,9-serve the general formula I. According to the invention the object is achieved in that one

a) 3,3-Dimethoxy-17a-ethynyl-gon-5 (10) -en -17ß-ole of the general formula II by ketal cleavage in a water-containing organic solvent in the presence of catalytic amounts of acid in 17a-ethynyl-gon-5 (10 ) -en-3-one of general formula III,

b) the 17a-ethynyl-gon-5 (10) -en-3-ones are converted by bromination / dehydrobromination into 17a-ethynyl-17β-hydroxy-gona-4,9-dien-3-oneb of general formula IV,

c) from the 17a-ethynyl-17ß-hydroxy-gona-4,9-dien-3-ones by ketalization produces the ketals of general formula V, wherein R ₅ and R ₆ = CH ₃ , C ₂ Hs or a cyclic ketal with 2 or 3 C-ring atoms which may be substituted on the carbon atoms by alkyl groups,

d) the ketals are converted by a base in an ether or an aprotic dipolar solvent, optionally with the addition of a solubilizer, into the acetylides and / or alcoholates which are optionally C- and / or O-alkylated with an alkylating agent or by hydroxymethylation of the ethynyl group converted with formaldehyde into gona-5 (10), 9 (11) -dienes of general formula VI,

e) from gona-5 (10), 9 (11) (by epoxidation synthesize the 5ci, 10a epoxides of general formula VII,

f) the 5a, 10a-epoxides with Arylmagnesiumhalogenid in the presence of a Cu 'salt at a reaction temperature of -30 ° C to + 3O ⁰ C react and compounds with a 17a-Propargylgruppe reduced, with 11 ß-aryl-5a-hydroxy -gon-9-ene of the general formula VIII arise, and

g) the 11β-aryl-5a-hydroxy-gon-9-enes by acid treatment in a water-miscible solvent, optionally with heating to 60 ° C to 70 ⁰ C, in gona-4,9-diene-3-ones which is derivatized to the 11 ß-aryl-gona-4,9-dien-3-ones of general formula I.

In the further embodiment of the method in step a) as the organic solvent acetone, methanol or a solvent combination consisting of methylene chloride and tert. Butanol, and as acids, oxalic acid, p-Toluensulfonsäuro or mineral acids, such as sulfuric acid, hydrochloric acid, perchloric acid or phosphoric acid,

in process step b)

for the bromination / dehydrobromination pyridine hydrobromide perbromide or bromine in pyridine, in process step c)

for the ketalization as alcohols methanol, ethanol, ethylene glycol or 2,3-dimethylpropanediol, as acids p-toluenesulfonic acid, oxalic acid, pyridinium tosylate or mineral acids, such as sulfuric acid or perchloric acid, as dehydrating agents triethyl and trimethyl trimethylates or a water entraining agent, such as cloroform, benzene or toluene,

in process step d)

as bases lithium alkyls such as lithium methyl, -n-butyl and -tert. butyl, calcium, lithium, sodium or potassium amides, lithium, sodium hydride, potassium hydroxide, lithium, sodium or potassium naphthalide, or produced by electrochemical reduction naphthalide ion, as the ether diethyl ether, tetrahydrofuran or dioxane, dimethyl sulfoxide, dimethylformamide, optionally used as Solubilizers benzene or toluene and as alkylating agents dialkyl sulfates such as dimethyl and diethyl sulfate, and alkyl halides such as methyl, ethyl, propyl, butyl, pentyl, hexyl, Isopropylhalogenide in the form of chlorides, bromides and iodides, and Methylchloralkylether with an alkyl radical in the meaning η = 1 to 6, in process step e)

as buffer Na ₂ CO ₃ , NaHCO ₃ , K ₂ CO ₃ , KHCO ₃ , Na ₂ KPO ₄ , NaH ₂ PO ₄ , NaOAc and KOAcsowie as inert solvent benzene, toluene, chloroform, dichloroethylene or methylene chloride,

in process step f)

as Arylmagnesiumhalogenide Phenylmagnesiumhalogenioe in the form of the chlorides and bromides, in p-position to the magnesium OCH ₃ , SCH ₃ , N (CH ₃ J ₂ , NHCH ₃ , CN, CH ₃ CHOH, R ₈ O-CH-OR ₅ , CH ₃ -CORe-OR ₅ group, wherein Rs = R6 = CH ₃ , C ₂ Hi or a cyclic ketal with 2 or 3-C-ring atoms which may be substituted on the carbon atoms by alkyl groups, as ether diethyl ether, Tetrahydrofuran and dioxane, as a solubilizer benzene and toluene, as Cu 'salts CuCN, CuI and CuCl and as a reducing agent for the 17a Propargylgruppe lithium alanate or hydrogen in the presence of Pd or Pt as hydrogenation catalysts in an ether or an alcohol and finally

in process step g)

for the acid treatment, aqueous acetic acid, p-toluenesulfonic acid or mineral acid, such as hydrochloric acid, sulfuric acid, phosphoric acid and perchloric acid, and used as the solvent aqueous methanol, ethanol and acetone.

In the preferred embodiment of the process, the alkylation of the 17a-ethynyl and 17ß-oxygen function or the hydroxymethylation of the 17a-ethynyl group is also carried out starting from the Eduktion according to formula I.

The proposed method can be prepared starting from a technically readily available starting material compounds with different substitution of C atom 17 with relatively simple raw materials and excipients. In this way, in addition to the 17a-ethynyl, the 17a-propynyl, 17a-hydroxypropinyl and also simultaneously the various 17ß-alkyl ethers available.

From the structure-activity relationships known hitherto, it is apparent that, in addition to an 11β-aryl substituent, the substitution pattern on the C-atom 17 is also crucial for competitive programmer antagonists, that a combination such as 17a-ethynyl, 170, -propynyl, 17a-hydroxypropenyl or 17a-hydroxypropyl with a 17ß-hydroxy group conditions for optimal antigestagenic effect.

Surprisingly, it has now been found that an alkoxy instead of a 17ß-OH group also fulfill this function, and that even the effect, as shown in rats, can be increased.

The accompanying reaction scheme illustrates the process according to the invention

Exemplary embodiments

Example 1 Step a

17a-ethynyl-17-hydroxy-13-methyl-gon-S (10) -en-3-one

10 g of 3,3-dimethoxy-17a-ethynyl-13-methyl-gon-5 (10) -en-17ß-ol are suspended in 165 ml of 80% aqueous acetone and treated with vigorous stirring with 0.2 ml of 25% sulfuric acid , Subsequently, it is stirred at room temperature until all the starting material has reacted. Then the steroid is precipitated by adding water, separated and dried. This gives 9 g of 3-keto-5 (10) compound, which can be recrystallized from acetone / water. fcRohp,. *, * ,: 173 "CbIsWC

Stage b

17a-Ethlnyl-17-hydroxy-13-methyl-gona-4,9-dlen-3-one

15g 17a-ethynyl-17-hydroxy-13-methyl-gon-5 (10) -en-3-one are dissolved in 219ml of pyridine and under cooling ⁽⁰ -5 C) with 18.6 g of pyridine hydrobromide perbromide are added at once. After 15 minutes, the cooling is removed and the slowly warming to room temperature solution stirred for about 15 minutes and then added 2 ml Meihylbuten to decompose excess brominating agent. The mixture is then stirred for 5 hours at room temperature and then stirred into ice-water to which a little hydrochloric acid has previously been added. After crystallization, the steroid is filtered off and optionally crystallized from ether. This gives 14 g of dienone (92.7% of theory).

Stage c

17a-ethynyl-3,3-ethylenedioxy-13-methyl-gona-5 (10), 9 (11) -diene-17-ol

2 g of 17-ethynyl-17β-hydroxy-13-methyl-gona-4,9-dien-3-one are dissolved in 3 ml of ethylene glycol, 5 ml of triethyl orthoformate and 30 ml of methylene chloride, and 0.1 g of p-toluenesulfonic acid are added. Some of the solvent is distilled off and a dark brown solution is obtained, which is stirred for 30 minutes at room temperature. Thereafter, an aqueous sodium bicarbonate solution is added and the steroid is extracted with methylene chloride. After concentration of the extracts, the oily residue is crystallized from ether / hexane to give 2 g of the ketal.

F .: 152 ^° C to 155 ^° C

IR [Cm " ¹ ]: no C = O, 3300 (ethynyl), 3600 (OH)

Stage c '

17a-Ethynyl-3,3-ethyl-dioxy-13-methyl-gona-5 (10), 9 (11) -diene-17β-ol

42.5 g of 17α-ethynyl-17β-hydroxy-13-methyl-gona-4,9-dien-3-one (crude product) are dissolved in 600 ml of benzene and admixed with 45 ml of ethylene glycol and 1.8 g of p-toluenesulfonic acid and (as long as ( About 2 hours) cooked on a water with intensive stirring until all the starting material is reacted. Then a sodium bicarbonate solution is added and the steroid is extracted with benzene. The oily residue after concentration is crystallized from ether to give 43 g of ketal.

F.:152°Cbis155"C

IRIcm " ¹ ]: no C = O, 3300 (ethynyl), 3600 (OH)

Stage d

3,3-Ethylendloxy-17a-ethlnyl-17-methoxy-13-methyl--gona-5 (10), 9 (11) -diene

7.5 g of 3,3-ethylenedioxy-17a-ethynyl-13-methyl-gona-5 (10), 9 (11) -diene-17ßol (22.07 mmol crude product) are dissolved in 25 ml of tetrahydrofuran and under inert gas with 55 ml (22mmol, 0.4m) of an ethereal lithium methyl solution in the cold (-10 ⁰ C). The addition of strong gas begins. After the addition, 5.7 ml of methyl iodide are added after 15 minutes and the reaction solution is warmed to room temperature. It is allowed to stand overnight at room temperature, then treated with water and extracted the steroid with ether. After concentration of the extracts is chromatographed on neutral alumina. The eluent used is a benzene / benzene-ethyl acetate mixture (5: 1). There are 4.3 g of 17ß methyl ether isolated in the form of an oil, which can be used directly in the next stage. Irlcm "']: no C = O, 3300 (ethynyl)

Stage d '

3,3-ethylenedioxy-17a-ethyl-17ß-methoxy-13-methyl-gona-5 (10), 9 (11) -dlen7g 3,3-ethylenedioxy-17a-ethynyl-13-methyl-gona-5 (10 ), 9 (11) -diene-17p-ol (20.6 mmol) are dissolved in 50 ml of tetrahydrofuran and treated under nitrogen with 1 g of naphthalene (7.8 mmol) and 0.2 g of lithium (28.57 mmol) and 5 hours stirred at about 70 ⁰ C (hotplate temperature). Thereafter, fresh lithium was removed and to the solution at room temperature was added 2.6 ml (41.72 mmol) of methyl iodide. The mixture is then gently heated for about 4 hours on the water bath and the steroid is extracted after addition of water η it ether. The crude product obtainable after concentration of the extracts is used without further purification in the next stage.

IRicrn " ¹ ): no C = O, 3300 (ethynyl)

Stage e

17a-ethynyl-3,3-ethylendloxy-17-methoxy-5a, 10a-oxldo-13-methyl-gon-9-ene

5 g of 17a-etninyl-3,3-ethylenedioxy-17β-methoxy-13-methyl-gona-5 (10), 9 (11) -diene are dissolved in 45 ml of methylene chloride and, after addition of ₂ g Na ₂ HPO ₄ , 1 g Na ₂ CO ₃ and 7.25 ml of 30% H ₂ O ₂ intensively stirred and then treated with 1.25 g (7.55 mmol) of chloral hydrate. It is stirred for about 20 hours at room temperature and then added to an aqueous sodium carbonate solution and the steroid extracted with methylene chloride. The organic phase is washed repeatedly with sodium carbonate solution, then separated, dried and concentrated. The remaining residue is flash chromatographed on basic alumina. The mobile phase is a mixture of benzene and ethyl acetate (20: 1 to 10: 1). The epoxide was isolated as an oil (2g) and used in the next step. IRIcnT ¹ ]: no C = O

Stage f

17a-Ethlnyl-3,3-ethylenedioxy-11ß- [4- (2'-methyl-1 ', 3'-dloxolan-2'-yl) phenyl-17-methoxy-13-methyl-gon-9-ene -5a-ol. Approximately 1.5 g of α-ethynyl-SS-ethylenedioxy-n-β-methoxy-Sa.iOa-oxido-IS-methyl-gon-gfiil-ene (4.05 mmol) in 10 ml of tetrahydrofuran are added to a freshly prepared, cooled to -15 ⁰ C cooled Grignard solution of 4- (2'-methyl-1,3'-dioxolan-2'-yl) phenylmagnesium bromide (15 mmol) and 0.15 g of CuCl in 30 ml of tetrahydrofuran. After the addition is stirred for about 30 minutes while the reaction mixture is gradually warmed to room temperature. Subsequently, it is mixed with an aqueous ammonium chloride solution and the steroid is extracted with ether. After concentration of the extracts, the remaining residue is flash chromatographed on basic alumina. The mobile phase is a benzene / ethyl acetate mixture (10: 1). 1.2 g of the 11β-aryl substituted compound are isolated, which can be crystallized from methanol or ethanol.

F: 181 ⁰ C to 189 ⁰ C [a] ₀ 31.1 °

Level g

11ß- (4-acetylphenyl) -17a-ethlnyl-17-methoxy-13-methyl-gona-4,9-dlen-3-one

0.5 g of 17α-ethynyl-3,3-ethylenedioxy-11β- [4- (2'-methyl-1 ', 3'-dioxolan-2'-yl) -phenyl] -17β-methoxy-13-methyl-gon -9-en-5a-ol (0.94 mmol) are mixed with 10 ml of 70% aqueous acetic acid and heated for 1 hour at 7O ⁰ C on a water bath. Then the steroid is precipitated by adding water and some ammonia. The isolated crude product is flash chromatographed on neutral alumina. Elution is carried out with benzene / ethyl acetate mixture (10: 1). 0.35 g of the 11β-acetophenyl compound obtained from methanol / water in amorphous crystalline form is obtained. F .: 87 ⁰ C to 91 ⁰ C [a] ₀ : 1: 9.3 "

Example 2 The preparation of stages a to e is carried out analogously to Example 1.

Stage f

11β- (4-dimethylaminophenyl) -3,3-ethylenedioxy-17α-propynyl-13-methyl-gon-9-ene-5a, 17β-diol A Grignard solution in tetrahydrofuran prepared from 1.92 g of magnesium, 0.05 ml of dibromoethane, 16.8 g of p-bromodimethylaminobenzene (80 mmol) and 120 ml of tetrahydrofuran, is cooled by means of dry ice to about -15 ⁰ C and treated with 0.4 g of CuCl. After 15 minutes of stirring in the cold about 9g S ^ -Ethylendioxy-oaJOa-oxido-na-propynyl-IS-methylgon-9 (11) -en-17ß-ol (crude product), which is dissolved in 15 ml of tetrahydrofuran, added dropwise. The mixture is then stirred for 30 minutes and the solution is allowed to warm slowly to room temperature. For working up, it is mixed with aqueous ammonium chloride solution and the steroid is extracted with ether. The organic phase is washed with an aqueous sodium disulfite solution and finally with water, dried and concentrated. The remaining residue is chromatographed on basic alumina. Elution is carried out with benzene / benzene-ethyl acetate mixture (10: 1). After recrystallization from ether / n-hexane, 5.1 g of Dimethylaminophenylverbindung be obtained.

F.:203°Cbis206°C

IR [Cm " ¹ ]: 3600 (OH), 3500 OH - associated)

Stage f

11β- (4-dimethylaminophenyl) -3,3-ethylenedioxy-17β-methoxy-T / α-propyl-13-methyl-gon-9-en-5a-ol 40ml of a Grignard solution (30mmol) in tetrahydrofuran, prepared from 0, 96 mg, 0.05 ml of dibromoethane, 8.4 g of p-bromodimethylaminobenzene in 60 ml of tetrahydrofuran are cooled by means of dry ice to -15 ° C and treated with 0.2 g CuCl. After stirring for 1 minute under nitrogen, 2.1 g of 3,3-ethylenedioxy-17β-methoxy-5a, 10α-oxido-17α-propynyl-13-methyl-gon-9 (11) -ene, which is dissolved in 10 ml Tetrahydrofuran is dissolved, added dropwise. Then the external cooling is removed and stirred for 30 minutes. For working up, it is mixed with aqueous ammonium chloride solution and the steroid is extracted with ether. Then it is washed with aqueous sodium disulfite solution and finally with water, the organic phase separated, dried and concentrated. The remaining residue is chromatographed on basic alumina. The mobile phase is benzene and a benzene / ethyl acetate mixture (10: 1). After recrystallization from ether / n-hexane, 1.5 g of the 11β-dimethylaminophenyl compound are obtained

F .: 124X to 127 ° C [a] _D -69.9 °

Level g

2.9 g of 11β- (4-dimethylaminophenyl) -3,3-ethylenedioxy-17α-propynyl-13-methyl-gon-9-ene-5a, 17β-diol are dissolved in 10 ml of 70% aqueous acetic acid and stirred for one hour the water bath (60 ° C to 7O ⁰ C) heated. Subsequently, the steroid is precipitated by addition of water and 25% ammonia. The resulting crude product (about 2.5 g) is chromatographed on basic alumina. Elution is carried out with benzene and benzene / ethyl acetate mixture (10: 1). After recrystallization from acetonitrile, 1.3 g of the dienone are obtained

F .: 178 ⁰ C to 181 ⁰ C

Stage g '

11ß- (4-Dimethylamlnophenyl) -17ß-methoxy-17a-proplnyl-13-methyl-gona-4,9-dlen-3-one

0.7 g of 11ß- (4-dimethylaminophenyl-3,3-ethylenedioxy-17ß-methoxy-17a-propynyl-13-methyl-gon-9-en-5a-ol are dissolved in 10 ml of 70% aqueous acetic acid and 1 hour on the water (6O ⁰ C to 7O ⁰ C.). Subsequently, precipitating the steroid by the addition of water and 25% ammonia in. the well abfrittbare crude product is flash chromatographed on basic aluminum oxide is eluted with benzene and benzene / Essigester-. mixture (10: 1). the obtainable after concentration of Dienonfraktionen residue is dissolved in acetic acid and the steroid by the addition of water and 25% ammonia precipitated, giving 0.35 g of 11.beta.-Dimethylaminophenyldienons F .: 101 ^{0 0} CbISiOo.. C [al ₀ : 129.5 °

Example 3

The preparation of stages a to c was carried out analogously to Example 1.

Stage d

3,3-Ethylendloxy-17a-proplnyl-13-methyl-gona-5 (10), 9 (11) -diene-17-ol

9g 17a-Ethynyl-3 _/ 3-ethylenedioxy-13-methyl-gona-5 (10), 9 (11) -diene-17β-ol (26.4 mmol) are dissolved in 70 ml of tetrahydrofuran and added with cooling (ca. 86.5 ml of lithium butyl (0.61 m) are added to the homogeneous solution are added 4 ml of methylene iodide (109.6 mmol), which is diluted with 4 ml of tetrahydrofuran, in the cold gradually and then allowed to stir slowly with stirring After 4 hours, water is added and the steroid is extracted with ether, and the oily residue (9 g crude product) obtainable after concentration can be crystallized from hexane IR (cm -1): no C = O, 3595 (OH)

Level ο

3,3-ethylenedioxy-5o, 10a-oxido-17a-propynyl-13-methyl-gon-9 (11) -en-17β-ol

9 g of 3,3-ethylenedioxy-17α-propynyl-13-methyl-gona-5 (10), 9 (11) -diene-17β-ol (crude product), 3 g of anhydrous Na ₂ HPO ₄ and ₂ g of Na ₂ CO ₃ are dissolved in 45 ml of methylene chloride and mixed with stirring at room temperature with 13.25ml H ₂ O ₂ (30%) and finally with 2.25 g of chloral hydrate. The mixture is stirred for 16 hours at room temperature, then an aqueous sodium carbonate solution is added and the steroid is extracted with methylene chloride. The organic phase is washed twice more with a sodium carbonate solution and finally with water, then dried and concentrated. The resulting crude epoxide product was used without further purification in the next stage

IRlcm ' ¹ ]: no C = O, 3600 (OH)

Example 4

The preparation of stages a to c was carried out analogously to Example 3.

Stage d

3,3-ethylenedioxy-17β-methoxy-17α-propynyl-13-methyl-gona-5 (10), 9 (11) -diene 5g 3,3-ethylenedioxy-17a-ethynyl-13-methyl-gona-5 ( 10), 9 (11) -diene-17ß-ol are dissolved in 40 ml of tetrahydrofuran and slowly added with cooling (-15 ⁰ C) with 48 ml of lithium butyl (0.61 m). To the homogeneous solution is added 4.4 ml of methyl iodide, diluted with 4.4 ml of tetrahydrofuran, slowly in the cold and then the solution is heated with stirring to room temperature. After a reaction time of 16 hours, water is added and the steroid is extracted with ether. The residue obtained after concentration of the ether extracts can be used without purification in the next stage. 5 g of the 17β-methoxy-17α-propynyl compound are obtained.

IR [cm "']: no C = O, no OH

MS: M ⁺ 368 ber.f. C ₂₄ H ₃₂ O ₃

Stage e

3,3-ethylenedioxy-17-methoxy-5a -en, 10-oxido-17a-proplnyl-13-methyl-gon-9 (11)

5 g of 3,3-ethylenedioxy-17β-methoxy-17α-propynyl- ¹ 3-methyl-gona-5 (10), 9 (11) -diene, 3 g of anhydrous Na ₂ HPO ₄ and ₂ g of Na ₂ CO ₃ are suspended in 25 ml of methylene chloride and with stirring at room temperature with 8ml H ₂ O ₂ (30%) and finally with 1.5 g of chloral hydrate. After the reaction, an aqueous sodium carbonate solution is added and the steroid extracted with methylene chloride. The organic Phtse is washed twice with a sodium carbonate solution and finally with water, then dried and concentrated. The resulting crude product was flash chromatographed on basic alumina. The mobile phase used was a toluene / toluene / ethyl acetate mixture (10: 1). 2.1 g of epoxy were isolated in the form of an oil which was used directly in the next step

 IR [cm "']: no C = O

Stage f

3,3-ethylenedioxy-17β-methoxy-11β- [4- (2'-methyl-1 '- ₍ 3'-dioxolan-2'-yl) -phenyl] -17a-propyl-13-methyl-gon-9- en-5a oil To a suspension of 0.72 g of magnesium turnings (30 mmol) in 5 ml of tetrahydrofuran is added 0.05 ml of dibromoethane and successively added 55 ml of a 7.35 g of p-bromo (2'-methyl-1 ', 3') under argon. -dioxolan-2'-yl) -benzene (30mmol) containing tetrahydrofuran solution so that the internal temperature does not exceed 45 ⁰ C. In the start-up is slightly heated (45 ⁰ C) and

Thereafter, the temperature is controlled by adding the alkyl halide. After the addition of the aryl halide is stirred for 2 hours at 45 ⁰ C again. From the prepared Grignard solution 30ml are removed and treated with cooling (-5 ⁰ C to -15 ⁰ C) with 0.15 g of CuCl. The mixture is stirred for 15 minutes while maintaining this temperature and then added in the cold, a solution of about 1g3,3-ethylenedioxy-17ß-methoxy-5a, 10a-oxido-17a-propynyl-13-methyl-gon-9 (11) - in 10ml of tetrahydrofuran. The mixture is then stirred for 1 hour with exclusion of moisture and nitrogen and the solution is gradually warmed to room temperature. After the reaction is treated with aqueous ammonium chloride solution and the steroid extracted with ether. After concentration of the extracts, the remaining residue of basic alumina is incorrectly chromatographed. The mobile phase is a benzene / ethyl acetate mixture (10: 1). 1.05 g of the target product are obtained in the form of an amorphous powder by precipitation by means of water from the methanolic solution. , IR [Cm " ¹ ]: 1600 (Aromat), 3500 (OH-associated)

Level g

11β · (4 · ΑοβΙνΙρΙιβηνΙ) -17β · ηιβΙΙιοχν-17ρ. · ΡΓορΙηνΙ-13 ηΐθΙΙινΙ 9θηβ · · 4.9 ^ Ιθη-3 · οη

0.15 g of 3,3-ethylenedioxy-11β- [4- (2'-methyl-1 ', 3'-dioxolan-2'-yl) -phenyl] -17β-methoxy-17α-propynyl-13-methyl-gon -9-en-5a-ol are dissolved in 10 ml of 70% aqueous acetic acid and heated on the water (6O ⁰ C to 70 ° C) for about 1 hour. Thereafter, the solution is added in the cold with water and a little ammonia, wherein the steroid is precipitated in amorphous crystalline form. After chromatography of the steroid on neutral alumina, as the mobile phase is a benzene / ethyl acetate mixture (10: 1), 0.09 g of 4,9-dien-3-one isolated, which can be crystallized from acetonitrile or ether. F .: 110 ° C to 113 ⁰ C Ia] _0: 102.3 °

Example 5

The preparation of stages a to c was carried out analogously to Example 1.

Stage d

3,3-Ethylendloxy-17a- (3'-hydroxy-1'-proplnyl) -17ß-mothoxy-13-methyl-gona-5 (10), 9 (11) -d s

4.3 g of 3,3-ethylenedioxy-17a-ethynyl-17β-methoxy-13-methyl-gona-5 (10), 9 (1!) - diene are dissolved in 10 ml of tetrahydrofuran and washed with 37.5 ml of freshly prepared lithium methyl solution (15 mmol , 0.4m). Subsequently, 1 g of paraformaldehyde is added at room temperature. The reaction starts immediately. After the reaction, water is added and the steroid is extracted with ether. After concentration, about 4.4 g of a crude product of the hydroxymethylated compound, which is used without purification in the next stage

IRIcrrr ¹ ]: no C = O, 3600 (OH)

Stage e

3,3-ethylenedioxy-17α- (3'-hydroxy-1'-propyl) -17β-methoxy-5a, 10α-oxo-13-methyl-gon-9 (11) -one about 4,4 g 3,3- Ethylenedioxy-17α- (3'-hydroxy-1'-propynyl) -17β-methoxy-13-methyl-gona-5 (10), 9 (11) -diene are dissolved in 45 ml of methylene chloride and, after addition of ₂ g of Na ₂ HPO ₄ , 1 g Na ₂ CO ₃ and 7.25 ml H ₂ O ₂ (30%) stirred vigorously and then treated with 1.25 g chloral hydrate (7.55 mmol). It is stirred for 5 hours at room temperature and kept in the refrigerator for 2.5 days. Thereafter, an aqueous sodium carbonate solution is added and the steroid extracted with methylene chloride. The organic phase is washed repeatedly with a sodium carbonate solution, then separated, dried and concentrated. The remaining residue is flash chromatographied on basic alumina. The mobile phase is a benzene / ethyl acetate mixture (4: 1 to 2: 1). It is isolated 3.5g of epoxy in the form of an oil, which is used directly in the next stage.

IR [Cm " ¹ ]: no C = O, 3600 (OH)

Stage f

3,3-ethylenedioxy-17a- (3'-hydroxy-1'-propynyl) -17ß-methoxy-11ß- [4- (2'-methyl-1 ', 3'-dioxolan-2'-yl) -phenyl ] -13-methyl-gon-9-en-5-ol

I g 3,3-ethylenedioxy-17a-'3'-hydroxy-1'-propynyl) -17β-methoxy-5a, 10α-oxido-13-methyl-gon-9 (11) -eno (2.5mmol) in 10ml of tetrahydrofuran is prepared fresh to a, ⁰ to -15 C cooled Grignard solution of 4- (2'-methyl-1 ', 3'-dioxolan-2'-yl) -phenylmagnesiumbromid (15 mmol) and 0.15 g of CuCl in 30 ml of tetrahydrofuran dropwise. After the addition, approx.

Stirred for 30 minutes and the reaction mixture slowly warmed to room temperature. After the reaction is treated with an aqueous ammonium chloride solution and the steroid extracted with ether. After concentration of the extracts, the remaining residue of basic aluminum oxide is flash chromatographed. The mobile phase used is a benzene / ethyl acetate mixture (4: 1 to 1: 1). 0.5 g of the 11β-aryl substituted compound was isolated in the form of an oil which is used directly in the next step.

IR [Cm ' ¹ ]: 3600 (OH), 3500 (OH - associated)

Level g

11β- (4-acetylphenyl) -17α- (3'-hydroxy-1 '(Z) -propenyl) -17β-methoxy-13-methyl-gona-4,9-dlen-3-one About 0.5 g 3, 3-ethylenedioxy-17α- (3'-hydroxy-1 '(Z) -propenyl) 17β-mθthoxy-11β- [4- (2'-methyl-1', 3'-dioxolan-2'-yl) -phenyl ] 13-methyl-gon-9-en-5a-ol (1.09 mmol) are mixed with 10 ml of 70% aqueous acetic acid and heated for about 1 hour at 7O ⁰ C on a water bath. Then it is mixed with water and a little ammonia and extracted the oily separating product with methylene chloride. The residue remaining after concentration of the extracts is flash chromatographied on neutral alumina. Elution is carried out with benzene / ethyl acetate (2: 1). This gives 0.25 g of the crystallizing from methanol

I1 β-acetophenyl compound.

F.:118°Cbis124°C [a) ₀ : 188,2 °

Stufo f

9 · θη-5α · οΙ

About 0.5 g of 3,3-ethylenedioxy-17a - {3'-hydroxy-1'-propynyl) -17p-methoxy-1-p- [4- (2'-methyl-1 ', 3'-dioxolane-2'- yl) -phenvl] -13-methyl-gon-9-en-5a-ol are dissolved in 8 ml of tetrahydrofuran and 0.75 ml of pyridine and after addition of 0.1 g of Pd / BaSO 4 (10%) at room temperature in a hydrogen atmosphere Hydrogenated under atmospheric pressure to standstill of hydrogen uptake. After a few minutes, the initially brown-colored oxide catalyst is reduced (black color). After one hour, the hydrogen uptake is completed. It is filtered off from the catalyst and the filtrate concentrated to dryness is used directly in the next stage.

, IR [cm "']: 3600 (OH), 3500 (OH - associated)

537 3

R- OH

R "OH

Claims (4)

claims: 1. A process for the preparation of 11 ß-aryl-gona-4,9-serve the general formula I ₁ wherein R ₁ = CH ₃ or C _? H ₅ , R ₂ = OCH ₃ , SCH ₃ , N (CH ₃ I ₂ , NHCH ₃ , CN, CHO, CH ₃ CO, CH ₃ CHOH, R ₃ = H, alkoxymethyl, alkanoyl or alkyl each having 1 to 6 carbon atoms and R ₄ = C = CH, CsCCH ₃ , C = CCH ₂ OH, C = CCH ₂ OAlkanoyl, HC = CHCH ₂ OAlkanoyl, CH ₂ CH ₂ CH ₂ OAlkanoyl each having 1 to 6 carbon atoms, HC = CHCH ₂ OH and CH ₂ CH ₂ CH ₂ OH, characterized in that a) 3,3-Dimethoxy-17α-ethynyl-gon-5 (10) -en-17β-older general formula II by ketal cleavage in a water-containing organic solvent in the presence of catalytic amounts of acid in 17a-ethynyl-gon-5 (10) converts en-3-one to general formula III, b) converting the 17a-ethynyl-gon-5 (10) -en-3-one by bromination / dehydrobromination into 17a-ethynyl, 17beta-hydroxy-gona-4,9-dien-3-one of general formula IV, c) from the 17a-ethynyl, 17ß-hydroxy-gona-4,9-dien-3-ones by ketalization produces the ketals of general formula V, wherein R ₅ and R ₆ = CH ₃ , C ₂ H ₅ or a cyclic Ketal with 2 or 3 C-ring atoms, which may be substituted on the carbon atoms by Aikylgruppen represents, d) the ketals are converted by a base in an ether or an aprotic dipolar solvent, optionally with the addition of a solubilizer, into the acetylides and / or alcoholates which are optionally alkylated with an alkylating agent C- and / or O-alkyl or by hydroxymethylation of Converted ethynyl group with formaldehyde into gona-5 (10), 9 (11) -dienes of general formula VI, e) from the gona-5 (10), 9 (11), by epoxidation, the 5a, 10a-epoxides of general formula VII are synthesized, f) the leaves 5a, 10a-epoxides with aryl magnesium halide in the presence of a Cu 'salt at a reaction temperature of -30 ⁰ C to +30 ⁰ C to react and compounds having a 17a-propargyl reduced, 11.beta.-aryl-5a-hydroxy- gon-9-enederallgemeinen formula VIII arise, and g) the 11ß-aryl-5a-hydroxy-gon-9-ene by acid treatment in a water-miscible solvent, optionally with heating to 6O ⁰ C to 70 ⁰ C, converted into gona-4,9-diene-3-one which is derivatized to the 11 ß-aryl-gona-4,9-dien-3-ones of general formula I. 2. The method according to claim 1, characterized in that in step a) as the organic solvent acetone, methanol or a solvent combination consisting of methylene chloride and tert. Butanol, and acids as oxalic acid, p-toluenesulfonic acid or mineral acids, such as sulfuric acid, hydrochloric acid, perchloric acid or phosphoric acid, in process step b) for the bromination / dehydrobromination pyridine hydrobromide perbromide or bromine in pyridine, in process step c) for the ketalization as alcohols methanol, ethanol, ethylene glycol or 2,3-dimethylpropanediol, as acids p-toluenesulphonic acid, oxalic acid, pyridinium tosylate or mineral acids, such as sulfuric acid or perchloric acid, as dehydrating agents triethyl and trimethyl formate or a water entraining agent, such as chloroform, Benzene or toluene, in process step d) as bases lithium alkyls such as lithium methyl, -n-butyl and tert.butyl, calcium, lithium, sodium or potassium amides, lithium, sodium hydride, potassium hydroxide, lithium, sodium or potassium naphthalide, wherein the naphthalide ion is also produced by electrochemical reduction, as Ether diethyl ether, tetrahydrofuran or dioxane, dimethyl sulfoxide, dimethylformamide, optionally used as a solubilizer benzene or toluene and as alkylating agent dialkyl sulfates such as dimethyl and diethyl sulfate, and alkyl halides such as methyl, ethyl, propyl, butyl, pentyl, hexyl , Isopropyl halides in the form of the chlorides, bromides and iodides, and methyl chloroalkyl ethers having an alkyl radical in the meaning η = 1 to 6, in process step e) as buffer Na ₂ CO ₃ , NaHCO ₃ , K ₂ CO ₃ , KHCO ₃ , Na ₂ HPO ₄ , NaH ₂ PO ₄ , NaOAc and KOAc and as inert solvent benzene, toluene, chloroform, dichloroethylene or methylene chloride, in process step f) as arylmagnesium halides phenylmagnesium halides in the form of the chlorides and bromides, in the p-position to the magnesium, an OCH ₃ , SCH ₃ , N (CH ₃ J ₂ , NHCH ₃ , CN, CH ₃ CHOH, R ₆ O-CH-OR ₆ , CH ₃ -CORe-OR ₆ -GrUPPe, wherein R ₆ = R ₆ = CH ₃ , C ₂ H ₆ or a cyclic ketal having 2 or 3 C-ring atoms which may be substituted on the carbon atoms by alkyl groups, as Ether Die'ihylether, tetrahydrofuran and dioxane, as a solubilizer benzene and toluene, as Cu'-salt & CuCN, CuJ and CuCl and as a reducing agent for the 17a-Propargylgruppe lithium alanate or hydrogen in the presence of Pd or Pt as hydrogenation catalysts in an ether or a Alcohol and finally
in process step g) for the acid treatment aqueous acetic acid, p-toluenesulfonic acid or mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and perchloric acid, and used as the solvent aqueous methanol, ethanol and acetone. Process according to claims 1 and 2, characterized in that the alkylation of the 17-ethynyl and the 17-oxygen function or the hydroxymethylation of 17-ethynyl also starting from the starting materials according to formula I performs. 4. The method according to claim 1 to 3, characterized in that the 11 ß-aryl-gon-9-en-5a-ols - 11ß- (4-dimethylaminophenyl) -3,3-ehtylendioxy-17ß-methoxy-17a ^ ropinyl-13-methyl-gon-9-en-5a-ol,