KR800000809B1 - Process for the preparation of d-homosteroid - Google Patents

Abstract

D-homosteroid(I;R6=H, F, Cl, methyl;R17a=hydroxy, acyloxy, alkoxy, lower alkyl; R21=H, F, Cl), having progestational activity, was prepd, by oxidation of compd. II. Thus, 1.15 g 3β-hydroxy-17aα-methyl-D-homo-5, 16-pregnadiene-20-one and a mixt. of 1.1 ml cyclohexano and 22 m1 toluene were boiled, and added 550 mg aluminium isopropylate and 2 ml toluene, destillated for 45 min to give 17aα-methyl-D-homo-4, 16-pregnadiene-3, 20-dione(m.p.181.5- ! 185.5≰C).

Description

Preparation method of D-homosteroid

The present invention relates to a method for preparing D-homosteroid of formula (I), which is useful as a hormone agent.

In the above structural formula

R ⁶ is hydrogen, fluorine, or a chlorine atom or a methyl group.

R ^17a is a hydroxy, acyloxy, alkoxy or lower alkyl group.

R ²¹ is hydrogen, fluorine or chlorine and the dotted line at position 6, 7 represents any carbon-carbon bond.

Acyloxy groups can be derived from saturated or unsaturated aliphatic carboxylic acids, cycloaliphatic carboxylic acids, aromatic aliphatic carboxylic acids or aromatic carboxylic acids and the acids preferably contain up to 15 carbon atoms. Examples of such acids are formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, enanthic acid, undecylenic acid, oleic acid, cyclopentylpropionic acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid. In particular, an alkanoyloxy group having 1 to 7 carbon atoms is preferable. The alkoxy group preferably contains straight or branched groups, in particular up to 15 carbon atoms, with lower alkoxy groups being particularly preferred methoxy and ethoxy groups. Lower alkyl groups are preferably those containing 1 to 4 carbons, especially methyl and ethyl groups.

Substituents at the 6-position in the 6,7-saturated D-homosteroids of the formula (I) are particularly preferably α-isomers if they can have α- or β-configuration.

Method for producing a D-homosteroid of formula (I) according to the present invention is as follows.

The 3-hydroxy-Δ ⁵ -group in the D-homosteroid of formula (II) is oxidized to form 3-keto-Δ ^4- , 3-keto-Δ ^4,6 -or 3-keto-Δ ^{1,4, 6} -get a group,

(Wherein R ⁶ , R ^17a and R ²¹ are the same as described above)

The D-homosteroid of formula (III) is represented in the 1,2-position and / or 6,7-position when R ¹ ′ and R ² ′ are each hydrogen atoms,

When R ¹ ′ and R ² ′ together form a carbon-carbon bond, dehydrogenation at the 6,7-position or R ¹ ′ and R ² ′ each represent a hydrogen atom. Dehydrogenation of the 6-dehydro derivative of

(Wherein R ¹ ′, R ² ′ each represent a hydrogen atom or together represent a carbon-carbon bond, and R ⁶ , R ^17a and R ²¹ are the same as described above).

The D-homosteroid of the following formula (V) is fluorinated or -chlorinated at the 6-position and if necessary the 6β-isomer isomerized to 6α-isomer, or

(R ¹ ′, R ² ′ in the structural formulas each represent a hydrogen atom or together represent a carbon-carbon bond. The dotted lines in the R ^17a , R ²¹ and 6,7-positions are the same as described above).

Methylated at the 6-position of the D-homosteroid of formula (V), or

(Wherein R ¹ ′ and R ² ′ each represent a hydrogen atom or together represent a carbon-carbon bond sum. R ^17a and R ²¹ are the same as described above).

Acylating the hydroxy group in the D-homosteroid of the following formula (VI), or

(Wherein R ¹ ′, R ² ′ each represent a hydrogen atom or together represent a carbon-carbon bond. The dashed lines at R ⁶ , R ²¹ and 6,7-position are the same as described above).

Next, a methylene group is added to the 1,2-double bond of the D-homosteroid of the formula (iii) to prepare a D-homosteroid of the formula (I).

(The dotted lines at positions R ⁶ ′, R ^17a , R ²¹ and 6,7 in the formula are the same as described above).

Oxidation of the D-homosteroid of formula (II) is carried out according to the Oppenauer method (ie using aluminum isopropylate) or using a trioxide such as chromium trioxide (ie Jones reagent) or the method carried out according to all fat or pyridine / sulfur trioxide-dimethyl sulfoxide / dicyclohexylcarbodiimide picheuneo with (a △ ⁵ △ ⁴ -3- -3- ketones are being isomerized to the ketone obtained in the initial) To use. When using the oxidants described above, 3-keno-Δ ⁴ -groups are obtained. When oxidizing agents such as bromine / lithium bromide / lithium carbonate in dimethylformamide are used or oxidized according to the Offenauer method in the presence of benzoquinone, 3-keto-Δ ^4,6 -groups are obtained. Suitable oxidizing agents for oxidation to 3-keto-Δ ^1,4,6 -steroids are, for example, 2,3-dichloro-5,6-dicyano-benzoquinone.

The 1,2-dehydrogenation of the D-homosteroid of formula III is known, e.g. microbiological or as selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, chloranyl , Dehydrogenating agents such as thallium triacetate or lead tetraacetate. Suitable microorganisms for 1,2-dehydrogenation include schizomysets, in particular atrocacter (eg A. Simplex ATCC 6946), Bacillus (ie lentus ATCC 13805 and B.Sphaericus 7055), Pseudomonas (eg P. erginoza). IFO 3505), Flavobacterium (e.g. F. Flavescens IFO 3058), Lactobacillus (e.g. L. Brevis IFO 3345) and Nocardiae (e.g. N. Opaka ATCC 4276).

Methods of introducing Δ ⁶ -double bonds into the D-homosteroids of structural formula (III) are described, for example, in substituted benzoquinones such as chloranyl [vol. 82, pp. 4293 (1960) and 81, 5951 (1959). ] Or using 2,3-dichloro-5,6-dicyano-benzoquinone or manganese dioxide (see, US Chemical Publication 75, page 5932 (1953)).

When 2,3-dichloro-5,6-dicyanobenzoquinone or chloranyl is used, 1,4,6-trisdehydro-D-homo directly from the compound of formula III wherein R ¹ and R ² are both hydrogen atoms Steroids can be obtained.

Halogenation of the D-homosteroid of formula (IV) at the 6-position converts the 6,7-saturated D-homosteroid of formula (IV) to 3-enolester or 3-enolether (e.g. 3-enolacetate) Or react the enol ester or enol ether with chlorine (US Chem. Vol. 82, 1230, 1960, 77, 3227, 1955), or with the appropriate N-haloimide, or US Chem. 82, 1230 (1960). : 77, 3827 (1955) or by reacting with perchloryl fluoride (American Chemical Society, Vol. 81, 5259, 1959, Chemistry, Vol. 1959, 1313). Trifluoromethyl hypofluoride can also be used as fluorinating agent.

Halogenation at the 6-position converts the 4,6-bis-dehydro- or 1,4,6-trisdehydro-D-homosteroid of formula (IV) to 6α, 7α-oxide (perpralic acid, treatment with peracids such as m-chloroperbenzoic acid or p-nitroperbenzoic acid) 6-, 7-oxides are treated with a suitable dimethylacetamide hydrohalide and 7-hydroxy groups are removed to introduce 6,7-double bonds. Water is removed from the hydroxy-6-halo-steroid.

The chlorination reaction may also be carried out using chromyl chloride or ether in methylene chloride.

Halogenation at the 6-position is as follows; By treating the aforementioned 6α, 7α-epoxide with an appropriate lithium halide in glacial acetic acid and converting the resulting 6β-chloro, 7α-hydroxy intermediate to the corresponding 7α-alkyl- or aryl-sulfonic acid ester and heating with a base , Ester group is removed to give 6-chloro-Δ ⁶ -D-homosteroid.

When isomer mixtures (mixtures of 6α- and 6β-halo-D-homosteroids) in the above methods are produced, these mixtures can be separated into pure isomers according to known methods such as chromatography.

The process for isomerizing 6β-halo-D-homosteroids to 6α-halo-D-homosteroids is carried out by reacting an acid, in particular a mineral acid such as hydrochloric acid or bromic acid, in a solvent (eg dioxane or glacial acetic acid).

The methylation reaction of the D-homosteroid of formula (V) is carried out as follows, for example, by converting the D-homosteroid of formula (V) to 3-enolether (e.g., the presence of an acid such as P-toluenesulfonic acid). Under the treatment of ortho formic acid ester, such as ethyl orthoformate, with the addition of the corresponding alcohol, if necessary, or dialkoxypropane, such as 2,2-dimethoxypropane dissolved in methanol / dimethylformamide in the presence of P-toluenesulfonic acid. the treatment), the methane produced enol ether to be tetra (such as: tetrabromomethane, dibromo dichloromethane or methyl bromide to methane to be) the reaction with the parent-tree-trichloro-ketone to give the △ ⁴ -3- do. By halogenation with a base, such as a de-hydrogenation △ ⁴ -3- ketone and collidine methylene dihalo-trihalomethyl can be obtained △ ⁴ -3- ketone, which under mild conditions (i.e. a palladium / strontium carbonate, rhodium catalyst to under the presence) catalytic hydrogenation mejeok desired 6α- methyl-can be converted to △ ⁴ -3- meton.

An advantageous methylation method for the D-homosteroid of formula (V), wherein R ¹ and R ² are both hydrogen atoms, converts the D-homosteroid of formula (V) to 3-enolether according to the method described above. The enol ether is reacted by a known method to obtain the corresponding 6-formyl derivative, and the formyl group is reduced with a hydroxymethyl group by sodium borohydride, followed by dehydration of the reduction product by removing the enol ether. To obtain a D-homosteroid intermediate.

R ²¹ and R ^17a in the structural formula are the same as described above.

The 6-methylene intermediate converts the D-homosteroid of formula (V) to 3-enamine (e.g. 3-pyrrolidinium-enamine), hydroxymethylates formaldehyde 3-enamine and gives P-toluene It can be obtained by removing water from the hydroxymethylated product using an acid such as sulfonic acid.

The method for isomerizing the 6-methylene intermediate product to obtain ⁶ -methyl-Δ ⁶ -D-homosteroid is a known method, for example, catalytically. Suitable isomerization catalysts are for example metal catalysts, ie those used for hydrogenation, in particular palladium in ethanol. In this isomerization reaction, a hydrogen donor such as cyclohexane is added as an activator of the catalyst. Unnecessary side reactions, i.e., hydrogenation by hydrogen donors, can be prevented by buffering the isomerization mixture. Furthermore, the corresponding 6-methyl-D-homosteroids can be obtained by hydrogenating the 6-methylene intermediates in a conventional manner using known hydrogenation catalysts.

Acylation of the 17a-hydroxy group in the D-homosteroid of formula (IV) may be carried out by reaction with a reactive acid derivative such as acyl halide or anhydride in the presence of PN, N-dimethylaminopyridine by known methods. .

1,2-methylation of the D-homosteroid of formula (VI) is carried out according to a known method in which a methylene group is added to a double bond to form a cyclopropyl-condensed ring structure. This can also be done according to the Corey procedure using dimethyl sulfoxium methylide. In this method, the D-homosteroid of the structural formula (IV) is reacted with a solution prepared from sodium hydride in, for example, trimethylsulfonium iodide and dimethyl sulfoxide. 1,2-methyleneation is carried out, for example, by attaching diazomethane and pyrolyzing the intermediate obtained.

Among the D-homosteroids of formula (I), R ⁶ is hydrogen, fluorine or chlorine atom or methyl group, R ^17a is hydroxy, acyloxy or alkoxy group and R ²¹ is hydrogen, fluorine or chlorine atom 6, The dashed lines in the 7-positions are those that represent any carbon-carbon bond.

More preferred D-homosteroids of formula (I) are those in which R ⁶ is hydrogen or a chlorine atom or a methyl group, R ^17a is a hydroxy or C _1-7 -alkanoyloxy group, and R ²¹ is hydrogen or a chlorine atom R ⁶ is hydrogen or a chlorine atom or a methyl group,

R ^17a is preferably a C _1-7 alkanoyloxy group having a double bond in the 6,7-position.

Examples of D-homosteroids of formula (I) include the followings.

17aα-acetoxy-6α-chloro-D-homo-4,16-pregnadiene-3,20-dione,

17aα-acetoxy-6α-fluoro-D-homo-4,16-pregnadiene-3,20-dione,

17aα-acetoxy-6α-methyl-D-homo-4,16-pregnadiene-3,20-dione,

17aα-acetoxy-D-homo-4,16-pregnadiene-3,20-dione,

17aα-acetoxy-6α-chloro-D-homo-1,4,16-pregnatriene-3,20-dione,

17aα-acetoxy-6α-fluoro-D-homo-1,4,16-pregnatriene-3,20-dione,

17aα-acetoxy-6α-methyl-D-homo-1,4,16-pregnatriene-3,20-dione,

17aα-acetoxy-D-homo-1,4,16-pregnatriene-3,20-dione,

17aα-acetoxy-D-homo-4,6,16-pregnatriene-3,20-dione,

17aα-acetoxy-6-fluoro-D-homo-4,6,16-pregnatriene-3,20-dione,

17aα-acetoxy-6-methyl-D-homo-4,6,16-pregnatriene-3,20-dione,

17aα-acetoxy-D-homo-4,6,16-pregnatriene-3,20-dione,

17aα-acetoxy-6-chloro-D-homo-1,4,6,16-pregnatriene-3,20-dione,

17aα-acetoxy-6-fluoro-D-homo-1,4,6,16-pregnatetraene-3,20-dione,

17aα-acetoxy-6-methyl-D-homo-1,4,6,16-pregnatetraene-3,20-dione,

17aα-acetoxy-D-homo-1,4,6,16-pregnatetraene-3,20-dione,

17aα-acetoxy-6α-chloro-1α, 2α-methylene-D-homo-4,16-pregnadiene-3,20-dione,

17aα-acetoxy-6α-fluoro-1α, 2α-methylene-D-homo-4,16-pregnadiene-3,20-dione,

17aα-acetoxy-6α-methyl-1α, 2α-methylene-D-homo-4,16-pregnadiene-3,20-dione,

17aα-acetoxy-1α, 2α-methylene-D-homo-4,16-pregnadiene-3,20-dione,

17aα-acetoxy-6-chloro-1α, 2α-methylene-D-homo-4,6,16-pregnatriene-3,20-dione,

17aα-acetoxy-6-fluoro-1α, 2α-methylene-D-homo-4,6,16-pregnatriene-3,20-dione,

17aα-acetoxy-6-methyl-1α, 2α-methylene-D-homo-4,6,16-0-pregnatriene-3,20-dione,

17aα-acetoxy-1α, 2α-methylene-D-homo-4,6,16-pregnatriene-3,20-dione,

6α-chloro-17α-methyl-D-homo-4,16-pregnadiene-3,20-dione,

6α-fluoro-17a-methyl-D-homo-4,16-pregnadiene-3,20-dione,

6α-17aα-dimethyl-D-homo-4,16-pregnadiene-3,20-dione,

17aα-methyl-D-homo-4,16-pregnadiene-3,20-dione,

6α-chloro-17aα-methyl-D-homo-1,4,16-pregnatriene-3,20-dione,

6α-fluoro-17aα-methyl-D-homo-1,4,16-pregnatriene-3,20-dione,

6α, 17aα-dimethyl-D-homo-1,4,16-pregnatriene-3,20-dione,

17aα-methyl-D-homo-1,4,16-pregnatriene-3,20-dione,

6-chloro-17aα-methyl-D-homo-4,6,16-pregnatriene-3,20-dione,

6-fluoro-17aα-methyl-D-homo-4,6,16-pregnatriene-3,20-dione,

6,17aα-dimethyl-D-homo-4,6,16-pregnatriene-3,20-dione,

17aα-methyl-D-homo-4,6,16-pregnatriene-3,20-dione,

6-chloro-17aα-methyl-D-homo-1,4,6,16-pregnatetraene-3,20-dione,

6-fluoro-17aα-methyl-D-homo-1,4,6,16-pregnatetraene-3,20-dione,

6α, 17aα-dimethyl-D-homo-1,4,6,16-pregnatetraene-3,20-dione,

17aα-methyl-D-homo-1,4,6,16-pregnatetraene-3,20-dione,

6α-chloro-17aα-methyl-1α, 2α-methylene-D-homo-4,16-pregnadiene-3,20-dione,

6α-fluoro-17aα-methyl-1α, 2α-methylene-D-homo-4,16-pregnadiene-3,20-dione,

6α, -17aα-dimethyl-1α, 2α-methylene-D-homo-4,16-pregnadiene-3,20-dione,

17aα-methyl-1α, 2α-methylene-D-homo-4,16-pregnadiene-3,20-dione,

6-chloro-17aα-methyl-1α, 2α-methylene-D-homo-4,6,16-pregnatriene-3,20-dione,

6-fluoro-17aα-methyl-1α, 2α-methylene-D-homo-4,6,16-pregnatriene-3,20-dione,

6,17a-dimethyl-1,2-methylene-D-homo-4,6,16-pregnatriene-3,20-dione,

17aα-methyl-1α, 2α-methylene-D-homo-4,6,16-pregnatriene-3,20-dione,

The method of preparing the D-homosteroid used as a starting material in the above method is not described, but is prepared similarly to the method in the examples described below.

By deprotonation with potassium tert-butylate in a suitable solvent (e.g. tetrahydrofuran or tert-butanol) followed by reaction with methyl iodide, a 17a-methyl group can be introduced into the D-homosteroid of the structure have.

(Wherein R is a group such as tetrahydropyranyl or methoxymethyl group)

The D-homosteroids of formula (I) in particular have a hormonal action on the endocrine system and are characterized by the selectivity of activity. Therefore, it can be used as a hormonal agent (ie progesterone), can be administered orally or parenterally, and a daily dose of about 0.005 mg / kg to 0.15 mg / kg is suitable.

D-homosteroids of formula (I) are, for example, organic or inorganic inert carriers suitable for oral, subcutaneous or parenteral administration, namely water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, poly It can be mixed with alkylene glycol and petroleum jelly to be used as a drug. These preparations can be made in the form of solids (eg tablets, dragees, suppositories or capsules) and semisolids (ointments) or liquids (solutions, suspensions or emulsions). These pharmacological agents may be sterilized and may contain auxiliaries such as preservatives, stabilizers, wetting agents, emulsifiers, salts or buffers for changing the osmotic pressure. Such agents may also contain other therapeutically useful substances in addition to the D-homosteroids of the invention.

The present invention is explained in more detail by the following examples.

Example 1

1.15 g of 3β-hydroxy-17aα-methyl-D-homo-5,16-pregnadien-20-one is boiled by heating with 1.1 ml of cyclohexanone and 22 ml of toluene and then 550 mg of aluminum isopropyl Treat with rate and 2 ml of toluene solution. After 45 minutes of distillation, the mixture is reacted with ether, washed with dilute sulfuric acid and water, and evaporated to dryness. The residue is chromatographed on silica gel and recrystallized from methanol to give 17aα-methyl-D-homo-4,16-pregnadiene-3,20-dione. Melting Point 181.5 ~ 185.5 ° C

UV: ε ₂₄₂ = 16,100

Starting materials are prepared as follows.

10 g of 3β-hydroxy-D-homo-5,17 (17a) -pregnadien-20-one is dissolved in 100 ml of tetrahydrofuran and 10 ml of 2,3-dihydro-4H-pyran and 0.1 ml It is stirred for 1 hour at room temperature with phosphorus oxychloride. The mixture is poured into ice water with stirring to add sodium bicarbonate and the separated precipitate is filtered off with suction and rinsed. The residue was taken up in methylene chloride and evaporated to dryness and recrystallized from diisopropylether to give 3β- (tetrahydropyran-2-yloxy) -D-homo-5,17- with a melting point of 153 ° C / 154 to 155 ° C. (17a) -pregnadien-20-one is obtained.

1.62 g of potassium tert-butylate is dissolved in 30 ml of anhydrous tetrahydrofuran and 45 ml of anhydrous tert-butanol. To the solution cooled in an ice bath is added 3.6 g of 3β- (tetrahydroparin-2-yloxy) -D-homo-5,17 (17a) -pregnadien-20-one under a stream of nitrogen. 1.65 ml of methyl iodide was added dropwise to the dark brown solution and the mixture was passed through nitrogen with stirring at 0 ° C. for 30 minutes. The mixture was poured into iced water and stirred to filter the precipitate, which was taken up in methylene chloride, washed with water and dried. The residue obtained after evaporation is chromatographed on silica gel to afford 3β- (tetrahydropyran-2-yloxy) -17aα-methyl-D-homo-5,16-pregnadien-20-one. The melting point of the sample recrystallized from diisopropyl ether was 169.5 to 170.5 ° C.

Oxalic acid in which 1.4 g of 3β- (tetrahydropyran-2-yloxy) -17aα-methyl-D-homo-5,16-pregnadien-20-one was dissolved in 6.5 ml of water in 27 ml of methanol Treat with 650 mg and heat reflux for 1.5 hours. The mixture was poured into ice water and stirred to separate the precipitates which were collected by suction filtration, taken in chloroform and dried. After evaporation 3β-hydroxy-17aα-methyl-D-homo-5,16-pregnadien-20-one was obtained.

Example 2

440 mg of 17aα-acetoxy-3β-hydroxy-D-homopregna-5,16-dien-2-0one was treated with 0.55 ml of Jones reagent in 30 ml of acetone, stirred for 5 minutes and then poured into water. And extracted with methylene chloride. The methylene chloride solution is washed with water, dehydrated and dried. The resulting oil is stirred in 8 ml of dioxane and 0.8 ml of 2-N hydrochloric acid at room temperature. The mixture is evaporated and the residue is chromatographed on silica gel. 17aα-acetoxy-D-homopregna-4,16-diene-3,20-dione having a melting point of 222 to 223 ° C. (from acetone / hexane) is obtained.

Starting materials can be prepared as follows.

3β, 17aα-dihydroxy-D-homopregna-5,16-diene-20-one is reacted in acetic anhydride and triethylamine in the presence of PN, N-dimethylaminopyridine to give 3β, 17aα-diacetoxy -D-homopregna-5,16-diene-20-one [melting point 179 to 180 ° C., [α] _D = 273 °, C = 0.1% (in dioxane)] to obtain calcium carbonate in methanol Partial saponification with 17aα-acetoxy-3β-hydroxy-D-homopregna-5,16-diene-20-one is obtained.

Example 3

1.35 g of 3β-hydroxy-17aα-ethyl-D-homo-5,16-pregnadien-20-one was heated with 1.4 ml of cyclohexane in 27 ml of toluene to give this mixture 650 mg of aluminum. Isopropylate is treated with a solution dissolved in 2 ml of toluene. The mixture is heated for 45 minutes with distillation slowly, then diluted with ether, washed with 2-N sulfuric acid and water and then evaporated and the residue obtained is chromatographed on silica gel. Recrystallization from diisopropyl ether gives 17aα-ethyl-D-homo-4,16-pregnadiene-3,20-dione with a melting point of 153 to 154 ° C.

UV = ε ₂₄₁ = 16,800

Starting materials are prepared as follows.

1.9 g of potassium tert-butylate are dissolved in 24.5 g of dimethylformamide and 3.75 ml of tert-butanol. 3.0 g of 3β- (tetrahydropyran-2-yloxy) -D-homo-5,17 (17a) -pregnadien-20-one are dissolved in the solution cooled in an ice bath under a stream of nitrogen. 1.38 ml of ethyl iodide is added within 15 minutes and the mixture is stirred for 40 minutes at an ice bath temperature. The mixture is poured into ice water and stirred, the precipitate is filtered off, washed well with water and taken up in methylene chloride. After evaporation, the residue was chromatographed on silica gel and recrystallized from methanol and then 3β- (tetrahydropyran-2-yloxy) -17aα-ethyl-D-homo-5,16-pre which has a melting point of 136 to 138 ° C. 1.8 g of gadiene-20-one are obtained.

1.8 g of 3β- (tetrahydropyran-2-yloxy) -17aα-ethyl-D-homo-5,16-pregnadiene-20-silver was treated with 300 mg of oxalic acid in 36 ml of methanol and 9 ml of water The mixture is heated to reflux for 45 minutes. The mixture was poured into iced water, stirred, and the precipitate was filtered and washed to yield 1.35 g of 3β-hydroxy-17aα-ethyl-D-homo-5,16-pregnadien-20-one.

Example 4

570 mg of 3β-hydroxy-17aα-butyl-D-homo-5,16-pregnadien-20-one in 11.5 ml of toluene and 0.57 ml of cyclohexanone, 280 mg of aluminum isopropylate in 1 ml The resulting mixture is treated similarly to the method described in Example 3 by treatment with a solution dissolved in toluene. Chromatography on silica gel yields 355 mg of 17aα-butyl-D-homo-4,16-pregnadiene-3,20-dione having a melting point of 82 to 85 ° C.

UV = ε ₂₄₁ = 15,600

Starting materials are prepared as follows.

2.5 g of potassium tert-butylate is dissolved in 40 ml of dimethylformamide and 8 ml of tert-butanol. 2.5 g of 3β- (tetrahydropyran-2-yloxy) -D-homo-5,17 (17a) -pregnadien-20-one is dissolved in the solution and cooled in an ice bath under a stream of nitrogen. 1.25 ml of 1-bromobutane is added dropwise within 15 minutes and the mixture is stirred for 2.5 hours at an ice bath temperature. The mixture was reacted to chromatography the residue on silica gel to yield 780 mg of 3β- (tetrahydropyran-2-yloxy) -17aα-butyl-D-homo-5,16-pregnadien-20-one. do. The melting point of the sample recrystallized from methanol is 139 to 140 ° C.

750 mg of impure 3β- (tetrahydropyran-2-yloxy) -17aα-butyl-D-homo-5,16-pregnadien-20-one in 15 ml of methanol and 3.75 ml of water and In a similar manner it is reacted with 375 mg of oxalic acid.

This mixture is treated similarly to Example 11 to yield 570 mg of impure 3β-hydroxy-17aα-butyl-D-homo-5,16-pregnadien-20-one.

Example 5

4.5 g of 17aα-methyl-D-homo-4,16-pregnadiene-3,20-dione is heated to reflux with 5.4 g of chloranyl for 18 hours with stirring in 90 ml of tert-butanol.

The mixture is concentrated in vacuo, the residue is taken up in ether, the unreacted chloranil is filtered off and the filtrate is washed with sodium bicarbonate solution and water. After evaporation, the residue was chromatographed on silica gel and recrystallized from diisopropylether / acetone to give 2.25 g of 17aα-methyl-D-homo-4,6,16-pregnatiene- having a melting point of 180 to 181.5 ° C. 3,20-dione is obtained.

UV = ε ₂₃₄ = 26,900

Example 6

10.0 g of 17aα-D-homo-4,16-pregnadiene-3,20-dione was added to 20 g of 2,3-dichloro-5,6-dicyano-benzoquinone for 18 hours in 200 ml of dioxane. And 1 g of P-toluene sulfonic acid. The mixture is concentrated in vacuo, the residue is taken up in ether, the undissolved hydroquinone is filtered off and the filtrate is washed with sodium bicarbonate solution and water. The residue after evaporation is chromatographed on silica gel. Recrystallization from diisopropylether / acetone yields 5.6 g of 17aα-methyl-D-homo-1,4,6,16-pregnatetraene-3,20-dione with a melting point of 172 to 174.5 ° C.

UV = ε ₂₂₃ = 11,700, ε ₂₅₃ = 9,880,

ε ₃₀₀ = 111,000.

Example 7

9.0 g of 17aα-methyl-D-homo-4,16-pregnadiene-3,20-dione is heated to reflux with stirring in 135 ml of methanol and 4.86 ml of pyrrolidine. After cooling in an ice bath, the separated precipitate is filtered off with suction and dried. 9.6 g of 3-pyrrolidino-17aα-methyl-D-homo-3,5,16-pregnatrien-20-one having a melting point of 184 to 196 ° C. (degradation slowly) are obtained.

UV: ε ₂₇₇ = 22,000

9.6 g of 3-pyrrolidino-17aα-methyl-D-homo-3,5,16-pregnatrien-20-one are dissolved in 1.35 L of ethanol and 676 ml of benzene in 17.7 ml of 40 in 10 minutes. Add dropwise to aqueous formaldehyde solution. The resulting mixture is stirred at rt for 1 h and concentrated in vacuo. The residue is chromatographed on silica gel to yield 4.1 g of 6β-hydroxy-methyl-17aα-methyl-D-homo-4,16-pregnadiene-3,20-dione.

4.1 g of 6β-hydroxy-methyl-17aα-butyl-D-homo-4,16-pregnadiene-3,20-dione was mixed with 13.25 ml of 5-N hydrochloric acid in 275 ml of dioxane for 2 hours. Stir together at room temperature. The hydrochloric acid is neutralized with excess sodium bicarbonate to filter the inorganic salts and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on silica gel and recrystallized from diisopropylether / acetone to have a melting point of 177-178 ° C. Obtain 2.3 g of dione.

1.0 g of 17aα-methyl-6-methylene-D-homo-4,16-pregnadiene-3,20-dione was added to 500 mg of anhydrous sodium acetate and 75 mg of 5% palladium in 35 ml of anhydrous ethanol for 8 hours. Heat reflux with / carbon catalyst and add 2 ml of 0.5% ethanolic cyclohexene solution dropwise for 1 hour each. This mixture is filtered from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue is taken up in methylene chloride, washed with water and evaporated. Recrystallization from diisopropyl ether gives 850 mg of 6,17aα-dimethyl-D-homo-4,6,16-pregnatriene-3,20-dione having a melting point of 160 to 161 ° C.

UV: ε ₂₉₀ = 22,600

Claims (1)

Oxidation of the 3-hydroxy-Δ ⁵ -group in the D-homosteroid of formula (II) to 3-keto-Δ ^4- , 3-keto-Δ ^4.6 -or 3-keto Δ ^1.4.6- Characterized in that the method for producing a compound of formula (I).

In the above structure, R ⁶ is hydrogen, fluorine or chlorine atom or methyl group, R ^17a is hydroxy, acyloxy, alkoxy or lower alkyl group, R ²¹ is hydrogen, fluorine or chlorine atom, and the dotted line at 6,7 position is It represents a carbon-carbon bond.