DE1593687B1 - Process for the production of new benzo [d, e] steroids of the androstane and pregnane series - Google Patents

Description

The invention relates to a process for the preparation of the general formula of new benzo [d, e] steroids of the androstane and pregnane series of the general formula

IO

wherein A is a hydroxy or acyloxy group or one of the following groupings

\ - he

(CH ₂ ) ,,

in which W is methyl or ethyl and η is 1 or 2 and B is hydrogen or a hydrocarbon radical containing 1 to 3 carbon atoms or A is acetyl, / 3-hydroxyacetyl or / 9-acyloxyacetyl and B is hydrogen, a hydroxy or acyloxy group R is hydrogen or methyl, X is hydrogen, a hydroxy or acyloxy group or a keto oxygen, Y is hydrogen is an S-hydroxy group or a keto oxygen and Z is hydrogen or halogen and X can be hydrogen, a hydroxy or acyloxy group, only if B, Y and Z represent hydrogen and A represents a hydroxyl or acyloxy group; The process is characterized in that corresponding 4-allylidene / I ⁵ -3-ketosteroids of the general formula

CH ₉

and / or corresponding 4-allenyl-zl ⁵ -3-ketosteroids in which A ^{1 is} a hydroxy or acyloxy group and B is hydrogen or a hydrocarbon ^{radical containing 1 to 3 carbon atoms or A 1 is} an acetyl, β-hydroxyacetyl or / S-acyloxyacetyl group and B represents hydrogen, a hydroxy or acyloxy group and R, Y and Z have the abovementioned meaning, heated in an organic diluent at a temperature of 50 to 180 ° C in the presence of platinum or palladium as a cyclodehydrogenation catalyst, then optionally the 17-acyloxy group hydrolyzed methods known per se, then optionally, only if A ^{1 is} a hydroxyl or acyloxy group and B, Y and Z are hydrogen,

a) by methods known per se, the 3-keto group with a metal hydride to the corresponding 3 / S-hydroxy group reduced and then optionally the compound obtained with esterified or optionally with a customary acylating agent

b) using methods known per se, the 3-keto group to form a corresponding 3-deoxo compound catalytically hydrogenated and then optionally esterified or the compound obtained with a customary acylating agent possibly

c) a 17/3 hydroxy compound according to methods known per se with dihydropyran or dihydrofuran in the presence of an acidic catalyst or optionally

d) by methods known per se, a 17 / S-hydroxy compound with a lower alkylenol ether and / or dialkyl acetal of cyclopentanone or cyclohexanone at a temperature above 70 ° C converts or optionally

e) a 17 / S-Hy-

hydroxy compound with the methyl or ethylenol

ether or dimethyl or diethyl acetal des

II Cyclopentanones or Cyclohexanones for one

Reacts temperature below 7O ⁰ C in the presence of an acidic catalyst.

The new benzo [d, e] steroids of the androstane and pregnane series which can be prepared according to the invention of formula I have valuable pharmacological properties. In particular, these compounds have an unexpected antigonadotropic effect and are therefore likely to reduce the formation of the Pituitary hormones useful.

65

Preferred compounds which can be prepared according to the invention of the androstane series are the benz [d, e] androstan-17 /? - ol-3-one of the formula

OH

H, C

ς-- OAcyl

and its 17-esters, especially the 17 /? - acetate. Such compounds show excellent antigonadotropic activity and good anabolic activity Effect without androgenic side effects.

Preferred compounds of the 19-nor-androstane series which can be prepared according to the invention are 19-norbenz [d, e] androstane-17β-ol-3-one the formula

OH

H, C

wherein acyl has the abovementioned meaning, the 3-keto-21-hydroxy-benzo [d, e] steroids of the formula

CH, 0H

CO

H, C

HO

OH

the 17a-ethynyl-19-nor-benz [d, e] androstan- Πβ-οΐ- 3-one of the formula

OH

H * C

and their 17-esters, especially the 17 / J-acetates. Such compounds have anti-ovulation properties.

Preferred compounds which can be prepared according to the invention of the pregnane series are the 3-keto-21-deoxybenzo [d, e] steroids of the formulas

and the 9a-halogen, especially the 9a-fluoro and 9a-chlorine derivatives, the 9a-halo-16a or -16 / 9-methyl derivatives, especially the 9a-fluoro-16a-methyl- and 9a-fluoro-16 ^ -methyl derivatives of said 21-hydroxy-benzo [d, e] steroids, as well as also the 17a and / or 21 esters of those listed above Links.

The first process stage consists of a catalytic cyclodehydrogenation of 4-allylidene-zl ⁵ -3-ketosteroids of the formula II or of 4-allenyl-zl ⁵ -3-keto steroids of the formula III or of mixtures of the compounds mentioned in an organic diluent.

In general, anhydrous organic solvents are used as diluents. Although one can work in both polar and non-polar medium, it is preferred to use polar solvents, in particular pyridine, α-, β- or γ-picoline, γ-collidine, quinoline, isoquinoline, pyrimidine, pyrazine, dimethylformamide, dimethylacetamide, dimethyl sulfoxide , Dimethylaniline, diethylaniline, dimethyl-o-toluidine, monochlorobenzene, o-dichlorobenzene, benzonitrile, cinnamic acid ethyl ester, n-butanol, n-pentanol, to use. Pyridine and dimethylformamide are the preferred diluents. The cyclodehydration is generally carried out by dissolving or suspending the starting material in the selected diluent, and the mixture is heated at a temperature from 50 to 180 ⁰ C, preferably from 100 to 155 ° C, 1 to 10 hours in the presence of palladium or platinum as cyclo dehydrogenation catalysts .

⁶ S The catalysts are generally used on suitable supports, such as carbon or asbestos supports, with a metal content of 2 to 30%. The preferred catalyst is palladium carbon.

The cyclodehydrogenation stage yields 3-keto-benzo [d, e] steroids the androstane or pregnane series of the formula

OW

—Ο

Structure c

(CH ₂ ) "

c-B

IV

wherein A ¹ , B, R, Y and Z are as defined above.

The 3-keto-benzo [d, e] steroids are usually from the reaction mixture, for. B. by evaporation of the solvent and recrystallization or by dilution with water and filtering off or undressing, isolated.

To prepare a compound of the formula I in which X is different from keto oxygen, the 3-keto-benzo [d, e] steroids of the formula IV, in which A ^{1 is} a hydroxy or acyloxy group and B, Y and Z are hydrogen, are used a reduction with a metal hydride according to the usual methods, e.g. B. by treatment with sodium borohydride, lithium aluminum hydride or tert-butoxyaluminum hydride, subjected. The 3-keto group is reduced to form a 3-hydroxy-benzo [d, e] steroid, and optionally the 3-hydroxy group can be esterified by treatment with a conventional acylating agent to form a 3-acyloxy-benzo [d, e] steroid .

Furthermore, the 3-keto group of the compounds of the formula JV, in which A ^{1 represents} a hydroxyl or acyloxy group and B, Y and Z represent hydrogen, can be catalytically hydrogenated by treating such compounds with hydrogen in the presence of palladium or platinum on suitable supports . This gives compounds of the formula I in which X is hydrogen.

If the 3-keto-benzo [d, e] steroid of the formula IV obtained has a 17JS-acyloxy group, can these usually, e.g. B. be hydrolyzed under acidic or alkaline conditions.

If the obtained 3-keto-benzo [d, e] steroid has a free secondary hydroxy group at the 17-position contains, this can with dihydrofuran or dihydropyran or with a functional compound of the Cyclopentanone or cyclohexanone are reacted to form 3-keto-benzo [d, e] steroids of the formula I, where A has one of the following structures:

in which η and W have the meaning given above. These compounds are the 17.0-tetrahydrofuryl ethers (structure a, η = 1), the 17/3 tetrahydropyranyl ethers (structure a, η = 2), the 17 / S- (l'-cyclopentenyl) ethers (structure b, η = 1), the 17jS- (l'-cyclohexenyl) ethers (structure b, η = 2), the 17 ^ - (l'-alkoxy) cyclopentyl ethers (structure c, η = 1) and the 17ß- ( r-Alkoxy) cyclohexenyl ethers (structure c, η - 2) of the 3-keto-benzo [d, e] steroids of the formula IV in which A ^{1 is} a hydroxyl group and B, Y and Z are hydrogen.

Such compounds can easily be made by known methods. The tetrahydrofuryl and tetrahydropyranyl ethers are prepared by reacting the 17 /? - hydroxy-3-keto-benzo [d, e] steroid with dihydrofuran or dihydropyran in the presence of an acidic catalyst. The cyclopentenyl and cyclohexenyl ethers are obtained by reacting the 17 ^ -hydroxy-benzo [d, e] steroid with a functional compound of cyclopentanone or cyclohexanone, in particular with a methylenol ether and / or dimethylacetal or with an ethylenol ether and / or dimethylacetal at one temperature manufactured above 80 ° C. The 17- (1'-alkoxy) cyclopentyl and -cyclohexyläther be prepared by reacting the 17-hydroxy-3-keto-benzo [d, e] steroids, with the methyl or diethyl acetal of the cyclopentanone or cyclohexanone below 70 ⁰ C. preferably at room temperature, in the presence of an acidic catalyst.

The 4-allylidene and 4-allenyl compounds of the formulas II and III, which are used as starting materials for the process according to the invention, represent a number of steroid compounds not yet described in the literature. They are prepared by 3-propargyl-enol ether of / l ⁴ -3-keto steroids of the androstane and pregnane series of the general formula

CHsC

-O

Structure a

-O

Structure b

(CH ₂ ) " where A ¹ , B, R, Y and Z have the abovementioned meaning, heated under the conditions of a Claisen rearrangement. By heating in a hydrocarbon-like diluent with a boiling point above 10O ⁰ C, the propargylenol ethers of the formula V provide a mixture of the 4-Allyliden- / I ⁵ -3-ketosteroids of the formula II and the corresponding

4-AUenyl-zl ⁵ -3-ketosteroids of the formula III.

To carry out the reaction, the 3-propargyl-enol ethers are in the hydrocarbon-like diluent, preferably in toluene or xylene, dissolved or suspended, and the mixture obtained is refluxed for 1 to 10 hours.

Under such heating, the propargyl radical converts to form the above-mentioned 4-allylidene and 4-A1-lenyl compounds around.

The mixture of the two compounds thus obtained can be used directly for the cyclodehydrogenation stage, but the individual 4-allylidene and 4-allenyl-J ⁵ -3-ketosteroids can be separated from the mixture by fractional crystallization and reacted individually. In general, it is preferred to carry out the cyclodehydrogenation without further purification on the mixture of 4-allylidene and 4-allenyl compounds.

The respective amount of the 4-allylidene and 4-allenyl-J ⁵ -3-ketosteroids obtained in the Claisen rearrangement depends both on the starting steroid and on the reaction conditions. In general, the 4-allenyl compounds are obtained in a smaller amount compared with the corresponding 4-allylidene compounds. Furthermore, the 4-allenyl-3-keto compounds of the formula III are relatively unstable and are easily converted into the more stable 4-allylidene compounds by simple chromatography of their solutions on clay.

The 3-propargyl-enol ethers of the formula V are in turn from the corresponding lower alkylenol ethers or from enol esters or from ketals by an exchange reaction with propargyl alcohol manufactured according to patents 1,119,264 and 1,159,940.

The following examples explain the process according to the invention.

example 1

A solution of 2 g of 3-propargyl-enol ether of testosterone acetate in 50 cm ^{3 of} toluene is refluxed for about 8 hours. After evaporation of the solvent, the residue is subjected to fractional crystallization. This gives 4-allenyl-i7 /? - acetoxy-J ⁵ -androstan-3-one; F. 135 to 137 ° C, [α] ί? = -84 ° (dioxane, c = 0.5%) and the 4-allylidene-17/3-acetoxy-J ⁵ -androsten-3-one; M.p. 130 to 133 ° C, [o] l ² = -84 ° (dioxane, c = 0.5%).

A solution of 2 g of 4-allylidene-17 / S-acetoxy-J ⁵ -androsten-3-one in 30 cm ^{3 of} pyridine is refluxed for 4 hours in the presence of 200 mg of 5% palladium-on-carbon. The catalyst is filtered off and the solvent is evaporated in vacuo. The residue recrystallized from methanol gives the 17 /? - acetoxy ~ benz [d, e] androstan-3-one; F. 143 to 145 ° C; [a]? = -14.5 ° (dioxane, c = 0.5%).

Example 2

A solution of 1 g of the 4-allenyl-17 /? -Acetoxy-J ⁵ -androsten-3- ^{one described in Example 1 in 30 cm 3 of} pyridine is refluxed for 4 hours in the presence of 100 mg of 5% palladium-on-carbon. The catalyst is filtered off and the solvent is evaporated in vacuo. The residue recrystallized from methanol yields 17 / S-acetoxybenz [d, e] androstan-3-one, which is identical to the product described in Example 1.

Example 3

A solution of 2 g of 3-propargyl-enol ether of testosterone acetate in 50 cm ^{3 of} toluene is refluxed for about 8 hours. After evaporation of the solvent, the residue consisting of a mixture of 4 - allylidene -1 7β - acetoxy - J ⁵ - androstened - 3 - one and 4 - allylidene - 17 /? - acetoxy - J ⁵ - androstened - 3 - one is dissolved in benzene dissolved and the solution chromatographed on clay. Elution with benzene, evaporation of the solvent and recrystallization, is obtained with 70% yield of pure 4-allylidene-1 ISS acetoxy J ⁵ - androsten - 3 - one. This compound is cyclodehydrogenated in pyridine in the presence of 5% palladium carbon as in Example 1. This gives 17 ^ -acetoxy-benz [d, e] -androstan-3-one.

Example 4

A solution of 2 g of 3-propargyl-enol ether of testosterone propionate in 50 cm ^{3 of} toluene is refluxed for about 8 hours. The solvent is evaporated to dryness in vacuo and that of a mixture of 4-allylidene-17 / i-propionoxy-J ⁵ -androsten-3-one and 4-allenyl-17 ^ -propionoxy-J ⁵ -androsten-3-one existing residue toosted in 50 cm ^{3 of} dimethylformamide. The resulting solution is heated at 115 ° C. for 4 hours in the presence of 200 mg of 5% palladium-on-carbon. The catalyst is filtered off and the solvent is evaporated in vacuo. The residue recrystallized from methanol gives the 17 /? - propionoxy-benz [d, e] androstan-3-one; F. 129 to 131 ⁰ C, [α] ² / = -13 ° (dioxane, c = 0.5%).

Example 5

A solution of 2 g of 3-propargyl-enol ether of testosterone butyrate in 50 cm ^{3 of} toluene is refluxed for 4 hours. The solvent is evaporated to dryness in vacuo and the mixture of 4-allylidene-17 / i-butyroxy-J ⁵ -androsten-3-one and 4-allenyl-17 / I-butyroxy-J ⁵ -androsten-3- on existing residue ^{boiled under reflux in 50 cm 3 of} dimethylformamide in the presence of 100 mg of 5% palladium carbon. The catalyst is filtered off and the solvent is evaporated in vacuo. The residue recrystallized from methanol gives the 17 /? - butyroxy-benz [d, e] androstan-3-one; mp 82 to 83 ° C; [a] f = -12 ° (dioxane, c = 0.5%).

Example 6

5 g of 3-propargyl-enol ether of 19-nortestosterone acetate are dissolved in 50 cm ^{3 of} toluene and the resulting solution is refluxed for 6 hours. After evaporation of the solvent is obtained from a mixture of 4-allylidene-17 /? - acetoxy-l 9-nor-J ⁵ -androsten-3-one and 4-allenyl-17/3-acetoxy-19-nor-J ⁵ androsten-3-one existing residue was dissolved in 50 cm ^{3 of} pyridine and the solution was refluxed for 4 hours in the presence of 300 mg of 5% palladium-on-carbon. The catalyst is filtered off and the solvent is evaporated in vacuo. After recrystallization, the 17 /? - acetoxy-19-nor-benz [d, e] androstan-3-one is obtained; M.p. 182 to 185 ° C, [a] f = -56.5 ° (dioxane, c = 0.5%).

Example 7

3 g of 3-propargyl-enol ether of 17a-ethynyl-19-nortestosterone acetate in 50 cm ^{3 of} toluene are refluxed for 5 hours. After evaporation of the solvent, the mixture of 4-allylidene-17a-ethinyl-17 / S-acetoxy-19-nor-J ⁵ -androsten-3-one and 4-allenyl-17a-ethinyl-17 /? - acetoxy -19-nor-J ⁵ -androsten-3-one existing residue dissolved in 30 cm ^{3 of} pyridine. The solution is for 5 hours in counter

109 547/471

ίο

was refluxed by 200 mg of 5% palladium carbon, the catalyst filtered off, the The solvent was evaporated and the residue was recrystallized. This gives na-ethynyl-nß-acetoxy-19-nor-benzo [d, e] androstan-3-one; M.p. 229 to 231 ° C; [a] f = -81 ° (dioxane, c = 0.5%).

Example 8 A solution of 2 g of 3-propargyl-enol ether of the solution for about 5 hours at 115 ° C. in the presence of 100 mg of 5% palladium carbon, then the solvent evaporates in vacuo and crystallizes the residue from methanol. This gives the benz [d, e] androstan-17/3-ol-3-one; F. 194 to 196 ° C; [α] κ = -2.5 ° (dioxane, c = 0.5%).

Example 12 A solution of the minerals described in Example 3

g g py g

Progesterone in 50 cm ^{3 of} toluene is refluxed for 6 hours with 4-allylidene-17/8-acetoxy-J ⁵ -androstene reflux, then the solvent for 3-one and 4-allenyl-17 ^ -acetoxy-J ⁵ -androsten-3-one evaporated to dryness in vacuo. The residue consisting of a 50 cm ^{3 of} o-dichlorobenzene is stored for 4 hours with a Tem mixture of 4-allylidene and 4-allenyl-zJ ⁵ -pregnen- temperature of about 135 ° C in the presence of 100 mg of 3,20-dione is heated in petroleum ether 5% palladium carbon. The reaction, followed by thin solution and the solution chromatographed on alumina 15 layer chromatography, gives phiert. Eluting with petroleum ether gives 17 ^ -acetoxy-benz [d, e] androstan-3-one. Yield of pure 4-allylidene-zJ ⁵ -pregnen-3,20-dione; F. 178 to 30%.
181 ⁰ C, lap = -26.5 ° (dioxane, c = 0.5%). B ei s ρ ie 1 13

A solution of 1 g of the 4-allylidene- / I ⁵ -pregnen-3,20-dione obtained in 30 cm ^{3 of} pyridine is refluxed for 4 hours in the presence of 100 mg of 5% palladium-on-carbon. The catalyst is filtered off and the solvent is evaporated in vacuo. After recrystallization from methanol A solution of 2 g of the obtained described in Example 1 4-allylidene-17/3-acetoxy ~ zl ⁵ -androsten-3-one in 50 cm ³ p-dichlorobenzene is 4 hours at 130 ⁰ C in the presence of Heated 5% palladium carbon. The catalyst is filtered off, the solvent in

the benzo [d, e] pregnane-3,20-dione; F. 214 to 25 vacuum evaporated and the residue from Me-

215 ° C; [a] f = + 53 ° (dioxane, c = 0.5%).

The same product is obtained by subjecting the mixture of 4-allylidene- and 4-allenyl-zl ⁵ -pregnen-3,20-dione directly to the cyclodehydrogenation.

recrystallized from ethanol. In this way, β-acetoxy -benz [d, e] androstan-3-one, which is identical to the product described in Example 1, is obtained.

Example 14

A solution of 1 g of the mixture described in Example 3 of 4-allylidene-17j3-acetoxy-J ⁵ -androsten-3-one and 4-AUenyl-17 /? - acetoxy-J ⁵ -androsten-3-one in 50 cm ³ Benzonitrile is 4 hours at 138 ° C in Ge

Example 9

A solution of 2 g of 3-propargyl-enol ether des

21-acetoxy-zl ⁴ -pregnen-17a-ol-3,20-dione (Reichsteins

Compound S) in 50 cm ^{3 of} toluene is heated for 6 hours under 100 mg of 5% palladium carbon in the presence of 100 mg.

Refluxed. After evaporation of the solution, the catalyst is filtered off, the solvent

evaporated in vacuo and the residue recrystallized from methanol. This gives the 17/3-acetoxy-benz [d, e] androstan-3-one, the one with the

by means of a mixture of 4-AUylidene-21-acetoxy- / I ⁵ -pregnen-17a-ol-3,20-dione and 4-allenyl-21-acetoxy-zl ⁵ -pregnen-17a-ol-3, 20-dione existing residue dissolved in pyridine and the solution 40 game 1 described product is identical. 4 hours in the presence of 5% palladium carbon
refluxed. Working as in Example 4 gives 21-acetoxy-benzo [d, e] pregnan-17a-ol-3,20-dione; 164 to 166 ° C, [a] F = + 58 °
(Dioxane, c = 0.5%).

Example 10

A solution of 2 g of 3-propargyl-enol ether of cortisone acetate in 30 cm ^{3 of} toluene is 4 hours

Example 15

1 of the mixture described in Example 3 g of 4 - allylidene -17/3 - acetoxy - J ⁵ - androsten - 3 - one and 4-allenyl-17 | _3-acetoxy-i d ⁵ -androsten-3-one in 20 cm ^{3 of} ethyl cinnamate dissolved and the resulting solution ^{heated for 5 hours at 120 0} C in the presence of 100 mg of 5% palladium carbon. The solvent is evaporated in vacuo and the residue

refluxed, then the solvent 50 is recrystallized from methanol. This is how you get it evaporated and from a mixture of 4-ally 17/3-acetoxy-benz [d, e] androstan-3-one, which with the

Iiden-21-acetoxy-zl ⁵ -pregnen-17a-ol-3, l 1,20-trione and 4-allenyl-21-acetoxy-J ⁵ -pregnen-17 «-ol-3,11,20-trione The residue dissolved in 30 cm ^{3 of} pyridine. Man

add 200 mg of palladium-on-carbon to the mixture, and a solution of 2 g of that described in Example 3 is refluxed for 4 hours. Working mixture of 4-allylidene-17/3-acetoxy-J ⁵ -androsten-

3-one and 4-allenyl-17 /? - acetoxy-J ^s -androsten-3-one in 30 cm ³ of cyclopentanone is heated for 4 hours at 12O ⁰ C in the presence of 100 mg of 5% palladium carbon. The catalyst is then filtered off, the solvent is evaporated and the residue is recrystallized from methanol. This gives the Πβ-acetoxy -benz [d, e] androstan-3-one, which is

product described in Example 1 is identical. Example 16

as in Example 1, 21-acetoxybenzo [d, e] pregnan-17a-ol-3, ll, 20-trione is obtained; M.p. 269 to 271 ° C; Ia] ² O ² = + 131 ° (dioxane, c = 0.5%).

Example 11

A solution of 2 g of 3-propargyl-enol ether of testosterone in 50 cm ^{3 of} toluene is refluxed for 4 hours, then the solvent is evaporated in vacuo and the mixture of 4-allylidene- ^{I 5} -androsten-17 / S- ol-3-one and 4-A-enyl-J ⁵ -androsten-17; Ö-ol-3-one existing residue dissolved in 30 cm ^{3 of} dimethylaniline. The product manufactured in game 1 is heated and is identical. Example 17

A solution of 1 g of the mixture of 4-allylidene-17j3-acetoxy-J ⁵ -androstan-

3-one and 4-allenyl-17 /? - acetoxy-J ^:> -androsten-3-one in 50 cm ³ η-amyl alcohol is refluxed for 4 hours in the presence of 5% palladium carbon. The reaction followed by thin layer chromatography provides 17 / S-acetoxybenz [d, e] androstan-3-one with a 30% yield.

Example 18

A solution of 1 g of the 4-allylidene-J ⁵ -pregnen-3,20-dione ^{described in Example 8 in 50 cm 3 of} pyridine is refluxed for 4 hours in the presence of 100 mg of platinum solids. By working as in Example 1, the benzo [d, e] pregnane-3,20-dione, which is identical to the product described in Example 8, is obtained.

Example 19

A solution of 2 g of the mixture of 4-allylidene-17/5-acetoxy-J ⁵ -androsten-3-one and 4-allenyl-17β-acetoxy-J ⁵ -androsten-3-one described in Example 3 in 30 cm ³ y-collidine is heated for 4 hours at 120 ° C. in the presence of 100 mg of platinum carbon. The catalyst is filtered off and the residue is recrystallized from methanol. The 17 ^ -acetoxy-benz [d, e] -androstan-3-one, which is identical to the product described in Example 1, is thus obtained.

Example 20

A solution of 2 g of the mixture described in Example 3 of 4-allylidene-17/3-acetoxy-J ⁵ -androsten-3-one and 4-allenyl-17 _J 3-acetoxy-J ⁵ -androsten-3-one in 30 cm ^{3 of} pyrazine is heated for 4 hours at 115 ° C. in the presence of 100 mg of 5% strength palladium carbon. The catalyst is filtered off, the solvent is evaporated in vacuo and the residue is recrystallized from methanol. In this way, β-acetoxy -benz [d, e] androstan-3-one, which is identical to the product described in Example 1, is obtained.

Example 21

A solution of 10 g of the mixture described in Example 3 of 4-allylidene-17 /? - acetoxy-J ⁵ -androsten-3-one and 4-allenyl-17 / J-acetoxy-J ⁵ -androsten-3-one in 100 cm ^{3 of} pyrimidine is refluxed for 3 hours in the presence of 300 mg of 5% palladium-carbon. The catalyst is filtered off, the solvent is evaporated in vacuo and the residue is recrystallized from methanol. This gives 17 /) - acetoxy-benz [d, e] androstan-3-one, which is identical to the product described in Example 1.

heated by carbon. The catalyst is filtered off, the solvent evaporated and the residue recrystallized from methanol. This is how you get the benzo [d, e] pregnane-3,20-dione, that with the one in the example 8 is identical.

Example 24

A solution of 1 g of the mixture described in Example 3 of 4-allylidene-17β-acetoxy-J ⁵ -androsten-3-one and 4-allenyl-17 / f-acetoxy-J ⁵ -androstan-3-one in 20 cm ³ Dimethyl sulfoxide are added to 100 mg of 10% palladium carbon. The mixture is heated for 3 hours at 115 ° C, then cooled, diluted with water and extracted from methylene chloride. The extracts, washed thoroughly with water, are concentrated to dryness. The residue taken up from methanol yields 300 mg of 17 / I-acetoxybenz [d, e] androstan-3-one, which is identical to the product described in Example 1.

Example 25

120 mg of sodium borohydride are added to a solution of 600 mg of the 17; 8-acetoxy-benz [d, e] androstan-3-one described in Example 1 in 15 cm ^{3 of tetrahydrofuran.} After standing overnight, the mixture is concentrated in vacuo and the residue is diluted with water. The precipitate obtained is filtered off and recrystallized from acetone. This gives 550 mg of 17 /? - acetoxy-benz [d, e] -androstan-3 / S-ol; M.p. 160 to 162 ⁰ C; [a] f = -12 ° (dioxane, c = 0.5%).

Example 26

A solution of 1.25 g of lithium aluminum hydride in 30 cm ^{3 of} ether is added dropwise with stirring to a solution of 2.5 g of 17 | 8-acetoxy-benz [d, e] androstan-3-one in 35 cm ^{3 of} tetrahydrofuran and 65 cm ³ Ether added. The mixture is warmed on a water bath, then carefully diluted with water. The reaction mixture is extracted with ether and the combined ether extracts evaporated. The oily residue is taken up with 15 cm ^{3 of} pyridine and 7.5 cm ^{3 of} acetic anhydride and left to stand overnight at room temperature. A precipitate separates out of the ice-cold mixture, which, after filtering off and recrystallization from methylene chloride-methanol, yields 2.22 g of 3j8,17 /? - dimethoxy-benz [d, e] androstane; F. 159 to 160.5 ⁰ C; [a] f = -47 ° (dioxane, c = 0.5%).

40

Example 22

A solution of 3 g of the mixture described in Example 3 of 4-allylidene-17/3-acetoxy-J ⁵ -androsten-3-one and 4-allenyl-17 /? - acetoxy-J ⁵ -androsten-3-one in 50 cm ^{3 of} α-picoline is refluxed for 5 hours in the presence of 200 mg of 5% palladium-carbon. The catalyst is filtered off, the solvent is evaporated in vacuo and the residue is recrystallized from methanol. This gives 17.0-acetoxy-benz [d, e] androstan-3-one, which is identical to the product described in Example 1.

Example 27

500 mg of 17jo-acetoxy-benz [d, e] androstan-3-one are dissolved in 10 cm ^{3 of} methanol and 10 cm ^{3 of} tetrahydrofuran and hydrogenated at room temperature in the presence of 200 mg of 5% palladium-on-carbon. After 3 mol of hydrogen have been absorbed, the catalyst is removed by filtration and the solution is evaporated to dryness in vacuo. The crystalline residue taken up from methanol yields 300 mg of 17j3-acetoxy-benz [d, e] androstane; F. 102 to 104 ⁰ C.

Example 23

1 g of 4-allylidene-J ⁵ -pregnen-3,20-dione is dissolved in 30 cm ^{3 of} quinoline and the resulting solution for 4 hours at 115 ° C in the presence of 100 mg of 5% palladium

65

Example 28

A mixture of 2 g of the procedure described in Example 1 4-allylidene-17 /? - acetoxy-J ⁵ -androsten-3-one in 50 cm ³ of dimethylformamide is heated for 4 hours at 120 ⁰ C in the presence of 5% palladium-carbon. The catalyst is filtered off and the solvent is evaporated in vacuo. The one from raw

17 | 5-acetoxy-benz [d, e] androstan-3-one existing The residue is saponified by treating with potassium carbonate. This is how you get the Benz [d, e] androstan-17 /? - ol-3-one, which is identical to the product described in Example 11.

A mixture of 1 g of benzf ^ ejandrostan-njö-ol-3-one, 3 cm ^{3 of} cyclopentanone dimethyl ketal, 5 cm ^{3 of} dimethylformamide and 10 mg of p-toluenesulfonic acid is refluxed for about 2 hours, then blunted with a few drops of pyridine and evaporated in vacuo . The residue recrystallized from methanol yields 17 / S- (l'-cyclopentenyloxy) -benz [d, e] -androstan-3-one; M.p. 152 to 154 ° C, [a] f = + 15 ° (dioxane, c = 0.5%).

Example 29

100 mg of pyridine tosylate and 1 cm ^{3 of} cyclohexanone methylene ether are added to a solution of 1 g of benz [d, e] androstan-17 / i-ol-3-one in 10 cm ^{3 of tert-butyl alcohol.} After standing overnight, the 17 / 9- (l'-methoxy-cyclohexyloxy-benz [d, e] androstan-3-one is obtained as a crystalline precipitate.

Example 30

2 cm ^{3 of} dihydropyran and 100 mg of p-toluenesulfonic acid are added to an anhydrous solution of 1 g of benz [d, e] androstan-17 / S-ol-3-one in 100 cm ^{3 of benzene.} After standing overnight at room temperature, the mixture is truncated, then the solvent is evaporated in vacuo. The residue recrystallized from methanol yields 17 / 3- (2'-tetrahydropyranyloxy) benz [d, e] androstan-3-one.

Example 31

9a-fluoro-17-acetoxybenzo [d, e] androstanlljS-ol-3-one, which melts ^{at 200 to 202 ° C.}

Claims (4)

Claims 1. Process for the production of new benzo- [d, e] steroids of the androstane and pregnane series the general formula 35 40 45 k-B wherein A is a hydroxy or acyloxy group or one of the following groupings 55 60 (CH ₂ ) ,, 65 - (CH ₂ ), in which W is methyl or ethyl and η is 1 or 2 and B denotes hydrogen or a hydrocarbon radical containing 1 to 3 carbon atoms, or A denotes an acetyl, jS-hydroxyacetyl or // - acyloxyacetyl group and B denotes hydrogen, a hydroxyl or acyloxy group, R denotes hydrogen or methyl, X denotes hydrogen, a hydroxyl or Acyloxy group or a keto oxygen, Y is hydrogen, a /? - hydroxy group or a keto oxygen and Z is hydrogen or halogen and X can be hydrogen, a hydroxy or acyloxy group, only if B, Y and Z are hydrogen and A is a hydroxy or acyloxy group represent, characterized in that corresponding 4-A1-lylidene-J ⁵ -3-ketosteroids of the general formula r ~~ B CH. and / or corresponding 4-allenyl-J ⁵ -3-ketosteroids of the general formula O = ¹ III where A ^{1 is} a hydroxy or acyloxy group and B is hydrogen or a hydrocarbon ^{radical containing 1 to 3 carbon atoms or A 1 is} an acetyl, / S-hydroxyacetyl or / S-acyloxyacetyl group and B is hydrogen, a hydroxy or acyloxy group and R, Y and Z have the abovementioned meaning, heated in an organic diluent at a temperature of 50 to 180 ⁰ C in the presence of platinum or palladium as a cyclodehydrogenation catalyst, then optionally hydrolyzed the 17-acyloxy group by methods known per se, then optionally, only if A ^{1 is} a hydroxy or acyloxy group and B, Y and Z are hydrogen, a) by methods known per se, the 3-keto group with a metal hydride to the corresponding 3/3-hydroxy group reduced and then optionally the compound obtained esterified with a customary acylating agent or optionally b) using methods known per se, the 3-keto group to form a corresponding one 3-deoxo compound catalytically hydrogenated and then optionally the compound obtained esterified with a customary acylating agent or optionally c) using methods known per se, a 17 / S-hydroxy compound with dihydropyran or converts dihydrofuran in the presence of an acidic catalyst or, if appropriate d) reacting a 17/5-hydroxy compound with a low Alkylenoläther and / or dialkyl acetal of the cyclopentanone or cyclohexanone by methods known per se at a temperature above 70 ⁰ C, or optionally e) by known methods a 17/8-hydr oxy compound with methyl or dimethyl or diethyl acetal or Äthylenoläther the cyclopentanone or cyclohexanone at a temperature below 70 ⁰ C in the presence of an acid catalyst is reacted. 2. The method according to claim 1, characterized in that one carries out the reaction in pyridine or dimethylformamide at 80-155 ⁰ C. 3. Process according to Claims 1 and 2, characterized in that there is 2 to 30% palladium-carbon used as a dehydrogenation catalyst. 4. Process according to Claims 1 to 3, characterized in that a mixture of 4-A1-lenyl- and 4-allylidene-zl ⁵ -3-keto steroids, which are obtained by heating a 3-propargyl enol ether of a J ⁴ -3- Ketosteroids of the androstane or pregnane series of the general formula CH ξ C - CH, - O wherein ASB ^ YandZ have the meaning defined in claim 1, was produced at a temperature above 100 ⁰ C in a hydrocarbon-like solvent, in particular in toluene, used as the starting material. 109547/471