DD144550A5 - PROCESS FOR THE PRODUCTION OF STEROIDS - Google Patents

Description

Title of the Erfinduna :.

Process for the production of steroids

Field of application of the invention ''. ·. ·.

The application of the present invention is in the field of anti-inflammatory drugs.

Characteristic of the known technical solutions:

Publications that the. present invention as the prior art are currently unknown.

Object of the invention:

The aim of the invention is to provide new drugs for combating inflammatory conditions.

Explanation of the essence of the invention:

The invention has for its object to provide new drugs for combating inflammatory conditions, which have a higher efficacy compared to conventional anti-inflammatory drugs.

The invention relates to a process for the preparation of steroid / 16 c, 17-b_ / cyclohexene and tetrahydronaphthalene-21-carboxylic acids of the general formula I.

 R

(D

in the '; , , \ . '·'. '..'. V. ". · _ .; X represents a hydrogen or halogen atom, Y represents a hydrogen or fluorine atom or a methyl group,

^R 4 ^{is a ch} l ° ^r - or fluorine atom or a hydroxyl group, and R ^. a hydrogen atom or R ₄ and R ₅ together form a group of the formula. = 0 mean,,

R ₂ and R _{3 are the} same or different and are hydrogen atoms, alkyl or aryl radicals or together with the double '

mm ^ y * - ·

25

bond to which they are attached mean a benzene ring,

R- and R- are the same or different and are hydrogen-ο /

atoms, formyl, phenyl or cyano groups or alkyl, alkoxy or 0 or additionally

Alkyl-C-0 radicals "":.

Hydroxyl groups, halogen atoms, carboalkoxy or alkylcarboriyl groups, when R ₂ and R _{3 are} separate radicals, with the proviso that, when they are one of the radicals, and R _{0 is} a hydrogen atom or a radical of the general

and R _{7 is} different and R _{7 is} a hydrogen atom

CH formula RR ^ _0, where R _g and R ₁₀ and are identical or different hydrogen atoms or alkyl radicals,

and of esters and 1,2-dehydro derivatives of these compounds, characterized in that "a compound of general formula II

CH ₂ OH

in which the individual radicals have the abovementioned meaning, oxidized or

 a compound of general formula IX

35

CH ₂ OH = 0

oxidized at the 21-hydroxyl group to form the 21-carboxylic acid group and then in the 16,17-position a cyclohexane or tetrahydronaphthalene radical of the general formula

fused.

... '' ._ '·. -. , , ''. , '"'". The dotted lines in the 1,2-position of the steroids of the invention signify the possible presence of an ethylenic double bond.

The terms "alkyl radicals" and "alkoxy radicals" mean, unless stated otherwise, straight-chain or branched radicals having 1 to 6 carbon atoms.

By the term "aryl radical" are meant phenyl groups or phenyl radicals substituted by one or more halogen atoms, alkyl or alkoxy radicals.

The term "halogen atom" means fluorine, chlorine, bromine or iodine atoms. γ

Suitable esters are the C ₁ -C ₁ -alkyl, aryl and aralkyl esters. The used as starting materials

Steroids of the general formula II are, for example

from U.S. Patents 3,927,702, 3,994,935 and 3,944,584.

, The steroids of general formula II can be prepared using a catalyst such as Kupferacetaty to the corresponding aldehyde of general formula III

10

R ~~

(III)

25 30 35

oxidize. The reaction is carried out in an alcoholic solvent. ,

In carrying out the above oxidation reaction in the presence of oxygen, for example by passing air through the reaction mixture, in addition to the steroid-21-aldehyde of the general formula III, the steroid formed in reaction with the alcoholic solvent R ₁ -OH is generally obtained. 21-acetal of general formula IV '

 R.

(IV)

213

The oxidation reaction is generally completed within a relatively short time, for example, about 1 hour.

If the above reaction is carried out for a longer time, for example more than about 24 hours, the main product formed is the 20-hydroxy-21-carboxylic acid ester of the general formula V -

• R-

(V)

20 25 30 35

If water is present as a cosolvent in the oxidation reaction and if the reaction is carried out for a prolonged time, in addition to the 20-hydroxy-21-carboxylic acid ester of the general formula V, the corresponding 20-hydroxy-21-carboxylic acid of the general formula VI is formed

 . ' '. ·. , o '. ·

• R.

(VI)

The steroids of the general formula V and VI are present as mixtures of 2Oof- and 20ß ~ hydroxysteroids. By conversion

Substitution of a steroid of the general formulas III or IV or a mixture thereof with an inorganic cyanide as catalyst, an oxidizing agent, an inert solvent, an alcohol and an organic acid gives the product of general formula I. More specifically, the product of the general Formula I obtained by reacting a steroid-21-aldehyde of the general formula III or the corresponding steroid-21-acetal of the general formula IV or a mixture thereof with a mixture of the following constituents:

, (I) An inorganic cyanide catalyst, for example an alkali metal cyanide, such as potassium cyanide /

(II) an oxidizing agent, for example a heavy metal oxide, such as activated manganese oxide or lead dioxide,

(III) an inert solvent, for example a halogenated hydrocarbon, such as dichloromethane or chloroform,

(IV) a primary or secondary alcohol of the formula

R '-OH (R' means any primary or secondary R-, -Reste) and

(V) an acid, for example acetic acid, for the neutralization of the alkali metal cyanide catalyst.

The above reaction gives compounds of general formula VII. ,

The 2Oc <- and 20ß-hydroxysteroids of general formulas V and VI can be to form the corresponding 20-ketosteroids of the general formulas Villa and VIIIb

OO

Il II

C-COR

1 R,

(Villa)

(VIIIb)

oxidize. Examples of corresponding oxidants are manganese dioxide and chromium dioxide. Upon oxidation of 20,000 and 20β-hydroxy steroids with an IIβ hydroxy substituent, the products of formula I are obtained as mixtures of IIβ-hydroxy and 11-ketosteroids. ,

The esters of the general formula I can also be prepared by esterification of the corresponding steroid-21-carboxylic acids of the general formula VIII. The steroids of the general formula VIII can be applied to the abovementioned

.-:. ^: ·. _ g __

purified manner or by esterification of a corresponding steroid-21-carboxylic acid ester of general formula I.

Another way to prepare the compounds of general formula I, wherein R- is a non-tertiary alkyl; is rest with 1 to 10 carbon atoms or an .Arylrest, consists in the transesterification of another ester of the general formula I. The starting steroid is with. 10 the corresponding alcohol in the presence of a basic

Alcoholate, for example sodium ethylate or aluminum isopropoxide, or preferably a source of cyanide ions, for example an alkali metal cyanide such as sodium or potassium cyanide, to give the product of transesterification. ".

The 21-hydroxy-Zl-steroids of the general formula IX

CH ₀ OH

20

(IX)

,

which, as mentioned above, with conversion of the 21-hydroxy group into a 21-carboxylic acid group with subsequent condensation of a cyclohexane, or Tetrahydronaphthalinrests in the 16,17-position to the compounds of general formula I can be implemented ^ and the corresponding 21 ~ Acyloxysteroide are known. The 21-Acyloxysteröide can be easily by conventional methods in the corresponding 21-hydroxy. convert steroids.

The steroids of the general formula IX can be converted to the corresponding aldehydes of the general formula X.

- IG -

HC = O

C = O

(X)

using oxygen or air and a catalyst such as copper acetate. The reaction can be carried out in an alcohol as a solvent.

20 25

If the above-described oxidation reaction is carried out in the presence of oxygen, for example while passing air through the reaction mixture, then in addition to the steroid-21-aldehyde of the general formula X, the steroid formed in reaction with the alcoholic solvent R-OH is generally obtained. 21-acetal of the general formula XI

CH (OR,) ~

30

(XI)

The oxidation reaction is generally completed within a relatively short time, for example, about 1 hour.

If the above reaction is carried out for a long time, for example about 24 hours, the main product obtained is the 20-hydroxy-21-carboxylic acid ester of the general formula

- '11 -

: (XII)

If water is present as a cosolvent in the oxidation reaction and the reaction is carried out for a prolonged time, the corresponding 20-hydroxy-21-carboxylic acid of the general formula XIII is formed in addition to the 20-hydroxy-21-carboxylic acid ester of the general formula XI

(XIII)

The steroids of general formulas XII and XIII are present as mixtures of the 20X and 20β steroids. By reacting the steroids of the general formulas X or XI 'or a mixture thereof with an inorganic cyanide as catalyst, an oxidizing agent, an inert solvent, an alcohol and an organic acid, a compound of the general formula I "A compound of the general formula XIV can be obtained by reacting a steroid-21-aldehyde of the general formula X or the corresponding steroid-21-acetal of the general formula XI or a mixture thereof with a mixture of

: .. /: ', / - :. ; '. - - 12 -;. \ £ I _{α:; ;} © * &' -.

implements the following components:

(I) An inorganic cyanide catalyst, for example, an alkali metal cyanide such as potassium cyanide,

(II) an oxidizing agent, for example a heavy metal oxide, such as activated manganese dioxide or lead

 .. 'xid, "' '' · '' '>;' , ';

(III) an inert solvent, for example a halo-gen. Hydrocarbon, such as dichloromethane or

Chloroform,

(IV). a primary or secondary alcohol R '-0H (such as' mentioned above, ^1, R _1st any non-.tertiären R ₁ radical) and

(V)

an acid such as acetic acid to neutralize the alkaline cyanide catalyst.

As the product of the above reaction, a compound of general formula XIV is obtained

0 0

OR '

(XIV)

The 2O <K and 20ß-hydroxysteroids of the general formulas XIE and XEH can be prepared to form the corresponding 20r-ketosteroids of the general formulas XV and XVI

J-L,

(XV)

(XVI)

10

15

20

oxidizing examples of such oxidizing agents are manganese dioxide and chromium dioxide. Oxidation of .2OcC- / and 20β-hydroxy steroids with a 11β-hydroxy substituent yields the steroids of general formulas XV and XVI in the form of mixtures of the IIβ-hydroxy and IIβ-ketosteroids.

The intermediates of general formula XV can also be prepared by esterification of the corresponding steroid-21-carboxylic acids of general formula XVI. The steroids of general formula XV can be prepared as described above or by saponification of a corresponding steroid-21-carboxylic acid ester of general formula XV produce.

25

30

35

A further procedure for the preparation of the intermediates of the general formula XV, in which R- is a non-tertiary radical, consists in the transesterification of another ester of the general formulas XIV or XV. The starting steroid is reacted with the corresponding alcohol in the presence of a basic alcoholate, such as: sodium ethylate or aluminum isopropylate, or preferably a source of cyanide ions, for example, an alkali metal cyanoacetate, such as sodium cyanide or potassium cyanide, to form the transesterification precursor.

The steroids of general formulas XIV, XV and XVI can be prepared by reaction with a benzocyclobutene of

ί general formula XVII

(XVII)

or with a butadiene of the general formula XVIII

R "HC = C

^R 2

C = CHR

R '

(XVIII)

converting into compounds of the general formula I by carrying out a Diels-Alder reaction.

When using the reagent of the general formula XVII, the reaction can be carried out without a solvent or in an inert solvent, for example o-dichlorobenzene or diethylbenzene. Preferably, the reaction is carried out in the absence of a solvent in an inert atmosphere at temperatures up to the boiling point of the solution. The mixture can be treated with a free radical inhibitor. '

When using a reagent of the general formula XVIII, preferred catalysts are anhydrous aluminum chloride or anhydrous aluminum bromide. The reaction may be carried out in an organic solvent, for example a halogenated hydrocarbon, such as dichloromethane. The above-mentioned Diels-Alder reaction is highly selective and takes place only at the double bond in the 16-position, even if the ZA'- 3-keto group is present. When the butadiene is unstable in the presence of a Lewis acid as a catalyst, the Diels-Alder reaction in the presence of an inhibitor of free

Γ '. .. ... Γ. :. , '.', ' .:''.., - .:' "'''...',' ^:. '-'" ·. '" 15 Radicals carried out at elevated temperatures.

If the steroid of the general formula XIV, XV or XVI contains an IIβ-hydroxy group, this group is preferred. protected from performing the Diels-Alder reaction. The skilled person is familiar with numerous possibilities for protecting the functional group in the 11-position. Particularly preferred is an acylation of this group. The acylation may be carried out using "an acid anhydride, for example, an acetic anhydride, in the presence of a Lewis catalyst, such as boron trifluoride etherate." Following the Diels-Alder reaction, the protecting group may be removed by a conventional procedure.

The steroids of general formula I are valuable ent. anti-inflammatory Wixkstoffe for topical application, which can be used in place of known glucocorticoids for the treatment of conditions such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema and anogenital pruritus. The steroids can be in the form of

conventional creams, ointments, lotions or sprays with a content of active ingredient of 0, oil to 5.0 percent by weight and preferably from 0.025 to 2.0 percent by weight. be administered. , '

Embodiments :,

, Be is pie I 1. -I

9-fluoro-1 ', 2', 3 ', 4' -tetrahvdro-llβ-hvdroxv-3, 20-dioxo : ': _ ^: ~~. ;

preqna-1,4-dieno / 16 <*, 17-b / naphthalene-21-carboxylic acid

'methyl'ester . .'_ "'.

9.0 g of 9-fluoro-1 ·, 2 ¹ , 3 ', 4 ^l- tetrahydro-llβ-21-dihydroxypregna-1,4-dieno / 16oC17-b_ / naphthalene-3,20-dione is found to be under heating dissolved in. 170 ml of anhydrous methanol. After cooling the solution to room temperature

Γ ·· '..V;.,.; ... · .//; / '; , :; v .: ";;;' :. ^: - "' -'"'. ^: - ^; ·:' -ν- '',. -. - 16 - _:

25 mg of copper (II) acetate hydrate added. Then, slowly with stirring, an air stream is introduced into the solution. Within 10 minutes, this disappears. Starting steroid. It essentially forms a single / less polar product, as can be determined by thin-layer chromatography. After extensive evaporation of the methanois under reduced pressure at room temperature, a certain amount of steroid precipitates. The concentrate is diluted with water and extracted with chloroform. The chloroform solution is diluted with a. , Ammonium chloride solution and water, washed over water. dried and evaporated free magnesium sulfate. This leaves G, 98 g of 9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-llβ-hydroxypregna-1,4-dieno / 16, 17-b-naphthalene-21-al-3 "20-dione" This product gives a single spot on silica gel thin layer chromatography using a mixture of chloroform and methanol (93: 7). The IR spectrum is consistent with the assumed structure. However, the NMR spectrum shows that the product is contaminated with a small amount of the corresponding 21-dimethylacetal. '..'...'

A mixture of 950 mg of this contaminated aldehyde, 50 ml of anhydrous methanol, 50 ml of anhydrous dichloromethane, 0.9 ml of glacial acetic acid, 200 mg of potassium cyanide and 2.1 g. 'Manganese dioxide is stirred for 10 hours at room temperature.' Next, the mixture is filtered through a bed of diatomaceous earth. The filter cake is resuspended in chloroform. Then heated under reflux and filtered again. The filtrates are combined, washed with a dilute sodium hydrogen carbonate solution and water and dried over anhydrous magnesium sulfate. After evaporation, 0.85 g of a solid are obtained. This solid is dissolved in a mixture of dichloromethane and methanol. After removal of the dichloromethane, under reflux, 675 mg of a solid precipitate. This solid is again corresponding

cleaned the above information. This gives 63o mg of the Titeiverbindung of F. 319 to 321 C (dec., Incipient discoloration at about 26O C). The spectral data agree with the assumed structure.

^C 3O ^H 33 ^FO 5 73 C 6 H 3, F calc .: 72 15 6 75 ; /. -3, 86 Found .: 85 95 65

For s ρ i e 1 2. _. . '

9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-L-β-hydroxy-3,20-diokoo-pregna-1,4-dieno / 16c, 17-b / naphthalene-21-carboxylic acid

V: ';. 1-methylät hylester. '. ^;

A suspension of 490 mg of 9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-LLβ-hydroxy-3,20-dioxopregna-1,4-dieno / 16c <. Methyl 17-naphthalene-21-carboxylate (see Example 1) in 30 ml of freshly distilled anhydrous isopropanol over magnesium turnings containing 10 mg of sodium cyanide is used as protective gas under nitrogen for 20 minutes. - heated for 20 ter reflux, "This results in a clear solution. Thin-layer chromatographic analysis shows complete conversion of the starting steroid to a less polar compound. The mixture is then evaporated under reduced pressure. The residue is sold in Chio

- '. "" ^ ^ ⁵ roform solved. The solution is washed with dilute brine and water, dried over anhydrous magnesium sulfate and evaporated. 516 mg of the title compound are obtained. Recrystallization from ethyl acetate gives an analytical sample (410 mg) of the title compound in the form of colorless needles of melting point 269-271 ° C. (dec., Incipient discoloration at about 25.degree. C.). The spectral data agree with the assumed structure ^:. , ". · -. A. ¹ .,;. ''.-·'.'-..'.:''"''

^{35 C} 32 ^H 37 ^FO 5

ber .: gef .:

C I 82 7 H 3 F 73 45 7 16 3 / 65 73 , 11 , 47

 '. '. , '·.: · Ν λ- ·.;. -.: - .18 -

Example 3

9-fluoro-1 ', 2', 3 '; 4'-tetrahydro-llβ-hydroxy-3,20-dioxopreqna-1,' 4-dieno / 16ct, 17-b / naphthalene-21-carboxylic acid

butyl ester ·

5 ':' -. , -. ; '''' · ''''^'·':'.·' · '"''" 800 mg of 9-fluoro-l ·, 2', 3 '>4'-tetrahydrö-LLSs, 21-dihydroxypregna-1 , 4-dieno / 16Gi, 17-b_ / naphthalene-3, 20-dione are dissolved with warming in 150 ml of n-butanol. After cooling the solution to room temperature, 250 mg of copper

• added jQ acetate hydrate. Änschliessend air is introduced into the solution for 30 minutes with stirring. Then, the majority of the methanol is evaporated at 40 to 42 C under reduced pressure. The concentrate is diluted with water and then extracted with chloroform. The chloroform extracts are combined, washed with dilute ammonium chloride solution and water, and dried over anhydrous magnesium sulfate. After evaporation, 85 mg of 9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-LLβ-hydroxypregna-1, 4-dieno / ~ 16öf, 17-b_ynaphthalene-21-al-3, 20-dione: This material is characterized spectroscopically. A thin-layer chromatographic test gives a major amount of compound / traces of starting material and traces of another impurity that is less polar than the starting material. It is believed that these are 9-fluoro-1 ', 2 •, 3 •, 4'-tetrahydro-LLβ-hydroxy-21,21-' '. , di-n-butoxy-pregna-1,4-dieno / 16 <X ", 17 ~ b_ / naphthalene-3, 20-dione.

840 mg of the above crude mixture are dissolved in a mixture of 20 ml of anhydrous n-butane and 50 ml of dichloromethane. After adding O, 8 ml of acetic acid, 200 mg of potassium acylate and 2.0 g of active manganese dioxide, the mixture is stirred for 60 hours at room temperature. (A shorter reaction time would be enough). The mixture is then filtered through a bed of diatomaceous earth. The solids are washed with chloroform. The filtrate and the washings are combined, washed with water.

wash and dried over anhydrous magnesium sulfate. After evaporation, a gummy crude product is obtained. From this is isolated by preparative thin layer chromatography (4x2, O mm silica gel plates using a mixture of chloroform and ethyl acetate in a ratio of 1: 1 as eluent) of Hauptbeständteil and identified as the title compound (487 mg). After a single crystallization from Essi'gsäureäthylester gives 381 mg of a sample of the title compound from. F; 245 to 246 C whose spectral data agree with the assumed structure,

^C 33 ^H 39 ^FO 5 74 C 7 H F 55 ber. s 74 13 7 35 3, 46 Found .: , 37 , 41 3,

... 'B e i s ρ i e 1 4

9-fluoro-l ', 2', 3 ', 4'-tetrahydro-LLSs-hydroxy-S, 20-dioxo preqna-1,4-dieno / 16 <x, 17-b / naphthalene-21-carboxylic acid

1,1-dimethyl ethyl ester . , ...

A) 9-Fluoro-1 ', 2', 3 ', 4'-tetrahydro-LLβ-hydroxy-3,20-dioxo- preqna-1,4-dieno / .16of, 17-b / naphthalene-21- carboxylic acid

A solution of 3.0 g of 9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-LLβ-hydroxypregna-1, 4-dieno / 16of, 17-b_ / naphthalene-21-al-3, 20- Aion (see Example 1) in a mixture of 150 ml of dichloromethane and 150 ml of tetrahydrofuran containing 3.0 ml of acetic acid and 4.10 ml of water is stirred for 20 hours with 6.0 g of activated manganese dioxide and 700 mg of potassium cyanide The mixture is then filtered off, the solids are washed with a warm mixture of chloroform and methanol (7: 3), the titrate and wash are combined and evaporated under reduced pressure, the residue is washed with water, dried, purified by chromatography, and crystallized from methanol / chloroform to give the title compound of mp 280-281 ° C (dec.).

B) 9-Fluoro-1 ', 2', 3 ', 4'-tetrahydro -11β- hydroxy-3,20-dioxopreqna-1,4-dieno / 16c (", 17-b / naphthalene-21-carboxylic acid -1,1-dimethylester .- '.;.

In a suspension of 325 mg of 9-fluoro-l ' , 2', 3 ', 4'-tetrahydro-hydroxy-hydroxy-3, 20-dioxopregna-l, 4-dieno / 16ör, 17-b __ / - naphthalene -21-carboxylic acid in 60 ml of anhydrous dioxane containing 0.4 ml of sulfuric acid-phosphoric acid catalyst (prepared by adding the calculated amount of phosphorus pentoxide to 96 percent sulfuric acid with the reaction of all the water) in a pressure reaction vessel an isobutylene stream (total addition about 6 ml) passed. The reaction vessel is then closed and stirred for 30 minutes at room temperature. The mixture is then poured into a solution of 5.0 g sodium acetate.

hydrate in 500 ml of water and extracted successively with chloroform and ethyl acetate. The extracts are washed with brine, combined, dried over anhydrous magnesium sulfate and evaporated. The residue is chromatographically purified on silica gel.

This gives 145 mg of the title compound having an F. 293-296 ° C (dec. _R incipient discoloration at about '275 ⁰ C), after crystallization from acetone / hexane ^

B e i s ρ i e 1 5

, · ..; , · ... -. ...... - -. , ·.

9-fluoro-l ', 2', 3 ', 4' -tetrahydro-ll ß-hydr oxy-3, 20-dioxopreqna-1,4-dieno / 16c (, 17-b / naphthalene-21-carboxylic acid 2 , 2-dimethylpropy! ester

A solution of 9-fluoro-l ', 2', 3 ', 4'-tetrahydro-LLβ-hydroxy-3, 20-dioxopregna-l, 4-dieno / 160 :, 17-b_ / naphthalene-21-carboxylic acid methyl ester in 20 ml of anhydrous dioxane (distilled over sodium) and 15 ml of anhydrous pyridine is refluxed for 18 hours under nitrogen as a blanket with 2.2 g of neopentyl alcohol and 100 mg of sodium cyanide. The resulting solution is evaporated under reduced pressure. The solution obtained after dissolving the residue in chloroform is washed with dilute sodium chloride solution and water, over anhydrous

-21-213

Dried sodium sulfate and evaporated under reduced pressure. The residue is dissolved in a mixture of chloroform and hexane (9: 1) and subjected to chromatography on a column packed with 35 g of silica gel. After elution with a mixture of chloroform and hexane (9: 1), 540 g of product., After crystallization from acetone / hexane to obtain 460 mg of a sample of the title compound, mp. 329.bis 331 ° C (Zers).

₅ C 42 7 H 3 F About: 74 39 7 , 53 3 , 46 Found .: 74 / 73 / 37

₁₀

<· 'V'. , . ',;'·.'-. ^: ""'''' · '·' .. · ..

  } ·. , ... '. , -. , , : · · ·. . , , '; ..

Examples

Methyl 9-fluoro-11β-hydroxy-3,3-O-dioxopregin-1,4 - dieno / 16oc, 17-d "7 - ceclohexene-21-carboxylic acid

A solution of 1.2 g of 9-fluoro-11β, 21-dihydropxypregna-l, 4-dieorip / 16οί, 17-d_ / cyclohexene-3 _f 20-dione and 300 mg of copper acetate in 150 ml of methanol is stirred for 1 hour at room temperature in which an air stream is passed through the solution. The solution is then evaporated at 30 C under reduced pressure. The residue is diluted with water and extracted with chloroform and then with ethyl acetate. The chloroform solution and the acetic acid * 25

Ethyl ester solution are mixed with lo-percent aqueous ammonia.

  NaCl and water, dried over anhydrous sodium sulfate, evaporated under reduced pressure and combined. This gives 1.3 g of solid. According to the NMR sinter, this solid turns out to be

'' - '' Approximately equimolar mixture of the 21-aldehyde and 21-Dimethylacetälderivate the starting steroid.

The solid product (1.3 g) obtained in the above reaction is etv: a for 16 hours at room temperature in a mixture of 50 ml of anhydrous methanol and 50 ml of anhydrous dichloromethane together with 2.0 g of activated

: '' ; ' ·. - '·. ^: . .- ':'. ' ^: . - 22 -

Manganese dioxide, 1.0 ml of glacial acetic acid and 200 mg of potassium cyanide. The suspension is filtered through a Hyflo bed and washed with chloroform. The filtrate and the washing are combined, washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gives 1.1 g of a solid. This solid is dissolved in chloroform and chromatographed on a column packed with 35 g of silica gel. After elution with chloroform, 930 mg of product are obtained. After crystallization from acetone / hexane, 650 mg of the title compound are obtained, mp 256-258 ° C., whose spectral structural formula agree.

^C 28 ^H 31 ^FO

F. 256 to 258 ° C, whose spectral data with the assumed

5 C 57 7 H F 29 About: 70 66 7 , 06 4, 02 gef. : 7O, , 11 4,

B ic ρ ie 1 7 9-Fluoro-LLβ-hydroxy-3, 2 0-dioxopregn al-1, 4-dieno / 16 CX, 1 7 ~ d7- cyclohexene-21-carboxylic acid 1-methyl ethyl ester .

A solution of 480 mg of 9-fluoro-LLβ-hydroxy-3,20-dioxopregna-l, 4-dienoj / 16 &, 17-d __ / cyclohexene ~ 21-carboxylic acid methyl ester (see Example 6) and 85 mg of sodium cyanide.

in 65 ml of anhydrous isopropanol is stirred for about 16 hours at 100 ° C under nitrogen as a protective gas. The resulting solution is evaporated under reduced pressure, the residue is dissolved in chloroform and washed with 25 ml

Washed water. The aqueous phase is washed with sodium-30

chloride and then extracted with chloroform.

The chloroform solutions are combined, dried over water-free sodium sulfate and evaporated under reduced pressure. The residue is dissolved in a mixture of chloroform and hexane (7: 3) and an.einer with

'. , '' .- / ....-. , '... Chromatograph 25 g of silica gel packed column. To

Elution with a mixture of chloroform and hexane (7: 3)

.23-213

370 mg of product are obtained. After recrystallization from acetone / hexane, 3OO mg of the title compound of mp 226 to 228 ⁰ C are obtained, the spectral data of which agree with the assumed structural formula ",. ;

^C 28 ^H 35 ^FO 5 71 C 7 H 4 F calc .: 71 / 46 7 50 3 , 04 Found .: • 47 / 4,4. , 82

B ei s pi el 8

9-Fluoro-L, N-hydroxy-3, 20-dioxopreqna-1, 4-dieno / 16c <, 17-d / -. > - - · cyclohexene-21-carboxylic acid b utylester.

, A mixture of 1.0 g of 9-fluoro-11β, 21-dihydroxypregna, 1,4-dieno / 16: oC 17-d-cyclohexene-3,20-dione and 25o mg

To _

Copper acetate in 50 ml of dichloromethane and 30 ml of n-butanol is stirred for 1 hour at room temperature, passing a slow stream of air through the solution. Since the rate of oxidation is very low, the dichloromethane is evaporated off and replaced by 50 ml of n-butanol, then another 200 mg of copper acetate are added, and the reaction is continued for 1 1/2 hours, during which the starting material disappears The mixture is then evaporated off under reduced pressure at 35 to 40 ° C. The residue is diluted with 200 ml of water and extracted with dichloromethane and then with ethyl acetate The dichloromethane solution and the ethyl acetate solution are treated with 1% strength ammonium chloride solution and washed with water, combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1.2 g of solid.The NMR spectrum of this solid shows that it is an approximately equimolar mixture of the 21-aldehyde and 21-di-n-butylacetal derivatives of the starting steroid is.

'35 / ''. - "- ... -."''.^;;;'.''. . '; .: -.

The. in the above reaction, solid pro- (1.2 g) is dissolved in 50 ml of anhydrous dichloromethane

^{·; r} -,. , , .: ': ·. ; - 24 -

and 3Ο ml of anhydrous n-butanol and stirred for about 16 hours at room temperature with 2.0 g of activated manganese dioxide, 1.0 ml of glacial acetic acid and 200 mg of potassium cyanide. In order to prevent the ingress of moisture, the piston is provided with a calcium chloride drying tube. After 20 hours another 2.0 g of activated manganese dioxide and 200 mg of potassium cyanide are added. The suspension is stirred for 7 hours at room temperature, then filtered through a Hyflo bed and rinsed thoroughly

^ washed with dichloromethane. The filtrate and washings are combined and saturated. Sodium bicarbonate solution and washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. A first attempt of the thin-film

¹ ^ matographisehen purification with removal of the title compound fails from the impurities on silica gel thin layer plates precoated. On silica gel thin-layer plates from E. Merck (grade 2 ram, eluent: mixture of methanol and chloroform in the ratio 2.5: 97.5), on the other hand, a purification is successful. 400 mg of a foamy product are obtained. After crystallization from ethyl acetate / hexane, 330 mg of the title compound of melting point 203-2O9 ° C, the spectral data with the assumed structural formula

²ⁱ * match. , · .; 'J;

C ₂₉ H ₃₇ FO ₅ ..,;. CHF;

Calculated: 71.87 7.70 3.92 Found: 71.98 7.73 3.62 -

For s ρ i e 1 9

9-fluoro-LLSs-hydroxy-l ' 2 '-dimethyl-3,20-dioxopreqna-1,4-dieno / 16of, l'7-d / cyclohexene-1-carboxylic acid methyl-

^; '' ester '". ''.'-'''·' .- ^',.'. '' .- ''^':''''·'. A solution of 4.9 g of 9-F-luor-LLSs, 21- dihydroxy-l ', 2'-dimethyl-3, 20-dioxopregna-l, 47-dieno / 16Λ17-d __ / cyclohexene and 1.1 g of copper acetate in 800 ml of methanol is reacted according to paragraph 1 of Example 1 with air Man

- 25 -> 13

V receives 5, Og of an approximately equimolar mixture of the 21-JÜ-dehyd- and 21-Dimethylacetalderivate the starting

, ; , steroids. ./ -. ". \ .- ... .. ''^; , '.' ,. '':

4.5 g of the solid product obtained in the above reaction are combined for about 16 hours at room temperature under nitrogen as inert gas: 7.0 g of activated manganese dioxide, 4.0 ml of glacial acetic acid and 700 mg of potassium cyanide in a mixture of 250 ml of anhydrous methanol and 250 ml

'Anhydrous dichloromethane stirred. The suspension obtained is filtered through a bed of diethyl ether and washed with a mixture of chloroform and methanol (9 μl). The filtrate and washings are combined and evaporated under reduced pressure. This gives 5.6 g of a solid. This solid is dissolved in a mixture of chloroform and hexane (9: 1) and chromatographed on a column packed with 100 g of silica gel. After elution with a mixture of chloroform and hexane (9: 1), 4.2 g of product are obtained. According to Umkri-

  ''

Preparation of 1.5 g of this product from acetone / hexane

one obtains 900 mg of a sample of the. Title compound from mp 256 to 258 ° C.

° 28 ^Η 35 ^ΡΟ 5 71 C 7 H 4 , 04 calc .: 71 , 46 7 5O 3 / 95 gef. : , 38 50

Be is ρ i e 1 '10' r

9-fluoro-LLSs-Hydroxy-l ', 2'-dimethyl-3,20-dioxopreqna-

_n 1, 4-dieno / 16CX, 17-d / cyclohexene-21-carboxylic acid ethyl ester

A) 9-fluoro-β-hydroxy-1 ', 2'-dimethyl-3, 2Q-dioxopreqna ~

1, '4-dieno / 16c', 17-d. / cyclohexene-1-carboxylic acid A solution of 2.5 g of 9-fluoro-11β-hydroxy-l, 2'-dimethyl-3,20-dioxopregna-l, 4-dieno / 16 <x, 17-d_ / methyl cyclohexene-21-carbene methyl ester in a mixture of 110 ml of methanol and 200 ml of tetrahydrofuran is stirred for 1.0 hour under nitrogen as a blanketing gas with a solution of 640 mg of potassium chloride.

hydroxide in 10 ml of water. The reaction mixture is then acidified with 5% hydrochloric acid and evaporated to dryness under reduced pressure. The resulting slurry is mixed with water and filtered. 700 mg of the title compound of

F. 234-238 ° C. :

The filtrate is evaporated under reduced pressure and washed with a mixture of chloroform and methanol (4: 1). After the solvents have been removed, 1.4 g of the hydrated title compound are obtained, mp 215.degree.-24.degree. , · ·; ^: ? - -;

B) 9-Fluoro-11β-hydroxy-1 ', 2'-dimethyl-3 ,. 20-dioxopreqna-1,4-dieno / 16 #, 17-d / cyclohexene-21-carboxylic acid ethyl ester ''. , ·: '''. A suspension of 235 mg of 9-fluoro-LLSs-hydroxy ~ l ·, 2 '~ dimethyl-3, 20 ~ dioxopregna- 1 ₁ 4-a. \ Eno / _ 16a, i7-d __ / cyclohexene-21-carboxylic acid in 5 ; O ml of anhydrous dichloromethane is successively with O, 5 ml of triethylamine and 0.068 ml of pivaloyl. , added to chloride. To. For 15 minutes stirring the resulting solution at room temperature, 0.116 ml of anhydrous. Methanol added. After 3.0 hours, the mixture is acidified with 50 percent hydrochloric acid, poured into water and extracted with chloroform. The chloroform extracts are combined, washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue gives, after preparative thin-layer chromatography, 97 mg

the title compound from mp 198 to 200 ⁰ C--

B e i s ρ i e 1 11

9-fluoro-LLβ-hydroxy-1 ', 2'-dimethyl-3,20-dioxopreqna-1,4-dieno / 16c, 17-d / cyclohexene-21-carboxylic acid 1,1-dimethylethyl radicals r

A solution of 700 mg of 9-fluoro-11ß-hydroxy-l ', 2'-dimethyls', 20-dioxopregna-l, 4 ~ äieno / 16 ° <, 17-d_ / cyclohexene-21-car-

, .- \ :: . -,,; ; '/ ; ; ; - 27 -

Bonsäure (see Example 10 A) in 6O ml of anhydrous Dio. xan containing 12 ml of isobutylene and 0.7 ml of sulfuric acid-phosphoric acid catalyst (prepared by the addition of phosphorus pentoxide to 96% sulfuric acid) is stirred for 24 hours at room temperature in a

leave reaction vessel. Subsequently, by the. Solution for removing excess isobutylene; passed dry nitrogen stream, .Anschluss wird

the mixture into a saturated Natriumhydrogencarbonätlö- . 10 solution poured, pas steroid is made by extraction with

Chloroform isolated. The Ghloroform solution is mixed with water. .. and dried over anhydrous magnesium sulfate. The residue obtained after evaporating the solvents (760 mg) is subjected to column chromatography on silica gel. 500 mg of the title compound are obtained, which, after crystallization from acetone / hexane, has a melting point of from 209 to 20 ° C.

B ic ρ ie 1 12 9-Fluoro-LLβ-hydroxy-3, 20-dioxopreqna-1,4-dieno / 16c <, 17-d 7-cyclohexeri-21-carboxylic acid 2,2-dimethylpropyl ester A solution of 25 mg Methyl 9-fluoro-LLβ-hydroxy-3,20-dioxopregna-1,4-dieno / 16g, 17-d __ / cyclohexene-21-carboxylate in 2.0 ml of anhydrous dioxane containing J ^. ^Twenty-five (40) mg of neo-pentyl alcohol and 5.0 mg of sodium cyanide are refluxed for 2 hours under anhydrous conditions. The mixture is then cooled, added to water and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is crystallized from ethyl acetate / chloroform. This gives 23 mg of the title compound of melting point 28.8 ° C. (decomposition incipient discoloration below the melting point).

 -. 28 -

213

B e "i s ρ i e 1 13 '

9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-l-hydroxy-3,20-dioxopreqna-1, 4-dieno / 16oC, 17-b / naphthalene-21-carboxylic acid methyl ester ':

A) 9-fluoro-LLβ-hydroxy-3,20-dioxopreae, Na ~ I, 4,16-trien-

21-carboxaldehyde and 9-F, fluoro-LLβ-hydroxy-21-dimethoxypreqna-1,4,1β-triene-3,20-dione

1/7 g of 9-fluoro-11β, 21-dihydroxypregna-l, 4,16-triene-3, 20- ". dione are dissolved with heating in 300 ml of methanol. After cooling to room temperature, the solution is mixed with 100 mg of copper acetate. Then, an air stream is introduced into the solution with stirring. After about 20 minutes, the starting material disappears to form a less strongly polar compound, as shown by the thin film.

''

layer chromatography results. The solution is then evaporated under reduced pressure. The remaining solid is washed successively with dilute ammonium chloride solution and water and dried

1/9 g of a substantially equimolar mixture of the

in the title mentioned aldehyde (in the form of a hydrate) and the

., In the title called acetal, as shown in the NMR spectroscopy. After drying for 2 hours under reduced pressure at 125 to 13O ° C / O, 5 Torr, 1.77 g of a substantially equimolar mixture of

  .- ·

aldehyde and the title acetal,

, : "as shown by NMR and IR spectra.

B) 9-fluoro-llβ-hydroxy-3, 20-dioxoprec7na-l, 4 _f 16-trieno *

21-carboxylic acid methyl ester r

A solution of 1.75 g of the mixture of aldehyde and acetal obtained in section A) in a mixture of 100 ml of anhydrous dichloromethane and 20 ml of anhydrous methanol is added successively with 4.0 g of activated manganese dioxide, 5OO mg of potassium cyanide and 0.51 ml of glacial acetic acid '. - ''. '.-offset. Within less than 1.0 hour, the starting materials disappear to form essentially

V union of a single, less strongly polar compound, as can be detected by thin layer chromatography. The reaction mixture is filtered through a bed of diatomaceous earth. The filter cake is washed several times with small amounts of a warm mixture of dichloromethane and methanol. The filtrate and washings are combined and evaporated. The solid residue is washed with water and dried. After crystallization of the resulting material from methanol / Di chlorogen (with removal of the pichlormethans by evaporation) to give 1.4 g of the title compound, mp 284-286 ° C. -

C) 9-fluoro-1 ', 2', 3 ', 4' -tetrahydro-LLβ-hydroxy-3,20-dioxo. .... preqha-1,4-dieno / 16cA, 17-b / naphthalene-21-carboxylic acid

methylester

A solution of 100 mg of 9-fluoro-LLSs-hydroxy-3,20-dioxopregna-1, 4, le-trieno ^ l-carboxylic acid methylester in 5.0 ml of benzocyclobutene having a content of 6.0 mg A, 4 ' -Thiobis-6- .. tert-butyl-m-cresol is refluxed for 10 hours under nitrogen as a protective gas-a solid separates out from the solution. The unreacted benzoylcyclobutene is recovered by distillation under reduced pressure. The residue in the flask is crystallized from methanol / dichloromethane (with evaporation of the dichloromethane). The title compound is obtained from F "325: to 326 ° C (beginning decolorization at about 295 ° C).

'B e i s pi el 14;

9-Fluoro-L, N-hydroxy-3, 20-dioxopreqna-l, 4,16-trieno- 2-1 -carboxylic acid . , ·. : ': -' '. ^: A solution of 100 mg of 9-fluoro-11β-hydroxy-3,20-dioxopregna-1,4,16-trieno-21-carboxylic acid methyl ester (see Example 1B) in a mixture of 15 ml of methanol and 15 ml of tetrahydrofuran is mixed with 1.0 ml of 3m sodium hydroxide solution. ^: 2 hours unter.Stickstoff stirred as a protective gas. The mixture is then acidified with 5% hydrochloric acid

213

and evaporated. The residue obtained is washed with water and crystallized from chloroform / methanol to give the title compound. The material changes color

when heated to 400 C black, but does not melt.

The steroid of this example can be esterified by conventional methods and then purified according to Example 13 C). ter formation of a product of general formula I are reacted with Benzocyclobuten. ;.

, '. · · .- .- .; '.' , .. ... . ' , ^: - '. ""'. '"." , , '·''.

Example 15

9-Fluoro-L-β-hydroxy-l '', 2'-dimethyl-3,20-dioxopreqna-1,4-dieno / 16 <X, 17-d / cyclohexene-21-carboxylic acid n-butyl ester .. ' .-... '. ',. , : '' · ·. '. ·. ·. : .. A) 9-Fluoro-11β-hydroxy-3,20-dioxopreqna-l, 4,16-triene-21-carboxaldehyde and 9-fluoro-11β-hydroxy-21-dimethoxypreqna-1,4,16-triene -3,20-dione

1.7 g of 9-fluoro-11ß, 21-dihydroxypregna-l, 4,16-triene-3,2O-

dione are dissolved with heating in 3OO ml of methanol. The 20th

Solution is cooled to room temperature. Then 100 ml of copper acetate are added and an air stream is introduced with stirring into the solution. After about 20 minutes, the starting material to form a less polar compound, as can be detected by thin layer chromatography, disappeared. The solution is then evaporated under reduced pressure. The remaining solid is washed successively with a dilute ammonium chloride solution and with water and then dried. This gives 1.9 g of a substantially equimolar mixture of the title aldehyde (in the form of the hydrate) and the title acetal, as can be seen from the NMR spectra .trum. After drying for 2.0 hours under reduced pressure at 125-13O ° C / 0 _# 5 torr, 1.77 g of a substantially equimolar mixture of the title

, · .-. ... , , '...... .. ·

aldehyde and the title acetal, as can be seen from the NMR and IR spectra.

-31-213

, B) g-fluoro-LLβ-hydroxy-B, 20-dioxopreqna-1, .4, 16-trieno

21-carboxylic acid methylester

A solution of the mixture of the aldehyde and the acetal obtained according to Section A) in a mixture of 100 '. 5 ml of anhydrous pichloromethane and 20 ml of anhydrous methanol are added successively with 4.0 g of activated manganese dioxide, 500 mg of potassium cyanide and 0.5 ml of glacial acetic acid. Within less than 1.0 hour, the starting material disappears to form substantially a single, less polar compound, as seen in thin layer chromatography. The reaction _:

C mixture is filtered through a bed of diatomaceous earth. , -. ·.;. , , , .: -, -. , - · The filter cake is used several times with small amounts of a

warm mixture of dichloromethane and methanol. The filtrate and washings are combined and evaporated. The resulting solid is washed with. Washed water and dried. After crystallization of the material from methanol / dichloromethane (with evaporation of the dichloromethane) gives 1.4 g of the title compound, mp 284-286 ° C.

C) LLβ- (acetyloxy) -9-fluoro-3,20-dioxopreqna ~ l, 4 ·, 16-

, trieno-21-carboxylic acid methyl ester ; A solution of 400 mg of 9-fluoro-LLβ-hydroxy-3,20-dioxo-C "... Pregna-1,4,16-trieno-21-carboxylic acid methyl ester in a mixture of 9 , 0 ml of glacial acetic acid and 9.0 ml of acetic anhydride containing 200 mg of p-toluenesulfonic acid is stirred for 24 hours at room temperature. Then, 300 mg of sodium acetate are added. The mixture is then poured into 200 ml of ice-water with stirring, separated by solid precipitation, and filtered with water. /. '. wash and dry. This gives 400 mg of the title compound which contains only trace amounts of impurities, as is evident in thin-layer chromatography.

  35 '' .. · .. · '. ., .. "'

gives. After crystallization of this product from ethyl acetate / hexane gives 35O mg of the title compound, mp 235-236 ° C.

- 213

D) -l-β - (. Acetyloxy) -9-fluoro-1 ', 2'-dimethyl-3,20-dioxopreqna ] l, 4-dieno / 16o (, 17- d / cyclohexene -21- carboxylic acid methyl ester :

A solution of 320 mg of LLβ- (acetyloxy) -9-fluoro-3,20-dxoxopregna-1,4-trieno-1-carboxylic acid in-ethyl ester in .25. ml of anhydrous dichloromethane containing 100 mg. Aluminum chloride is added with stirring 0.25 ml of 2, 3-Dimethy 1-1., 3-butadiene. The mixture is stirred at room temperature for 11/2 hours, then poured into water and extracted with dichloromethane. The Dichlorormethanexträkt is washed with water and dried over magnesium sulfate. After evaporation, 300 mg of a residue are obtained. This residue gives, in 'column chromatography on 10 g of silica gel, 265 mg of the title compound, after crystallization from ethyl acetate / hexane, 16O mg of acicular product of melting point 172.degree.-173.degree

E) 9-fluoro-11β-hydroxy-1 ', 2'-dimethyl-3,20-dioxopreqna ; 1,4-dieno / 16cC17-d / cyclohexene-1-carboxylic acid

A solution of 235 mg of methyl (II .beta .- (acetyloxy) -9-fluoro-1 ·, 2'-dimethyl-3, 20-dioxopregna-1,4-dieno / 16 <X, 17-d_ / cyclohexene-21-carboxylate in 100 ml of a mixture of 90% methanol and 10 ml of tetrahydrofuran with ei-25 '. The content of 2.0 ml of 3 M sodium hydroxide solution is stirred for 2 to 3 hours under nitrogen as a protective gas in a bath of 60 to 70 ° C. Then, the mixture with the least possible amount of 5 percent hydrochloric acid. acidified and evaporated under reduced pressure. The ^ ⁰ residue is worked up with water and dried. 195 mg of the title compound are obtained. After crystallization from a mixture of chloroform and methanol, an analytical sample of the title compound of mp 35 is obtained

236 to 239 ° C.

-33- 213 8

1 F) 9-fluoro-LLβ-hydroxy-1 ', 2'-dimethyl-3,20-dioxopreqna -1,4-dieno / 16ρ <, 17-d / cyclohexene-21-carboxylic acid-n-

'' butyl ester · ^: ...: "'....

A solution of 175 mg of 9-fluoro-LLβ-hydroxy-1 ', 2'-dimethyl-

/.-... 5 3, 20-dioxopregna-l, 4-dieno / Ιβοζ, 17-d_ycyclohexene-21-car-

I ..... bonsäure in 40 ml of dichloromethane containing a

j. methanol is dissolved with an excess of

, , solution of diazo butane in diethyl ether. After 5 Mx

! is the excess Diazöbutan by addition of

decomposed a few drops of acetic acid. The solution will

' ' then evaporated to dryness and the residue from acetone /

"Hexane crystallizes, giving 1-27 mg of the title compound.

C of the F. 209 to 211 ° C. , '

' ' . ' ''''; , "e -."'''....':'.'

For example, I 16 (IIβ, 16β) -9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-11-hydroxy-3,20-dioxopreqna-1,4-dieno / 16,17-b / naphthalene-21-carboxylic acid octyl ester . '

A solution of 500.mg (0.96 mmol) of (LLSs, 16c ') - 9-fluoro-1 ·, 2', 3 ·, 4 ^I tetrahydro-ll-hydroxy-3,20-dioxopregna-l, 4 -. , dienoX 16,17-b __ / naphthalene _; 1 -21-carboxylic acid-l-methyl ethyl ester and 40 mg of sodium cyanide in 40 ml of anhydrous Octa-nol-1 (distilled over calcium hydride) is stirred for 11/2 hours under nitrogen a-1s inert gas at 13Ό C. The

<25 solution obtained is concentrated under reduced pressure. , '.' · .-. . '

, evaporated. The residue is dissolved in dichloromethane, with

'' Washed water, dried over v / acid-free Na ^ SO ₄ and evaporated under reduced pressure. The residue is dissolved in a mixture of chloroform and hexane (7: 3) and chromatographed on a column packed with 20 g of silica gel. After elution with a mixture of chloroform and hexane (7: 3), 485 mg (97 percent of theory) of product are obtained. After crystallization from acetone / hexane to obtain 37O mg (74 percent of theory) of product F. 215 to 216 ⁰ C = -

; -35. .-. , , , '.' , , ..; , -. : ·. , , ^;

^C 37 ^H 47 ^FO 5 C 22 8th H 3 F calc .: 75, 34 8th , 02 3 , 22 Found .: 75, , 23 , 21

Claims (19)

• Erfiridurigsarispruc h:. ;.: 1. A process for the preparation of steroids of the general formula I _: . , . C-CO ₂ H _R _ in the X represents a hydrogen or halogen atom, Y represents a hydrogen or fluorine atom or a methyl group,. R. a chlorine or fluorator or a hydroxyl group. , ' ' and ' .· ' . , , : -. ·. ' '- R, - a hydrogen atom or R, and R, - together represent a group of the formula = 0, R ₂ and R _{3 are} identical or different and hydrogen • atoms, alkyl or aryl radicals or together with of the double bond to which they are attached mean a benzene ring, R, and R- are the same or different and Wasserte / atoms, formyl, phenyl or cyano groups, alkyl, alkoxy or ° radicals mean or additionally Alkyl ~ C-O Hydroxyl groups, halogen atoms, carboxyalkyl or alkylcarbonyl radicals, when R and R-. are separate radicals, with the proviso that when R _fi and R ₇ are different, one of R, and R "represents a hydrogen atom, and. 15 R _{0 is} a hydrogen atom or a radical of the general formula _r CH-RgR _lo , where R _g and R-. are the same or different and represent hydrogen atoms or alkyl radicals, and of their esters and of 1, 2-dehydro derivatives of these carboxylic acids and esters, characterized in that a corresponding 21-hydroxysteroid of the general formula II '. . ' "". '. (II) 20 25 30 35 oxidized. 2. Process for the preparation of steroids of the general formula I - ί. -.. in the· ' . '...., -...''".''' * '/ -. -' . ' X, a hydrogen or halogen atom, Y is a hydrogen or fluorato or a methyl group,
R is a chlorine or fluorine atom or a hydroxyl group , -: and . . ·. '.''.'-, - \''····' ... '.'''' · "R _{5 is} a hydrogen atom or R. and R ₅ together represent a group of the formula = O, R. and R are the same or different and are water. atoms, alkyl or aryl radicals or together with • the double bond to which they are attached mean a benzene ring. ^_-:: R ^ and R _{n are the} same or different and are    '· O. /. '. , Substituents, formyl, phenyl or cyano groups, alkyl, alkoxy or O radicals mean or additionally Alkyl-C-O- Hydroxyl groups, halogen atoms, carboxyalkyl or alkylcarbonyl radicals, when R and R 1 are separate radicals, with the proviso that when R ₆ and R 2 are different, one of the radicals R 1 - and R 2 denotes a water radical o / represents the substance, and R _{Q is} a hydrogen atom or a radical of general my formula -CH-RgR ₁ , where Rg and R; are the same or different and are hydrogen atoms or. Represent alkyl radicals, and of their esters and of the 1,2-dehydro derivatives of these carboxylic acids and esters, characterized in that first the 21-hydroxy group of a steroid of the general formula IX ^; 30 ':. ''''. .... , , , . , .;. '-' .. R CiI ₂ OH C = O (IX) oxidized to a 21-carboxylic acid group and then in the 16,17-position a cyclohexane or Tetrahydronaphthaiinrest the general formula fused. 3. The method according to item 1 or 2, characterized in that 25 is a compound of the general formula 0 Il Π C-COR _n or their 1,2-dehydro derivative, wherein R _{1 is} a C, -C ₁₀ alkyl, aryl or arylalkyl radical. 4i Method according to item 1 or 2, characterized in that a compound of the general formula or their 1,2-dehydroderivative produces, wherein R _{1 is} a C, -C ^, .- alkyl, aryl or arylalkyl radical, X is a hydrogen or halogen atom, Y is a hydrogen or fluorine atom or a methyl group, R , a chlorine or fluorine atom or a hydroxy group and R _{5 is} a hydrogen atom or R ₄ and R ₅ together form a group of the formula = 0, R f and R _{7 are} identical or different, are 'and hydrogen or halo, formyl , Hydroxyl, · phenyl or cyano groups, alkyl, alkoxy, carboalkoxy, V ο ''';' ο. ^; : '. ...; ·. · '' -. ' ^: -; - · Il. , Il ·. '. Alkyl-C or alkyl-CO radicals mean, with the proviso that when R 1 and R _{7 are} different, one of R, - and R- represents a hydrogen atom, and , ο I. , R _{0 is} a hydrogen atom or a radical of the general o · ''. '. my formula -CH-RR _1, wherein R _g and R ₁₀ are identical or different and represent hydrogen atoms or alkyl radicals. 10 5. The method according to item 1 or 2, characterized in that a product of the general formula 15 20 30 35 or their 1,2-dehydroderivative produces, wherein R is a C ₁ -C ₁₀ -AlkYl-, aryl or arylalkyl radical, Rp and'R- are the same or different and are hydrogen atoms, alkyl or aryl radicals, R. a hydrogen atom and Rj- a hydroxy group or R ^ and R ^ together represent a group of formula = 0, X represents a hydrogen or halogen atom and Y represents a hydrogen or fluorine atom or a methyl group. 6. Method according to item 1 or 2 ,. characterized in that a compound of the general formula C-COR, 1. or their 1,2-dehydro derivative is prepared, wherein R _{1 is} a C.-CQ-alkyl, aryl or arylalkyl radical, R ₂ and R _{3 are} identical or different and are hydrogen atoms, alkyl or Arylres te, R _{4 is} a hydrogen atom and R ₁ . a hydroxyl group or R ₄ and R j together form a group of formula = 0 and Y is a hydrogen or fluoroatom or a Me = = ·· ethyl group. ^; ,; -. ' 7. Method according to item 1 to 4, characterized da-; in that X represents a fluorine atom. 8. The method according to item 1 to 7, characterized in that Y represents a hydrogen atom. 15: · ν; ' , ''. ' ·. ' , '.-. , ^: . , V. - ^; , , '. '. .- " 9 .. The method of item 1 to 8, characterized in that R is hydroxy and R ₅ is a hydrogen atom ... ". 10. The method according to item 1 to 4, characterized in that R and R _{n are} hydrogen atoms. ο /. , , , 11. Method according to items 1 to 4, characterized C. ²⁵ in that R _{0 is} a hydrogen atom. ρ 12. The method according to item 1 to 4 ', characterized in that R _{0 is} a methyl group. 13. Method according to items 1 to 4, characterized in that 9-fluoro-1 ·, 2 ', 3', 4'-tetrahydro-11β-hydroxy-3,20-dioxopregna-1,4-dieno / 16c <, 17-b_ / naph-. ··· thalin -21-carboxylic acid methyl ester. 14. Method according to items 1 to 4, characterized by reacting 9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-LLβ, hydroxy-3, 20-dioxopregna-1,4-dieno / 16O {, 17-b_ / naphthalene-21- carboxylic acid 1-methyl ethyl ester. .213 T 15.The method according to item 1 to 4, characterized by reacting 9-fluoro-l ', 2', 3 ', 4'-tetrahydro-LLß-hydroxy ^ 3,20-dioxopregna-l, 4 ~ dienq / 16eC , 17-b_ / naphthalene-21-carboxylic acid butyl ester. 16. The method according to item 1 to 4, characterized in that 9-fluoro-l ' , 2 ', 3 ', 4' tetrahydro-LLß-hydroxy-3, 20-dioxopregna-l, 4-dieno / 16rt , 17-b_ / naphthalene> 21-carboxylic acid l, l-dimethyl dimethyl ester. ';. · .; ".. ^; :: · - .. '.'';.''^;'.'. ·. -' 17. The method according to item 1 to 4, characterized in that 9-fluoro-l ', 2' / 3 ·, 4'-tetrahydro-LLß-hydroxy- «· 3, 20-dioxopregna-l, 4-dieno / 16 «*, 17-b __ / naphthalene-21-carboxylic acid 2,2-dimethylpröpylester manufactures. .. .. ""; '' ''. ' ':' .. -.: '. /::,' '. 18. The method according to item 1, 2, 3, 5 and 6, characterized in that 9-fluoro-LLβ-hydroxy-3,20-dioxopregna-l, 4-dieno / 16d, 17-d_ / cyclohexene-21- carboxylic acid methyl ester. 19. The method according to item 1, 2, 3, 5 and 6, characterized in that 9-fluoro-LLβ-hydroxy-3,20-dioxopregna-l, 4-dieno / 16c /, 17-d_ycyclohexen-21-carboxylic acid Produces 1-methyl ethyl ester. 20. The method according to item 1, 2, 3, 5 and 6, characterized in that 9-fluoro-LLβ-hydroxy-3,20-dioxopregna-l, 4-dieno ^ / 16C (, 17-d __ / cyclohexene 21 ~ carboxylate-making. 21. The method according to item 1, 2, 3, 5 and 6, characterized in that 9-fluoro-LLβ-hydroxy-l ', 2'-dimethyl-3/20-dioxopregna-l, 4-dieno / 16 <X, 17-d __ / cyclohexene-21-carboxylic acid methyl ester. ·. '- ·.' , '' '..-' 1 22. The method of item 1, 2, 3> 5 and 6, characterized in that 9-fluoro-LLβ-hydroxy-l ', 2'-dimethy1-3,20-dioxopregna-l, 4-dieno / 16oi , 17-d __ / cyclohexene-21-carboxylic acid ethyl ester. , 5 '..'. · .; '': - ^: · : ' ..' · .'-; - ',' - -. , ; .:::: V '. ' ^: - ... , '.;;:.; .7. '··; - '. 23. Method according to item 1, 2, 3, 5 and 6, characterized ';'.. ·. by preparing 9-fluoro-LLβ-hydroxy-3,20-dioxo-pregna-1,4-dieno / 16 (X, 17-d_ / cyclic hexene-21-carboxylic acid 2> 2-dimethylpropyl ester. • ίο / ^'': .. '.'. ''/. . ' , '.-'^{'-:; ::} · ": '·''' V ''':':''" -. ' · ·' ^:. , .24. Process according to items 1, 2, 3, 5 and 6, characterized in that 9-fluoro-LLβ-hydroxy-1 ', 2'-dimethyl-3,20-dioxo-pregna-1,4-dieno / 16c (17 -d_ / cyclo- »hexene-21-carboxylic acid 1, 1-dimethylethyl ester produces« 15 ''. . '' _: . '·''. · ·. ·. ';''.