CS208159B2 - Method of making the steroid 16 alpha,17-b cyclohexenandtetrahydronphtalene-21-carboxyl acids of the pregnan series - Google Patents

Abstract

Steroids having the formula <IMAGE> wherein X is hydrogen or halogen; Y is hydrogen, methyl or fluorine; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are = O; R2 and R3 are the same or different and are hydrogen, alkyl or aryl or taken together with the double bond to which they are attached form a benzene ring; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl, <IMAGE> phenyl or cyano and in addition hydroxy, halogen carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; R8 is hydrogen or CHR9R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl may be used as intermediates in preparing compounds having antiinflammatory activity. The invention extends to acetals of the 21-aldehydes.

Description

(54) Process for the preparation of sterol [1,6α, Γ7-Β] cyclohexene- and tetraacetate-dronate> aiene-21-carboxylic acids of the pregnan series

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of ethereal [16a, 17-bicycohexene] and thetoahydrate, in addition to the talein-21-carboxylic acids of the pregnanoic series and their esters.

The aforementioned steroids corresponding to formula I

O č

and esters thereof are useful as possessing ^anti-i 'tdi.vá agent к topical administration.

In formula I and - throughout; below the various symbols are as ^follows:. meanings:

X represents a hydrogen atom or a fluorine atom;

R @ 2 and R @ 8 are each independently hydrogen, C1 -C4 alkyl or, together with the double bond to which they are attached, form a benzene ring.

As. ish-ara said esters are contemplated to be α2 kyleoters having 1 to 2. 10 carbon atoms in the alkyl moiety, arythesters and arylalkyls;

In accordance with the invention, the asteroids of formula (I) above may be prepared by oxidation of the corresponding steroid [16a, 17-b] cycloeines bearing a hydroxyl group at position 21,

wherein the individual symbols have the meanings given above. Steroids of the above. of Formula II are generally known in the art (see, for example, U.S. Patent Nos. 3,927,720, 3,994,935, and 3,944,584).

The steroid of formula II can be oxidized to the corresponding aldehyde of formula III using a catalyst such as copper (I) acetate.

ноо

This reaction may be carried out in an alcoholic solvent.

If _(the above described oxidation reaction is carried out in the presence of oxygen (for example putting the air into the reaction mixture], with formed in general, besides the steroidal 21-aldeihydu above formula III is also appropriate steroid 21-acetal formed by reaction with alcoholic solvent ( R1-OH], i.e. a steroid corresponding to formula IV.

Said oxidation reaction is generally completed within a relatively short time, i.e. about 1 hour.

If the above reaction is allowed to proceed for a longer period of time, for example for more than 24 hours, the 20-hydroxy-21-carboxylic acid ester corresponding to the general formula V is obtained as the main product.

When water is present in the reaction mixture as a co-solvent in the oxidation reaction and the reaction is allowed to proceed for a prolonged period of time, in addition to the 20-hydroxy-21-carboxylic acid ester of formula V, the corresponding 20-hydroxy-21-carboxylic acid an acid, i.e., a steroid compound corresponding to formula VI.

no

C-OH

(VI)

The steroids of formulas V and VI exist in the form of mixtures of 20a- and 20/3-hydroxys teroids.

Reaction of the steroid of formula III or IV, or a mixture thereof, with an inorganic cyanide catalyst, an oxidizing agent, an inert solvent, an alcohol and an inorganic acid <yields the product of formula I. In more detail, the product of formula I can be obtained by reaction of a steroid 21-aldehyde (i) an inorganic cyanide catalyst (e.g., an alkali metal cyanide such as potassium cyanide); (ii) an oxidizing agent, such as a heavy metal oxide, as an activated (iii) an inert solvent, for example a halogenated hydrocarbon solvent such as dichloromethane or chloroform, (iv) a primary or secondary alcohol of formula R1'-OH (Rf throughout the text refers to any primary or secondary Kupina R) and _(T v) of an acid such as acetic acid, which serves к neutralize the catalyst an alkali metal cyanide.

The products of the above reaction correspond to the general formula VII.

The 20α and 20β-hydroxyisteroids of formulas V and VI can be oxidized to the corresponding 20-ketosteroids of formulas VIIIa, reisp, VIIIb.

d

H (VU / ь)

О О

Examples of suitable oxidizing agents include manganese dioxide and bromine dioxide. When oxidized 20α and 20β-hydroxysteroids carry a β-hydroxyl group, the resulting products of formulas I and VIII are mixtures of β-hydroxy and 11-ketosterroids.

The acid esters of formula (I) above may also be prepared by esterifying the corresponding steroid 21-acids of formula (VIII) (the steroid of formula (VIII) may be prepared as described above, or alternatively by saponification of the ester of the corresponding steroid of 21).

Another method of preparing products of formula (I) having 1 to 10 carbon atoms having a non-tertiary alkyl group or an aryl group is to transesterify another ester of formula (I). The starting steroid is reacted with the corresponding alcohol, in addition to the alcohol. % of sodium oxide or sodium isopropoxide or, preferably, in the presence of a source of cyanide ions (for example an alkali metal cyanide such as sodium cyanide or potassium cyanide) , to form a trans-esterified product.

The steroids of formula (I) are useful anti-inflammatory agents for topical application, which can be used in place of known glucoocoirticoids to treat various diseases such as dermatitis, psoriasis, sunburn, neurodeirmatitis, eczema and ainogenital pruritus. The steroids described can be applied in the form of conventional creams, ointments, lotions or sprays at a concentration of from 0.01 to 5.0% by weight, preferably from 0.025 to 2.0% by weight.

The invention is illustrated by the following non-limiting examples.

EXAMPLE I Methyl 1-fluoirl 9 ', 2', ³ ', 4'-tetrahydroisoquinoline

- 11β-hydroxy-3,20-dioxoipregn: α-1,4-dieino [16a, 17-b] naphthalene-21-acid

1.0 g of 9-fluoro-1 ', 2', 3 ', 4'-tetrahydiro-11,4,21-dihydroxy-pregna-1,4-dieino (16,4,174)] naphthalene-3,20-dione The solution is cooled to room temperature, 250 mg of copper (II) acetate hydrate are added thereto, and air is slowly added to the solution while stirring. By monitoring the progress of the reaction by thin layer chromatography, all of the starting steroid becomes virtually only one less polar material within 10 minutes. Most of the methanol was evaporated in vacuo at room temperature, whereupon some of the steiroid precipitated. The concentrate was diluted with water and extracted with chloroform. The chloroform solution was washed with dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated. 0.98 g of 9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-11'-hydroxypropyl-1,4-dieno [16a, 17-b] n. al-3,2O-dione. This material gave a single layer by thin layer chromatography (silica gel, chloroform-methanol 93: 7). the stain and its IC spectrum corresponds to the stated structure. However, the NMR spectrum shows that this product is contaminated with a small amount of the corresponding 21-dimethylacetal.

A mixture of 950 mg of impure aldehyde, 50 ml of anhydrous methanol, 50 ml of dry dichloromethane, 0.9 ml of glacial acetic acid, 200 mg of potassium cyanide ^1, and 2.1 g of active manganese dioxide was stirred at room temperature for 10 hours. The reaction mixture is filtered through a pad of diatomaceous earth, the filter cake is suspended in chloroform at reflux and the suspension is filtered again. The filtrates were combined, washed with dilute sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and evaporated. 0.86 g of a solid residue is obtained, which is dissolved in a mixture of dichloromethane and methanol. D ^; The chloromethane was evaporated at reflux, whereupon 675 mg of solid material precipitated. This material was subjected to the same purification as above to give 63.0 mg of the title compound, melting at 319-321 ° C (decomposing from approximately 2'60 ° C) with decomposition, the spectral data of which were consistent with the structure.

Analysis calculated for C30H33FO5:

73.15% C, 6.75% H, 3.86 _0/0 F Found:

72.85% C, 6.95% H, 3.65% F.

Example 2

9-fluoro-1 ', 2', 3 ', 4'-tetramethyl-11-β-h-d-d-xo-3,2-dioxopregna-1,4-dieno 1-methylethyl ester [ 16a, 17-b] Naphthalene-21-oic acid i

A suspension of 490 mg methylesteiru for <L '2 _1'> 3 ', 4'-Teti ^ and ^ l ^ 5 ^ di ^ o - ^ liydrc Ll.J-hydroxy-3,20-di'Oxqpregna-l, 4 Dieno [16a] (17b) naphthalene-21-acid (see Example 7) in 30 ml of dry iso-proproyl alcohol (freshly distilled with magnesium shavings), Olb. ml of sodium cyanide is refluxed for 20 minutes under a nitrogen atmosphere to a clear solution. At this stage of the reaction, the sample of the reaction mixture is subjected to thin-layer chiromatography, which indicates that the starting steroid has completely switched to the less polar compound. The reaction mixture is evaporated in vacuo, the residue is dissolved in chloroform, washed with dilute sodium chloride solution and water, dried over anhydrous magnesium sulphate and evaporated. This afforded -576 mg of the title compound. After recrystallization from ethyl acetate, 470 mg of analytically pure product are obtained in the form of colorless needle crystals melting at 2-69 DEG-277 DEG C. (decomposition, color change starting from about 250 DEG C.) with corresponding spectral data.

Analysis calculated for C32H37FO5:

73.82% C, 7.76% H, 3.65% F, found:

% C, 73.45;% H, 3.47% F.

Example 3

9-Fluoro-1 ', 2'-13'-14'-ethanol-11Sihydr' (oxyi3,20-dioxo-гpгegnegnl1414141414 | | | | | | 1 1 1) |

7 ^ 00 mg of _{9-fluoro-ll-one} l'12'13'14'btetolhyeIo 31i

Dissolve 21-dihyeroxypiperidine-1,4-hydroxy-76,7,7]] thiophthalene-312,0-dione in 750 ml of n-butanol, cool the solution to room temperature, 250 mg of copper (II) acetate hydrate are added and the solution is stirred for 30 minutes with air. Most of the n-butanol was evaporated in vacuo at 40 ° to 4.2 ° C, the concentrate was diluted with water, and extracted with chloroform. The chloroform extracts were combined, washed with dilute ammonium chloride solution and water, and dried over anhydrous. -sulphate -opentium1 and -evaporate. There were obtained 850 mg of 9-Flu · ¢ lr-l ^{<12 <13'14'-te:} t · rai Hyer-113ihyeoO'Xypregn and ^ι! -L, 4-dieιno1 76 (l117-b] naphthalene-21-II (This material has been characterized spectroscopically.) Thin layer chromatography shows that the material contains one predominant compound, traces of the starting material, and traces of other contaminants less polar than the starting material. ¹ znečištěniinou that this is a 9-fluoro-l'12 ^{<13 <14'-tetrahydro} · Oi -l13-hydroxy-21121i'di Ώ butoxypτegnli714bdi-eno-1 ^^ Zb] Nafi ^ h ^ t ^ ^ n3J2 - dh ^ n ^.

840 mg of the above crude material was dissolved in a mixture of 20 ml of dry n-butanol and 50 ml of methylene chloride. 0.8 ml of acetic acid, 200 mg of potassium cyanide and 2.0 g of active manganese dioxide were added. the mixture was stirred at room temperature for 60 hours (reaction time could be shorter). The reaction mixture is filtered through a pad of silica, the solids are washed with chloroform, the filtrate is combined with washings, the mixture is washed with water and dried over anhydrous magnesium sulphate and evaporated. The crude product is obtained in the form of a resinous residue from which the main component is isolated by thin-layer chromatography (four childlike layers with a silica gel layer of 2.0 mm thickness, solvent system, chloroform-ethyl acetate 7: 7). . 487 mg of product is obtained, which is identified by the title compound. One time in ethyl acetate gave 387 mg of analytically pure title compound, melting at 245-246 ° C. Spiral data confirm the structure.

Analysis calculated for C33-H39FO5:

74.73% C, 7.35 -% H 3.55 _0/0 F Found:

74.37% C, 7.47% H, 3.46% F.

Example 4 9--dtmethyleleylester fluoiIl'12'I3'14 ^<b itetrahy0l0l71 / b-Уe0гoyy-3,2bbiixcoρregn.ai -N-dienyl N-Pnaphthalene-21ioic acid

A. 941uolb ', 2', 3 ', 4'elahydro-113-he ^, dooxy-3,20-dioxopregna-7,4-idieno [16,111ib] naphthalene-21-acid

A solution of 3.0 -g ^9-d lιюгIl'12'13'14 itetτlheeo -BL-lb (3-hydroxypoegnl-b, 4-dieno [^ ι, Π-]] naphthalen-21-A - 3: 20- of dione (see Example 7) in a mixture of 750 ml of eichlo-methylene and 750 ml of tetrachloride, containing 3.0 ml of acetic acid and 4.0 ml of water, are stirred for 20 hours with 6.0 g of activated manganese dioxide and 700 mg of potassium cyanide. The mixture was filtered and the solids were washed with a warm 7: 3 mixture of chloroform and methanol, the filtrate was combined with the washings and evaporated in vacuo, the residue was washed with water, dried, and purified by chromatography. co-distilled from methanol / chloroform to give the title compound, melting at 280-287 ° C with decomposition.

B. 1,7-dimethylethylesteo 94100-, 2,3,4-tetrahydro-113-hydroxy-3120-dioxoprogRa-1-dieno [16,1177-b] naphthalic acid

In-suspension 325 mg - 941110? 1, 3? 4?

tetrahydro-11S-hydroxy-3,2-dioxoipregene-1,4-dieno [16,17-b] naphthalen-21-enoic acid in 60 ml of dry dioxane containing 0.4 ml of a catalyst consisting of: by combining sulfuric acid and phosphoric acid (prepared by adding a calculated amount of phosphorous pentoxide to 96% sulfuric acid so as to agglomerate all water present), the isobutylene stream is added in the pressure reaction vessel (about 6 ml of isobutylene is added in total). The reaction vessel was sealed and stirred at room temperature for 30 hours. The reaction mixture is poured into a solution of 5.0 g of sodium acetate hydrate in 500 ml of water and extracted successively with chloroform and ethyl acetate. The extracts were washed with sodium chloride solution, combined, dried over anhydrous magnesium sulphate and evaporated. Vyčištěním- dhromatografií residue on silica ISE, a gain of 145 mg of the title compound which pokrystalizaci from acetone and hexane tajeza decomposition at 293-296 ° C (discoloration starts from approximately 275 ^A; C].

Example - 5

2,2-Dimethyl | propyl ⁱ ster fluoιrll-9 ^{<2 <,} 3 ', 4 ^t t Etra-dihydro-11 / - Hydro xy-3,20-dioxopregna-1,4-diene [16a, 17 -b] naphthalene-21-acid

- A solution of 9-i ^] ^ L ^ ^ fluoro ^ ', ^2', 3 ', 4'-tetrahydro-llβ-hydroxy! Rxxy-3,2O-diΏxopιregna-l, 4-dieno [16, 17- b]; n. naphthalene-2 ^L- 1-acid in 20 ml of dry dioxane - (distilled with sodium) - and 15 ml of - dry pyridine together with - 2.2 g of inopentyl-alkanol and 100 mg of sodium cyanide for 18 hours The mixture was heated to reflux in a nitrogen atmosphere. The resulting solution was evaporated in vacuo and the residue was dissolved in chloroform. The chloroform solution was washed with dilute sodium chloride solution and water, dried with anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in a 9: 1 mixture of chloroform and hexane and chromatographed on a column of 35 g of silica gel. Elution with chloroform gave 540 mg of material which, by crystallization from a mixture of acetone and hexane, afforded 460 mg of analytically pure title compound, melting at 329-331 ° C with decomposition.

For C34H41FO5 calculated:

74.42% C, 7.53 o / o H, 3.46 F, found ·

% C, 74.39;% H, 7.73;% F, 3.37.

Example 6

9-Fluoro-113'-hydroxy-3,20-dioxo-dioxa-1,4-dieno [1,6α, 17-d] cyclohexane-21-oic acid methyl ester

To a solution of 1.2 g of 9-fluoro-11 / 3,21-dihydroxy10 p1-g-1,4-di [1,4a, 17-d] cyclohexene- 3,20-dien-a 300 mg of the acetate of copper in 150 ml of methanol was -for stirring at room temperature for 1 hour O- air stream. From the resulting mixture was stirred at - 30 ° C in vacuo ^l solvent left a residue The mixture was diluted with water and extracted first with chloroform and then with ethyl acetate, and the chloroform solution and the ethyl acetate solution were washed with a 10% aqueous sodium chloride solution and water, dried with anhydrous sodium sulfate, evaporated in vacuo and the residue. were combined. 1.3 -g give a solid which is identified by NMR spectrum formed around eιí ^ \ ^ ii ^ _l 4Dláг the mixture of the 21-aldehyde and 21-dimethylacetal starting steroid.

1.3 g of solid product from the reaction described above are stirred with 2.0 g of activated manganese dioxide, 1.0 ml, for about 16 hours at room temperature in a mixture of 50 ml of dry methanol and 5-0 ml of dry dichloromethane. glacial acetic acid and 200 mg of potassium cyanide. The resulting suspension is filtered through a pad of diatomaceous earth and the residue on the filter is washed with chloroform. The filtrate was combined with the wash liquids, washed with water and dried with magnesium sulfate. After evaporation of the solvent under vacuum, 1.1 g of solid material are obtained, which is dissolved in chloroform and chromatographed on a 35 g silica gel column. Elution with -chloroform gave 930 mg of product which, after crystallization from acetone-hexane, gave 650 mg of the title compound, melting at 256 DEG-2158 DEG C. and conforming to spectroscopic data. .

Analysis: calculated for CsaHsiFOs:

70.57 o / o c, - 7.06% H, 4.29% F, found:

% H, 7.11;% F, 4.02.

Example 7

9-Fluoro-113-hydroxy-3,20-dioxopregna-1,4-dieno [16a, 17-d] cyclohexen-21-enoic acid 1-methyl ester

A solution of 480 mg of 9-Piperazo-hydroxy-3,20-dioxopregna-1,4-dieno [16a, 17d] cyclohexin-21-ylacetate methyl ester (see Example 1 and 85 mg of sodium cyanide in 65 ml of dry isopropanol) was added. The reaction solution was evaporated in vacuo, the residue was dissolved in chloroform, washed with 25 ml of water, and the aqueous layer was saturated with sodium chloride, and extracted with chloroform. The chloroform solutions were combined, dried over anhydrous sodium sulphate and evaporated in vacuo, dissolved in chloroform / hexane (7: 3) and chromatographed on silica gel (25 g) eluting with chloroform. and hexane (7: 3) gave 370 mg of material which, after crystallization from acetone-hexane, yielded 300 mig of the title compound, melting at 226-228 ^° C, consistent with spectral data.

C28H35FO5 calculated:

71.46 _0/0 C, 7.50% H, 4.04% F; found:

% C, 71.47;% H, 7.44;% F, 3.82.

Example 8

9-Fiorior-11/3-hydroxy-3,2O-dioxopregna-1,4-dieino [16a, 17-d] -cyclohexen-21-enoic acid butyl ester

To a mixture of 1.0 g 9-fluoro-11 / 3,21-dihydroxypregna-1,4-dieno [16 ', 17-d] cyclohexene-3,20-dione and 250 mg copper (II) acetate in 50 ml dichloromethane and 30 ml The n-butanol was introduced in a slow stream of air with stirring at room temperature for 1 hour. Since the oxidation proceeds extremely slowly, the dichloromethane is evaporated and replaced with 50 ml of n-butanol. An additional 200 mg of copper acetate was added and the reaction continued for 1.5 hours after which time the starting material disappeared from the reaction mixture. The solvent is evaporated in vacuo at 35-40 ° C, the residue is diluted with 200 ml of water and extracted first with dichloromethane and then with ethyl acetate. The dichloromethane and ethyl acetate solution is washed with a /0 / 0 solution; ammonium chloride and water, combined, dried over anhydrous sodium sulfate and evaporated in vacuo. 1.2 g of solid product are obtained which, according to the NMR spectrum, is a roughly equimolar mixture of 21-aldehyde and 21-di-n-butylacetal of the starting steroid.

1.2 g of the solid from the previous reaction were dissolved in 50 ml of dry dichloromethane and 30 ml of dry n-butanol and the solution was ca. It was stirred at room temperature for 16 hours with 2.0 g of activated manganese dioxide, 1.0 ml of glacial acetic acid and 200 µg of potassium cyanide. In order to prevent the ingress of moisture, the flask is closed with a dry calcium chloride drying tube. After 20 hours, additional 2.0 g of activated manganese dioxide and 200 mg of potassium cyanide are added, the suspension is stirred at room temperature for 7 hours, filtered through a pad. diatomaceous earth and the filter residue is washed thoroughly with dichloromethane. The filtrate was combined with the washings, washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The title compound contained in the residue cannot be successfully separated from the impurities by silica gel thin-layer plate chromatography, but can be successfully purified on a silica gel adsorbent plate (E. Merck precoated silica gel TLC plate: 2 mm) in a methanol solvent system— Chloroform 2.5: 97.5 Crystallization from ethyl acetate / hexane gave 33Ό mg of the title compound, melting at 203-209 ° C, consistent with spectral data.

Analysis calculated for C29H37FO5:

71.87% C, 7.70% H, 3.92% F, found ·:

71.98 a / _o C, 7.73% H, 3.62% F.

Example 9

9-Fluoro-11/3-hydroxy-1,2'-diimeithyl-3,2,10-dioxopregna-1,4-idino [16a, 17-d] cyclohexen-21-enoic acid methyl ester

A solution of 4.9 g of O-fluoro-ll ^ ^{Z-dihydroxy-4-dimethyl-3,20-dioxopregna-l,} 4-dieino [16íz, 17-d] cyklohexeinu and 1.1 g of cupric acetate in 800 ml of methanol to process ¹ described in the first paragraph of Example 1 is reacted with air to give 5.0 g a mixture of roughly ^{eikviímolární!} 21-aldehyde and 21-dimethylacetal of the starting steroid.

4.5 g of solid product from the above reaction are stirred at room temperature under nitrogen atmosphere with 7.0 g of activated manganese dioxide, 4.0 ml of glacial acetic acid in a mixture of 250 ml of dry methanol and 250 ml of dry dichloromethane for about 16 hours. 700 mg of potassium cyanide. The resulting suspension was filtered with chloroform / methanol [9: 1]. The filtrate was combined with the wash liquids and evaporated in vacuo. 5.6 g of solid residue are obtained, which is dissolved in a mixture of chloroform and hexane [9: 1] and chromatographed on a column of 100 g of silica gel. Elution with chloroform-hexane [9: 1] gave 4.2 g of material, from which 1.5 g 'was crystallized from acetone / hexane to give 900 mg of an analytically pure sample of the title compound, m.p. 258 ° C.

C28H35FO5 calculated:

71.46 ° C, 7.50% H, 4.04% F,

ΤΊ A Pl P 7P *

71.38 a / _o C, 7.50% H, 3.95% F.

Example 10

Ethyl G-fluoro-l-hydroxy-l ^ * - ^DIM: eithyl-3,20-dioxQpregna-l, 4-dieino [16tt, 17-d] cyclohexene-21-oic acid

A. 9-Fluoro-11/3-hydroxy-11,2'-dimethyl-3,20-dioxopregna-1,4-dieino [δδα, ΓΖ-ύΙοΙ cyclohexen-21-acid

Miethylesteru solution of 2.5 g of 9-fluoro-13-hydírox ^ ^^ '^ - L _^<y 2'-Di'] ^^ i ^ Ithylo-3,20-dioxopi '€ g / L to 4 dieno [16a, 47-d] cyclohexen-21-enoic acid in a mixture of 110 ml of methanol and 200 ml of tetrahydrofuran was added. under nitrogen atmosphere for 1 hour with a solution of 640 mg of hydroxide in 10 ml of water. The reaction mixture was acidified with 5% hydrochloric acid and evaporated in vacuo. The resulting suspension was treated with water and filtered to give 700 mg of the title compound, melting at 234-238 C ^q.

The filtrate was evaporated in vacuo and the residue was washed with chloroform / methanol (4: 1). Evaporation of the solvents gave 1.4 g of the hydrated form of the title compound, mp 215-240 ° C.

B. 9-Fluoro-1,3-Hydroxy-1,2,2-dimethyl-3,20-dioxo-opregn α-1,4-dieno [eta] &lt; 16 &gt; -17-d] cyclohexyl-6-cyclohexylacetic acid ethyl ester

To a suspension of 235 mg of 9-fluoro-11S-hydroxy-1,1 &apos;, 2 &apos; -dimethyl-3,20-dioxo [alpha] -indna-1,4-dieno [16a, 17-d] cyclohexen-21-enoic acid in Add 5.0 ml of dry dichloromethane sequentially with 0.5 ml of triethylamine and 0.068 ml of pivalcyl chloride. The resulting solution was stirred at room temperature for 15 minutes, then 0.116 mL of absolute ethanol was added, after 3 hours the mixture was acidified with 50% hydrochloric acid, poured into water and extracted with chloroform. The chloroform extracts were combined, washed with water and brine ^. After drying over anhydrous magnesium sulfate, it is evaporated. The residue was subjected to preparative thin layer chromatography to give 97 mg of the title compound, melting at 198-200 ° C.

Example 11

9-Fluoro-11-hydroxy-1 H -dimethyl-4 O -dioxopregna-1,4-dieno [16a, 17-d] cyclohexen-21-enoic acid 1,1-dimethylethyl ester

Solution 700 mg 9-11πο ^! η 11/3-γυΛγοχυ-1 ^< , 2 ^< -dimethyl-3,2d-diOxopregna-1,4-dieno [16a, 17-d] cyclohexen-21-oic acid (see Example 10A) in 60 ml dry dioxane , containing 12 ml of isobutylene and 0.7 ml of a catalyst based on sulfuric acid and phosphoric acid (prepared by adding phosphorus pentoxide to 96% sulfuric acid) is reacted in a pressure reaction vessel at room temperature for 24 hours. To remove excess isobutylene, a stream of dry nitrogen was added to the resulting solution and then poured into a saturated sodium bicarbonate solution. The steroid is isolated by extraction with chloroform, washing the chloroform solution with water, drying with anhydrous magnesium sulfate and evaporating the solvents. The residue (760 mg) was chromatographed on a silica gel column to give 500 mg of the title compound, melting after crystallization from acetone / hexane at 209-210 ° C.

Example 12!

9-fluoro-11,3-hydroxy-3,20-dioxo-2,2-dimethylpropyl ester (2-dimethylamino-1,4-dieno [16a, 17-d] cyclohexene 2,2-dimethylpropyl ester) -21-acids

A solution of 25 mg of 9-fluoro-113-hedoxy-3,20-dl-oxo-regna-1,4-diene [16a, 17-d] cyclohexene-21-quinone acid in 2.0 ml dry dioxane, containing 400 mg dry non-pentyl alkane and 5.0 mg sodium cyanide, was heated under reflux for 2 hours under anhydrous conditions. reflux condenser. The reaction mixture was cooled, poured into water and extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulphate and evaporated. The residue was crystallized from ethyl acetate / chloroform to give 23 mg of the title compound, melting at 288 ° C with decomposition (color change before reaching melting point). .

Example 13

(11 / 3,16a) -9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-11-eyedroey-3,2O-dioxQrregna-1,4-diene [16,17b] per ft ai en-21-acids

A solution of 500 mg (0.96 mmol) of 1-methyl-1-methyl-11-3,16-α-O-fluoro-1,4-dimethyl-tetrahydro-1-methyl-2-carboxylic acid ^. - 11-hydroxy-2S-dioxo-regna-1,4-dieno [16,17fb] 1-naphthalene-21-acid and 40 mg of sodium cyanide · in 40 ml of dry · 1-0 ^ 3 ^ (distilled over hydrideimide calcium) under a nitrogen atmosphere 1, The mixture was stirred at 130 ° C for 5 hours and the resulting solution was evaporated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in a 7: 3 mixture of chloroform and hexane and chromatographed over 10 g of silica gel. Elution with CHCl3 / hexane (7: 3) afforded 485 mg (97%) of the product, which upon crystallization from acetone / hexane gave 370 mg (74%) of the desired product, m.p. 215 DEG-216 DEG. C.

Analysis calculated for C37H47FO5:

75.22% C, 8.02% H, 3.22% F, found:

% H, 3.23;% F,% C, 75.34;

Claims (1)

object of the invention A process for the preparation of the steroid [16 ', 17-b] cyclohexene- and tetrahydro-4-carboxylic acid of the pregnane series of formula I to which they are attached, forming a benzene ring, and esters thereof, characterized in that the corresponding 21-hydroxysteroid of formula II is oxidized, CHQ in which X is hydrogen or fluorine, and R 2 and R 5 are each independently hydrogen, C 1 -C 4 alkyl, or together with a double bond to which each of the general symbols is present. are as defined above.