HU215852B - Process for producing new pregna-4,9(11), 17(20)-trien-3-one derivatives - Google Patents

Abstract

The novel compounds of the present invention are represented by the following formula (I): Hal is chlorine or bromine, R is C 1-6 alkyl or C 7 -C 15 aralkyl, K is an oxo protecting group, n is 2 or 3, and the wavy bond is the possible isomeric forms and denotes mixtures thereof. The compounds of formula (I) may be used as intermediates in the 4,9 (11), 16-triene-3,20-dione steroid derivatives. ŕ

Description

The present invention relates to the preparation of novel pregna-4,9 (11), 17 (20) -triene-3-one derivatives which are useful as starting materials for the preparation of steroid derivatives of the type 4,9 (11), 16-triene-3,20-dione.

More particularly, the present invention relates to a process for the preparation of pregna-4,9 (11), 17 (20) -triene-3-one derivatives of formula (I):

Fish means chlorine or bromine,

R is C 1-6 alkyl or

C 7 -C 15 aralkyl,

K is an oxo protecting group of formula (a), (b) or (c), n is 2 or 3, and the wavy bond represents the possible isomeric forms and mixtures thereof.

Exemplary alkyl radicals in R include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl. An example of an aralkyl group represented by R is benzyl or phenethyl.

Preference is given to compounds of formula I wherein Hal is chlorine,

R is (C 1 -C 3) alkyl and K is (c) wherein n is 3.

Particularly preferred is methyl 20-chloro-3,3 - [(1,2-ethanediyl) bis (thio)] pregna-4,9 (11), 17 (20) -triene 21-olate.

According to the present invention, compounds of formula I can be prepared by treating a compound of formula II with acetic anhydride in the presence of a strong acid followed by reaction with an acidic hydrolyzing agent to give the 3-oxo group of the resulting compound of formula III with HO- (CH ₂ ) _n -OH. with a diol of formula III, a thiol of HO- (CH ₂ ) _n -SH or a dithiol of HS- (CH ₂ ) _n -SH, wherein n is as above, selectively protected to give the compound of formula IV K is reacted with a compound of the formula Hal ₃ C-CO ₂ R, wherein Hal and R are as defined above, in the presence of zinc and a Lewis acid.

Paratoluenesulfonic acid, methanesulfonic acid, perchloric acid, hydrochloric acid, hydrobromic acid and sulfuric acid are preferably used as strong acids in the reaction of the compound of formula (II) with acetic anhydride. The strong acid is preferably used in catalytic amounts.

The hydrolysis of the acetate intermediate prepared in situ is preferably carried out with an aqueous acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, most preferably formic acid.

To block the 3-oxo group, the compound is reacted with diol, thiol or dithiol in an acidic medium. The reaction is preferably carried out with ethanedithiol in the presence of a catalytic amount of concentrated hydrochloric or hydrobromic acid or a Lewis acid such as zinc chloride, titanium tetrachloride or boron trifluoride. The Lewis acid is preferably used as an etherate.

Zinc chloride, aluminum chloride, diethylaluminum chloride or titanium tetrachloride are preferably used as Lewis acids in the reaction of the compound of formula IV with trihalogen acetate.

The reaction is preferably carried out in the presence of a cyclic ether such as tetrahydrofuran or dioxane.

The compounds of formula (I) according to the invention may be used as starting materials for the preparation of compounds of formula (A) wherein R 1 is C 1 -C 8 acyl.

This may be done, for example, by reacting a compound of formula I with a phenol of formula XVIII in an alkaline medium wherein R _a and R _b are the same or different and may be hydrogen, C 1 -C 4 alkyl,

C 1-4 alkoxy or hydroxy, the resulting compound of formula (V) wherein K, R, R _a and R _b are as defined above are reacted with a reducing agent in the resulting compound of formula (VI) wherein K, R _a and R _b is deprotected at the 3-position of the oxo group described above, the resulting compound is reacted with an epoxidant, the corresponding derivative bearing the epoxide group at the 17,20-position is hydrolyzed in an acidic medium, the hydroxyl groups of the resulting compound VII are acylated ) of the formula:

R 1 is as defined above for the 17-position alpha-OR.

The reaction of the compound of formula (I) with the phenol is carried out in the presence of a base, for example an alkali or alkaline earth metal hydroxide or carbonate such as sodium, potassium, barium or calcium hydroxide or carbonate, hydride. an alcohol, an alkali amide such as sodium, potassium or lithium amide, and an alkyllithium, preferably butyllithium.

The reaction is carried out in an organic solvent. Suitable solvents are, for example, a ketone such as acetone or methyl ethyl ketone, and a mixture of ketone and halogenated hydrocarbons such as methylene chloride or ethers such as dioxane or tetrahydrofuran.

The alkyl radicals of R _a and R _b are, for example, ethyl, straight or branched propyl, straight or branched butyl, or preferably methyl. The alkoxy group may be, for example, an ethoxy group, a linear or branched propoxy group, a linear or branched butoxy group, or preferably a methoxy group. R _a and R t, preferably hydrogen, hydroxy or methyl.

Suitable reducing agents are, for example, hydrides such as lithium double hydride, diethyl sodium aluminum hydride, diisobutyl aluminum hydride or sodium dihydrobis (2-methoxyethoxy) aluminate. The reaction is carried out in a solvent such as toluene or tetrahydrofuran.

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The reducing agent can also be an alkali borohydride, such as sodium borohydride, optionally using a lithium salt or lithium borohydride as the catalyst.

The 3-oxo protecting group of the ketal form is preferably removed with an acid in the presence of water. In the case of dithioketal, the protecting group is preferably removed using iodine in the presence of a base such as alkaline bicarbonate or catalytic amounts of iodine in the presence of an oxidizing agent such as hydrogen peroxide or methyl iodide, glyoxylic acid or metal salts such as mercury or cadmium. The reaction is usually carried out in a solvent such as a lower alkanol such as methanol or ethanol or in the presence of water in the presence of alcohols and halogenated hydrocarbons such as methylene chloride. In the case of oxathiolane, deprotection can be effected, for example, with a mercury salt such as mercury chloride in the presence of acetic acid / potassium acetate buffer at about 100 ° C or with Raney nickel under the above reaction conditions and hot hydrochloric acid / acetic acid.

As the epoxidizing agent, various peracids such as methachloroperbenzoic acid, perphthalic acid, pervolfamic acid or hydrogen peroxide may be used alone or in the presence of hexachloro or hexafluoroacetone.

The epoxidizing agent may also be a hydroperoxide such as tert-butyl hydroperoxide in the presence of a catalytic amount of vanadium acetylacetonate.

The reaction is preferably carried out in an organic solvent such as toluene, methylene chloride, chloroform, tetrahydrofuran, dioxane or ethyl acetate.

Hydrolysis of the 17,20-positioned epoxide was performed using aqueous acid. Preferred acids are mineral acids such as hydrochloric, sulfuric or nitric acid. The reaction is usually carried out in a buffered medium.

The acylating agent is preferably anhydride or chloride of formic acid, acetic acid, propionic acid, butyric acid or benzoic acid in the presence of a base such as an amine such as triethylamine, pyridine or dimethylaminopyridine, acetate or alkali carbonate.

The acylating agent is preferably acetic anhydride or acetyl chloride.

The introduction of the 17-position and 21-position acyl groups can be associated with the partial acylation of the 3-position enol form. The 3-acylated derivative can then be readily hydrolyzed with a suitable acid such as aqueous hydrochloric acid such as methylene chloride.

For the removal of the OR 1 group, for example, an alkali metal, alkaline earth metal or amine, preferably sodium or potassium salt of a base, such as an acid corresponding to the acyl group, may be used. The reaction is carried out in a polar solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide, preferably at a temperature of 90 to 140 ° C.

It is also possible in preparing the compounds of formula (A), a compound of general formula (I) in an alkaline medium is reacted with R ₂ -SO ₂ -Q alkali szulfmáttal formula wherein R ₂ is methyl, phenyl, tolyl or a silyl group, the resulting compound is saponified and decarboxylated to give the compound of formula IX, wherein

K. and R ₂ are as defined above, reacted with formaldehyde in the presence of a base, to give a compound of formula (X), wherein K and R ₂ are as defined above, by reaction with an epoxidizing agent in an alkaline medium, to give a compound of formula XI, where and R ₂ is as defined above, the epoxide group thereof in an alkaline medium in the presence of R 10 O ions, wherein R 1 is as defined above, is deprotected and deprotected at the 3-oxo group of the resultant compound of formula XII.

The reaction with the alkali sulfate is carried out in an alkaline medium to provide the conditions necessary for the saponification of the ester. Suitable bases include, for example, an alkali metal carbonate such as sodium or potassium carbonate, an alkali metal hydroxide such as sodium or potassium hydroxide. The base is preferably used in excess. The reaction is carried out in an aprotic polar solvent such as dimethylformamide or dimethylsulfoxide. The decarboxylation is preferably carried out at a temperature of about 100 ° C. This operation is preferably carried out in a homogeneous phase.

Sodium toluene sulfinate is preferably used as the alkali sulfate.

The base used in the formaldehyde reaction is a weak base such as sodium or potassium carbonate or bicarbonate. Also, an alkali metal or alkaline earth metal hydroxide may be used. The condensation is preferably carried out in dimethylformamide or dimethylsulfoxide at a temperature in the region of 60 ° C.

Hydrogen peroxide is preferably used as the epoxidizing agent. The reaction is usually carried out in the presence of a base such as an alkali metal or alkaline earth metal hydroxide or carbonate such as sodium, potassium or barium hydroxide or carbonate. Also suitable as the epoxidizing agent are peracids, in an alkaline medium such as tert-butyl hydrogen peroxide, optionally in the presence of a metal such as vanadium, tungsten or titanium catalyst, and oxone. The reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran or methanol / methylene chloride.

The epoxide opening is carried out with an alkali metal, ammonium or amine salt of an acid of formula R, OH.

The opening of the epoxide group is preferably carried out with an acetate such as sodium, potassium or ammonium acetate, or an alkylamine or acetic acid / triethylamine in an organic solvent such as dimethylformamide, dimethylsulfoxide, methylethylsulfone or polyethylene glycol. The reaction mixture is gently heated if desired.

The opening of the epoxide group may also be accomplished by the use of a basic resin such as an acetate resin.

The protecting group for the 3-oxo group is preferably removed as described above.

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The compounds of formula (A) may also be prepared by reacting a compound of formula (I) with an alkali sulfate of formula R ₂ -SO ₂ -Q in the presence of a base to give a compound of formula (XIII) wherein K, R and R ₂ is as defined above, reacted with a halogenating agent in the presence of a base, saponified and decarboxylated to give a compound of formula (XIV), wherein

K and R ₂ are as defined above,

Hal, halo, is reacted with formaldehyde in the presence of a base and the resulting compound (XI) is converted to compound (A) as described above.

Sodium tolylsulfate is preferably used as the alkali sulfate. The reaction is usually carried out in the presence of a base which protects the ester group under the reaction conditions. The base may be an alkali metal carbonate or hydroxide, preferably sodium or potassium carbonate or hydroxide, and imidazole, morpholine, N-methylmorpholine, triethylamine, piperidine, N-methylpiperidine, pyrrolidine, N-methylpyrrolidine, tricalcium phosphate, alumina, triethylethanolamine, piperazine,,, Ν-dimethylpiperazine, hexamethyldisilazane, diazabicyclooctane, dimethylpropylene urea or hexamethylene tetramine. The base is preferably used in an amount less than the stoichiometric amount.

The reaction is usually carried out in an aprotic solvent such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone or acetonitrile, methyl isobutyl ketone at a temperature of 50-120 ° C.

The halogenation of the compound of formula (XIII) is generally carried out with an alkali metal hypohalogenite, N-halosuccinimide or halogen. Sodium hypochlorite or hypobromite _is preferred and Hal _{t is} preferably chlorine or bromine. The reaction may be carried out in the presence of a base such as an alkali metal or alkaline earth metal hydroxide, preferably sodium or potassium hydroxide, or an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate, in a solvent such as ether or dioxane. in tetrahydrofuran or a halogenated hydrocarbon, preferably methylene chloride or dichloroethane, at room temperature or below. The reaction is optionally carried out in the presence of a phase transfer catalyst such as triethylbenzylammonium chloride or tetrabutylammonium bromide.

The saponification and decarboxylation of the ester derivative is preferably carried out with a strong base such as an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide or calcium or barium hydroxide, optionally in the presence of an alkanol such as methanol or ethanol. The reaction mixture is gently heated if desired. The intermediate is then reacted with a mineral acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid or phosphoric acid.

It is noted that saponification and decarboxylation may occur partially during halogenation if the halogenation of the compound of formula (XIII) is carried out in an alkaline medium.

Reaction of the compound of formula XIV with formaldehyde in situ produces a halohydrin derivative which can be converted to the desired epoxide. The reaction is carried out in the presence of a strong base, preferably an alkali metal hydroxide or carbonate, such as sodium or potassium hydroxide or carbonate, or tetramethyl or tetraethylammonium hydroxide, in an organic solvent, preferably methylene chloride and in the presence of a phase transfer catalyst.

Compounds of formula (A) may also be prepared by converting a compound of formula (XI) with an alkali halide to form a compound of formula (XV):

K has the meaning given above,

Hal ₂ is a chlorine, bromine or iodine atom, which is converted, using an acyloxylating agent, into the compound (XII) in an alkaline medium to give the desired compound (A) as described above.

Preferred alkali halides are lithium chloride, sodium chloride or potassium chloride, bromide or iodide, in particular lithium bromide.

The reaction is generally carried out in an organic solvent such as an alkanol such as methanol, ethanol or isopropanol or an aprotic polar solvent such as dimethylformamide or dimethylsulfoxide.

Preferred acyloxylating agents are the alkali metal, ammonium or amine salts of acids R, OH. Within this, sodium, potassium, ammonium or alkylamine acetate or a mixture of acetic acid and triethylamine are preferably used.

The reaction is carried out in a solvent, preferably dimethylformamide, dimethylsulfoxide, acetone, methyl ethyl ketone or methylene chloride. Potassium acetate in dimethylformamide is preferably used. The reaction may also be carried out in a mixture of acetic acid and water. It can also be used in potassium acetate in methylene chloride in the presence of one of the aforementioned phase transfer catalysts and in water.

The compounds of formula (A) may also be prepared by treating a compound of formula (I) with a reducing agent, reacting the resultant compound of formula (XVI), wherein K and Hal are as defined above, with the oxidizing compound of formula (XVII). ), wherein K and Hal are as defined above, is reacted with an acyloxylating agent, and the compound of formula XII is converted to the desired compound of formula A as described above.

The reduction of the compounds of formula (I) is preferably carried out in the same manner as the reduction of the compounds of formula (V).

Suitable oxidizing agents are, for example, pyridine / SO ₃ complexes, wherein the oxidation is preferably carried out in dimethylsulfoxide in the presence of a weak base such as triethylamine or dicyclohexylcarbodiimide or in dimethylsulfoxide in the presence of phosphoric acid. Any oxidizing agent known to oxidize an alcohol group to an aldehyde group may be used as the oxidizing agent.

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The acyloxylation of the compound of formula XVII is preferably carried out in the same manner as the acyloxylation of the compound of formula XV.

The following novel intermediates are used in the processes of the invention:

- Compounds of formula B in which

K, R _a and R _b are as defined above,

X is -CH ₂ -OH or -CO ₂ R where R is as defined above,

- Compounds of general formula (C) in which

K. and R ₂ are as defined above,> C = Y is> CH ₂ ,> C = CH _2, or (d),

- compounds of the formula XII,

- Compounds of formula (D) wherein, wherein R and R ₂ are as defined above,

Z is -CO ₂ R where R is as defined above or halogen,

- compounds of the formula XV,

- Compounds of formula (E): wherein:

K and Hal have the meanings above,

W is -CH ₂ OH or -CHO.

The compounds of formula (A) are useful intermediates for the preparation of various drugs, such as those described in French Patent No. 1,241,109.

Compounds of formula II are known, for example, from U.S. Patent No. 3,023,229.

The invention is further illustrated by the following examples, which are not to be construed as limiting the scope thereof.

Example 1

Methyl 20-chloro-3,3 - [(1,2-ethanediyl) bis (thio)] pregna-4,9 (11), 17 (20) -triene-21-oate Step A

Androsta-4,9-diene-3,17-dione

500 g of 9a-hydroxyandrost-4-ene-3,17-dione and 1 liter of acetic anhydride are stirred under inert atmosphere and then 50 g of para-toluenesulfonic acid are added at room temperature. After stirring for 3 hours, 500 ml of formic acid was added slowly at room temperature. After stirring for an additional 16 hours, it is poured slowly into 3.5 liters of water and stirred at room temperature for 2 hours. After separation, washing with water and drying, 463.9 g of the title compound are obtained.

_{α D} ²⁰ = + 212 ° (c = 1% DMF).

Step B.

3,3 - [(1,2-Ethane-diyl) -bis (thio)] - androsta-4,9-diene-17-one g of the compound of Step A, 30 ml of methanol and 1 ml of ethanedithiol are stirred under inert atmosphere. At 20-25 ° C, 0.1 ml of 36.23% hydrochloric acid was slowly added. The reaction mixture was cooled to 0-5 ° C, stirred for 1 hour, and the crystals were separated, washed with methanol then water and dried. 3.65 g of the title compound are obtained. Melting point: 179 ° C.

IR (CHC1 _3): 1733 and 1405 (17 keto), 1645 (C = C delta4) cm ^-1

Step C

Methyl 20-chloro-3,3 - [(1,2-ethanediyl) bis (thio)] pregna-4,9 (11), 17 (20) -triene-21-oate

Zinc powder (21.8 g) was added under stirring to 150 ml of tetrahydrofuran with stirring, followed by the slow addition of 13.7 ml of titanium tetrachloride at (-15) to (20) ° C. The mixture was stirred for 15 minutes at -15 ° C, followed by 30 g of 3,3 - [(1,2-ethanediyl) bis (thio)] androst-4,9-diene 17 and 15 ml of methyl ether. of trichloroacetate in 150 ml of tetrahydrofuran was added slowly at -20 ° C. After stirring for 10 minutes at -20 ° C, the mixture is allowed to warm to 20 ° C and after 1.5 hours 150 ml of water / pyridine 4: 1 are added at 10-15 ° C. After stirring for 1 hour, the mixture was acidified with 50 ml of concentrated hydrochloric acid and 150 ml of ice-cold water at 10-15 ° C. It is then extracted with methylene chloride, washed with water, dried and the solvent removed. The resulting crude product (40 g) was dissolved in methylene chloride and treated with silica / alumina. After filtration, the solvent was partially removed, the residue was diluted with isopropyl ether, the solvent was partially removed again, and the residue was cooled and the crystals separated. 35 g of crystalline title compound are obtained in two portions as a mixture of isomers.

IR (CHCl ₃ ): 1649 [C = C (4,5)], 1719-1436 (CO ₂ CH ₃ ), 1637-1605 (2 C = C band) cm -1.

NMR (CDCl3, 400 MHz, ppm)

Isomer 1: 18 CH ₃ = 0.95 - 19 CH ₃ = 1.19

- CO ₂ CH ₃ = 3.79 - H, = 5.42.

Isomer 2: 18 CH ₃ = 1.00 - 19 CH ₃ = 1.18

- CO ₂ CH ₃ = 3.81 - H _n = 5.37.

H 5.49 _{4-CH 2} and S = 3.30.

Example 2 1-Acetoxy-pregna-4,9 (11), 16-triene-3,20-dione

Methyl-3,3 - [(l, 2-ethanediyl) bis (thio)] - 20-fenoxipregna-4,9 (11), 17 (20) -triene-21-oate

130 ml of methyl ethyl ketone, 13 g of methyl 20-chloro-3,3 - [(1,2-ethanediyl) bis (thio)] - pregna-4,9 (II), 17 (20 ml) were stirred under inert atmosphere. ) triene-21-oate, 8.12 g of phenol and 11.95 g of potassium carbonate. After stirring at reflux for 26 hours, most of the solvent was distilled off, the residue was taken up in aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried and the solvent removed. The product was recrystallized from methanol to give 6.85 g of the title compound. Mp 184 ° C. The mother liquor was chromatographed on silica gel eluting with methylene chloride / cyclohexane 7: 3 to give an additional 3.21 g of the title compound, a mixture of two isomers.

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NMR (CDCl ₃ , 400 MHz, ppm):

Isomer 1: 19 CH ₃ = 1.13 (s) - 18 CH ₃ = 0.87 (s),

- CH ₂ -S = 3.2-3.4 - CO ₂ CH ₃ = 3.62 (s)

H, 5.32 (d).

Isomer 2: 19 CH ₃ = 1.20 - 18 CH ₃ = 1.10 CO ₂ CH ₃ = 3.66 - H 1 = 5.44 (d) - H ₄ = 5.29 (s) H aromatic = 6.88.

Step B.

3,3 - [(1,2-Ethane-diyl) -bis (thio)] - 21-hydroxy-20-phenoxy-pregna-4,9 (11), 17 (20) -triene ml of toluene is stirred under inert gas.

8.3 g of the compound of Step A are cooled to 0-5 ° C and 29 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene are added slowly at 5-7 ° C. . After stirring for 1.5 hours at 5 ° C, 1 ml of methanol, 5 ml of 30% sodium carbonate and 20 ml of water are slowly added at 10-15 ° C. After 1 hour at 10 ° C, the mixture was filtered, and the filtrate was washed with water and then 10% methanol in methylene chloride. The organic phase was discarded, washed with water, dried and the solvent removed. The crude product is taken up in 30 ml of methanol, cooled in ice and separated. 6.67 g of the title compound are obtained. Melting point: 228 ° C.

NMR (CDCl ₃ , 300 MHz, ppm): 18 CH ₃ = 0.85 (s)

- 19 CH ₃ = 1.13 (s) - CH ₂ -S = 3.1-1.4 CH ₂ OM = 4.16 - H _n = 5.33 - H ₄ = 5.47 - H aromatic = 6 , 92 (d), 6.98 (t) and 7.26 (t).

Step C

21-Hydroxy-20-phenoxy-pregna-4,9 (11), 17 (20) -trien-3-one

1.349 g of Step B is stirred at room temperature with 13.5 mL of 5: 1: 1 methanol: methylene chloride: water and stirred for 30 minutes. Then 54 mg of iodine was added, then 0.4 ml of 110 volumes of hydrogen peroxide was added over 3 hours and the mixture was stirred for an additional 1 hour. The mixture was then neutralized with 0.2N sodium thiosulfate, extracted with methylene chloride, and the organic layer was washed with water, dried and the solvent removed. The crude product was eluted on silica gel with cyclohexane / ethyl acetate 6: 4 to give 1.005 g of the title compound. Melting point: 149 ° C.

IR (CHC1 _3): 1662, 1613 and 866 (delta4-3-one); 1596-1491 (phenyl-O); 3609 (free OH); 1596 + shoulder at 1591 cm ^-1 (phenyl-OC = C).

Step D.

Pregna-4,9 (11L) -diene-17β, 21-diol-3,20-dione

1.5 g of the compound of Step C are mixed with 15 ml of toluene under an inert gas atmosphere, then cooled to 5 ° C and 13.8 mg of vanadium acetylacetonate are added. At 5 ° C, 0.5 ml of 70% tert-butyl hydroperoxide was added over 5 minutes, stirred at 5 ° C for 15 minutes, then allowed to warm to room temperature and stirred for 1 hour. Then 0.1 ml of tert-butyl hydroperoxide was added, the mixture was stirred for 2 hours and 15 minutes, and then 2 ml of 0.5 M sodium thiosulphate solution was added. The mixture was stirred for 15 minutes, 6 ml of 2N hydrochloric acid was added and stirred for 3 hours. It is then extracted with methylene chloride (10% w / w ethanol), and the organic phase is washed with brine, dried and evaporated to dryness. The residue was taken up in ethanol / methylene chloride under reflux, the methylene chloride removed, the residue cooled in ice and separated to give 1.14 g of the title compound which was treated with methylene chloride / methanol. 1.015 g of pure compound are obtained. Melting point: above 264 ° C.

NMR _(CDCl3 + deuterated pyridine - 300 MHz, ppm):

CH ₃ = 0.62 (s) - 19 CH ₃ = 1.33 (s) CO-CH ₂ -OH = 4.35 (d) and 4.79 (d) H _n = 5.5 (d) - H ₄ = 5.46 (s) - additional protons = 5.71.

This step

17a-21-Diacetoxy-pregna-4,9 (11)-diene-3,20-dione 4 g of Step D compound, 0.15 g of dimethylaminopyridine, 16 ml of toluene and 5.9 g of acetic anhydride are stirred under an inert gas atmosphere. . The mixture was refluxed for 20 hours, cooled, water (1 mL) was added and evaporated to dryness. The residue was taken up in methylene chloride and 1.2 ml of 36.23% hydrochloric acid was added. After stirring at room temperature for 1 hour, it is washed with water, dried and evaporated to dryness. 4.9 g of crude product are obtained, which is dissolved in 40 ml of methylene chloride in the presence of alumina. After stirring for 10 minutes, it is filtered, diluted with about 1 volume of methanol and the solution is concentrated until crystallization begins. The crystals were cooled, separated, washed with methanol and dried. 2.9 g of the title compound are obtained.

IR (CHC1 _3): no detectable OH, 1735 (OAc), 1665 and 1614 ^cm-1 (delta4-3 C.).

Step F 1-Acetoxy-pregna-4.9 (1 L), 16-triene-3,20-dione 180 ml of dimethylformamide are stirred under inert gas atmosphere with 3 g of potassium acetate and the mixture is heated to reflux. After slowly distilling off 60 ml of dimethylformamide, the resulting mixture was cooled to 115 ° C and 30 g of the compound of Step E was added. After 3 hours at 115 ° C, some of the solvent was distilled off, the residue was cooled to about 40 ° C and diluted with water (200 mL) with stirring. After stirring for an additional 1 hour at room temperature, the crystals formed were separated and dried. They are taken up in 50 ml of methanol, heated to 45 ° C and then cooled to 0 ° C. The resulting crystals were separated and dried. 16.2 g of the title compound are obtained.

_{α D} ²⁰ = + 166 ° ± 2.5 ° (c = 1%, DMF).

Example 3 1-Acetoxy-pregna-4,9 (11), 16-triene-3,20-dione

3,3 - [(l, 2-ethanediyl) bis (thio)] - 17 - [[(4-methylphenyl) sulfonyl)] - methyl] androsta-4,9 (11) -16- triene 12 ml dimethylformamide, 200 mg phenol, 300 mg potassium carbonate, 2 g sodium tolylsulfinate and 2 g

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The compound of Example 1 is stirred under inert gas at room temperature. After 22 hours at 105 ° C, 0.7 g of potassium carbonate and 1.5 ml of water were added. After 1 hour at 100 ° C, 10 ml of 2N sodium carbonate solution was added and the mixture was heated at 100 ° C for 4 hours. After cooling to 10 ° C, the reaction mixture was poured slowly into 60 ml of 2N hydrochloric acid, stirred for 30 minutes, and the product was separated. This was taken up in methylene chloride; washed with water, dried and the solvent removed. The residue was eluted on silica gel with cyclohexane / ethyl acetate 8: 2. Recrystallization from methanol gave 1.65 g of the title compound. Melting point: 198 ° C.

IR (CHCl ₃ ): 1643 (delta 4), 1598, 1494, 1317, 1303 and 1150 cm ^-1 (tosyl).

NMR (CDCl ₃ , 400 MHz, ppm): 18 CH ₃ = 0.63 (s),

- 19 CH ₃ = 1.16 (s) - H ₄ = 5.37 - H ₄ = 5.49 H ₁₆ = 5.77 - H ethanediyl = 3.20-3.40 (m) H aromatic = 7.33 (d), 7.75 (d) (J = 8 Hz) - tosyl CH ₃ = 2.45 (s) - H _{2 O} = 1, 0.1, 1.44 and 1.77-2.42 ( m), 3.76 (d) and 3.82 (d) (J = 15 Hz).

Step B.

3,3 - [(l, 2-ethanediyl) bis (thio)] - 20 - [(4-methylphenyl) sulfonyl] pregna-4,9 (11), 16,20-tetraene

1.5 ml of dimethylformamide, 0.3 g of the compound of Step A, 0.1 g of potassium carbonate and 0.1 g of paraformaldehyde are stirred at room temperature under an inert gas atmosphere and stirred for 20 hours. It is then heated to 60 ° C and maintained at this temperature for 3 hours. The mixture was cooled to 10 ° C, diluted with water (10 ml), stirred for 30 minutes and then separated. The crystals were taken up in methylene chloride, dried and the solvent removed. The residue was purified on silica gel eluting with cyclohexane / ethyl acetate 7: 3 to give the title compound (0.28 g).

IR (CHCl ₃ ): OH not detectable.

NMR (CDCl ₃ , 300 MHz, ppm): 18 CH ₃ = 0.67 (s)

- 19 CH ₃ = 1.15 (s) - H ₄ = 5.34 (m) H ₄ = 5.48 - H ethanediyl = 3.20-3.40 - H ₁₆ = 6.40 (m) H _2] = 5.94 and 6.48 - H aromatic = 7.28 and 7.68 (d) - tosyl CH ₃ = 2.42 (s).

Step C

20,21-epoxy-3,3 - [(l, 2-ethanediyl) bis (thio)] - 20 - [(4-fenity-sulfonyl] pregna-4,9 (11), 16-triene 2 g of the compound of Step B, 12 ml of dioxane and ml of water are stirred at room temperature under an inert gas atmosphere, then 3.23 ml of 2N sodium hydroxide solution and 0.39 ml of 50% wt. The reaction mixture was stirred at room temperature, and after 2 hours, 0.3 ml of 2N sodium hydroxide solution and 0.06 ml of 50% w / w hydrogen peroxide, and after another 7 hours, 0.03 ml of hydrogen peroxide were added. After 16 hours, the reaction mixture was poured into a saturated sodium chloride solution, extracted with methylene chloride, and the extract was washed with 0.5 M sodium thiosulfate solution, water, dried and the solvent removed. The residue was purified on silica gel eluting with methylene chloride / hexane 8: 2 to give 1.55 g of the title compound.

NMR (CDCl ₃ , 300 MHz, ppm): 18 CH ₃ = 0.31 (s) and 0.66 (s) - 19 CH ₃ = 1.12 (s) and 1.13 (s) - CH ₃

- phenyl = 2.44 (s) and 2.47 (s) - CH ₂ -0 epoxide = 2.85 (d), 2.99 (d) and 3.68 (d) - thioketal = 3.2- 3.4 - H '= 5.19 and 5.32 - H ₄ = 5.47 H ₁₆ = 6.29 (m) and 6.39 (m) - phenyl SO ₂ = 7.33 (m) and 7 , 73 (m).

Step D.

21-Acetoxy-3,3 - [(1,2-ethanediyl) bis (thio)] pregna4,9 (11), 16-trien-20-one

7.5 ml of polyethylene glycol, 1 g of Step C compound and 0.8 g of sodium acetate are stirred under an inert gas atmosphere. The mixture was heated to 48 ° C in a water bath for 2 hours 45 minutes, cooled to 0-5 ° C, poured into ice cold water, stirred for 30 minutes, separated, washed with water and dissolved in methylene chloride. The solution was dried and evaporated to dryness. The residue was taken up in methylene chloride, diluted with isopropyl ether and the methylene chloride removed. After cooling, the resulting crystals are filtered. The filtrate was evaporated to dryness and the residue was eluted on silica gel with methylene chloride. 0.62 g of the title compound is obtained. Melting point: 172 ° C.

IR (CHCl ₃ ): acetate 1748 cm -1, conjugated ketone-C = 1589 cm ^-1 , delta 4 at 1644 cm -1.

NMR (CDCl ₃ , 300 MHz, ppm). 18 Me = 0.85 (s) 19 Me = 1.19 (s) - OAC = 2.19 (s)

-CO-CH ₂ O = 4.91, 5.05 (d, J = 16) _n = H, 5.45 (m) - 5.50 H ₄ - H _lÖ 6.76 (m).

This step

21-Acetoxy-pregna-4.9 (11), 16-triene-3,10-dione (1 g) and 12 ml of methanol / water / methylene chloride (5: 1: 2) were stirred at room temperature. 0.042 g of iodine was added and stirred for 15 minutes, followed by addition of 0.32 ml of 50% hydrogen peroxide over 3 hours. The resulting mixture was stirred for 16 hours and then 6 ml of 0.2 N sodium thiosulfate solution was added. The mixture was extracted with methylene chloride, and the extract was washed with water, dried and evaporated to dryness. The residue was purified on silica gel eluting with cyclohexane / ethyl acetate 1: 1 to give 0.66 g of the title compound, which was recrystallized from isopropyl ether. Mp 128 ° C.

IR (CHC1 ₃₎ 1748 (acetate), 1684, 1664, 1614 and 1590 ^cm-1 (conjugated ketone).

NMR (CDCl 3, 300 MHz, ppm): 18 CH ₃ = 0.89 (s) 19 CH ₃ = 1.36 (s) - H ₄ = 5.5 (m) - H ₄ = 5.76 (d)

H ₂₁ = 4.91 and 5.06 (d, J = 16 Hz).

Example 4

21-Acetoxy-pregna-4,9 (II), 16-triene-3,20-dione Step A

Methyl-3,3- [1,2-ethanediyl) bis (thio)] - 20 - [(4-methylphenyl) sulfonyl] pregna-4,9 (ll), 16-triene-21-oate 60 ml of dimethylformamide, 25 ml of toluene, 10 g of sodium tolylsulphinate, 1 g of phenol, 2 g of sodium carbonate.

The mixture was stirred at room temperature under inert gas atmosphere and 0.56 ml of tris [2- (2-methoxyethoxy) ethyl] amine was added. The mixture was heated to the boiling point of toluene and the water was distilled off. The resulting mixture was cooled to 90-100 ° C and treated with 10 g of the compound of Example 1. After 10 hours at 100 ° C, 2 g of sodium tolylsulfinate was added and the mixture was heated for an additional 6 hours. The mixture was cooled to 5-10 ° C and slowly poured into 500 ml of ice water containing 7 g of sodium phosphate. The resulting mixture was extracted with methylene chloride, and the organic phase was washed with water, dried and evaporated to dryness. The residue was purified on silica gel eluting with cyclohexane / ethyl acetate 90:10 to give 9.9 g of the title compound.

IR (CHCl ₃ ): 1743 cm-1 (C = O), 1330, 1148 cm-1 (SO ₂ ), 1598, 1493 cm- ¹ (aromatic), 1645 cm- ¹ (C = C-delta4).

NMR (CDCl 3, 400 MHz, ppm): 18 CH ₃ = O, 65 (s) - 19 CH ₃ = 1.17 (s) - Hi 4 = 1.04 and 1.45 - 2.45 (m) - phenyl _-CH3 = l, 45 (s) _{-S-CH2 -CH2} -S = 3.24 to 3.40 (m) - COOCH ₃ = 3.66 and 3.72 (2s) = 4 H _20, 53 and 4.55 (2s) - H _u = 5.38 (m) H ₄ = 5.50 (s) - H ₁₆ = 6.00 and 6.15 (2s) - H ₃ and H ₅ phenyl = 7 , 33 (d, J = 8Hz) - H ₂ and H ₆ = 7.72 and 7.77 (2d, J = 8Hz).

Step B.

17- [Chloro - [(4-methylphenyl) sulfonyl] methyl] -3,3 [(1,2-ethanediyl) bis (thio)] - androsta4.9 (11), 16 ( 17) -triene ml of dioxane and 6.4 g of the compound of Step A are stirred under an inert gas atmosphere. At 20-25 ° C, a mixture of 13 ml of sodium hypochlorite and 3.4 g of potassium carbonate particle is added slowly and the reaction mixture is stirred for 1.5 hours, then cooled to 10 ° C and treated with 1.4 g of sodium hydroxide. A solution of thiosulfate 5H ₂ O in 1.4 mL of water was added slowly followed by 1.4 mL of 25.5 wt% sodium hydroxide. The reaction mixture was allowed to warm to 20-25 ° C and then held at 40 ° C for 3 hours. It is then cooled to 10 ° C and 60 ml of 2N hydrochloric acid are added slowly. After stirring in an ice bath for 1 hour, the crystals formed are filtered off, washed with water and taken up in methylene chloride. The solution was dried and the solvent removed. The residue was eluted on silica gel with methylene chloride to give 3.73 g of the title compound. Melting point: about 250 ° C.

NMR (CDCl ₃ , 300 MHz, ppm): 18 CH ₃ = 0.75 and 0.81 - 19 CH ₃ = 1.19 (s) - CH ₃ -phenyl = 2.47 S-CH ₂ -CH ₂ - S = 3.2-3.4 - SO ₂ -CH = 5.01 and 5.04 - 5.41 H _H - H ₄ = 5.50 - 6.20 and H = ₁₆ 6.41 - - phenyl-SO ₂ = 7.36 (d), 7.83 (d).

Step C

20,21 -Epoxy-3,3 - [(1,2-ethanediyl) bis (thio)] - 20 - [(4-methylphenyl) sulfonyl] -pregna-4,9 (11), 16- triene 2.7 ml of methylene chloride, 0.55 g of the compound from Step B, 0.2 g of paraformaldehyde, 0.03 g of benzyltriethylammonium chloride and 2 ml of 25.5% w / w sodium hydroxide in an inert gas atmosphere at 10 ° C. stirring at temperature. The reaction mixture was allowed to warm to 20-25 ° C with stirring. After 2.5 hours, 0.075 g of paraformaldehyde was added and stirred for an additional 1 hour. The mixture was poured into a saturated sodium chloride solution, extracted with methylene chloride, dried and evaporated to dryness. The residue was eluted on silica gel with methylene chloride to give 0.462 g of the title compound.

NMR (CDC1 _3, ppm) = 0.31 to 0.66 19 18 CH ₃ CH ₃ = 1.12 to 1.13 - H '= 5.19 (d), _5.32-CH2 -CH _2- S = 3.24 (m-1H), 3.36 H ₄ = 5.47 - H ₁₆ = 6.30 and 6.39 - CH ₂ epoxide = 2.86 (d), 299 (d), 3.68 - ₃ phenylCH = 2.44 (d), 2.47 and 7.33 (d), 7.73 (d).

Step D.

21-Acetoxy-pregna-4,9 (11), 16-triene-3,20-dione The title compound was prepared as described in Example 3, Steps D and E.

Example 5

21-Acetoxy-pregna-4,9 (11), 16-triene-3,20-dione Step A

-Bromo-3,3 - [(1,2-ethane-diyl) -bis (thio)] - pregna4,9 (11 L), 16-trien-20-one

1.55 g of the compound of Example 4, Step C and 8 ml of methylene chloride are stirred under an inert gas atmosphere. The mixture was cooled to -1 ° C and +1 ° C, lithium bromide (0.95 g) was added followed by methanol (0.18 ml), and the mixture was stirred at this temperature for 7 hours. Water (6 ml) was added at 22 ° C, stirred for 10 minutes, the organic phase was discarded and washed with water, decolorized with charcoal and dried. This gives a solution of the title compound in methylene chloride which can be used directly in the next step.

A portion of the product was isolated by removing the solvent for analysis.

NMR (CDCl ₃ , 300 MHz, ppm): 18 CH ₃ = 0.85 (s) -19 CH ₃ = 1.20 (s) -thioketal = 6.83 (m).

Step B.

21-Acetoxy-3,3 - [(1,2-ethane-diyl) -bis (thio)] - pregna4,9 (11), 16-trien-20-one

About 9.5 mL of the 21-bromo derivative of Step A was concentrated to half volume in methylene chloride solution, 4 mL of dimethylformamide was added and the methylene chloride residue was distilled off. 0.8 g of potassium acetate, 0.08 ml of acetic acid and 0.04 ml of water are then added to the resulting suspension under an inert gas atmosphere and at a temperature of about 25 ° C. The reaction mixture was stirred at 25 ° C for 1 hour, then heated at 60 ° C for 1 hour and then slowly diluted with water (1.4 ml). The mixture was cooled to 20 ° C, the crystals separated, washed with water / dimethylformamide and dried to give 1.54 g of the title compound, which is identical to the compound of Example 3, Step D and can be purified as described therein. .

Step C

21-Acetoxy-4,9 (ll), 16-triene-3,20-dione

HU 215 852 Β

The title compound was prepared in the same manner as in Example 3, Step E.

Example 6

21-Acetoxy-pregna-4,9 (11), 16-triene-3,2-dione

The step

20-Chloro-3,3 - [(1,2-ethanediyl) bis (thio)] - 21 -hydroxy-4,9 (ll), 17 (20) -triene

Toluene (100 mL) and the compound of Example 1 (6 g) were stirred under an inert gas atmosphere, cooled to -20 ° C, and diisobutylaluminum hydride (38 mL) was added slowly. After stirring for 1 hour, methanol (3 mL) and water (50 mL) were added slowly. After stirring for a further 30 minutes, it was diluted with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness. The residue was taken up in isopropyl ether (20 mL), cooled in ice, filtered, and dried. 5.113 g of the title compound are obtained. Melting point: 198 ° C.

NMR (CDCl 3, 300 MHz, ppm): 18 CH ₃ = 0.88 and 0.90 - 19 CH ₃ = 1.18 (s) - H 2 = 5.40 (m) and

5.49 (m) - S-CH ₂ -CH ₂ -S = 3.2-3.4 H ₄ = CH ₂ OH - 4.19 (m) - 4.27 (dd) and 4.40 (d) dd).

Step B.

20-Chloro-3,3 - [(1,2-ethane-diyl) -bis (thio)] - pregna4,9 (11), 17 (20) -triene-21-ol g. of dimethyl sulfoxide (3.3 ml) and triethylamine (3.3 ml) were stirred at room temperature under an inert gas atmosphere. After 15 minutes, 1.47 g of pyridine / SO ₃ complex is slowly added at 20-22 ° C. After stirring for 16 hours at this temperature, the mixture was poured into a mixture of 15 ml of 2N hydrochloric acid and 20 ml of ice-cold water and stirred for 30 minutes. Insoluble matters are removed, washed with water and taken up in methylene chloride. The organic solution was dried and the solvent removed. The residue was eluted on silica gel with cyclohexane / ethyl acetate 8: 2 and recrystallized from 5 ml of isopropyl ether. 0.622 g of the title compound is obtained. Melting point: 230 ° C.

NMR (CDCl ₃ , 300 MHz, ppm): 18 CH ₃ = 0.99 (s), 1.08 (s) - 19 CH ₃ = 1.20 (s) - H 4 = 5.44 (m) - _{s-CH2 -CH2} -S = 3.2-3.4 (m) - H ₄ 5.52 (s) C7 / O = 9.73 (s), 9.91 (s) - H ₁₆ and other protons, 40-2.95 (m).

Step C

21-Acetoxy-3,3 - [(1,2-ethanediyl) bis (thio)] pregna4,9 (11), 16-trien-20-one ml dimethylsulfoxide and 0.7 g sodium acetate was stirred under an inert gas atmosphere, the mixture was heated to 60 ° C, and 1.2 g of the compound of Step B was added slowly. After stirring for 3 hours at 70 ° C, the reaction mixture was cooled, treated with 20 ml of saturated sodium chloride solution and stirred for 30 minutes. The reaction mixture was separated and the residue was washed with water and taken up in methylene chloride. It is dried and the solvent is removed. The residue was eluted on silica gel with cyclohexane / ethyl acetate 8: 2. 0.89 g of the title compound is obtained, which can be recrystallized from isopropyl ether. Melting point: 183 ° C.

NMR (CDCl ₃ , 300 MHz, ppm): 18 CH ₃ = 0.85 (s) -19 CH ₃ = 1.19 (s) -H _n = 5.45 (d) S-CH ₂ -CH ₂ - S = 3.2-3.4 - H ₄ = 5.50 (s) - acetyl CH ₃ = 2.19 (s) - CH ₂ 21 = 4.91 (d, J = 16), 5.06 ( d, J = 16).

Step D.

21-Acetoxy-pregna-4,9 (11), 16-triene-3,20-dione The title compound was prepared from Step C as in Example 3, Step E.

Example 7

Benzyl-20-chloro-3,3 - [(1,2-ethanediyl) bis (oxy)] pregna-4,9 (ll), 17 (20) -triene-21-oate

Zinc powder (3.02 g) was added under stirring to 20 ml of tetrahydrofuran under stirring and then 1.9 ml of titanium tetrachloride was added slowly at -15 to 20 ° C. The mixture was stirred for 15 minutes at -15 ° C, followed by 3.8 g of 3,3 - [(1,2-ethanediyl) bis (oxy)] androst-4,9-diene 17 and 2 A solution of benzyl trichloroacetate (5 mL) in tetrahydrofuran (15 mL) was added slowly at -20 ° C. After stirring for 10 minutes at -20 ° C, the mixture is allowed to warm to 20 ° C and after 1.5 hours 150 ml of water / pyridine 4: 1 are added at 10-15 ° C. The mixture was stirred for 1 hour and then poured into a mixture of 2 g of acetic acid, 2 g of potassium acetate and 10 ml of water. The reaction mixture was extracted with ethyl acetate, washed with water, dried and the solvent removed. 4.1 g of the title compound are thus obtained in the form of a mixture of two isomers.

IR (CHCl ₃ ): 1649-1607 (C = C), 1713 (CO), 1598-1493 (aromatic) cm ^-1 .

NMR (CDCl3, 400 MHz, ppm):

CH ₃ = 0.98-1.03, 19 CH ₃ = 1.21-1.22, -CO ₂ CH ₂ = 1.33-1.34 and 4.2-4.35, ketal = 3.95 , H ₆ -H _n = 5.40-5.55.

Claims (7)

PATENT CLAIMS Pregna-4,9 (II), 17 (20) -trien-3-one derivatives of the general formula (1) Fish means chlorine or bromine, R is C 1-6 alkyl or C 7 -C 15 aralkyl, K is an oxo protecting group of formula (a), (b) or (c), n is 2 or 3, and the wavy bond represents the possible isomeric forms and mixtures thereof. Compounds of general formula (1) according to claim 1, wherein Fish means chlorine, R is C 1-3 alkyl, K is a group of formula (c), n is 2 or 3. HU 215 852 Β 3. Methyl 20-chloro-3,3 - [(1,2-ethanediyl) bis (thio)] pregna-4,9 (11), 17 (20) -triene-21-olate. 4. A process for the preparation of pregna4,9 (11 L), 17 (20) -triene-3-one derivatives of the formula (I): Fish means chlorine or bromine, R is C 1-6 alkyl or C 7 -C 15 aralkyl, K is an oxo protecting group of formula (a), (b) or (c), n is 2 or 3, and the wavy bond represents the possible isomeric forms and mixtures thereof, characterized in that a compound of formula (II) is treated with acetic anhydride in the presence of an acid hydrolyzing agent, the 3-oxo group of the resultant compound of formula (III) is reacted with a diol of the formula HO- (CH ₂ ) _n -OH, HO- (CH ₂ ) _n -SH or HS- (CH ₂₎ ) with a dithiol of the formula _n -SH, wherein n is as above, is selectively protected, and the resulting compound of formula IV, wherein K is as defined above, is reacted with a compound of formula Hal ₃ C-CO ₂ R Hal and R are as defined above, in the presence of zinc and a Lewis acid. The process of claim 4, wherein the 3-oxo group of the compound of formula (III) is protected with a dithiol of the formula HS- (CH ₂ ) _n -SH, wherein n is 2 or 3, and the resulting The compound of formula IV is reacted with a compound of formula C ₃ C-CO ₂ R in which R is C 1-3 alkyl. The process according to claim 4 or 5, characterized in that - para-toluenesulfonic acid as the strong acid in the reaction of the compound of formula II with acetic anhydride, - formic acid as an acid hydrolyser, - ethanedithiol in the presence of a catalytic amount of concentrated hydrobromic acid or hydrogen chloride to protect the 3-oxo group of the compound of formula (III), - The titanium tetrachloride is used as Lewis acid. 7. A process according to any one of claims 1 to 3, wherein ethanethiol is used to protect the 3-oxo group of the compound of formula (III) and the compound of formula (IV) is reacted with methyl trichloroacetate.