CS200507B2 - Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4- genon-3-ones - Google Patents

Description

BACKGROUND OF THE INVENTION This invention relates to a process for the preparation of 17- (3-R 2 -oxypropyl) -17 H -oxy-4-gonen-3-ones

where it means

R1 is a hydrogen atom, an organic acid residue of up to 3 carbon atoms or a nitro group.

R @ 2 is hydrogen, alkyl of up to 2 carbon atoms, aralkyl of up to 19 carbon atoms, the remainder of the organic acid of up to 12 carbon atoms or nitro.

R3 is methyl or ethyl,

R6 is hydrogen or methyl,

R 5 is an alkyl group of up to 4 carbon atoms and

R6 is a hydrogen atom or a methyl group at the a position.

Suitable organic acid residues are those derived from non-toxic acids, which are generally derived in particular from alkanoyl acids having 1 to 12 carbon atoms, in particular 2 to 8 carbon atoms, for example derived. from a monohydric alkanoylic acid such as formic, acetic, propionic, butyric, isobutyric, α-ethylbutyric, pivalic, valeric, α-ethylvaleric, trimethylacetic, enanthic or caprylic acid or derived from a cyclic acid, in particular a cycloaliphatic acid such as cyclopropylideneacetic acid, cyclobutylcarboxylic cyclopentylcarboxylic, cyclopentylacetic, 3-cyclopentylpropionic, cyclohexylcarboxylic or also derived from carbocyclic aryl or arylic acid such as benzoic, 2-, 3- or 4-methylbenzoic acid.

Since the chemical nature of the acyl group is not relevant to the compounds produced by the process of the invention, unless the acyl group is toxic or forms an ester with the primary hydroxyl group, other aliphatic and aromatic substituted and unsubstituted mono-, di- and polybasic carboxylic acids, saturated or unsaturated aliphatic, arylaliphatic and aromatic carboxylic acids with up to 12 carbon atoms, but in particular up to 8 carbon atoms

Mention may be made, for example, of undecylic acid, dodecanoic acid, 3-cyclohexylpropionic acid 2,3-, 2,4-, 2,6-, 3,4- and 3,5-dimethylbenzoic acid, ethylbenzoic acid, naphthoic acid, 3-methyl-naphthoic acid. -phenylpropionic, diphenyl acetic and n-naphthylacetic or dibasic alkarioyl acids, for example oxalic, maleic, fumaric, fantaric, malonic, glutaric, n-methylglutaric, 3-methylglutaric, R, 3-dimethylglutaric, adipic, piperacic, adip, dibasic aromatic acids capable of forming internal anhydrides such as phthalic acid, carbamic acids such as carbamic acid, phenylcarbamic acid, n-butylcarbamic acid, dimethylcarbamic acid, diethylcarbamic acid and allophanic acids or heterocyclic acids such as acid

3-furylcarboxylic, pyrrolecarboxylic, 3-pyrrolidinopropionic, N-methylpyrrolidino-2-carboxylic, 6-hydroxyindolyl-3-acetic, N-methylmorpholino-2-carboxylic and pyrrole-2-carboxylic or sulfonic acids of 1 to 12 carbon atoms , such as alkanesulphoric acids, for example methanesulfonic acid, and arylsulfonic acids, for example benzenesulfonic and p-toluenesulfonic acids.

The acyl radicals of the invention may be substituted with one or more substituents.

Optional substituents include, but are not limited to, hydroxy, halogen, alkoxy, acyloxy, sulfoinyloxy, amido, sulfate, nitro, mercapto, and cyano, for example, glycolic, lactic, citric, tartaric, gluconic, maleic, and maleic, salicylic or amino acid residues such as glycine, aminopropionic acid, diglycolamine and triglycolamine, methylglycine, dimethylglycine, diethylglycine, p-aminosalicylic acid, p-aminobenzoic acid, ethylmercaptoacetic acid, benzylmercaptoacetic acid, chloroacetic acid, trifluoroacetic acid, trifluoroacetic acid, trichloroacetic acid, trichloroacetic acid, trichloroacetic acid 3,4-trimethoxybenzoic, phenoxyacetic and α-naphthyloxyacetic.

Particularly suitable are dibasic saturated and unsaturated carboxylic acids.

The salts are derived from the respective hemiacylates of these dibasic acids. Suitable cations are, in particular, the alkali metals sodium and potassium as well as ammonium. However, divalent alkaline earth metals such as calcium are also suitable, with 2 mol equivalents of hemiacylate per mole equivalent of calcium.

Suitable alkyl radicals R @ 2 are methyl and ethyl.

Alkyl R 5 means radicals having up to 4 carbon atoms, such as methyl, ethyl, propyl, n-butyl, isobutyl and tert-butyl.

The compounds obtainable by the process according to the invention either have pharmacologically valuable properties themselves or are intermediates for the production of well-known drugs. Thus, for example, 17- (3-hydroxypropyl) -1H-3-hydroxy-7α-thioacetyl-4-androsten-3-one is advantageously useful as an intermediate for the production of the known aldosterone blocking agent, spironolactone [3- (17β) lactone]. -hydroxy-7'-thioacetyl-3-oxo-4-androsten-17'-yl] propionic acid].

The compounds obtainable by the process according to the invention also act as aldosterone antagonist-type diuretics, i.e.. by reversing the effect of desoxycorticosterone on sodium and potassium excretion. Compounds such as 17β-hydroxy-17β- (3-hydroxypropyl) -7 α-thioacetyl-4-androsten-3-one, 17β-hydroxy-17β- (3-hydroxyproyl) -7β-ethylthio -4-androsten-3-one, 17β-acetoxy-17 '- (3-acetoxypropyl) 17α-thioacetyl-4-androsten-3-one, 17β-hydroxy-17' - (3-acetoxypropyl) -7 ' -thioacetyl-6α-methyl-4-androsten-3-one, 17β-hydroxy-17- (3-hemisuccinyloxypropyl) -6-methyl-4,6-androstadien-3-one potassium salt and sodium salt 17 Β-hydroxy-17- (3-hydroxysuccinyloxypropyl) -4,6-androstadiene-3-one exhibit in the Hollmann test model [G. Hollmann et al. Tubulare Wirkungen and Renale Elimination of Spirolactonen, Naunyn-Schmiedebergs Arch. Exp. Path Pharmac 247 (1964) 419, P. Marx, Renale Wirkungen des d-Aldosterons and Seines Antagonist Spironolacton, Diss Med Fak FU Berlin 1966] surprisingly higher effect than known similar compounds (for example Kalium-Canrenoat).

The compounds of the formula I are prepared according to the invention in that Δ ^{46 6} -unsaturated 3-ketogonadienes of the formula II,

where

R 1, R 2, R 3, R 4 are as defined above and R 5 is hydrogen or methyl, reacted with a thioalkanoic acid of up to 4 carbon atoms in a protic organic solvent or a mixture of such solvents, optionally in the presence of a solvent to aid dissolution; optionally etherifying, esterifying and optionally hemiacylates of formula III,

where

R3, R4, R5 are as defined above,

R 6 is a hydrogen atom or a methyl group in the "-" position and n is 1 to 3, to be converted to their salts.

A particular variant of the process according to the invention is that in the case where R @ 2 is a dibasic acid residue, the hemiacylate is converted into an ammonium salt, an alkali metal salt or an alkaline earth metal salt.

For the preparation of the compounds of the formula I which contain, in the 7-position, the "S" -CO-R 5 group with the meaning of R 5 as mentioned above, the starting material of the formula II is dissolved in a protic solvent or mixture thereof. HS-COR 5, wherein R 5 is as defined above, and the reaction mixture is heated to a temperature between room temperature and the boiling point of the solvent. Suitable solvents are methanol, acetone, tetrahydrofuran or mixtures thereof. Optionally, solvent-assisted solvents such as diisopropyl ether, benzene and heptane do not interfere with the reaction.

If it is expedient to protect free hydroxyl groups, nitryloxy groups may be introduced, for example, according to the method described in DOS No. 1,618,998.

If the compounds of the formula I contain esterified hydroxyl groups, for example protecting groups which have been introduced during the manufacturing process, the ester linkages can be hydrolyzed by known methods. Suitably, the nitryloxyester groups are reduced to a hydroxyl group by zinc in acetic acid solution.

If the free hydroxyl group is to be etherified, such as the primary hydroxyl group on the 17α-propyl moiety, known methods can be used. The etherification is preferably carried out with an appropriate alkyl halide. Suitable halides are chlorides, bromides and especially iodides. For example, the hydroxy compound is dissolved in a polar solvent and heated in the presence of a base with an alkylating agent to temperatures ranging from room temperature to 100 ° C. Suitable bases are, for example, barium oxide, sodium hydride, potassium carbonate and alkali metal alcoholates such as sodium ethylate. Suitable polar solvents are dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, ketones such as acetone and methyl isobutyl ketone, as well as alcohols such as ethanol, butanol, tert-butanol.

The esterification of the primary hydroxy or hydroxypropyl group is carried out by known methods. A suitable method is, for example, reaction with an acid anhydride or acid halide in the presence of a tertiary amine, for example pyridine, collidine, triethylamine or 4-dimethylaminopyridine at least at room temperature. The primary hydroxy group can also be esterified with an acid anhydride in the presence of a strong acid such as p-toluenesulfonic acid, or the appropriate acid and trifluoroacetic anhydride at room temperature.

If the free hydroxyl group, such as the primary hydroxyl group on the 17α-propyl moiety, is to be partially esterified, then known methods can be used herein. Especially suitable is the esterification of the heavy metal salts of the corresponding acid, for example lead acetate or lead ethoxyacetate, in the presence of an appropriate acid anhydride, for example acetic anhydride or ethoxyl acetic anhydride, at temperatures around room temperature.

For the production of compounds of formula I in which R and / or R represent the residue of an organic acid, are reacted 17/3 -hydroxy-17 "- (3-hydroxypropyl) -Δ ⁴ -3-keto steroids already substituted on the ring B or A ⁴⁶ -3-ketosteroids with an alkanoic anhydride, wherein the primary hydroxyl group is esterified first and then the tertiary 17/3 hydroxyl group is esterified after a prolonged reaction time or at an elevated temperature. To this end, the starting steroid is expediently dissolved in a basic solvent such as pyridine, piperidine, collodine, triethylamine or lutidine, and the corresponding acid anhydride is added. The addition of an esterification catalyst, such as dimethylaminopyridine, is also favorable for esterification.

The primary hydroxyl group is esterified after only a short time, i.e. after 2 to 5 hours, while esterification of the tertiary hydroxy group requires additional esterification times. The reaction can naturally be accelerated by heating, for example by heating up to the boiling point, while reducing the reaction time to several hours.

200307 .7

The process according to the invention can also be carried out by first esterifying the primary hydroxy group with one acid and then the tertiary hydroxy group with the other acid. Esterification of the primary hydroxy group can also be accomplished by simply heating the 17α- (3-hydroxypropyl) compound with an appropriate thioalkanoic acid, such as thioacetic, thiopropionic or thiobutyric acid.

The process may also be conducted so that starting from ⁴ · Δ ^{6-unsaturated} steroid of formula II, wherein R and R is hydrogen are prepared by first a diester, the primary acyl group is de-esterified by known methods and is coupled with thioalkanová acid.

The saponification is expediently carried out under mild conditions, such as methanolic cold potassium hydroxide solution.

However, it is also possible, in addition to the introduction of the 7-acylthio group, to esterify simultaneously the primary 23-hydroxyl group. To this end, the reaction is carried out with the appropriate thioacid in the heat without the use of an additional solvent.

If the primary 23-hydroxyl group has been esterified with a dibasic acid, the hemiacylate can be converted to the corresponding alkali metal salt by reaction with, for example, sodium or potassium methylate - in a methanol solution. For the preparation of the ammonium salt. a solution of ammonia in methanol is expediently used.

The reaction products of formula (L) are separated and purified, for example by chromatography and / or recrystallization, by known methods, such as precipitation, filtration or extraction.

For example, the starting ^46- unsaturated 3-ketoandrostadiene can be obtained by first preparing from 3-keto-4-androsten-17-one 17 (3-hydroxy-17a- (-) - according to the method described in DOS No. 2,327,448). 3-hydroxypropylJ-4-androstene and then introducing a double bond Δ ^6, for example as described by Agnello et al., J. Amer. Soc. 82 (1960) 4293rd

Starting 17 (3-hydroxy-17a- (3-hydroxypropyl) -18-methyl-4,6-estradien-3-one) can be prepared as follows:

To a suspension of 6.85 g of potassium tert-butylate in 32 ml of absolute tetrahydrofuran is added 50 g of 3-methoxy-18-methyl-1,3,5 (10) estratrien-17-one [C. Rufer et al., Liebigs Ann. Chem. 732, 1 (1971)] and a solution of 1.7 ml of propargyl alcohol in 3.5 ml of tetrahydrofuran is added dropwise such that the internal temperature does not exceed 35 ° C. It is stirred for 3 hours at 35 degrees Celsius and the reaction mixture is acidified with 13 ml of 20% sulfuric acid to pH 3 and stirred for a further 10 minutes at reflux. The reaction mixture was poured into ice water and the precipitate was filtered off. It is taken up in ethyl acetate, washed with water, dried and evaporated. 5.5 g of 17 (3-hydroxy-17a- (3-hydroxypropinyl) -3-methoxy-18-methyl-1,3,5 (10) estratriene) are obtained.

A solution of 5 g of 17 (3-hydroxy-7, α- (3-hydroxypropinyl) -3-methoxy-18-methyl-1,3,5 (10) -estratriene in 50 ml of tetrahydrofuran is shaken with 500 mg of palladium on calcium carbonate (5%) under hydrogen at room temperature and atmospheric pressure until the uptake of hydrogen was complete, then the catalyst was filtered off and the filtrate was evaporated to give 4.8 g of 17 (3-hydroxy-17-) - (3-hydroxy). oxypropyl) -3-methoxy-18-methyl-1,3,5 (10) -estratriene.

A solution of 5 g of 17 (3-hydroxy-17a- (3-hydroxypropyl) -3-methoxy-18-methyl-1,3,5 (10) -estratriene in 200 ml of absolute tetrahydrofuran is mixed with liquid ammonia at -60 ° C. and then add 5 g of lithium in small pieces

2.5 hours at -60 [deg.] C. and then quenched by the dropwise addition of ether to color. The ammonia is then evaporated, the residue is taken up in ether and washed with chloride solution. sodium to neutral, dried and _; evaporate. The residue was dissolved in 150 ml of methanol and 65 ml of methylene chloride and heated to boiling with 15 ml of 3 N hydrochloric acid for 1 hour. After cleavage of the enol ether, the solution is concentrated, the residue is taken up in methylene chloride and the solution is washed neutral with sodium bicarbonate solution, dried and evaporated. 2 g of 17 (3-hydroxy-17a- (3-hydroxypropyl) -18-methyl-4-estren-3-one) are obtained.

A solution of 2 g of 17? - (3-hydroxypropyl) -18-methyl-17 (3-hydroxy-4-estren-3-one, 1.35 g of chloroaniline and 0.03 g of p-toluenesulfonic acid in 200 ml of xylene is added It was then evaporated in vacuo and the residue purified by silica gel column chromatography to give 140 mg of 17 (3-hydroxy-17a- (3-hydroxypropyl) -18-methyl-1-4). 6-estradien-3-one in the form of an amorphous substance, UV: δ 285 = 22 000 (methanol).

Starting 17 (3-hydroxy-17.a- (3-hydroxypropyl) -4,6-estradien-3-one) can be prepared as follows:

To 900 ml of liquid ammonia is added at -60 ° C a solution of 10 g of 17- (3-hydroxypropyl) -3-methoxy-1,3,5 (10) -estratien-17 (3-ol [GEArth et al. , J, Med. Chem., 6, 618 (1963)] in 400 ml of absolute tetrahydrofuran, then 10 g of lithium are added in small portions, then stirred at -60 ° C for 2.5 hours. The residue is taken up in ether, washed with sodium chloride solution until neutral, dried and evaporated, the residue is dissolved in 300 ml of methanol and 159 ml of methylene chloride and heated to boiling with 30 ml of 3 N hydrochloric acid for 1 hour. concentration of the solution is taken up in methylene chloride, washed neutral with sodium bicarbonate solution and water, dried and evaporated to give 7.1 g of 17α- (3-hydroxypropyl), 17i (3-hydroxy-4-estren-3-one), m.p. 166-167 ° C (isopropyl ether / methylene chloride), UV: ε24ε = 17,100 (methanol).

A solution of 4.0 g of 17- (3-hydroxypropyl) -17 / 3-hydroxy-4-estren-3-one, 3.3 g of chloranil and 0.05 g of p-toluenesulfonic acid in 400 ml of xylene was heated for 1 hour. to boil. It was then evaporated in vacuo and the residue was purified by silica gel gradient elution chromatography. There were obtained 350 mg of 17 (3-hydroxy-17- (3-hydroxypropyl) -4,6-estradien-3-one, m.p. 193-194.5 ° C (acetone / hexane), UV = 26 900 ( methanol).

The pharmacologically active compounds of the formula I can be used for pharmaceuticals, in particular for oral administration, by known methods.

The doses of the compounds of formula I in humans are 20 to 500 mg / day.

The compound 17a- (3-hydroxypropyl) -17β-hydroxy-7H-thioacetyl-4-androsten-3-one is useful as an intermediate for the preparation of my prior art ^. spirono-lactone. To this end, 17 '-( 3-hydroxypropyl) -17 ' -hydroxy-17 ' -thioacetyl-4-androsten-3-one is oxidized to spirolactone by known chromic acid methods, as follows:

0.5 g of 17? - (3-hydroxypropyl) -17? -Hydroxy-7? -Thioacetyl-4-androsten-3-one was suspended at 0 ° C in 10 ml of acetone. To this suspension was slowly added dropwise 0.52 ml of Jones reagent so that the temperature did not exceed 5 ° C. Stir 1 hour at 0-5 ° C. Excess Jones reagent is destroyed with methanol, precipitated chromium salts are filtered off, the filtrate is concentrated to dryness and recrystallized by addition of methanol. After aspiration and drying, 0.38 g of 3- (17β-hydroxy-7'-thioacetyl-3-oxo-4-androsten-17α-yl) propionic acid lactone, m.p. 202 DEG-205 DEG C., is obtained.

The process according to the invention is explained in more detail in the Examples below.

Example 1 g of 17- (3-hydroxypropyl) -1 H -hydroxy-4,6-androstadien-3-one was dissolved in 5 ml of methanol and 0.43 ml of thioacetic acid was added while warm. The reaction mixture is then kept at reflux for 1 hour. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was recrystallized from acetone. The crystals are aspirated and dried. 0.75 g of 17- (3-hydroxypropyl) -17H-miydroxy-7'-thioacetyl-4-androsten-3-one is obtained, m.p. 187-192 ° C, UV: ε239 = 18 400.

Example 2

3.4 g of crude 4,7 '-( aminomethylidin-5-cyano-17H-nitryloxy-17 '-( 3-nitryloxypropyl) -5,3-androstan-3-one are heated in 100 ml of 1 N acid The reaction mixture was cooled, the resulting 4α, 7α-carbonyl-5-cyano-17β-nitryloxy-17β- (3-nitryloxypropyl) -5β-androstan-3-one was filtered off with suction. , washed with water and dried in vacuo.

Dissolve 2.1 g of sodium in 200 ml of ethanol, add 3 g of 4 ', 7'-carbonyl-5-cyano-17,5-nitryloxy-17' - (3-nitryloxypropyl) -5 / 3-androstane-3 and heated at reflux for 23 hours. The solution was concentrated in vacuo, poured onto ice and acidified with sulfuric acid. The resulting product is filtered off with suction, washed with water, dried and recrystallized from methanol.

1.7 g of 17β-nitryloxy-17- (3-nitryloxypropyl) -3-oxo-4-androstene-7-carboxylic acid ethyl ester of melting point 178-180 ° C are obtained.

In order to reduce the ester thus obtained, 1.6 g of the ester in 10 ml of tetrahydrofuran and 10 ml of glacial acetic acid are stirred

3.5 g of zinc dust for 10 minutes at 0-5 C. The zinc dust is filtered off, the filtrate is concentrated in vacuo and poured into ice water. The precipitated 17β-hydroxy-17α- (3-hydroxypropyl) -3-oxo-4-andr-ostene-7'-carboxylic acid ethyl ester is filtered off with suction and recrystallized from acetone-hexane. Melting point: 152-153.5 ° C.

Example 3

4a, 7a-Carbonyl-5-cyano-17β-nitryloxy-17- (3-nitryloxypropyl) -5 (3-androstan-3-one) was converted to sodium methyl ester 17 in a manner similar to that described above. The p-nitryloxy-17- (3-nitryloxypropyl) -3-oxo-4-androstene-7α-carboxylic acid and the protecting groups were removed by reduction.

There was obtained methyl 17 [beta] -hydroxy-17 [alpha] - (3-hydroxypropyl) -3-oxo-4-androstene-7 ' -carboxylic acid methyl ester of melting point 181 DEG-183 DEG.

Example 4

To 1 g of 17 ₍ 3-hydroxy-17a- (3-hydroxypropyl) -7H-acetylthio-4-androsten-3-one in 20 ml of dimethylformamide is added 1.2 g of lead ethoxyacetate and 10 ml of ethoxyl acetic anhydride and left to stand 68 hours at room temperature, precipitated in ice water, filtered off with suction, washed with water and dried, and recrystallized twice from acetone / hexane to give 790 mg of 17/3-hydroxy-17- (3-ethoxyacetoxypropyl) -7'-acetylthio-4. m.p. 130-131 ° C.

EXAMPLE 5 g of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-androstadiene-3-one is heated in 8 ml of methanol with 1 ml of thiopropionic acid.

1.5 hours under reflux. It is then evaporated in vacuo and the residue is recrystallized from acetone / hexane.

There were obtained 17β-Hydroxy-17α- (3-hydroxypropyl) -7, α-propionylthio-4-androsten-3-one, m.p. 165-167 ° C.

Example

EXAMPLE 11 g of 17β-nitryloxy-17, .alpha .- (3-nitryloxypropyl) -4,6-androstadiene-3-one was heated to reflux in 10 ml of methanol and 2 ml of thioacetic acid for 1.5 hours. It is then evaporated in vacuo and the residue is recrystallized from acetone / hexane. 850 mg of 7α-acetylthio-17- (3-nitryloxy-17a- (3-nitrylolxypropyl) -4-androsten-3-one, m.p. 178 DEG-179 DEG C.) are obtained,

Example 7

A solution of 1 g of 17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-4,6-estradien-3-one in 5 ml of methanol is heated with 1 ml of acid.

Pothioacetic 1/2 hour on the steam bath. The reaction mixture is concentrated under nitrogen and the residue is taken up in ethyl acetate. The solution was washed with sodium bicarbonate solution and water and evaporated. 0.35 g of 7α-acetylthio-17 (3-hydroxy-17- (3-hydroxypropyl) -18-methyl-4-estren-3-one, melting point 188-190 ° C (methanol), UV) is obtained. = £ 238 = 19,900 (methanol).

Example 8

According to Example 7, 17 (3-hydroxy-17? - (3-hydroxypropyl)) is obtained from 17? -Hydroxy-17? - (3-hydroxypropyl) -18-methyl-4,6-estradien-3-one by reaction with thiopropionic acid. -18-methyl-7α-propionylthio-4-estren-3-one, m.p. 179-188 ° C (methanol).

Example 9

To a solution of 400 mg of 7α-acetylthio-17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-4-estren-3-one in 3 mL of pyridine was added 200 mg of propionyloxyacetyl chloride and allowed to stand at room temperature for 24 hours. The reaction mixture was then poured into ice water and the precipitate was filtered off. The residue was dissolved in methylene chloride, washed, dried and evaporated. 320 mg of 2-acetylthio-1 H -hydroxy-18-methyl-17α- (3-propionyloxyacetoxypropyl) -4-estren-3-one are obtained as an oily substance, UV (methanol): δ 238 = 18 700. Example 10

To a solution of 800 mg of 17β-hydroxy-17β- (3-hydroxypropyl) -18-methyl-6- [3,7] (1-methylene-4-estren-3-one) in 5 mL of pyridine is added 400 g of acid chloride The reaction mixture was poured into ice water and worked up as described in Example 9. 730 mg of 17/2-hydroxy-17- (3-acetoxyaceto) was obtained, m.p. xypropyl) -18-methyl-6,7,7,3-methylene-4-estren-3-one as an oily substance, UV (methanol): δ 265 = 18 300.

250 mg of 7α-acetylthio-17 H -hydroxy-17α- (3-hydroxypropyl) -18-methyl-4-estren-3-one are dissolved in 2 ml of pyridine, 1 ml of acetic anhydride is added and allowed to stand at room temperature. at room temperature for 20 hours. Precipitation with ice water is then carried out, the substance is taken up in methylene chloride, the solution is washed, dried and evaporated. 180 mg of 7α-acetylthio-17β-hydroxy-17α- (3-acetoxypropyl) -18-methyl-4-estren-3-one is obtained, m.p. 85-90 ° C (hexane / methylene chloride), UV (methanol). ): ew ~ 18,400.

Example 12

According to the procedure of Example 11, 17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-6,7,7 (3-methylene-4-estren-3-one) is reacted with acetic anhydride and prepared. 17? -Hydroxy-17? - (3-acetoxypropyl) -18-methyl-6? 3,7-methylene-4-estren-3-one, m.p. 60-68 ° C (pentane), UV ( methanol): 263 263 = 18 300.

Example 13

To a solution of 5 g of 7α-acetylthio-17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-4-estren-3-one in 50 mL of absolute dimethylformamide was added 15 mL of methyl iodide and 18 g of barium oxide powder. The reaction is allowed to proceed at about 40 ° C with vigorous stirring. After 6 hours, the reaction mixture is taken up in methylene chloride and filtered from the residue. The organic phase was washed, dried and evaporated. The residue was purified by gradient elution. 2.3 g of 7α-acetylthio-17 (3-hydroxy-17α- (3-methoxypropyl) -18-methyl-4-estren-3-one) are obtained in the form of an oily substance, UV (methanol): £ 237 = 18,500. Example 14

To a solution of 1.4 g of triphenylchloromethane in 5 ml of absolute pyridine is added 1.62 g of 7α-acetylthio-17/3-hydroxy-17, α '(3-hydroxypropyl) -18-methyl-4-estren-3-oine and Allow to stand at room temperature for 3 days. The mixture was then poured into ice water, the precipitate was filtered off and washed with water until neutral. The residue was purified by gradient elution chromatography. 1.25 g of 7α-acetylthio-17 (3-hydroxy-18-methyl-17α- (3-triphenylmethoxypropyl) -4-estren-3-one) are obtained in the form of an oily substance, UV (methanol):

Λ £ 204 45,800 EA (221 14 300) (230 11 200) (238 18 100).

Example 15

A solution of 1 g of N-hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one in 5 ml of methanol was heated with 1 ml of thioacetic acid on a steam bath for 1/2 hour under a nitrogen atmosphere. The reaction mixture was evaporated under a nitrogen atmosphere and the residue was taken up in ethyl acetate. The solution was washed with sodium bicarbonate solution and water and evaporated. 0.4 g of 7? -Acetylthio-17? -Hydroxy-17? - (3-hydroxypropyl) -4-esten-3-orium is obtained, m.p. 177-179 ° C (acetone / hexane), UV: ε20β = 19 000 (methanol j.

Example 16

According to Example 15, 17β-hydroxy-17α- (3-hydroxypropyl) -7α- is obtained from 17β-hydroxy-17β- (3-hydroxypropyl) -4,6-estradien-3-one and thiopropionic acid. 164 DEG-175 DEG C. (acetone / hexane), UV: > = 18,800 (methanol).

Example 17

To a solution of 800 mg of 7α-acetylthio-17β-hydroxy-17- (3-hydroxypropyl) -4-estren-3-one in 5 mL of pyridine was added 400 mg of propionyloxyacetyl chloride and allowed to stand at room temperature for 24 hours. The reaction mixture was then poured into ice water and the precipitate was filtered off. The precipitate was dissolved in methylene chloride, washed, dried and evaporated. 650 mg of 7α-acetylthio-17β-hydroxy-17α- (3-propionyloxyacetyloxypropyl) -4-estren-3-one are obtained as an oily substance, UV (methanol): δ 238 = 18 700.

EXAMPLE 1 8 g of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-androstadiene-3-one are stirred in 20 ml of pyridine and 20 ml of ethyl mercaptan in a glass autoclave at 50 ° C for 20 hours. After cooling, 4 ml of triethylamine are added and stirred for a further 25 hours at 50 ° C. It is then poured into an ice saturated sodium chloride solution, the precipitated product is filtered off with suction and recrystallized from acetone and hexane. The 7α-ethylthio-17 (S-hydroxy-17α- (3-hydroxypropyl) -4-androsten-3-one) thus obtained has a melting point of 205-207 ° C.

Example 19

500 mg of 7α-acetylthio-17β-hydroxy-17α- (3-hydroxypropyl) -4-estren-3-one are dissolved in 2 ml of pyridine, 1 ml of acetic anhydride is added and allowed to stand at room temperature for 20 hours. The reaction mixture is then precipitated in ice-water, taken up in methylene chloride, washed, dried and evaporated. 375 mg of 7α-acetylthio-17 H -hydroxy-1 H- 5-acetoxypropyl 1 H -estren-3-one are obtained, m.p. 77-80 ° C (pentane / isopropyl ether), UV: 237 237-19000 ( methanol).

Example 20

0.5 g of 17? -Hydroxy-17? - (3-hydroxypienyl) -4,6-androstadiene-3-ol is stirred at boiling point in 10 ml of piperidine and 10 ml of butyl mercaptan in a glass autoclave and then left for 42 hours at room temperature. The reaction mixture was then evaporated in vacuo and the residue crystallized from acetone / hexane. There was obtained 17β-hydroxy-17β- (3-hydroxypropyl) -7α-butylthio-4-androsten-3-one, m.p. 196-205 ° C (dec.).

Example 21

To a solution of 500 mg of 7α-acetylthio-17β-hydroxy-17- (3-hydroxypropyl) -4-estren-3-one in 5 mL of absolute dimethylformamide was added 1.5 mL of methyl iodide and 1.8 g of powdered powder. barium oxide. With vigorous stirring, the temperature is allowed to slowly rise to 40 ° C with cooling. After 6 hours, the reaction mixture is taken up in methylene chloride and filtered from the residue. The organic phase is washed, dried and evaporated. The residue was purified by gradient elution chromatography. 270 mg of 7? -Acetylthio-17 H -hydroxy-17? - (3-methoxypropyl) -4-estren-3-one are obtained as an oily substance, UV (methanol):? 238 = 18 300.

Example 1 2

To a solution of 2.8 g (10 mmol) of triphenylchloromethane in 10 ml of absolute pyridine is added 3.2 g (8 mmol) of 7α-acetylthio-17'-hydroxy-17α- (3-hydroxypropyl) -4-estren-3-one and Allow to stand at room temperature for 3 days. The reaction mixture was then poured into ice water, the precipitate was filtered off and washed with water until neutral. The residue was purified by gradient elution chromatography. It is obtained

2.5 g of 7α-acetylthio-17 (3-hydroxy-17α- (3-triphenylmethoxypropyl) -4-estren-3-one as an amorphous substance, UV (methanol):

λ C 205 46,900 EA (222 14 500) (231 11000) 238 17 950.

Example 23

1.5 g 7a-acetylthio-17 (3-hydroxy-17a- ^(3! Hydroxypropyl) -4-estren-3-one are dissolved in 5 ml of pyridine and heated for 3 hours with 0.75 g of succinic anhydride under Ar The solution was poured into ice water acidified with sulfuric acid and extracted with ethyl acetate, washed with saturated sodium chloride solution until neutral, dried and evaporated to give a residue. acetylthio-17? -hydroxy-17? - (3-hydroxysuccinyloxypropyl) -4-estren-3-one, m.p. 168/169-170 ° C, UV: ε e = 19,500 (methanol).

Example 24

500 mg of the hemisuccinate produced according to Example 23 are dissolved in 15 ml of absolute methanol. The solution is adjusted to pH 8 with 5.5 ml of 0.1 N potassium methylate solution, concentrated in vacuo and precipitated with 200 ml of ether. The precipitated potassium salt is filtered off with suction, dissolved in methanol and purified by repeated precipitation with ether. 190 mg of amorphous 7'-acetylthio-17 (β-hydroxy-17 '' (3 hydroxy succinyloxypropyl) -4-estren-3-one are obtained in the form of the potassium salt, m.p. 150 DEG C. (dec.), UV (methanol). : ε239 = 11,200.

Example 25

500 mg of 17β-Hydroxy-17- (3-hydroxypropyl) -6-methyl-4,6-androstadien-3-one is stirred in 5 ml of thioacetic acid for 6.5 hours at 100 ° C. It was then diluted with ether, washed with water and saturated sodium bicarbonate solution, dried and evaporated. The residue was purified by preparative thin layer chromatography. There were obtained 330 mg of 7 «- acetylthio-17a- (3-acetoxypropyl) _{-17) of} 3-hydroxy-6-methyl-4-androsten-3-one as an oil. UV: 238 = 19 £ 200th

Example 26

To 1.0 g of N-hydroxy-17α- (3-hydroxypropyl) -6-methyl-4,6-androstadien-3-one in 10 ml of methanol was added 2 ml of water and 2 ml of thioacetic acid and stirred for 18 hours. hours at 50 degrees Celsius. It was then diluted with ether, washed with water and saturated sodium bicarbonate solution, dried and evaporated. After chromatography on silica gel, it is recrystallized from a mixture of diisopropyl ether and acetone. There are obtained 650 mg of 7α-acetylthio-17, 3-hydroxy-17α- (3-hydroxypropyl) -6α-methyl-4-androsten-3-one, m.p.

175.5 ° C, UV: £ 239 = 18,500.

Example 27

250 mg of 7α-α, cetylthlo-17β-hydroxy-17α- (3-hydroxypropyl) -6α-methyl-4-androsten-3-one were allowed to stand in 0.5 mL butyric anhydride in 1 mL of pyridine for 24 hours at room temperature. After precipitation in ice water, the precipitated oil is filtered off, taken up in ether, washed with water and dried. The evaporation residue was purified by preparative thin layer chromatography to give 210 mg of 7α-acetylthio-17α- (3-butyryloxypropyl) -17 / 3-hydroxy-6α-methyl-4-androsten-3-one as an oil , UV: £ 239 = 18,600.

Example 28

400 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -6-methyl-4,6-androstadiene-3-one is stirred in 4 ml of methanol with 0.8 ml of water and 0.8 ml of thiopropionic acid for 48 hours at 50 degrees This was further worked up as described in Example 3 and purified by preparative thin layer chromatography to give 210 mg of 17 (3-hydroxy-17α- (3-hydroxypropyl) -6α-methyl-7α-propionylthio-4-androstene-). 3-one, UV: £ 239 = 18,200.

Example 1 9

350 mg of 17 (3-hydroxy-17a- (3-hydroxypropyl) -6-methyl-4,6-androstadien-3-one) was heated under reflux in 3.5 ml of pyridine and 350 mg of succinic anhydride for 1 hour. The mixture is poured with stirring into ice-water, the precipitated oil is filtered off, taken up in methylene chloride, dried and evaporated, and the residue is chromatographed on silica gel to give 420 mg of 17H-hydroxy-6-methyl-17a- (3-hemisuccinyloixypropyl) -4. 6-androstadiene-3-one in the form of an amorphous substance, UV: £ 291-20,500.

Example 30

420 mg of 17β-hydroxy-6-methyl-17α- (3-hemisuccinyloxypropyl) -4,6-androstadiene-3-one are dissolved in 20 ml of absolute methanol and reacted with 6.4 ml of methanol. 1 N sodium methylate solution up to the point of equivalence. The reaction solution is precipitated in absolute ether, the precipitate is filtered off with suction, washed with ether and dried. 340 mg of 17 (3-hydroxy-6-methyl-17a- (3-hemisuccinyloxypropyl) -4,6-androstadiene-3-one) are obtained in the form of the amorphous potassium salt, m.p. 130 DEG C. (with decomposition). , UV: £ 291 = 21,300.

Example 31

As described in Example 29, reaction of 17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-4,6-estradien-3-one with succinic anhydride in pyridine affords 17β-hydroxy-17α- (3- 18-methyl-4,6-estradien-3-one in the form of an amorphous substance, UV: 234 234-2400 (methanol).

Example 32

As described in Example 30, from the 17β-hydroxy-17α- (3-hydroxysuccinoxyl 1β-18-methyl-4,6-estradien-3-one) the potassium salt was obtained as an amorphous substance, UV: ε235 = = 22,900 (methanol).

Example 33 g of 7α-acetylthio-11β-hydroxy-17α- (3-hydroxypropyl) -4-androsten-3-one was dissolved in 50 ml of pyridine in 200 ml, 4.5 g of succinic anhydride were added and heated to boiling for 30 minutes. After cooling, it is stirred in ice-water acidified with sulfuric acid, the precipitated product is filtered off with suction, washed neutral and dried, and recrystallized from a mixture of methanol and methylene chloride to obtain 10.4 g of 7α-acetylthio-17β-hydroxy-17α- ( 201 DEG-203 DEG C. (with decomposition), m.p. 201 DEG-203 DEG C. (decomposition): 3-hydroxysuccinyloxypropyl-4-androsten-3-one.

Example 34

1.1 g of the hemisuccinate produced in Example 33 are dissolved in 150 ml of absolute methanol and adjusted to pH 8 with 0.1 N potassium methylate solution in methanol. The solution is concentrated in vacuo, the concentrate is precipitated with ether and the potassium salt is filtered off with suction. After several precipitation, 850 mg of 7α-acetylthio-17β-hydroxy-17α- (3-hydroxysuccinylpropyl) -4-androsten-3-one are obtained in the form of the potassium salt with a decomposition temperature of 150 ° C.

EXAMPLE 3 5 g of 7'-acetylthio-17 (1-hydroxy-17'- (3-hydroxypropyl) -4-androsten-3-one are stirred in 4 ml of pyridine, 10 ml of dimethylformamide, 2 ml of acetic anhydride. and 100 mg of dimethylamino pyridine at room temperature for 72 hours, precipitated with ice water, washed with water and dried, and recrystallized from ether / pentane to give 17H-acetoxy-17α- (3-acetoxypropyl) -7α-acetylthio-4-andr osten-3-one, m.p. 110-112 ° C.

Example 36

0.64 g of 17? - (3-propionyloxypropyl) -17 (3-hydroxy-17? -Propionylthio-4-androsten-3-one [prepared from 2 g of 17? -Hydroxy-17? - (3-hydroxypropyl) -4] 6 -drostrostien-3-one in 5.4 ml thiopropionic acid with stirring and heating at 90 ° C under argon for 4 hours, evaporation in vacuo and chromatography of the residue on silica gel, eluting with hexane / ethyl acetate 1: 1, obtained 1.89 g of oily 17- (3-propionyloxypropyl) -17 (3-hydroxy-7α-propionyithio-4-androsten-3-one),

UV: esse-17200] was dissolved in 2.5 ml of pyridine, 1.25 ml of acetic anhydride and 60 mg of 4-dimethylaminopyridine were added and stirred at room temperature for 67 hours. Ice water was added, extracted with methylene chloride, the solution was washed with 1 N sulfuric acid and water and evaporated in vacuo. Purification of the residue by layer chromatography gave amorphous 17α- (3-propionyloxypropyl) -17 (3-acetoxy-7α-propionylthio-4-androsten-3-one, UV: ε238 = 17,800 (methanol)).

Example 37 (3-Hydroxy-17α- (3-acetoxypropyl) -7α-acetylthio-4-androsten-3-one [prepared from 2 g of 17α- (3-hydroxypropyl) -17 (3-hydrpxy-4,6-androstadiene) Of the 3-one by heating in 1.8 ml of thioacetic acid for 30 minutes at 90 degrees Celsius, then removing excess thioacetic acid under reduced pressure by distillation and chromatography of the residue to give 1.1 g of 17 (3-hydroxy-17 -). 135 DEG-140 DEG C. (decomposition)] was acetylated in analogy to Example 36. 17 .beta.-Acethoxy-17 .alpha .- (3-acetoxypropyl) was obtained. 17a-Acetylthio: 4-androsten-3-one, identical to the compounds produced in Example 35.

Example 38

150 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -6- (3,7 | (3-methylene-4-androsten-3-one) was heated in refluxing 2 ml of pyridine with 1 ml of acetic anhydride under argon for 8 hours. After working up as in Example 36, 17 (3-acetoxy-17a- (3-acetoxypropyl) -6,3,7 (3-methylene-4-androsten-3-one) is obtained, UV: esas = 18100 (methanol) .

Example 39

300 mg. 17 (3-Hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one was heated in boiling 2 ml of pyridine and 1 ml of acetic anhydride for 24 hours under reflux conditions. After work-up and chromatographic purification, 140 mg were obtained. 170-acetoxy-17a- (3-acetoxypropyl) -4,6-estraden-3-one; 100 mg of the thus obtained 17 (3-acetoxy-17a- (3-acetoxypropyl) -4,6-estradien-3-one) are dissolved in 1 ml of methanol and heated with 0.5 ml of thioacetic acid for 1 hour under reflux. After evaporation and chromatographic purification, 17β-acetoxy-17α- (3-acetoxypropyl) -7α-acetylthio-4-estren-3- m.p. 192-197 ° C (hexane / methylene chloride, UV: ε238 = 18,700 (methanol)).

Example 1 a d 4 0

5 mg of 17 (3-hydroxy-17a- (3-hydroxypropyl) -4,6-estradien-3-one) was heated in 2 ml of thiopropionic acid at 90 [deg.] C. under stirring under argon for 4 hours. The residue is chromatographed on silica gel with hexane / acetone (2: 1) to give 120 mg of 17- (3-propionyloxypropyl) -17β-hydroxy-7α-propionyl-thio-4-estren-3-one which is left as in Example 2, reacted with 1.2 ml of acetic anhydride in 2.4 ml of pyridine in the presence of 50 mg of dimethylaminopyridine for 67 hours at room temperature, and further worked up to give 17a- (3-propio200507 nyloxypropyl) - 17/3-acetoxy-7.alpha.-propionylthio-4-estren-3-one in the form of an amorphous substance, UV (methanol): ε238 = 18,500.

Example 41

100 mg of 17 (3-Hydroxy-17a- (3-hydroxypropyl) -7'-thioacetyl-4-androsten-3-one is stirred in 2 ml of pyridine with 2 ml of undecylic anhydride with addition of 30 mg of dimethylaminopyridine for 7 hours at 50 ° C. The reaction mixture is then poured into ice water, stirred with pentane and filtered off with suction, the residue is extracted with methylene chloride, washed with 1 N hydrochloric acid and water and the residue is concentrated to give 17 (3-hydroxy-17α- (3-undecyloxypr). opyl) -7α-thioacetyl-4-androsten-3-one in the form of an oil, UV (methanol)? 237 - 17 500.

Example 42 g of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-androstadiene-3-one is heated to boiling under argon atmosphere for 40 hours in 40 ml of pyridine and 20 ml of acetic anhydride. After working up and chromatography, 17, .beta.-acetoxy-17.alpha .- (3-acetoxypropyl) -4,6-androstadiene-3-one is obtained; 3 g of the diacetate thus obtained are dissolved in 12 ml of methanol and 12 ml of methylene chloride, cooled to 0 DEG C. and a solution of 0.18 g of potassium hydroxide in 6 ml of methanol is added. The mixture was stirred at 20 ° C for 10 hours under argon, neutralized with acetic acid and evaporated in vacuo. The residue was dissolved in methylene chloride, washed with water and evaporated. After stirring with isopropyl ether, 2.6 g of amorphous 17 (3-acetoxy-17a- (3-hydroxypropyl) -4,6-androstadien-3-one) was obtained;

g of the thus obtained 17β-acetoxy-17- (3'-hydroxypropyl) -4,6-androstadien-3-one is heated in 5 ml of methanol and 0.5 ml of thioacetic acid. 1 hour under reflux. Evaporation in vacuo and recrystallization from acton / hexane gave 17β-acetoxy-17α- (3-hydroxypropyl) -7α-acetylthio-4-androsten-3-one, m.p. 135-140 ° C.

Example 4 3 g of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one is reacted as described in Example 42 in 10 ml of pyridine with 5 ml of acetic anhydride to 17/3 -acetoxy-17a- (3-acetoxypropyl) -4,0-estradien-3-one; 1 g of the diacetate thus obtained is dissolved in 5 ml of methanol and 5 ml of methylene chloride, cooled to 0 DEG C. and stirred with a solution of 0.6 g of potassium hydroxide in 2 ml of methanol for 60 minutes at 20 DEG C. under an argon atmosphere. After neutralization with acetic acid, it is evaporated and worked up. After chromatographic purification, 0.8 g of 17β-acetoxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one is obtained; 0.5 g of the thus obtained 17β-acetoxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one is reacted in 3 ml of methanol and 0.5 ml of thioacetic acid. After working up and purification, 17β-acetoxy-17α- (3-hydroxypropyl) -7H-acetylthio-4-estren-3-one is obtained, m.p. 180 DEG-187 DEG C. (acetone / hexane), UV (methanol). : £ 238 = 18,300.

Example 1 4

1.5. g of 1 H -hydroxy-4- (3-hydroxypropyl) -4,6-androstadiene-3-one are dissolved in 5 ml of pyridine, 1.5 g of succinic anhydride are added and the mixture is refluxed for 1 hour under an argon atmosphere. After cooling, it is stirred into ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The acetate extract was washed with water until neutral, dried over sodium sulfate and evaporated in vacuo. 2 g of 17 are obtained ^! β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-androštadien-3-one as an amorphous substance, UV: δ 285 = 23,700.

Example 4 5

300 mg of the hemisuccinate prepared in Example 44 are dissolved in 15 ml of absolute methanol and the pH is adjusted to 8 with 5.5 ml of 0.1 N sodium methylate solution. The solution is concentrated in vacuo and precipitated in 200 ml of ether. The precipitated sodium salt is filtered off with suction, dissolved in methanol and reprecipitated in ether. 210 mg of 17β-hydroxy-17α- (3-hydroxy oxycinyloxypropyl) -4,6-androstadiene-3-one sodium salt, m.p. 120 ° C (dec.), UV: δ 285 = 24 100, are obtained.

Example 46

400 mg of the hemisuccinate prepared in Example 44 are dissolved in 20 ml of absolute methanol and the pH is adjusted to 8 with 5.4 ml of 0.1 N potassium methylate solution. After precipitation in ether as in Example 45, 285 mg of the potassium salt 1Z / J are obtained. m.p. 145 DEG C. (decomp.); hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-androstadiene-3-one;

Example 47

Analogously to Example 44, it was prepared by esterification of glutaric anhydride in pyridine followed by reaction with potassium methylate as in Example 46, 17 / S-hydroxy-17α- (3-hydroxyglutaryloxypropyl) -4,6-androstadiene-3-one potassium salt. mp 98 ° C (dec.).

Example48

A solution of 1 g of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one in 4 ml of pyridine was heated to boiling with 1 g of succinic anhydride for 1 hour under argon. Allow to cool and stir in ice water, acidify with dilute hydrochloric acid and extract with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate and evaporated to dryness. 1 g of crude 17β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one is obtained in the form of an amorphous substance, UV: εζδ4 - 26,800 (methanol).

Example 1 4 9

A solution of 500 mg of 17 / S-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one in 15 ml of absolute methanol is adjusted to pH 8 with 0.1 N sodium methylate solution using a pH meter, It is concentrated in vacuo and precipitated with 200 ml of ether. The sodium salt is filtered off with suction, dissolved in methanol and precipitated again with ether. 350 mg of 17H-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one sodium salt are obtained, UV: ε 285 = 25 900 (methanol).

Example50

A solution of 600 mg of 17 (3-hydroxy-17a- (3-hydroxy-oxysuccinylolxypropyl) -4,6-estradien-3-one in 30 ml of absolute methanol is adjusted to pH 8 with 0.1 N potassium methylate solution. of ether, as described in Example 45, 320 mg of 17β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one potassium salt is obtained,

UV: ε284 = 26,300 (methanol).

EXAMPLE 5 As described in Example 48, it is prepared by esterifying 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one with glutaric anhydride in pyridine followed by reaction with methylate Potassium salt of 17β-Hydroxy-η 7 - (3-hydroxyglutaryloxypropyl) -4,6-estradien-3-one in the form of an amorphous powder, UV (methanol): ε285-2400.

EXAMPLE 5 2 g of 17.alpha.-hydroxy-17.alpha .- (3-hydroxypropyl) -4,6-androstadien-3-one is heated in 350 ml of pyridine with 70 g of triphenylmethyl chloride on a steam bath for 40 minutes. The reaction mixture was cooled, poured slowly into 8 L of ice water, the precipitated substance was filtered off with suction, washed with water and dried. The crude product is chromatographed on silica gel and recrystallized from ether / pentane. 61.4 g of 17.beta.-hydroxy-17.alpha .- (3-triphenylmethyloxypropyl) -4,6-androstadien-3-one, melting at 168 DEG-169 DEG C., is obtained.

EXAMPLE 53 g 17- (3-Hydroxypropyl) -17 / 3-hydroxy-4,6-androstadiene-3-one is suspended in 15 ml of acetone and 6 ml of methanol, 1.29 ml of thioacetic acid is added and heated to 45 ml. minutes to boil. The work-up after completion of the reaction was carried out in a similar manner as in the example. 2.4 g of 17? - (3-hydroxypropyl) -17 (3-hydroxy-7? -Thioacetyl-4-androsten-3-one), m.p. 187-192 ° C, UV: ε239 = 18 400, are obtained.

Example 54

0.5 g of 17? - (3-hydroxypropyl) -17? -Hydroxy-4,6-androstadien-3-one is suspended in 2.5 ml of tetrahydrofuran and 1 ml of methanol and 0.22 ml of thioacetic acid is added. After heating under reflux for 1 hour, it was treated as in Example 1. 0.34 g of 17- (3-hydroxypropyl) -17? -Hydroxy-7α-thioacetyl-4-androsten-3-one, m.p. 187-192 ° C, was obtained. G, UV: ε239 = 18,400.

Example 5 5

To 1.5 g of 17β-hydroxy-17α- (3-hydroxypropyl) -6,7,7 (3-methylene-4-androsten-3-one in 5 ml of pyridine) was added 1.5 ml of acetic anhydride and stirred for 105 minutes at 22 [deg.] C. After treatment and trituration with helxane, 1.7 g of amorphous 17 [beta] -hydroxy-17 [alpha] - (3-acetylpropyl) -6 / 3,7, d-diethylene-4-androstene- 3-onu,

UV: ε268 = 18,300 (methanol).

Example 56

A solution of 0.75 g of 17? -Hydroxy-17? - (3-hydroxypropyl) -4,6-estradien-3-one in 15 ml of piperidine and 15 ml of ethyl mercaptan was stirred in a glass autoclave under argon at 50 ° C for 5 hours. and then left at room temperature for 50 hours. The solution was then concentrated in vacuo, the residue recrystallized from acetone / hexane to give 17β-hydroxy-17α- (3-hydroxypropyl) -7α-ethylthio-4-estren-3-one as an amorphous solid, mp 183 to 188 ° C (hexane / acetone), UV: ε239 = 18,900 (methanol). Example 57

According to the data of Example 56, 0.8 g of 17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-4,6-estraden-3-one is converted to 17β-hydroxy-17α- (3- hydroxypropyl) -7α-ethylthio-18-methyl-4-estren-3-one, which forms an amorphous substance, m.p. 190-198 ° C (hexane / acetone), UV: ε238-1870 (methanol). Example 58

To 500 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-androstadien-3-one was added 10 mg sodium methylate in 15 ml diethyl carbonate and heated under stirring at 140 ° C for 10 minutes under argon. It is then cooled, neutralized with acetic acid and evaporated in vacuo. After purification by layer chromatography, 400 mg of 17β-hydroxy-17α- (3-ethoxycarbonyloxypropyl) -4,6-androstadiene-3-one is obtained in the form of a colorless oil, UV: ε28 = 26100.

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of 17a- (3-R 2 -oxypropyl) -17 (3-R 1 -oxy-4-gonen-3-ones of the general formula I, Re is a hydrogen atom or a methyl group in the or position, characterized in that Δ ⁴ · ⁶ —unsaturated 3-ketogonadienes of the general formula II, where R1 is a hydrogen atom, an organic acid residue of up to 3 carbon atoms or a nitro group, R2 is hydrogen, alkyl of up to 2 carbon atoms, aralkyl of up to 19 carbon atoms, the remainder of the organic acid of up to 12 carbon atoms, or nitro, R 5 is methyl or ethyl, R 6 is a hydrogen atom or a methyl group, R 5 is an alkyl group of up to 4 carbon atoms and wherein R 1, R 2, R 3, R 6 are as defined above, and R 6 is hydrogen or methyl, reacted with a thioalkanoic acid of up to 4 carbon atoms in a protic organic solvent or mixture of such solvents, optionally in the presence of a solvent to aid dissolution etherify, esterify, and optionally hemiacylates of formula III, R 3, R 6, R 8 are as defined above, R 8 is a hydrogen atom or a methyl group in the a position and n is 1 to 3, are converted to their salts. 2. The method of item 1 for producing 17a- (3-R 2 -oxypropyl) -1 H -R 1 -oxy-4-gonen-3-ones R1 is a hydrogen atom or a residue of an organic acid having 3 carbon atoms, Ra is hydrogen, alkyl of up to 2 carbon atoms, aralkyl of up to 19 carbon atoms, or an organic acid residue of up to 12 carbon atoms, R3 is methyl or ethyl, R 6 is a hydrogen atom or a methyl group; R is alkyl of up to 4 carbon atoms, wherein the Δ ⁶ · ^{4-unsaturated} 3-ketogonadieny formula IIa About where R1, R2, R3 and R4 are as defined above, reacted with a thioalkanoic acid of up to 4 carbon atoms in a protic organic solvent mixture of such solvents, optionally in the presence of a solvent to aid dissolution and optionally etherification, esterification and optionally hemiacylates of formula IIIa, - (CKjrO-C- (CUkC-OH) Λ d 'A' O O S-CO-R * (1Na-Ί where n is 1 to 3) is converted to their salts. R 3, R 4 and R 5 are as defined above and