CS200508B2 - Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4,6-gonadien-3-ones - Google Patents

Description

R1 is hydrogen or an organic acid radical of up to 3 carbon atoms,

R @ 2 denotes hydrogen, an alkyl group of up to 2 carbon atoms, an aralkyl group of up to 19 carbon atoms or an organic acid residue of up to 12 carbon atoms,

R 3 represents a methyl or ethyl group and

R4 represents a hydrogen atom or a methyl group.

Possible acid residues are those derived from non-toxic acids which are especially derived from alkanoyl acids having 1 to 12 carbon atoms, in particular up to 8 carbon atoms, for example derived from monobasic alkanoylic acids, such as formic, acetic, propionic, butyric, isobutyric, .alpha.-ethylbutyric, pivalic, valeric, isovaleric, .alpha.-ethylviral, trimethylacetic, enanthic or caprylic acids, or derived from a cyclic acid, in particular a cycloaliphatic acid such as cyclopropylideneacetic acid, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopopentylacetic, derived from a carbocyclic aryl or aralkyl 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 having up to 12 carbon atoms, in particular up to 8 carbon atoms.

Mention may be made, for example, of undecylic acid, dodecanoic acid, 3-cyclohexyl, xypropionic acid, 2,3-, 2,4-, 2,6-, 3,4- and 3,5-dimethylbenzoic acid, ethylbenzoic acid, naphthoic acid, 3200508

-methyl-or-naphthoic, [beta] -phenylpropionic, diphenylacetic and n-naphthylacetic or dibasic alkanoylic acids, for example oxalic, maleic, fumaric, succinic, malonic, glutaric, os-methylglutaric, 3-methylglutaric, [3, (S) - dimethylglutaric, adipic, pimelic and sebacic, 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 or heterocyclic acids such as [3-f] , β-pyrrolidinopropionic, N-methylpyrrolidino-2-carboxylic acid, 6-hydroxyinrinlyl-3-acetic acid, N-methylmorpholino-2-carboxylic acid and pyrrole-2-carboxylic acid or sulfonic acids with 1 to 12 carbon atoms, such as alkanesulfonic acid, e.g. methane- and ethanesulfonic acids, and arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid .

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, sulfonyloxy, amido, sulfate, nitro, mercapto, and cyano, for example, glycolic, lactic, citric, tartaric, gluconic, maleic, and maleic acid, glyceric, 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, fluoroacetic acid, trichloroacetic acid, trifluoroacetic acid, trifluoroacetic acid, trifluoroacetic acid, trifluoroacetic acid, 3,4-trimethoxybenzoic, phenoxyacetic and .alpha.-naphthyloxyacetic.

Particularly suitable are especially 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 R2 are methyl and ethyl.

The compounds obtainable by the process of the invention either possess pharmacologically valuable properties themselves or are intermediates for the production of well-known drugs. Thus, for example, 17? - (3-hydroxypropyl) -17? -Hydroxy-7? -Thioacetyl-4-androsten-3-one is advantageously useful as an intermediate for the production of the known aldosterone spironolactone blocking agent [3- (17R-Hydroxy-7H-thioacetyl-3-oxo-4-androsten-17a-yl) -propionic acid].

The compounds obtainable by the process of the invention also act as aldosterone antagonist-type diuretics, i.e., they reverse the effect of desoxycorticosterone on sodium and potassium excretion. Compounds such as 17β-hydroxy-17β- (3-hydroxypropyl) -7β-thioacetyl-4-androsten-3-one, 17β-hydroxy-17β- (3-hydroxypropyl) -7β-ethylthlo-4 -androsten-3-one, 17d-aethoxy-37α- (3-acethxypropyl) -7'-thioacetyl-4-androsten-3-one, 17β-hydroxy-17α- (3-acetoxypropyl) - 7α-thioacetyl-6α-methyl-4-androsten-3-one, η 4 -hydroxy-1 H- (3-hemisuccinyloxypropyl) -6-methyl-4,6-androstadien-3-one potassium salt and sodium salt 17 (3 -hydroxy-17- (3-hydrosuccinyloxypropyl) -4,6-androstadiene-3-one exhibit in the Hollmann test model (G. Hollmann et al. Tubular Wirkungen and Renale Elimination of Spirolactonen, Nunyn-Schmiedebergs Arch. Exp. Path.). Pharmac., 247 (1964) 419, P. Marx, Renale Wirkungen des d-Aldosterons und Seines Antagonisten 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 the 4-andro-sten-3-ones of the formula II,

where

R 5 and R 6 are as defined above, isomerized by enamination or enolation to the corresponding Δ ³ · ^{5 s} compound, Δ ⁵ voj a formaldehyde is added to the vazbu 5 d double bond from the resulting 6-hydroxymethylene compound, the 6-exomethylene steroid thus obtained is cyclohexene in the presence of a noble metal catalyst and then optionally etherification, esterification and optionally the hemiacylate of formula III,

-IPCJrO-C-CHI _with C-OH A3 (A '),)

O o (lli I where

R 3 and R 1 are as defined above and n is 1 to 3, converted to its salt. A particular variant of the process according to the invention consists in this. 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 enamination, the starting steroid is heated, for example, with pyrrolidine or morpholine, in a suitable solvent such as methanol, methylene chloride or benzene, optionally with the addition of p-toluenesulfonic acid.

To prepare the enol ether, the starting steroid is conveniently heated with, for example, acetone dimethyl ketal, orthoformic acid ester or benzyl alcohol in a suitable solvent such as benzene, dimethylformamide or dioxane in the presence of p-toluenesulfonic acid or sulfuric acid.

Formaldehyde is added to the 3,5-dienamines or 3-alkoxy-3,5-dienes thus formed. For this purpose, formaldehyde was added slowly at room temperature to a Δ ^3-5 -steroids dissolved in a suitable solvent. Suitable solvents are aliphatic alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, as well as cycloaliphatic hydrocarbons such as cyclohexane.

Water is then cleaved from the 6-hydroxymethylene compound thus formed. To this end, the 6-hydroxymethylsteroid in a protic solvent is treated with acid. For example, a combination of dioxane or tetrahydrofuran and hydrochloric or p-toluenesulfonic acid or methanesulfonic acid chloride in pyridine, optionally with the addition of lithium bromide under the effect of heat, is suitable.

The 6-exomethylensteroid thus obtained is then isomerized to 6-methyl- ^{6 6} -steroid. To this end, the 6-exomethylene steroid is heated for a longer time in, for example, cyclohexene in the presence of a noble metal catalyst such as palladium. At the boiling point, the reaction is complete in a few hours. The addition of sodium or potassium acetate shortens the reaction, which is conveniently carried out in a protic solvent such as methanol or ethanol.

If the free hydroxyl group is to be etherified, as the primary hydroxyl group on the 1-n-propyl radical, 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. As! polar solvents include 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 17 ' -propyl moiety, is to be partially esterified, then known methods can also be used here. 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 the corresponding acid anhydrides, for example acetic anhydrides or ethoxyacetic anhydrides, at temperatures around room temperature.

For the preparation of compounds of the formula I in which R @ 1 and / or R @ 2 represent an organic acid residue, 17 (3-hydroxy-17a- (3-hydroxypropyl) -? ⁴ -ketosteroids already substituted on ring B or Δ ^{4 are} reacted ^{, 6} -3 -ketosteroidy alkanokyseliny anhydride, wherein the first esterifying the primary hydroxy group and then the tertiary 17 (3-hydroxyl group after extended reaction time, optionally at elevated temperature. For this purpose suitably the starting steroid is dissolved in baziském solvent such as pyridine , piperidine, collodine, triethylamine or lutidine, and the corresponding acid anhydride is added, and the addition of an esterification catalyst such as dimethylaminopyridine is also beneficial 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 longer esterification times. The reaction can naturally be accelerated by heating, for example by heating up to the boiling point, and the reaction time is reduced to several hours.

When 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. Suitably, a solution of ammonia in methanol is used to prepare the ammonium salt.

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

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

Example 1 ml of acetic anhydride was cooled to -10 degrees Celsius and 29.5 ml of nitric acid (h -1.51) was added dropwise, to which 10 g of 17/3-hydroxy-17? - (3- hydroxypropyl) -4,6-androstadiene-3-one, dissolved in 200 ml of chloroform, is slowly added dropwise such that the temperature does not rise above -5 DEG C. The reaction mixture is stirred at -5 DEG to -10 DEG C. for 20 min. then pour into ice water.

The chloroform phase is separated, the aqueous phase is extracted with methylene chloride, the combined organic extracts are washed neutral and evaporated in vacuo. There was obtained 17β-nitryloxy-17α- (3-nitryloxypropyl) -4,6-androstadien-3-one.

To 6.5 g of 17/3-nitryloxy-17a- (3-nitryloxypropyl) -4,6-androstadiene-3-one in 65 ml of methanol, 8 ml of ethyl acetate and 20 ml of water is added 5 g of potassium cyanide and heated to 6 g. hours under reflux. It is then concentrated in vacuo, water is added to the residue and neutralized with dilute hydrochloric acid. The resulting product is filtered off with suction, washed with water, dried, suspended in methylene chloride and extracted several times with 6 N hydrochloric acid. The HCl extract is neutralized with sodium hydroxide while cooling with ice, and the precipitated precipitate is filtered off with suction, washed with water and dried.

3.4 g of crude 4,7a- (aminomethylldine) -5-cyano-17,5-nitryloxy-17a- (3-nitryloxypropyl) -5,3-androstan-3-one are obtained.

3.4 g of crude 4,7- (aminomethylidin) -5-cyano-17 H- (3-nitryloxypropyl) -5 / 3-androstan-3-one are heated in 100 ml of 1 N hydrochloric acid. hours with stirring on a steam bath. The reaction mixture was cooled, and the resulting 4α, 7α-carbonyl-5-cyano-17β-nitroxy-17β- (3-nitryloxypropyl) -5,3-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 4α, 7α-carbonyl-5-cyano-17β-nitryloxy-17β- (3-nitryloxypropyl) -5 (β-androstane-3- The solution was concentrated in vacuo, poured onto ice and acidified with sulfuric acid, and the product was filtered off with suction, washed with water, dried and recrystallized from methanol.

1.7 g of 17/3-nitryloxy-17, .alpha .- (3-nitro-propyl) -3-oxo-4-androstene-7a-carboxylic acid ethyl ester of melting point 178 DEG-180 DEG C. are obtained.

In order to reduce the ester thus obtained, 1.6 g of ester in 10 ml of tetrahydroifuran and 10 ml of glacial acetic acid were stirred with 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-andrene-7α-carboxylic acid ethyl ester is filtered off with suction and recrystallized from acetone-hexane. Melting point: 152-153.5 ° C.

Example 1 a d 2

4α, 7α-Carbonyl-5-cyano-17 (S-n -tryloxy-17α- (3-nitryloxypropyl) -5) -S-androstan-3-one was converted to sodium methyl ester 17 as described in the previous example. The 3-nitryloxy-17, α '- (3-nitryloxypropyl) -3-oxo-4-andrene-7α-carboxylic acid and protecting groups are removed by reduction.

There was thus obtained 17β-hydroxy-17α- (3-hydroxypropyl) -3-oxo-4-androstene-7α-carboxylic acid methyl ester of melting point 181-183 ° C.

Example 3

15.0 g of 17.beta.-hydroxy-17- (3-hydroxypropyl) -4-androsten-3-one was heated in 75 ml of methanol and 7.5 ml of pyrrolidine for 15 minutes under reflux. After cooling in an ice bath, the crystalline precipitate is filtered off with suction and washed with a small amount of ice-cold methanol. 12.0 g of 17α- (3-hydroxypropyl) -3-pyrrolidino-3,5-androstadiene-17/3-ol are obtained, UV: εΖ76 = 21 300.

11.5 g of 17- (3-hydroxypropyl) -3-pyrrolidino-3,5-androstadiene-17 / S-ol are dissolved in 794 ml of ethanol and 397 ml of benzene, then 20.8 ml of a 40% formaldehyde solution are added dropwise. and stirred for 1 hour at room temperature. The solution is then concentrated in vacuo as much as possible and the residue is chromatographed on silica gel. 5.25 g of 17 H -hydroxy-6/3-hydroxymethyl-17α- (3-hydroxypropyl) -4-androsten-3-one is obtained, UV: smi = 11100.

5.25 g of 17.alpha.-hydroxy-6 ' -hydroxy-ethyl-17-l- (3-hydroxypropyl) -4-androsten-3-one are stirred in 260 ml of dioxane and 15.2 ml of 5N hydrochloric acid 2, 5 hours at room temperature. Excess sodium bicarbonate was then added to the reaction solution, the insoluble residue was filtered off and the filtrate was evaporated to dryness in vacuo. The residue is chromatographed on silica gel. 3.8 g 17 | / 3-hydroxy-17cs- (3'hydroxypropyl J-6 ' -methylene ^j * androsten'3 4-one. Sample recrystallized from acetone m.p. 178 DEG

179.5 ° C, UV: ε26 ° = 11 ° C.

To 3.5 g of 17.alpha.-hydroxy-17.beta .- (3 &apos; hydroxypropyl) -6-methylene-4 &apos; -androsten-3-one is added 1.75 g of anhydrous sodium acetate and 257 ml of 5% palladium carbon in 122 ml of ethanol; frn forvl niv νουιι hXb om Q Ή on <4 n

IN*. In VUiU in XXVM.4.1X in portions of 0.7 ml cyclohexene in 20 ml ethanol. Then the catalyst is filtered off and the filtrate is concentrated as much as possible in vacuo. The residue was taken up in methylene chloride, washed with water, dried, evaporated and chromatographed on silica gel. 1.9 g of 17 [beta] -hydroxy-17 [alpha] - (3-hydroxypropyl) 6-methyl-4,6 ' and 4 ' -diene-3 ' is obtained, a sample recrystallized from diisopropyl ether and acetone, m.p. C, UV: ε 29ΐ = 21100,

Example 4

1.8 g of trimethylsulfoxonium iodide and 2.8 g of sodium hydroxide are stirred for 15 minutes in 32 ml of dimethylsulfoxide under an argon atmosphere. Then 1 g of 17,8-hydroxy-17a- (3-hydroxypropyl) -4,6-androstadiene-3-one is added and stirred for 24 hours at 35 ° C, still under argon amtosphere, then poured into ice water. acidified with acetic acid, the precipitated product is filtered off with suction and dissolved in methylene chloride, the methylene chloride extract is washed with water, dried over sodium sulphate and evaporated in vacuo and the residue is purified by chromatography on a bed of chloroform-methanol 9: 1. acetone gives 530 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -6,7,7 (3-methylene-4-androsten-3-one), m.p. 170-172 ° C, UV: ¢ 203- = 18 300.

Example 1 a d 5

350 mg of 17 (3-hydroxy-8-methyl-7α- (3-hemisuccinyloxypropyl) -4,6-androstadien-3-one) is reacted with sodium methoxide solution and treated to give 310 mg of 17H-hydroxy-6. methyl-17α- (3-hemisuccinyloxypropyl) -4,6-androstadiene-3-one in the form of the sodium salt, UV: £ 291 = = 21,000.

Example 6

350 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -6-methyl-4,6-androstadiene-3-one is heated in refluxing for 3.5 hours in 3.5 ml of pyridine and 350 mg of succinic anhydride. The solution was poured into ice water with stirring, the precipitated oil was filtered off, taken up in methylene chloride, dried and evaporated. The residue is chromatographed on silica gel. 420 mg of 170-hydroxy-6-methyl-17? (3-hemisuccinyloxypropyl) -4,6-androstadiene-3-one are obtained in the form of an amorphous substance, UV: ε29ΐ = 20 500.

Example 7

420 mg of 17: [beta] -hydroxy-6-methyl-17 [alpha] - (3-hemisuccinyloxypropyl) -4,6-androstadien-3-one is dissolved in 20 ml of absolute methanol and reacted with 6.4 ml of methanol 0.1N Potassium methylate solution was dissolved in absolute ether, the precipitate was filtered off with suction, washed with ether and dried. 340 mg of 17β-hydroxy-6-methyl-17 - ((3-hemiscuinyloxypropyl) -4,6-androstadien-3-one in the form of the amorphous potassium salt, m.p. 130 ° C (dec.) , UV: ε29ΐ = 21,300.

Example

As described in Example 6, the reaction of 17β-hydroxy-17β- (3-hydroxypropyl) -18-methyl-4,6-estradien-3-one and succinic anhydride in pyridine affords 17β-hydroxy- 17α- (3-hydroxysuccinyl) oxypropyl β-18-methyl-4,6-estradien-3-one in form / amorphous substance, UV: δ 284 = 24 100 (methanol).

Example 9

As described in Example 7, its potassium salt is obtained from N, N-hydroxy-17- (3-hydroxysuccinyloxypropyl) -18-methyl-4,6-estradien-3-one as its amorphous substance, UV: δ 285 = 22 900 (methanol).

Example 10

100 mg of 17.0-hydroxy-17α- (3-hydroxypropyl) -7α-thloacetyl-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 was then poured into ice water, stirred with pentane and filtered off with suction, the residue was extracted with methylene chloride, washed with 1 N hydrochloric acid and water, and the residue was concentrated to give 17β-hydroxy-17iof- (3-undecyloxypropyl) -7a. thioacetyl-4-androsten-3-one in the form of an oil, UV (methanol J? 237 - 17 500).

Example 11

Dissolve 1.5 g of 17/2-hydroxy-17a- (3-hydroxypropyl) -4,6-androstadiene-3-one in 5 ml of pyridine, add 1.5 g of succinic anhydride and heat under argon for 1 hour. to boil. 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 17β-hydroxy-17β- (3-hydroxysuccinyloxypropyl) -4,6-androstadiene-3-one are obtained in the form of an amorphous substance, UV: δ 285-23.700.

Example 12

300 mg of the hemisuccinate prepared in Example 11 were dissolved in 15 ml of absolute methanol and the pH was adjusted to 8 with 5.5 ml of 0.1 N sodium methylate solution. The solution was concentrated in vacuo and precipitated in 200 ml of ether. The resulting salt is filtered off with suction, dissolved in methanol and reprecipitated in ether. 210 mg of 17? -Hydroxy-17? - (3-hydroxysuccinyloxypropyl) -4,6-androstadien-3-one sodium salt, m.p. 120 DEG C. (dec.), UV:? 285-2400, are obtained.

Example 13

400 mg of the hemisuccinate produced in Example 11 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, 285 mg of 17/3-hydroxy-17a potassium salt are obtained. - (3-hydroxysuccinyloxypropyl) -4,6-androstadiene-3-one, m.p. 145 DEG C. (dec.).

Example 1 4

Analogously to Example 11, the esterification of glutaric anhydride in pyridine and subsequent reaction with potassium methylate was prepared by the potassium salt of 17β-hydroxy-17α- (3-hydroxyglutaryloxypropyl) -4,6-androstadien-3-one, m.p. 98 ° C. (with decomposition).

Example 15

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 under argon for 1 hour under argon anhydride. 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: 284 284- = 26 800 (methanol).

Example 16

A solution of 500 mg of 17β-hydroxy-17β- (3-hydroxysuccinyloxypropyl) -4,6-estraden-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 17β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one sodium salt are obtained, UV: ε 285 = 25 900 (methanol).

Example 17

A solution of 600 mg of 17β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one in 30 ml of absolute methanol is adjusted to pH 8 with 0.1 N potassium methylate solution. After precipitation in ether, as described in Example 12, 320 mg of 17? -hydroxy-17? - (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one potassium salt is obtained, UV:? 284 = 26 300 (methanol).

Example 18

As described above, by esterification of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one glutaric anhydride in pyridine and subsequent reaction with potassium methylate, the 17β-hydroxy-17α- potassium salt is prepared. (3-hydroxyglutaryloxypropyl) -4,6-estradien-3-one in the form of an amorphous powder, UV (methanol): δ 285 = 24 100. Example 19 g 17/3-hydroxy-17α- (3-hydroxypropyl) -4, Of 6-androstadiene-3-one was heated in 350 ml of pyridine with 70 g of triphenylmethyl chloride on a steam bath for 40 minutes. The reaction mixture is cooled, poured slowly into 8 l of ice-water, the precipitate is 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 17β-hydroxy-17α- (3-triphenylmethyloxypropyl) -4,6-androstadien-3-one, m.p. 168-169 ° C, are obtained.

Example 20

To 1.5 g of 17, 3-hydroxy-17a- (3-hydroxypropyl) -6 ([3,7] p-methylene-4-androsten-3-one) in 5 ml of pyridine was added 1.5 ml of acetic anhydride and stirred 105 min at 22 [deg.] C. After treatment and trituration with hexane, 1.7 g of amorphous 17 [beta] -hydroxy-1H-(3-acetylpropyl) -6 (3,7 (3'-methylene-4-androstene-3)) is obtained. Example 21

500 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-iandrostadiene-3-one in 15 ml of diethyl carbonate was added with 10 mg of sodium methylate and heated at 140 ° C under argon for 10 minutes. It was then cooled, neutralized with acetic acid and evaporated in vacuo.

After purification by layer chromatography, 400 mg of 17/3-hydroxy, 17- (3-e, thoxycarbonyloxypropyl) -4,6-androstadiene-3-one is obtained in the form of a colorless oil, UV: ε2 = 5 10000.

SUBJECT

Claims (3)

SUBJECT Production Method 17 - (3-R 2-oxypropyl) -17 _: 3-R 1 -oxy-4,6-gonadien-3-ones of formula I, wherein: R1 is hydrogen or an organic acid residue of up to 3 carbon atoms, R 2 denotes hydrogen, an alkyl group of up to 2 carbon atoms, an aralkyl group of up to 19 carbon atoms, or an organic acid residue of up to 12 carbon atoms, R 3 represents a methyl or ethyl group and R4 represents a hydrogen atom or a methyl group, characterized in that the 4- (4-androsten-3-ones) of formula (II) are: OF THE INVENTION where R 5 and R 4 are as defined above, formaldehyde is added to the Δ ⁵ -double bond by isomerization by Rnawination or enolation to the corresponding Δ ³⁵ -compound; in the presence of a noble metal base catalyst and then optionally etherification, esterification and optionally the hemiacylate of formula III, R3 and R4 are as defined above, and π is 1 to 3, converted to its salt. 3everogratia, a. P., Plant 7, Most