DE1058507B - Process for the production of í¸-19-nor-steroids - Google Patents

Description

Process for the preparation of 4 4-19-nor-steroids The invention relates to a process for the preparation of new biologically active d4-19-nor compounds of the androstane and pregnane series which do not have any oxygen-containing substituents in the 3-position. In particular, it relates to new 19-norsteroids of the general formula in which R, H, (H) CH or = 0, provided that R2 is (H) COC H3, (H) COCH20R3 or (OH) COCHZOR3, where R3 is a hydrogen atom or an acyl group which is different from a carboxylic acid with 1 to 10 carbon atoms and in which R1 (H) 0 is H or = 0, provided R2 (H) OR3, R40 R3, or = 0, where R3 has the same meaning as above and R4 is a methyl, ethyl or vinyl group represents. The new compounds have very powerful inhibitory effects against sex hormones.

These new compounds also possess anabolic, androgenic properties and progestative properties.

The inventive method is characterized in that a d 4-3-Hydroxy-19-norsteroid of the androstane or pregnane series, which are in the 3-position etherified or esterified, with an alkali metal in liquid ammonia or is treated in a lower aliphatic primary amine, thereby removing the substituent is split off in 3-position.

The d 4-3-hydroxy-19-nor-steroids to be used as starting material can be obtained by reducing the corresponding 3-keto compounds. These Reduction can be done with the help of one of the usual reducing agents such as an alkali borohydride or from aluminum isopropylate in isopropanol.

After the hydroxyl group is etherified or esterified in the 3-position the cleavage according to the invention can be carried out. The ether group may be an alkoxy, aryloxy or aralkoxy group, e.g. B. a methoxy, ethoxy, Isopropoxy, pentoxy, phenyloxy, benzoxy or triphenylmethoxy group.

The splitting off of the substituent in the 3-position takes place when one the starting material dissolved in a suitable solvent with an alkali metal in the presence of liquid ammonia or a lower aliphatic primary amine treated with 1 to 6 carbon atoms. The solvent can be, for example a lower aliphatic ether such as dimethyl ether, methyl ethyl ether, diethyl ether as well as dioxane or tetrahydrofuran. The alkali metal to be used in the reaction can be lithium, sodium or potassium. Lithium has proven to be advantageous.

Examples of lower aliphatic primary amines are: Methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine and n-amylamine.

When the reduction is in the presence of a lower aliphatic primary Amine is made, the reaction in question, e.g. B. at the boiling point this Amines. However, if the boiling point of this amine exceeds 0 ° C, is it is advisable to carry out the reduction below 0 ° C.

If the 3-keto-steroid compound to be reduced is one or more Contains keto groups in addition to the 3-position keto group, these groups can before the Reduction, e.g. B. be protected by ketalization. If these keto groups don't have been protected, they are converted into hydroxyl groups in the course of the reduction, which in turn are converted into keto groups by oxidation in the usual way can.

If the d 4-3-hydroxysteroid obtained after the reduction is additional Containing a hydroxyl group in the 17- or 21-position will in most cases the corresponding 17- or 21-acylate is formed when the 3-hydroxy group is esterified. Optionally, the 17- or obtained after cleavage of the 3-acyloxy group 21-esters can be saponified and, if necessary, re-esterified.

After the 3-position ether group has been split off, those obtained in the Compound g; if necessary Existing esterifiable hydroxyl groups be esterified.

The esterification is preferably carried out with an aliphatic, aromatic or araliphatic carboxylic acid with 1 to 10 carbon atoms or with their functional ones Derivatives carried out, e.g. B. with acetic acid, propionic acid, butyric acid, valeric acid, Caproic acid,: socaproic acid, succinic acid, tartaric acid, cyclophenyl- ° acetic acid, ß-Cyclopentylpropionic acid, cyclohexyl acetic acid, y-cyclohexylbutyric acid, phenylacetic acid, ß-phenylpropionic acid, benzoic acid, glycine, alanine and phenyltlanine. Example 1 To a solution of 3.0g d 4-11 ß, 17ß-dihydroxy-3-keto-17a-methyl-19-nor-androstene 1.4 g of sodium borohydride are added to 150 ml of methanol. After standing for 20 minutes the reaction mixture is neutralized with ice @ ssig and then reduced to 25 in vacuo ml singed. The residue is poured into 200 ml of water, before the J4-3, 11ß, 17ß-trihydroxy-17a-methyl-19-nortndroster, crystallized out.

The suction-filtered crystals are dissolved in 112 ml of methanol, whereupon 1.6 ml of 36% hydrochloric acid can be added to this solution. The resulting solution is stirred for 1 hour) ei room temperature, whereupon the reaction mixture with sodium bicarbonate neutralized and concentrated to 25 ml. The residue is poured into 200 ml of water, then the resulting crystals of 9 4-3 -methoxy-lß, 17ß-dihydroxy-17a-methyl-19-nor-rusts are grounded suctioned off and then re-crystallized from acetone.

2.3 g of this compound are dissolved in 25 ml of dry ether, whereupon a solution of 2 g of lithium in @ 0 g of ethylamine was added dropwise to this solution will. After stirring for 10 minutes, the excess lithium is removed by slowly adding removed from 15 ml of methanol to the reaction mixture. After the reaction mixture has been tinted the ethylamine is evaporated m vacuum. The residue is taken up in ice water, whereupon the mixture is extracted several times with ether. The collected ether extracts «-Erdei washed, and then the ether is evaporated in a vacuum. The residue will between '0 ° o methanol and Pctrolether distributed, the petroleum ether layer separates, dried and finally evaporated to Prockne. After recrystallizing ? etroläth ° r represents the residue of J4-11ß, 17ß-diivdroxv-17a-metlivl-19-i, or-androsten there-. This connection shows characteristic bands in the IR spectrum at '., 79 u., 6.00 u, and 12.38 #t.

A solution of 1 g of this compound in 3.2 g of acetic anhydride and 4.0 g of pyridine is placed on a steam bath under a nitrogen atmosphere for 1 hour heated and poured into ice water. The precipitate is separated off and from a Mixture recrystallized from methanol and etrolatlier, the 44-11ß, 17ß-Dihvdroxv-17a-mctlivl-19-nor-ar.-droster.-17-acetate received. This compound has characteristic barals in the IR spectrum at 2.78 u., 6.01 u, and 12.39 u.

The esters of this compound are obtained in a corresponding manner, which are derived from caproic acid, 3erist, insäu-_e, Cvclopentvlacigsäure and ß-phenylpro) ionic acid.

Example 2 In a manner analogous to that described in Example 1, is the 44-3-keto-11ß, 17ß-dihydroxy-17a-vinyl-19-nor-androsten to the corresponding 3-Hydroxy compound °, which is then converted into the appropriate with isopropanol and hydrochloric acid 3-isopropoxy compound is converted.

Following the procedure of Example 1, this compound is with a Treated solution of sodium in methylamine, whereby the d 4-11ß-17ß-dihydroxy-17a-vinyl-19-nor-androsten is obtained. This compound shows characteristic bands in the IR spectrum 2.79 6.04 #t, 11.15 #t and 12.38 #t.

The esterification of this compound is analogous to that described in Example l Process leads to the 17-esters, which differ from propionic acid, tert-butyl acetic acid, Derive nonanecarboxylic acid and γ-cyclohexylbutyric acid.

In a corresponding manner and starting from d4-3,11-diketo-17ß-hydroxy-17a-ethyl-19-nor-androstene the J 4-11-keto-17ß-hydroxy-17a-ethyl-19-nor-androstene is obtained. This connection exhibits characteristic bands at 2.79 & ,, 5.87 #L and 12.39 in the IR spectrum on. The 17-esters of this compound were then prepared, which differ from the Derive acetic acid, nonanecarboxylic acid and cyclopentylpropionic acid. Example 3 3.04 g Na B H4 are pregnen a solution of 2.9 g I 4-21-hydroxy-3,20-diketo-19-nor- added in 400 ml of methanol. The reaction mixture is 1 hour at room temperature stirred, then the pH was adjusted to 5.4 with glacial acetic acid, then in vacuo concentrated to about 30 ml and finally diluted with 200 ml of water. The solution is extracted with chloroform, the extract with ice-cold 1N sodium hydroxide solution and then washed with water until neutral. After drying and Evaporation of the solvent will give the crude J 4-3,20,21-trihydroxy-19-nor-pregnen obtain.

This is dissolved in 8 ml of pyridine, then with 4.2 g of propionic anhydride offset. The reaction mixture is stirred for 20 hours at room temperature, whereupon the solution is decomposed by adding water. The mixture is then evaporated to dryness, after which the residue is recrystallized from methanol. The 4 4-3,20,21-tripropionyloxy-19-nor-pregnen is obtained.

The extracted crystals are dissolved in 120 ml of absolute ether. A solution of 0.9 g of sodium in 25 ml of methylamine is then added to the solution. The blue solution is then stirred for 2 hours at -15 ° C., after which 18 ml of absolute Ethanol can be added to the reaction mixture. Then you evaporate the methylamine, dilute the residue with water and extract the mixture a few times with ether. The collected ether extracts are washed with water and dried over sodium sulfate and evaporated to dryness. The residue is made up of methanol and then off Petroleum ether recrystallized, whereby the J4-20,21-dipropionyloxy-19-nor-pregnen receives. This compound has characteristic bands at 6.00 u in the IR spectrum. and 12.39 u.

The saponification of this compound by treatment for 15 minutes with a 0.5% sodium hydroxide solution at room temperature leads to J4-20,21-dihydroxy-19-nor-pregnen. This compound has characteristic bands at 2.79 and, 5.99 in the IR spectrum u. and 12.38u.

3 g of this compound are dissolved in 15 ml of dioxane and then 5 ml Pyiidine and 0.9 ml of acetic anhydride were added. The reaction mixture is 24 hours stirred at room temperature, whereupon it is evaporated to dryness in vacuo. Of the dry residue, consisting of J4-20,21-dihydroxy-19-nor-pregnen-21-acetate, is dissolved in 30 ml of acetone. While stirring is at 0 ° C to this solution a chromic acid solution is added drop by drop. The chromic acid solution is prepared by dissolving 84 g of chromium trioxide in 120 ml of water and 62 ml of concentrated sulfuric acid, whereupon the solution was made up to 300 ml with water. The chromic acid solution will added dropwise until a constant yellow color appears. The reaction mixture is then evaporated to almost dryness in vacuo, whereupon the residue is dissolved in `` water is recorded. The aqueous mixture is extracted with chloroform, after which the Separated chloroform layer, with dilute sulfuric acid and then with cold dilute sodium hydroxide solution and finally with water until neutral Reaction washed. After the solvent has evaporated, the d 4-21-hydroxy-20-keto-19-nor-pregnen-21-acetate becomes obtain. This compound shows characteristic bands at 5.73 in the IR spectrum u., 5.80 #t and 12.38 #t. By saponifying with dilute sodium hydroxide solution the unesterified compound is obtained therefrom.

By saponifying this compound with butyric anhydride, ß-cyclopentylpropionic anhydride or succinic anhydride in pyridine gives 21-butyrate, 21-ß-cyclopentylpropionate as well as the 21-half ester of succinic acid.

Example 4 3.04 Na BH ,, are obtained from 2.9 g of d4-3,20-diketo-19-norpregnation added in 400m1 of methanol. The reaction mixture is at room temperature for 1 hour stirred, then the pH was adjusted to 5.4 with glacial acetic acid, whereupon in vacuo about 30 ml is evaporated and finally diluted again with 200 ml of water. the The solution is extracted with chloroform and the extract with ice-cold ln sodium hydroxide solution and then washed with water until neutral. After drying and evaporation of the solvent will pregnen the crude d 4-3,20-Dihvdroxy-19-nor- obtain.

It is dissolved in 65 ml of methanol and then concentrated with 1.5 ml Hydrochloric acid decomposes. The resulting solution is at room temperature for 40 minutes stirred, then neutralized with sodium carbonate and evaporated to 15 ml. The residue is poured into 200 ml of water, the d4-3-methoxy-20-hydroxy-19-nor-pregnen crystallized out.

The extracted crystals are dissolved in 120 ml of absolute ether, whereupon 120 ml of liquid ammonia and then 0.9 g of sodium cut into small pieces be admitted. The blue solution is then stirred for 2 hours at -35 ° C, 80 ml of absolute methanol are then added. Then the ammonia is evaporated, the residue is diluted with water and the mixture is extracted a few times with ether. The collected ether extracts are washed with water and dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from methanol and petroleum ether, whereby the d 4-20-hydroxy-19-norpregnen is obtained. This compound exhibits in the IR spectrum characteristic bands at 2.78 #t, 5.99 #t and 12.39.

0.5 g of this compound are dissolved in 25 ml of acetone. While stirring a chromic acid solution is added dropwise to this solution at 0 ° C. The chromic acid solution is made by dissolving 70 g of chromium trioxide in 100 ml of water and 55 ml concentrated sulfuric acid, whereupon the solution is made up to 250 ml with water will. The chromic acid solution is added dropwise until it remains yellow coloring occurs. Then the reaction mixture is in vacuo almost to dryness evaporated and then the residue taken up in water. The aqueous mixture is extracted with chloroform, the chloroform layer is separated off with dilute Sulfuric acid and then with a cold dilute sodium hydroxide solution and finally washed with water until neutral. After evaporation of the solvent the d 4-20-keto-19-nor-pregnen is obtained. This connection is in the IR spectrum characteristic bands at 5.86 #t, 7.37 &, and 12.38 #t.

In a corresponding manner, the d 4-17a-hydroxy-3,20-diketo-19-nor-pregnen converted into the corresponding 3,17a, 20-dihydroxy compound using sodium borohydride and then into the by treatment with triphenylchloromethane in the presence in pyridine d4-3-triphenylmethoxy-17a, 20-dihydroxy-19-nor-pregnen.

This compound is then pregnen into the A4 "17a, 20-dihydroxy-19-nor-pregnen by means of sodium and isopropylamine using the procedure of the example 3 transferred. The oxidation of this compound by means of chromic acid leads to aceto n for d 4-17a-hydroxy-20-keto-19-nor-pregnen. This compound exhibits in the IR spectrum characteristic bands at 2.80 #t, 5.87 #t, 5.91 #t and 12.39 #t.

Example 5 "Following the procedure described in Example 3, the d4-17a, 21-dihydroxy-3,11,20-triketo-19-nor-pregnen into the d4-3-methoxy-17a, 20β, 21-trihydroxy-II-keto-19-nor-pregnen by reduction with sodium borohydride and subsequent treatment with methanol and concentrated hydrochloric acid.

Subsequent treatment with potassium, and methylamine will after the process described in Example 1, the d 4-17a, 20ß, 21-trihydroxy-11-keto-19-norpregnen obtain. This compound shows characteristic bands at 2.80 in the IR spectrum #t, 5.88 and 12.38V.

0.3 g of this compound are dissolved in 1.5 ml of dioxane, whereupon 75 ml of pyridine and 70.5 ml of acetic anhydride are added. The reaction mixture vzrd24 Stirred for hours at room temperature and then evaporated to dryness in vacuo. Of the dry residue, consisting of A 4-17a, 20ß, 21-trihydroxy-11-keto-19-nor-pregnen-21-acetate is dissolved in 45 ml of acetone and oxidized in the manner described in Example 5.

It becomes d4-17a, 21-dihydroxy-11,20-diketo-19-norpregnen-21-acetate obtain. This compound shows characteristic bands at 2.79 in the IR spectrum #L, 2.85 #t, 5.71 #L, 5.78 & ,, 5.86 #t and 12.38 #t. The saponification of this Compound by treatment for 10 minutes with a 0.5% sodium hydroxide solution at room temperature leads to d 4-17a, 21-dihydroxy-11,20-diketo-19-nor-pregnen. This compound has characteristic bands at 2.95 #L, 5.86 in the IR spectrum #t, 5.99 &, and 12.38 #L.

By esterification with butyric anhydride, succinic anhydride and ß-phenylpropionic anhydride converts this compound into the corresponding 21-ester convicted.

1 gd 4-17a, 21-dihydroxy-11,20-diketo-19-nor-pregnen-21-acetate is suspended in 27 ml of methanol and 6.5 ml of dimethylformamide. 0.7 g of semicarbazide HCl and a solution of 0.43 g of sodium carbonate in 5 ml of water are added to this mixture. The reaction mixture is then refluxed for 3 hours under a nitrogen atmosphere and finally kept at 45 ° C. for 24 hours. 35 ml of water are then added to the mixture, the mixture is cooled to 0 ° C., whereupon the 20-mozosemicarbazone, which precipitates out after several hours, is filtered off and dried in vacuo. The dry residue obtained is suspended in 12 ml of water and 50 ml of tetrahydrofuran, whereupon the suspension is heated until a clear solution is formed. A solution of 220 mg of sodium borohydride in 5 ml of water is added to .fieser solution, which is cooled to room temperature, while stirring in a nitrogen atmosphere. The reaction mixture is then stirred for 5 hours and brought to a pH of 6 to 7 with glacial acetic acid. Ne mixture is evaporated to almost dryness in vacuo, then the residue is taken up in a mixture of 15 ml of chloroform and 15 ml of 2N sulfuric acid. It is refluxed for 5 minutes and then cooled. The chloroform layer is then separated and the remaining aqueous layer is extracted with chloroform. The combined chloroform extracts are washed with a dilute sodium hydroxide solution and then with water until a neutral reaction is obtained. After drying and evaporation of the solvent, the residue is recrystallized from a mixture of methanol and acetone, giving 44-11β, 17a, 21 trihydroxy-20-keto-19-nor-pregnen-21-ace-: at. In the IR spectrum, this compound has characteristic bands at 2.79 #t, 2.86 #t, 5.70 #t, 5.78 #t, 5.00 [, and 12.38 #t.

The saponification of this compound by treatment for 15 minutes with a 0.5% sodium hydroxide solution) at room temperature results in the d4-11ß, 17a, 21-trizydroxy-20-keto-19-nor-pregnen. This compound has characteristic bands in the IR spectrum at 2.93, 5.87 #t, 6.01 p. and 12.37 #t.

According to the process described in Example 3, 21-esters of this compound are prepared, which are derived from valeric acid, succinic acid, β-phenylpropionic acid and from glycine. Example 6 2.75 g of NaBH4 are added to a solution of 5.5 g of d 4-17-hydroxy-3-1, eto-19-nor-androstene in 200 ml of methanol at room temperature. After standing for 20 minutes, the reaction mixture is neutralized with glacial acetic acid and then concentrated to 25 ml in vacuo. The residue is poured into 200 ml of water, after which the 4 4-3,17-dihydroxy-19-nor-androstene crystallizes out.

The suction-filtered crystals are dissolved in 15 ml of pyridine, whereupon 10.2 g of acetic anhydride are added to this solution. The reaction mixture is Maintained at room temperature for 20 minutes and then treated with 20 ml of water. The mixture is evaporated to dryness and then the residue is recrystallized from methanol; the d4-3,17-diacetoxy-19-nor-androstene is obtained.

2 g of the compound thus prepared are dissolved in 25 ml of dry ether, whereupon a solution of 2 g of lithium in 90 g of ethylamine is added dropwise to this solution. After stirring for 10 minutes, the excess lithium is removed by slowly adding 15 ml of methanol to the reaction mixture. After the reaction mixture is decolorized, the ethylamine is evaporated in vacuo. The residue is taken up in ice water, whereupon the mixture is extracted several times with ether. The collected ether extracts are washed, whereupon the ether is removed in vacuo. The residue is partitioned between 70% methanol and petroleum ether, the petroleum ether layer is separated off, dried and finally evaporated to dryness. When crystallizing from petroleum ether, the d 4-17β acetoxy-19-nor-androsten is obtained from the residue. The saponification of this compound by treatment with a dilute methanolic sodium hydroxide solution gives the d 4-17ß-hydroxy-19-nor-androsten with a melting point of 98 ° C.

Example 7 To a solution of 5.8 g of 44-3-keto-11ß-dihydroxy-19-nor-androstene 2.79 g of sodium borohydride in 200 ml of methanol are added at room temperature. After standing for 20 minutes, it is neutralized with glacial acetic acid and reduced to 25 ml in vacuo constricted. The residue is poured into 200 ml of water, whereupon the 44-3,11ß, 17ß-trihydroxy-19-nor-androsten crystallized out.

The extracted crystals are dissolved in 25 ml of pyridine, whereupon 30.3 g of cyclopentylpropionic anhydride are added to the solution. The reaction mixture is refluxed for 30 minutes, after which 25 ml of water are added. the The mixture is then evaporated to dryness and then the residue from methanol-petroleum ether recrystallized. The d 4-3,11ß-17ß-trihydroxy-19-nor-androstene-3,17ß-dicyclopentyl propionate is obtained.

2 g of the compound so prepared are in 25 ml of dry ether dissolved, whereupon this solution was added dropwise to a solution of 2 g of lithium in 90 g of ethylamine is added. After stirring for 10 minutes, the excess lithium is reduced by slow Adding 15 ml of methanol removed. After the reaction mixture is decolorized, the ethylamine is removed in vacuo. The residue is taken up in ice water, whereupon the mixture is extracted several times with ether. The collected ether extracts are washed, whereupon the ether is evaporated in vacuo. The residue is between 70 ° / 0 methanol and petroleum ether distributed, the petroleum ether layer separated, dried and finally evaporated to dryness. When crystallizing from petroleum ether the d 4-11ß, 17ß-dihydroxy-19-nor-androstene-17ß-cyclopentylpropionate is obtained from the residue. Saponification of this compound by treatment with a dilute methanolic Sodium hydroxyl solution leads to d4-11ß, 17ß-dihydroxy-19-norandrosten. This connection shows characteristic bands in the IR spectrum at 2.78 p., 6.00 #t and 12.38.

Following the procedure described in Example 1, this compound converted into the 17-ester, which differs from the caproic acid, cyclohexylacetic acid and derive hexahydrobenzoic acid.

In addition, the above-described d4-11ß, 17ß-dihydroxy-19-nor-androstene with a chromic acid solution mixed with water and acetic acid to the corresponding 44-11,17-diketo-19-nor-androstene oxidized. This compound exhibits in the IR spectrum characteristic bands at 5.74 V., 5.84 &., 7.10 p. and 12.39 #t. example 8 Corresponding to the manner described in Example 1, 4 is 4-17ß-hydroxy-17a-methyl-3-keto-19-nor-androstene reduced to the corresponding 3-hydroxy compound with sodium borohydride.

4.9 g of this compound are then dissolved in 105 ml of ethanol, whereupon 2.8 ml of concentrated hydrochloric acid are added. The treatment of this reaction mixture takes place as described in Example 1, after which the d 4-3-ethoxy-17ß-hydroxy-17a-methyl-19-nor-androsten receives.

3 g of this compound are dissolved in 125 ml of absolute ether. 120 ml of liquid ammonia and then 0.9 g of lithium cut into small pieces are added to this solution. The blue solution is then stirred for 2 hours at -35 ° C, after which 20 ml of absolute ethanol are added at the same temperature so that the blue color disappears. The ammonia is evaporated, the residue is diluted with water and the resulting mixture is extracted several times with ether. The collected ether extracts are washed with water, dried over sodium sulfate and evaporated to dryness. The residue is partitioned between petroleum ether and 70% methanol (1: 1), the petroleum ether layer is separated off, the petroleum ether is evaporated to half its volume, whereupon the crystallization of d 4-17β-hydroxy-17a-methyl-19-nor-androstene takes place. This compound has a melting point of 147 to 151 ° C.

Exactly according to the procedure described in this example, the d 4-17ß-Hydroxy-17a-ethyl 3-keto-19-norandrosten via the 3-methoxy compound the d 4-17ß-hydroxy-17a-ethyl-19-nor-androstene reduced. This connection has one Melting point from 76 to 78 ° C.

Claims (3)

PATENT CLAIMS: 1. Process for the preparation of d 4-19-nor-steroids, characterized in that a compound of the formula in which R1 is an acyl, alkyl, aryl or aralkyl group, R2 is H2, (H) 0 H or = 0 and R3 = 0, (H) C 0 C H3, (H) COCH, OR4, (OH) COCH, OR4, (H) OR4, or (R6) 0 R4, where R4 is a hydrogen atom or an acyl group derived from a carboxylic acid having 1 to 10 carbon atoms and R5 is a methyl, ethyl or vinyl group, with an alkali metal in the presence of ammonia or a lower aliphatic primary amine having 1 to 6 carbon atoms. 2. The method according to claim 1, characterized in that the alkali metal is lithium used. 3. The method according to claim 1, characterized in that the reaction below 0 ° C.