DE1093360B - Process for the production of stable, anti-estrogenic compounds of the estran series - Google Patents

Description

Process for the preparation of stable antiestrogenic compounds of the estrogen series The invention relates to a process for the preparation of stable antiestrogenic compounds of the estrogen series of the general formula where R is hydrogen or a methyl group and R 'is hydrogen or an acyl radical of an organic mono- or dicarboxylic acid. The process is characterized in that a compound of the general formula is obtained by known methods in which R has the meaning given above, reduced to the corresponding trienenol ether, the trienenol ether acidically cleaved, the 3-keto compound obtained reduced in the known `` '' iron and, if appropriate, the 3,17-dihydroxy obtained = 5 (10), 7-oestradien to the corresponding mono- or diester esterified. The cleavage of the 3-enolether can preferably be carried out under mild conditions, in particular with acetic acid or oxalic acid. so that the products are mixtures of these isomers.

As a starting compound for the syntheses described below. Equilin is used, which can be isolated from natural sources in the usual way can. First equilin (I) is made with the help of dimethyl sulfate and aqueous alkali converted into its methyl ether (1I). A hydroxyl group is then positioned 17ß-continuously introduced. This can be achieved by reduction with lithium aluminum hydride achieve, whereby the 17ß-dihydroequilin-3-methyl ether (11I a) is obtained, or by Reaction with methyl magnesium halide to form 17a-methyldihydroequilin.-3-methyl ether (IIIb). As a third stage, (IIIa) or (IIIb) with an alkali metal is preferred Lithium, and alcohol in liquid ammonia to form 3-methoxy-17ß-hydroxy-2,5 (10) 7-oestratriene (IVa) or 3-methoxy-17a-methyl-17β-hydroxy-2,5 (10) 7-oestratriene (IVb) reduced. As the fourth reaction stage, (IV a) or (IV b) becomes acidic under mild conditions, z. B. with acetic acid or O, ialic acid, split, with 17ß-hydroxy-5 (10), 7-oestradien-3-one (Va) or 17a-methyl-17ß-hydroxy-5 (10), 7-oestradien-3-one (Vb) is formed. In one fifth reaction step is the keto group in the 3-position of (Va) or (V b) with Lithium aluminum hydride or sodium borohydride to the 3,17β-dihydroxy-5 (10), 7-oestradiene (VIa) or 3,17ß-dihydroxy-17a-methyl5 = (10), 7-oestradien (VIb) reduced. Possibly can in a sixth stage (VIa) or (VIb) to the corresponding mono- or diesters these diols are esterified: Suitable esters are the acetates, propionates, the Half-esters of succinic acid, 4,4-dimethylvaleric acid ester, oenanthic acid ester, Benzoic acid esters and phenylacetic acid esters. The diesters are particularly preferred derived from propionic acid and benzoic acid.

The reaction steps indicated above are to be explained by the following reaction equations. It was found that the dihydroxyoestradienes VIa and VIb and their esters show antiestrogenic effects. The esters are pharmacologically equivalent to the diols VIa and VIb, but are considerably less hygroscopic and have a longer shelf life, that is, they do not darken under the influence of air and light. Accordingly, they are preferred when such greater stability is desired.

The following examples explain the process according to the invention.

Example 1 a) Preparation of equilin methyl ether 11 25 g equilin (I) in 500 ml of ethanol are boiled under reflux alternately in 40 ml portions with 200 ml of 500/0 aqueous potassium hydroxide solution and 200 ml of dimethyl sulfate within 1.5 Hours shifted. After stirring for a further 30 minutes, 400 ml of water are added. The mixture is cooled, the precipitate is washed well with water, dried and recrystallized from methylene chloride - methanol. The equilin methyl ether melted at 161 to 163 ° C. [a114 ° -1-290 ° (c = 10/0 in chloroform).

C19 H22 02 "Calculated ... C 80.810 H 7.86 ° / o; found ... C 81.16 011, H 7.67 ° / o.

b) Preparation of 17β-dihydroequilin-3-methyl ether (III a) To 3.1 g lithium aluminum hydride in 400 ml ether becomes a solution of 12.9 g equilin methyl ether (II) placed in 250 ml of benzene and the mixture under reflux with stirring for 2 hours heated to boiling. After decomposing excess lithium aluminum hydride with ethyl acetate just enough water is added to remove the inorganic To precipitate salts, and then the mixture is filtered off. The filtrate is in vacuo evaporated, 13 g of 17ß-dihydroequilin-3-methyl ether remaining.

c) Preparation of 17β-hydroxy-3-methoxy-2,5 (10), 7-oestratriene (IVa) The product (III a) obtained above was dissolved in 720 ml of ether, and about 1200 ml of liquid ammonia were added to this solution . Then 13.9 g of lithium chips are added to the solution. 130 ml of absolute ethanol were then added dropwise with stirring over the course of one hour. After the ammonia has evaporated, water is added and the ether layer is separated off. The aqueous phase is extracted once with ether and the combined ether solutions are washed with a solution of 35 g of caustic potash in 25 ml of water and 100 ml of methanol and then with water and dried over magnesium sulfate. The residue remaining after evaporation of the solvent in vacuo was recrystallized from a mixture of absolute methanol and hexane and then from absolute ethanol. The 17β-hydroxy-3-methoxy-2,5 (10), 7-oestratriene. melted in an evacuated capillary at 176 to 182 ° C and showed a rotation value of [a] D ° = + 195 ° (c ^ 10/0 in chloroform). In the infrared spectrum, bands were found at 1685, 1668 and 1222 cm- '.

C19 H26 02, Calculated ... C 79.68 0/0, H 9.15 0/9 found ... C 79.640 / 0, H 9.5000. d) Preparation of 17β-hydroxy-5 (10), 7-oestradien-3-one (Va) A suspension of 6.0 g of 17β-hydroxy-3-methoxy-2,5 (10), 7-oestratriene (IVa ) in 121 ml of methanol was heated to boiling under reflux, and 12 ml of glacial acetic acid were added. After refluxing for 15 minutes, 210 ml of water are added. The crystals obtained after cooling were recrystallized from aqueous methanol. The 17β-hydroxy-5 (10), 7-oestradien-3-one melted in an evacuated capillary at 145 to 147 ° C and showed an optical rotation of [ajö ° 251.1 ° (c = 10/0 in dioxane) . A band appeared at 1721 cm- 'in the IR spectrum.

C18 H24 () 2 # Calculated ... C 79.360 / 0, H 8.800 / 0; Found ... C 79.68 0/0, H 8.65 0/0.

e) Representation of 3,17ß-dihydroxy-5 (10), 7-oestradien (VI a) to one refluxed suspension of 1.8 g of lithium aluminum hydride in 140 ml of ether became a solution of 3.7 g of 17ß-hydroxy-5 (10), 7-oestradien-3-one (Va) given in 35 ml of benzene and the mixture with stirring for 2.5 hours under reflux Boiling heated. After decomposing excess hydride with ethyl acetate only enough water was added to precipitate the inorganic salts, after which the mixture was filtered off. The one remaining after the solvent has evaporated The residue was recrystallized from methanol. Mp 160-167 ° C; [a] D ° = + 171.5 ° (c = 10/0 in dioxane).

C18H2602-Calculated ... C 78.770 / 0, H 9.55 found ... C 78.74 ° / 0, H 9.43 ° / 0.

Example 2 a) Preparation of 17a-methyldihydroequilin-3-methyl ether (III b) To a solution of methyl magnesium iodide, which consists of 76 g of methyl iodide and 13 g of magnesium in 100 ml of ether has been prepared, a solution of 15.0 g of equilin methyl ether is added (II) in 180 ml of benzene. The mixture is refluxed under nitrogen for 7.5 hours heated to boiling and stirred and stirred for a further 12 hours at room temperature. To precipitate the inorganic salts, the reaction mixture is saturated with aqueous Ammonium chloride solution is added, the organic phase is separated off and evacuated in vacuo. The residue is dissolved in 170 ml of methanol with 20.0 g of Girard T reagent, the hydrazide of the carboxymethyltrimethylammonium chloride, and 10 ml of acetic acid are added and the Solution heated to boiling under reflux for 1 hour. The cooled solution is in 1.51 Ice water containing 6.2 g of caustic soda was poured and the product was extracted with ether. After recrystallization from ether - hexane, the 17a-methyldihydroequilin-3-methyl ether fell with a melting point of 133.5 to 135.5 ° C. [a] D ° = +. 170.8 ° (c = 10/0 in Chloroform).

C20112602, calculated ... C 80,500 / 0, H 80,780 / 0; found ... C 80.42 0/0, H 8.66 b) Preparation of 17a-methyl-17ß-hydroxy-3-methoxy-2,5 (10), 7-oestratriene (IVb) To a solution of 19 , 7 g of 17a-methyldihydroequuin-3-methyl ether (III b) in 600 ml of tetrahydrofuran were added about 1200 ml of liquid ammonia and then 19.7 g of lithium chips. The mixture was stirred for 1 hour, a condenser cooled with dry ice being attached to avoid the evaporation of ammonia. 190 ml of absolute ethanol and 190 ml of ether were then added to the mixture over the course of 70 minutes. After most of the ammonia had evaporated, water was added to the mass and most of the tetrahydrofuran was removed in vacuo. The product is taken up in ether and the ethereal solution is washed with 0.5N potassium hydroxide solution and then with water and finally dried over magnesium sulfate. After evaporation of the ether, the residue was recrystallized from methanol. The 17a-methyl-17ß-hydroxy-3-methoxy-2,5 (10), 7-oestratriene melted in an evacuated capillary at 183 to 184 ° C. [a] D- * ° = 167.1 ° (c = 10 /, in chloroform).

C20 H28 02 # Calculated ... C 79.98%, H 9.39%; found ... C 79.98%, H 9.19%.

c) Preparation of 17α-methyl-17β-hydroxy-5 (10), 7-oestradien-3-one (V b) A suspension of 2.0 g of 17α-methyl-17β-hydroxy-3-methoxy-2,5 (10), 7-oestratriene (IVb) in 35 ml of methanol was heated to boiling and 3.5 ml of acetic acid were added. The mixture was kept boiling for 15 minutes and the crude product, which was obtained after the addition of water on cooling, was recrystallized from methanol and then from a mixture of acetone and petroleum ether. In an evacuated capillary, the product showed a melting point of 160 and 162 ° C. and an optical rotation value of [a] D ° = 219.0 ° (c = 10 /, in dioxane). A band appeared at 1723 cm- 'in the IR spectrum.

C19 H26 02 »Calculated ... C 79.68 ° / 0, H 9.15 ° / 0; found ... C 79.82%, H 9.17%.

d) Preparation of 17a-methyl-3,17ß-dihydroxy-5 (10), 7-oestradiene (VIb) To a solution of 5.85 g of 17a-methyl-17ß-hydroxy-5 (10), 7-oestradien- 3-one (Vb) in 58 ml of methanol was given a solution of 5.85 g of sodium borohydride in 30 ml of methanol. After standing for 3 hours at room temperature, the mixture is filtered off and acidified to pH 6 with 20% aqueous acetic acid. After adding water, the compound precipitated and was recrystallized from aqueous methanol and then from a mixture of benzene and hexane. The product melted in an evacuated capillary at 152 to 162 ° C and showed an optical rotation value of MIT = -f- 168.9 ° (c = 10 /, in dioxane).

C19 H28 02 * Calculated ... C 79.120 / 0, H 9.790 / 0; found ... C 79.410 / 0, H 9.72%. Example 3 Preparation of the diacetate of 3,17β-dihydroxy-5 (10), 7-oestradiene 1 g of 3,17β-dihydroxy-5 (10) -oestradiene (VIa) was dissolved in a mixture of 5 ml of pyridine and 10 ml of acetic anhydride and let the solution stand overnight at room temperature. For purification, the crude diacetate was chromatographed in 1: 1 benzene-petroleum ether on 30 g of aluminum oxide. After evaporation of the solvent, the diacetate remained as a colorless, viscous oil; [a] 14 '- f - 127.4 ° (c - 10/0 in chloroform). C22 H39 04 # Calculated ... C 73.720 / 0, H 8.44 found ... C 73.810 / " H 8.54%. Example 4 Preparation of the dibenzoate of 3,17ß-dihydroxy-5 (10), 7-oestradiens 2.0 ml of benzoyl chloride are added to a solution of 1.0 g of 3,17ß-dihydroxy-5 (10), 7-oestradien (VIa) in 10 ml of pyridine while cooling in an ice bath The mixture is poured onto ice at room temperature and the product is extracted with a mixture of ether and ethyl acetate. After washing with dilute hydrochloric acid, sodium bicarbonate solution and water, the solution is dried over magnesium sulfate and the solvent is removed in vacuo. The crude dibenzoate was dissolved in benzene-petroleum ether 1: 4 chromatographed on 60 g of aluminum oxide. The crystals obtained from the first 100 ml of the eluate showed, after recrystallization from acetone -methanol, a melting point of 174.5 to 177.5 ° C; [a] D ° _ -f- 152.3 ° (c = 10/1) in chloroform).

C32 H34 04 »Calculated ... C79.660 /" H7.100 / ,; found ... C 79.82%, H 7.03 Example 5 Preparation of the 3,17β-dihydroxy-5 (10), 7- oestradiendioenanthic acid ester 0.3 g of 3,17β-dihydroxy-5 (10), 7-oestradien in 3 ml of pyridine were reacted with 1.5 ml of oenanthic anhydride overnight at room temperature The solution, after dilution with water, is extracted with ether, the extract Washed with 3N hydrochloric acid, then with 1N sodium hydroxide solution and finally with water After evaporation of the dried solution, a pale yellow resin remained which was dissolved in petroleum ether, b.p. 40 to 60 ° C., and chromatographed on 5 g of aluminum oxide. After elution with benzene ether 1: 1 and evaporation, a colorless resin was obtained which, after being dissolved with petroleum ether, was treated with activated charcoal. The product was a colorless resin; [a] D ° _ + 68.8 ° (c = 0.96% in dioxane).

C32 H59 04 * Calculated ... C77.060 / "H10.110 / 0; found ... C77.320 /" H 9.98 Example 6 Preparation of the diester of 4,4-dimethylvaleric acid of 3,17ß-dihydroxy 5 (10), 7-oestradiens 0.5 g of 3,17ß-dihydroxy-5 (10), 7-oestradien in 1 ml of pyridine and 3 ml of benzene are mixed with 0.5 ml of 4,4-dimethylvaleric acid chloride in 1 ml of benzene dropwise added with shaking. The reaction mixture is left to stand at room temperature for 44 hours, diluted with benzene, washed with 1N sodium hydroxide solution, then with 3N hydrochloric acid and finally with water and dried over sodium sulfate. After evaporation, a colorless resin remained which was dissolved in a mixture of petroleum ether, boiling point 40 to 60 ° C., and benzene (1: 1, 100 ml) and chromatographed on 10 g of aluminum oxide. The same solvent mixture was used for elution, and the product obtained was a colorless resin with [a] δ ° = + 103.8 ° (c = 1.2% in dioxane).

C32 Hso 04, calculated ... C77.060 /,), H 10.11%; found ... C76.960 / " H 9.85 Example 7 Preparation of the diphenylacetic acid ester of 3,17ß-dihydroxy-5 (10), 7-oestradiene To an ice-cold solution of 0.5 g of 3,17ß-dihydroxy-5 ( 10), 7-oestradien in 1 ml of pyridine and 3 ml of benzene, 0.5 ml of phenylacetyl chloride in 1 ml of benzene was added and the reaction mixture was left to stand at room temperature overnight. Hydrochloric acid and washed with water and, after drying, the solvent was evaporated. The yellow resin was dissolved in 100 ml of benzene and chromatographed on 2.5 g of aluminum oxide. After elution with the same solvent, the colorless resin showed a rotation value of [a] δ ° - + 53.1 ° (c = 1.02% in chloroform).

C24 H38 04 * Calculated ... C 80.00%, H 7.45%; found ... C 80.26l) / 0, H 7.64 ° l0 Example 8 Preparation of the di-half ester of succinic acid of 3,17ß-dihydroxy-5 (10), 7-oestradiene 0.5 g of 3,17ß-dihydroxy 5 (10), 7-oestradien in 25 ml pyridine were heated with 0.5 g succinic anhydride for 3 hours on the steam bath. After adding a few drops of water, about 50% of the solvent was drawn off in vacuo. The strongly colored concentrate was diluted with water and extracted with ether. The ether extract was then extracted twice with 10% sodium carbonate solution and the alkaline extracts were combined and acidified with 1N hydrochloric acid. The resin which separated out was extracted with ether and the extract was washed with water and dried over sodium sulfate. The brown resin obtained after evaporation was dissolved in methanol and treated with activated charcoal. After evaporation, the product was obtained as a brittle, colorless resin. [a] ö ° = -f- 66 ° (c @ 1.03 l) /, in chloroform).

C2BH3408, Calculated ... C 65.83%, H 7.17%; found ... C 66.12 l) / o, H 6.97 ° / o. Example 9 Preparation of the dipropionic acid ester of 3,17β-dihydroxy-5 (10), 7-oestradiene 5 g of 3,17β-dihydroxy-5 (10), 7-oestradiene in 50 ml of pyridine are treated with 25 ml of propionic anhydride for 12 hours. The solution is diluted with water, extracted with ether and the ether extract is washed with 3N hydrochloric acid, 10% soda solution and water. After drying the ethereal solution with sodium sulfate, the ether is evaporated, whereby a cloudy resin was obtained, which was dissolved in 200 ml of petroleum ether and chromatographed on 100 g of aluminum oxide. After elution with a mixture of petroleum ether - benzene (1: 1) and evaporation, 3 g of a colorless resin were obtained which solidified on standing. After two recrystallizations from aqueous methanol, the colorless flakes melted at 65 to 68.degree. [a] δ ° = -E- 100 ° (c = 1.10 / 0 in chloroform).

C24H3404. Calculated ... C 74.61 "/ o, H 8.80%; found ... C 74.40 %, H 8.23%.

Example 10 Preparation of the 3-acetate of 3,17ß-dihydroxy-17amethyl-5 (10), 7-oestradiens A solution of 0.15 g of 3,17β-dihydroxy-17a-methyl-5 (10), 7-oestradien in 2 ml of pyridine and 2 ml of acetic anhydride was allowed to stand overnight at room temperature. The crude product obtained after evaporation in vacuo is dissolved in benzene and chromatographed on 3 g of aluminum oxide. 3,17β-Dihydroxy-17a-methyl-5 (10), 7-oestradien-3-acetate was obtained as a colorless varnish, which in the IR spectrum at 3660 cm- 'has an O H band and exhibited an ester carbonyl band at 1738 cm- '.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of stable anti-estrogenic compounds of the estran series of the general formula where R is hydrogen or a methyl group and R 'is hydrogen or an acyl radical of an organic mono- or dicarboxylic acid, characterized in that a''compound of the general formula is obtained by known methods in which R has the meaning given above, reduced to the corresponding trienenol ether, the trienenol ether acidically cleaved, the 3-keto compound obtained reduced and, if appropriate, the 3,17-dihydroxy-5 (10), 7-oestradiene obtained esterified to the corresponding mono- or diester . 2. The method according to claim 1, characterized in that that the cleavage of the 3-enolether under mild conditions, in particular with Acetic acid or oxalic acid.