DD246113A1 - METHOD OF GENERATING NEW 17 ALPHA-SUBSTITUTED 5 ALPHA-ESTR-8 (14) -EN-3-ONE - Google Patents

Abstract

The preparation of 17a-substituted 5a-estr-8 (14) -en-3-ones which are of therapeutic interest because of their antihormonal properties is described. The starting product of the synthesis is 5a-estr-8 (14) -en-3,17-dione which, after conversion into the 3-dimethylketal, is converted with dimethylsulfonium methylide into the 17b-spirooxirane. Reaction of the latter with nucleophilic agents, especially sodium cyanide, sodium azide and pyridinium hydrochloride, followed by acidic hydrolysis of the ketal group leads to the 17a-substituted 5a-estr-8 (14) -en-3-ones.

Description

in which X stands for N ₃ , CN and Cl, which, owing to their valuable biological properties, in particular their anti-hormonal effects, can be advantageously used in pharmaceutical preparations for reproductive control in humans and in livestock. The compounds which can be prepared by the present process are new. Their preparation has hitherto not been described in the literature and in patents.

Object of the invention

The aim of the invention is the preparation of 17a-CH ₂ X-substituted steroid derivatives with 5a-Estr-8 (14) -en-3-one structure.

Explanation of the essence of the invention

The invention has for its object to provide a technically easy to implement and economically favorable process for the preparation of 17a-CH ₂ X-substituted 17 <* - hydroxy-5a-estr-8 (14) -en-3-ones. According to the invention, this object is achieved in that 5a-Estr-8 (14) -en-3,17-dione (II) in a conventional manner by treating with methanol in the presence of catalytic amounts of p-toluenesulfonic in the 3.3 -Dimethoxy-5a-estr-8 (14) -en-17-one (III). This is dissolved after isolation and purification in dimethyl sulfoxide and at about 10 ⁰ C room temperature with dimethyl sulfonium in the 17/3-spiro-1 ', 2'-oxirane (IV), which after isolation and

Purification with normal nucleophilic agents under acidic, neutral or alkaline conditions in organic solvents of normal or elevated temperature to give 17a-CH ₂ X-substituted 3,3-dirnethyloxy-5a-estr8 (14) -en-17/3-ols (V) is implemented. By treatment with p-toluenesulfonic acid in acetone or with dilute acids in aqueous-organic. Solvents are converted to the corresponding 17a-substituted-17/3-hydroxy-5a-estr-8 (14) -en-3-ones (I). The individual reaction steps of the process according to the invention are illustrated by the following scheme:

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The process according to the invention is advantageously carried out as follows:

The 5cx-Estr-8 (14) -en-3,17-dione (II) used as starting material for the process according to the invention belongs to the prior art and can be prepared by per se known method by treatment with methanol in the presence of p-toluenesulfonic acid in 3,3-dimethoxy-5a-estr-8 (14) -en-17-one (III). The conversion of the thus obtained 3,3-dimethoxy-5a-estr-8 (14) -en-17-one (III) in the spirooxirane (IV) is carried out with excess dimethylsulfonium in DMSO, - preferably proceeding so that to a solution of trimethylsulfonium iodide and steroid ketone in DMSOKliumtert.-butoxide at about 10 ° C adds. After completion of the addition is stirred for a short time, then the approach is added to ice water, the resulting oxirane precipitate filtered off with suction and recrystallized from methanol.

As nucleophilic agents for the cleavage of the spirooxirane (IV) to the 17a-CH ₂ X-substituted 3,3-dimethoxy-5a-estr-8 (14) -en-17/3-ols (V) come Natriumacid, alkali cyanides and pyridinium in pyridine. The choice of solvent depends on the solubilities of the spirooxirane used and the nucleophilic agent used and can be varied within wide limits. Well suited z. As ethers, DMSO, ethylene glycol, DMF and alcohols, optionally ynter addition of water. The temperature at which the reaction is carried out, can be varied within wide limits and is generally in the range between 20 ⁰ C and 100 ⁰ C.

The cleavage of the thus obtained 17a-CH ₂ X-substituted dimethyl ketals (V) is generally carried out by dissolving or suspending the compounds in a water-miscible solvent, in particular acetone, methanol, ethanol or pyridine and adding an aqueous solution of an acid , As acids, especially organic acids such as p-toluenesulfonic acid, acetic acid, oxalic acid, citric acid or succinic acid are used, but also dilute mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or perchloric acid are suitable. The isolation and purification of the thus obtained 17a-CH ₂ X-substituted 5a-Estr-8 (14) -en-3-ones (I) is carried out according to the methods customary in chemistry.

embodiments

The following examples are intended to explain the process according to the invention in more detail without restricting it in any way:

1. 17a-Cyanomethyl-17/8-hydroxy-5a-estr-8 (14) -en-3-one

A.) 4g (14.6 mmol) 5 a-Estr-8 (14) -en-3,17-dione are dissolved in 50 ml of absolute methanol. A small spatula tip of p-toluenesulphonic acid is then added at room temperature with stirring. Within a few minutes, the dimethylketal formed precipitates out. In the DC, after about 10 minutes of reaction time, complete reaction can be seen. The precipitate is filtered off with suction after about 15 to 30 minutes and optionally recrystallized from methanol. This gives 4.3 g (92% of theory) of 3,3-dimethoxy-5a-estr-8 (14) -en-17-one, mp. 145-147 ° C.

B.) 2.5g (7.85mmol) of 3,3-dimethoxy-5o; -estr-8 (14) -en-17-one and 3.2g (15.6mmol) of trimethylsulfonium iodide are dissolved in 40ml of DMSO and under argon and stirring the reaction solution in an ice bath in portions 3.5 g (27.3 mmol) of potassium tert-butoxide added. After completion of the addition of the base, the temperature is maintained between 10 and 20 ° C. After about 1 h and previous TLC analysis, the reaction solution is added to ice-water. The precipitation of the crude oxirane is filtered off and recrystallized from methanol. This gives 1.32 g (50.6% of theory) of 3,3-dimethoxy-5a-estr-8 (14) -en-17/3-spiro-1 ', 2'-oxirane from mp. 96 to 99 ⁰ C. [α] § ⁵ + 45.0 ° (c = 1, chloroform). From the mother liquor still yield 900 mg crystalline substance of mp. 80 to 84 ° C.

C.) 0.6g (1.8mmol) of 3,3-Dimethoxy-5a: -estr-8 (14) -en-17/3-spiro-1 ', 2'-oxirane are dissolved in 15ml-.80% aqueous ethanol. dissolved and added O, 5g (10.2 mmol) of sodium cyanide. The suspension is stirred for about 30 minutes to 1 hour and then left for 16 hours at room temperature. After preliminary TLC analysis, the reaction solution is stirred into ice-water. The resulting precipitate is filtered off with suction in the refrigerator and dried in a vacuum desiccator over calcium chloride. This gives 0.6 g (92v6% of theory) of S ^ -Dimethoxy- ^ a-cyanomethyl-Baestr-8 (14) -en-17/3-ol, mp 150 ⁰ C, which without further purification in the next level is used. - D.) 0.2 g (0.55 mmol) of dimethoxy-17a-cyanomethyl-5a-estr-8ti14) -en-17/3-ol are stirred with 30 to 35 ° G bath temperature in 10 ml of 80% aqueous acetone Then 0.6 ml of an acetonic sulfuric acid prepared by mixing 1 ml of concentrated sulfuric acid, 3 ml of water and 80 ml of 50% acetone are added to the solution. At constant bath temperature, the mixture is stirred for about 1 hour and the reaction solution is then stirred into ice-cold dilute sodium bicarbonate solution. After extraction with ether and evaporation of the solvent in vacuo, 0.25 g of oil remain. After preparative layer chromatography on silica gel PF ₂₅₄ and elution of the main fraction with acetone, followed by recrystallization from ether, 0.08 g (45.9% of theory) of 17a-cyanomethyl-17β-hydroxy-5a-estr-8 (14) en-3-one of mp. 135 to 136 ° C; [a] o ^s + 51.2 ° (c = 1, chloroform)

2. 17a-Azidomethyl-17H-hydroxy-5a-estr-8 (14) -en-3-one

A.) 3.1 g (9.0 mmol) of 3,3-dimethoxy-5a-estr-8 (14) -en-17/3-spiro-1 ', 2'-axirane, which according to the above Example 1 (AB) are suspended in 200 ml of ethylene glycol and 100 ml of acetone and stirred after addition of 6 g (92.3 mmol) of sodium azide at room temperature for 27 hours and then allowed to stand for about 80 hours. After this time, the reaction mixture is cooled in a cold bath (ice / brine) and added dropwise ice water. After filtering off the precipitate and drying in a desiccator over calcium chloride (vac.), 3.4 g (97.1% of theory) of 3,3-dimethoxy-17a-azidomethyl-5a-estr-8 (14) -en- 17β-ol, which is used without further purification in the next stage.

B.) 3.4 g (9.0 mmol) of 3,3-dimethoxy-17a-azidometnyl-5a-estr-8 (14) -en-17/3-ol are dissolved in 170 ml of acetone and 170 mg p Toluenesulfonic acid, dissolved in 20 ml of water was added. TLC analysis after approx. 30 minutes shows complete reaction. The acetone reaction solution is then added dropwise to a cooled dilute sodium bicarbonate solution, the precipitate is filtered off with suction, dried in a desiccator over calcium chloride (vac.) And recrystallized from acetone. This gives 1.59 g (53.4% of theory) of 17a-Azidomethy! -17 / 3-hydroxy-5a-estr-8 (14) -en-3-one, mp. 146-149 ° C; [a] § ⁵ + 62,0 ° (c '= 1, chloroform)

3. 17 a-chloromethyl-17/3-hydroxy-5 <x-estr-8 (14) -en-3-one

0.3 g (0.9 mmol) of 3,3-dimethoxy-5o: -estr-8 (14) -en-17/3-spiro-1 ', 2'-oxirane are dissolved in 6 ml of pyridine and 0.4 g (3.46 mmol) of pyridinium hydrochloride was added. After heating for 5 to 10 minutes on the steam bath, the batch is cooled to room temperature, a few drops of water are added and allowed to stand for about 2 to 4 hours. DC analysis after this time shows complete sales. The reaction solution is then added to ice-cold dilute sulfuric acid. The precipitate is extracted with ether. This gives 0.2 g of oil. After preparative layer chromatography of the oil on silica gel PF ₂ 64 and elution of the main fraction with acetone, followed by recrystallization from acetone yield 0.11 g (44.6% of theory).

n-S-one of mp. 188-189 ° C; [α] "+ 48.9 ° (c = 1, chloroform)

Claims (4)

Invention claim: 1. Process for the preparation of 17a-substituted 5a-estr-8 (14) -en-3-ones of the general formula I, in which X is N ₃ , CN and Cl, characterized in that 5a-Estr-8 (14) -en-3,17-dione in a conventional manner in the 3,3-dimethoxy-5a-estr-8 (14) -en-17-one, this with trimethylsulfonium iodide and potassium tert -butylate converted to 17/3-spiro-1 ', 2'-oxirane, this with nucleophilic agents in an organic solvent at normal or elevated temperature to the 17a-substituted 3 , 3-dimethoxy-5a-estr-8 (14) -en-17/3-olene, then this by treatment with dilute acids in aqueous-organic solvents to the 17a-substituted 17y8-hydroxy-5o: -estr- 8 (14) -en-3-ones of the general formula (I). 2. The method according to claim 1, characterized in that the reaction of the 3,3-dimethoxy-5a-estr-8 (14) -en-17-onsz to the corresponding 17/3-spirooxirane with dimethylsulfonium in dimethyl sulfoxide takes place. 3. The method according to claim 1, characterized in that the cleavage of the 3,3-dimethoxy-5a-estr-8 (14) -en-17 ^ -spiro-1 ', 2'-oxirane with nucleophilic agents under acidic, neutral and alkaline conditions and preferably a water-miscible organic solvent is used as the solvent. 4. The method according to claim 1, characterized in that the hydrolysis of the 17 α-substituted 3,3-dimethoxy-5a-estr-8 (14) -en-17/8-ols in a water-containing organic solvent, preferably acetone, aliphatic alcohols or pyridine and as acids organic carboxylic acids, such as. B. p-Toluensulfonsäuren, acetic acid, oxalic acid, citric acid or succinic acid or a dilute mineral acid used _f as hydrochloric acid, hydrobromic acid, sulfuric acid or perchloric acid. Field of application of the invention The invention relates to a process for the preparation of 17a-substituted 5a-estr-8 (14) -en-3-ones of general formula I,