DD251142A1 - PROCESS FOR THE PREPARATION OF 16 ALPHA, 17 ALPHA-CYCLOHEXANO-17 BETA ACETYL GONEN-3-ONES - Google Patents

Abstract

It describes the preparation of 16a, 17a-cyclohexano-17b-acetyl-gonen-3-ones of the general formulas I and II, which have a high gestagene activity. In their preparation is based on 16a, 17a-cyclohexano-3-methoxy-17b- (2-hydroxyethyl) -gona-2,5 (10) serve the general formula III, which by enol ether cleavage with acid in aqueous acetone solution and by subsequent oxidation with Jones reagent in acetone in 16a, 17a-cyclohexano-17b-acetyl-gon-5 (10) -en-3-one of the general formula I be converted and by bromination-dehydrobromination with pyridine hydrobromide in pyridine in 16a, 17a -Cyclohexano-17b-acetyl-gona-4,9-dien-3-one of general formula II can be converted. The order of the last two reaction steps is reversible.

Description

Field of application of the invention

The invention relates to a process for the preparation of 16a, Na-cyclohexano-nß-cetyl-gonen-S-onen of the general formulas I and II

wherein R = CH ₃ or C ₂ H ₅ .

Compounds of the general formula I and II have a high gestagenic activity and are potential contraception agents.

Characteristic of the known technical solutions

The compounds which can be prepared by the process according to the invention are novel, their presentation has not yet been described.

Object of the invention

The aim of the invention is the preparation of 16a, Na-cyclohexano-ß-acetyl-gonen-S-onen of the general formulas I and II.

Explanation of the essence of the invention

The invention has for its object to provide a simple, technologically easy to implement process for the preparation of 16a, ITa-cyclohexano-nß-acetyl-gonen-S-onen of the general formulas I and II.

This object is achieved by reacting 16a, 17a-cyclohexano-3-methoxy-17 ^ - (2'-hydroxyethyl) -gona-2,5 {10) -dienes of general formula III,

R.

CO

Ui

in which R = CH ₃ or C ₂ H ₅ , by enol ether cleavage with dilute mineral acid in aqueous acetone, if appropriate with addition of a solubilizer such as methylene chloride in 16a, 17a-cyclohexano-17 / 3- (2'-hydroxyethyl) -gon-5 ( 10) -en-3-ones of the general formula IV,

where R = CH ₃ or C ₂ H ₅ , and these are reacted with pyridine hydrobromide perbromide or bromine in pyridine to give 16a, 17a-cyclohexano-17 / 3- (2'-hydroxyethyl) -gona-4,9-diene-3 onen of the general formula V, in which R = CH ₃ or C ₂ H ₅ , brominated and dehydrobrominated,

OH

and by chromic acid oxidation with Jones reagent in acetone to 16a, ^ a-cyclohexano- ^ ß-acetyl-gona- ^ S-dien-S-onen of the general formula II, wherein R = CH3 or C ₂ H ₅ means reacted.

or otherwise, first, by chromic acid oxidation with Jones reagent in acetone in 16a, α-cyclohexano - / J-acetyl-gon-5 (10) -en-3-one of the general formula I, wherein R = CH ₃ or C ₂ H ₅ ;

from which by bromination and dehydrobromination with pyridine hydrobromide or bromine in pyridine 16a, 17 a-cyclohexano - / S-acetyl-gona- ^ ii-diene-S-one of the general formula II, wherein R = CH ₃ or C ₂ H ₅ means to be produced.

The individual reaction steps of this process are illustrated by the following reaction scheme.

The 16a, 17a-cyclohexano-3-methoxy-17 ^ - (2'-hydroxyethyl) -gona-2,5 (10) -dienes III used as starting materials for the process have already been proposed.

The enol ether cleavage of compounds of general formula III is advantageously carried out with catalytic amounts of dilute sulfuric acid in aqueous acetone with the addition of methylene chloride.

Bromination-dehydrobromination is advantageously carried out with pyridine hydrobromide perbromide in pyridine. Upon addition of the brominating agent, the reaction solution is cooled down to 0 to -5 ° C. After bromination, excess halogenating agent is added by adding an olefin such as 2-methyl-2-butene or 2-pentene and then stirred at room temperature.

It is advantageous to carry out the bromination-dehydrobromination step at the stage of the 20-alcohols of the general formula IV.

The compounds of the general formulas I and II which can be prepared by the process are biologically active substances having high gestagenic activity. In the McPhail test, type I compounds have an activity that roughly matches the strength of progesterone, while type II compounds are much more potent than progesterone.

-4- 251 142 embodiments

The following exemplary embodiments are intended to explain the method according to the invention.

1. 16a, Na-cyclohexano - ^ / S-acetyl-IS-methyl-gon-O-O-en-S-on

1.1. 16a, 17a-cyclohexano-17 / 3- (2'-hydroxyethyl) -13-methyl-gon-5 (10) -en-3-one

1.38 g (3.72 mmol) of 1Qa , 17a-cyclohexano-3-methoxy-17 / M2'-hydroxyethyl) -13-methyl-gona-2,5 (10) -diene are dissolved in 32.4 ml of 80% acetone suspended and then treated with 1.2 ml of 0.15 molar sulfuric acid in 80% acetone. Then 3.3 ml of methylene chloride are added and the mixture is stirred for about 30 hours at room temperature. After the reaction, add water and extract the steroid with methylene chloride. Concentration of the extracts gives 1.26 g of 16a, 17a-cyclohexano-17a- (2'-hydroxyethyl) -13-methyl-gon-5 (10) -en-3-one, which in the form of its isomeric 20-alcohol as oil present and can be used without separation in the next stage.

1.2. 16a, n-cyclohexano-n-acetyMS-methyl-gon-BdOl-en-S-on

0.96 g (2.8 mmol) of 16a, 17a-cyclohexano-17 / 3- (2'-hydroxyethyl) -13-methyl-gon-5 (10) -en-3-one are dissolved in 30 ml of acetone, the solution on Cooled to 0 to 10 ° C and added with stirring with 1.5 ml of Jones reagent within 2 minutes. The mixture is stirred for a further 5-10 minutes and then added about 1 ml of isopropanol to destroy excess oxidizing agent. Thereafter, the steroid is precipitated in the cold by adding water. This gives 0.907 g of 16a, Na-cyclohexano-n / O-acetyl-IS-methyl-gon-ÖliOl-en-S-on, which can be recrystallized from acetone. M.p .: 162-166 ⁰ C [a] _D: + 178.6 ° (CHCl _3, c = 0.98)

2. 16a, ^ a-cyclohexano-n-acetyl-IS-methyl-gono-dien-S-on

2.1. 16a, 17a-Cyclohexano-17β- (2'-hydroxyethyl) -13-methyl-gona-4,9-dien-3-one

1.327 g (3.72 mmol) of 16a, 17a-cyclohexano-17 / 3- (2'-hydroxyethyl) -13-methyl-gon-5 (10) -3-one which is prepared according to the instructions given in Example 1, are dissolved in 26.5 ml of pyridine, the solution cooled to -5 to 0 ⁰ C and treated under stirring and under argon within 30 to 40 minutes with 1.445 g (3.98 mmol) pyridine hydrobromide perbromide. Then it is stirred for 30 min. With cooling and then 2-methyl-3-butene to eliminate excess bromine added. The mixture is then stirred for a further 5 hours at room temperature then water is added and the steroid is extracted with methylene chloride. The extracts are concentrated to dryness in vacuo and the residue is crystallized from acetone. This gives 1.06 g of 16a, ^ a-cyclohexano-i 7 j3- (2'-hydroxyethyl) -13-methyl-gona-4,9-dien-3-one, which without separation of the isomeric 20-alcohols in the next level can be used.

2.2. 16a, ^ a-Cyclohexano-nyS-acetyl-IS-methyl-gono-dien-S-on

0.679 (1.91 mmol) of 16a, 17a-cyclohexano-17 / 3- (2'-hydroxyethyl) -13-methyl-gona-4,9-dien-3-one are dissolved in 30 ml of acetone, then the solution is brought to 0 cooled to 10 ° C and added within 2 minutes with stirring with 1 ml of Jones reagent. After 10 minutes, add 0.5 ml of isopropanol to destroy excess oxidizing agent and extracted after adding water with methylene chloride. The residue obtained after evaporation of the methylene chloride is chromatographed on silica gel. Elution is with toluene / acetone 40: 1. After recrystallization from ether / n-hexane gives 0.543g 16a, Na-cyclohexano-n / J-acetyl-IS-methyl-gona-diene-S-on. F.: 115 to 119 ° C] a] _D : -168.5 ° (CHCl ₃ , c = 1.06)

3. 16a, α-Cyclohexano-β-β-acetyl-IS-methyl-gonaAg-diene-S-one

0.37 g (1.05 mmol) of 16a, Na-cyclohexano-n-acetyl-IS-methyl-gon-BOOl-en-S-one, prepared according to Example 1, are dissolved in 7.4 ml of pyridine and dissolved under argon with stirring the cold at 0 to -5 ° C with 0.403g (1.11 mmol) pyridine hydrobromide perbromide. After the last addition of the brominating agent is stirred for a further 30 minutes and then added 0.5 ml of 2-methyl-2-butene and then stirred for 5 hours at room temperature. After the reaction, water is added and the steroid is extracted with methylene chloride. The extracts are concentrated to dryness in vacuo and the residue is chromatographed on silica gel. Elution is with toluene / acetone 40: 1. Recrystallization from ether / n-hexane gives 0.23g of 16a, mp: 115-149 ° C] a] _D : -168.5 ° (CHCl3, c = 1.06).

Claims (3)

Invention claim: 1. A process for preparing 16a, α-cyclohexano-β-acetyl-gonen-s-ones of the general formulas I and II, wherein R = CH ₃ or C ₂ H ₅ , characterized in that 16a, 17a-cyclohexano-3-methoxy-17 / 3- (2'-hydroxyethyl) -gona-2,5 (10-dienes of the general formula III, in wherein R = CH ₃ or C ₂ H ₅ , by enol ether cleavage with dilute mineral acid in aqueous acetone, optionally with the addition of a solubilizer such as methylene chloride, in 16a, 17a-cyclohexano-17j8- (2'-hydroxyethyl) -gon-5 (10 ) -en-3-one of general formula IV, ti J wherein R = CH ₃ , or C ₂ H ₅ means, and these on the one hand with pyridine hydrobromide or bromine in pyridine to 16a, 17a-cyclohexano-17 / 3- (2'-hydroxyethyl) -gona-4,9-diene-3 -ones of the general formula V, wherein R = CH ₃ or C ₂ H ₅ , brominated and dehydrobrominated, and by chromic acid oxidation with Jones reagent in acetone to 16a, ^ a-cyclohexano-nß-acetyl-gonon-dien-S-onen of the general formula II , wherein R = CH ₃ or C ₂ H ₅ , reacted. or on the other hand, first by chromic acid oxidation with Jones reagent in acetone in 16a, 17a-cyclohexano- ^ ß-acetyl-gon-önoj-en-S-one of general formula I, wherein R = CH ₃ or C ₂ H ₅ , converts . from which by bromination and dehydrobromination with Pyridinhydrobromidperbromid or bromine in pyridine 16a, na-Cyciohexano-ITjß-acetyl-gonaAS-dien-S-one of the general formula Ii, wherein R = CH ₃ or C ₂ H ₅ , are prepared the last two reaction steps are interchangeable. 2. The method according to item 1, characterized in that the Enoletherspaltung of compounds of general formula III is advantageously carried out with catalytic amounts of dilute sulfuric acid in aqueous acetone with the addition of methylene chloride. 3. The method according to item 1 and 2, characterized in that the reaction solution is cooled down to 0 to -5 ⁰ C in the addition of the brominating agent and after the bromination excess halogenating agent by addition of an olefin such as 2-methyl-2-butene or 2-pentene binds and then stirred at room temperature.