DD143781A1 - PROCESS FOR THE PREPARATION OF 17-KETOGENE DERIVATIVES - Google Patents

Abstract

It is the production of 17-ketogonene derivatives, especially those with a A5 (10) Double bond and one carbonyl or ketal function in 3-position from the corresponding ones 170-hydroxy compounds described. The oxidation of the 170-hydroxy group is carried out by Pyridiniumchlorochromat in the presence of a buffer substance, wherein neither a hydrolysis of the Ketalgruppierung still occurs isomerization of the double bond. This will be essential Disadvantages of chromic acid oxidation used in the art for such tasks are avoided.

Description

Title of the invention

Process for the preparation of 17-ketogonene derivatives

Field of application of the invention

The invention relates to a process for the preparation of 17-. Eetogonene derivatives of the general formula I.

in which R represents a methyl or ethyl radical and E. represents two alkoxy groups, an ethylenedioxy group or an oxygen atom, from the corresponding 17β-hydroxy compounds »

Such substances are important intermediates for the synthesis of hormonal agents, such as horethhisterone, noräthinodrel, norgestrel, and others that are widely therapeutic. z "B" for fertility control.

Characteristic of the known technical solutions

The obtainable by the process according to the invention 17-Eetoverbindungen the general formula I are known. To their 'representation from the corresponding 17-hydroxy derivatives, use is usually the Ciiromsäureoxydation in the embodiment according to Jones, d _o .h _o using a aqueous sulfuric acid solution of chromic acid in acetone to oxidize "This method, however, is known to have several drawbacks * In particular Performs the acidic reagent often to a considerable extent

Hydrolysis of the ketal moiety and can cause isomerization of the double bond in the undesired Λ ^ - ^ - position * Furthermore, an oxidative attack of the double bond to form a 1013-hydroxy-O ^ keto- A ^ derivative is possible »

In this way, in the chromic acid oxidation of 17β-hydroxy compounds, by-products are formed in not inconsiderable quantities, which on the one hand greatly reduce the yield of the desired product, but on the other hand raise considerable difficulties in its isolation and purification.

When converting the 1-hydroxy-3-hydroxy group into the corresponding de keto function. Although the hydrolysis of the ketal groups and the isomerization of the double bond are prevented by Oppenauer oxidation, their performance is known to be very material. time-consuming, so that for economic reasons it is usually no alternative to chromic acid oxidation for the technology *.

Object of the invention

The aim of the invention is the preparation of 17-ketogonene derivatives of general formula I from the corresponding 17β-hydroxy compounds while avoiding the deficiencies inherent in the known processes.

Explanation of the essence of the invention

The invention has for its object to provide _s an industrially feasible process that permits it, 17ß * -hydroxy "gone derivatives to be converted into the 'corresponding 17 ™ keto compounds of the general Pormel I, without causing hydrolysis of the ketal groups in 3' position, a loomerization of the double bond or a hydroxylation in 10 ~ takes place »

According to the invention, this object is achieved by reacting hydroxygonomes of the general formula II,

% J> V * J

II

where R is a methyl or ethyl radical and R.sup.2 alkoxy groups, an ethylenedioxy group or an oxygen atom is in a suitable solvent, in particular a halohydrocarbon such as chloroform or methylene chloride at low temperature, preferably in the temperature range between 0 ⁰ C and -15 ⁰ C in the presence of a buffering agent such as Z ₀ B · Natriuraacetat with pyridinium treated after oxidation, excess oxidant and reduced chromium complex either precipitated by addition of ether or adsorbed on silica gel and filtered and the resulting 17-keto compound of general Pormel I according to the Chemistry usual methods isolated and pure «

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

embodiments

to 3,3-dimethoxy- "13β-methyl-gon-5 (i0) -en-17" on 17.2 g (0.08 mol) of pyridinium-2-chlorochromate and 7 g of water-free sodium acetate are suspended in 150 ml of methylene chloride and the suspension to about -15 ⁰ C _e · cooled While stirring, 11.5 g (0.04 mol) 3,3-5imethoxyH3ß-> methyl · - * gon-5 (NG) -en ~ ~ ol dissolved in 17ß 50 ml of methylene chloride added to the cooled suspension within 45 min. After about 5 hours of stirring in a temperature range of "10 to -3 ⁰ C virtually complete reaction is achieved. To the reaction solution is then added dropwise with stirring ether and the temperature of the solution during the dropwise addition

"Held 5 ⁰ C bis. 3 ⁰ C. The resulting precipitate is filtered off, washed again with ether and the combined filtrates concentrated in vacuo

Yield: 10.3 g (90 fo d _o Th,), recrystallization from methanol gives colorless needles of mp, 116 ⁰ C, ßj ψ + 209 ° (ο ~ Ο, 5, chloroform),

13ß-methyl-gon ~ 5 (NG) -ene-3,17-dione

78.8 g (0.36 mol) of pyridinium chlorochromate are suspended in 400 ml of methylene chloride and, after addition of 30.0 g (0.36 mol) of anhydrous sodium acetate under constant rest, cooled to 0 ⁰ C to -5 ⁰ C. For this purpose, a solution of 50 g (0.183 mol) of 17β-hydroxy-13β-methyl-gon-5 (i0) -en-3-one in 800 ml of methylene chloride is now added dropwise rapidly. Then still about ₉ Y2 hour at 0 ⁰ C is stirred to -5 ⁰ C, then removed to the cooling bath and the batch is allowed to come to room temperature * Now 200 g of silica gel G are added portionwise to the reaction mixture without interrupting the stirring ,, After the addition The mixture is stirred for a further 15 min, then the solid components are filtered off and washed with methylene chloride. Upon concentration of the filtrate in vacuo, 40 to 44 g (80 to 88% d "Th *) of the M-ketone obtained · recrystallization from 80 tigern methanol gives colorless crystals, mp _0144-146 ⁰ C / oij ψ + 287 ° (c = 0.5, chloroform).

3,3-dimethoxy-13ß-ethyl-gon-5 (i0) -en-17-one

3.35 g (0.01 mol) of 3,3-dimethoxy-13ß-ethyl-gon ~ 5 (i0) -en- '17 oil dissolved in 30 ml methylene chloride, as described in Example 1 to a on about -10 ⁰ C cooled solution of 4 ₅ 3 g (0.02 mol) of pyridinium chlorochromate in methylene chloride added * Man stirred at -3 ⁰ C to -10 ⁰ C for about 4 hours and then worked as in Example 1 * written on _e is obtained 2.9 g (81 ίο d _e Th.) 3,3-dimethoxy-13ß ~ ethyl-gon ~ 5 (i0) -en-17-one, m.p., 83 to 87 ⁰ C, C ^ ⁰ J Ψ * " ¹ ^ ⁰ C ° = 0j5; chloroform) after recrystallization from Hexaiu

4 * 13β-ethyl-gon-5 (10) -o-3,17-dione

8.9 g (Oy31 mol) of 17-hydroxy-13i3-ethyl-gon-5 (i 0) -en-3-one • are as described in Example 2, is reacted with pyridinium · obtained 5> 8 g (about "65 $ d, Th.) Diketone, which, after recrystallization from 813 aqueous methanol, gave colorless crystals Cc = .0.5; Chloroform).

Methanol, colorless crystals of melting point ₀ 133 ⁰ C, £ o <J ψ + 223 °

Claims (1)

Invention claim. Process for the preparation of 17-ketogonene derivatives of general formula I wherein E represents a methyl or ethyl radical and R represents two alkoxy groups, an ethylenedioxy group or an oxygen atom, characterized in that 17ß-Hydroxygonene eggs general Pormel wherein E and R have the abovementioned meaning in a suitable solvent, in particular a halohydrocarbon such as chloroform or methylene chloride at low temperature, preferably in the temperature range between 0 ⁰ C and -Ί5 ⁰ C in the presence of a buffer substance such as z, B _P Ufatriumacetat treated with pyridinium chlorochromate, then excess oxidizing agent and Chromkomp ^ ex precipitated by the addition of ether or adsorbed on silica gel and filtered off and the thus obtained 17-keto compounds of the general Pormel I isolated according to the methods customary in chemistry and pure ·