CH376911A - Process for the preparation of esters of new halogenpregnane compounds - Google Patents

Description

  

  Process for the preparation of esters of new halopregnane compounds The subject of the present patent is a process for the preparation of esters of new 17a-hydroxypregnenes of the formula
EMI0001.0004
    where X is fluorine or chlorine and R is an acyl radical of a carboxylic acid.

   It consists of having a 45; 17 (20) -3fl, 20-diacyloxy-16a-methyl-pregnadiene of the formula
EMI0001.0009
    where Ac denotes an acyl group, oxidized with a per acid, then hydrolyzed the acyloxy groups, in the 3,17a-dihydroxy-5a, 6a-oxido-16a-methyl-pregnan-20-ones obtained, the 3-hydroxy group is oxidized to the keto group and before or after this oxidation the 5a, 6a-oxido group to 6p,

  5a-fluorohydrin or chlorohydrin opens, the 5a-hydroxyl group is split off with formation of the 4,5 double bond, the 6p-halogen compounds obtained isomerized to 6a-halogen compounds and at any reaction stage after the oxidation in 3-th positions - the 17a-hydroxy group is esterified. In the 44-3 won,

  20-Dioxo-17a-acyloxy-16a-methyl-6a-fluoro- or -6a-chloro-pregnenen can also be introduced into a double bond in the 1,2-position.



  The procedure is illustrated in the formula below:
EMI0002.0001
    For the process according to the oxidation of the starting materials used z. B. organic peracids, especially perbenzoic acid, monoperphthalic acid or peracetic acid, in the presence of a suitable solvent such as ether and; or halogenated hydrocarbons.



  The acyloxy groups in the 5,6; 17,20 diepoxides formed are advantageously hydrolyzed with alkaline agents. One uses z. B. Solutions of alkali metal carbonates, bicarbonates or hydroxides in aqueous methanol or ethanol, dioxane or tetrahydrofuran. In addition, amines, such as.

   B. diethylamine, ethylenediamine or o-phenylenediamine, can be used. It is advisable to use the predominant amount of 5a, 6a-oxido-3ss, 17a-dihydroxy-16a-methyl-20-oxo-pregnane in the hydrolysis product by crystallization and / or chromatography on aluminum oxide from 5P, Separate 6ss isomers.



  For the oxidation of the hydroxyl group in the 3-position to the keto group, such Oxy dationsmittel that leave the side chain unchanged, z. B. chromic acid-pyridine complex, or with kur zer reaction time and chromic acid-sulfuric acid-acetone mixture, also N-chloro- or N-bromo carboxamides or imides, z. B. bromosuccinimide or bromoacetamide in aqueous solutions, e.g. B.

         aqueous acetone or pyridine.



  The splitting of the 5a, 6a-epoxide to form the 6ss-fluorine or 6ss-chloro-5a-hydroxy compounds takes place, as mentioned, before or after the oxidation of the 3-hydroxy group to the 3-keto group. For this you can use chloric or hydrofluoric acid in a solvent medium, for.

   B. in alcohols, ketones, ethers, halogenated hydrocarbons, such as methylene chloride or chloroform, preferably in lower aliphatic carboxylic acids such as glacial acetic acid or propionic acid, etc., or in mixtures of the solvents mentioned, advantageously at temperatures between 0-30.

   Instead of hydrogen chloride or hydrogen fluoride, pyridine or collidine hydrochloride or boron trifluoride etherate in benzene can also be used to split the 5a, 6a-epoxide. In these reactions, the 5α-hydroxy compounds with a 6ss fluorine or chlorine atom are obtained. 3-Hydroxy compounds are now oxidized to the corresponding 3-ketones, it being possible to use the oxidizing agents listed above.

   To split off water, the 3-oxo-5a-hydroxy-6ss-halogen compounds with bases, e.g. B. potassium hydroxide, or acids, e.g. B. hydrochloric acid, are treated. The 44-3-keto-6ss-halogen compounds are obtained. Depending on the used reaction conditions, e.g. B. Opening of the epoxy by means of hydrochloric acid gas in glacial acetic acid, the 44-3-keto-6a-halogen compounds can be formed in one reaction stage.

   The isomerization of the J4-3-keto-6ss-halogen compounds to the 44-3-keto-6a- halogen compounds is expediently carried out using hydrogen chloride gas in glacial acetic acid.



  The esters of the 17a-hydroxy compounds obtained are obtained by z. B. in well-ter manner with halides or anhydrides of z. B. aliphatic carboxylic acids, e.g. B. acetic, propionic, butyric acid, especially caproic acid, to set, advantageously in the presence of a catalyst such as pyridine, p-toluenesulfonic acid or perchloric acid.



  The introduction of the 1,2 double bond in the 44-3,20-dioxo-17a-acyloxy-16a-methyl-pregnenen obtained, which have a fluorine or chlorine atom in the 6a-position, can be carried out by means of dehydrogenating selenium compounds, e.g. B. selenium dioxide or selenious acid, in a tertiary alcohol such as amylene hydrate or tert. Butanol, or by microbiological de-hydrogenation.

   Various microorganisms known for this reaction are suitable for the microbiological dehydration, such as e.g. B. Di- dymella lycopersici, Corynebacterium simplex, Bacillus sphaericus, Mycobacterium lacticola, Fusarium solani, Calonectria decora.



  The d5; 17 ("0) - 3,20-diacyloxy-16a-methyl-pregnadienes used as starting materials are new; they can be obtained by the process described in Swiss Patent No. 368490.



  The 17a-esters obtained as end products and their d1-derivatives, such as 17a-acetates, 17a-capronates of 44-6a-fluoro-16a-methyl-17a-hydroxypregnen-3,20-dione, 44-6a-chloro-16a- methyl-17a-hydroxy-pregnen-3,20-dione, d1-4-6a-fluoro-16a-methyl-17a-hydroxy-pregnadiene-3,20-dione and 41,4-6a-chlorine-16a- methyl-17a-hydroxy-pregnad'ien-3,20-dione are characterized by a high progestative effect,

   which is superior to that of the natural hormone progesterone.



  In the examples below, which only describe embodiments of individual stages of the process according to the invention, the temperatures are given in degrees Celsius. <I> Example 1 </I> 4.1 g 45:17 (2o) -3ss, 20-diacetoxy-16a.-methyl-pregnadiene, dissolved in 30 ml ether, are mixed with 52 ml of a 0.575 molar, ethereal Phthalmonoperacid solution added and left to stand for 48 hours in the dark at room temperature,

   after which the phthalic acid and excess phthalic monoperacid formed are removed by shaking with aqueous sodium carbonate solution. After the ethereal solution has been dried with magnesium sulfate and the solvent has evaporated, the residue is crystallized by trituration with methanol. The diepoxide obtained in this way is a mixture of the four possible isomers, which differ due to the configuration in positions 5, 6 and 20.

   The 5a, 6a; 17a, 20-dioxido-3ss, 20-diacetoxy-16a-methyl-pregnane isomer pair can be obtained in pure form by fractional crystallization from ether. The melting point of the mixture of the two isomers, which differ only in their different configuration in position 20, is between 265 and 190, depending on the ratio of the two isomers.



  4 g of the isomer mixture of 5a, 6a; 17a, 20-dioxido-3ss, 20-diacetoxy-16a-methyl-pregnane, dissolved in 160 ml of methanol, are mixed with a solution of 2 g of potassium carbonate in 40 ml of water. The clear reaction mixture is refluxed for 11/2 hours and then diluted with twice the volume of hot water while stirring. After cooling to 0, the product which has crystallized out is filtered, washed with water until free from alkali and dried at 80 in a vacuum.

   The 5a, 6a-oxido-3ss, 17a-dihydroxv-16a-methyl-pregnan-20-one thus obtained melts at 245.



  <I> Example 2 </I> 0.25 g of 5a, 6a-oxido-3ss, 17a-dihydroxy-16a-methyl-pregnan-20-one, dissolved in 2.5 ml of pyridine, become a mixture of 0.25 g chromium trioxide poured into 2.5 ml pyridine. The reaction mixture is shaken well and left to stand at room temperature for 24 hours. The pyridine is then carefully evaporated in vacuo, the residue is triturated thoroughly with 100 ml of ether, the ethereal solution is washed with dilute acetic acid, sodium carbonate and water, dried and evaporated.

    The amorphous residue is made to crystallize by spraying with ether, filtered and washed with a little ether, the 5a, 6a-oxido-16a-methyl-17a-hydroxy-pregnane-3,20-dione being obtained. <I> Example 3 </I> 3.3 g of 5a, 6a-oxido-16a-methyl-17a-hydroxy-preg-nan-3,20-dione are dissolved in 400 ml of benzene ether (1: 1), the solution with 3.3 ml of boron trifluoride ether sets ver and the reaction mixture left to stand for 8 hours at room temperature.

   The reaction solution is then washed with 50% aqueous sodium bicarbonate solution and water, dried with magnesium sulfate and evaporated. Purification by crystallization from acetone-hexane leads to 5a, 17a-dihydroxy-6, ss-fluoro-16a-methyl-pregnane-3,20-dione.



  If the same starting material is treated with hydrochloric acid gas in glacial acetic acid instead of with boron trifluoride ether for 18 hours, evaporated, washed acid-free, dried and recrystallized from acetone-hexane, the 44-6a-chloro-16a-methyl-17a-hydroxy-pregnen is obtained -3,20-dione.



  To convert into the 17a-acetate, 1 g of I4-6a-chloro-16a-methyl-17a-hydroxy-pregnen-3,20-dione is dissolved in 10 ml of acetic anhydride, 120 mg of p-toluenesulfonic acid are added and left for 24 hours at room temperature stand. It is then poured into water, warmed briefly on the water bath, filtered and the dried residue is crystallized from acetone-hexane, the 44-6a-chloro-16a-methyl-17a-acetoxy-pregnen-3,20-dione being obtained.



  In an analogous manner, higher 17a esters, such as. B. produce the 17a-capronate of d4-6a-chloro-16a-methyl-17a-hydroxy-pregnen-3,20-dione.



  <I> Example 4 </I> 2.1 g of 5a, 6a-oxido-3ss, 17a-dihydroxy-16a-methyl-pregnan-20-one are dissolved in 300 ml of a mixture of benzene and ether (1: 1) and treated with 2.1 ml of boron fluoride etherate. After 6 hours the reaction mixture is washed with aqueous sodium bicarbonate solution and then with water, dried with magnesium sulfate and evaporated in vacuo.

   In the residue is the desired 3ss, 5a, 17a-trihydroxy 6ss-fluoro-16a-methyl-pregnan-20-one, which is obtained by oxidation in acetone with excess 8-n. Chromic acid at 0 can be converted into the 5a, 17a-dihydroxy-6ss-fluoro-16a-methyl-pregnane-3,20-dione described in Example 3. <I> Example S </I> In a solution of 1.6 g of 5a, 17a-dihydroxy-6ss-fluoro-16a-methyl-pregnane-3,20-dione in 16 ml of acetic acid is dry at 15 for 2 hours Hydrochloric acid gas introduced and then left to stand for 18 hours at room temperature.

   The reaction mixture is now diluted with water and extracted with ether. The ethereal solution is washed with aqueous bicarbonate solution, dried with magnesium sulfate and evaporated. The crude d1-6a-fluoro-16a-methyl-17a-hydroxy-pregnen-3,20-dione obtained in this way can be purified by chromatography on silica gel.



  The d4-6a-fluoro-16a-methyl-17a-hydroxy-pregnen-3,20-dione described above can be esterified in the 17-position analogously to the information in Example 4. One wins z. B. in this way the 17a-acetate, 17a-propionate or 17a-capronate of J4-6a-fluoro-16a-methyl-17a-hydroxy-pregnen-3,20-dione.

 

Claims (1)

PATENT CLAIM Process for the preparation of esters of new halogen precursors of the formula EMI0004.0078 where X is fluorine or chlorine and R is the acyl radical of a carboxylic acid, characterized in that a 45; 17 (20) -3 #), 20-diacyloxy-16a-methyl-pregnadiene of the formula EMI0004.0083 where Ac denotes an acyl group, oxidized with a peracid, then the acyloxy groups hydrolyzed, in the 3,17a-dihydroxy-5, a, 6a-oxido-16a-methyl-pregnan-20-ones obtained the 3-hydroxy group oxidized to the keto group and before or after this oxidation the 5a, 6a-oxido group to 61) 3,5a-fluorohydrin or chlorohydrin opens: the 5a-hydroxyl group is split off with formation of the 4,5 double bond, the 6ss-halogen compounds obtained isomerized to 6a-halogen compounds and opened Any reaction stage after the oxidation in the 3-position esterifies the 17 (c-hydroxyl group. SUBClaims 1. Process according to claim, characterized in that in the obtained d4-3,20-dioxo-17a-acyloxy-16a-methyl-6a-fluoro- or -6a-chloro-pregnenen in the 1,2-position by dehydrogenation a double bond introduces. 2. The method according to claim, characterized in that the peracid used is perbenzoic or perphthalic acid. 3. Process according to claim, characterized in that the acyloxy groups are hydrolyzed with alkaline agents. 4. The method according to claim, characterized in that the latter is separated from the mixture of the epimers he obtained 5ss, 6ss- and 5a; 6a-epoxies for further processing. 5. The method according to claim, characterized in that the 3-hydroxyl group is oxidized to the 3-oxo group using a chromic acid-pyridine complex. 6. The method according to claim, characterized in that the 5a, 6a-epoxides are split up by means of fluoric or hydrochloric acid. 7. The method according to claim, characterized in that the 3-oxo-5a-hydroxy-6ss-halogen compounds obtained are dehydrated with glacial acetic acid-hydrogen chloride to give the 44-6a-halogen compounds. B. Process according to patent claim, characterized in that the t14-6ss-halogen compounds obtained are isomerized to 44-6a-halogen compounds by treatment with glacial acetic acid-hydrogen chloride. 9. The method according to claim and the dependent claims 1-4, characterized in that the starting material used is the 45:17 (zo) -3ss, 20-diacet-oxy-16a-methyl-pregnadiene,