DE1157608B - Process for the production of unsaturated í¸-21-Bishomo-21b-carboxylic acids of the Pregnan, Allopregnan-, Pregnen or Pregnadiene series - Google Patents

Description

Process for the preparation of unsaturated 421 (21a) -21-bishomo-21b-carboxylic acids of the Pregnan, Allopregnan-, Pregnen or Pregnadien series It is already known that methyl iodide with triphenylphosphine-carbäthoxymethylene to form propionic acid can implement (see, for example, H. J. Bestmann et al., Tetra = hedron Letters, No. 4 [1960], p. 5). In the first reaction stage, the methyl iodide forms with the acylylide the triphenyl-carbäthoxyäthyl-phosphoniumjodid, which hydrolytically with alkali can cleave to propionic acid.

It has now been found that unsaturated 421 (21a) _21-bishomo-21b-carboxylic acids the Pregnan-, Allopregnan-, Pregnen- or. Pregnadia series can be established by a 21-bromine or iodine steroid of the Pregnan, Allopregnan-, Pregnen or Pregnadien series with 2 equivalents of a triphenylphosphine lower carbalkoxymethylene, expedient in the presence of an inert solvent in which the resulting during the reaction Triphenyl-lower ca.rbalkoxy-methylphosphonium iodide or bromide sparingly soluble is, treated and then the ester group in the 21b position with water and alkali saponified in a known manner.

As starting materials for the method according to the invention, for. B. the following «-halogen ketones into consideration: 21-iodine-d4-pregnen-3,20-dione, 21-iodine-pregnane-3,20-dione, 21-iodine-44-pregnen-3,11,20-trione -17a-ol, 21-iodine-41 # 4-pregnadien-3,11,20-trione-l7a-01, 21-iodine-44-pregnen-3,20-dione-11ß, 17 «-diol, 21-iodine-d 1,4-pregnadiene-3,20-dione-I 1 ß, 17a-diol, 21-iodine-6a-methyl-d1,4-pregnadiene-3,20-dione 11β, I7 «-diol, as well as the corresponding 21-bromo-steroids. The implementation proceeds as follows Formula schemes: In the formulas "Hal" means a bromine or iodine atom, and R stands for a low molecular weight alkyl group, e.g. B. for a methyl, ethyl, propyl or butyl group. The success of the reaction is largely independent of the structure of the steroids used. For example, the steroids can contain hydroxyl groups in the 11- or 17-position, methyl groups in the 2-, 16- and / or 6-position, fluorine atoms in the 6- or 9-position and double bonds in the 1-, 4-, 16- or 9-position (11 ) Position without disturbing the course of the reaction.

The production of the new 421.21a-steroid-21-bishomo-carboxylic acids-21b is carried out without isolation of intermediates.

In the first stage of the reaction, the 21-haloketones mentioned as starting materials react with an equimolar amount of an acylyhde of the formula wherein R is a low molecular weight alkyl radical, e.g. B. a methyl, ethyl, propyl or butyl group, means, with the formation of a corresponding phosphonium salt. The latter compound, together with a second mole of acylide, which acts as a base, yields a γ-keto-acrylic acid ester with Hofmann degradation of the formula CH - CH - COOR I. CO D. where R has the meaning given. As a by-product z. B. Triphenyl carbäthoxymethylphosphonium iodide or bromide of the formula and triphenylphosphine.

It is expedient to work in an inert solvent, such as benzene, Dioxane or ethyl acetate, in which z. B. the triphenyl-carbäthoxymethyl-phosphonium iodide or bromide is sparingly soluble and therefore easily through after completion of the reaction Suction can be separated. The reaction temperatures are generally between 0 ° C and the boiling point of the solvent used. Reaction time and reaction temperature depend to a large extent on the structure of the 21-haloketone used addicted. In general, the reaction takes between 1 and 20 hours.

In the second stage, without isolating the ester formed as an intermediate product, the reaction mixture is converted into the desired end product of the formula in a water-miscible organic solvent by treatment with water and subsequently with alkalis with saponification of the ester group convicted. As a solvent, for. B. into consideration: ketones such as acetone, cyclic ethers such as dioxane or tetrahydrofuran, polyhydric alcohols such as ethylene glycol or propylene glycol.

The hydrolysis is known per se by alkaline saponification Way completed. One works without isolating the intermediate products formed and expediently uses the same solvent as in the hydrolytic cleavage with water. As basic agents come z. B. alkali hydroxides, such as sodium or Potassium hydroxide, alkali carbonates or bicarbonates, such as sodium carbonate or potassium bicarbonate, or alkali metal alcoholates, such as sodium methylate or potassium ethylate, into consideration. Advantageous the basic component is added dissolved in water and saponified by prolonged exposure Leave to stand at room temperature or by refluxing for several hours. After the reaction has ended, that which may have arisen as a result of side reactions Triphenylphosphine oxide together with the triphenylphosphine by repeated extraction separated with a suitable solvent, for example diethyl ether. By When the aqueous phase is acidified, the 421,21a-21-bishomo-21b-carboxylic acids are precipitated.

The new process products are themselves pharmacologically effective or are intermediates for the production of pharmaceutically interesting follow-up compounds Example 1, j4.21 (21a) -Pregnadiene-3,20-dione-21-bishomocarboxylic acid-21b a) from 21-iodine-44-pregnen-3,20-dione 2.2 g (^ - 5 mmol) of 21-iodine-44-pregnen-3,20-dione with 3.5 g (^ - 10 mmol) triphenylphosphine carbethoxymethylene in 60 ml ethyl acetate heated with mechanical stirring and reflux. After about 5 minutes it starts a crystalline precipitate of triphenyl-carbethoxymethyl-phosphonium iodide to precipitate, the amount of which increases over the course of hours. After cooling it was 2.26 g triphenyl-carbethoxy-phosphonium iodide sucked off, d. i.e., 95% of the iodine was in Form of iodide ions removed from the mixture.

The ethyl acetate is concentrated under reduced pressure and the resinous residue is dissolved in 100 ml of acetone. After adding 20 ml of water, the pH of the solution is around 8.5. The reaction mixture is then heated on the steam bath for 2 hours, the pH of the solution falling to 6. A solution of 2 g of sodium carbonate in 20 ml of water is then added and the mixture is refluxed for 4 hours. Then 60 ml of water are added and the resulting triphenylphosphine is extracted three times with 150 ml of ether. After acidification of the aqueous solution, 1.3 g of 44.21t21a> -pregnadiene-3,20-dione-21-bishomocarboxylic acid-21b with a melting point of 244 ° C. are obtained. After recrystallization from acetone, the melting point is 258 ° C.

b) from 21-bromo-44-pregnen-3,20-dione 2.1 g of 21-bromo-44-pregnen-3,20-dione are with 3.5 g triphenylphosphine-carbäthoxymethylene in 90m1 ethyl acetate Heated for 5 hours with stirring and under reflux. One sucks off. resulting triphenyl carbethoxymethyl phosphoniujljodid. i from and the filtrate works according to the example 1, a) specified regulation. 1.0 g of 44.21 (21a) _pregnadiene-3,20-dione-21-bishomocarboxylic acid-21b are obtained with a melting point of 240 ° C.

Example 2 44.21 (21a) _pregnadien-3,11,20-trione-17a-ol-21-bishomo-ca Rbonsäure-21b -2.35 g of 21-iodine-44-pregnen-3,11,20-trione-17a-ol are in 260 ml of ethyl acetate dissolved and added 3.5 g of triphenylphosphine carbethoxymethylene. It will be 7 hours heated under reflux, the equivalent amount of triphenyl-carbethoxy-phosphonium iodide separates. After the phosphonium salt has been filtered off with suction, the filtrate becomes dry evaporated and the pale yellow resin obtained dissolved in 80 ml of dioxane and 20 ml of water admitted. After storing overnight at room temperature, it becomes a solution of 2 g of sodium carbonate in 20 ml of water and stirred for 24 hours at room temperature touched. It is then diluted with water and the triphenylphosphine with ether extracted. After acidification of the aqueous solution, 0.8 g of 44.2o (21a) -Pregnadiene is obtained - 3,11,20 - trione -17a - o1 - 21- bishomo - carboxylic acid-21b, melting point 255 up to 260 ° C. Example 3 6a-methyl-41.4,21 (21a) -pregnatriene-3,20-dione-lβ, 17a-diol-21-bishomo-carboxylic acid-21b 2.9 g of 21-iodo-6a-methyl-41,4-pregnadiene-3,20-dione-11ß, 17a-diol are mixed with 3.5 g of triphenylphosphine carbethoxymethylene heated under reflux for 7 hours in 200 ml of ethyl acetate. During this time 2.0 g of triphenylcarbethoxymethylphosphonium iodide separate. After suction the light yellow solution is evaporated to dryness and the resulting resin in 100 ml of acetone and 20 ml of water dissolved. It is refluxed for 2 hours and then boiled with 2 g of sodium carbonate in 20 ml of water for a further 4 hours. It is diluted with water and the triphenylphosphine oxide is extracted with ether. the aqueous solution is acidified. 1.1 g of 6a-methyl-A 1,4,21 (21a) -Pregnatriene-3,20-dione-11 are obtained β, 17a-diol-21-bishomo-carboxylic acid-21b, melting point 240 ° C. Example 4 41,4.21c 21 a> -Pregnatriene-3,20-dione-11 ß, 17 a-diol-21-bishomo-carboxylic acid-21b 2.35 g 21 - Iodine - 41.4 - pregnadiene - 3.20 - dione III, 17a-diol are dissolved in 600 ml of ethyl acetate dissolved and added 3.5g triphenylcarbethoxymethylene. After heating for 1 hour 500m1 of ethyl acetate are distilled off. The residue is taking another 6 hours Heated to reflux. Then the resulting phosphonium salt is suctioned off and distilled the ethyl acetate under reduced pressure. The resin is in 100 ml of acetone and 20 ml of water taken up and heated under reflux for 1 hour. After adding 2 g of sodium carbonate, dissolved in 20 ml of water, heated for 4 hours. The reaction mixture is then diluted with water and extract the triphenylphosphine as usual with ether. From the aqueous Solution gives 0.95 g of 1 1,4,21 (21a) _pregnatrien-3,20-dione-11β, 17a-diol-21-bishomo-carboxylic acid-21b of melting point 235 ° C.

Claims (1)

PATENT CLAIM: Process for the preparation of unsaturated 421 (21a) -21-bishomo-21b-carboxylic acids the Pregnan, Allopregnan-, Pregnen or Pregnadia series, characterized in that that you have a 21-iodine or bromine steroid of the Pregnan, Allopregnan-, Pregnen or Pregnadien series with 2 equivalents of a triphenylphosphine - lower - carbalkoxymethylene, expedient in the presence of an inert solvent in which the resulting during the reaction Triphenyl-lower-carbalkoxymethylphosphonium iodide or bromide sparingly soluble is, treated, and then the ester group in the 21b position with water and alkali saponified in a known manner.