DE1593213C3 - Process for the preparation of steroidazines excretion from 1248653 - Google Patents

Description

CH,

(I)

The present invention relates to a method for the production of new steroids, which have a high anabolic effectiveness and are free of side effects are androgenic, progestin, cortical and antihypophyseal and the formula

IO

in which R and R 'are each hydrogen or methyl and R "is the radical of an aliphatic carboxylic acid means with 2 to 10 carbon atoms, characterized in that one Steroid compound of the general formula II

OH

in which R and R 'have the above meaning, according to methods known per se with ethyl formate in Presence of sodium methylate, sodium hydride or sodium amide and tetrahydrofuran or dioxane reacts as a strongly polar solvent and then the 2-formyl compound obtained in the presence of gaseous hydrogen chloride and palladium on carbon as a catalyst in the same Reaction vessel and medium at atmospheric pressure up to the uptake of 2 moles of hydrogen hydrogenated per mole of 2-formyl derivative, the resulting 2 <z-methyl derivative after removal of the Solvent and the catalyst with an anhydride or chloride of an aliphatic carboxylic acid esterified with 2 to 10 carbon atoms in the presence of pyridine and the mixture neutralized and the 17-acylate obtained after concentrating the solution with hydrazine hydrate in the presence of catalytic amounts of concentrated hydrochloric acid in the strongly polar solvent implements.

CH, R

N H

R CH,

R "0

in which R and R 'are each hydrogen or methyl and R "is the remainder of an aliphatic Means carboxylic acid having 2 to 10 carbon atoms. These steroids are made by being called Starting materials the compounds of the formula

35 used, in which R and R 'have the above meaning, according to methods known per se with ethyl formate in the presence of sodium methylate, sodium hydride or sodium amide and tetrahydrofuran or dioxane as a strongly polar solvent and then the 2-formyl compound obtained in the presence of gaseous hydrogen chloride and palladium on carbon support as a catalyst in the same reaction vessel and medium at atmospheric pressure until 2 moles of hydrogen per mole of 2-formyl derivative are absorbed, the 2a-methyl derivative obtained after removal of the solvent and the catalyst with an anhydride or chlorine

rid of an aliphatic carboxylic acid with 2 to 10 carbon atoms esterified in the presence of pyridine and neutralized the mixture and the obtained 17-acylate after concentrating the solution with hydrazine hydrate in the presence of catalytic amounts of concentrated Reacts hydrochloric acid in the strongly polar solvent.

The use of such highly polar solvents has been found essential to successful synthesis found. They require shorter reaction times and the use of remarkably lower amounts of solvents and reactants compared to the previous method. Furthermore they are advantageous because they contain the sodium salt of the methylene group in the α-position to the 3-ketone, which is to The beginning of the reaction is formed, solubilize and because they are miscible with water, which makes them am End of the reaction the desired product by di-. result in right precipitation.

In addition, they enable the reaction sequence to be continued directly. When you get into tetrahydrofuran and dioxane works, the hydroxymethylene group becomes when gaseous hydrogen chloride is added and the carbon supported palladium catalyst actually reduced directly to the methyl group.

It has been found that the addition of the hydrogen chloride is very important because it reduces at atmospheric pressure, the reaction time to about V20 that time which is when performing a reduction w required without the addition of acid and it is a double yield of 2 «-Methylverbindung which so can be crystallized directly.

This can be explained by the fact that the acid is the hydrogenolysis of the hydroxymethylene group promotes, and also brings the axial 2 / i-methylepimer by performing a rear attack, which is transformed into the more stable equatorial 2a-methyl position.

The mixture is finally neutralized, the catalyst filtered off and the solvent completely distilled off and the product with the anhydride or chloride of an aliphatic carboxylic acid with 2 implemented up to 10 carbon atoms. This is followed by the reaction with hydrazine hydrate and catalytic Amounts of hydrogen chloride, the 17β-esters being obtained according to the invention.

The invention will now be explained further with the aid of the following examples.

example 1

a) 2a-methyl-5'-androstane-17 / ^ - ol-3-one-azine-17-caproate

5.4 parts of sodium methylate and 8.4 parts of ethyl formate are gradually added at short intervals to a solution of 14.5 parts of 5a-androstan- Πβ-οϊ-3-οη in 100 parts of anhydrous tetrahydrofuran, working with stirring in a stream of nitrogen and keeps the temperature at around 15 ° C. 36.5 parts of a hydrogen chloride solution in tetrahydrofuran (1,3-n) are added after 30 minutes with external cooling, and the mixture is hydrogenated in the presence of 14.5 parts of 5% palladium on carbon. The catalyst is then removed and the solution neutralized and evaporated in vacuo. The residue is treated with 87.0 parts of pyridine and 43.5 parts of caproic anhydride. After 14 hours at room temperature, the reaction mass is steam distilled, the residue is extracted with ether, washed with 3N hydrochloric acid, water and 1N sodium hydroxide solution and then washed neutral with water. The organic layer is evaporated and the crystalline product (17.7 parts) dissolved in 15 parts of ethyl alcohol, and 1.05 parts of 98% hydrazine hydrate and 0.074 part of concentrated hydrochloric acid are added. After 8 hours, the separated product is filtered off, and recrystallization from methyl alcohol gives 13.25 parts of 2a-methyl-5u-an-. drostan -1 eat - oil - 3 - on - azin -17 - caproate; Mp 208-212 ° C; 240 to 242 ^° C; [a] "= 114 ° (chloroform).

A product is obtained by filtration after 8 hours at room temperature, which upon crystallization from methyl alcohol gives 12 parts of 2a-methyl-5'-androstane-17 /? - ol-3-one-azine-17-caproate; Mp 208-212 ° C; 240 to 242 ^° C; [<z] ₀ = + 114 ° (chloroform).

Example 2

2a-methyl-5a-androstane-17 /? - ol-3-one-azine-17-acetate

Using the same procedure as in the previous example, but treating the residue from the hydrogenation with pyridine and acetic anhydride and then reacting with hydrazine hydrate and concentrated hydrochloric acid as described above, 10.27 parts of 2a-methyl - 5a - androstane - are obtained Π β - oil - 3 - one - azine -17 - acetate; M.p. 267 to 269 ^° C; [a] ₀ = + 95 ° (chloroform).

Example 3

2a-methyl-5u-androstane-17ß-ol-3-one-azine-17-enanthate

Using the same procedure as in the previous example and treating the residue from the hydrogenation with pyridine and oenanthic anhydride and subsequent reaction with hydrazine hydrate and concentrated hydrochloric acid as described above, 12.8 parts of 2a-methyl-5'-androstane-17 ^ -ol are obtained -azin-17-enanthate; Mp 206-208 ° C; [«] ₀ = + 112 ° (chloroform).

b) 2α-methyl-5α-androstane-17α-ol-3-one-azine-17-caproate

To a solution of 13 parts of 2u-methyl-5a-androstane-17ß-ol-3-one-17-caproate 0.074 part of concentrated hydrochloric acid and 1.05 part of 98% hydrazine hydrate are added in 15 parts of ethyl alcohol.

Example 4

2a-methyl-5a-androstane-17ß-ol-3-one-azine-17-decanoate

Using the same procedure as in the previous example and treating the vacuum-dried residue from the hydrogenation with pyridine and capric acid chloride and subsequent reaction with hydrazine hydrate and concentrated hydrochloric acid as described above, 12.16 parts of 2cl-methyl-5u-androstane-17 / ^ -ol-3-onazine-17-decanoate; Mp 194-196 ° C; [a] ₀ = + 104 ° (chloroform).

B e i s ρ i e 1 5

2u-methyl-5a-estran-17ß-ol-3-one-azine-17-propionate

To a solution of 5.7 parts of 5 "-Ustran-17ß-ol-3-one 57 parts of freshly distilled, anhydrous dioxane are 1.32 parts of sodium amide and 2.84 parts Ethyl formate was gradually added at short intervals (10 to 15 minutes), taking under Stirring in a stream of nitrogen works and the temperature keeps at about 20 to 23 ° C. The mixture will Stirred for 5 hours, and then 14 parts of a 4 η solution of gaseous hydrogen chloride in dioxane are added added. The mixture is then hydrogenated in the presence of 5.7 parts of 5% palladium on charcoal, until the amount of hydrogen equivalent to 2 moles has been absorbed, which takes 1 hour. The catalyst is then removed and the solution neutralized and evaporated to dryness. The residue is with 18 parts of pyridine and 9 parts of propionic acid

treated anhydride. After 18 hours at room temperature, the mixture is steam distilled and extracted with ether. After the usual washing with 2η-hydrochloric acid, water, 2η-sodium hydroxide solution and water, a crude product is obtained on evaporation of the solvent from the organic layer, which is dissolved in 25 parts of ethyl alcohol and treated with 0.41 parts of 98% hydrazine hydrate and 0, 03 parts of concentrated hydrochloric acid are added. After 8 hours, the product obtained is filtered off, and recrystallization from methyl alcohol gives 4.21 parts of 2 "- methyl - 5a - estran -17 / ϊ - oil - 3 - one - azine-17-propionate; Mp 241-243 ° C; O] ₀ = + 100 ° (chloroform).

Example 6

2a-methyl-5a-estran-17 // - ol-3-one-azine-17-enanthate

Using the same procedure as in the previous example, but starting from 5.7 parts of 5'-uranium-17 // - ol-3-one as raw material and treating the residue from the hydrogenation with pyridine and unanthic anhydride and subsequent reaction with hydrazine hydrate and concentrated hydrochloric acid as described above, 4.43 parts of 2'-methyl-5'-oestran-17 /) -ol-3-onazin-oenanthate are obtained; Mp. 247 to 250 ⁰ C; O] ₀ = + 102 ° (chloroform).

Claims (1)

Claim: Process for the preparation of steroidazines of the general formula I. CH, R H N rrY