DE1204221B - Process for the preparation of 7alpha-alkylthio-steroids - Google Patents

Description

A process for preparing 7cc-alkylthio-steroidal From USA. Patent 2,908,694 include 7a-alkylthio-testosterone derivatives of the general formula 1 (R, = H or an acyl group, R2 an alkyl group with a maximum of 5 carbon atoms) became known. The compounds are anabolic and have only a slight virilizing effect. The manufacturing process in the above-mentioned USA patent is the implementation of a J4,6-3-keto steroid of the formula II (R, = H or an acyl group) with a mercaptan of the formula R2 - SH (R2 has the meaning given) in the presence of a mineral acid and in glacial acetic acid as the solvent.

Reworking has shown that the compounds of the formula II can only be prepared in very low yield by this known process. According to the known method, for example, in the production of 7a-methylthiotestosterone acetate, 7a-ethylthio-testosterone acetate, 7a-n-propylthio-testosterone acetate and 7a-isopropylthio-testosterone acetate, only yields of 44, 55, 25 or 18% of theory achieved. It has now been found that, surprisingly, significantly higher yields are obtained if, instead of mineral acid, basic compounds are used as the catalyst.

The invention thus provides a process for the preparation of alkylthio-steroids of the general formula 1 from A4,6-3-ketosteroids of the general formula 11, which consists in that one A4,6-3-ketosteroid of the general formula II with a Alkyl mercaptan, which has a maximum of 5 carbon atoms, is reacted in the presence of a basic catalyst such as pyridine, piperidine, sodium methylate or sodium hydroxide. The alkyl mercaptans are attached to the 6 (7) double bond of the compounds of the formula II in a smooth reaction. In most cases the alkyl mercaptan itself serves as the solvent. However, the reaction can also be carried out in the presence of an inert organic solvent such as dioxane, benzene, dimethylformamide or tertiary alcohols. A basic catalyst is added during the reaction; suitable are e.g. B. pyridine, piperidine, sodium methylate or sodium hydroxide. In general, it is advantageous to warm the reaction components or to reflux them for some time. Of course, the reaction can also be carried out at room temperature, in which case the reaction mixture is expediently shaken.

The alkyl radical of the mercaptans to be used can be straight or branched be; Methyl and ethyl mercaptan are particularly suitable.

In the treatment of starting steroids of the formula II, in which R, acyl means, is under the given reaction conditions, especially when heated of the reaction mixture in some cases the ester group due to the influence of the basic Saponified catalyst.

According to the method of the invention, for. B. the following compounds are produced: 7a-ethylthio - testosterone, 7a - ethylthio - testosterone - acetate, 7a-ethylthio-testosterone propionate, 7a-methylthiotestosterone, 7a-methylthio-testosterone-acetate, 7 # -methylthio - testosterone - propionate, 7a - n - Propylthiotestosteron - acetate, 7a - iso - propylthio - testosterone acetate.

The process products are intended to be used as pharmaceuticals in human medicine be used. You let to all the usual pharmaceuticals Process preparation forms. For example, you can use it to make pills, tablets, Drag6es, emulsions, solutions, capsules or injection solutions using the usual auxiliaries.

Example 1 5 g of 6-dehydro-testosterone are refluxed for 28 hours in 30 ml of ethyl mercaptan together with 3 ml of piperidine. The reaction mixture is then concentrated in vacuo and the 7a-ethylthio-testosterone is crystallized from ether. M.p. 214 to 216'C; 241 mV., [al "34,2 '(dioxane).

For the purpose of further characterization, this compound can be esterified in a known manner to give 7a-ethylthio-testosterone acetate [F. 197 to 198 "# ';A""# = 240 ml, [a] " , = 11 ' (chloroform)] or to 7a-ethylthio-testosterone propionate; mp 160 to 163'C; A.ax = 240.5 ml; = -26.6 '(dioxane). Yield: 73% of theory, based on the starting product 6-dehydro-testosterone.

Example 2 2 g of 6-dehydro-testosterone propionate are dissolved in 10 ml of dioxane, 1 ml of piperidine is added and 10 ml of methyl mercaptan are added while cooling, and the mixture is shaken in the autoclave at 35 ° C. for 24 hours. The reaction mixture is then concentrated in vacuo and the 7α-methylthiotestosterone ropionate is crystallized from methanol. F. 222 to 2230C; [al, = -13.1 '(dioxane); 2 ", # = 24OmV .; Yield: 530jo of theory. Example 3 20g 6 # dehydro-testosterone are shaken in 418m1 of dioxane, together with 10 ml of piperidine and 200 ml of methyl mercaptan 48 hours in an autoclave at 600C. The reaction mixture is then concentrated to dryness under reduced pressure and the residue is recrystallized from methanol. The 7a-methylthio-testosterone melts at 227 to 229'C; ral, = -16 ' (dioxane); A. "x- = 241 m # t; further characterization in a known manner This connection leaves. esterify themselves for the purpose of white 7a-methylthio-testosterone-acetate. M.p. 207 to 208'C; Aa, = 240m # t-, [a], +4 '(chloroform); Yield: 691) jo the theory, based on the starting product 6-dehydro-testosterone. Example 4 2 g of 6-dehydro-testosterone acetate are heated to 35 ° C. for 26 hours in 10 ml of dioxane with Im] piperidine and 10 ml of n-propylmer, captan. The reaction mixture is then concentrated under reduced pressure and the 7a-n-ProP'ylthio-testosterone-acetate # istallized from methanol. M.p. 202-204'C; A. "# = 241 m # t; [a] " = -21 '(chloroform). Yield: 59% of theory.

EXAMPLE 5 2 g of 6-dehydro-testosterone acetate are heated to 35 ° C. for 30 hours with stirring in 12 ml of isopropyl mercaptan with the addition of 1 ml of pipe ridine. The reaction mixture is concentrated under reduced pressure and the 7a-iso-propylthiotestosterone acetate is crystallized from methanol. M.p. 170 to 172'C; Aa, = 241 m # L; [al, = - 12 '(chloroform). Yield: 51 % of theory.

Example 6 10 g of 6-dehydro # tesiosteroh-acetate are refluxed in 60 ml of n-propyl mercaptan together with 6 ml of piperidine for 26 hours. The reaction mixture is then diluted with chloroform, washed with dilute hydrochloric acid and water, dried with sodium sulfate, filtered and distilled to dryness under vacuum. 9.5 g of 7a-n-propylthio-testosterone acetate (77.5% of theory) crystallize from an ethereal solution of the residue.

Claims (1)

Claim: Process for the preparation of 7a-alkylthiosteroids of the general formula I. (111 = H or an acyl group, R2, an alkyl group with a maximum of 5 carbon atoms) from A4,6-3-ketosteroids of the general formula I below, characterized in that an A4,6-3-ketosteroid of the general formula II in which Ri has the meaning given , is reacted with an alkyl mercaptan containing at most 5 carbon atoms in the presence of a basic catalyst, in particular piperidine.