DE1243681B - Process for the preparation of 4-mercapto derivatives of the testosterone or 19-nor-testosterone series and of S-alkyl and S-acyl derivatives of the same - Google Patents

Description

INDESREPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int.CL:

C07c

C 0 7 y

German class: 12 ο-25/04

Number: 1 243 681

File number: M 52866IV b / 12 ο

Filing date: May 16, 1962

Opened on: July 6, 1967

It has been found that new 4-mercapto derivatives of the testosterone or 19-nor-testosterone series of general formula 1,

Ri

R ₃

wherein Ri is a hydrogen atom or an alkyl or alkoxy group each having 1 to 3 carbon atoms, R _{2 is} a hydrogen atom or an alkyl or alkoxy group each having 1 to 3 carbon atoms, R3 is a hydrogen atom or an alkyl, alkoxy or alkylthio group each having 1 to 3 carbon atoms. R4 is a hydrogen or fluorine atom, R5 is a hydrogen atom or a hydroxyl group, Re is a hydrogen atom or an alkyl, alkenyl or alkynyl group each having 1 to 3 carbon atoms, R _{7 is} a hydrogen atom or an acyl group. Rs denotes a hydrogen atom or a methyl group, and S-alkyl and S-acyl derivatives of the same have very good anabolic properties.

The invention accordingly provides a process for the preparation of 4-mercaplo derivatives the testosterone or 19-nor-testosterone series of general formula I as well as S-alkyl and S-acyl derivatives thereof, characterized in that one

a) a 3-ketosteroid of the general formula II.

OR ₇

H ₃ C

II

where Ri to R »have the meaning given above have, with sulfur in the presence of a base, expediently in an inert organic solvent, treated or process for the production of 4-mercapto derivatives of the testosterone resp. 19-nor-testosterone series as well as S-alkyl and S-acyl derivatives of the same

Applicant:

E. Merck Aktiengesellschaft,

Darmstadt, Frankfurter Str. 250

Named as inventor:

Dipl.-Chem. Dr. Josef Krämer, Darmstadt-Arheilgen;

Dipl.-Chem. Dr. Klaus Irmscher, Darmstadt

b) a 3-ketosteroid of the general formula III,

OR ₇ H ₃ CI .R ₆

Ri

R ₃

wherein Ri to Rg have the meaning given above and X is a hydroxyl group or a chlorine or bromine atom, with hydrogen sulfide or a metal sulfide or hydrogen sulfide or ammonium hydrogen sulfide treated or in a manner known per se

c) a 3-keto-4,5-oxidosteroid of the general formula IV,

OR ₇

'-R ₃

709 609.463

where R). to R »has the meaning given above have, with hydrogen sulfide or a metal sulfide or hydrogen sulfide, with elimination of water in the 4,5-position, and that, if appropriate, in a manner known per se, one in the 17-position of the products obtained existing hydroxyl group is esterified or an ester group located at this point is saponified and / or the mercapto group of the 4-mercaptosteroids obtained is alkylated or acylated. to

According to the process of the invention, the new compounds can be prepared by:

a) Reaction of a corresponding zl ⁴ -3-keto steroid with sulfur in the presence of a base according to the scheme (in this and the following reaction schemes, for the sake of clarity, only the unsubstituted ring A of a steroid otherwise corresponding to formula I is shown):

In this process, it is expedient to work in such a way that the steroid is converted into a solution or adding a suspension of a base in a suitable inert organic solvent, then expediently with stirring, the sulfur enters and at room temperature, if necessary while cooling or warming, stir for some time. Basically, the reaction takes place even in the presence of air or water, but the yields are considerably better, if one with the exclusion of moisture and atmospheric oxygen, z. B. under dry nitrogen, is working. Atmospheric oxygen promotes oxidation in the 4-position as well as the formation of the corresponding Disulfides; both are undesirable side reactions.

Alkali metal alcoholates such as sodium methylate or potassium tert-butylate, sodium amide or finely dispersed alkali metals or organic bases such as piperidine, pyrrolidine, triethylamine can be used as bases. Suitable solvents are, for example, alcohols such as methanol, ethanol, isopropanol, tert. Butanol, hydrocarbons such as benzene, toluene, xylene, ether, tetrahydrofuran, dioxane. The calculated amount of sulfur can be added; it is more advantageous to work with an excess of sulfur. The reaction is complete after a few hours at room temperature, and after a correspondingly shorter time on heating. There is no harm in letting the reaction mixture stand for a long time, provided that atmospheric oxygen is kept away.
Suitable starting materials are, for example: testosterone, 1.7 "- methyl testosterone, Ha-ethyl testosterone, androstan-17/3-ol-3-one, nri-ethynyl-19-nor-testosterone, 17a-allyl testosterone, l-methoxytestosterone-17-acetate , 2-methyltestosterone -17 - phenylpropionate, la - ethylthiotestosterone, 17a- methyl - 9a - fluorine- .1 ⁴ - androsten-11ß , 17 /? '- diol-3-one.

60

b) Reaction of a corresponding I ⁴ -3-keto steroid, which is substituted in the 4-position by a hydroxyl group, chlorine or bromine, with hydrogen sulfide or a metal sulfide or metal hydrogen sulfide or ammonium hydrogen sulfide.

H ₂ S
MeSH
Me ₂ S
NH ₄ HS

(X = OH, Cl, Br; Me = metal).

With this method you can work in such a way that one z. B. the metal hydrogen sulfide of a solution of the steroid is added in a suitable inert solvent and then heated. Man but can also the solution of the steroid to a solution or suspension of the hydrogen sulfide add. Examples of suitable solvents are those mentioned under a). Presence of air or water is harmful in principle not, but the yields are higher when working with the exclusion of oxygen. At higher temperatures, hydrogen sulfide can escape, so it can be beneficial be to introduce hydrogen sulfide during the reaction and, if necessary, under Pressure to work. Ammonium hydrogen sulfide can also be used in place of the metal hydrogen sulfide and, under certain conditions, use metal sulfides (see H ο u b e η - Wc y 1, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart [1955], below referred to as "Η ο u b e η - W e y 1", vol. 9, p. 7). For example, sulfide solutions can be found due to equilibrium

Na ₂ S + H ₂ O = # = NaHS + NaOH

always also hydrogen sulfide anions, which can react in the desired sense. Is working if you use hydrogen sulfide itself, it may be advisable to add a base to to bind the resulting hydrogen halide. Catalysts, e.g. B. activated aluminum, encourage the reaction.

Suitable starting materials for this procedure are, for example: 4-hydroxy, 4-chloro- or 4-bromestosterone, 4-bromo-17u-ethinyl-19-nor-testosterone, 4-chlorotestosterone-17-benzoate, 4-hydroxy-7-ethoxy-19-nortestosterone-17-propionate.

c) Implementation of corresponding keto-4,5-oxidosteroids with hydrogen sulfide or a Metal sulfide or metal hydrogen sulfide with elimination of water in the 4,5 position:

H ₂ S

\ Me ₂ S \
MeHS

The reaction mixture is expediently heated for a long time. The epoxy ring can be in a- or / 9-position; it can also be a mixture of the two stereoisomers

can be used. The dehydration can be carried out by conventional methods, for example by the action of mineral acids or of alkali or by heating in the presence of a solvent.

According to the method of the invention, one can also use the methods a) to c) obtained compounds of the formula I by methods known per se into their S-alkyl, S-acyl or 17-O-acyl derivatives by converting the Mcrcapto group alkylated or acylated in the 4-position and / or the 17-OH group is esterified.

Particularly suitable agents for alkylating the 4-mercapto group are alkyl halides, for example Methyl iodide. The alkylation according to the process can generally according to the Houben - Weyl, Vol. 9, pp. 103 ff., 120ff., Described Methods are done.

The usual acylating agents are suitable as agents for acylating the 4-mercapto group, for example Acetic anhydride, acetyl chloride, benzoyl chloride, p-toluenesulfochloride or ketene. In accordance with the procedure the 4-mercapto group can be according to those described in H ο u b e η - W e y 1, Vol. 9, pp. 749 ff Methods are acylated.

As means for esterifying the 17-OH group are all those acids or their for esterification suitable derivatives can be used which give physiologically acceptable esters, e.g. B. carboxylic acids, such as acetic acid, propionic acid, butyric acid, trimethyl acetic acid, cyclopentyl propionic acid. Phenylpropionic acid, Phenylacetic acid, caproic acid, caprylic acid, stearic acid, undecylenic acids, but also Benzoic acid or hexahydrobenzoic acid, as well as halocarboxylic acids, 2. B. chloroacetic acid. Possibly you can also use the 17-hydroxyl group for the purpose of preparing water-soluble derivatives Dicarboxylic acids, hydroxy, amino or alkylaminocarboxylic acids or esterify with phosphoric or sulfuric acid. In this way, z. B. produce: succinates, oxalates or the acid addition salts of aminocarboxylic acid esters, e.g. B. from Aspartic acid or diethylaminoacetic acid lecc.

According to the procedure, it is possible to learn, if necessary obtained 17-O-acyl derivatives of the formula 1 according to saponify methods known per se 2u. You can work in an acidic or alkaline medium, for example with dilute hydrochloric or sulfuric acid, dilute sodium or potassium hydroxide solution, expedient in the presence of an organic solvent such as methanol, ethanol or dioxane, if appropriate also with suitable ion exchangers. Such saponification can contribute as a side reaction all of the above procedures are carried out in which long enough in one sufficient strong basic or acidic medium is used.

The starting stroids used according to the process are either known or can be used per se methods known from the literature can be produced.

Yields the 4,5-oxido compound (IV) by oxidation of the mostly known l ⁴ -3-Kctone (II) with hydrogen peroxide in alkaline medium. The 4-hydroxy compounds (III, X - OH) are accessible by splitting the oxides IV with sulfuric acid-acetic acid, by hydrolysis of the 4-chlorine compounds (III, X = Cl) with potassium hydroxide or by converting the ^{I 4} -3-ketones II with Osmium tetroxide — hydrogen peroxide to the 4,5-dihydroxy derivatives and subsequent dehydration

with methanolic potassium hydroxide solution, the 4-chloro compounds (III, X = Cl) by reaction of the ketones II with chlorine in carbon tetrachloride-pyridine at -5 ⁰ C or with thionyl chloride in pyridine or by reaction of the Oxidovcrbindungen IV with hydrogen chloride. The 4-bromine compounds (III, X = Br) can be obtained from the oxides IV with hydrogen bromide.

The products of the process can be mixed with conventional pharmaceutical carriers in the human and Veterinary medicine can be used. The carrier substances used are organic or inorganic Substances in question that are suitable for parenteral, enteral or topical application and which do not react with the new compounds, such as water, vegetable oils, polyethylene glycols, gelatine, lactose, starch, magnesium searate, talc, petrolatum, cholesterol etc. Solutions, preferably oily or aqueous, are used in particular for parenteral application Solutions, as well as suspensions, emulsions or implants. Suitable for enteral application Tablets or dragees, ointments or creams for lopical use, which may be sterilized or with auxiliaries such as preservatives, stabilizers or wetting agents or salts for influencing the osmotic pressure, or are mixed with buffer substances.

example 1

With the exclusion of moisture and atmospheric oxygen, a solution of 7.82 g of potassium in 200 ml of absolute tert. Butane oil added 9.56 g testosterone at room temperature. 10 g of dried sulfur are added with stirring, then the mixture is stirred for a further 6 hours at room temperature. After leaving to stand overnight, the batch is carefully neutralized, most of the alcohol is stripped off in vacuo, the residue is mixed with water, extracted with ether and ethyl acetate, and the extracts are washed and dried. The residue is chromatographed over aluminum oxide. With a mixture of benzene-chloroform ⁽¹ Vo 50 and 75) the desired substance is eluted and the more crystallized from ether. The thus obtained 4-Mercaptotcstostcron has the F. 190 ^c, [<.] / C - mrx + 120 ° (in chloroform), Wr = 298!; E | 'l - 210. The corresponding disulfide with a temperature of 267 to 268 "C, [a] V -; ■ 12O ^C (chloroform), ?, _Mar = 258 μ; Eil = 388 is obtained as a by-product.

Example 2

Analogously to Example 1, 17a-methyltestosterone becomes

the 4-mercapto-17a-methyltcstostcron shown.

M.p. 157 to 158 ° C; w, = 298 ηι _μ : L |; "215; [u] V = '108- (in chloroform). (Disulphide: F. 250 to 252 ⁰ C; /.,,,,· = 258 πΐμ: E) I -. [u] f ^ -J-106 ^:) .

Example 3

⁶ S 3.8 g of 4-chlorotestosterone propionate are dissolved in 50 ml of anhydrous tetrahydrofuran, 5.6 g of sodium hydrogen sulfide are added and the mixture is refluxed for 5 hours with exclusion of moisture and oxygen.

cooked and stirred. The tetrahydrofuran is then stripped off in vacuo, the residue is mixed with water and extracted with chloroform. 4-Mercaptotestosterone propionate is isolated from the chloroform solution and recrystallized from ether. Mp = 133 ° C; [a]! ^J - + 120 ° (in chloroform), λ _ηατ = 298 ΐημ, EJ * = 210. (Disulfide: F. 244 to 245 ' ^J C; [a}' J = -1-122.8 ° [in chloroform] ).

Example 4 Example 5 Example 7

IO

Under nitrogen, in a solution of 12.6 g of barium hydroxide octahydrate in 1600 ml of 75% strength aqueous ethanol introduced hydrogen sulfide to saturation. With continued initiation of hydrogen sulfide is a solution of 6.3 g of 4,5-epoxy] 7a-methyltestosterone in 50 ml Ethanol was added dropwise to the reaction mixture over the course of 2 hours. The introduction of hydrogen sulfide is continued for another 1 1/2 hours. The barium ions are then converted into bariurocarbonate by introducing carbon dioxide pleases. This is filtered off with suction, washed with ethanol, the filtrate concentrated in vacuo, with Water was added and the mixture was extracted with chloroform. The extract is dried with sodium sulfate and sold the solvent. The residue crystallizes on trituration with acetone and is with identical to the 4-mercapto-17a-methyltestosterone obtained in Example 2.

3 °

To a suspension of 96 g of sodium sulfide nonahydrate in 200 ml of ethanol, a solution of 12.7 g of 4,5-epoxy-17u-methyltestosterone is made under nitrogen added dropwise in 50 ml of ethanol. The reaction mixture is then stirred for 15 hours refluxed. Most of the alcohol is then distilled off, and the residue is also distilled off Water was added and the mixture was extracted with chloroform. The extract is dried with sodium sulfate, then the chloroform stripped off in vacuo. The crude product is chromatographed over neutral aluminum oxide, where the desired 4-mercapto-17a-methyltestosterone with chloroform-benzene (1: 1) is eluted.

Example 6

11.2 g 4-chloro-17 <i-methyltestosterone in 50 ml Ethanol are added to a suspension of 18 g of sodium sulfide nonahydrate in 200 ml of ethanol Stirring and passing in nitrogen were added dropwise and the reaction mixture was then boiled for 15 hours. The further work-up takes place as in Example 5. The residue obtained from chloroform is in Acetone dissolved, the desired 4-mercapto-17 «-methyltestosterone precipitated by adding ether, filtered off and recrystallized from chloroform-ether.

60

8.4 g of sodium hydrogen sulfide are added to a solution of 4.56 g of 4,5-epoxytestosterone in 25 ml of absolute ethanol and the mixture is then stirred for 90 minutes at room temperature. The batch is then slightly acidified with acetic acid, mixed with water and extracted with chloroform. The extract is washed with water and then dried over sodium sulfate. The residue remaining after the chloroform has been evaporated off is chromatographed on silica gel. The 4-mercaptotestosterone is eluted with a mixture of benzene and chloroform (1: 1). F. - 19O ⁰ C: X _max - 298 πΐμ; EJ * = 210; [α]? = + 120 ° (chloroform).

Example 8

3.6 g of 4,5-epoxytestosterone propionate, dissolved in 80 ml of absolute alcohol, are added dropwise at room temperature to a suspension of 5.6 g of sodium hydrogen sulfide in 25 ml of absolute ethanol. The whole is then stirred for 60 to 90 minutes at room temperature. Then the batch is made slightly acidic, mixed with water and extracted with chloroform. The extract is washed and dried over sodium sulfate. The residue that remains after the chloroform has been evaporated off is chromatographed on silica gel. The desired 4-mercaptotestosterone 17/3 propionate is eluted with benzene. M.p. = 133 "C;" Mnax = 298 ΐηµ; EJl - 210; [a] 'i = + 120 ° (chloroform).

Example 9

3.36 g of 4-chloromethyl-17a-methyltestosterone are dissolved in 50 ml of absolute tetrahydrofuran, 5.6 g of sodium hydrogen sulfide are added and the mixture is refluxed in a nitrogen atmosphere for 5 hours with stirring. The whole is then evaporated to a residue, water is added and the mixture is extracted with chloroform. The chloroform solution is washed neutral with water, dried and evaporated. The residue is crystallized from ether. 4-mercapto-17 «-methyltestosterone is obtained, m.p. - 157 to 15S ^a C; X _max - 298 πΐμ; Ε1 * - 215, [a] f - = + 108 ° (chloroform).

Example 10

In 30 ml of absolute tetrahydrofuran, 2.8 g 4-bromo-l-methyltestosterone dissolved and taken together with 5.1g sodium hydrogen sulfide for 4 hours With exclusion of moisture and oxygen, refluxed and stirred. The work-up how under Example 3, gives pure 4-mercapto-1-methyltestosterone. IR spectrum (KBr): bands at 3500, 2540, 1660 and 1565 cm *.

Example 11

Hydrogen sulfide is passed into a solution of 6 g of barium hydroxide octahydrate in 800 ml of 75% strength aqueous ethanol with the exclusion of oxygen until it is saturated. While continuously passing in hydrogen sulfide, a solution of 3.9 g of 4-bromo-1-methoxytestosterone in 25 ml of ethanol is added dropwise over the course of 2 hours. The hydrogen sulphide is continued for another 1 ¹ It hours. The barium ions are then precipitated as barium carbonate by introducing carbon dioxide. This is quickly suctioned off in a nitrogen atmosphere, washed with ethanol, the filtrate is weakly acidified with acetic acid, concentrated in vacuo, mixed with acetic water and extracted with chloroform. The extract, dried over sodium sulfate, is concentrated to dryness and the crude 4-mercapto-1-methoxytcstosterone obtained is purified by chromatography over neutral aluminum oxide. IR spec

strand (KBr): bands at 3550, 2600, 1665, 1570 and 1100 cm " ¹ .

Example 12

A solution of 1.6 g of 4-chloro-2-methyltestosterone and 2.6 g of sodium hydrogen sulfide in 25 ml of ethanol is refluxed for 3 hours in a nitrogen atmosphere. The ethanol is in vacuo distilled off, the residue acidified with acetic water and extracted with chloroform. From the dried extract is obtained as a residue of crude 4-mercapto-2-methyltestosterone, which by Crystallization from ether is purified. IR spectrum (KBr): bands at 3575, 2580, 1650 and 1570 cm '.

Example 13

1.7 g of 2-ethoxy-4-chlorotestosterone and 2.6 g of sodium hydrogen sulfide are used as in Example 12 described, implemented. 2-Ethoxy-4-mercaptotestosterone is obtained in pure form from acetone-ether. IR spectrum (KBr): bands at 3560, 2560, 1660, 1565 and 1140 cm *.

Example 14

A solution of 0.5 g of 4-chloro-7-ethoxytestosterone (obtained from 4-chloro-7-bromotestosterone by exchange with ethanol on aluminum oxide) in 10 ml of absolute tetrahydrofuran is mixed with 1.2 g of sodium hydrogen sulfide Boiled and stirred under exclusion of air for 3 hours. The work-up analogous to the example 3 gives pure 4-mercapto-7-ethoxytestosterone. IR spectrum (KBr): bands at 3550, 2580, 1665, 1565 and 1110cm- '.

Example 15

1.4 g of 4-chloro-7-methylthiotestosterone (obtained by the 6,7 addition of methyl mercaptan to 4-chloro-4,6-androstadien-17 /? - ol-3-one) are dissolved in 15 ml of absolute tetrahydrofuran and combined boiled with 2.4 g of sodium hydrogen sulfide in a nitrogen atmosphere for 4 hours with stirring. Working up according to Example 7 gives pure 4-mercapto-7-methylthiotestosterone. IR spectrum (KBr): bands at 3575, 2600, 1660 and 1580 cm- ¹ .

When using 1.5 g of 7-ethylthio or 1.8 g of 7-isopropylthiotestosterone in analog Way 4-mercapto-7-ethylthio or 4-mercapto-7-isopropylthiotestosterone obtain.

Example 16

To a suspension of 9.6 g of sodium sulfide nonahydrate in 20 ml of ethanol, a solution of 1.3 g of 4-chloro-17a-ethyltestosterone in 5 ml of ethanol is added dropwise under nitrogen. The mixture is refluxed with stirring for 8 hours, then the ethanol is distilled off in vacuo, the residue is acidified with dilute acetic acid and extracted with chloroform. The extract is dried with sodium sulfate, the chloroform is distilled off and the residue is purified by chromatography on silica gel. Pure 4-mercaplo-17a-ethyltestosterone (IR spectrum (KBr): bands at 3490, 2550, 1665 and 1565 cm " ¹ ) next to its disulfide is eluted with benzene.

With an analogous conversion of 1.4 g of 4-chloro-17rt-propyltestosterone, 1.4 g of 4-chloro-17 «-isopropyltestosterone, 1.5 g of 4-chloro-17a-allyl testo $ tcron, 1.5 g 4-chloro-17o-propenyltestosterone, 1.6 g 4-chloro-17a-ethinyltestosterone or 1.6 g of 4-chloro-17u-propargyltestosterone with 9.6 g of sodium sulfide nonahydrate each are 4-mercapto-17u-propyltestosterone, 4-mercapto-Ha-isopropyltestosterone, 4-mercapto-Ha-allyltestosterone, 4-mercapto-17 "-propenyltestosterone, 4 - mercapto -17" -äthinyltestosteron resp. 4-Mercapto-17 "-propargyl testosterone obtained.

Example 17

ίο ■ A solution of 0.7 g of 4-chloro-19-nor-testosterone in 5 ml of absolute tetrahydrofuran is added to a suspension of 1.3 g of sodium hydrogen sulfide in 5 ml of absolute tetrahydrofuran were added dropwise and the whole thing for 4 hours with the exclusion of moisture and oxygen refluxed and stirred.

Working up as in Example 12 gives pure 4-mercapto-19-nor-testosterone. IR spectrum (KBr):

Bands at 3650, 2600, 1665 and 1570cm- '.

0.8 g of 4-chloro-17r, t-methyl-19-nortestosterone, 1,0g4-chloro-17n-ethyl-19-nor-testosterone and 1.0 g of 4-chloro-17a-ethinyl-19-nor-testosterone with sodium hydrogen sulfide in absolute tetrahydrofuran implemented. The same work-up as in Example 12 gives 4-mercapto-17a-methyl-19-nor-testosterone, 4-mercapto-17 "-ethyl-19-nortestosterone and 4-mercapto-17" -äthiny] -19-nor-testosterone.

Example 18

To a solution of 1.1 g of 4-chloro-9a-fluorol7ct-methyl-4-androsten-11 / ?, l7ß-dio] -3-one 1.2 g of sodium hydrogen sulfide are added to 10 ml of absolute tetrahydrofuran and the whole thing for 10 hours stirred in a nitrogen atmosphere at 30 ° C.

The tetrahydrofuran is distilled off in vacuo, and the residue is treated with dilute acetic acid and extracted with chloroform. The washed and dried extract is concentrated and turned on Alumina chromated. With chloroform the 4-mercapto-9a-fluor-17a-methyl-4-androsten-II, e, 17 /.? -Diol-3-one eluted, which crystallized from acetone-ether. IR spectrum (KBr): bands at 3450, 2540, 1655 and 1565 cm "'.

Analogously, 1.1 g of 4-chloro-9n-fluoro-4-androstene-11,17,17-diol-3-one are obtained and 1.2 g of sodium hydrogen sulfide 4-mercapto-9u-fluoro-4-androstenll / U7 /? - diol-3-one.

Example 19

A solution of 1.5 g of 4-hydroxytestosterone and 2.7 g of sodium hydrogen sulfide in 20 ml of absolute ethanol is refluxed under nitrogen for 5 hours. Working up according to Example 3 gives 4-mercaptotestosterone, which is converted into the 4,17-diacetate by allowing it to stand with acetic anhydride in pyridine overnight. F. - 188 to 189 ^° C; Xmax - 234.5 ma, EJ * = 263.

Example 20

Under nitrogen, 3.7 g are added to a solution of 0.25 g of sodium in 50 ml of absolute ethanol of the 4-mercaptotestosterone obtained according to Example 1 is added, plus a solution of 2 g of ethyl bromide dropped into 10 ml of absolute ethanol and refluxed for 3 hours in a nitrogen atmosphere cooked. The ethanol is distilled off, the residue extracted with chloroform, with Washed with water and dried over sodium sulfate

■. : ■ · 709 609/463

dries. The crude 4-ethylthiotestosterone, which is obtained pure from ether, is isolated from the extract. M.p. 146 to 148 ° C; \ _max = 246.5 and 310.5πψ, Έ} ?. = 321 and 361.

B e j s ρ i e 1 21

1 g of the 4-mercaptotestosterone-17-propionate obtained according to Example 8 is boiled with 25 ml of 0.1 N HCl in methanol for 1 hour under nitrogen. After the methanol has been removed, water acidified with acetic acid is added, the mixture is extracted with chloroform, and the extract is dried over sodium sulfate and concentrated. 4-mercaptotestosterone is obtained with a temperature of 19O ⁰ C.

Claims (1)

Claim: Process for the production of 4-mercapto derivatives of the testosterone or 19-nor-testosterone series of the general formula I, OR where Ri is a hydrogen atom or an alkyl or alkoxy group each having 1 to 3 carbon atoms, R2 is a hydrogen atom or an alkyl or alkoxy group each having 1 to 3 carbon atoms, R3 is a hydrogen atom or an alkyl, alkoxy or alkylthio group each having 1 to 3 Carbon atoms, Ri is a hydrogen or fluorine atom, R5 is a hydrogen atom or a hydroxyl group, Re is a hydrogen atom or an alkyl, alkenyl or alkynyl group each with 1 to 3 carbon atoms, R _{7 is} a hydrogen atom or an acyl group, R _{8 is} a hydrogen atom or a methyl group, and of S-alkyl and S-acyl derivatives thereof, characterized in that one a) a 3-ketosteroid of the general formula II, OR ₇ 35 40 45 55 II wherein Ri to Rg have the meaning given above have treated or treated with sulfur in the presence of a base, advantageously in an inert organic solvent b) a 3-ketosteroid of the general formula III, R ₁ R ₃ wherein Ri to Rg have the meaning given above and X is a hydroxyl group or a chlorine or bromine atom, with hydrogen sulfide or a metal sulfide or hydrogen sulfide or ammonium hydrogen sulfide treated in a manner known per se or c) a 3-keto-4,5-oxidosteroid of the general formula IV wherein Ri to Rg have the meaning given above have reacted with hydrogen sulphide or a metal sulphide or hydrogen sulphide, with elimination of water in the 4,5-position, and that if necessary, in a manner known per se, a 17-pitch the hydroxyl group present in the products obtained is esterified or an ester group located at this point is saponified and / or the mercapto group of the 4-mercaptosteroids obtained is alkylated or acylated. R ₃ Considered publications:
Advances in Drug Research, Vol. 2
(1960), p. 119.