DE1217375B - Process for the production of 4-alkylthio-testosterone or -19-nortestosterone derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

German class: 12 ο -25/04

Number: 1 217 375

File number: M 53914IV b / 12 ο

Filing date: August 16, 1962

Opening day: May 26, 1966

It has been found that a number of new sulfur-containing derivatives of testosterone or 19-nor-testosterone series of general formula I.

R ₅

R ₃

wherein 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 Hydrogen atom or an alkyl, alkoxy or alkylthio group each with 1 to 3 carbon atoms, R4 is a hydrogen or fluorine atom, R5 is a hydrogen atom or a hydroxyl group, Re is Hydrogen atom or an alkyl, alkenyl or alkynyl group each with 1 to 3 carbon atoms, R7 is a hydrogen atom or an acyl group, Rs is a hydrogen atom or a methyl group, R9 is a Hydrocarbon radical with 1 to 10 carbon atoms means very good anabolic or gestagenic Possess properties. In particular, they show an increased index of anabolic to androgenic effectiveness.

Process for the preparation of 4-alkylthiotestosterone or -19-nor-testosterone derivatives

Applicant:

E. Merck Aktiengesellschaft,
Darmstadt, Frankfurter Str. 250

Named as inventor:
Dipl.-Chem. Dr. Josef Kramer,
Dipl.-Chem. Dr. Klaus Irmscher, Darmstadt

The invention relates to a process for the production of 4-alkylthio-testosterone or -19-nor-testosterone derivatives of the general formula I.

According to the process of the invention, these new compounds are prepared by adding a corresponding zl ⁴ -3-keto-steroid, which is substituted in the 4-position by a hydroxyl group or by chlorine or bromine, with a mercaptan of the general formula R ₉ SH, wherein R9 has the meaning given above, or reacts with a corresponding metal mercaptide in solution according to the following reaction scheme, in which, for the sake of clarity, only the unsubstituted ring A of a steroid otherwise corresponding to formula I is shown,

R ₉ SH + or R ₉ SMe

(X = OH, Cl, Br ^x

Me = alkali or alkaline earth metal)

and that, if appropriate, in a manner known per se, one in the 17-position of the compound obtained existing hydroxyl group is esterified or an ester group located at this point is saponified.

According to the process, one can work in such a way that, if appropriate with cooling, the metal mercaptide prepared by adding the mercaptan to a methanolic or ethanolic metal alcoholate solution, then the steroid as such or dissolved in an inert solvent is added and then

left to stand or heated until the reaction has ended. But you can also use the mercaptan as add such or dissolved in an inert solvent to a solution or suspension of the steroid. Suitable solvents are, for example, alcohols such as methanol, ethanol, isopropanol, tert. Butanol, hydrocarbons such as benzene, toluene, xylene, ether, tetrahydrofuran, dioxane. presence of air or water does not harm in principle, but the yields when working under oxygen

609 570/578

exclusion higher, especially if the solvent used is blown with pure and boiled dry nitrogen. In reactions with the lower, volatile mercaptans it can be advantageous to work under pressure during the reaction.

Examples of the starting materials suitable for the process according to the invention are: 4-hydroxy-, 4-chloro- or 4-bromine-testosterone, 4 - bromine - 17a - äthinyl -19 - nor - testosterone, 4 - chlorine - testosterone - 17 - benzoate, 4 - hydroxy-7-ethoxy-19-nor-testosterone-17-propionate. As a mer-

IO captans are suitable in free form or as metal mercaptides, for example, the following: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, amyl, isoamyl, hexyl, heptyl, octyl, nonyl, decyl, 2-ethylhexyl, allyl, propargyl, cyclopentyl, cyclohexyl, phenyl, o-tolyl, m -To-IyI-, p-tolyl-, p-ethylphenyl-, xylyl-, mesityl-, a-naphthyl-, / 5-naphthyl-, benzyl-, α-phenylethyl, ß-phenylethyl mercaptan.

In particular, process products of the formulas below have proven to be particularly effective proven:

45

Ri to R7 have the meaning given above; Rg can be

a) an aliphatic straight-chain or branched residue,

b) a cycloaliphatic radical,

c) an araliphatic residue,

d) an aromatic radical with up to 10 carbon atoms each.

The new compounds obtained according to the process can be mixed with conventional medicament carriers used in human and veterinary medicine. Come as carrier substances those organic or inorganic substances in question which are for parenteral, enteral or topical application are suitable and do not come into reaction with the new compounds, such as Water, vegetable oils, polyethylene glycols, gelatine, lactose, starch, magnesium stearate, talc, petroleum jelly, Cholesterol, etc. Solutions, preferably oily, are used in particular for parenteral administration or aqueous solutions, as well as suspensions, emulsions or implants. For enteral application are tablets · or dragees, ointments or creams suitable for topical application, if necessary sterilized or with auxiliaries such as preservatives, stabilizers or wetting agents or salts to influence the osmotic pressure, or are mixed with buffer substances. .

The compounds prepared according to the invention are preferably used in a dosage of 1 to R-

R ₃

10 mg for oral use, from 10 to 100 mg for parenteral use Gift used.

example 1

12.0 g of 4-chloro-testosterone, dissolved in 100 ml of absolute ethanol, are slowly added dropwise to a solution of sodium ethyl mercaptide prepared by dissolving 5 g of sodium in 200 ml of absolute ethanol in air with exclusion of moisture and adding 12.4 g of ethyl mercaptan. The reaction mixture is then refluxed for 5 hours, the solvent is then stripped off in vacuo, the residue is mixed with water and extracted with chloroform. The extract is then washed and dried, the chloroform is distilled off and the residue consisting of 4-ethylmercapto-testosterone is recrystallized from ether. M.p. 146 to 147 ^° C; [a] f = + 120 ° (chloroform); l _max = 247 ΐημ, Eil = 321 and 312 ηΐμ, Eil = 61 (ethanol).

Analogously, starting from 1.5 g of 4-bromestosterone and 1.4 g of propyl mercaptan, 0.6 g of 4-propyl mercapto testosterone is obtained. l _ma x - 247 πΐμ, EU = 315; Xmax = 310 πΐμ, Eil = 60.

When using 1.7 g of isobutyl mercaptan and 1.5 g of 4-bromo-testosterone as the starting material, 0.5 g of 4-isobutylniereaptotestosterone is obtained accordingly. /, ““. ,· = 247.5 πΐμ, EJI = 320; l _max = 309 ηΐμ, EH = 60. ■

In an analogous manner, starting from 1.9 g of cyclopentyl mercaptan and 1.5 g of 4-bromo-testosterone,

0.55 g of 4-cyclopentylmercapto-testosterone were obtained. Xmax = 245 πΐµ, E} 1 = 312; X _max = 308 m ^, ^ I cm ⁼ · '"·

Using the same procedure, the

2.0 g of cyclohexyl mercaptan and 1.5 g of 4-bromo-testosterone and 0.5 g of 4-cyclohexyl mercapto-testosterone were obtained. X _max = 246 mm EU = 313; X _max = 308 mμ, EJl = 60,

Example 2

^r

Analogously to Example 1, 4-ethylmercapto-17a-methyltestosterone with a melting point of 144 ° to 145 ° C. is prepared from 4-hydroxy-17a-methyltestosterone and ethyl mercaptan. [a] ² i = + 110 ° (chloroform); X _max = 247 πΐμ, EJl = 307; X _m , ix - 312 Γημ, EU = 61 (ethanol).

Starting from 1.6 g of isopropyl mercaptan and

1.1 g of 4-hydroxy-17a-methyl-testosterone are obtained in an analogous manner, 0.4 g of 4-isopropylmercapto-testosterone. X _ma x = 247 πΐμ, EJl = 324; X _max = 310 ηΐμ, EJl = 61.

In an analogous way, when using 1.8 g of butyl mercaptan and 1.1 g of 4-hydroxy-17a-methyl testosterone as starting material, 0.5 g of 4-butyl mercaptan testosterone is obtained. X _max = 246 ταμ, EU = 318; Xmax = 311 ηΐμ, EJi = 59.

Example 3

12.0 g of 4-chloro-testosterone, dissolved in 100 ml of absolute ethanol, are slowly added dropwise to a solution of sodium methyl mercaptide prepared by dissolving 5 g of sodium in 200 ml of absolute ethanol in air with exclusion of moisture and adding 10.5 g of methyl mercaptan. The reaction mixture is then refluxed for 3 hours and then worked up as indicated in Example 1. The 4-methylmercapto-testosterone obtained melts at 138 to 139 ° C. [a] 1 ^s = + 156 ° (chloroform); X _max = 246πΐμ, EJl = 322; Xmax = 312 ΐημ, E} 1 = 70 (ethanol).

Analogously, 4-methylmercapto-17a-methyl-testosterone is produced from 4-bromo-17a-methyl-testosterone and methyl mercaptan. Mp 144-145 ° C; [aYi = + 102.3 ° (chloroform); X _max = 245 πΐµ, EJi = 318; Xmax = 310 mm E} 1 = 96 (ethanol).

Analogously, starting from 2 g of cyclohexyl mercaptan, reaction with 4-bromo-17a-methyl-testosterone gives 0.6 g of 4-cyclohexylmercapto-17a-methyl-testosterone. X _max = 245 πΐµ, EJi = 315; Amax = 309 ηΐμ, EJi = 63.

In an analogous way, 0.3 g of 4-n-decylmercapto-17α-methyl-testosterone are produced from 2.3 g of n-decyl mercaptan by reaction with 4-bromo-17a-methyltestosterone. X _max = 244 ηΐµ, EJI = 305; Xmax = 307 mm EJl = 58.

Example 4

2.3 g of 2-methyl-4-chloro-testosterone, dissolved in 10 ml of absolute ethanol, are reacted with the required amount of a solution of sodium ethyl mercaptide in absolute ethanol as in Example 1 and worked up. 0.7 g of 2-methyl-4-ethylmercapto-testosterone are obtained. X _ma x = 245 ηΐμ, EJI = 320; X _max = 310 ηΐμ, EU = 70.

Analogously, starting from 1.6 g of isobutyl mercaptan, reaction with 2-methyl-4-chlorotestosterone gives 0.4 g of 2-methyl-4-isobutylmercapto-testosterone. X _max = ■ 244 πΐμ, EJl = 305; Xmax = 309 Χημ, EJl = 65.

Example 5

1.2 g of 1-methyl-4-chloro-testosterone are reacted with the required amount of methyl mercaptan in sodium ethylate-ethanol as in Example 3 and worked up. 0.6 g of pure 1-methyl- amethylmercapto -testosterone is obtained from ethanol. Xmax = 241 τηµ, EJi = 325; X _max = 312 mm

Example 6

6 g of the 4-ethylmercaptotestosterone obtained according to Example 1 are dissolved in 30 ml of dry pyridine, mixed with 30 ml of propionic anhydride and left to stand overnight. The reaction mixture is stirred into ice water, neutralized and the separated oil extracted with chloroform. The extract is washed thoroughly and dried over sodium sulfate. After the solvent has been stripped off, the residue is recrystallized from methanol. There is obtained 4-Äthylmercapto-testosterone propionate, mp 79-80 ⁰ C. [a] f = + 120 ° (chloroform); X _max = 247 ηΐµ, EU = 264; X _max = 312 ηΐμ, Ε}! = 51 (ethanol).

Example 7

Analogously to Example 6, 4-methylmercaptotestosterone propionate is prepared from the 4-methylmercaptotestosterone obtained according to Example 3 and propionic anhydride in pyridine. Mp 107 ° C; [a \ ² i = + 127.8 ° (chloroform); X _ma i = 2A5 πΐµ, E] I = 290; Xmax = 310 ηαμ, E} 1 ⁼ 64 (ethanol).

Example 8

1 g of the 1-methyl-4-methylmercapto-testosterone obtained according to Example 5 is boiled in 5 ml of dry pyridine with 5 g of önanthic anhydride for 1 hour on the steam bath. The solution is then cooled and stirred into ice water. After extracting with chloroform and washing the extract with water, it is dried over sodium sulfate. After the solvent has been distilled off, crude 1-methyl-4-methylmercapto-testosterone-17-oenanthate is obtained, which is purified by recrystallization from ethanol. X _ma x = 243 πΐμ, E} 1 = 310; Xmax = 306 Πΐμ, E] I = 59.

Example 9

1 g of 4-methylmercapto-testosterone propionate (obtained by reacting equimolecular amounts of 4-chloro-testosterone propionate and sodium methyl mercaptide as in Example 3) is refluxed in 5% aqueous-ethanolic solution of potassium carbonate for 1 hour under nitrogen. It is then diluted with water, the precipitate is filtered off and recrystallized from ether. 0.6 g of 4-methylmercapto-testosterone with a melting point of 137 to 138 ^° C. is obtained.

In an analogous manner (obtained by reacting equimolecular amounts of 4-chloro-testosterone propionate and Natriumäthylmercaptid analogously to Example 3) 4-Äthylmercapto-testosterone, mp. 147 to 148 ⁰ C obtained from 4-Äthylmercaptotestosteronpropionat.

Claims (1)

Claim: Process for the preparation of 4-alkylthiotestosterone or -19-nor-testosterone derivatives of general formula I. R ₃ 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, R4 a hydrogen or fluorine atom, R5 a hydrogen atom or a hydroxyl group, Rq a hydrogen atom or an alkyl, alkenyl or alkynyl group each with 1 to 3 carbon atoms, R7 a hydrogen atom or an acyl group, Rs a hydrogen atom or a methyl group, Rg means a hydrocarbon radical with 1 to 10 carbon atoms, since - characterized in that a ^ ⁴ -3-keto-steroid of the general formula II R ₃ wherein Ri to Rs have the meaning given above and X is a hydroxyl group or a chlorine or bromine atom, with a mercaptan of the general formula R9SH, in which R9 has the meaning given, or a corresponding one Treated metal mercaptide in solution and that, if appropriate, in a manner known per se, a 17-position of the obtained Compound existing hydroxyl group esterified or one located at this point Saponified ester group.