DE1274126B - Process for the preparation of 1ª ‡ -alkylthio-3-keto-4-androstenes - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY GERMAN ^ VQ ^ PATENT OFFICE

EDITORIAL

Int. Cl .:

German class:

Number:
- File number:
Registration date:
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C07c

A61k

12 ο-25/04

30 h-2/10

P 12 74 126.3-42 (M 55037)

December 6 , 1962

1st August 1968

It has been found that in the 4 (5) position unsaturated la-alkylthiosteroids of the general formula I.

wherein Ri has two hydrogen atoms or a hydrogen atom in the α-position and a hydroxyl group in the / i-position or an oxygen atom, Ra a hydrogen atom or an acyl group with 1 to 10 carbon atoms, Rs a hydrogen atom or a saturated or unsaturated hydrocarbon radical with 1 to 3 carbon atoms, Ra is a hydrogen atom or a fluorine atom, Ra is a hydrogen atom or a methyl group and R _{6 is} an alkyl radical with 1 to 3 carbon atoms, have a better anabolic effect or a better index of anabolic to androgenic effect than the corresponding compounds unsubstituted in the 1-position.

It is known to use alkyl mercaptans (cf., for example, J. Org. Chemistry, Vol. 26 [1961], p. 3915 ff.) Or thio fatty acids (cf., for example, J. Am. Chem. Soc, Vol. 81 [1959 ], P. 1224 ff.) To attach to double bonds of steroids in an acidic medium or using an acidic catalyst, the corresponding alkylthio or acylthiosteroids being formed. When attempting to prepare compounds of the formula I from the corresponding 1 ^K4 -3-ketosteroids using this procedure, however, only low yields were achieved. In the further attempt to use basic catalysts, preferably amines, such as piperidine, instead of acidic catalysts, even worse results were initially achieved; only starting material was recovered.

It has now been found that, surprisingly, the reaction even in the presence of basic Catalysts succeed in that, moreover, the yields in this procedure are very much higher and pure products are obtained more easily than with the known procedure in acidic medium, if it is ensured that the basic catalyst is removed from the reaction mixture prior to work-up for the production

of 1 »- alkylthio-3-keto-4-androstenes

Applicant:

E. Merck Aktiengesellschaft,

6100 Darmstadt, Frankfurter Str. 250

Named as inventor:

Dipl.-Chem. Dr Klaus Irmscher, 6100 Darmstadt; Dipl.-Chem. Dr. Karl-Heinz Bork,

6103 Griesheim;

Dr. Hans-Günther Kraft, 6100 Darmstadt

is removed. In the usual work-up (evaporation of the reaction solution) was namely under the Influence of the base mercaptan split off, the starting material being reformed.

The basic catalyst can be removed, for example, by taking up the reaction mixture in an inert solvent such as ether and washing with acid, e.g. B. with dilute hydrochloric acid.

The invention accordingly provides a process for the preparation of la-alkylthio-3-keto-4-androstenes of the general formula I, which is characterized in that an alkyl mercaptan having 1 to 3 carbon atoms is added. l ¹⁴ -3-ketosteroid of the general formula

OR ₂

wherein Ri to R5 have the meaning given, in The presence of a basic catalyst, preferably in the presence of an amine such as piperidine, is added and before the compound obtained is isolated, the basic catalyst is removed from the reaction mixture and, if appropriate, an in 17 / J position of the connection received Hydroxyl group esterified in a manner known per se.

809 SBS / 4 & 1

3 4

The alkyl mercaptans are stored in smooth reac ointments or creams, which may be sterilized tion to the l (2) double bond of the above or with auxiliaries such as preservatives, stabilizers / I ^ -S-keto steroids. The alkyl mercaptanizing or wetting agents or salts for influencing serve as a solvent, but you can flow the osmotic pressure, or with a buffer in an inert organic solvent, 5 substances are added. The dosage is 1 to such as dioxane, benzene, dimethylformamide or ter- 10 mg orally, 10 to 100 mg parenterally per dose, tertiary alcohols, work. When responding will

a basic catalyst added, such as pyridine, B e i s o i e 1 1 Piperidine, morpholine, an alkali alcoholate or

Alkali hydroxide. The reaction can be carried out at room temperature 1.7 g of 1-dehydro-testosterone acetate in 30 ml

temperature can be carried out. However, it runs smoothly. Ethyl mercaptan dissolved. The solution will be

Lighter and smoother if you heated or boiled 0.7 ml of piperidine in a bomb tube

and / or under pressure, e.g. B. in the bomb tube, works. Heated to 90 to 100 ^° C. for 20 hours. After leaving

Suitable mercaptans are methyl, ethyl, cool is diluted with ether and the solution after n-propyl and isopropyl mercaptan. 15 washed each other with dilute hydrochloric acid, water, sodium under the specified reaction conditions hydrogen carbonate solution and water, it can happen, especially when the reaction mixture is heated and dried at 40 ° C under reduced pressure, that the molecule is approximately pre-evaporated, the la -Ethylthio-testosterone-present ester groups due to the influence of the catalytic acetate precipitates. It can be saponified from ether recrystallized sators. One so in the obtained ver 20. Yield 1.03g; M.p. 138 to 140 ⁰ C; X _ma .r bonds created or already before 241 πΐμ; EJ * _m 386; [α] κ + 135 ° (dioxane). existing 17 /? - hydroxyl group can optionally

be esterified by methods known per se. . -19 All acids B e 1 s ρ 1 e 1 2 or their derivatives suitable for esterification can be used as esterification agents Propyl mercaptan is added with 0.7 ml of piperidine, e.g. B. carboxylic acids, such as acetic acid, propionic added and 24 hours' heated to 90 ° C in a bomb oven under acid, butyric acid, trimethyl acetic acid, cyclopentyl shaking. After the work-up carried out as in beipropionic acid, phenylpropionic acid, caproic acid, game 1, caprylic acid, stearic acid, undecylenic acid, benzoic acid is dissolved in benzene and chromatic acid or hexahydrobenzoic acid and also halogen graphed over a column of silica gel. The benzene-ether eluates (9: 1) become carboxylic acids, such as chloroacetic acid. Dicarbon-pure la-n-propylthio-testosterone acetate is also isolated. Extract acids, amino or alkylaminocarboxylic acids, as well as loot 3.5 g; F. 106-107 ⁰ C, [a] o + 140 ° (dioxane). inorganic acids such as phosphoric or sulfuric acid can be used. In this way, z. B. 35 _R. . . prepared: succinates, oxalates or Säureaddi- Example S addition salts of aminocarboxylic acid esters, such. B. from Example 2 are 1.9 g of 1-dehydro-testo-aspartic acid or diethylaminoacetic acid esters. sterone acetate in 20 ml of dioxane with 10 g of methyl mer-

The starting compounds can be obtained and 0.5 ml of piperidine heated in a bomb furnace,

the usual chemical or microbiological 40 After chromatography over silica gel becomes pure

1 (2) -Dehydration of the underlying, l ⁴ -3-keto-lu-methylthio-testosterone acetate obtained. yield

steroids. '1.05 g; M.p. 198 to 201 ° C; [a] _D + 119 ° (dioxane);

According to the invention, the λ, ".", 241 · ηΐμ, E} '° _m 387th following thioethers and their 17-esters can be prepared, for example

^{become: 45} Example 4

la-methylthio-testosterone acetate, ^. , 1 -7 '1 γλ u j η .ui

la-Ethyithio-testosterone acetate, ^{Das Gem} ^ ^ch , % ^us _u / ' ⁷ S l-Pehydro-nrx-methyl-

la-n-propylthio-testosterone acetate, testosterone 30 ml ethyl mercaptan and 0.7 ml P.pen-

la-methylthio-testosterone propionate, J ^nw ' ^{rd 2} °,? ^unde "™, ^Bomb f ^pipe / ^uf * ¹⁵ £ er

la-methylthio-methyltestosterone, ⁵ ° heats. After cooling, it is diluted with ether

la-ethylthio-methyltestosterone, ^{and the} solution one after the other with diluted salt

la-n-propylthio-methyltestosterone. ⁵ ^ ^and water washed, dried and at

40 C evaporated under reduced pressure. Of the

The process products can be used as anabolic steroids in the residue is dissolved in the necessary amount of benzene

Mixture with common excipients in the 55 and filtered through silica gel. The eluates become

Human or veterinary medicine can be used. after rubbing with hexane pure lu-ethylthio-

Such organic 17a-methyltestosterone are obtained as carrier substances. Yield 1.19 g;

or inorganic substances in question, which are suitable for the paren- F. 136 to 139 "C; [«] «+ 120 ° (dioxane); /., to ".,·

Teral, enteral or topical application suitable 242.5 ΐημ, Ej °° _m 368.

and those with the new connections are not in 60

Reaction occur, such as, for example, water, vegetable B e i s η i e 1 5 borrowed oils, polyethylene glycols, gelatine, milk sugar,

Starch, magnesium stearate, talc, Vaseline, Choleste- The solution of 3 g of l-dehydro-nu-methyltesto-

rin, etc. For parenteral administration, in particular, n-propyl mercaptan in 45 ml is used with 0.9 ml

special solutions, preferably oily or aqueous 65 piperidine, and put in a bomb oven for 24 hours

Solutions, as well as suspensions, emulsions or heated to 100 C with shaking. After the as in

Implants. For enteral application, example 4 work-up carried out is suitable

Tablets or dragees, for topical application silica gel chromatographed. From the benzene ether

Eluates (4: 1) are obtained la-n-propylthio-17a-methyltestosterone. Yield 1.79 g; M.p. 82 to 85 ° C (hexane); [α] _β + 121 ° (dioxane); X _max 242ηΐμ, E = 13 500.

Example 6

The mixture of 1.7 g l-dehydro-na-methyl testosterone, 50 ml of methyl mercaptan and 0.5 ml piperidine is heated for 20 hours at 100 ⁰ C in a sealed tube. After the reaction mixture has cooled, it is diluted with ether and the solution is washed successively with dilute hydrochloric acid and water, dried and evaporated under reduced pressure. The crude Ia-methylthio-17tt-methy! Testosterone thus obtained is recrystallized from ether. Yield 1.0g; M.p. 158 to 160 ⁰ C; [α] _Λ + 120 ° (dioxane); X _nax 242 ηΐμ, EJ * 398.

Example 7

Analogously to Example 3, 0.96 g of 1-methylthio-testosterone propionate are prepared from 1.9 g of 1-dehydrotestosterone propionate. M.p. 145 to 146 ° C; [o \ d + 102 ° (dioxane); Wr 241 ηΐμ, Ε | * 370.

30th

35

Example 8

a) 2 g of 1-dehydrotestosterone are heated for 24 hours in the bomb oven under shaking at 9O ⁰ C with 11.6 ml of n-propyl mercaptan and 0.32 ml of piperidine. After working up as in Example 1, 1.1 g of la-n-propylthio-testosterone with a melting point of 156 ° to 157 ° C. are obtained.

b) 0.4 g of la-n-propylthio-testosterone are left to stand overnight at room temperature in a mixture of 2.5 ml of pyridine and 2.5 ml of acetic anhydride. It is then poured into 50 ml of ice water, the precipitate is filtered off with suction and recrystallized from hexane. 0.32 g of la-n-propylthio-testosterone acetate ^{with a melting point of 106 to 107 °} C., which does not show any depression of the melting point with the substance prepared according to Example 2, is obtained.

Claims (1)

Claim: Process for the preparation of la-alkylthio-3-keto-4-androstenes the general formula wherein Ri is H, H or aH, β-OR or O, R2 is a hydrogen atom or an acyl group having 1 to 10 carbon atoms, R3 is a hydrogen atom or a saturated or unsaturated hydrocarbon radical having 1 to 3 carbon atoms, R4 is a hydrogen atom or fluorine atom, R5 is a hydrogen atom or a methyl group, Re is an alkyl group having 1 to 3 carbon atoms, characterized in that an alkyl mercaptan with 1 to 3 carbon atoms at a J ^1-4 -3-keto steroid of the general formula OR ₂ wherein Ri to R5 have the meaning given, in the presence of a basic catalyst, in particular in the presence of piperidine, and before the isolation of the compound obtained the basic catalyst is removed from the reaction mixture and that optionally an in 17 /? - position of the compound obtained in the hydroxyl group present in a known per se Esterified way. 45 Publications considered:
Journ. Org. Chem. 26: 3915 (1961);
Journ. At the. Chem. Soc, 81: 1224 (1959).