NO154549B - PROCEDURE FOR PREPARING ETHYLENDIA ACETATE. - Google Patents

Abstract

Alkylidene diesters are prepared by reacting carboxylic anhydrides with hydrogen in the presence of a cobalt carbonyl catalyst.

Description

Process for the production of 2a,3a-epithio-steroids with therapeutic effect.

The present invention relates to a

process for the production of 2a, 3a-epithiosteroids with antiestrogenic action and a favorable ratio between strong androgenic and strong anabolic action and with the general formula

in which R is an alkyl group, an alkenyl group or an alkynyl group each with no more than 5 carbon atoms, and the peculiarity of the method according to the invention is that a steroid with the following general formula

wherein R has the above meaning, R' is a cyano group or an alkanoyl group of not more than 6 carbon atoms, and R" is a hydrogen atom, an alkanoyl group of not more than 6 carbon atoms, an alkyl sulfonyl group with not more than 5 carbon atoms, a phenyl-sulfonyl group or an alkyl-phenyl-sulfonyl group with not more than 11 carbon atoms is reacted with a basic reacting agent.

The starting compound can be prepared from the corresponding 2|3,3|3-epoxy-steroid by a number of methods. One of the methods can be illustratively represented by the following scheme, which only shows the A ring in the steroid nucleus:

wherein R' has the above meaning, R"' is an alkanoyl group of not more than 6 carbon atoms, such as acetyl, propionyl or butyryl, an alkyl-sulfonyl group of

not more than 5 carbon atoms, such as methanesulfonyl or ethanesulfonyl, a phenylsulfonyl group or an alkylphenylsulfonyl group of not more than 11 carbon atoms,

such as toluenesulfonyl or xylenesulfonyl, and X is a halogen atom, such as chlorine or bromine, or a hydroxyl group.

Examples of the starting compound include 3α-thiocyanate-17α-ethyl-5α-androstane-2(3,17[3-diol, 3α-thiocyanate-17α-vinyl-5α-androstane-2(3,17[3-diol, 3a-thiocyanate-17a-ethynyl-5a-androstane-2p,17|3-diol, 2|3-methanesulfonyloxy-3a-thiocyanate- 17a-methyl-5a-androstane-17p-ol, 2j3-methanesulfonyloxy-3a- thiocyanate-17a-vinyl-5a-androstan-17|3-ol, 2|3-toluenesulfonyloxy-3a-tlocyanate-17a-ethyl-5a-androstan-17|3-ol, 2|3-acetyloxy-3a-thiocyanate -17a-methyl-5a-androstan-17|3-ol and 2|3-propionyloxy-3a-propionylthio-17o-vinyl-5a-androstan-17p-ol.

In the method according to the invention, the starting material is treated with a basic agent to give the corresponding 2a,3a-epithio-steroid. A weak base such as e.g. aluminum oxide hydrate and a strong base such as potassium hydroxide and sodium hydroxide. Other basic agents such as e.g. sodium carbonate and potassium carbonate can also be used! if desired. The reaction temperature depends on the starting material and the basic agent. For the preparation of the desired compounds in good yield, it is usually preferred to carry out the reaction in an inert solvent, such as methanol, ethanol, propanol, benzene, toluene, petroleum ether or dimethyl glycol dimethyl ether, under relatively mild conditions -ser, i.e. at a temperature not exceeding 100°C.

The 2a,3a-epithio-steroids that can be produced by the method, especially 2a,3a-epithio-17a-methyl-5a-androstan-17|3-ol and 2a,3a-epithio-17a-ethyl-5a-androstane -17α-ol, exhibits a beneficial antiestrogenic effect.

Furthermore, strong androgenic and anabolic effects with a favorable anabolic-androgenic ratio were confirmed by 2a,3a-epithio-17a-methyl-5a-androstan-17|3-ol (ME) and 2a,3a-epithio-17a-ethyl -5α-andros-tan-17α-ol (EE) in a comparative test in castrated young male rats weighing approximately 50 g, equal to the standard compound methyltestosterone (MT). The connections were respectively administered orally for 10 consecutive days at the indicated total dose per rat and the endpoints (weight of seminal vesicle, Ventral Prostate and Levator Ani Muscle) were determined after 11 days at autopsy. The results are summarized in the following table I.

The result of the calculations is summarized in table II, in which the excellent ratio between anabolic/androgenic (3-7), compared to the ratio = 1 for standard methyltestosterone, is shown.

The following examples represent illustrative and exemplary embodiments of the method according to the invention. The ratio between parts by weight and parts by volume is the same as between grams and milliliters.

Example 1.

Preparation of 2a,3a-epithio-17a-ethyl-5a-androstan-17(3-ol.

To a solution of 3a-thiocyanate-17a-ethyl-5a-androstane-2|3,17(3-diol (3.74 parts by weight) in dioxane (60 parts by volume) is added a solution of potassium carbonate (5.5 parts by weight) in water (30 parts by volume) and methanol (100 parts by volume), and the resulting mixture is allowed to stand at room temperature (about 15°C). The reaction mixture is concentrated under reduced pressure and water is then added. The precipitate is collected by filtration, crystallized from a mixture of ether and petroleum ether and recrystallized from a mixture of acetone and hexane so that 2a,3a-epithio-17a-ethyl-5a-androstan-17|3-ol (2.49 parts by weight) is obtained as crystals melting at 146-148°C .(a) V's + 8.5 ± 2° (c - 1.029 in chloroform).

IR: 3660, 3630 cm-<1>.

Analysis calculated for C21H34<O>S: C,75.39; H 10.24; S 9.58.

Found: C.75.52, H, 10.35, S, 9.74. The starting material in this example, 3α-thiocyanate-17α-ethyl-5α-androstan-2β, 17(3-diol can be prepared by reacting 2(3, 3|3-epoxy-5α-androstan-17-one (J. Fajkos

et al.: Chem. Abstracts Vol. 53, page 5343

(1959)) with potassium acetylide in a mixt

of tetrahydrofuran and ether at room temperature, catalytically reducing the resulting 2p,3(3-epoxy-17a-ethynyl-5a-androstan-17p-ol using palladium-calcium carbonate in ethyl acetate and reacting the resulting 2p,3p -epoxy-17α-ethyl-5α-androstan-17β-ol with a solution of thiocyanic acid in ether at room temperature.

Example 2.

Preparation of 2cx,3a-epithio-17a-vinyl-5a-androstan-17p-ol.

3a-thiocyanate-17a-vinyl-5a-androstane-2p,17p-dlol is treated with potassium carbonate in a mixture of dioxane and water as in Example 1, giving 2a,3a-epito-17a-vinyl-5a-androstane-17p- etc. as crystals that melt at 136-138°C.

(a) V5 + 17.5 ± 2° (c = 1.043 in chloro-, T_ Nu jol form).IR:r Max

3348, 3088, 1642, 1014, 924, 910 cm-<1>.

Analysis calculated for <C>21H32OS: C.75.85;

H, 9.70; S, 9.64.

Found: C,75.98; H, 9.80; P.9.86. The starting material in this example, 3α-thiocyanate-17α-vinyl-5α-androstane-2β,

17p-diol, can be prepared by catalytic reduction of 2p,3p-epoxy-17a-ethynyl-5a-androstan-17p-ol using Lindlar catalyst in ethyl acetate and reacting the resulting 2p,3p-epoxy-17a-

vinyl-5α-androstan-17:|3-ol with a solution of thiocyanic acid in ether at room temperature.

Example 3.

Preparation of 2α,3α-epithio-1-7α-ethynyl-5α-androstan-17|3-ol.

3a-thiocyanate-17arethynyl-5a^androstane-2(3,17(3-diol) is treated with potassium carbonate in a mixture of dioxane and water as in example 1, giving 2a,3a-epithio-17a-ethynyl-5a-androstane -17(3-ol as crystals melting at 177—1.78°C.

(a) V<5> — 19-0 ± 2° (C = 1.038 in chloro-, ___ Nujol form). IR:r m^

3405, 3294, 1047 cm-<1>.

Analysis calculated for C2LH30OS: C.76.31; H.9.15; P.9.70.

Found: C.76.38;. H.9.00; P.9.79.

The starting material 1 this, for example, 3α-thiocyanate-17α-ethynyl-5arandrostane-2(3„ 17§-diol can be prepared by reacting

3-prepoxy.-1'7a-ethynyl-5a-androstan^17§-ol with a solution of thiocyanic acid in ether at room temperature.

Example 4.

Preparation of 2α-3α-epithio,-17α-methyl-5α-androstane-1.7β-oL.

To a slurry of 2|3-methanesulfonyloxy-3a-thiocyanate-17a-methyl-5a-androstan-17)3-ol (2.15 parts by weight) pure mixture of methylene glycol dimethyl ether (50 vol. deTer)' and tetrahydrofuran* (10- parts by volume), a solution of potassium hydroxide (2.5 parts by weight) in water (4: parts by volume) is added and the resulting solution is stirred overnight at room temperature (approx. 15 °C). Water is added to the reaction mixture; and the resulting mixture is shaken* with dichloromethane. The dichloromethane layer is washed with water, dried and evaporated to dryness. The residue is chromatographed on aluminum oxide (35 parts by weight). The eluates with a mixture of petroleum ether and benzene (1:2), benzene and a mixture, of benzene and ether (95 : 5)' are combined; concentrated^ and crystallized from aqueous acetone to give 2a, 3a-epithio-17a-methyl-5a-androstan-17|3-ol (0.91 parts by weight) as needles melting at 168—169° C. (a) \7 ;- 5 + 3:4 ± 2°. (>c = l<i>.045 in chloro-Nuiol-.

shape). IR:y m^x 3356 cm-1.

Analysis calculated for C20H3„QS:. C.74.94; H.1-0-.06;. 840-00.

Found G]75lll;: H,r0sH7-;: S',9186.. Is the starting material r this example? 2p-methane-sulfynyloxy-3d-thiocyanate-17a-methyl-Sct-androstan-1Tp-ol, can be prepared by treating 2-a-bromo-17a-methyl-1'7p-hydroxy-5a-androstan- 3-on' (CounselF et al.: J. Org. Chem. Vol. 27, page 248 (1962)) with lithium tri-t-butoxy aluminum hydride, treat the resulting product with potassium hydroxide in isopropanol, treat dtefr resulting^ 2(}3p:-epoxy-1-7a-methyl-Sa-androstane-ITfV-ol with 1 thiocyanic acid in ether and treating the resulting 2|3-hydroxy-3a-thiocyanate-17a-methyl-5a-androstane -17(3-ol with methanesulfonyl chloride in pyrldine..

Example 5.

Preparation of 2a,3a-epithio-17a-ethyl-5a-androstan-17f3-ol.

A solution of 2fS-methanesulfonyl-oxy-3a-thiocyanate-17a-ethyl-5a-androstan-17(3-ol (3.5 parts by weight) in tetrahydrofuran (20

parts by volume) is added to a solution of

potassium hydroxide (3.5 parts by weight) in isopropanol (70 parts by volume) and the resulting

mixture is stirred. The reaction mixture

homogenize with a small amount of water,

and leave overnight. A larger quantity of water is added, and the resulting solution is shaken with dichloromethane. The dichloromethane layer is chromatographed on aluminum oxide (80 parts by weight). The eluates with

benzene and a mixture of benzene and ether

(95 : 1, 9 : 1) are combined, crystallized from

a mixture of ether and methanol, and recrystallized from a mixture of dichloromethane

and methanol to give 2α,3α-epithio-17α-ethyl-5α-androstan-17'|3-ol hydrate (2.46 parts by weight) as needles melting at 146-148°C.

The needles are crystallized from a mixture of

acetone and hexane and gives 2a,3«-epithio-17a-ethyl-5a-androstan-17|3-ol (2.11 parts by weight)

which melts at 147-149°C.

(a) V'<5> + 8.5 ± 2° (c = 1.029 in chloroform). IR: y 3660, 3630 cm-<1>.

Analysis calculated for C21H34<O>S: 0.75.39;

H.10.24; P.9.58.

Found: 0.75.52; H, 10.35; P.9.74.

The starting material in this example,

2|3-methanesulfonyloxy-3a-thiocyanate-17a-ethyl-5a-androstan-17j3-ol can be prepared

by treating 3α-thiocyanate-17α-ethyl-5α-androstane-2|3,17|3-diol with methanesulfonyl chloride in pyridine.

Claims (1)

Process for the production of 2a, 3a-epidodosteroids with antiestrogenic activity ning and a favorable relationship between strong androgenic and strong anabolic action and with the general formula in which R is an alkyl group, an alkenyl group or an alkynyl group with each not exceeding 5 carbon atoms, characterized in that a steroid with the following general formula in which R has the above meaning, R' is a cyan group or an alkanoyl group of not more than 6 carbon atoms, and R" is a hydrogen atom, an alkanoyl group of not more than 6 carbon atoms, an alkyl-sulfonyl group of not more than 5 carbon atoms, a phenyl-sulfonyl group or an alkylphenyl-sulfonyl group of not more than 11 carbon atoms are reacted with a basic reacting agent.