DE1204671B - Process for the preparation of 1beta-methyl-delta-5alpha-androstene-17beta-ols - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

C07c

German class: 12 ο -25/04

Number: 1204 671

File number: Sch 33579IV b / 12 ο

Filing date: July 18, 1963

Opening day: November 11, 1965

The invention relates to a process for the preparation of l ^ -Methyl-zl ² -5a-androstene-17 ^ -ols of the general formula

CH ₃

wherein R ^{1 is} hydrogen or an acyl group and R ^{2 is} a lower saturated or unsaturated alkyl group.

The process according to the invention consists in introducing a 17a-alkyl group into l ^ -methyl-J ² -5a-androsten-17-one (V) in a manner known per se either by Grignardation or

CH ₃

Process for the preparation of Ij3-methyl-
A ² -5 a-androstene-17 ß-cAsn.

Applicant:

Schering Aktiengesellschaft,

Berlin N 65, Müllerstr. 170/172

Named as inventor:

Dr. Hans Müller,

Dr. Rudolf Wiechert, Berlin

followed by an analogously introduced 17a-ethynyl group reduced to the vinyl group and optionally the free 17/3 hydroxy compounds obtained in acylated in a manner also known per se.

OH

CH ₃

CH ₃

IX

^{The 1/3-methylzl 2} -5a-androsten-17-one (V) which serves as the starting material and has not yet been described in the literature can be prepared by methods known per se by, for example, lß-methyl-5a-androstane 17/3-ol-3-one-17-acetate (I) reduced with sodium borohydride to a mixture of the two 3 - epimeric iß - methyl - 5a - androstane - 3, Πβ - diol-17-acetate (II). This mixture is tosylated without prior separation and filtered through neutral aluminum oxide, 1 / S-methyl-zl ² -5a-androstene-17/9-ol-17-acetate (III) being formed. After saponification of the 17-acetoxy group, oxidation of the free lβ-methyl-, / l ² -5a-androstene-17/3-ol (IV) with chromosulfuric acid ^{gives the desired l / γ-methyl-, d 2} -5a-androstene -17-on (V).

For the preparation of this compound, protection is not given in the context of the present invention desired.

The new compounds which can be prepared according to the invention are valuable pharmaceuticals.

509 737/410

The l ^ na-dimethyl - ^ - Sa-androsten-n ^ -ol (VI) is, as the following table shows, an extremely effective anabolic perorally without any noteworthy androgenic side effects. The peroral anabolic and androgenic activity was determined according to standard methods on the castrated male rat in the levator-ani test or in the seminal vesicle test, based on 17a-methyl-zI ⁴ -androsten-17 /? - ol-3-one, as the standard substance.

substance

a) 17a-Methylzl ⁴ -androsten-17 | S-ol-3-one

b) 17a-methyl-J ² -5a-androsten-
Πβ-όΡ)

c) la, 17a-dimethyl
Δ ² -5 «-android- Πβ-οΨ)

d) Ij8,17a-dimethyl
<d ² -5a-androsten-
Πβ-ολ

Anabolic Androgens 1 effectiveness 1 1 0.17 3 0.1 3 7th

Ratio anabolic to androgenic

18th

70

*) See Chem. And Ind., 1961, p. 1962; U.S. Patent

2,996,524,
² ) See German patent application Sch 33126 IVb / 12 ο (German Auslegeschrift 1199 767).

You can see that d) not only in relation to the corresponding 1-desmethyl compound b), but even compared to the corresponding la epimer c) not only an unpredictable extraordinary increase in anabolic effectiveness, but at the same time a surprisingly favorable shift in the anabolic to androgenic ratio of action shows.

The l ^ -Methyl-17a-äthinyl-zl ² -5a-androsten-17 ^ -ol (VII) has the ability to inhibit the release of gonadotropins, since after its application a. Inhibitory effect on the growth of testes and prostate can be observed.

example 1

To the cooled Grignard solution, prepared from 3.94 g of magnesium shavings in 44 ml of absolute ether and 10.2 ml of methyl iodide in 28.4 ml of absolute ether, 3.6 gl ^ ^{-Methyl-I 2} -5a-androsten-17-one ( V) was added dropwise in 130 ml of absolute benzene and stirred for 4 hours at room temperature under nitrogen. Then, with external cooling with ice, concentrated aqueous ammonium chloride solution is carefully added; it is acidified with dilute hydrochloric acid and extracted with ether. The ethereal phase is washed neutral, dried and evaporated. The crystalline residue is chromatographed over silica gel (10% water content). Eluting with carbon tetrachloride and with methylene chloride-carbon tetrachloride (3: 1) gives 2.75 gl / ?, 17a-dimethyl-zl ² -5a-androsten- ylß-o \ (VI), which recrystallizes from pentane at 146 to 147 Melting ° C.

Example 2

The cooled Grignard reagent from 936 mg of magnesium turnings in 9.6 ml of absolute tetrahydrofuran and 2.92 ml of ethyl bromide in 9.2 ml of absolute tetrahydrofuran becomes 16 ml of absolute tetrahydrofuran given, through which acetylene has previously been passed for 20 minutes. The "temperature" rises at 45 ° C. Acetylene continues to be passed in until the temperature drops again. Then 450 mg

ίο lß-methyl-zl ² -5a-androsten-17-one (V) in 9.6 ml of absolute tetrahydrofuran was added dropwise. Acetylene is still being introduced during the dropwise addition. The reaction mixture is then heated under nitrogen and with stirring in a 70 ° C. oil bath for 21 hours. After cooling to 5 ° C., concentrated aqueous ammonium chloride solution is slowly added until no further reaction occurs. It is then extracted with ether, the organic phase washed neutral with water, dried over sodium sulfate, evaporated to dryness in vacuo and the residue chromatographed over silica gel (10% water content). Eluting with equal parts of carbon tetrachloride and methylene chloride gives 260 mg of 1 / S-methyl-17a-äthinyl-zl ² -5a-androsten- Ylß-oX (VII); M.p. 118 to 119 ° C (from pentane).

312 mg of the 1 / S-methyl-17a-äthinyl-zl ² -5a-androsten-17jS-ols (VII) obtained as above are dissolved in 50 ml of pyridine and, with the addition of 60 mg of 5% palladium-carbon catalyst, up to hydrogenated to absorb 1 mmol of hydrogen. The catalyst is then filtered off and the solution is concentrated to dryness in vacuo. The residue consists of 160 mg of l ^ -Methyl-17a-vinyl-zl ² -5a-androsten-17 / ί-οΙ (VIII); M.p. 118 to 119 ° C and 129 to 130 ° C (from pentane; crystal polyamorphism).

Example 3

To the cooled Grignard solution, prepared from 3.94 g of magnesium shavings in 44 ml of absolute ether and 10.2 ml of ethyl iodide in 28.4 ml of absolute ether, 3.6 g of lß-methyl-zl ² -5a-androsten-17-one ( V) was added dropwise in 130 ml of absolute benzene and stirred for 6 hours at room temperature under nitrogen. Then concentrated aqueous ammonium chloride solution is added with external cooling with ice; it is acidified with dilute hydrochloric acid and extracted with ether. The ethereal phase is washed neutral, dried and evaporated. The residue is chromatographed over silica gel with carbon tetrachloride and with methylene chloride-carbon tetrachloride (3: 1). 1.2 gl /? - methyl-17a-ethyl- / l ² -5a-androsten-17ß-ol (IX) are obtained; F. 78 to 80 ° C (from pentane).

Example 4

1 gl £, 17a-dimethyl -. / L ^{2-5a-androstene-17-ol} S _j is heated in 5 ml of pyridine with 5 ml of acetic anhydride for 4 hours at 130 to 140 ° C. After cooling, the reaction mixture is stirred into an ice-cold sodium chloride solution. The semi-solid precipitate obtained is filtered off, washed neutral with water and then dissolved in ethyl acetate. The ethyl acetate solution is washed again with water, treated with activated charcoal, dried over sodium sulfate and, after filtration, concentrated to dryness. This gives 850 mg of semicrystalline 1 | 8,17a-dimethyl- / 1 ² -5a-androstene-17/3-ol-17-acetate, [a] f = -2 ° (CHCl ₃ ; -c = 1.07 ).

Claims (1)

Claim: Process for the preparation of lß-methyl- / l ² -5a-androsten-17 | 8-ols of the general formula ORi CH ₃ wherein R ¹ denotes hydrogen or an acyl group and R ² denotes a lower saturated or unsaturated alkyl group, characterized in that in l / ii-methyl- ^ ² -5a-androsten-17-one in a manner known per se either introduces a 17α-alkyl group by Grignardation or a 17α-ethynyl group introduced analogously is then reduced to the vinyl group and optionally acylated the resulting free ^ -hydroxy compounds in a manner likewise known per se. 509 737/410 11.65 © Bundesdruckerei Berlin