DE1238019B - Process for the preparation of 1beta-methyl-delta 2-5alpha-androsten-17beta-ol, its 17-esters and ethers - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

int. Cl,

C07

CC 07 J

German class: 12 ο -25/04

Number: 1238 019

File number: Sch 35918IV b / 12 ο

Filing date: October 8, 1964

Opened on: April 6, 1967

The invention relates to a process for the preparation of I / S-methyl- <d ² -5a-androsten-17 / I J-ol, its 17-esters and ethers.

The process according to the invention consists in that, by methods known per se, an ester of l / 3-methyl-5a-androstane-17 / S-ol-3-one, preferably the acetate, with sodium borohydride to form a mixture of the two 3-epimeric l /?-Methyl-5.x-androstan-3, 17 /? - diol-17-ester reduced, the resulting mixture of epimers tosylated without prior separation and the tosylate filtered through neutral aluminum oxide, the corresponding 17-ester of the 1 / S- Methyl- / 4 ² -5Ä-androsten-17 / S-ols is formed. Subsequent saponification of the 17-ester group yields the free 1/9-methyld ² -5 * -androstcn-17 / S-ol which, if necessary, can be converted into the desired acid by renewed acylation with the desired acid or a reactive derivative thereof in a manner known per se 17-ester is converted or etherified by methods known per se.

The compounds that can be prepared according to the invention are not only valuable starting materials for the production of anabolically highly effective 17ix-alkyl-l /? - methyM ² -5 "-androsten-17 / f-ols, but have also proven themselves to be highly effective as peroral in clinical trials Anabolic steroids proven. This finding is surprising since animal experiments showed only a very weak effect in the direction mentioned with peroral application.

In animal experiments, for example, l ^ -methyl-zl ² -5 "-androsten47jS-ol showed only 0.3 times the effect of 17 <x -methyltestosterone when administered orally, while l / S, 17" -dimethyl-I ² -5oi-androsten-17 / J-ol showed the 7-fold effect of 17 * -methyltestosterone.

In contrast, the 10-methyl-zl ² -5 "-androsten-17/9-ol caused an average nitrogen retention of 3 to 6 g per day in clinical studies with daily doses of 20 to 40 mg, while with Ij8,17" -dimethyl - T ² -5. * - androsten-17 /? - ol with daily oral doses of 10 mg a nitrogen retention of 2 to 3 g per day was observed.

So in the clinic you get 1 /? - methyl-I ² -5 "-androsten-17 /? -Ol with an increase in the dose to about double that for 1 / ?, 17" -dimethylzl ² -5Ä-androsten -17 /? - ol required, while the animal experiments indicated that an increase to around 20 times was necessary.

This effect is surprising in another respect as well. It is known that l-methyl-J ¹ -5 "-androsten-17 ^ -ol-3-one and its 17-esters, despite the absence of 17-alkylation, are peroral anabolic processes for the preparation of
l / i-methyl-z | s-5 "-androsten-17/3-ol,
its 17 esters and ethers

Applicant:

Schering Aktiengesellschaft,

Berlin 65, Mullerstr. 170/172

Named as inventor:

Dr. Hans Müller,

Dr. Rudolf Wiechert, Berlin

Possess effectiveness. The l / 3-methyl-5 (x-androstan-17 /? - ol-3-one and its 17-esters, however, are subeutane and perosanabolically inactive. So it was not to be foreseen that the lß-methyl-zis-SÄ-androsten-nß-ol could have considerable anabolic activity per os.

B e i s ρ i e 1 1

In a solution of 9.2 gl / J-methyl-six-androstari-17j3-ol-3-one-17-acetate (I) [preparable according to dissertation: A. P ο ρ ρ er, TU Berlin, 1958] in 400 ml of methanol and 19.4 ml of water are added 1.21 g of NaBH ₄ in portions at room temperature with stirring. When everything has been entered, the mixture is stirred for a further 20 minutes, and the reaction mixture is then poured into an ice-cold sodium chloride solution. The deposited precipitate is filtered off, washed neutral and taken up in methylene chloride while still moist. The methylene chloride phase is dried and evaporated. What remains is a crystallizate which ^{melts between 115 and 121 °} C. and represents a mixture of 3 <x and 3 / S-OH compounds (II). The yield is almost quantitative. The starting compound, the 3-ketone, can no longer be recognized in the thin-layer chromatogram.

8.45 g of epimer mixture (II), 8.45 g of p-toluenesulphonyl chloride and 24 ml abs. Pyridine are left to stand at room temperature overnight. Then that will Stir reaction mixture into 1 liter of sodium bicarbonate solution. The precipitate is filtered off in methylene chloride dissolved, washed neutral, dried and evaporated.

.. · -. , -v-. · ...:, ·. ·· 709 548/427

12 g of 1 are obtained

ol-3-tosylate-17-acetate with the melting point F: 121 to 125 ° C. UV: « ₂₂₆ = 10,200 (MeOH).

The crude product is dissolved in benzene and passed through a column with 1 kg of aluminum oxide (neutral, 1% water content). By eluting with benzene with increasing amounts of ethyl acetate · 6.4 g of β-methyl- / l ^:! -5Ä; -androsten-17/9-o! -17-aeetat. (III), which was recrystallized from isopropyl ether at 140 to 140.5 ⁰ C melt. ^:

Example 2

5 g of 1 / i-methyl-z! ² -5 "-androsten-17y5-ol-17-acetate (1Π) in 68 ml of methanol are heated with 6.8 g of potassium carbonate in 17.5 ml of water for 90 minutes under nitrogen and reflux. 6.8 ml of glacial acetic acid are then added. The reaction mixture is cooled and diluted with water. The precipitate is filtered off, washed neutral and dried. The white residue consists of 1 / J-methyl-Zl ² -5a-androsten-17/3-ol (IV) which, recrystallized from isopropyl ether, melts at 143.5 to 144 ° C. The yield is 4.1 g.

Example. 3

5 g of Lβ-MethyM ^ Six-androsten-njS-ol (IV) are mixed with 20 ml of abs. Pyridine and 10 ml of enanthic anhydride are ^{heated to 125 °} C. for 1.5 hours, then 0.4 ml of water are added and the mixture is ^{heated to 100 °} C. for 1 hour. Then pyridine and excess enanthic anhydride are distilled off with steam. The reaction product is extracted with methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated. 4.53 g / I-methyl-Z ^ -Sa-androstene-niS-ol-17-oenanthate (V) is obtained as an oil.

■: · - · Example 4

Ig 1 ^ -MethyM ² -5a-androsten-17 / J-ol prepared according to Example 2 is dissolved in 23 ml of pyridine (abs.) And 0.38 ml of dichloroacetyl chloride are added to Hüter ice-cooling. The mixture remains at -6 ⁰ C for 40 hours. It is then chromatographed in benzene over 200 g of silica gel (5% water content). 224 mg of l / 9-methyl-I ² -5 "-androstene-17/3-ol-17-dichloroacetate (VI) are obtained as an oil.

B e i s ρ i e 1 5

1 g of 1 / J-methyl-d ² -5 "-androsten-17jS-ol prepared according to Example 2 is dissolved in 100 ml of ether, 0.05 ml of BF ₃ etherate is added and, while stirring and ice cooling, ethereal diazomethane ( prepared from 5 g of nitrosomethylurea) was added dropwise. After about 2 hours, the colorless solution is made neutral with water, dried and evaporated in vacuo. The crude product is chromatographed over 150 g of silica gel (5 ° / ₀ water content) with hexane. 255 rag 1/3-methyl-zl ² -5 "-androsten-17 _/ 5-ol-17-methyl ether (VII) are obtained as an oil.

Example 6

A solution of 1 g of 1 / S-MethyM ² -5 «x-androsten-17 ₁ # -ol prepared according to Example 2 in 25 ml of abs. Benzene is distilled off to 20 ml. In the same way, a solution of 10 mg of p-Tdluolsulfonsäure in 12 ml of benzene is dried by azeotropic distillation; Both solutions are combined at 20 ^° C. and 0.6 ml of dihydropyran is added: after one hour, the reaction mixture is _{chromatographed with benzene over basic Al 2} O ₃ (without the addition of water). This gives 650 mg of 1 / ^S-methyl-2 Zl -5 "-androsten-17 _j-17 3-ol tetrahydropyranyl ether (VIII) with a melting point of 59 F. to 6I ⁰ C.

Claims (1)

· ': · Claim: Process for the preparation of l / J-methyl-J ² -5 "-androsten-17 / J-ol, its 17-esters and ethers, characterized in that an ester of lß-methyl-5o; -androstan-17 / J-ol-3-one, preferably the acetate, reduced with sodium borohydride, the resulting mixture of the two 3-epimeric 1β-methyl-Sa-androstan-Sn / i-diol-17-ester tosylated without prior separation , the 3-tosylate obtained is filtered through neutral aluminum oxide, the 17-ester of lß-methylzl ² -5ix-androsten-17 /? -ol obtained is saponified in a manner known per se, if necessary, and the resulting free 1 / S-methyl Zl ² -5 "-androsten-17 /? - ol optionally acylated again with the ultimately desired acid or a reactive derivative thereof, or the 1 / J-methyl- A ² -5" -androsten-17/9-ol obtained etherified. 709 548/427 3.67 © Bundesdruckerei Berlin