DD153875A1 - PROCESS FOR PREPARING SUBSTITUTED 5BETA, 14BETA-ESTRA-3,17-DIONES - Google Patents

Abstract

The invention relates to the preparation of substituted 5 beta, 14 beta-estra-3,17-diones which, in addition to optionally further substituents, carry a 14-beta-hydroxy group. They are valuable intermediates for the synthesis of steroid drugs, in particular with cardiac efficacy and can themselves be used as potential drugs. The starting material used is 14.17 beta-dihydroxy-14β-estr-4-en-3-one. After hydrogenation of the 4-position double bond to get the new compound 14,17 beta-dihydroxy-5 beta, 14 beta-estran-3-one. By Oxidationon with Cr high + 6 compounds in sufficiently large sedimentation, the also new compound 14-hydroxy-5 beta, 14 beta-estran-3,17-dione is synthesized.

Description

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Title of the invention _:.

Process for the preparation of substituted 5β, 14β-Estra ~ 3,17-diones

 Field of application of the invention

The invention relates to the preparation of substituted 5β, 14β-estra-3,17-diones which, in addition to optionally further substituents, carry a 14β-hydroxy group and which are valuable intermediates for the synthesis of steroidal drugs, in particular with cardiac activity, or which themselves are potential drugs represent.

Characteristic of the known technical solutions

Simple steroids of the industrial series are known to have .bej. the hydrogenation due to the shielding effect of their 1 0 B- standigeη 19-methyl group are fixed to the catalyst so that ultimately results in a 53-H derivative ^ Organic Reactions- in Steroid Chemistry, ToluiBe I, Tan iiostrand Reinhold Company, p-111 /. .._ .. · .......-

It is also known, however, that due to the lack of this methyl group in the Bstran series, this orienting effect is lost to Organic Reactions in Steroid Chemistry, Tolume I, Tan Nostrand Reinhold Company, p. 111 /.

2Tiel of the invention

The aim of the invention, starting from the corresponding 3- keto-4-eno-steroids, the contained double bond as possible

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stereospecific, from abzusättig / and finally the. 14β, 17β-bihydroxy grouping into a 14β-hydroxy-17-ketone moiety, which is ultimately required as a reactive center for targeted further synthesis.

the essence of the invention

In order to realize the object of the invention, it is necessary to find, in the first step, a method which makes it possible to produce strongly the 5β-H derivative and, in the second step, the most quantitative conversion of the 14β, 17β-dihydroxy moiety in the 4β-hydroxy-17-oxo grouping to ensure ... -.

In addition, since the estrane derivatives to be hydrogenated according to the present invention have a 14β ™ -contiguous hydroxy group with unnatural linking - the rings C and D, it was quite surprising that "hydrogenation of the 14β, 17β-dihydrox.y-14β-estra 4-en-3-one still mixtures can be obtained, which consist predominantly of 5ß-B derivatives "exist.

The resulting isomers are so similar that they are difficult to separate by gas chromatography with packed columns, so that it was surprising that the im. Propan-2-ol dissolved Isomerengesisch and immediately gave about 95 $ 5ß-H-product.

In the second step, it was found that the oxidation with compounds of chromium in the oxidation state TI ⁺ with the addition of concentrated sulfuric acid. Achieves the intended target when oxidized in sufficiently high dilution, preferably in acetone, ethyl acetate or mixtures of both ^. This was not self-evident since it is known that the 14β-hydroxy group is relatively easily eliminated in acidic medium.

Finally, it has been found that it is favorable to subject the virtually quantitatively obtained hydrogenation mixture to this oxidation and first to remove entrained 5oC-H isomer B, whereupon solvents such as acetone or ethanol, optionally with added water, are advantageous.

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have meadows.

The compounds according to the invention and the ways of their preparation are new.

Ausführungsb ei games Example ^1:

Under inert gas, a solution of 840 mg of KOH in 180 ml of ethanol is prepared and 310 g of a Sfilgen catalyst clay Pd are added to activated charcoal after the protective gas has been displaced by hydrogen. 1,2.g 14,17ß- Dihydroxy-14β- * estr-4-en-3-one is added and shaken until the starting steroid has been completely hydrogenated,

 which was the case after 1 hour. - - '.

In the workup, the catalyst is first separated, then neutralized and i. T. brought to dryness. The residue is freed of salts, but not taken up in chlorine, washed with water and again i. T, is brought to dryness. Finally, it is taken up in a little propan-2-ol and finally it is placed in the freezer to crystallize. After several days, it is aspirated and the purification operation repeated until a sufficiently clean 14,17β-dihydroxy-5i3,14J3-estran-3-one is obtained. The pure compound shows mp: 158 to 161 ⁰ C and ^ tC / q ^{= 6} ° ⁱⁿ chloroform and 9 in methanol.

Example 2

3 g of 14,77β-dihydroxy-14β-estr-4-en-3-one are dissolved in 66 ml of ethanol and treated under protective gas with 308 mg of KOH. When the KOH has dissolved, 150 mg of catalyst (5 fo Pd on carbon) are added and after the blanket has been replaced by hydrogen, shaken until the starting steroid has decreased to = 0.3 $ (about 5 hours). For working up under inert gas is first separated from the catalyst, then neutralized and.i. V. z. Tr. brought. As soon as the salts have been removed as in Example 1, a crystalline residue is obtained, which

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neither processed as in Example 1 or more conveniently than the crude product dissolved in 105 ml of acetone and under cooling with 3o ml of oxidation mixture C5> 5 g CrO- * dissolve in about 50 ml of water; Add 5 ml of concentrated sulfuric acid and make up to 100. ml with water) is added so that 25 ⁰ C are not exceeded.

The mixture is stirred for 1.5 hours and then stops the oxidation by addition of sodium acetate until pH 6 is reached. The acetone is largely distilled off, the residue taken up in chloroform, washed salt-free and ¥ / ieder i. Y. to dryness, which results in a slight residual acetone addition, a crystalline residue which is finally dissolved in acetone under reflux and made cold to crystallize after still water was added. After, a few days at et via -15. ⁰ C is filtered off with suction and washed with a mixture of acetone and water.

This gives about 2.4 g of air-dry 14-hydroxy-5ß, 14ß-estran-3j17-dione, mp.: 120 to 124/179 to 183 ⁰ C. re-crystallization from acetone and, if necessary, drying shows the 14-hydrosyl 5ß, 14ß- ^ Ästran-5,17-dipn mp .: 187 to 189 ⁰ C and ££? Ψ = 42 ° in chloroform, and 49 ° methanol .. - -

Example 5

Dissolved 23 g of 14.17β-Dihydrσχτ-14β-estr-4-ene-one in 0.5 l of ethanol, placed under protective gas and admixed with 2.4 g of KOH. Once the KQH has been dissolved, add 0.8 g of catalyst Q5 fo Pd to charcoal), displace the shielding gas through "drum fluid and stir until no more starting steroid is detectable" (about 2 hours) replaced by inert gas, the catalyst is separated off, washed with ethanol and the KOH is neutralized by adding the equivalent amount of about 25% sulfuric acid is suctioned off from K2SO4, washed with ethanol and either processed according to Example 1 or concentrated to about 45 ml i.v., mixed with 45 ml of ethyl acetate, concentrated again to 45 ml, last under moderate vacuum, and repeated this process

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Finally, the syrup is taken up in 830 ml of acetone or ethyl acetate, "brought to 20." to 25 ^° C. and, at this temperature, 420 ml of oxidizing solution are stirred for 1 hour, which is prepared by adding 25 g of CrO *. and 25 ml of concentrated sulfuric acid in water, dissolve and finally make up to 500 ml with water.

Subject another 30 minutes -70 ml of saturated sodium acetate solution was stirred, the organic solvent is largely distilled off in vacuo and the greasy residue taken up in chloroform. It is separated, extracted, washed with water, dried with sodium sulfate and "i. V. To dryness, ilan receives 20.3 .g crystalline residue, which, cleaned according to Example 2 -18 g of air-dry 14-hydroxy-5ß, 14ß-Estr'an-3,17-dione, which after drying in the drying gun Mp.: 182 to 186 C shows.

Hydrogenations in less ethanol, with larger KOH concentrations or oxidations in acetone-ethyl acetate mixtures give very similar results.

Claims (1)

9 O 2 - 6 Claim. A process for preparing τοπ substituted 5ß, 14ß-Bstra-3 _} 17 ~ dionen, characterized in that one starts τοη 14,17ß ~ dihydroxy - t4ß ~ estr-4-en ~ 3-one, in this the 4-staged Hydrogenated double bond and then the 17ß-hydroxy group in sufficiently large thinning, Torz-example in acetone, ethyl acetate or mixtures of both oxidized, wherein in the first Terfahren the new compound 14,17ß ~ dihydroxy-5ß, 14ßestran-3-one and in the second f4 ~ hydroxy-5β, 1'4β-estran-3, ΛΤ- dione.