DD144267A1 - PROCESS FOR PREPARING DELTA HIGH 14-17-KETOSTEROIDS OF THE OESTRAN AND ANDROSTANIUM - Google Patents

Abstract

It is the production of Δ14-17 ketosteroids of the estranund Androstanreihe the general partial formula I described. The ; Compounds become more bio.logical as intermediates for the total synthesis Active ingredients, in particular cardiac active and fertility-inhibiting Used steroids. The process according to the invention compounds prepared are known, the method of their Production is new. In the implementation of one goes from 17,17-ethylenedioxy-1 6-bromo-steroids III, which are obtained in one suitable solvents, preferably dimethyl sulfoxide, Hexamethylphosphoric triamide, triglycol or diglycol in Presence of an alkaline earth or alkali hydroxide, optionally with the addition of an alcohol, heated and the resulting Product mixture by treatment with anhydrous acid in Transferred Δ14 ketals V and then by ketal cleavage in Δ ^ -Ketone I converts.

Description

Field of application of the invention

The invention relates to a process for the preparation of Λ 17-ketosteroids of the Östran- and Androstanreihe with the general part of formula I,

wherein R represents a methyl or ethyl group _{s are} the intermediates for the total synthesis of biologically highly active agents, especially cardiac active and fertility-inhibiting steroids.

Characteristic of the known technical solutions

The compounds which can be prepared by this process are known. In the hitherto known process for their preparation is generally based on bromoketones or bromo ketals of the general part formulas II and III.

ΓΊ

II

In the treatment of bromoketones of the general partial formula Ii

With lithium bromide and calcium carbonate in dimethylformamide, Δ * «» ketones I are obtained with yields of 39 to 50 percent. Since in this synthesis the lifting products I4ß «» Δ - ^? The ^{separation of} ketosteroids in relatively large quantities, the separation of which is relatively laborious, has hardly any technical significance for this version of the synthesis, D, K, Phillips, J, med. ΛΛ (1968), 924 $ J "Pataki, G" Siade _? _ J _e org _e Chemo 22 (1972) 2127j Rassmusson, Steroids 22 (1973), ΙΟ ?;

* ί4

In the production of Δ ** 17 cortosteroids, therefore, the bromoketals III _{s were used} predominantly, and the hydrogen bromide splitting by means of diazabicy © IQ / 4 _? 5s0 / unde-5-en, (R _e Emiliozzi _s oo Oondomj M "Audinot, Bull" Soc _d chim · Erance 1 ^ 21 -CD "131) with 64% yield, or potassium tertiarylitylate in toluene, xylene or dimethyl sulphoxide (B _ft W _e Cantrallj ro Littel ₉ S _e Bern ". Jiorg.Uhem stones · 2g (1964) ^ 214? W _e S" Johnson ^ W "P _{e s} John J * Amer, ohem.Öoc. £ 2 ( 1957)? 2005? 'D, plates, US 35 _77410? ref _"Ο β Α · 75 (1971)? 49448 g) in a yield of about 80 per *" zeö.t first in 4 ^ "" IY ketals are converted «, The Λ ^ & e«

14 acids are iso-azerized by acid to the Δ- ketals Y (De Teller, US 35 774-10, ref. _{0 0 0} 75 (1971) 49448 g and after subsequent ketal cleavage with acetone ₅ water and p-toluene oil * »

* 14

fonsäure in Zj * »17-Ketone ^ converted»

π *

The process variant in which diazabicyclo / 4 _? 5 is "0 / undec". "5" ⁱ s used ₈ appears for a technical Hutzung ₉ both the yields are too low because not suitable and the reagent used is too expensive "

The disadvantage of the other method is that the reactions "butylate ₃ which requires on the one hand expensive and on the other hand in its manufacture costly safety precautions with Kaliunwtertiär" feasible, In addition, the yields of ά '' are ketone I still in need of improvement

Object of the invention

a 14 · object of the invention is the production of Λ -17-keto steroids of the androstane and östran- the general partial formula I according to one economically favorable method.

Explanation of the essence of the invention

The invention has for its object to provide a simple method for the production of Λ '-17-keto steroids of the estranged

and Androstanreihe the general part of formula I indicate that avoids the essential disadvantages of the known method and in particular with improved yield bypasses the use of expensive potassium tert-butyrate.

The solution of this problem according to the invention is based on the surprising finding that bromoketals of the estrane and androstane series of general sub-formula III,

III

wherein R represents a methyl or ethyl group and Br can take both ^ - and B configuration, in a suitable solvent, preferably dimethyl sulfoxide, hexamethylphosphoric triamide, triglycol or diglycol in the presence of an alkaline earth or alkali metal hydroxide, optionally with the addition of a primary, secondary or tertiary alcohol, at temperatures between 90 and 150 ⁰ O and the resulting steroid mixture consisting of Δ -Ketal IV, A Ketal V and A »^ dienol ether VI, in a siprotischer, absolutely anhydrous solvent, preferably benzene, toluene, methylene chloride or chloroform, by treatment with anhydrous acid in Δ -17 Eetal V transferred and then in

A 14 ·

In itself "known way by ketal cleavage in 4 - ketone of the general part formula I converts.

The following reaction scheme illustrates the process according to the invention:

 aar w vs »

The inventive method is advantageously carried out as follows?

The bromine 'ketals III which are used as starting materials for the process include the state of the art. The hydrogen bromide splitting off is preferably carried out in dimethyl sulfoxide in the presence of potassium hydroxide or potassium hydroxide / methanol at about 100 ^° C. _e

The resulting product mixture ,. consisting of Δ -''- ketal IV, V and Δ A ketal '-Dienolether, is treated with anhydrous

Λ 14

p-Toluenesulfonic acid in benzene smoothly converted to Δ, "-Ketal V»

14- a 14-

The cleavage of the Λ -Ketals V to ^ -Keton I is preferably carried out in a solvent mixture consisting of water, isopropanol and acetone and optionally benzene _s by means of p-toluenesulfonic acid.

The smooth elimination of hydrogen bromide from the Bromketalen III is surprising, since in particular with small Alkoholatresten such as methylate, ethylate or isopropoxide or hydroxyl ions, an ether or Alkohalbildung should be favored / s. Houben Weyl 6/3 p.29 / *

Furthermore, the dienol ether VI obtained as a lifting product proved to be suitable for the preparation of Δ- ketone I according to this synthesis variant.

The following exemplary embodiments are intended to explain the method according to the invention without restricting it in any way.

3-Methoxy-estra-1,3,5 (10), 14-tetraene-17-one

Stage A Hydrogen bromide elimination

a) 50 g of 3-methoxy-16 <^ bromo-17 »17-ethylenedioxy-estra-1,3,5 (1O) ^ trien are dissolved in 500 ml of dimethyl sulfoxide and then treated with 29.6 g of potassium hydroxide. The reaction mixture is stirred for about 3 hours at 100 ⁰ G and cooled after the reaction. Thereafter, the steroid is ausge¬ by addition of water. falls and then separated, washed neutral with water and dried. For the further reactions, the crude product obtained (39 S = 97.5 % yield) was used without further purification.

30 g of 3-methoxy-16 ^ -broin- ^ i ^ ethylenedioxy-estra-1,3,5 (10) -triene are dissolved in 300 ml of dimethyl sulfoxide and mixed with 13 ml of methanol and 17.75 g of potassium hydroxide is stirred for 3 hours at 100 and cooled after the reaction. Thereafter, the steroid is precipitated by the addition of water and then separated, washed neutral with water, washed and dried. For the further reactions, the crude product obtained (24 g → 99 % yield) was used without further purification.

Stage B isomerization and ketal cleavage 3-methoxy-17,17-ethylenedioxy-estra-1,3,5 (10), tetraene

39 S of the obtained by hydrogen bromide cleavage from 3-Me.thoxy i6 ^{iÄ /} bromo-17,17-ethylenedioxy-estra-1,3, "5 (10) -triene crude product are dissolved in 500 ml of anhydrous benzene and with 1.72 g p-toluenesulphonic acid (dehydrated) is added and the mixture is allowed to stand at room temperature for 20 minutes and then an aqueous sodium bicarbonate solution is added. The steroid is extracted with benzene and, after evaporation of the solvent, a crystalline residue which recrystallizes from ethanol, 37 g (95 %) of 3-methoxy-17,17-ethylene

dioxy ~-estra-1,3 »5 (10)? 14-tetraene of melting point P: 116 to 118 ⁰ ?

3-methoxy-estra-1,3? 5 (10), 1.4-tetraene-17

The product obtainable by isomerization of 3 ~ methoxy-17 _s 17 · ethylenedioxy-estra-1 _'3} 5 (1O), 14 ~ tetraen / s "above) without intermediate isolation in the still acidic benzene solution with 500 ml Tsopropanol, 200 ml Acetone and 80 ml of water and boiled for about 2 hours at reflux. Subsequently, it is neutralized with an aqueous sodium bicarbonate solution and the steroid is extracted with benzene. After concentration of the extracts, the residue is recrystallized from ethanol. This gives 30.3 g (90%) of 3 ~ methoxy-ö'stra-1 _i 3.5 (10), 14-tetraene ~ 17 ~ on of melting point F .: 102 to 104 ⁰ G.

2 · 3ß ~ hydroxy-5 ^ -andro st ~ 14 ~ en ~ 1? -One

Stage A hydrogen bromide cleavage

100 mg of 17i17-ethylenedioxy-16 <-> - tome - 5 ^{0 </} - androstane-3ß ~ ol acetate are dissolved in 2 ml of dimethyl sulfoxide and treated with 59 J & g of potassium hydroxide The reaction mixture is stirred for 3 hours at 100 ^{0 0} * After the reaction is allowed to cool and precipitates the steroid by adding water. The steroid mixture is separated, washed with water, washed neutral _$ and used without further purification in the next step (78 mg = 97.5% yield) ·

Stage B isomerization and ketal cleavage

3β-hydroxy-5-α-andro-st-14-ene-17-cn

78 mg of the product isolated according to Example 2 step A are dissolved in 3.25 ml of anhydrous benzene and treated with 11 mg of anhydrous p-fololsulfonsäure * is allowed to stand for 20 minutes at room temperature, until everything

Product is converted into 17,17-Bthylenedioxy-aiidrost ~ 14 "en ~ 3β-ol. Thereafter, a solvent mixture is added

consisting of 3 »2 ml of isopropanol, 1.3 ml of acetone and 0.5 ml of water, refluxed for 3 hours and neutralized after the reaction, the cooled Reaktionsgenisch with aqueous sodium bicarbonate solution. The steroid is extracted with benzene, the solvent is evaporated off and the residue is crystallized from ether / hexane. 40 mg (51 %) of 3β-hydroxy-5 ° U-'androst-14-en-17-one of melting point are obtained. 143 ⁰ C.

Claims (1)

& 3 invention claim
, " _U -17-ketosteroids of the -ostran- and Androstanreihe of the general partial formula I, in which R denotes a methyl or ethyl group, characterized in that bromoketals of the estrane and androstane series of general sub-formula III, OB J III. wherein R is a methyl or ethyl group and Br can take bothcf and ß configuration, in a suitable solvent, preferably dimethylsulfoxide, Hexamethylphosphorsäiiretriamid, triglycol or diglycol in the presence of an alkaline earth or alkali metal hydroxide, optionally with the addition. a primary, secondary or tertiary alcohol, reacted at temperatures between 90 and 150 ⁰ O and the resulting steroid mixture consisting of Δ'' -ketal IV, Δ -Ketal V and dienol ether VI, in an aprotic, absolutely anhydrous solvent, preferably benzene , Toluene, methylene chloride or chloroform, converted by treatment with anhydrous acid in & -Ketale V and then in per se known- / 14 way by ketal cleavage in Zl -Ketone the general Part formula I converts. ^