DE2203886A1 - Delta high δ-salpha hydroperoxy or hydroxysteroids and processes for their preparation - Google Patents

Description

DR. IXG. F. AVUKSTHOFF DR. IXG. I). BEIIKEXS DIPL ·. IXG. U. GOETZ PATENT LAWYERS

θ MUNICH OO SCHWEICHIHSTRASSE

TtLIFOS '(0811) 6U20 TKLKX 5 24 070

TKLEOKAMME: PHOTEOTI'ATKST MUNICH '

1A-40 867

Description of the patent application

N.V. Organon

Kloosterstraat 6, 03S, The Netherlands

concerning:

"^ -fo ^ hydroperoxy- or for their production "

»Hydroxysteroids and procedures

The invention relates to new Δ -steroids of the estran series and Process for their manufacture. It particularly relates to new Δ - ^ oc-Hydroperoxy- or Hydroxysteroids of the general Formula:

in the R ^ a Alkylgrupp · »it 1 bit 4 carbon atoms, E2 ei · ¹¹ oxygen atom or the group (SSP) (aq), where

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P is a free, esterified or etherified hydroxyl group and Q is a hydrogen atom, an alkyl, alkenyl or alkmyl group with 1 to 4 carbon atoms and R ^ is a hydroxyl, an aücyloxy or acyloxy group, a hydrogen atom, a Is alkyl or acyl group.

The compounds of the invention can be prepared by reacting a steroid of the estran series of the general Formula:

in which R ,, and Rp have the meaning given above, with activated oxygen, whereupon the resulting A - ^ a-Hydroperoxysteroid to the ^ \ -5 <x-hydroxy compound reduced and / or - if not already present, the substituents required in the 17-position after introduces any process known per se and / or esterifies the 5a-hydroperoxy or 5> a-hydroxy group or etherified.

The A ^ ^ -3-deoxo compounds can be obtained by Enolacylation of a Δ -3-keto compound to the corresponding

olacylie

'^' -3-acyloxy compound and conversion of the latter Connection to the Δ ^ '-3-hydroxysteroid by selektiy fieduction and hydrolysis, conversion of the ^ -hydroxyl group into a 3-halogen or 3-sulfony ^ group and finally reductive

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22Ü3S86

Elimination of the substituents in the 3-position.

Among the activated oxygen used for the method of the present invention, oxygen is in a higher level To understand energy supply as the basic state.

Good results are achieved particularly with oxygen in the singlet- : Condition preserved.

The activated oxygen can be obtained by one from oxygen gas, possibly with another Gas, e.g. nitrogen, is mixed, runs out. However, it is also possible to use connections that either themselves or in combination with other substances split off activated oxygen or which directly deliver oxygen to the oxidizing compound can transfer.

Usual methods for generating activated oxygen are that one

a) the reaction mixture in which oxygen is dissolved, one exposed to strong radiation, e.g. sunlight,

b) a sensitizer is added to the reaction mixture, which contains sufficient oxygen ^ and the mixture with visible and / or irradiated with ultraviolet light. Suitable sensitizers include hematoporphyrin, Eosin, methylene blue, bengal pink, hypericin, fluorescein, and riboflavin;

c) Use of a substituted phosphite ozonide, which activated when heated above its decomposition temperature Splits off oxygen. The substituents normally occurring in the phosphite ozonide are alkyl, aralkyl or Aryl groups, with triphenyl phosphite in particular ozonide is suitable;

: · ■ υ π ο 3 L1 115 6

d) Use of a substituted phosphite ozonide that activated »oxygen that binds / aficias phosphate is transferred to a suitable temperature, namely a temperature below the decomposition temperature can;

e) adding hydrogen peroxide together with an alkali or Alkaline earth hypochlorite or an alkali or alkaline earth hypobromite to the reaction mixture.

The oxidation of the starting material according to the invention is carried out in a suitable solvent, for example an unsaturated one or saturated hydrocarbon such as hexane, cyclohexane, pentane or benzene, a substituted saturated one or unsaturated hydrocarbons, such as chlorobenzene, trichloromethane or dichloromethane, a dialkyl acylamide, such as dimethylformamide and diethylacetamide, an ether such as diethyl ether, dioxane and tetrahydrofuran, an alcohol, such as ethanol and methanol, a heterocyclic compound such as pyridine and piperidine or a mixture of these solvents carried out.

The reaction temperature is not subject to any strict limitation. When irradiating the mixture using a sensitizer, the oxidation reaction is usually carried out at room temperature. If the activated Oxygen is generated using a compound that can split off or transfer such oxygen, the temperature may be lower on the whole, depending on the selected connections.

Depending on the reaction conditions, it is also possible to obtain the ^^ steroid as a by-product in addition to the desired A -5a-hydroperoxysteroid. The zulejbzt mentioned

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Compound can take place under suitable conditions, e.g. if left in a suitable organic for some time Solvent, such as chloroform, allowed to stand in the desired Δ -5a-hydroperoxysteroid converted to ground.

The A -5ot-hydroperoxysteroid obtained by the process according to the invention can optionally be esterified or etherified by any process known per se, as indicated later for the 5oc-hydroxy and 17-hydroxy substituents.

The reduction of the 5ct-hydroperoxy group to the 5oc -hydroxy group can be carried out by any reduction process known per se, e.g. by reduction with an alkali aluminum hydride such as lithium aluminum hydride, by reduction with a trialkyl phosphite such as triethyl phosphite, by reduction with an alkali metal sulfite or alkali metal bisulfite such as sodium bisulfite, by reduction with an alkali iodide such as sodium iodide or by reduction with hydrogen in the presence of a suitable catalyst such as palladium / barium sulfate.

The alkyl group present in the 13-position is preferred a lower alkyl group such as a methyl, ethyl, propyl, butyl, isopropyl or isobutyl group.

The substituents in the 17-position can already be in the Starting material must be available. However, you can also in the stage of the 5oc-hydroperoxy compound or the 5a-hydroxy compound to be introduced.

To introduce a 17-alkyl, I7a-alkenyl or I7a-alkyl

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group is the 17-keto compound with a metal derivative condensed of such a hydrocarbon. The 17-keto compound is obtained by oxidation of the 17β-hydroxysteroids normally according to Oppenauer or with Chrumtrioxi

The metal derivative can be a Grignard compound, e.g. be a magnesium bromide of the hydrocarbon to be introduced. A special process for making a 17β-Hydroxy-17a-alklTiyl compound consists in that one the 17-keto steroid with a triple unsaturated hydrocarbon in the presence of an alkali metal compound, such as an alkali amide or alkali alcoholate. The introduction of the I7a hydrocarbon can also be found in two steps can be carried out: the substance can first be alkynylated and then to the desired alkenyl or Alkyl compound are reduced. The in the final product in Hydrocarbons present in the I7a position can, for example, be a Methyl, ethyl, propyl, butyl, vinyl, propenyl, allyl, methallyl, ethynyl, propargyl, butynyl, butadienyl, Butadiinyl or isopropylr group.

The 17β-hydroxyl group can optionally be esterified or be etherified. In the esterification, inorganic acids such as phosphoric acid or saturated and unsaturated organic acids having 1 to 18 carbon atoms can be used. The preparation of these esters can after any a process known per se by reacting the 17-hydroxysteroids with the acid anhydride or the acid halide or by reaction of the condensation of the 17-keto steroid with a metal derivative of an unsaturated carbon

be carried out without prior hydrolysis.

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Preference is given to the esterification and / or etherification such processes are used that are not carried out under acidic conditions, otherwise it is easier to form a Dien and cleavage of the ^ oc-hydroxy or 5a-hydroperoxy group comes.

Examples of organic carboxylic acids that can be used for esterification are: ant, vinegar, propionic, Butter, valerian, capron, undecyl, lauric, tridecyl, myristic, pentadecyl, oleic, palmitic, stearic, trimethyl. vinegar, diethyl acetic acid, hexahydrobenzoe, oyclopentylpropion, Oyclohexylbutter-, Oyclohexylpropion-, Phenylpropion-, Phenyl butter, malonic, amber, glutar, pimeline and Tartaric acid.

The 17β-ether group can be derived from an aliphatic, aromatic, araliphatic or heterocyclic hydrocarbon. Depending on the reaction conditions and the type of 17β-hydroxyl group (secondary or tertiary), the 5 <x -hydroxyl group possibly esterified or etherified · Under certain conditions it is also possible to use this To carry out esterification or etherification in two stages, with different esters or ethers in the 17- and 5-positions can be introduced.

A particularly important group of compounds are those of the general formula:

2 (J 9 8 3 U 1 1 1 5 6

in which X is a hydrogen atom or an acyl group with 1 to 18 carbon atoms, Y is an alkyl, alkenyl or alkynyl group with 1 Ms A carbon atoms and R is a hydrogen atom or a methyl group.

The new compounds of the invention have proven to be very good Proven valuable due to their strong progestational, anti-ovulatory, pregnancy-sustaining and estrogenic effects. The combination of ovulatory and estrogenic properties is particularly valuable in a compound, as such a compound is the two active ingredients of common contraceptives can replace.

The compounds according to the invention can be used parenterally or orally in the form of suspensions, solutions, emulsions or solid pharmaceutical dosage units, such as tablets, Pills and dragee: to be administered usually after them with additives or possibly other effective substances

;: ο 9 8 34/115 η

- 9 - ζen have been mixed.

The invention is further illustrated by the following examples explained.

Example 1

10 gA -17ß-hydroxy-i7a-eth, iiaylöstren were dissolved in 400 cm * pyridine. 80 mg of haematoprophyrin were added to this. Oxygen gas was bubbled through the solution with stirring. The temperature was kept at approximately 20 ^° C. After irradiating with ultraviolet light for 2 hours using a water-cooled lamp (Philips 125 W, type 57 256 / E 70) which was in the reaction mixture, this reddish-brown mixture was concentrated in vacuo. The concentrate was dissolved in benzene and treated with activated charcoal. After filtering off, the filtrate was concentrated to a yellow oil. This oil was diluted with a little ethanol and poured into ice water. The diluted oil was recrystallized from methanol. 7 »0 g were obtained

Δ '^ 5a-Hydroperoxy-17β-hydroxy-17a-ethinyl estrogen, J ¹ P-141 to C; / "a_7 _D = -24" (CH ₅ OH).

6.3 g of the A -5a hydroperoxy compound were added in 100 cnr Dissolved chloroform and 10 min with a solution of 7j5 g of sodium bisulf it shaken in 50 cnr water. The chloroform layer was washed several times in water and dried over sodium sulfate. The solvent was evaporated and the residue is chromatographed over silica gel with benzene / ethyl acetate (8: 2) as the eluent. After the Recrystallize from diisopropyl ether a total yield of

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- ίο -

4.2 gA ⁶ -5a, 17β-13iliydroxy-17a-ethinyl-oestrene; M.p. 212 to 215 ^° C; fv-Jv = -73 ° (CHGl ₃ ).

In the same way, the Δ-17β-hydroxyl-17aäthylöstren and the A ^ -i7ß-hydroxy-17a-ethinyl-18-methylestrene were converted into the corresponding zv -5a-Hydroperoxyver "connections, which in turn, as described, to /^-5oc,17ß-.Dihydroxy-i7a-äbhyl-östren and Δ -5a, i7ß-Dihydroxy-i7aäthinyl-18-methyl-estren were reduced.

Example 2

1.4 g A ' ^? -i7ß-Hydroxy-17a-ethinyl esters were dissolved in 70 ciir methylene chloride. While air was continuously passed through, the mixture was exposed to sunlight for 14 χ 24 hours. Then the mixture was evaporated to an oil. After chromatography on silica gel with benzene / ethyl acetate (8: 2) as the eluent, some Zi? -5a-hydroperoxy-17ß-hydroxy-17a-ethinyl-oestrene, melting point 141 to 143 ° C., was obtained.

Example 3

5 gA-17-ketoestrene were dissolved in 500 cur chloroform, to which 37 »5 mg of hematoporphyrin had been added. Oxygen was bubbled through the mixture with stirring. The mixture was turned on for 16 hours with a 500 V tungsten lamp irradiated, the ^ iS a distance of 5 cm from the Glass vessel was located. The temperature of the reaction mixture was maintained at approximately 20 ° C. After the reaction the mixture was treated with activated charcoal, filtered and concentrated. The concentrate was poured over silica gel Benzene / ethyl acetate (8: 2) as eluent chromatographed.

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Initially, A -5a-hydroperoxy-17-keto-esters were obtained and then Δ - '' '- ^ a-Hydroperoxy - ^ - keto-oestrene.

2 g of the Δ thus obtained. -5a-Hydroperoxy-17-keto-oestrous were in a mixture of 10 cnr ethanol and 4 cur tetra-

O ⁷ y

hydrofuran dissolved. Then 1.3 cnr triethyl phosphite were at OC added and the mixture stirred for 1 ti at room temperature.

The reaction was continued with 3.5 v water and 30% hydrogen peroxide 3J5 cnr. The mixture was stirred for 1 hour, the crystalline precipitate was filtered off and the filtrate was extracted with methylene chloride.

The methylene chloride was dried and concentrated. The residue was washed over silica gel with benzene / ethyl acetate chromatographed as eluent (8: 2). One received

150 ° C.
example

6th
a total of 0.9 g of A -5a-hydroxy ~ i7-keto-esters, melting point 147 bis

2 6δ ~ 7u-hydroperoxy-17-keto-esters were made in chloroform solved. The mixture was then 6 χ 24 hours at room temperature held uud then evaporated the solution. Of the The residue was chromatographed over silica gel with benzene / ethyl acetate (8: 2) as the eluent. One received Δ. -5a-Hydrooperoxy-27-keto-esters.

B ice ρ i oil 5

In 50 ciiK J1 (ethylene chloride, 15.5 g of triphenyl phosphite were added

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-78 ° C. and ozone was passed through the solution for 2 hours. The blue solution was decolorized by bubbling nitrogen gas through it, which removed the excess ozone. Then a solution of 5.0 gA ^ -17ß-hydroxy-i7a-äthinyl-oestrene in 20 cm ^ methylene chloride was added. The Eeaktionsgemisch was maintained for 3 h at -35 ° C and then the temperature was increased 10 hours at 0 ⁰ C. After evaporation of the solvent, the residue was chromatographed over silica gel using benzene / ethyl acetate (8: 2) as the eluent. A m.p. 141 bis was obtained

example

obtained A -5a-hydroperoxy-17ß-hydroxy-17a-ethinyl-oestrene;

Acetylene was passed through a solution of 2.0 g of potassium tert-butoxide in 25 cnr of tetrahydrofuran for 2 hours. The temperature was ^{kept at 0} ° C. during this. The solution was cooled to -10 ⁰ C and then a solution of 2.0 g A. -5a-Hydroperoxy-17-keto-esters in 20 cnr tetrahydrofuran were added dropwise. Acetylene was then passed through the solution again for 4 hours and the mixture was then poured into ice water. The precipitate was washed with water, dried and recrystallized from "methanol. 1.8 g of Δ.5α-hydroperoxy-17β-hydroxy-17α-ethinyl-oestrene; melting point 141 to 143 ° C.; / ~ a_7 _D = -24 ° (CH ₅ OH).

In a corresponding manner, the 17-keto compound was in the 17β-Hydroxy-17a-methyl and 17β-hydroxy-17a-alkyl compounds by reacting the 17-keto compound with converted to the corresponding Grignard derivative.

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Example 7

3 6 Δ -5a, 17β-dihydro: ^ - 17a-ethinyl-esters were dissolved in 90 cnr ethyl acetate and hydrogenated with hydrogen using a palladium / barium sulfate catalyst. After 2 mol of hydrogen had been absorbed, the catalyst was filtered off and the filtrate was evaporated. Chromatography over silica gel with benzene / ethyl acetate (8: 2) as the eluent gave A ⁶ -5a, 17β-dihydroxy-17a-ethyl-oestrene; Mp 175-178 ° C; C * JQ = -34 ° (CHCl ₃ ).

In the same way, the Δ -5oc, 17ß-Dihydroxy-17aäthinyl-18-methyl-oestrene, which had been obtained according to Example 1, to the corresponding 17 <x -ethyl compound reduced.

Example 8

8 gA-i7ß-hydroxy-17a-ethinyl-oestrene-17ß-acetate were dissolved in 600 cm ^ pyridine, to which 0.12 g hematoporphyrin had been added. Oxygen was passed through at a temperature of approximately 20 ° C. with stirring. The mixture was irradiated with a water-cooled lamp (Philips 125 W, type 57 236 / E 70) was in the reaction mixture, wherein a mixture arose which was concentrated in vacuo at a temperature of 5O ⁰ C. The concentrate was then dissolved in 50 cm * methanol at 0 ^° C. and 4.8 cur triethyl phosphite were added to this. The mixture was stirred at room temperature for 1 hour and then 25> 6 cm 15% hydrogen peroxide was added

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admitted. The resulting mixture was poured into water and extracted with ether. The ether extracts were washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over 400 g of SiO ₀ using toluene / ethyl acetate (8: 2). A -5a-17β-dihydroxy-17a-ethinyl-oestrene-17β-acetate was obtained; Pp to W ⁰ C; fO.JQ - - 75 ° (CHGl ₃ ). ·

In the same way the 17-ester A-5a were 17-dihydroxy-17a-ethynyl-estrene and üer> corresponding 18-Methyl-connection of butyric acid, önanthinsäure, beta-phenylpropionic acid and caproic received.

PATENT CLAIMS:

Claims (10)

PATENTANS PR Ü CHE ^ Cj ^ a Hydroperoxy or hydroxysteroids of the general Formula: in which E ^ is an alkyl group with 1 to 4 carbon atoms, E _{2 is} an oxygen atom or the group βP (aQ), where P is a hydroxy, acyloxy or alkyloxy group and Q is an oxygen atom or an alkyl, alkenyl or alkynyl group with 1 to 4 carbon atoms, and E _{7 is} a hydrogen atom or an alkyl, acyl, hydroxyl, alkyloxy or acyloxy group. 2) Compounds according to claim 1, characterized in that E- is a methyl or ethyl group, Ep is the group BP (ocQ), where P is a hydroxyl group or an acyloxy group of an organic carboxylic acid has 1 to 18 carbon atoms and Q is a hydrogen atom, is an alkyl, alkenyl or alkynyl group of 1 to 4 carbon atoms. 3) Δ - ^ otj 4) Δ ⁶ -5α, 2 ". £ 8m / 11? <5 5) A ⁶ -5a, ^/ 17β-dihydroxy-18-methyl-17a-ethinyl-oestrene. 6) Process for the preparation of compounds according to claim 1 to 5 »" characterized that one can use a steroid of the estran series of the general formula: in which E, - and Ep ^ i e - have the meaning given above, reacts with activated oxygen and then the resulting Δ. -Jpcx hydroperoxysteroid if appropriate reduced to the -Δ -3> a-hydroxy compound and / or the in the 17-position required substituents - as far as they yet, are not present - through something in itself introduces known process and / or the 5 <x -hydroxy or 5a-hydroperoxy group esterified or etherified. 7) Method according to claim 6, characterized in that there is active oxygen in the u ' Singiet state used. 8) Method according to claim 6 or 7 »characterized in that one is used to produce activated oxygen oxygen gas through the reaction mixture. passed through, to which a sensitizer has been added and the mixture with visible and / or irradiated with ultraviolet light. 209834/1156 9) Method according to claim 6 or 7 »characterized in that one is used to produce active oxygen a phosphite ozonide, especially one substituted phosphitozonide used. 10) Method according to claim 6 to 9 _}, characterized in that the resulting ^ ^ '^ a-hydroperoxysteroid is converted into the desired A -5a-hydroperoxysteroid. 62ΧΧΪΥ 209834/1156