DE1033199B - Process for the preparation of dehydrosteroids - Google Patents

Description

Method of Preparing Dehydrosteroids The invention relates to refers to a method for the preparation of dehydrosteroids, in particular of 3-oxodehydro compounds of the cyclopentanopolyhydrophenanthrene series, which has a double bond in the 1 (2) - undj or the 4 (5) position, and their functional derivatives. These connections are extremely important as they contain great substances besides real steroid hormones biological activity, such as 1-dehydrocortisone, 1-dehydro-hydrocortisone, 1-dehydroaldosterone and its 2-alkyl- and / or 9- and 12-halogen derivatives and substances of great industrial importance, e.g. B. d 1,4-androstadien-2-on-17-one or -17-o1 lock in.

There are already methods known to double bonds between the Using carbon atoms 7 and 8, 8 and 9 or 9 and 11 of steroids. of selenium dioxide to introduce. However, these processes offered no indication that one could use selenium compounds one or more double bonds between carbon atoms 1 and 2 and / or 4 and 5 of steroid compounds.

The known methods for introducing a double bond into the 1 (2) - and / or the 4 (5) position of steroids consists in the fact that one halogen atoms introduces into the 2- and / or the 4-position and then splits off hydrogen halide or that one carries out a biochemical dehydration of compounds that are attached to the are at least partially saturated. This procedure requires but cumbersome and time consuming cleaning methods and is not that specific like the method according to the invention.

The dehydro compounds mentioned are prepared by the process according to the invention in a simple manner by having 3-oxosteroids, which are in at least one of the a-positions to the 3-position oxo group are saturated, or their functional derivatives with Treated selenium dioxide or selenous acid and optionally the obtained d'-, d4- the 41,4-steroids converted into their functional derivatives. In this way the d4-3-keto compounds, the A'-5a-3-keto compounds and the 41> 4-3-keto compounds can be represented. The d4-3-keto compounds are formed from the 5ß-3-ketones saturated in ring A, the d1-5a-3-keto compounds from the saturated 5a-3-ketones, while one for the representation of the 41,4-3-keto compounds both the saturated 5ß- and the 5a-3-ketones and likewise can use the d4 and d 1-3 ketones. The one used for dehydration The amount of selenium is adapted to the number of double bonds to be introduced, whereby one a little more than one equivalent Se0 is used for each double bond.

The starting substances can have any steric configuration and also exist as racemates. You can. to the 3-ketones of the compounds of Cholestan-, Spirostan-, Furostan-, Cholan-, Norcholan-, Bisnorcholan-, Pregnan- or belong to the androstane series. One can also use the 3-keto-18 or the 19-nor compounds as well as the 18,19-bis-nor compounds and also the C-nor and the D-homo-steroids use as raw materials. They can be saturated or contain double bonds, z. B. in the 1- or 4-position and also in the 5-, 6-, 7-, 8-, 9- (11-), 11-, 14-, 16- or 17-position and can contain further substituents, for example free or functionally converted oxy-; Oxo-, oxymethyl, formyl, carboxyl or Oxalyl groups, alkyl, e.g. B. methyl groups, epoxy groups or halogen atoms, e.g. B. in the 2-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 14-, 15-, 16-, 17-, 18-, 19-, 20- or the 21 position. Particularly important starting substances are progesterone, 11-dehydro-progesterone, 11-, 12-, 14-, 15-, 16-, 17-, 18- or 19-oxyprogesterone, 11-deoxycorticosterone, Cortisone, hydrocortisone, 11-epi-hydrocortisone, aldosterone, 18 - oxy - corticosterone, 11- Epi -18 - oxy- corticosteron, 17u-oxy-aldosteron, 18-oxy-hydrocortisone, 18-oxy- and 18-Oxo-cortisone, 18-Oxy- and 18-Oxo-cortexon, 17a-Oxycortexon, 17a, 18-Dioxycortexon, corresponding ones saturated in the 1 or in the 4 and 6 position instead of in the 4 position Connections, e.g. B.

d 4, 6-17 a, 21-dioxy-3,11,20-trioxo-pregnadiene, 4 4 # 6-11 ß, 17 a, 21-trioxy-3,20-dioxo-pregnadiene, d 4.11-1 1 ß, 21-dioxy-3,20-dioxo-pregnadiene, 4 4, 6-21-oxy-3,11,20-trioxo-pregnadiene, d 4, g-21-oxy-3,20-dioxo-pregnadiene, 4 4, 6-17 a, 21-dioxy-3,20-dioxo-pregnadiene, 4 4 # 6-11 ß, 21-dioxy-3,20-dioxo-pregnadien-18-al, d 4.g-11 a, 21-dioxy-3,20-dioxo-pregnadiene, d 4 # F-11 a, 17 a, 21-trioxy-3,20-dioxo-pregnadiene, d 4, g-11β, 17a, 21-trioxy-9a-fluoro-3,20-dioxo-pregnadiene, d 4, g-11β, 17a, 21-trioxy-9a-chloro-3,20-dioxo-pregnadiene , 44, g-11ß, 17a, 21-trioxy-9a-bromo-3,20-dioxo-pregnadiene, 4 4, g-17a, 21-dioxy-9a-fluoro-3,11,20-trioxo-pregnadiene, 44. g-17a, 21-dioxy-9a-chloro-3,11,20-trioxo-pregnadiene, 4 4, g-17a, 21-dioxy-9a-bromo-3,11,20-trioxo-pregnadiene, d 4, s-2-methyl-11ß, 17a, 21-trioxy-3,20-dioxo-pregnadiene, 44.6-2-methyl-17a, 21-dioxy-3,11,20-trioxo-pregnadiene, d4, g-2-methyl-11β, 17, a21-trioxy-9-halogen-3,20-dioxopregnadiene, d 4 # 8-2-methyl-17a, 21-dioxy-9-halogen-3,11,20 -trioxopregnadiene, d 4, g-3,20-dioxo-12a-fluoro-lß, 21-dioxy-pregnadiene and the corresponding 11-keto compounds. Other important starting substances are pregnane-3,20-dione; Allopregnan-3,20-dione; Pregnan and allopregnan-3,11,20-trione-17a, 21-diol; Pregnan and allopregnan-3,20-dione-11β, 17a, 21-triol; Pregnan-and allopregnan-3,18,20-trione-11β, 21-diol; Pregnan and allopregnan-3,20-dione-liß, 18,21-triol; Pregnan-and allopregnan-3,20-dione-18,21-diol; the corresponding 21-oxo compounds and / or the 2-bromine, 2-chlorine, 4-bromine, 4-chlorine, 9a and 12a-halogen derivatives, for example the 9a-fluoro and the 12a-fluoro derivatives, the 2-alkyl, e.g. B. 2-methyl derivatives and the 9,11-epoxies, e.g. B. 9a-fluorocortisone; 9 a-fluoro-allodihydro-bydrocortisone ; 9 α-fluorohydrocortisone; 9a-fluoro-aldosterone and 9a-fluoro-18-oxy-corticosterone; 2-methyl-9a-fluoro-hydrocortisone, e.g. B. 3,20-dioxo-11β, 17a-dioxy-12a-fluoro-pregnane; d4-3,20-Dioxollß-oxy-12a-fluoro-pregnen; 44-3,20-dioxo-11ß, 21-dioxo-12a-fluoro-pregnen; 2-methyl-hydrocortisone; 9,11β-oxidocortexon; 9,11ß-hydrocortexon, 9,11ß-oxido-17a-oxycortexon and -Hydro-cortexon, Androstan- or Testan-3-on-17-ole, -3-on-17-one, -3,11,17-trione, -3-one-11,17-diols, corresponding ones unsaturated in the 4- or 1- or 4- and 6-position Derivatives, for example 44-3-oxo-17ß-oxyandrostenes, which are in the 2- and 'or 17-positions Alkyl groups, for example methyl, ethyl or ethynyl groups, carry and / or in the 9a position halogen atoms, especially fluorine atoms, also A4, g-3,17-dioxo-androstadiene, 44, g-3-oxo-17ß-oxy-androstadiene and 44 # g-3-oxo-17ß-oxy-17a-methyl-androstadiene and Finally, functional derivatives of all of the above compounds that are in the 3-position contain a free oxo group. In the case of the starting materials, the functionally converted Oxy groups, for example one with an aliphatic, aromatic or heterocyclic Carboxylic acid, for example acetic acid, trimethyl acetic acid, benzoic acid or furancarboxylic acid, esterified or an etherified oxy group, for example the tetrahydropyranyloxy-benzyloxy- or the triphenylmethoxy group. Functionally converted oxo groups are advantageous ketalized oxo groups, especially those derived from a dihydric alcohol derive, for example ethylenedioxy groups.

In addition to selenium dioxide, the z. B. can be in sublimated form, selenious acid can also be used. The dehydration of the process according to Invention can be in an aqueous or a non-aqueous organic solvent be done in an open or closed vessel. Preferably leads the reaction is carried out in the presence of a tertiary alcohol, for example tert.-butanol or tertiary amyl alcohol. As a solvent, one can also use the following, especially mixed with the alcohols mentioned, use: dioxane, glacial acetic acid, acetic anhydride, Methanol, ethanol, isopropanol, polyhydric alcohols, e.g. B. ethylene glycol, benzene, Toluene, hexane, ethyl ether, dibutyl ether, tetrahydrofuran, cellosolve, ethylene glycol monoethyl ether, Carbon tetrachloride, anisole, pyridine, ethyl acetate, acetonitrile, and mixtures thereof Solvent.

The reaction is caused by the presence of an inorganic or organic Acid accelerates, preferably an organic acid such as acetic acid, propionic acid or benzoic acid. The organic acid, e.g. B. acetic acid and propionic acid, can in some cases also serve as a solvent for the reactants. When you start the reaction in the presence of water or one that is miscible with water Solvents, e.g. B. an alcohol, is the addition of another acid than H, Se03, which is used as a dehydrating agent, is not necessarily used for acceleration the reaction necessary.

It is advantageous to use a suitable solvent or mixture of solvents to choose and, if necessary, to heat the compound to be dehydrogenated under pressure or reflux them with the dehydrating agent. To introduce a Double bond one usually uses the calculated amount of selenium compound or a certain excess. An excess of dehydrating agent, e.g. B. selenium dioxide, can after carrying out the reaction, for. B. by means of lead acetate, sulfur dioxide or other reducing agents. After the reaction has finished, this will be The mixture of selenium formed is filtered off and the reaction product from the filtrate isolated in a manner known per se. The removal of selenium and selenium derivatives is carried out according to methods known per se.

In the reactions carried out according to the invention can also 41,4-3-oxo-selenium steroids are also formed from the dehydro compounds. Outgoing from Z. B. Methyltestosterone, testosterone and hydrocortisone are formed biologically active monoselene derivatives, which are converted into 1,4-bisdehyde derivatives by thermal cleavage transferred «to earth.

The further purification of the reaction products can be done in particular make by chromatography, e.g. B. on aluminum oxide or silica gel (known under the tradename silica gel), by distribution methods, e.g. B. according to the countercurrent process or by a separation using the Girard reagent, for example trimethylammonium or pyridinium acetic acid hydrazide. After cleaning or in its place can one recrystallize the products from organic or aqueous organic solvents.

The reaction products shown in the process can be found in an known manner in their functional derivatives, z. B. Esters, ethers, enol esters, Enol ethers, ketals, thioethers and thioketals, and also in hydrazones, oximes or enamines convict. In these compounds, the oxy groups and / or the oxo groups be completely or partially functionally converted.

In the case of the esters and the enol esters, the acid portion can be any desired organic or inorganic acid, e.g. B. an aliphatic, alicyclic, araliphatic, aromatic and heterocyclic, carboxylic acid, from a thiocarboxylic acid, Thiol carboxylic acid or sulfonic acid, preferably formic acid, acetic acid, Chloroacetic acids, trifluoroacetic acid, propionic acid, butyric acids, valeric acids, Trimethyl acetic acid, diethylene acetic acid, from caproic acid, enanthic acid, caprylic acid, Palmitic acid or isomers thereof, crotonic acid, undecanoic acid, undecylenic acid, Oxalic acid, succinic acid, pimelic acid, maleic acid, lactic acid, carbamic acids, Alkoxycarboxylic acids, ß-cyclopentyl propionic acid, hexahydrobenzoic acid, benzoic acid, Phenylacetic acid, cyclohexylacetic acid, y-cyclohexylbutyric acid, phenylpropionic acids, Trimethylgallic acid, phthalic acid, Furan-2-carboxylic acid, isonicotinic acid, Methanesulfonic acid, toluenesulfonic acid, sulfuric acids, hydrohalic acids or Phosphoric acids.

Functionally converted oxy or oxo groups can optionally be used convert into free groups in the compounds obtained. That way you can Functionally converted groups are used, especially in the case of polysubstituted derivatives also release partially. This can be done, for example, by chemical or enzymatic means Achieve hydrolysis, e.g. B. using acidic or basic agents Transesterification or transacetalization. Partially functional from those obtained in this way or directly converted, for example esterified or etherified derivatives can be through subsequent functional transformation, e.g. B. esterification or etherification, polysubstituted Represent derivatives and especially mixed esters, ethers or ester-ethers.

d 1,4-3-Oxo-9,11 ß-oxidopregnadienes and -androstadienes, which can be passed through the process according to the invention directly or from 41,4,9-3-oxopregnatrienes or -androstatrienes can be obtained by means of a hydrohalic acid, in particular Fluoric or hydrochloric acid, converted into the corresponding 9a-halogen-11ß-oxyverbindungen. From l-dehydro-9, llß-oxido-17a-oxycortexone, 1-dehydro-9a-fluorine can be obtained in this way. or 1-dehydro-9a-chlorohydrocortisone obtained by reaction with Hydrofluoric or hydrochloric acid. Both compounds are high on the glycogen test active.

The following examples illustrate the process according to the invention. Example 1 1 g of cortisone acetate and 400 mg of selenium dioxide are mixed with 1 cm3 of acetic anhydride and 50 cm3 of tert-butanol covered. The mixture is 48 hours to the exclusion of Moisture heated to reflux and then decanted from the precipitated selenium. The selenium is washed with a little acetone and the combined solutions after addition evaporated to dryness from alcohol. The brown residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with dilute potassium carbonate solution and water, dried and then evaporated. The residue is chromatographed on 27 g of silica gel and successively with chloroform, mixtures of chloroform and tert-butanol in the ratio from 99: 1, 98: 2, 96: 4 and finally developed with acetone. The combined chloroform-tert-butanol-98 : 2 eluates are evaporated in vacuo, the residue is dissolved in acetone and the solution treated with a small amount of activated carbon. Crystallized from the evaporated solutions after adding a small amount of ether or isopropyl ether 1-dehydrocortisone acetate, which turns out to be in paper chromatography with the system propylene and glycol-toluene turns out to be a uniform substance and melts with decomposition at 226 to 232 ° C.

By analogous reaction of 1 g of allo-4,5-dihydrocortisone acetate with 800 mg of selenium dioxide and working up in the same way, 1-dehydrocortisone acetate is obtained, which melts at 226 to 232 ° C. with decomposition. Example 2 1 g of 3,11,20-trioxo-17a-oxy-21-acetoxypregnane and 800 mg of selenium dioxide are boiled for 48 hours in a mixture of 1 cm3 of acetic anhydride and 50 cm3 of butanol. The reaction product is worked up and purified as described in Example 1, 1-dehydrocortisone acetate which melts at 226 to 232 ° C. with decomposition. Example 3 1 g of cortexone acetate and 400 mg of selenium dioxide are covered with 1 cm3 of acetic anhydride and 50 cm3 of tert-butanol. The mixture is refluxed for 48 hours with exclusion of moisture and the precipitated selenium is then separated off. The selenium is washed with acetone and the combined solutions are evaporated in vacuo after adding alcohol. The residue is then chromatographed on 30 g of aluminum oxide, developing successively with benzene, ether and acetone. Pure 1-dehydrocortexone acetate with a melting point of 203 to 206 ° C. can be isolated from the residue obtained by evaporation of the ether eluate by recrystallization from a mixture of acetone and isopropyl ether. Example 4 1 g of 3,11,20-trioxo-17a-oxy-21-acetoxy-allopregnane and 800 mg of selenium dioxide are mixed with 50 cm3 of butanol. This suspension is refluxed for 48 hours, the solution is decanted from the precipitated selenium, the selenium is washed with acetone and the solvent mixture is evaporated in vacuo. The residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with freshly prepared ammonium sulfide solution, dilute potassium bicarbonate solution and water, then dried and evaporated in vacuo. The residue is then dissolved in a small amount of isopropanol and cooled. After the solution has stood, 650 mg of 1-dehydrocortisone acetate crystallize out. The crystals melt at 200 ° C, and needles or prisms then form in the melt, which only fuse completely at 220 ° C. The crude product is purified by treating it with a small amount of activated charcoal in acetone solution and then the product is recrystallized from acetone or a mixture of acetone and isopropyl ether. In this way, pure 1-dehydrocortisone acetate is obtained, which melts at 226 to 232 ° C. and has a specific rotation [a] D = -f-186 ° in dioxane. Further amounts of pure 1-dehydrocortisone acetate can be isolated from the mother liquors by chromatography on >> silica gel <<, as described in the previous examples.

Starting from the free 21-oxy compound, 1-dehydrocortisone is obtained, which melts at 231 to 234 ° C. and has a specific rotation of XD = -f-169 ° in dioxane. Example 5 1 g of 44-3-oxo-17ß-acetoxy-androstene (testosterone acetate) and 500 mg of selenium dioxide are covered with 50 cm "of butanol. The suspension is refluxed for 48 hours, cooled and the solution is decanted from the precipitated selenium, This is washed with acetone and the combined solutions are evaporated in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with freshly prepared ammonium sulfide solution, water, dilute potassium carbonate solution and water, dried and evaporated. The residue is then chromatographed on aluminum oxide Evaporation of the benzene, benzene-ether and ether eluate residues give, on recrystallization from a mixture of ether and pentane, needles of 41,4-3-oxo-17ß-acetoxyandrostadiene (1-dehydrotestosterone acetate) with a melting point of 151 to 152 ° C.

Example 6 1 g of 3,20-Dioxo-11ß, 17a-dioxy-21-acetoxy-allopregnan and 800 mg of selenium dioxide are boiled under reflux for 48 hours. in 50 cm3 of tert-butanol. Then you decant the solvent from the precipitated selenium off, the selenium is washed with acetone and the solvent mixture is evaporated in vacuo. The residue is dissolved in ethyl acetate, the ethyl acetate solution with freshly prepared Ammonium sulfide solution, dilute potassium bicarbonate solution and water and then washed dried and evaporated in vacuo. The residue is dissolved in a small amount Isopropanol and cools down. After standing, 600 mg of 1-dehydro-hydrocortisone acetate crystallized the end. The crude product is cleaned by treating it with a small amount of activated carbon in acetone solution and then the product crystallizes from acetone or a mixture of acetone and isopropyl ether. In this way, pure 1-dehydrohydrocortisone acetate is obtained, that melts at 238 to 241 ° C. From the mother liquors one can by chromatography to »Silikagek, - further in the manner described in the previous examples Isolate quantities of pure 1-dehydro-hydrocortisone acetate. Example 7 1 g of 3,20-dioxo-9a-flour-11ß, 17a-dioxy-21-acetoxy-allopregnane and 800 mg of selenium dioxide are covered with 50 cm3 of tert-butanol. The suspension will Boiled under reflux for 48 hours and the solution after cooling from the precipitated Selenium decanted. The selenium is washed with acetone and the combined solutions are evaporated in vacuo. The residue is dissolved in ethyl acetate, the solution with freshly prepared ammonium sulfide solution, water, dilute potassium carbonate solution and water, then dried and evaporated. The residue is then on "Silica gel <r chromatographed. The residues of the evaporated benzene, benzene ether and the ether eluate result on recrystallization from a mixture of ether and Pentane crystals of 1-dehydro-9a-fluorohydrocortisone acetate, which melts at 239 ° C. Example 8 1 g of 9a-fluoro-hydrocortisone acetate and 500 mg of selenium dioxide are boiled 48 Hours in 50 cm2 tert-butanol. The reaction product is worked up and purified it as in the example? described, being 1-dehydro-9a-fluoro-hydrocortisone acetate with a melting point of 239 ° C. Example 9 1 g of 3,20-dioxo-9,11ß-oxido-17a-oxy-21-acetoxy-allopregnane and 800 mg selenium dioxide are in 50 cm3 tert-butanol for 48 hours with exclusion refluxed from moisture. The solution is then separated from the precipitated one Selenium from. The selenium is washed with acetone and the combined solutions are evaporated in the Vacuum after adding alcohol. The residue is dissolved in ethyl acetate and washed the ethyl acetate solution with dilute potassium carbonate solution, water, freshly prepared Ammonium sulfide solution and water, then dry and evaporate in vacuo. Then chromatographed the residue on 30 g of aluminum oxide using successively benzene, Ether and acetone. From those obtained by evaporation of the benzene and ether eluate Residues are isolated from 1,4-3,20-dioxo-9,11ß-oxido-17a-oxy-21-acetoxy-pregnadiene. The same compound is obtained if 4-3,20-dioxo-9,11ß-oxido-17a-oxy-21-acetoxy-pregnen from d goes out.

100 mg of the above d 1,4-3,20-dioxo-9,11 ß-oxido-17a-oxy-21-acetoxy-pregnadiene, dissolved in 10 cm3 of dioxane, is mixed with 2.5 cm3 of 2.5N hydrochloric acid and let the whole thing stand for 1 hour. Then water is added and it is extracted with a mixture of chloroform and ether (1 : 3). Washing the resulting solution with water, drying it and evaporating the solvent in vacuo gives 1-dehydro-9a-chlorohydrocortisone acetate.

By analogous reaction of A1,4-3,20-dioxo-9,11 ß-oxydo-17a-oxy-21-acetoxy-pregnadiene with a solution of hydrofluoric acid: in chloroform, this is obtained in Example 17 and 1-dehydro-9 a-fluoro-hydrocortisone described. Example 10 100 mg aldosterone 21 monoacetate and 50 mg of selenium dioxide are refluxed for 48 hours in 5 cm3 of butanol. To When the mixture is cooled, the solution is decanted off from the precipitated selenium, the selenium is washed with acetone, and the combined solutions are in vacuo evaporated. The residue is dissolved in ethyl acetate and the ethyl acetate solution with freshly prepared ammonium sulfide solution, water, dilute ice-cold potassium bicarbonate solution and water, dried and evaporated. From the residue you get through Chromatography on silica gel and crystallization from acetone and isopropyl ether 1-Dehydro-aldosterone-21-monoacetate with a melting point of 182 to 185 ° C.

In an analogous manner, starting from aldosterone diacetate, one can be 1-dehydro derivative, based on 18-oxy-corticosterone, 1-dehydro-18-oxy-corticosterone, starting from 18-oxycortexon, the 1-dehydro-18-oxy-cortexon and, starting from 18-oxo-cortexon, obtained the 1-dehydro-18-oxo-cortexon. Example 11 1 g of 11a, 17a-dioxyprogesterone and 500 mg selenium dioxide are covered with 50 cm3 of tert-butanol and 5 cm3 of water. The mixture is heated to reflux for 24 hours, then cooled and the solution decanted from the precipitated selenium, washed the selenium with acetone and the combined solutions evaporated in vacuo. The residue is then dissolved in ethyl acetate dissolved, the ethyl acetate solution with freshly prepared ammonium sulfide solution, water, diluted Washed potassium carbonate solution and water, dried and evaporated. Then chromatographed the residue of aluminum oxide. From the evaporation of the benzene ether and 1-Dehydro-11a, 17a-dioxyprogesterone is isolated.

By reacting 1 g of 9, (11) -dehydro-17a-oxyprcgesterone with 500 mg Selenium dioxide in 50 cm3 butanol in the manner described and working up in the same way This gives 1,9, (11) -bis-dehydro-17a-oxy-progesterone.

By reacting 1 g of progesterone with 500 g of selenium dioxide in 50 cm3 tert-butanol and 0.5 cm3 of glacial acetic acid in the manner described and similar work-up 1-dehydroprogesterone is obtained. Example 12 A suspension of 1 g of 17α-methyltestosterone and 330 mg of selenium dioxide in 30 cm3 of tert-amyl alcohol and 0.3 cm3 of glacial acetic acid is under Stirring in a nitrogen atmosphere heated to 70 ° C, which is done after 10 hours there are another 300 mg of selenium dioxide. After 24 hours the solution is cooled from separated from the precipitated selenium, washed with a little acetone and the solvent concentrated in vacuo. The brown residue is taken up in ethyl acetate. The ethyl acetate solution is successively with diluted potassium bicarbonate solution, freshly prepared ice cold Ammonium sulfide solution, ice-cold dilute ammonia solution, water, dilute hydrochloric acid and water, dried and concentrated. The residue is dissolved in benzene and chromatographed on aluminum oxide. When recrystallizing from an acetone-ether mixture the concentrated benzene eluates result in 1-dehydro-17a-methyl-testosterone with a Melting point from 163 to 164 ° C.

The monoselene derivative with a melting point of 282 to 284 ° C. is obtained from the further concentrated ether eluates on recrystallization from acetone. It gives the following analytical values: CzoH "0aSe Calculated ... C 63.31, H 7.43, Se 20.81; found ... C 62.59, H 7.21, Se 19.95. Infrared spectrum in methylene chloride : Among other bands at 2.77 #t "6.08 #t, 6.16 #t" 6.25 #t "7.30 #t, 8.87 and 10.61 By sublimation of the monoselene derivative in a high vacuum at about 230'C a sublimate is obtained from which 1-deliydro-17a-methyl-testosterone can be isolated.

The 1-dehydro-testosterone is obtained in an analogous manner during the implementation of testosterone and 4 5-17ß-oxyandrosten-3-one with selenium dioxide. When dehydrated with Se 02, 17a-ainyl-testosterone results in 1-dehydro-17a-ethinyl-testosterone from Melting point 228 to 233 ° C. Example 13 A suspension of 1 g of cortexon-21-trimethyla (.etat (Deoxycorticosterone trimethylacetate) and 550 mg selenium dioxide in a mixture of 50 cms of tert-amyl alcohol and 500 mg of trimethyl acetic acid are added under nitrogen 18 Refluxed for hours. The procedure is as in the previous examples described carried out. The crude 1-deliydro-cortexon-21-trimethylacetate can be used Purify by recrystallization from acetone. In paper chromatogram using of the formamide-cyclohexane system at 40'C, the new compound moves somewhat more slowly continues as cortexone trimethylacetate and does not emit any fluorescence in sodium hydroxide solution in UV light.

In an analogous manner, 11-dehydrocorticosterone-21-acetate is obtained 1,11-bisdehydro-corticosterone-21-acetate with a melting point of 231 to 234'C. Example 14 A suspension of 2 g of cortisol-21-trimethylacetate and 1.4 g of selenium dioxide in a mixture of 60 cm3 of tert-butanol and 0.3 g of trimethyl acetic acid is used under Nitrogen is refluxed for a total of 24 hours, and this is added after 15 hours a further 0.2 g of selenium dioxide was added. The procedure is as described in Example 12 carried out. The brown residue obtained is chromatographed on aluminum oxide. The residue of the evaporated benzene-ether eluates is made from acetone or ethyl acetate recrystallized to give pure 1-dehydrocortisol-21-trimethylacetate from the melting point 234 to 236'C.

In an analogous manner, 1-dehydro-corticosterone-21-acetate with a melting point of 159 to 161 ° C. is obtained from corticosterone-21-acetate and 1-deliydro-cortisol-21-acetate, which is obtained from cortisol-21-acetate Decomposes at 237 to 239`C melts.

Example 15 A suspension of 1 g of cortisone and 450 mg of selenium dioxide in 50 cm 'tert-butanol is refluxed under nitrogen for 48 hours. That The procedure is carried out as described in Example 12. The preserved brown The residue is chromatographed on A> silica gel .: developing first with chloroform will. The other chloroform-tert-butanol eluates (24: 1) are evaporated. Of the The residue is crystallized from isopropanol ether or acetone ether; where one isolates 1-dehydrocortisone, which melts at 231 to 234 ° C with decomposition.

In an analogous manner, 1-dehydro-17a-oxycortexane-21-acetate is obtained from 17a-oxycortexon-21-acetate with a melting point of 218 to 222 ° C, 1-dehydrocortisone-21-trimethylacetate from cortisone trimethylacetate with a melting point of 274 to 278 ° C and from d1-3,11,20-trioxo-17a-oxy-21-acetoxy-allopregnane 1-dehydrocortisone-21-acetate with a melting point of 226 to 232 ° C. Example 16 A suspension of 1 g of 3,11,20-trioxo-9a-fluoro-17a-oxy-21acetoxy-allopregnane and 0.7 g of selenium dioxide in 30 cm3 of tert-amyl alcohol and 0.2 cm "of glacial acetic acid is under Nitrogen heated to reflux for 36 hours. The procedure is such. B. in example 12 carried out. The residue obtained after evaporation becomes aluminum oxide chromatographed. Obtained from the evaporated benzene and benzene ether eluates 41.4-3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-pregnadiene (1-dehydro-9a-fluoro-cortisone acetate), which melts with decomposition at 273 to 276 ° C.

The 3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-allopregnane can be used in an analogous manner zum d1 # 4-3,11-20-trioxo-9a-chloro-17a-oxy-21-acetoxy-pregnadiene (1-dehydro-9a-chloro-cortisone acetate) dehydrate. 3,20-Dioxo-9a-chloro-11ß, 17a-dioxy-21-acetoxypregnane can also be used under the same conditions to 41.4-3,20-dioxo-9a-chloro-11ß, 17a-dioxy-21-acetoxypregnadiene Dehydrate (1-dehydro-9a-chlorocortisol acetate).

The abovementioned starting substances can be based on the following, for example Kind of represent: A solution of 1 g of d a (11) -3,20-Dioxo-17a-oxy-21-acetoxy-allopregnene in 27 cm3 of tert-butanol and 6 cm3 of water is mixed with 720 mg of n-bromoacetamide while stirring and 6 cm3 of 4 ° sulfuric acid mixed at 15 ° C. After a few minutes there a little sodium sulfite solution and a lot of water are extracted until discoloration the mixture with chloroform-ether (1 .3) and washes with ice-cold soda solution and Water. Obtained by evaporating the dried chloroform-ether solution in vacuo the 3,20-dioxo-9a-bromo-llß, 17a-dioxy-21-acetoxy-allopregnane.

A solution of 1.1 g of the obtained bromohydrin in 20 cm3 of dried Pyridine is made in the dark together with 1.5 g of freshly precipitated and dried silver oxide Shaken for 24 hours. Then the silver oxide is filtered off and the filtrate im Evaporated in vacuo. The residue is for post-acetylation in 10 em3 pyridine and 0.5 cm3 of acetic anhydride dissolved and left to stand at room temperature for 14 hours. Then the mixture is poured into cold, dilute sulfuric acid, the precipitated Reaction product added to chloroform-ether (1: 3) and the extract with dilute Sulfuric acid, sodium bicarbonate solution and water. After drying and evaporation the chloroform-ether solution in vacuo gives the 3,20-dioxo-9,11 ß-oxido-17a-oxy-21-acetoxy-allopregnane.

The above-mentioned oxidative compound (1 g) is dissolved in 100 cm 3 of dioxane, mixed with 25 cm 3 of 2.5N hydrochloric acid and then left to stand at 20 ° C. for 1 hour. Then add water and extract the whole thing with chloroform-ether (1: 3). After washing with water, drying and evaporation of the solvent in vacuo, 3,20-dioxo-9a-chloro-11ß, 17a-dioxy-21-acetoxy-allopregnane is obtained. When the above oxido compound is reacted with hydrofluoric acid instead of hydrochloric acid, 3,20-dioxo-9a-fluoro-11ß, 17a-dioxy-21-acetoxy-allopregnan is obtained after analogous work-up. Oxidation of the two halohydrins with chromic acid in glacial acetic acid gives 3,11,20-Trioxo-9a-chloro-17a-oxy-21-acetoxy-allopregnan or 3,11,20-Trioxo-19a-fluoro-17a-oxy-21-acetoxy-allopregnan. Example 17 A solution of 1 g of 3,20-dioxo-9a-chloro-11ß, 17a-dioxy-21-acetoxy-pregnane in 40 cm3 of tert-amyl alcohol is mixed with 0.7 g of selenium dioxide and 0.25 cm3 of glacial acetic acid and added Boiled nitrogen under reflux for 40 hours. The process is carried out as described in Example 12, for example. The residue obtained after evaporation is chromatographed on aluminum oxide and the benzene and benzene-ether eluate evaporated, from which 41,4-3,20-dioxo-9a-chloro-11ß, 17a-dioxy-21-acetoxy-pregnadiene ( 1-dehydro-9achlorocortisol acetate) is obtained. In the paper chromatogram (propylene glycol-toluene) it migrates somewhat more slowly than the starting material.

The 3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-pregnane can be used in an analogous manner to 41.4-3,11-20-trioxo-9a-chloro-17a-oxy-21-acetoxy-pregnadiene (1-dehydro-9a-chloro-cortisone acetate) dehydrate, the 3,20-dioxo-9a-fluoro-11ß, 17a-dioxy-21-acetoxy-pregnane to 41,4-3,20-dioxo-9a-fluoro-1 lβ, 17a-dioxy-21-acetoxy-pregnadiene (1-dehydro-9a-fluoro-cortisol acetate) and the 3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-pregnane for d 1.4-3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-pregnadiene (1-dehydro-9a-fluoro-cortisone acetate).

The abovementioned starting substances can be prepared according to Example 16 , for example. In this way, the d9 (11) -3,20-dioxo-17a-oxy-21-acetoxy-pregnene is converted into 3,20-dioxo via the 3,20-dioxo-17a-oxy-21-acetoxy-pregnane -9,11ß-oxydo-17a-oxy-21-acetoxy-pregnan um. Furthermore, the oxido compounds are converted into 3,20-dioxo-9a-fluoro-11ß, 17a-dioxy-21-acetoxy-pregnane either by means of hydrofluoric acid or by means of hydrochloric acid into 3,20-dioxo-9a-chloro-11ß, 17a-dioxy-21-acetoxy-pregnane. Both derivatives can be converted to 3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-pregnane and 3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy- oxidize pregnan. Example 18 A solution of 2 g of 2-methyl-3,20-dioxo-9a-fluoro-11β, 17a-dioxy-21-acetoxy-allopregnane in 70 cm3 of tert-amyl alcohol is mixed with 0.7 g of selenium dioxide and 0.5 cm3 of glacial acetic acid are mixed and refluxed under nitrogen for a total of 40 hours, a further 0.7 g of selenium dioxide being added after 20 hours. The procedure is as described in Example 12. The residue obtained after evaporation is chromatographed on aluminum oxide and the benzene and benzene-ether eluate evaporated in vacuo, from which the 41.4-2-methyl-3,20-dioxo-9a-fluoro-11ß, 17a-dioxy-21- acetoxy-pregnadiene (1-dehydro-2-methyl-9a-fluorocortisol acetate). In the paper chromatogram (propylene glycol-toluene) it migrates somewhat more slowly than the saturated starting material.

2-Methyl-3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-allopregnane can be used in an analogous manner to 41,4-2-methyl-3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-pregnadiene (1-dehydro-2-methyl-9a-fluoro-cortisone acetate) dehydrate. 2-Methyl-3,20-dioxo-9a-chloro-1 can also be used in an analogous manner lβ, 17a-dioxy-21-acetoxy-allopregnane and 2-methyl-3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-allopregnane zum 41, L2-methyl-3,20-dioxo-9a-chloro-11ß, 17a-dioxy-21-acetoxy-pregnadiene (1-dehydro-2-methyl-9a-chloro-cortisol acetate) or to d1,4-2-methyl-3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-pregnadiene (1-dehydro-2-methyl-9a-chloro-cortisone acetate) dehydrate.

The above-mentioned starting substances can be represented according to Example 116.

In this way you can 48 (11) -2_Methyl-3,20-dioxo-17a-oxy-21-acetoxy-allopregnen, that one z. B. from 2-methyl-cortisol acetate by hydrogenating the 4 (5) double bond and cleavage of the 11-position hydroxyl group by means of phosphorus oxychloride in pyridine obtained via the 2-methyl-3,20-dioxo-9a-bromo-11 ß, 17a-dioxy-21-acetoxy-allopregnane Convert into the 2-methyl-3,20-dioxo-9,1l ß-oxido-17a-oxy-21-acetoxy-allopregnane. This is then either converted into 2-methyl-3,20-dioxo-9a-fluoro-11ß, 17a-dioxy-21-acetoxy-allopregnane by means of hydrofluoric acid or by means of hydrochloric acid into 2-methyl-3,20-dioxo-9a-chloro-11ß, 17a-dioxy-21-acetoxy-allopregnane above. Both compounds can be obtained with chromic acid in the 11-position to 2-methyl-3,11,20-trioxo-9 a-fluoro-17a-oxy-21-acetoxy-allopregnane or 2-methyl-3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-allopregnane dehydrate. Example 19 A solution of 2 g of 2-methyl-3,20-dioxo-9a-fluoro-11β, 17a-dioxy-21-acetoxy-pregnane in 70 cm3 of tert-amyl alcohol is mixed with 0.7 g of selenium dioxide and 0.5 cm3 of glacial acetic acid and refluxed under nitrogen for a total of 40 hours Hours a further 0.7 g of selenium dioxide is added. It is described as in Example 12 procedure. The residue obtained after evaporation is chromatographed on aluminum oxide and the benzene and benzene ether eluate are evaporated in vacuo, resulting in one 41,4-2-methyl-3,20-dioxo-9 a-fluoro-11 ß, 17a-dioxy-21-acetoxy-pregnadiene (1-dehydro-2-methyl-9a-fluoro-cortisol-21-acetate ) receives. In the paper chromatogram (propylene glycol - toluene) it migrates a little more slowly as the starting material.

2-Methyl-3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-pregnane can be used in an analogous manner dehydrate to d1 # 4-2-methyl-3,11,20-trioxo-17a-oxy-9a-fluoro-21-acetoxy-pregnadiene. The dehydration of 2-methyl-3,20-dioxo-9a-chloro-11ß, 17a-dioxy-21-acetoxy -pregnane and from 2-methyl-3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-pregnane gives 41,4-2-methyl-3,20-dioxo-9a-chloro-11ß, 17a- dioxy-21-acetoxy-pregnadiene (1-dehydro-2-methyl-9a-chloro-cortisol acetate) or 41.4-2-methyl-3,11,20-trioxo-9 α-chloro-17a-oxy-21-acetoxy-pregnadiene (1-dehydro-2-methyl-9a-chloro-cortisone acetate).

The abovementioned starting substances can be prepared according to Example 16. The d9 (11) -2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-pregnen is converted in this way via 2-methyl-3,20-dioxo-9a-bromo-11ß, 17a-dioxy-21-acetoxy-pregnane into 2-methyl-3,20-dioxo-9,13-oxido-17a-oxy-21 -acetoxy-pregnan around. The oxido compound is then converted into 2-methyl-3,20-dioxo-9a-fluoro-11 using hydrofluoric acid β, 17a-dioxy-21-acetoxy-pregnane or by means of hydrochloric acid into 2-methyl-3,20-dioxo-9a-chloro-11β, 17a-dioxy-21-acetoxy-pregnane above. Both derivatives can be converted into 2-methyl-3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-pregnane with chromic acid or oxidize to 2-methyl-3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-pregnane. example 20 A solution of 1 g of 44-2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-pregnen in 30 cm3 tert. Amyl alcohol is mixed with 0.7 g of saline dioxide and 0.2 cm3 of glacial acetic acid and boiled reflux under nitrogen for 24 hours. It is described as in Example 12 procedure. The residue obtained by evaporation is chromatographed on aluminum oxide and the benzene and benzene-ether eluate evaporated in vacuo, resulting in d1> 4-2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-pregnadiene receives. In the paper chromatogram (propylene glycol - toluene) it migrates a little more slowly as the starting substance.

If the d4-2-methyl-3,11,20-trioxo-17a-oxy-21-acetoxy-pregnen in an analogous manner reacted with selenium dioxide, 41.4-2-methyl-3,11,20-trioxo-17a-oxy-21-acetoxy-pregnadiene is obtained (1-Dahydro-2-methylcortisone-21-acetate).

In an analogous manner, the d 4-2-methyl-3,20-dioxo-11 ß, 17a-dioxy-21-acetoxy-pregnen with selenium dioxide to d1,4-2-methyl-3,20-dioxo-11ß, 17a-dioxy-21-acetoxypregnadiene Dehydrate (1-dehydro-2-methyl-cortisol-21-acetate). Example 21 A solution of 1 g of 44-2-methyl-3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-pregnene in 20 cm3 of tert-amyl alcohol mix with 0.4 g of selenium dioxide and 0.2 cm3 of glacial acetic acid and boil under nitrogen a total of 36 hours at reflux, after 18 hours a further 0.3 g of selenium dioxide admits. The procedure is as described in Example 12. The one obtained after evaporation The residue is chromatographed on aluminum oxide and the benzene and the evaporated Benzene ether eluate in vacuo, from which the dl # 4-2-methyl-3,11,20-trioxo-9a-fluoro-17a-oxy-21-acetoxy-pregnadiene receives.

If the 44-2-1Zethyl-3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-pregnen in an analogous way, 44-3,20-dioxo-9a-fluoro-llß, 17a-dioxy-21-acetoxy-pregnen and 44-3,20-dioxo-9a-chloro-llß, 17a-dioxy-21-acetoxypregnen Reacts with selenium dioxide, the corresponding 1-dehydro compounds are obtained. example 22 A solution of 1 g of 44-2-methyl-3,20-dioxo-9,11ßoxido-17a-oxy-21-acetoxy-pregnen in 30 cm3 of tert-amyl alcohol is mixed with 0.4 g of selenium dioxide and 0.25 cm3 of glacial acetic acid and reflux under nitrogen for a total of 24 hours, after 12 hours a further 0.3 g of selenium dioxide is added. The procedure described in Example 12 is followed.

The residue obtained after evaporation is chromatographed on aluminum oxide aphiert and the benzene and benzene-ether eluate # evaporated in vacuo, from which 41.4-2-methyl-3,20-dioxo-9,11ß-oxido-17a-oxy-21-acetoxy-pregnadiene is obtained.

If the 41,4-2-methyl-3,20-dioxo-9,11ß-oxido-17a-oxy-21-acetoxy-pregnadiene is obtained Reacts with hydrochloric acid or with hydrofluoric acid in a dioxane solution, after evaporation in vacuo at 20 ° C., 41.4-2-methyl-3,20-dioxo-9a-chloro-11 is obtained β, 17a-dioxy-21-acetoxy-pregnadiene or 41,4-2-methyl-3,20-dioxo-9 a-fluoro-11 ß, 17a-dioxy-21-acetoxypregnadiene.

Both halogen derivatives can be converted into d1,4-2-methyl-3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-pregnadiene using chromic acid or oxidize the corresponding fluorine compound. The above-mentioned starting substance you can z. B. according to Example 16, while the 44, e (11) -2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-pregnadiene via the 44-2-methyl-3,20-dioxo-9a-bromo-llß, 17a-dioxy-21-acetoxy-pregnen in the A4 t> transferred. Example 23 A solution of 1 g of 44, s (11) -3 20-dioxo-17a-oxy-21-acetoxy-pregnadiene 40 cm3 of tert-amyl alcohol is mixed with 0.4 g of selenium dioxide and 0.3 cm3 of glacial acetic acid and refluxed under nitrogen for a total of 22 hours Hours another 0.3 g of selenium dioxide is added. It is described as in Example 12 procedure. The residue obtained by evaporation is chromatographed on aluminum oxide and evaporates the benzene and benzene-ether eluate in vacuo, resulting in 41,4.s (11) -3,20-dioxo-17a-oxy-21-acetoxy-pregnatrien receives. In the paper chromatogram (propylene glycol - toluene) it migrates a little more slowly as the starting substance.

The obtained d1,4, s (i1) -3,20-dioxo-17a-oxy-21-acetoxy-pregnatriene can be converted into the following compounds according to Example 16: d l> 4-3,20-Dioxo-9 a-bromo-11 ß, 17 a-dioxy-21-acetoxypregnadiene, d 1, 4-3,20-dioxo-9,11 ß-oxido-17 a-oxy-21-acetoxypregnadiene, 1, 4-3,20-Dioxo-9 a-chloro-11 ß, 17 a-dioxy-21-acetoxypregnadiene, d 1, 4-3,20-Dioxo-9 a-fluoro-11 ß, 17 a-dioxy-21-acetoxypregnadiene, 41 # 4-3,11, 20-trioxo-9 a-chloro-17 a-oxy-21-acetoxypregnadiene, d 1, 4-3,11,20-trioxo-9 a-fluoro-17 a-oxy-21-acetoxypregnadiene. Example 24 A solution of 1 g of 44, s (11) -2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-pregnadiene in 30 cm3 of tert-amyl alcohol is mixed with 0.4 g of selenium dioxide and 0.2 cm3 of glacial acetic acid and heated with stirring in a nitrogen atmosphere to 70 ° C for a total of 40 hours, after 20 hours, a further 0.3 g of selenium dioxide is added. It will be like in the example 12. The residue obtained by evaporation becomes aluminum oxide chromatographed and the benzene and benzene-ether eluate evaporated in vacuo, from which the d 1, 4, s (11) -2-methyl-3,20-dioxo-17 a-oxy-21-acetoxy-pregnatrien receives.

The Pregnatrien obtained can be according to Example 16 in the following Compounds transfer 41, 4-2-methyl-3,20-dioxo-9 a-bromo-11 ß, 17 a-dioxy-21-acetoxy-pregnadiene, i.e. 4-2-methyl-3,20-dioxo-9,11β-oxido-17α-oxy-21-acetoxy-pregnadiene, 41,4-2-methyl-3,20-dioxo-9a-chloro-11 ß, 17a-dioxy-21-acetoxy-pregnadiene, d 1,4-2-methyl-3,20-dioxo-9a-fluoro-11 ß, 17a-dioxy-21-acetoxy-pregnadiene, 41.4-2-methyl-3,11,20-trioxo-9a-chloro-17a-oxy-21-acetoxy-pregnadiene, 41.4-2-methyl-3,11,20-trioxo-9 α-fluoro-17 α-oxy-21-acetoxy-pregnadiene.

Example 25 A solution of 1 g of 2-methyl-3,20-dioxo-17 a-oxy-21-acetoxy-allopregnane, obtained by hydrogenation of 2-methyl-17a-oxy-cortexon-21-acetate, in 30 cm-, tert-amyl alcohol is mixed with 0.8 g of selenium dioxide and 0.2 cm $ Glacial acetic acid mixed and refluxed under nitrogen for a total of 18 hours, wherein one after 9 hours a further 0.6 g of selenium dioxide is added. It is described as in Example 12 procedure. The residue obtained after evaporation is chromatographed on aluminum oxide and evaporate the benzene and benzene-ether eluate in vacuo, giving d 1,4-2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-pregnadiene receives.

If in an analogous manner the 2-methyl-3,11,20-trioxo-17a-oxy-21-acetoxy-allopregnan or the 2-methy13,20-dioxo-11ß, 17a-dioxo-21-acetoxy-allopregnane with selenium dioxide the d1> 4-2-methyl-3,11,20-trioxo-17a-oxy-21-acetoxy-pregnadiene is obtained or the d 1.4-2-methyl-3,20-dioxo-11 ß, 17a-dioxy-21-acetoxypregnadiene.

In an analogous manner, the following pregnane derivatives can also be used Dehydrate normal series with selenium dioxide: 2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-pregnane to d1,4-2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-pregnadiene, 2-methyl-3,11,20-trioxo-17aoxy-21-acetoxy-pregnane to d1,4-2-methyl-3,11,20-trioxo-17a-oxy-21-acetoxy-pregnadiene and 2-methyl-3,20-dioxo-11ß, 17a-dioxy-21-acetoxy-pregnane to 41,4-2-methyl-3,20-dioxo-11β, 17α-dioxy-21-acetoxy-pregnadiene. Example 26 A solution of 1 g of d 9 (11) -3,20-dioxo-17a-oxy-21-acetoxy-allopregnen in 30 cm3 tert-amyl alcohol is mixed with 0.8 g of selenium dioxide and 0.2 cm3 of glacial acetic acid and refluxed under nitrogen for a total of 20 hours, after 10 hours another 0.6 g of selenium dioxide is added. Proceed as in example 12. The through The residue obtained by evaporation is chromatographed on aluminum oxide and the benzene and the benzene-ether eluate evaporated in vacuo, - before the d1.4, s (") _ 3,20-Dioxo-17a-oxy-21-acetoxy-pregnatriene receives. In the paper chromatogram (propylene glycol-toluene) the triene migrates somewhat more slowly as the starting substance.

The d9 (11) _3,20-Dioxo-17a-oxy-21-acetoxy-pregnen is used in an analogous manner with selenium dioxide, the d1,4.9 (11) -3,20-dioxo-17a-oxy-21-acetoxy-pregnatriene receives. According to Example 16, this triene can be converted into d1,4-3,20-dioxo-9,13-oxydo-17a-oxy-21-acetoxypregnadiene, the d1.4-3,20-dioxo-9a-chloro- or the -9 a - fluoro-11 ß, 17 a - dioxy-21-acetoxy - Convict pregnadia. Example 27 A solution of 1 g of d9 (11) _2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-allopregnene 30 cm3 of tert-amyl alcohol is mixed with 0.8 of selenium dioxide and 0.2 cm3 of glacial acetic acid and refluxed under nitrogen for a total of 20 hours, after 10 Hours another 0.6 g of selenium dioxide is added. It is described as in Example 12 procedure. The residue obtained after evaporation is chromatographed on aluminum oxide and the benzene and benzene-ether eluate evaporate in vacuo, resulting in d1,4, s (11) -2-methyl-3,20-dioxo-17a-oxy-21-acetoxy-pregnatriene receives.

The same compound is obtained by dehydrogenating d 9 (11) -2_Methyl-3,20-dioxo-17a-oxy-21-acetoxypregnene.

The triene obtained can be converted into d1.4-2-methyl-3,20-dioxo-9, llß-oxido-17a-oxy-21-acetoxy pregnadiene and d1.4-2-methyl-3,20- Dioxo-9a-chloro- and the -9a-fluoro-llß, 17a-dioxy-21-acetoxy-pregnadiene. Example 28 A suspension of 1 g of d4-3,11,20-trioxo-17a-methyl-21-acetoxy-pregnene in 30 cm3 of tert. Amyl alcohol is mixed with 0.4 g of selenium dioxide and 0.2 cm3 of glacial acetic acid and refluxed under nitrogen for a total of 18 hours, a further 0.3 g of selenium dioxide being added after 9 hours. The procedure described in Example 12 is followed. The residue obtained by evaporation is chromatographed on aluminum oxide and the benzene and benzene-ether eluate are evaporated off in vacuo. The residues obtained are recrystallized from acetone-petroleum ether or aqueous methanol, whereby d 1,43,11,20-trioxo-17α-methyl-21-acetoxypregnadiene (1,11-bisdehydro-17a-methvl-corticosterone- 21-acetate) with a melting point of 189 to 201 ° C. Example 29 A suspension of 1 g of cortisone acetate in 40 cm3 of ethylene glycol monoethyl ether (known under the trade name Cellosolve and 0.4 cm of glacial acetic acid is mixed with 400 mg of selenium dioxide and heated to 100 ° C. for 30 hours.

The selenium formed is then decanted off and mixed with a little acetone washed. The acetone is evaporated off in vacuo, the clear solution with plenty of water mixed and extracted with ethyl acetate. The ethyl acetate solutions are according to example 1 worked up, whereby 1-dehydrocortisone acetate can also be isolated.

If you start the reaction at an elevated temperature, for example at the boiling point Carries out the mixture, you can advantageously shorten the reaction time somewhat. Example 30 A suspension of 1 g of cortisone acetate in 50 cm "of benzene and 0.5 cm3 Glacial acetic acid is mixed with 500 mg of selenium dioxide and refluxed for 48 hours. The reaction mixture is worked up according to Example 1, also using the Can isolate 1-dehydrocortisone acetate. Example 31 A suspension of 1 g of 9α-fluoro-11β-oxy-testosterone and 330 mg selenium dioxide in 30 cm3 tert-amyl alcohol and 0.3 cm3 acetic acid is under Stirring in a nitrogen atmosphere heated to 70 ° C, after 10 hours more 300 mg selenium dioxide is added. After 24 hours, the solution is allowed to cool and separated from the selenium formed, this washes with a little acetone and the filtrate is evaporated in the Vacuum a. After working up as in Example 12, 1-dehydro-9a-fluoro-11ß-oxy-testosterone is obtained.

1-Dehydro-9a-fluoro-11ß-oxy-17a-methyl-testosterone can be prepared from 9a-fluoro-11ß-oxy-17a-methyltestosterone and 1-dehydro-9a-fluoro-11-oxo-17a -methyl-testosterone obtained from 9a-fluoro-ll-oxy-17a-methyl-testosterone. Example 32 50 cm3 of tert-butanol and 1 cm3 of glacial acetic acid are poured onto 250 mg of 9a-fluorocortisone acetate and 125 mg of selenium dioxide. The mixture is refluxed for 24 hours, a further 125 mg of selenium dioxide are added, the mixture is boiled for a further 24 hours and then the selenium formed is decanted off. The selenium is washed with methanol and the combined solutions are evaporated in vacuo. The residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with dilute potassium carbonate solution, ice-cold, freshly prepared ammonium sulfide solution, ice-cold ammonia solution and finally with water and then dried and evaporated. The residue obtained is now chromatographed on paper using the formamide-benzene-chloroform (1: 1) system. The spots determined in UV light and containing the dehydro compound are cut out and extracted with a 50% methanol-water mixture. The solution obtained is concentrated and extracted with ethyl acetate and the extract is evaporated and dried. The residue is recrystallized from methanol or a mixture of acetone and isopropyl ether, pure 1-dehydro-9a-fluoro-cortisone acetate, which melts with decomposition at 273 to 276 ° C and a rotation of [a] ö = - shows r156 ° ± 4 °. Example 33 250 mg of 44-9a-fluoro-3,20-dioxo-11ß, 17a-dioxy-pregnen are reacted as described in Example 32 with selenium dioxide. The crude 41.4-9a-fluoro-3,20-dioxo-11ß, -17a-dioxy-pregnadiene obtained is also purified as indicated and obtained crystals which melt with decomposition at 313 to 315 ° C and in pyridine a rotation of [a] '- -E-45 show ± 2 °. Example 34 50 cm3 of tert-butanol and 1 cm3 of glacial acetic acid are poured onto 1 g of d4-3,20-dioxo-11β-oxy-12a-fluoro-pregnene and 400 mg of selenium dioxide. The starting substance can be obtained from the 11,12ß-epoxide of d4-3,20-dioxo-pregnen by treating this compound with hydrofluoric acid. The mixture is refluxed for 48 hours and then decanted from the selenium formed. The selenium is washed with a little acetone and the combined solutions are evaporated in vacuo. The residue is dissolved in ethyl acetate. The ethyl acetate solution is washed at O 'C with dilute potassium carbonate solution, water, freshly prepared ammonium sulfide solution, dilute ammonia solution and water and dried and evaporated. The residue formed is chromatographed on 27 g of silica gel and then eluted with chloroform, chloroform-tert-butanol in a ratio of 99: 1, 98: 2.96: 4 and 90:10 and finally with acetone. The combined chloroform-tert-butanol eluates in a ratio of 98: 1 to 96: 4 are evaporated in vacuo. The residue mainly contains 41,4-3,20-dioxo-11ß-oxy-12a-fluoropregnadiene, which moves somewhat more slowly than the starting material on the paper chromatogram when using the propylene glycol-toluene system. Example 35 19 44-3,11,20-Trioxo-12a-fluoroprene is reacted as described in Example 3 with selenium dioxide. The crude reaction product obtained is also purified as indicated and 41,4-3,11,20-trioxo-12a-fluoropregnadiene is obtained, which migrates somewhat more slowly than the starting material on the paper chromatogram using the propylene glycol-toluene system. The starting material can be obtained, for example, as follows: 2 gd 4-3,20-dioxo-11 ß-oxy-12 a-fluorine pregnen, which is obtained by treating the 11,12ß-epoxide of 44-3,20-dioxo pregnen with hydrofluoric acid are dissolved in 100 cm- 'glacial acetic acid and 10 cm-' ethylene chloride and mixed at O 'C with a solution of 450 mg chromium trioxide in 10 cm3 water. The solution is left to stand at 20 ° C. for 15 hours. A little sodium bisulfite solution is then added and the solution is then concentrated in vacuo with the addition of water. The residue is shaken with ethyl acetate. The ethyl acetate solutions are washed with dilute soda solution and water, dried and evaporated. The d4-3,11,20-trioxo-12a-fluoro-pregnen is obtained as a residue.

Example 36 250 mg of d4-3,20-dioxo-11ß, 17a-dioxy-12a-fluoropregnene sets as described in Beispie132 with selenium dioxide. The crude product obtained cleans one also as indicated. In the paper chromatogram using the system Propylene glycol toluene migrates the dl> 4-3,20-dioxo-11ß, 17a-dioxy-12a-fluoropregnadiene slightly slower than the starting substance.

The d4-3,11,20-trioxo-17a-oxy-12a-fluorine can be pregnen in the same way dehydrate to 41.4-3,11,20-trioxo-17aoxy-12a-fluoro-pregnadiene. Example 37 250 mg of 3,20-dioxo-11ß, 17a-dioxy-12a-fluoro-pregnane are used as described in Example 32, each time with 250 mg selenium dioxide. The cleaning of the Raw product carried out. The 41.4-3,20-dioxo-11ß, 17a-dioxy-12a-fluoro-pregnadiene obtained in this way migrates somewhat more slowly on the paper chromatogram than the starting substance. According to The same procedure can be used to obtain the 3,11,20-trioxo-17a-oxy-12afluoropregnane 41> 4-3,11,20-Trioxo-17a-oxy-12a-fluoropregnadiene dehydrate. Example 38 1 g of 3-Oxo-5 a, 22a-spirostane and 700 mg selenium dioxide are covered with 50 cm3 of tert-butanol. The suspension is refluxed for 48 hours and, after cooling, the precipitated material is separated off Selenium by decanting off, washing with acetone and evaporating the combined solutions in a vacuum. The residue is dissolved in ethyl acetate and the ethyl acetate solution is washed one after the other with dilute potassium carbonate solution, water, freshly prepared ammonium sulfide solution, Water, dilute hydrochloric acid and water, dries and evaporates. The residue is recrystallized from acetone or a mixture of acetone and isopropyl ether, 41,4-3-oxo-22α-spirostadien are obtained. Example 39 1 g of 3,11-dioxo-5a-22a-spirostane and 700 mg of selenium dioxide are refluxed for 48 hours in a mixture of 1 cm3 acetic anhydride and 50 cm "butanol with exclusion of moisture. After After cooling the mixture, the precipitated selenium is separated off by decanting. That Selenium is washed with a small amount of acetone and the combined solutions are evaporated with the addition of alcohol in vacuo. The brown residue is dissolved in ethyl acetate solved. The ethyl acetate solution is washed with dilute potassium carbonate solution, dilute Hydrochloric acid and water, dries and evaporates. By recrystallizing the residue from acetone or a mixture of acetone and isopropyl ether, 41,4-3,11-dioxo-22a-spirostadiene is obtained. Example 40 1 g of 3-oxo-9.11 ß-oxido-5 a-22 a-spirostane and 700 mg of selenium dioxide boil 48 hours under reflux in 50 cm3 of tert-butanol. After cooling, they are separated the precipitated selenium by decanting, washes it with acetone and steams the combined solutions in a vacuum. The residue is dissolved in ethyl acetate and washed the ethyl acetate solution successively with dilute potassium bicarbonate solution, water, freshly prepared ammonium sulfide solution, water, dilute hydrochloric acid and water, dries and evaporates. The residue is recrystallized from acetone, whereby d 1.4-3-Oxo-9, lß-oxido-22 a-spirostadien is maintained.

100 mg i.e. 4-3-oxo-9.11 ß-oxido-22 a-spirostadiene are dissolved in 10 cm3 Dioxane, mixed with 2.5 cm3 of 2.5 N hydrochloric acid and left to stand for 1 hour. Then you give Add water and extract the whole thing with chloroform-ether (1: 3). After washing with Water, drying and evaporation of the solvent in vacuo gives the dl> 4-3-Oxo-9 a-chloro-11 ß-oxy-22 a-spirostadien. Example 41 1 g d9 (11) -3_Oxo-5a-22a-spirosten and 700 mg of selenium dioxide are refluxed for 48 hours with the exclusion of Moisture in a mixture of 1 cm3 acetic anhydride and 50 cm3 butanol. To after cooling, the precipitated selenium is separated off by decanting and is washed with it a little acetone and evaporate the combined solutions with the addition of alcohol in vacuo a. The brown residue is dissolved in ethyl acetate and the ethyl acetate solution is washed with dilute potassium carbonate solution, water, freshly prepared ammonium sulfide solution, dilute hydrochloric acid and water, dry and evaporate in vacuo. By recrystallization the residue from acetone or acetone-isopropyl ether mixtures gives d1,4> 9 (11) -3-oxo-22a-spirostatriene. Example 42 A suspension of 1 g of 3-oxo-9 a-bromo-11 ß-oxy-5a, 22 a-spirostane, the by reacting 49 (11) _3_Oxo-5a, 22a-spirostane, hypobromous acid is obtained, and 700 mg selenium dioxide in 30 cm3 tert-amyl alcohol and 0.3 cm3 glacial acetic acid are boiled Reflux for 24 hours under nitrogen. The cooled suspension is filtered off Selenium formed, washed with a little acetone and evaporated the clear brown solution in a vacuum. The residue is taken up in ethyl acetate.

The ethyl acetate solutions are washed successively with dilute potassium carbonate solution, Water, dilute hydrochloric acid and water, dry and evaporate in vacuo. That dl # 4-3-oxo-9a-bromo-flß-oxy-22aspirostadien obtained in this way is dissolved in 20 cm3 dry Pyridine, the solution is mixed with 1.6 g of freshly precipitated silver oxide and shaken it in the dark for 24 hours. Then the silver oxide is filtered off and the steam is evaporated Filtrate in a vacuum and receives from it the dl> 4-3-Oxo-9,11ßoxydo-22 a-spirostadien.

1 g of this oxo compound is dissolved in 100 cm3 of dioxane, mixed with 25 cm3 of 2.5N hydrofluoric acid and left to stand at 20 ° C. for 1 hour. Then water is added and the whole thing is extracted with chloroform-ether (1 : 3). After washing with water, drying and evaporation of the solvent in vacuo, 41,4-3-oxo-9a-fluoro-11β-oxy-22 a-spirostadiene is obtained.

By oxidation of the halohydrins obtained with chromic acid in ethyl acetate the d1> 4-3,11-dioxo-9 a-fluoro-22 a-spirostadiene is obtained. Example 43 3 g of d 4-3,17-dioxo-androstene is dissolved in 50 cm3 of glacial acetic acid. 1.8 g of selenium dioxide are then added and the mixture is boiled 17 hours under reflux. After working up, the 41,4-3,17-dioxo-androstadiene is obtained with a melting point of 168 ° C and a rotation in dioxane of [a], = + 22 ° C.

Example 44 1.8 g of 17a-21-dioxy-3,11,20-trioxo-pregnane-21-acetate and 0.55 g of selenium dioxide is dissolved in 35 cm3 of tert-butanol and 7 cm of glacial acetic acid. After 45 minutes The reaction mixture is worked up by boiling under nitrogen. Obtained from acetone one crystals of d4-17a-21-dioxy-3,11,20-trioxo-pregnen-21-acetate, which at 238 melts up to 242 ° C. Example 45 0.3 g of 17a, 21-dioxy-3,11,20-trioxo-allopregnan-21-acetate and 0.15 g of selenium dioxide are dissolved in 10 cms of toluene and 2 cm3 of glacial acetic acid. After 5 hours The reaction mixture is worked up by boiling and examined by paper chromatography. Two spots similar to that of d 1-1. 7 a, 21-Dioxy-3,11,20-trioxo-allopregnene-21-acetate and that of Al, 4-17a, 21-dioxy-3,11,20-trioxo-pregnadiene-21-acetate correspond, could be determined. Example 46 0.6g 11β, 17a, 21-trioxy-3,20-dioxopregnane-21-acetate (Melting point 215 to 216 ° C) and 0.18 g of selenium dioxide are in 8 cm3 of tert-butanol and 1.5 cm3 of glacial acetic acid and the mixture was boiled under nitrogen for 1 hour. at the process produces d4-11ß, 17a, 21-trioxy-3,20-dioxo-pregnen-21-acetate, which melts at 221 to 223 ° C. Example 47 A suspension of 0.5 g of d4, B-17a, 21-dioxy-3,11,20-trioxo-pregnadiene-21-acetate and 200 mg of selenium dioxide in 50 cm3 of tert-butanol are boiled under reflux and under Stir for 24 hours in a nitrogen atmosphere. After about 6 hours everything is in Solution gone. The precipitated selenium is filtered off and the resulting product is evaporated Filtrate to a small volume and diluted with chloroform. Then you wash the chloroform solution with cold, dilute sodium hydroxide solution and water. After drying The solvent is evaporated to dryness under reduced pressure over sodium sulphate. The resulting residue gives crystals of d1,4, g-17a, 21-dioxy-3,11,20-trioxo-pregnatriene in an alcoholic solution. The melting point is 225 ° C. In UV light the substance shows the characteristic Maxima at 222, 254 and 298 mp. Example 48 A suspension of 0.5 g of 44.g-llß, 17a, 21-trioxy-3,20-dioxo-pregnadiene-21-acetate and 200 mg of selenium dioxide in 50 cm3 of tert-butanol are refluxed under nitrogen and with stirring for 24 hours. After 6 hours, the reaction has ended, after which one the resulting dl, 4, e-11ß, 17a, 21-Trio.y-3,20-trioxo-pregnatrien after the im Example 47 isolated.

The d1.4 # e-17a, 21-dioxy-9-halogen-3,11,20-trioxo-pregnatriene compounds can be used in the same way and the d1,4.e-11ß, 17a-21, trioxy-9a-halogen-3,20-dioxo-pregnatriene compounds represent the corresponding d 4, 3-3-ketones. Example 49 1.5 g of d4-17a-Oxy-11a, 21-diacetoxy-3,20-dioxo-pregnen and 750 mg of selenium dioxide are suspended in 75 cm3 of tert-butanol. The mixture is boiling the clear solution is decanted from the precipitated solution under reflux for 72 hours Selenium from, this washes in acetone and the combined solutions are evaporated in vacuo a. The residue is dissolved in chloroform and the chloroform solution is washed with cold Caustic soda and water, dries and evaporates. The residue is dissolved in benzene and chromatographed it over @) silica gel; c. d 1, 4-17 a-Oxy-11 a, 21-diacetoxy-3,20-dioxo-pregnadiene with a melting point of 230 to 232 ° C is obtained from the benzene-10 0 / ö acetone fraction.

In the same way as described above, d 4-11 a-Oxy-21-acetoxy-3,20-dioxo-pregnen (11-epi-corticosterone acetate) converted into dl # 4-lla-oxy-21-acetoxy-23-dioxopregnadiene. Example 50 1 g of hydrocortisone acetate and 400 mg of selenium dioxide are dissolved in 50 cm 3 of tert-butanol and 2.5 cm3 of acetic acid. After refluxing for 22 hours, the precipitated one becomes Selenium filter off +, the filtrate evaporated, the residue dissolved in chloroform and the chloroform solution washed with cold sodium hydroxide solution and water, dried and evaporated. The crystallization of the residue from acetone gives d l-dehydro-hydrocortisone acetate. The monoselene derivative is obtained from the mother liquors, which decomposes at 299.degree melts.

Analysis for C23H3200Se: Calculated ... C57.38, 1 16.28, Se 16.3; found .... C56.90, 1 16.14, Se 15.7.

The infrared spectrum shows, among other things, bands at 6.02, 6.16 and 6.23, u.

The monoselene derivative of testosterone propionate is obtained in the same way with a melting point of 170 to 172 ° C; Selenium content 17.30; o.

Claims (6)

PATENT CLAIMS: 1. Method for the preparation of dehydrosteroids by selenium dehydration, characterized in that 3-oxosteroids, which are in at least one of the a-positions to the 3-position oxo group are saturated 3 °, or their functional derivatives treated with selenium dioxide or selenous acid and optionally the obtained d 1, d 4 or d 1,4 steroids are converted into their functional derivatives. 2. The method according to claim 1, characterized in that 4c is the dehydration in a tertiary alcohol, optionally mixed with another solvent, undertakes. 3. The method according to claim 1 and 2, characterized in that the Carries out dehydration in tertiary butanol or tertiary amyl alcohol. 4. Procedure according to claim 1 to 3, characterized in that the dehydrogenation is carried out in the presence an acid. 5. The method according to claim 1 to 4, characterized in that one AL, A4 or d 4. 0-3-oxosteroids as well as pregnanes and androstanes saturated in ring A, in particular cortisone, hydrocortisone, 11-epihydrocortisone, corticosterone, 11-deoxycorticosterone , Aldosterone, 18-oxycorticosterone, 18-oxycortexone, 18-oxocortexone, also pregnan-or allopregnan-3,20-dione, pregnan-or allopregnan-3,11,20-dione-17a, 21-diol, pregnan-or allopregnan -3,20-dione-11ß, 17a, 21-triol, d4-androsten-3-one-17-ols, androstan- or testan-3-one-17-ols, 9,11ß-oxydo-, 9a- or 12a-fluorine or chlorine derivatives of cortisone, hydrocortisone, 11-epihydrocortisone, corticosterone, aldosterone, 18-oxycorticosterone, pregnan-or allopregnan-3,11,20-trione-17a, 21-diol, pregnan-3 or allopregnan-3, 20, dione-17a, 21-diols, pregnan-or allopregnan-3,20-dione-11ß, 17a, 21-triols, furthermore the 2-methyl derivatives of hydrocortisone, 9a-fluorohydrocortisone, cortisone and 9a-fluorocortisone, furthermore 3- Oxo compounds of spirostane or fur ostan series which are saturated in ring A, in particular 3-oxo 5a, 22a-spirostane, especially 3,11-dioxo-5a, 22a-spirostane, 3-oxo-11,12ß-oxydo-5a, 22a-spirostane, 3, 12-dioxo-11 a, 23-dibromo-5 a, 22 a-spirostane, 4 9 (11) -3_Oxo-5a, 22 a-spirosten, 3-oxo-9,11 ß-oxydo-5 a, 22 a - spirits or their functional derivatives are used as starting substances. 6. The method according to claim 1, characterized in that the obtained d 1, 4-3-Ooxo-9,11 ß-oxydo-pregnadienes with a hydrohalic acid, especially with hydrofluoric or hydrochloric acid converted into the corresponding 9α-halogen-11β-oxy compounds. Considered Publications: Journ. Chem. Soc., 1936, p. 462; 1933, p. 387; Arch. Bioch., Vol. 14, 1947, p. 125.