BE656770A - - Google Patents

Description

       

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  A process for the preparation of a 3-keto-4,6-bisdehydro-9ss, 10Ó-steroid.



   Belgian patent no. 577,615 describes a new group of steroids with remarkable pharmacological properties and differing from sterols: normal ones with regard to the configuration at the 9 and 10 carbon atoms. While the normal steroids have a 9Ó configuration. , 10ss, the pharmacologically relevant steroids of the new group have a 9ss, 10O configuration. These normal steroids are hereinafter referred to as "steroids". while compounds of the new group will be referred to as "9ss, 10O-steroids".



   The new 9ss,10O-steroidsw are prepared by irradiating a normal 5,7-bisdehydro-steroid with ultraviolet light, the operation may be followed, if desired, by removal.

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 and / or the introduction of substituents and / or double bonds, as other methods heretofore are not available to achieve the 9ss.10Ó configuration.



   In the irradiation process, a 3-hydroxy-5,7-bis-dehydrosteroid is very suitable as a starting compound, especially because natural steroids comprising a 3-hydroxy group (or an esterified or etherified 3-hydroxy group) and a double bond at position 5 are available in abundance, while the double bond at position 7, possibly non-existent, can be created very easily. In practice, the 3-hydroxy group is oxidized to a, 3-keto group after irradiation, mainly because the most pharmacologically interesting compounds include a. 3-keto group.



   In general, the oxidation of a 3-hydroxy-steroid to a
3-Ketosteroid does not cause any difficulty, since there are many methods available which give high yields. In particular, good results are obtained by applying the process. of Oppenauer oxidation.



  By "Oppenauer oxidation" is meant here the oxidation of a secondary alcoholic group using a ketone in the presence of a catalyst, the ketone behaving as a hydrogen acceptor and the catalyst generally being a. aluminum alcoholate, for example aluminum isopropoxide. however, it appeared that the oxidation of a 3-hydroxy-
9ss.10Ó-steroid to a 3-keto-9ss, 10Ó-steroid gives lower yields than the same oxidation in the normal series.



   The Applicant has now discovered that by reversing the classical order, comprising first the irradiation in the ultraviolet of a 3-hydroxy-5,7-bisdehydro-steroid (or of its esters or ethers ) then the Oppenauer oxidation of the irradiated product, we can achieve the desired results, namely a higher overall yield, when the Oppenauer oxidation of a 3-hydroxy-9ss.10Ó- steroid is followed therefore by 'an irradiation in the ultraviolet of a

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 EMI3.1
 3-hydroxy-5,6-bia-d6hydro-atérotde.



   Therefore, it should be considered fundamental for the purposes of the invention that, for the process of preparing a 3-keto
 EMI3.2
 4,6-bisdehydro-9fl, 10a-stétotde by ultraviolet irradiation of a 5.7-biodehydro-steroid and, by Oppenauer's oxidation of a 3-hydroxy group, the Oppenauer oxidation precedes the irradiation in the ultraviolet, if one wishes to obtain the best yields.



   More particularly, the process according to the invention,
 EMI3.3
 which consists in preparing a 3-keto-4,6-bisdehydro-9,10a-atdroid by ultraviolet irradiation of a 5-7-bisdehydro-steroid and by Oppenauer's oxidation of a 3-hydrocy-ateroid, is characterized in that Oppenauer's oxidation of 3-hydroxy-sterlde precedes irradiation in the ultraviolet, S, 7-b1sdehldro-9,10a-steroid. obtained after irradiation then being converted into a 3-keto, 6-bisdehydro-9fl, 10a-stétolde.



   It should be noted that it is not necessary in the process according to the invention that the irradiation immediately follow the Oppenauer oxidation, nor that the transformation of the system.
 EMI3.4
 5,7-bisdehydro in 4,6-bisdehydro system takes place immediately after irradiation.

   Provided that the order of the following reactions is observed, namely: a) oxidation of the 3-hydroxy group by the Oppenauer process, b) irradiation of the 5,7-bisdehydro system and
 EMI3.5
 c) transformation into the 3-edto-4..6-bieddhydro system, any intermediate reaction can be inserted between stages a) and b) or b) and c), and in particular an esterification of 3-hydroxy groups , a saponification of the 3-hydroxy group
 EMI3.6
 esterified, a ketalization of a 3-keto group, a decetal1satlon of a 3-keto keto group, an allylic halogenation of an esterified 3-hydroxy group 5-dehydro, a halogenation in the allyli- position
 EMI3.7
 than a 3-keto-ketalised-5-dehydro group,

   dehydrohalogenation of a 5-dehydro-7-halo group or isomerization of a 7-dehydro bond to a 6-dehydro bond.

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   While the above reactions all involve reactions at one or more of carbon atoms 3, 4, 5, 6, 7 and 8, it is also possible that intermediate reactions are carried out at the level. other carbon atoms of the steroid backbone, for example carbon atoms 1, 2, 11, 17, 20 and 21. Such reactions may involve intro-
 EMI4.1
 duction of substituent, for example of hydroxy or alkyl groups, or of halogen atoms, side chain degradations in case the compound in question comprises, for example, the side chain of ergosterol, at the level of carbon atom 17.



   It should further be noted that the oxidation of
 EMI4.2
 Oppenauer of a 3-hydmxy-5,7-bisdehydro-steroid leads to the formation of a 3-ce% o-4,7-bisdehydro-steroid which cannot be irradiated to give 99,10a-etérolde $ because it does not have the appropriate system of conjugated double bonds. For this reason, in
 EMI4.3
 in this case, the deoppenauer oxidation product must be subjected to a cetalization which, according to Antonuccl, J. Orge Chem. It pages 1369 to 1374 (1952), gives a 3-keto ketalised-5,7-bisdehydto group.



   According to one of its preferred embodiments, the invention consists in subjecting to the Oppenauer oxidation a 3-
 EMI4.4
 hydroxy-5-dehydro-sterolde to give a 3-cto -.- dhydro- atéroldes and then to ketalize the latter compound into a 3-ketal-5-dehydro-steroldee to then introduce a double bond in position 7, to be subjected to the 'ultraviolet irradiation of the 3-ketal-5.7-bisdehydro-steroid obtained to form the corresponding 3-k6tal-5,7-, bisdehydto-9 #, 10α-steroid, which is decetalized and transformed into a 3-keto. ,, 6-bisdehydro-95,10a-strolde.



  Suitable starting compounds for this series of reactions are, for example, hydroxy-androsta-5-ene-1? -One and 3/3-hydroxy-pregna-S-bne-20-o11e.



   According to another interesting embodiment of the invention, a 3-hydroxy-5,7-bisdehydro-steroid is subjected to a
 EMI4.5
 Oppenauer oxidation to form a 3-keto-4., 7-bisdehydro-steroid,

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 EMI5.1
 which this ketalized in a 3-oetal-5,7-b18dehydeo-8terotde,
 EMI5.2
 which is then irradiated with ultraviolet light to give the
 EMI5.3
 Corresponding 3-aetaa. 5 "9biadéhydrp-9,10a-atéroxde, which is then decimal and converts to a 3-ce% o-4,6-biadéhydro-9fi, 10a-
 EMI5.4
 steroid.



  Suitable starting compounds for this suite of
 EMI5.5
 reactions are, for example, iergosta-5722-trine-3-ox and 3-hYdroxypregna-5,? - dine-20-one ...
 EMI5.6
 



  For example, the reactions below can be carried out by the process according to the invention (see table of formulas in the appendix).
 EMI5.7
 



  A. 39-hydroxy-pregna-5-bne-20-one (I) is acetal
 EMI5.8
 in 3-acetate corresponded (II). This compound is brominated '' in position
 EMI5.9
 7 using R-bromosucein1m1de, then dehydrobrominated to 3ydroxy. progna-5.7-diene-20-one-3-acetate (III), a compound which after
 EMI5.10
 saponification of the ester group at carbon atom 3
 EMI5.11
 (IV), is subjected to an oxidation of OPPe4auel 'to give pregna-4,7-diene-3,20-dione (V), which is then ketalized to pregna-5.7-diene-3,20-dione- 3,20-bis-ethylene-ketal (VI), which is then irradiated with ultraviolet light to give the corresponding 9fi, loa-steroide (VII). This compound is decetalized in 9S, 10a. pregna-4.7-diene-3,20-dione (VIII), which, after isomerization of the 7-dehydro bond, gives '90,10a-pregna-4.6-diene-3j, 20-
 EMI5.12
 dione (IX).
 EMI5.13
 



  B. Etgosta-5,7,22-ttene-3fl-ol (X) is subjected to Oppenauer oxidation to give etgosta-4,7,22-ttene-3-one (XI), compound which is ketalized with the aid of ethylene glycol to ergosta- i, 7,22-ttene-3-one-3-6-ethylene-ketal (XII). The latter compound is irradiated with ultraviolet light to give 9fl, loa-etgoJ% a-5.7,22-triene-3-one-3-ethylene-ketal (XIII), which is decetalized in 9fl, 10a-ergosta-4, 7,22-triene-3-one (XIV), compound which, on isomerization, gives 9fl, 10a-ergosta-4,6,22-triene-3-one (XV).



  C. 3fl-hydroxy-androsta-5-en-17-one (XVI) is su-

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 EMI6.1
 put to Oppenauer oxidation giving an androata .. ,,. ne3l? - dione (XVII), which is ketalised to androata-Sene-3,17-dione-3,1? , bia-ethylene-oeta1 (XVIII). This latter compound is brominated in the allylic position using N-bromosuoo1n1m1.de, then dehydrobrominated to androsta - $, 7-diene-3,17-dione-3,17-bis-ethylene-ketal (XIX). This compound 1 is irradiated with ultraviolet light to form the corresponding compound 9ss.10Ó. This latter compound is treated as indicated.
 EMI6.2
 . in A and / or in B, to give 9fi, 10a-androJ% a-4,6-diene-3,17-dione (XXI).
 EMI6.3
 



  , D .. 3fi-hydroxy-pTegna-5-en-20-one (XXII) is subjected to Oppenauer's oxidation to give pTegna-4-en-3,20-dione (XXIII), compound which is edtalised to pregaa-5-ene-3,20-dione-3,20-binethylene-ketal (XXIV). The latter compound intrbrominated in the allylic position using N-bromosuccinimide, then dehydro-brominated to pregna-5, J-diene-3,20-dione-3,20-bis-ethylene-ketal (XXV).



  This compound is irradiated with ultraviolet light to give the corresponding 9ss.10Ó compound (XXVI). This last compound is treated,
 EMI6.4
 as indicated under C, to give 90,10a-pregna-4.6-diene-3020-dione (XXVII).



   Note that in Examples A through D, the
 EMI6.5
 The latter two steps, namely the decetalization and isomerization of a 7-dehydro bond into a 6-dehydro bond, are preferably carried out in one step, as further described below.



   As regards the processes mentioned in the description above, or their particular embodiments, it is appropriate to ;; refer to the methods described in the literature.



   Oppenauer's reactions, for example, are described in detail by Roger Adams, Organic Reactions VI, pages 207-272. An applicable method is described by MacPhillamy and Scholz (J. Biol.
 EMI6.6
 



  Chem1stry page 39 (1949, according to this method the oxidation is carried out using cyclohexanone and aluminum isopropoxide in anhydrous toluene.



   Ketalization reactions are, in general, carried out

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 EMI7.1
 z teea using glycola or dioxolanes, such as ethylene glycol or 2-methyl-4,4-ethylene-dioxypen% ene-2 of formula -
 EMI7.2
 
 EMI7.3
 or alternatively 2-methyl-2-ethyl-1,3-dioxolane. The ketalization reaction should be carried out under conditions such that the double bond between carbon atoms 4 and 5 is brought to the 5.6 position. This requires ketalization under mild acidic conditions which can be conveniently obtained using
 EMI7.4
 g-toluenesulfonic acid or boron tritluoride etherate in catalytic amounts.

   The details of the ketalization reactions are given by Loewenthal in nTetrahydronw, pages 287 to 290 (1959), by Fieser and Fieser in "Steroida", pages 307 to 310 (1959) and by Lettré-inhotten-Tsesche in "Ueber Sterine , Gallensâuren und verwandte Naturatoffe "1. pages 260 to 262.
 EMI7.5
 



  Very suitable methods are described by Antonnuccl et al in J. Org. Chem. 16. 1891 (1951) and by Dauben in J.Am.Chem.soc. 76 1359 (1954). i
The best results have been obtained by the Applicant by ketalization in glycol in the presence of p- acid.
 EMI7.6
 toluenesultonic, with elimination of water formed during the reaction.



   The introduction of a 7-dehydro bond into a 3-ketal-5-dehydro-steroid is described by Bernstein et al. In J. Org. chem. 18, pages 1418-1426 (1953), and the introduction of a
 EMI7.7
 7-dehydro bond in an esterified 3-hydro, xy-sterolde is described in US Patent No. 2,442,091. A suitable method is the reaction with N-bromosuccin1de or with N, H'-dibromodtméthl1-hydantolne ,,
Ultraviolet irradiation is carried out, preferably, using light with a wavelength between 220 and 320 m / u, for example, that given normally by lamps.

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 high pressure mercury vapor, such as the "Philips HO lamp
2000 ".

   The duration of irradiation depends on various factors including the amount of material to be irradiated, the intensity of the light source and the distance between the light source and the material to be irradiated. The substance must be in the state of solution, as is quite obvious.

   Preferably, the irradiation wavelength is chosen so that the substance is irradiated, during the first irradiation phase, with short-wavelength ultraviolet light, of which more than 20% of the energy. radiant have a wavelength between 220 and 290 m / u,
 EMI8.1
 then, during a second phase, by long wavelength ultraviolet light of which less than 20% of the radiant energy has a wavelength of 220 to 290 m / u and the remainder has a length of 'wave greater than 290 m / u, but mainly less than 350 m / u.
 EMI8.2
 



  The decetalization of a 3-ketal-5,7-bisdehydro-9S, 10a-steroid to a 3-keto -., 7-bisdehydro-9,10a-sterode can be accomplished by reaction with an excess of a ketone, such as acetone or butanone-2, or by hydrolysis, for example using a mixture of acetic acid and water.
 EMI8.3
 



  The transformation of a 3-keto-4,7-bisdehydro-9S, 10a- atérolde into a 3-oeto-4,6-bisdehydro-9fl, 10a-sterolde can be easily carried out by isomerization of the compound in substantially non-acidic medium. aqueous, as described in Belgian Patent No. 575,696
According to this publication, the isomerization of a 3-keto
 EMI8.4
 '' 7-bisdehydro-9B, 10a-sterofde to 3-keto-4'6-bisdehydro-9p, 10a-steroldo is easily made, with relatively high yields of the last compound, in a substantially anhydrous acidic medium, in which an interior aliphatic alcohol serves as a solvent.



   The acid is preferably a halogenated hydracid, advantageously hydrochloric acid.



   According to a particularly inferior embodiment,
 EMI8.5
 According to the invention, a 3-ketal-5,7-bisdehldro-9,10a-steroid is transformed in one stage into a 3-keto-w, 6-bisdehydro-9,10a-

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 steroid. This amazing reaction, in the course of which the ketal group is separated and the 5,7-bisdehydro system is isomerized
 EMI9.1
 simultaneously in a 4,6-bisdehydro system, is carried out by treating the starting compound, in a substantially anhydrous aliphatic alcohol of 1 to 6 carbon atoms, with a halogenated hydracid
 EMI9.2
 At least 30% of the weight of the alcohol, which may also contain other solvents in solution as long as these are substantially anhydrous.

   
 EMI9.3
 The aliphatic alcohol is, for example, methanol, ethanol, propanol, 2-propanol, butanol or pentanol, preferably ethanol. The reaction medium should contain less than about 1% by weight of water. The halogenated hydracid is, for example hydrochloric acid, hydrobromic acid or hydroiodic acid, but preferably hydrochloric acid. The other solvents are, for example, halogenated lower hydrocarbons, such as methylene dichloride, chloroform, 1,2- or 1,1-di-
 EMI9.4
 ethloroethane, ethyl bromide, trichlorethylene, 1,1,1- or 1,1,2-trichlora-ethane, or mixtures thereof.

   A ratio of 1 part of aliphatic alcohol to 1 part of another solvent gives interesting results, but as a ratio of 1 part of lower aliphatic alcohol to 30 parts of other solvents, is still interesting (parts are in weight). In any case, the amount of the other solvents cannot compete for compliance with the rule of the minimum amount of halogenated hydracid relative to the amount of aliphatic alcohol.



   The reaction is preferably carried out at a temperature of -10 C to +60 C, for 15 minutes to 4 hours.



   The reaction is preferably carried out for the trans-
 EMI9.5
 formation of 9,10a-pregna-5,? - dine-3,20-dione 3,20 diketal in 9l10a-pregna-4, b-diene-3,20-dione, 9fl, 10a-ergosta-5,7 , 22-triene-3-ohe-3-ketal in 9fl, 10a-etgosta-4,6,22-ttene-3-one or even 9,10a-androsta-5,? - dine-3,1? - Dione-3,1? -diketal 9,6,10a-androsta-4,6-diene-3, 17-dione. For these preferred reactions, the ketal group is advantageously an ethylene-ketal group.

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   EXAMPLES. -
1. Following the method described by Phillamy and Scholz., J.



   Biol. Chem 178, 37 (1949), 100 g of 3ss-hydroxy-pregna-5-en-20-one are converted into 85 g of progesterone and 50 g of the progesterone obtained are mixed with 700 cm3 of ethylene glycol and 150 mg p-toluenesulofoniqe acid. The mixture is heated gently with stirring in a nitrogen atmosphere. Ethylene glycol is slowly collected by distillation under a pressure of 14 mm of mercury at a temperature of about 106 ° C. After about 30 minutes, the distillation is stopped. The residue is a thick crystalline precipitate of progesterone 3,20-diketal. After cooling to room temperature the crystalline product is. neutralized with 15 cm3 of a 2% solution of KOH in ethanol (96%).

   The mixture is extracted twice with quantities of methylene chloride totaling 400 cm 3 to dissolve the diketal.



   The solution in methylene chloride is then extracted twice with quantities of water representing in total
200 cm3. then dried over sodium sulfate and filtered through bleaching clay. The solvent is removed by vacuum distillation and the residue is dissolved by boiling in 500 cm3 of ethyl acetate. The diketal is crystallized at -25 C. After repeated recrystallization from the mother liquor, a total yield of 90% (59.3 g) of the 3,20-diketal of progesterone (PF 178.5-181) can be obtained. VS).



   With stirring, 40 g of this 3,20-diketal of progesterone are dissolved in a nitrogen atmosphere in 2100 cm3 of petroleum ether (boiling range 60-80 C). The solution is added with 15.4 g of N, N'-dibromo-dimethylhydantoid, then immediately with 20 cm3 of collidine. The mixture is heated to the boil for 3 to 4 minutes.



   The reaction mixture is cooled to room temperature and filtered. The solid mixture consists mainly

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 with N, N'-dimethylhydantoin and with the 7-bromine derivative of the starting compound. The mixture is washed with 1000 cm3 of carbon tetrachloride to dissolve the 7-brominated compound.



   The solutions in petroleum ether and carbon tetrachloride are combined and concentrated by evaporation in vacuo.



   An additional 140 cm 3 of collidine is added to the residue of 7-brominated compound, in a nitrogen atmosphere and with stirring.



   Dehydrobromination is carried out for 15 minutes at 120 C.



   The reaction mixture is then cooled to room temperature.



   300 cm3 of water and 300 cm3 of benzene are then added.



   The benzene layer is separated and the aqueous layer is extracted again with 150 cm3 of benzene. The benzene solutions are washed several times with ice in 2N sulfuric acid to remove the collidine, then washed with water, sodium bicarbonate and water. Next, the benzene solution is dried over sodium sulfate, filtered and concentrated by evaporation, then the residue is washed with 3 portions of 25 cm3 of acetone. The crude product has a content of 92% of pregna-5,7-diene-3,20-dione 3,20-bisethylene-ketal. The crude product is recrystallized from ethyl acetate at -25 C ..



   20 g of 3,20-bisethylene-ketalde pregna-5,7-diene-3,20-dione are dissolved in 2000 cm3 of ethyl acetate and 2 em3 of triethylamine. The solution is irradiated using a 1500 watt high pressure mercury vapor lamp (Philipa H.O.P.



   1500) for 2 hours \ and 10 minutes. The light source is immersed in the solution which is kept in constant circulation during irradiation. Between the light source and the solution is a filter absorbing ultraviolet light with a wavelength of less than 290 m / u. After irradiation, the solvent is concentrated by evaporation to obtain a residue of 200 cm3.



   The solution deposits 11.85 g of crystals of the initial starting compound.

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 changed then another 0.85 g of this compound after a further concentration to 100 cm3. After further concentration to a volume of about 20 cm3, 20 cm3. 96% methanol is added. The mixture is cooled to -5 C, after which the
 EMI12.1
 3,20, -bisethylene.-9fl, 10a-pregna-5,7-diene-3,20-dione crystallizes (m.p. 140-143 C). The crude product is recrystallized from ethyl acetate. The pure product melts at 155-156 C. -. "% D5 = +157.5 in CHCl3 and x max 271.5 m / u 81 9.400.



  I.R. at 1665, 1610, 1250, 1230, 1105, 1070, 1050, 960, 870, 815 cm-1.
 EMI12.2
 5.65 g of the above 9.10a..diketal (88.5%) are dissolved in 75 cm3 of methylene dichloride. The solution is cooled to -10 C and added, with stirring, to 75 cm 3 of a solution of 53 g of gaseous hydrochloric acid in 100 g of anhydrous ethanol (cooled to -10 C). The mixture is maintained for 0.5 hour at -10 ° C. The reaction mixture is then poured into 160 cm3 of water and 180 g of ice. The organic layer is separated and the aqueous layer is extracted with 40 cm3 of methylene dichloride.



  The combined organic layers are washed successively with a) 40 cm3 of water, b) 40 cm3 of a 2% aqueous solution of sodium bicarbonate and c) 3 times with 40 cm3 of water.



   The organic solution is filtered and dried over sodium sulfate, then concentrated by evaporation of the solvent.



  The residue is taken up in a small amount of a mixture of equal parts of methylene dichloride and diethyl ether.



  The solution is concentrated until most of the methylene dichloride is removed. When crystallization begins, the mixture is cooled to -25 ° C to complete crystallization.



  Two fractions are collected, one having a melting point of 162.5 to 166.5 & C and the other of 160 to 166.5 C. The residue is

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   isomerized again in a mixture of 34 cm3 of methylene dichloride and 34 cm3 of a solution of 53 cm3 of hydrochloride
 EMI13.1
 drric in ethanol erJ1 ydre at a temperature of -10 C for 0.5 hour. The somerization product is treated as described above. After concentrating the methylene dichloride, the residue is dissolved in benzene, the solution is decolorized by treatment with active clay, and then concentrated by evaporation.



  The residue from this opéraiion is taken up in a mixture of parts
 EMI13.2
 methylene dichloride and ethyl ether, then concentrated by evaporation until crystallization begins. AT
 EMI13.3
 From this point on, the 1 stal118atlon is carried out at a temperature of -25 C.



  2. Andros'ti ne-41one is prepared in 85% yield from 3fl-hydto; y-andtosta-5-en-l7-one, by applying Oppenauer's method and benzene medium to using cyclohexanone and aluminum isopropoxide as a catalyst.
 EMI13.4
 



  10 g <'andros% a-4-en-3,17-dione are suspended in 200 cm3 of glycol and 20 mg of p-toluene sulfonic acid,
The mixture is subjected to vacuum distillation (temperature of the boiling liquid 10 ° C.). In three hours, 100 cm3 of glycol are distilled off. To the residue is added 10 cm3 of 2N potassium hydroxide in 196% ethanol) and 200 cm3 of benzene. The ethylene glycol layer is separated and extracted once using
50 cm3 of benzene. The benzene layers are combined and washed with water until neutral reaction, then the solvent is removed by evaporation and the residue is recrystallized from acetate.
 EMI13.5
 ethyl at -5 C.

   Rendemer, t 9.16 g (70.2%) in 3,, 17-bis-ethylene-androsta-5-ne-3,17-dlone (PF 172-1730C), The yield is brought to 90 % by cetallating the mother liquor, then crystallizing it.
 EMI13.6
 



  7.48 g of 3,17-bis-ethylene-ce% al are dissolved in 250 because

 <Desc / Clms Page number 14>

 petroleum ether, (boiling range 60-80 C) and 1 cm3 of collidine. The solution is heated to a boil and added
 EMI14.1
 of z g of N, N-dibromo-dimethylhydantane. The mixture is heated to the boil for 5 minutes. The mixture is then cooled to room temperature. The precipitate formed is washed with carbon tetrachloride until the precipitate has dissolved. A residue of 1.4 g of dimethylhydantole remains on the filter. The combined filtrates are added with 30 cm3 of collidine, then the mixture is freed from low-boiling solvents by distillation; , under vacuum.

   The residue is heated at 140 ° C. for 10 minutes in a stream of nitrogen. Diethyl ether is added after cooling to room temperature, then the mixture is washed successively with water, three times with 2N sulfuric acid (to remove collidine) with a solution. aqueous sodium bicarbonate and three times with water until neutral reaction. The solution is then dried over sodium sulphate, then filtered, after which the solvent is evaporated and the residue is recrystallized from acetone at -5 ° C. Melting point 153.5-155 C. Compound content 5,7-bisdehydro: 84.5% (according to the ultraviolet spectrum).



   23.6 g of androsta- 3,17-bis-ethylene-ketal are dissolved.
 EMI14.2
 5,? - dien-3,1? -Dione (corresponding to 20 g of pure compound 5 # 7-bisdehydro) in 2000 cm3 of diethyl ether. The solution is irradiated for 2 hours, as in the example of execution already described.



   The irradiated solution is concentrated under vacuum to a volume of 200 cm3, then cooled to -10 C. The solution crystallizes and gives 8.24 g of unchanged starting material (m.p. 156-157 C, content 77%). The mother liquor is diluted with 100 cm3 of methanol (96%). At room temperature 3.25 g of unchanged starting compound (m.p. 156.5-157.5 C; content 72%) crystallizes.



   A -25 C, 4.16 g of 3,17-bis-ethylene-ketal of 9,10a-androsta-5,7-
 EMI14.3
 Impure diene-, 17-dione crystallize from mother liquor, m.p. 112-125 C The product is recrystallized from acetone. P.F. 161-162 C.

 <Desc / Clms Page number 15>

 
 EMI15.1
 



  Q 25 + 81 C. ± J1 max 271 m / u at 9.650.



  I.R. 1660, 1605, 1115, 1098, 1040, 1019, 997, 953, 819 cm: - '.



   1 g of crystallized diketal (85% pure product content) is dissolved in 50 cm3 of methylene dichloride. The solution is added to 15 cm3 of a solution prepared by dissolving 50 g of gaseous hydrochloric acid in 100 g of anhydrous ethanol. The reaction mixture is maintained for 0.5 hour at 0 ° C. The reaction product is treated as described in the preceding example. The
 EMI15.2
 product obtained is 9p, 10a-androsta-4,6-diene-3,17-dione.



  M.p. 189-190 C. max = 25,400. Maximum infrared spectrum: 1735, 1652, 1625 cm-1,
To a solution of 60 g of anhydrous gaseous hydrochloric acid in 120 cm3 of anhydrous ethanol at 0 C is added a solution of
 EMI15.3
 10 g of 9µ, 10ù-ergosta-5,7,22-triene-3-one-3-ethylene-ketal in 140 cm3 of anhydrous methylene dichloride, at a temperature of 0 C
 EMI15.4
 The mixture is maintained for 0.5 hour <, at 000th then poured in tms 160 cm3 of water and 180 g of ice. The organic layer is separated and the aqueous layer is extracted with 40 cm3 of methylene dichloride.

   The combined organic layers are washed successively with a) 40 cm3 of water b) 40 cm3 of a 2% aqueous solution of sodium bicarbonate and c) 3 times with 40 cm3 of water.



   The organic solution is dried over sodium sulfate, then the solvent is evaporated off. The residue is taken up in 20 cm3 of e-
 EMI15.5
 ther of boiling petroleum (boiling range l0 = 60C). The solution is allowed to crystallize by cooling to -258. Which gives 9>, 10a-orgosta-4p6 # 22-teïèinè-3-Unb% M.P. 100-101 C
The ketals and bis-c6tals described herein are useful intermediates for the synthesis of

 <Desc / Clms Page number 16>

 
 EMI16.1
 composed phaPmaco1oiSquament active.



  Thus, 9,10Q-pre "na-S, 7-d1àne-2,20-dione-3,20-bis-ketal gives, by hydrolysis and isomerization, 94,10a-pregne-4,6- diene 3,20 "dione, which has a proleatational activity on 9, 'Oa-andras- rga? de.'idi, this, 1ie-Qtal gives, on hydrolysis and isom4r1.at1on, 9-Qa-andos, - bcné-,.? - d3one that can be. f9mSfo # neo in 1? fi * hy4PQgy-9µ, lùo * awTùs% a-4,6-diene-3-one-17-acetate having anabolic activity; 9polOu-ergosta-5e7-diene-3-one-3-ethylbne-ketal gives, by hydrolysis and isomerization, 9,10a-ezgasta -., - dlene-3-ane, which, after removal of the side chain) , can be transformed into, 10u-pregna-h6-diene-3,20-dione having progestational activity.



  4. 50 g of pregna-537-diene-3 20-dione-3,20-di-6ylene-ketal are dissolved in 1 liter of acetone. This compound is prepared according to the process described in Example 1. The solution is stirred and added with 500 cm3 of acetic acid and 40 cm3 of water. The mixture, after having been kept at 60 ° C. for 20 minutes, is poured onto crushed ice. The solid precipitate is separated, washed with water and with sodium bicarbonate solution.
 EMI16.2
 



  The rearrangement of ethyl acetate gives 34.4 g (77%) of pregna - $, 7-en-3,20-dione-3-ethylene-ketal.



  (popp 202-207 "C).



  The presns - ,, 7-d1ene-3,20.dione-3-6thylene ketal (34.4 s) is dissolved in 2.3 liters of methyl acetate and irradiated for 2.5 hours as described in Example 1. The solvent is evaporated to a volume of 240 cm3, after which 200 cm3 of methanol is added. After crystallization at -15 ° C., 17.3 g of unchanged starting compound are obtained, then another 0.96 g of this compound after a new concentration of the mother liquors. After evaporation of the solvent, the residue is dissolved in 100 cm3 of methanol.
 EMI16.3
 



  Crystallization at -25 ° C gives 2.6 g of impure 9p, 10a-pregna-5,7-aiéne-e.20-dione-3-ethylene-ketal. Recrystallization from a mixture of methylene dichlopide and ethanol gives a product

 <Desc / Clms Page number 17>

 
 EMI17.1
 which was found to contain 85% 9polOo-pregna-5p7-diene-3,20-dione '.



   3-ketal by calculation based on its absorption spectrum in the ultraviolet.



   1.68 g of this 9,10O-ketal (85%) are dissolved in 25 cm3 of methylene dichloride. The solution is cooled to -50C and added, with stirring, to 25 cm3 of a solution of 53 g of hydrochloric acid in 100 g of anhydrous ethanol (cooled to -5C).



   After 30 minutes the reaction mixture is treated as, described in Example 1, Due to its melting point and mixed melting point, as well as its UV, and IR absorption spectra the product may be identified as 9p, 10a-pregna-4,6-diene-3,20-dione.
 EMI17.2
 



  5. 17a-ethynyl-androsta-5-ene-3,170-diol is subjected to Oppenauer's oxidation in a medium containing toluene, cyclohexanone and aluminum isopropoxide, the latter com - posed as a catalyst, 17a-ethynyl-testosterone is ketall-
 EMI17.3
 found in 17α-ethynyl-endrosta-5-one-17µ-ol-3-one-3-ethylene-ketal.



  125 g of this compound are suspended in 2.5 liters of methanol, then 20 g of a Pd / CaCO catalyst are added, and the hydrogenation is carried out until 125.2 liters of sodium have been absorbed. hydrogen. The reaction mixture is heated until the organic compound has dissolved, the catalyst is filtered off. The solvent is evaporated in vacuo until crystallization, then the mixture is left to stand at -15 ° C. overnight. The yield is 100 g of 17-ethyl-
 EMI17.4
 androsta-5-ene-17p-ol-3-one-3-ethylene-ketal, having a melting point of 186-193 C. Recrystallization from methanol and ethyl acetate gives an analytically pure sample having a melting point of 197-199 C. Maxima IR absorption; 795, 860, 1000, 1010,
1100, 2820 and 3510 cm-1.



   [a] 25 = -52
100 g of this monocetal are dissolved in a mixture of 2 liters of petroleum ether (boiling range 40-600 ° C.), 800 cm3 of methylene dichloride and 20 cm3 of collidine. The solution is

 <Desc / Clms Page number 18>

 
 EMI18.1
 added 41.2 g of N.Nt-dibromodimethylhydantoln & and heated to boiling with stirring for 15 minutes. The reaction mixture is cooled to room temperature and filtered. The solids consist of dimethylhydantolne and the solution is evacuated.
 EMI18.2
 porée under vacuum after addition of 600 em3 of 9-collldine, When the temperature reaches 90 C under vacuum, nitrogen is introduced into the reaction vessel and the temperature is raised to 130 C, value at which the solution is maintained for 15 minutes.

   The reaction mixture is worked up as described in Example 1, then the product is recrystallized from ethyl acetate. 51 g of product are obtained
 EMI18.3
 at 81% of 17u-ôthyl-androsta-5,7-diene-17-01..3-one-3-ethylene-ketal, melting at 161-164 C /.



   20 g of the above ketal are dissolved in 2 liters of ethyl acetate and the solution is irradiated for 85 minutes as described in Example 1. The mixture is concentrated to 100 cm 3 by evaporation of the solvent. After cooling, various fractions of a crystalline compound are obtained which, due to its U.V. absorption spectra, appear to be a mixture of the starting material and the corresponding compound 9ss, 10a. The mixture is acetalized to separate
 EMI18.4
 the compound 9,10a of the corresponding normal steroid.

   17-ethyl-9, - 10a-androsta-5,7-diene-17p-ol-3-one-3-ethylene-keta1-17-acetate presents the following analytical data PF 172-1730, (. M ¯ 271 m / u) = 10,600; maxima of the I.R. spectrum at 3050, 2820, 1730, 1245, 1100, 1040, 1050, 819 cm-1.
 EMI18.5
 r o 125 + .16l !.



   D CE compound is hydrolyzed as described in the previous examples
 EMI18.6
 in 17a-ethyl-9,10a-androsta-4,6-diene-17-0l-1? -acetate ..



  6. Applying to Oppenauer's process, andros-ta-5-en-3,17-diol-17-acetate is oxidized in toluene and cyclohexanone in the presence of aluminum isopropylate as a catalyst to obtain - nir testone acetate with a yield of 82%. 128 g of testosterone acetate are placed under vigorous stirring in suspension in

 <Desc / Clms Page number 19>

 1280 cm3 of ethylene glycol and the mixture is subjected to vacuum distillation for 3 hours, after addition of 3.2 g of p-toluene sulfonic acid in 750 cm3 of ethylene glycol. The reaction mixture is cooled to room temperature and added with 3.5 liters of diethyl ether and 1.5 liters of a 5% aqueous solution of sodium bicarbonate.

   The organic layer is separated and washed with water until neutral reaction. After drying over sodium sulfate, the solvent is evaporated off and the residue is recrystallized from 650 cm3 of acetone. The yield is 74 g of androsta-5-en-17p-
 EMI19.1
 01-3-one-3-ethylne-ketal-1? -Ac6tate, m.p. 201-202 Another fraction is isolated from the mother liquor.



   40 g of the above ketal are dissolved in 3.5 liters of petroleum ether (boiling range 60-80 ° C). and after addition of 16.8 g of N, N'-dibromo-dimethylhydantoin and 40 cm3 of s-collidin, the mixture is stirred and heated to boiling for
20 minutes. The reaction mixture is cooled to room temperature and filtered. The solids are washed with 1.5 liters of hot CC14 and the combined filtrates are subjected to vacuum distillation.



   The residue is added with 400 cm3 of s-collidine and the solution is heated for 20 minutes at 120 ° C. in a nitrogen atmosphere.
The reaction mixture is worked up as in Example 1 and the product is recrystallized from 400 cm3 of acetone. The yield is 25 g of product having a melting point of 183-186 C. Recrystallization from acetone gives a product having a melting point.
 EMI19.2
 fusion of 186-189 C and containing 55% dyandrosta-5i? -diene-17p-ol-3-one-3-ethylene-ketal-17-acetatee the calculation being established according to the U.V. absorption spectrum.
 EMI19.3
 



  50 g of a mixture of 45% of androsta-5-ene-17p-ol-3-one-17-acetate-3-ethylylene ketal and 55% of androsta-5,7-diene-17k are dissolved. -ol-3-one-3-ethylene-ketal-17-acetate in 2 liters of ethyl acetate, then the mixture is irradiated for 112 minutes as described in Example 1. The solution is concentrated. to 175 cm3

 <Desc / Clms Page number 20>

 
 EMI20.1
 and Upgrade A -15c. After cooling, 29 g of the starting compound are obtained, of which 6.5 g are also obtained from the mother liquor.



   The solvent is evaporated off and the residue is dissolved in 20 cm3 of methanol. Recrystallization at -25 ° C gives 4.5 g of 9ss.10O-impure compound, (55%). Different recrystallizations in various
 EMI20.2
 The solvents gave 2.96 g of 9b, loa-androsta-5,7-diene-17% -ol-3-one-3-et: ylene-ketal-1? -acetate, 82%.



   1 g of the latter compound is dissolved in 16 cm3 of methylene dichloride, the solution is cooled to 0 ° C. and with stirring,
 EMI20.3
 it is introduced into 15 cm3 of a solution of 53 g of hydrochloric acid in 100 g of anhydrous ethanol (cooled to 0 ° C.) The mixture is maintained for 30 minutes at 0 ° C. The reaction mixture is then poured into 50 cm3 of water and 50 g of ice. The organic layer is separated and treated as described in Example 1. The crude product is chromatographed on silica and recrystallized from a mixture of n-hexane and acetone. The compound is identified, due to its melting point (133-135 C), its U. V. and I.R. absorption spectra and its mixed melting point with an authentic sample.
 EMI20.4
 as being 9p, 10a-androsta-4,6-diene-17p-ol-3-one-17-acetate.



  7. Applying the Oppenauer process, 16Ó-methyl progesterone, PF 135-136 C, is prepared in an 84% yield from 16µ-methyl-pregnenolone in toluene and cyclohexanone, at using aluminum isopropylate as a catalyst.



   60 g of 16α-methyl-progesterone are suspended in 600 cm3 of ethylene glycol and 240 mg of acid are added to the suspension.
 EMI20.5
 p-toluenesultonique) e Zo'elange is subjected to distillation under
 EMI20.6
 vacuum with stirring. F3 C hours, 350 cmJ of glycol are distilled. The residue is add.tic:. :: é <bzz em3 of 3N potassium hydroxide in methanol and of methylene dichloride. The ethyl-glycol layer is separated once subjected to extraction with 1 $ using 100 ml of methylene dichloride. Solutions in dichloride

 <Desc / Clms Page number 21>

 methylene are combined, washed until neutral reaction and freed from solvent, after which the residue is recrystallized from 750 cm 3 of ethyl acetate.

   The yield is 52.6 g (69.1%) in
 EMI21.1
 16a-methyl-pregna-5-en-3p2O-dione-3p2O-bisethylene-ketalp Pep.



    198-20100, A further fraction can be crystallized from the mother liquor. The product is recrystallized from ethyl acetate (85% yield), m.p. 201-203 C.
 EMI21.2
 



  The latter diketal is converted into 16a-methr1-pregna-5,7-diene-3,20-dione-3-ethylene-ketal by bromination then dehydro-bromination in the same way as in Example 5. The product is recrystallized. in ethanol, mp 176-178 C.



   Maxima of the I.R. spectrum 810, 1100, 1650, 1700, 3040 cm-1
This spectrum indicates that the 20-ketal group is hydrolyzed, which hydrolysis may have taken place during washing of the reaction mixture with 2N sulfuric acid.



   The U. V absorption spectrum makes it possible to establish a
 EMI21.3
 in compound 5,7-bisdehydro of 85%.



   17.4 g of this monocetal are dissolved in 2 liters of methyl acetate and the mixture is irradiated for 60 minutes as described in Example 1. The solution is concentrated to 150 cm3 and cooled to -15 ° C. after addition of 150 cm3 of methanol. The starting compound crystallizes in an amount of 8.5 g and the mother liquor makes it possible to obtain two fractions of 16a-methyl-9p, 10a-pregna-
 EMI21.4
 Crude 5,7-alene-3,20-dione-3-ethylene-ketal. Recrystallization from various solvents gives the pure compound, m.p. 163-175. f (#max = 271 m / u) = 10.400, Maxima in the I.R. at 815, 1100, 1660, 1700, 3050 cm-1.



   13J mg of the latter compound are dissolved in 10 because of
 EMI21.5
 Methylene dichloride, 4 piiès, cooled to -5 ° C, 10 cm3 of a solution of E (-5 c) of 5 × 4 g of hydrochloric acid in 10 cm3 of hydrochloric acid was added. After that, the reaction mixture was kept for 30 minutes at -5 ° C., then poured into cold water. The mixture is subjected to extraction with ether

 <Desc / Clms Page number 22>

 
 EMI22.1
 diethyl and the combined extracts are washed with water, then the solvent is removed in vacuo and the residue is recrystallized from ether. Recrystallization from ether and methanol gives the
 EMI22.2
 lba-methyl-9p-10a-pregna -., b-dine-, 20-dione, having a melting point of 11? -118 C (E> max: a 285 mp) at 26,200.

   The compound appears to be identical to an a.9thent sample.



  Some of these l, b-bisdehydro-9p, 10a-sterodes ,, have
 EMI22.3
 the following pharmacological properties:
 EMI22.4
 9p, 10a-pregna-4,6-diene-3,20-dione is progestin. 9y, loa-androsta-4,6-diene-3,17-dione is progestin, uterotro-
 EMI22.5
 pe and non-androgenic;
 EMI22.6
 1? a-ethyl-9p.0a-androsta -., b-diene-3-one-1? p-ol-1? -acetate
 EMI22.7
 slows down the activity of the pituitary gland;
 EMI22.8
 16a-methyl-9k-loa-pregna-4,6-diene-3,2o-dione is antiphlogisti-
 EMI22.9
 that and uterotropic.


    

Claims (1)

EMI23.1 CLAIMS. EMI23.2 1.- Process for the preparation of a 3-keto-4, b-bisdehydro: 9, 10a.steroide by irradiation in the ultraviolet of a 5,7-bisdehydro- EMI23.3 steroid and Oppenauer oxidation of a 3-hydroxy group, characterized in that Oppenauer oxidation precedes irradiation in the ultra- EMI23.4 violet and the 5.7-bisdehydro-9,10a-steroid obtained is converted after irradiation into 3-keto-4,6-bisdehydro-910a-steroid. 2.- A method according to claim 1, characterized in that EMI23.5 that a 3-hydroxy-5-dehydrosteroid is subjected to Oppenau- er's oxidation to give a 3-keto-4-dehydro-steroid, which is ketalized in EMI23.6 a 3-ketal-5-dehy4ro-steroid which, by the introduction of a EMI23.7 double bond in position 7, then irradiation with ultra- light EMI23.8 violet of the 3-ketal-5.7-bisdehydro-steroid obtained forms a 3-ketal-5.7-bisdehydro-9p, 10a-steroid, which is decetalized and then transformed into a 3-keto-4,6-bisdehydro-9,10a- methyl steroid. EMI23.9 3. - Method according to claim 1, characterized in EMI23.10 that a 3-hydroxy-5.7-bisdehydro-steroid is subjected to Oppenauer's oxidation to give a 3-keto-4 # 7-bisdehydro-steroid which is ketalized to a 3-cébl-5,7- bisdehydro-steroid, which is irradiated with ultraviolet light to form 3-ketal-5i7-bisdehydro-9p, 10a-methyl-steroid, which is then .qecetalized and converted into 3-keto-6 bisdehydro-9,10a-methyl -steroid. EMI23.11 4.- A method according to claim 1 or 2, characterized EMI23.12 in that 31: -hydrox, yr-pregna-5-ne-20-one is subjected to oppenauer oxidation to..preina-4-en-3,2o-dioneAui is Oppenauer's dation en pregna-4-en-3t20-dioneui is cetaflsée .ei p2giar / 5-en-3rZQ-djale-3,20-bis-ketal, which is halogenated in position 7 with the aid of a halogenating agent capable of 'introduce an atom EMI23.13 halogen in the allylic position relative to a double bond, EMI23.14 1 then dehydrohalogenated into pregna-507-diene-3820-tione-3,20-bis-ketal, which is irradiated with ultraviolet light to form 9p, 10Q-pregna-5.7-diene-3 # 20-dione-3 # 20-bis-ketal which isbhydrolyzed and isomerized to 9,10a-pregna-, 6-diene-3,20-dione. <Desc / Clms Page number 24> 5.- Process according to claims 1 and 2, characterized EMI24.1 in that a 3> -bydroxy-androsta-5-en-17-one is suoiso to the oxidation of Oppenauer to androsta-4-bne-3.tl7-dioneg which is that-, read as androsta -5-ene-3017-dione-3., 17-bis-ketal., Which is subjected to halogenation in the allylic position with respect to the double bond to form a 7-halogen derivative, which is dehydrohalo g aene EMI24.2 to adrosta-5,7-diene-3,17-dione-3,17-bis-ketal, which is subjected to. "<, irradiation with ultraviolet light to give 9p-10ù- androsta-5e7-diene-3017-dione-33,17-bis-ketalo which in turn is hydrolyzed and isomerized to 9,10a-androsta-, 6- dlene-3,17-dione. 6. - Process according to claims 1 to 5, characterized in that the ketalization is carried out using a glycol or a dioxolane under weakly acidic conditions. 7. A method according to claim 6, characterized in that the weakly acidic conditions are created by the use ', ¯ of catalytic amounts of strong acids ... 8. A method according to claims 6 and 7, characterized in that the ketalization is carried out using ethylene glycol or EMI24.3 2-methyl-2-ethyl-l, 3-dioxolane or even 2-methyl-h, l, -ethylane- 'dïoxy-pentene-2. laughed, 9. A process according to claims 1 to 5, characterized) in that the Oppenauer oxidation is carried out in a solvent using cyclohexanone and in the presence of aluminum isopropoxide. 10. - Process for the preparation of a 3-keto-4,6-bisdehydro- EMI24.4 9>, 10a-steroid, characterized in that a 3-ctay-5,7-bisdehydro- 9>, 10a-steroid is treated in a substantially anhydrous aliphatic alcohol of 1 to 6 carbon atoms using of a halogenated hydracid taken in an amount of at least 30% by weight, based on the weight of the alcohol, in which other essentially anhydrous solvents may be present. 11. A method according to claim 10, characterized in that the halogenated hydracid is hydrochloric acid. <Desc / Clms Page number 25> 12. A process according to claims 10 and 11, characterized in that the reaction medium contains less than 1% water. 13. A process according to claims 10 to 12, characterized in that a halogenated hydrocarbon of 1 to 3 carbon atoms is present as a further solvent. 14. A process according to claims 10 to 13, characterized in that the aliphatic alcohol: halogenated aliphatic hydrocarbon ratio is between 1: O and 1: 30. 15. A process according to claims 10 to 14, characterized in that the lower aliphatic alcohol is ethanol. 16. - Process according to claims 10 to 15, caraco terized in that the other solvent is methylene dichloride. 17. - Process according to claims 10 to 16, characterized in that the reaction is carried out at a temperature of -10 to 60 C for 15 minutes to 4 hours. 18.- A method according to claims 10 to 17, charac- EMI25.1 ized in that the 9p, 10a-preôna-5,7-diene-3,20-dione-3,20-diketal is converted into 9 #, loa-pregna-4,6-diene-3,20-dione. 19. A process according to claims 10 to 17, characterized in that the 9 #, 10e-ergosta-5,7,22-triene-3-one-3-oetal is converted into 9µ, 10a-ergosba- 4,6,22-briene-3-one. 20.- Process according to claims 10 to 17, characterized in that the 9p, 10a-androsta-5,7-diene-3,17-dione-7-diketal is converted into 9,10a-androsta-4, 6-dine-3,17-dione. 21. - Process for preparing a steroid, in substance as described above with reference to the examples. EMI25.2 22.- 9pylOu-pregna-587-diene-3,20-dione-3e2O-bis-edtale 23.- 9p, 10a-ergosta-5,7,22-triene-3-one-3-ketal. 24.- 9,10a-androsta-5,7-triene-3,17-dione-3,1T -bia-ketal. 25.- 99,10α-Pregna-5,7-diene-3,20-aione-3,20-bis-ethylene-ketal. EMI25.3 26.- The 9µ, 10a-ergosba-5,7 <Desc / Clms Page number 26> EMI26.1 27.- 9,10a-androsta-5,? - diene-3,1? -Dlone-3,1? -Bis-ethylene-ketal. 28.- 1? A-ethyl-9, .Oa-androsta-5,? - diene-1? -01-3-one-3-ethylene-ketal-17-acetate. EMI26.2 EMI26.3 29.- 9p, 10a-androsta-5,? - diene-17-07.-3-one-3-thylene-ketal-1? .. ac6tato. 30.- Lerl6a-methyl-9pylOa-5.7-diene-3e2O-dione-3-ethylene- EMI26.4 ketal, EMI26.5 31. Iba-methyl-pregna-5? -Aieae-320-dione-ethylene .. ketal. EMI26.6 32. - Steroid obtained by a process according to one or the other of the preceding claims. '