BE507987A - - Google Patents

Description

       

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  PROCESS FOR THE PREPARATION OF COMPOUNDS OF THE STEROID SERIES, HAVING A
OXYGENATED FUNCTION IN POSITION 11.



   Great importance is attributed to steroids having an oxygen function at position 11. An important representative of this class of compounds is, for example, cortisone, # 4-3,11,20-triketo-17 [alpha], 21 -dioxy-pregnene.



  The processes known hitherto for obtaining steroids of this type synthetically start from deoxycholic acid, or its derivatives, that is to say from compounds having a hydroxyl group in position 12. However, it has been found that the transfer of oxygen from position 12 to position 11 is very complicated and requires several operations. Moreover, the deoxycholic acid serving as a starting material can only be obtained in a relatively small quantity, so that, for example, it is practically impossible to manufacture by this route, in sufficient quantity, the cortisone required in therapy. It is therefore necessary to create new sources of preparation of this drug.

   The easy-to-obtain stereins such as ergosterine, stigmasterin or sitosterin, in particular cholesterin, have already been important starting substances for the production of sex hormones for many years. However, until now, they were of no importance for obtaining compounds containing an oxygen function in position II., - of the intact framework of steroids @
The present invention relates to a process for the preparation of compounds of the series of steroids having an oxygen function in position 11, starting for example from the sterins mentioned above or their transformation products.

   This process consists of treating with agents allowing the introduction of oxygen, unsaturated 7-keto-steroids at 8,9, their enolic derivatives or the corresponding diene compounds, unsubstituted in position 7, to be made. .act hydrolyzing or isomerizing agents on the epoxides formed, in reacting the 7,11-dihydroxyl compounds formed with dehydrogenation agents;

   in treating with reducing agents the compounds having a double bond or an epoxy group in the ring rB, in particular in position 8,9, if necessary after introduction of oxygen in p o

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 position 7, for example of a keto group, and finally, in compounds having a substituent in position 7, to replace it with hydrogen.



   One embodiment of the process of the present invention is illustrated for example by the following diagram of partial formulas:
 EMI2.1
 
The steroids used according to the invention as starting substances belong to the series of cyclopentanopolyhydrophenanthrene or polyhydrochrysene. Of particular importance are the derivatives of cholestane, coprostane, sitostane, stigmastane, cholane, allocholan, pregnan, androstane and etiocholane. These derivatives are, according to the present process, 8 8,9-7-keto-sterols, their enol derivatives or the corresponding diene compounds, unsubstituted at the 7-position.



  As regards the enolic derivatives, these are # 6,7; 8,9-steroids and A 7,8; 9,11-steroids having, in position 7 :, a functionally modified hydroxyl group, for example a hydroxyl group etherified with an organic or inorganic acid, such as an acetoxy group or a halogen atom, or a hydroxyl'alkoxyl group, for example an alkoxy or aralkoxy group, such as a methoxy group or benzyloxyo The diene compounds unsubstituted in position 7 'correspond, as regards the position of the two diene double bonds, with the 7-enole derivatives mentioned, that is to say that they are compounds # 6, 7; 8,9-diene or # 7; 8;

  9,11-diene. In addition, the starting substances may be substituted in the ring or in the side chain, for example at the 3-, 5-, 6-, 17-, 20- and / or 21- position, by hydroxyl groups. or free or functionally modified oxo, for example by -acyloxy groups, such as acetoxy, propionyloxy, benzoyloxy or tosyloxy groups; with alkoxy groups, for example methoxy or ethoxy; with oxo groups in the form of acetals; by a carboxylic group

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 free or functionally modified, for example a nitrile group or an esterified carboxylic group;

   with a substituted or unsubstituted acyl group, for example acetyl or oxyacetyl, or with a lactone, for example with the butenolide group. The starting substances mentioned have any configuration and may contain other double bonds, for example in position 5,6 or 22,230. If they are double bonds capable of reacting, they are then advantageously protected. oxidation according to the present process, for example by addition of halogens or of a hydracid halo-
 EMI3.1
 uncomfortable. To protect the 5,6 double bond, 4,596steroids can be converted to 3) 5-cyclosteroidSo Some of the starting materials of the present invention are new.

   The still unknown β-ketosteroids are readily obtained from the corresponding 7-oeto-o compounds, for example by bromination and subsequent cleavage of hydrobromic acid. Enolization gives the enolic compounds Q Sg91 or /).0,7,8,9, for example the enol esters or ethers. The same compounds are also obtained by the action of dehydrogenating agents, for example mercury acetate.
 EMI3.2
 re (II) on the enolic derivatives of 7-oeto-steroTdeSo The compounds which are unsubstituted in position 7 corresponding to these enolic derivatives are obtained by causing dehydrogenating agents to act on steroids having in ring B a double bond leaving from the carbon atom 7 or 8.



   In order to introduce oxygen into the starting substances mentioned, according to the present process, which introduction can also be carried out in stages, it is possible to use chemical, biochemical or electrochemical methods. , carry out the oxidation using hexavalent chromium compounds, such as chromic acid or tertiary butyl chromate, with permanganate, dioxide.

   selenium,
 EMI3.3
 peroxides, such as perbensoic acid, phthalic monoperacid, hydrogen peroxide, where appropriate in the presence of osmium tetroxide, or with oxygen in the presence of catalysts causing oxidation, in particular in the presence enzymes. In this case, the operation is carried out in the presence of diluting agents, for example anhydrous or water-containing solvents, such as low molecular weight aliphatic acids, such as glacial acetic acid, alcohols. , for example tertiary butyl alcohol, ketones or halogenated hydrocarbons.

   Depending on the nature of the starting substance and the kind
 EMI3.4
 of the oxidizing agent, 9,11-eproxysteroids, A 9? ll = 7-keto-sterols, 7,11-diketosteroids or directly 11-ketosteroidsa are obtained, for example, starting from, 4798; 9911-dienes, with chromic acid, potassium permanganate, hydrogen peroxide and peracids, under vigorous conditions and even, surprisingly,
 EMI3.5
 with ozone, the A gs9 or 8,9-epoxy-7,11-diketones, On the other hand it is possible, by a gentle oxidation, for example by a moderate treatment with peracids, to achieve the o compounds A7,8. =. 9n = epoxy starting from 7,8; 9,] 1 -dienes.

   In addition, the L 1,8; R, llmdines can be transformed, under mild conditions, by chromic acid into 9,11-7-ketones and by oxygenated water into 9,11-epoxy-7 -ketones. The A 9,11¯7-ketones can then be further oxidized to give 9,11epoxy7 ketoneso The 4µ7,8-9,11-epoxides formed by the oxidation in accordance with the process can be split hydrolytically, with simultaneous isomerization. this effect, in particular, mild hydrolysis agents, such as dilute inorganic acids, for example dilute sulfuric acid, in the presence of solvents, such as alcohols or ketones, for example a-
 EMI3.6
 ketone or on the other hand dioxane.

   Further suitable are hydrolysis or isomerization agents for the treatment of 9,11-epoxy-steroids, more or less concentrated organic or inorganic acids; or their anhydrides, for example formic acid, trichloroacetic acid, oxides or halides of phosphorus, such as phosphoric anhydride or phosphorus tribromide, boron trifluoride, inorganic salts, for example chloro - zinc ride, ferric chloride, alkaline reaction agents, such as
 EMI3.7
 alkali metal or aloalino-earth compounds or aluminum oxide One obtains, for example, by treatment of 7,8¯9, II-epoxy compounds with sul- acid.

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 furic diluted, under mild conditions, for example at room temperature
 EMI4.1
 ambient, A8,9-7,11-dihydroxy compounds,

   while at higher temperature, α8,9-7-ketones are obtained By the action of boron trifluoride on # 7,8¯9,11-epoxides, # 8,9-11 are formed. - ketones. These latter compounds can be transformed by the di-
 EMI4.2
 direct or indirect, in A 8,9- or in 8,9-epoxy-7,11-diketones The compounds j, - ?, 11-dïhydroxylés are, according to the present invention, dehydrogenated. For this, the dehydrogenating agents indicated above, in particular chromic acid, are used.

   Under energetic conditions
 EMI4.3
 and with an excess of oxidizing agent, then A, 8; 9- or 8,9-epoxy-7, li-diketones are obtained. If the oxidation is carried out under mild conditions, one obtains 8,9-epoxy-7,11-dihydroxy- or, d $ 9-11-hydroxy-7-ketone compounds, which can then be further oxidized to 8,9-epoxy or, A 9- ?, 11-diketones. For this dehydrogenation, it is also possible to use other chemical, or also biochemical or electrochemical, oxidizing agents. It is possible, for example, to oxidize with tertiary butyl chromate or permanganates, or to carry out the dehydrogenation by means of alcoholates or phenolates of metals and carboxylic compounds (exchange of the oxidation phases), or with a metal powder, hot and with the action of vacuum.



   The reduction of epoxy or oxo groups, or of a double bond in ring B, can be carried out chemically, biochemically, or electrochemically, for example with hydrogen in the presence of solvents or chemicals. diluting agents and metal catalysts, such as platinum, palladium, nickel or copper. Nascent hydrogen can also be used, as obtained, for example, by the reaction of alkali metals or their amalgams with alcohols, water or wet solvents, or by the reaction of metals. or their salts, for example zinc, of stannous chloride or of iron, with organic or inorganic acids.

   Double reduction
 EMI4.4
 Binding in 8,9-ii-ketones is effected with particular advantage using organic metal compounds or complex compounds of light metal hydrides, such as lithium boron hydride, hydride of bo- and sodium, for example. When treating with reducing agents, an epoxy group can be removed in stages.

   This is how an 8,9-epoxy-11-hydroxy-7-ketone is converted using zinc and aceti-
 EMI4.5
 that glacial enl \ 8,9-ll-hydroxy-7-ketone and that the latter compound is transformed with the aid of amalgam of zinc and hydrochloric acid into the saturated compound 11-hydroxy-, with simultaneous elimination of the 8.9 double bond and the 7-ketone group,.!. For the usual transformation of the 7-ketone group into a group
 EMI4.6
 eg methyleniqusoh'prepared the corresponding 7-mercaptols and they are reduced with Raney nickel or the procedure is carried out according to the method of Wolffkishner or Clemmensen.
 EMI4.7
 



  The present invention also encompasses all process modifications whereby one starts with a compound obtainable as an intermediate at one stage of the process and all or some of the remaining stages of the process are carried out.



   The products according to this process can find therapeutic use or serve as intermediates for the manufacture of valuable therapeutic compounds.



   The present invention also relates, by way of new industrial products, to the products conforming to those obtained by the process defined above; however, these products are not protected by the present patent in themselves, as they are used in human therapy.



   The following examples illustrate the invention without however limiting it. The ratio of parts by weight to parts by volume is the same as that between gram and cubic centimeter. Temperatures are given in degrees centigrade.



   Example 1
 EMI4.8
 1 part by weight of `` '' - 3-acetoxy-ergostatriene is dissolved in 45 parts by volume of glacial acetic acid, heated to 40 and

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 0.5 part by weight of chromium trioxide is added dropwise over 15 minutes in 5 parts by volume of a 90% aqueous solution of acetic acid.



  The solution is stirred for several hours at the same temperature, then the unused oxidizing agent is destroyed by adding methanol, and the reaction solution is poured into 200 parts by volume of water. The oxidation product is taken up in ether and the ethereal solution is washed several times with dilute ice-cold sodium hydroxide solution, and finally washed with water. It is recommended that the crude product obtained be purified by chromatography. By recrystallization from diluted alcohol,
 EMI5.1
 the $ 9 sz33p-acetoxy7,11diketoergostadiene with a melting point of 132 - 1350 is obtained which, unlike the starting material, gives only, with the tetranitromethane, only a colored reaction of a pure lemon yellow .

   The ultra-violet absorption spectrum of an alcoholic solution of this pro-
 EMI5.2
 duit presents at 272 mp (lodged. = 3.94), a strong maximum. In the infrared absorption spectrum appear, next to the carbonyl band of the 3-acetoxy group at 1730 cm-1, two characteristic bands, very intense, at 1660 and 1670 cm-la
 EMI5.3
 If we run the oxidation. de laj '$ s g9113s23 3laetox3r st gostatriene aVli2c;

   a "greater amount of chromium trioxide, it forms 4 z3m3actocym $, g epoxy '7.11diketomergostene which, after recrystallization in a: j.mixture of methanol and water, melts at; 130 -". 131 and has a specific optical rotation 0 = -730 (in chloroform) ,, This product shows, in 1Q. ± S & qotre absorption daps: 3.inframruge, at; 96 $ cmml, the frequency of the double-bond, at 1710 cm-1 a strong band due to carbonyl and at 1730 cm-1 the band from the acetate group. In the ultraviolet absorption spectrum, this oxidation product shows only a band at 290 m # (logfi = 2.0).
 EMI5.4
 



  0.22 2- =! The oxidation of 4 '$ s'11p2.3 3 acetoxymergostatriene to 3 acetoxy 7.11 diketomergostadiene can also be carried out by the action of potassium permanganate in acetone, hydrogen peroxide in glacial acetic acid or d 'ozone,
To reduce the double bond at position 8.9, 1 per-
 EMI5.5
 tie by weight of to 8 $ 9; 22y23-3-acetoxy-7,11-diketoergostadiene in 40 parts by volume of glacial acetic acid and is added in small portions, at the boiling temperature, 5 parts by weight of powdered zinc. The solution was heated for some time, filtered to remove unused powdered zinc, diluted with 200 parts by volume of water and the reaction product extracted with ether.

   By washing the ethereal solution: with a dilute, cold solution of sodium hydroxide, the aceti-
 EMI5.6
 than. By usual treatment, Azz9233acetoxy ï, llmdiketomergo stene with a melting point of 195.5 - 19C is obtained; (q D = -29 (c = 0.88 in chloroform, which shows, in the absorption spectrum in ultra-violet, only a weak maximum at 280 - 290 m # (lodged = 1 , 8). In the infrared absorption spectrum, next to the band of the acetoxy group appears,
 EMI5.7
 at 1730 cm-1; a new very strong band at 1700 cm 1, which is caused by the two ketone groups separated at positions. 7 and 11.



  The at z2'23 -? aeetoxr ï, 11 diketoergostene can also be obtained by treatment of at 22.23 = 3 = acetoxy = 8.9-epoXY-7.11 = diketo = ergostene, dissolved in glacial acetic acid, with zinc powdery.



   As with zinc and glacial acetic acid, the selective saturation of the 8.9-double bond can also be caused by catalytic hydrogenation.



   For the selective removal of the carbonyl group in position 7,
 EMI5.8
 1 part by weight of d 93 3 acetoxy 7.11 diketo ergostene is dissolved in 1.5 parts by volume of absolute chloroform and 1 part by volume of ethylene dithioglycol and the solution is treated for a period while cooling. health, with a strong stream of dry hydrochloric gas. The hydrochloric acid and chloroform are then removed by careful evaporation in vacuo.



  The residual viscous mass is taken up in ether and the solution washed with a cold dilute solution of sodium hydroxide. The 7-mono-mer-

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 Crude captol is then dissolved in absolute ether or dioxane and heated for some time with a freshly prepared nickel catalyst obtained from 10 parts by weight of Raney nickel. After having re-arranged
 EMI6.1
 tyled the product formed, one obtains, by this route, 2z93m3cëtox3r Zl-keto-ergostene, with a melting point of 125-126;

   (and ...) 1) = +13 (c = 1.50 in chloroform), which in the absorption spectrum. in the infra-red, next to the typical band of the acetoxy group, at 1730 cm -1, shows another absorption at 1704 cm-1, This compound reacts neither with hydroxylamine nor with se-
 EMI6.2
 micarbazide, while allowing itself to be converted into the known 3P-acetoxy-ergostane, by a vigorous Glemmensen reaction with amalgamated zinc and hydrochloric acid and subsequent catalytic reduction.
 EMI6.3
 



  For the transformation of A22,23-3-acetoxy-7,11-diketo-ergostene into A 2z233acetoxy 11-keto-ergostene, the first compound can also be transformed with the aid of hydroxylamine or hydrazine or its derivatives. , in corresponding 7-mono-condensation products, isolate these or else treat them directly in the raw state, with strong bases, under heat, and then proceed to a subsequent acetylation.
 EMI6.4
 



  For example, if one treats at room temperature for 24 hours, 1 part by weight of 22sz3m3acetoxy7,11 diketom ergostene with 100 parts by volume of a solution of acetate. of semiqarbazide, prepared from 100 parts by weight of semicarbazide hydrochloride and 200 parts by weight of potassium acetate in 700 parts by volume of methanol. The separate needles (0.9 part by weight) are filtered; they are pure enough for further processing. This product is the 7-
 EMI6.5
 3-3P-aoetoxy-7,11-diketo-ergostene mono-semicarbazone, which melts at 21.1E-248 with decomposition.

   For the selective reduction, the 7-mono-semicarba-zone, dried at 100 under a high vacuum, is heated for 6 hours at 200 in a closed tube with 100 parts by volume of a sodium ethoxide solution, prepared from 5 parts by weight of sodium in 100 parts by volume of absolute ethanol. The reaction product is taken up in ether and the ethereal solution is treated in a known manner. The crude product obtained gives, after acetylation with acetic anhydride and pyridine, 0.7
 EMI6.6
 part by weight of 22.23m3 acetaxy-llceto-ergost'ene with a melting point of 124-126.



    Example 2.
 EMI6.7
 



  1 part by weight of L19g; 9'11322.23m3 acetoxymergosm tatriene is dissolved in 10 parts by volume of ether, 8 parts by volume of an ethereal solution of phthalic monoperacid containing 1.1 equivalents of active oxygen are added. The reaction solution is left on its own for a long time at 0 and then at room temperature, then washed with aqueous sodium bicarbonate solution and water, dried and concentrated. By recrystallization from mixtures of ether and methanol or ether and al-
 EMI6.8
 ketone, the, r?, gs2Z, 23m3 acetylxym9,11 = epoxy ergostadine is separated from the unmodified starting material. The epoxy compound melts at 20 l; td.p = -39.5 (c = 0.783 in chloroform).

   The tetranitromethane test made with this product gives a pure yellow color against the starting material.
 EMI6.9
 The oxidation of Q '° 9'1122.23m3, acetoxy = ergostatriene can be carried out with other peracids or hydrogen peroxide in a similar manner.



   For isomerization, 1 part by weight of # 7,8; 22,23 is dissolved
 EMI6.10
 -3-acetoxy-9,11-epoxy-ergostadiene in 200 parts by volume of benzene and leave the solution to itself for a long time at 35 with boron trifluoride etherate. The reaction mixture is diluted with ether, the ether solution is washed with water, sodium bicarbonate solution and water, dried and concentrated. It is advantageous to purify the crude product obtained by chromatography. By this way we get the
 EMI6.11
 ,, 99z2.23m3 acetoxy llmcétoergostadiéne melting at 122 - 723 and.

   D = +90 (c = 0.951 in chloroform), whose absorption spectrum in the ultra-violet shows a maximum at 250 nq (109 E = 4.0) and whose absorption spectrum infrared, next to the acetate band at 1730 cm-1, exhibits a strong characteristic absorption for 1660 cm-1.

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   This product does not react under the usual conditions with ketone reagents, by vigorous oxidation under the conditions described in
 EMI7.1
 Example 1, it can be converted into L1 '% 82z, 23 3 acetox 7,1, = dikétoaer gostadiene described in said example, melting at 132 - 13 5 The isomerization of B 7' 22'23 3 acetoxy g, ll epoxyergostad.ne can also be carried out using mineral acids and other isomerizing reagents, such as aluminum oxide, silicic acid or also thermally.
To remove the 8.9 double bond, 1 per-
 EMI7.2
 tie by weight of Lb g922,23m3acetoay llmcetoergostadine in 100 parts by volume of a neutral solvent, such as alcohol, dioxane or acetic ester, and hydrogenated under low pressure with a platinum catalyst,

   until
 EMI7.3
 absorption of 1 mol of hydrogen. he 22, Z3 3 acetoxy 11 ketomergostne thus obtained is identical to the product described in example Ie '9s22'23 3 acetoxy 11 ketoergostadiene can also be selectively reduced with nascent hydrogen in A 22,23-3µ-acetoxy -11- ketomergostenea Example 3.



  1 part by weight of n 7'gs22'23 3 acetoay 9.11 epoxy = ergostadiene described in Example 2 is dissolved in 200 parts by volume of acetone, 20 parts by volume of water and 1 part by volume of water are added. 2n sulfuric acid and freeze the mixture to itself for some time at low temperature. Most of the 1-acetone is then evaporated off in vacuo, the residue taken up in chloroform containing alcohol and the reaction product isolated in the usual manner.

   This product is treated with trichloroacetic acid, then dissolved in 50 parts by volume of benzene and vigorously stirred for some time at room temperature with 1 part by weight of chromic acid dissolved in 50 parts. by volume of an aqueous solution
 EMI7.4
 50% acetic acid. , e g, 9,22923 3, 'i, ll the obtained tricêto ergostadiene is selectively reduced, for example by treatment with 100 parts by weight of 1% sodium amalgam in 50% acetic acid and by acetylation
 EMI7.5
 subsequent, in 899,22,23 = 3-acetoxy-7,11-diketo = ergostadiene identical to that described in Example 1, flux. 132 - 13500 ...,. <.-. \;

   Example, 4.nhr 1 part by weight of 9s2223 3acétoxym9, llmépoxy ergosta.diéne9 described in Example 2 is dissolved in 50 parts by volume of absolute ether and added, while stirring vigorously, a solution of 1 part by weight of lithium aluminum hydride in 35 parts by volume of ether.

   The reaction mixture is heated for a while at the boiling point, then cooled and cautiously added with dilute acetic acid.
 EMI7.6
 the reaction product in the usual manner, the 3fi, ii-dioxy-ergostadiene obtained, twice unsaturated, is dissolved in 100 parts by volume of benzene and the whole is shaken vigorously, for a certain time, at temperature room, with 0.5 part by weight of chromic acid, dissolved in 50 parts by volume of a 50% aqueous solution of acetic acid.,
 EMI7.7
 he '922,2 3,11 diketo ergostadiene obtained after usual treatment is dissolved in 100 parts by volume of ethanol and hydrogenated at room temperature using a platinum catalyst,

   until absorption of the quantity of hydrogen calculated for 2 equivalents. Then, the reduction product is acetylated in the usual manner with acetic anhydride to
 EMI7.8
 the presence of pyridine. The reaction product is identical to the 4 23-3 p-acetoxy-11-keto-ergostene described in Examples 1 and 2.



   The successive reactions described in Examples 1 - 4 apply
 EMI7.9
 also to 7e89911-3ê-acetoxy-cholestadîene, which 1? '' sll androstdiene and 9g9létiocholadiene known, as well as to derivatives of these substituted in position 3 and 17 by oxygen functions It is particularly advantageous to use as starting material, for the successive reactions de-
 EMI7.10
 written above, 911g22,23m3 acetoxym5 hydroxy6 = kétomergostatrzén

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 easy to obtain by dehydrogenation, with mercury (II) acetate,
 EMI8.1
 , a 758; 24,23-3ê-acetoxy-5-hydroxy-6-keto-ergostadiene known.

   We then get the l! 59v9.23m3hydroxy ll.ceto-ergostadiene The latter compound is a particularly suitable starting material for the manufacture of 11-hydroxy- or 11-aeto-cortico-steroTdesa. As further starting materials, there may be mentioned 1 methyl ester Acid A?, gs99113oc-acetoxymcholadiene and acid methyl ester A?, gi, 3 a.macetoxyetiocholadiene, as well as pregnane derivatives having the same structure, easy to obtain from the compounds at 9.1l -3%% -diacetoxy-12-ketones corresponding.



  Example 5.



  1 part by weight of 3p-acetoxy- = 7-keto-cholestane enol acetate (obtained by treating 3f'-aoetoxy-7-keto-cholestane with acetic anhydride, with the addition of p- acid toluenesulfonic acid, at the boiling temperature, or by treatment at the boiling point in a mixture of equal parts by volume of acetyl chloride and acetic anhydride) is dissolved in 20 parts by volume of carbon tetrachloride absolute and mixed with an equi-
 EMI8.2
 are worth bromo-succinimide. The mixture is heated for some time under reflux.



  The succinimide is removed and the solvent is carefully evaporated in vacuo. The reaction product is recrystallized at very low temperature in pentane.



   The crude product obtained is dissolved in 45 parts by volume of glacial acetic acid and the solution is mixed with 0.5 part by weight of chromium trioxide in 5 parts by volume of a 90% aqueous solution of acid. acetic. When the reaction is complete and after isolating
 EMI8.3
 the reaction product in the usual way, is obtained α8,9-3 # -acetoxy-7,11-diketo-cholestene which is identical with the product produced according to Example 1 from at 7.8; 9511-3p- acetoxy-cholestadiene.



  Example 60 6.3 parts by weight of A 2 'gz2'23-3 acetoxr9,11m epoxy-ergostadiene, described in Example 2, are dissolved in 1000 parts by volume of dioxane, mixed with 100 parts by volume of water and 7.2 parts by volume of 2n sulfuric acid and stand at room temperature for 3 days. The reaction mixture is then diluted with water, the flakes which separate are filtered off with suction and taken up in ether. The ether solution is washed with sodium bicarbonate solution and water, dried and concentrated in vacuo. To purify it, the crystalline residue is chromatographed with aluminum oxide and then
 EMI8.4
 recrystallized from methanol. The A g, 9922.23m3-acetoxy-mcetomergostadiene thus obtained melts at 210-212; (tk) 20 =? 6 (c = 0.685 in chloroform).



   The isomerization can also be carried out as follows:
 EMI8.5
 1.02 part in: weight of A 7 8; 22, 23 = 3 ... a.cetoXY-9, ll-epoxy = ergostadiene in 45 parts by volume of glacial acetic acid, mixed with 4 parts in volume of water and 1 part by volume of concentrated sulfuric acid and = heating about 5 minutes will be 100. The strongly fluorescent solution is treated-
 EMI8.6
 as described above. We obtain in this way Ze 0 ', 922,' 3 = 3acétoxym 7-keto-ergostadiene with a melting point of 210 - 212 0 Le A8,9,22,23-3f'-acetoXY = 7 = keto = ergostadiene is oxidized to A8.9; 22.23 = 3 = acetoXY = 7.11-diketo = ergostadiene with a melting point of 132 - 135 and the latter compound is transformed into A 22.23 3 s ketoxy 1.- -ketoergostene with a melting point of 125-126 in a manner analogous to that described in Example 1.



   Example 7
 EMI8.7
 2 parts by weight of? 9322923m3J aceto are dissolved. m 9 11. Epoxy-ergostadiene, described in Example 2, in 50 parts by volume of benzene and mixed with 0.5 part of bromine trifluoride etherate. The solution is left for about 72 hours at room temperature,

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 then diluted with ether, the ethereal solution washed with water, sodium bicarbonate solution and again with water, dried and evaporated.
 EMI9.1
 pore the ether. By crystallization in methanol one obtains leA922,23 3 = acetoxy = 11 = keto = ergostadièe with a melting point of 122 - Z.29 ja.D. 2 (or 0.873 in chloroform).

   In addition, we get a small one. number of. at?, $ 9,1122,2, (acetoy ergostadine with a melting point of 169 - 170 0 Starting from A 9 9, acetoxy = llmceto ergostadiene, one obtains by a vigorous oxidation, in a manner analogous to the indications of Example 1, at A 8 to 9; 22, 23 = .3 = acetoXY = 7, ll = diketo = ergostadiene with a melting point of 132 - 135.



   Example 8.
 EMI9.2
 



  0.2 part by weight of the? '$' 2z'2 acetoxy, ll epoxy ergostadiene, described in Example 2, is dissolved in 150 parts by volume of dioxane, 27 parts by volume of 2n sulfuric acid are added and vigorous stirring is carried out. , for about 3 minutes at room temperature. The reaction solution is immediately treated with ether and sodium bicarbonate solution.



  The ether solution is quickly washed with water, dried and concentrated. The crystallized crude product gives, after recrystallization from alcohol.
 EMI9.3
 ketone, 0.14 parts by weight of / 9 $ 99.22 2 3 'acetor ?, 11 dioxy ergostadine mp 269-2700. jot.) 2 - - 82 (c = 0.331 in chloroform) 0.2 part by weight of $ 9g922.2 acetoey ?, 11 finely pulverized dxoxy ex gosta diene is mixed, while cooling with ice, with 48 parts by volume of a solution of chromic acid and glacial acetic diacid, containing 0.00113 part by weight of active oxygen per part by volume and 0.5 part by volume of sulfuric acid 2 No The mixture is stirred in a manner intense lesson for about 3 minutes, after which the substance is dissolved;

  The solution is left to stand for about 14 hours at room temperature, then water and methanol are added thereto. After about two hours the oxidation product is taken up in ether and the ethereal solution washed with dilute ice-cold sodium hydroxide solution, and then with water. In this way 0.19 part by weight of a neutral oxidation product is obtained. By fractional crystallization in methanol, one obtains
 EMI9.4
 1e12p2 =, acetoy $, 9 épxy = 'Z, 11 diketo ergostene with a melting point of 130 - 1.1 s CD ¯ -73 (c = 0.501 in chloroform), as well as a small amount of 8.92, 23-3 & -acetoxy-7, 11-diketo = ergostadiene with a focal point of 132 - 13.



  3 parts by weight of ,, A22,23-3p-acetoxy-8,9-epoxy-7,11-diketo-er- ,, gostene are dissolved in 250 parts by volume of glacial acetic acid in the cold solution. introduced 2.5 parts by weight of inco powder
 EMI9.5
 Then the mixture is heated in about 30 minutes to the boiling temperature and after the start of the boiling, is added, over the course of about 25 minutes, in five times, each time 1.15 parts. weight of zinc powder. The cooled solution is filtered off any unused zinc and diluted with ether. The ethereal solution is washed with water until neutral reaction, dried and evaporated.

   After recrystallization from acetone, # 22,23- is obtained in practically quantitative yield.
 EMI9.6
  acetoxy? 911 diketo = exgostne mp 195.5 - 1960, -fv.) 20 = -70 (c = 0.85 in chloroform).



  In an analogous manner, the / $ s22,? 'D, acetoy = ?, 11 diketo ex gostadiene or a mixture of A 8, can be reduced to A 22923-3-acetoxy-7,11-keto-argostene, 92.233acetoXY = 7.11 = dieeto = ergostadiene and 92. (acé toxy $, j epoxy Z.4dicé, .ergosténeo To eliminate the ketone group in position '7, we mix 1.5 parts by weight -, this d' , 2s2.r3acetoxr 91 diketo gmstene with 100 parts by volume of triethyleneglybolo To the suspension formed, enough methanol is added, while heating in a water bath, so that everything is dissolved. Then, it is added to the above solution. 2 parts by weight of hydrazine hydrate and heated for about 15 minutes in a water bath.

   We then add again

 <Desc / Clms Page number 10>

 Once in the solution 1.6 parts by weight of hydrazine hydrate, as well as 10 parts by weight of sodium hydroxide and 20 parts by volume of water and the whole is heated in about one hour at 180, the easily volatile components then being removed by distillation. Then the mixture is heated for another 2 hours at 180. After having separated the reaction product in the usual manner, it is heated for 1/2 hour in a water bath with 50 parts by volume of acetic anhydride and 50 parts by volume of pyridine, then concentrated in vacuo and the residue chromatographed at aluminum oxide.

   The fractions eluted with petroleum ether-benzene (9; 1) and (8: 2) give, after recrystallization.
 EMI10.1
 satation in a mixture of methanol and water, A 2z923m3macetoxy11cetoergostene with a melting point of 125-126; 1 ') D = +12.5 (c = 1.576 in chloroform).



   The 7-ketone group can also be removed by operating as follows:
 EMI10.2
 1.3 part by weight of Q2223m3 acetoxym7, lZ-diketoergostene is dissolved in 24 parts by volume of ethylene dithiol and passed through
 EMI10.3
 the solution 0'9 psd approximately one hour, a strong current of hydrochloric gas The hydrochloric gas is then eliminated by evacuating, at room temperature, then the excess ethylenedithiol is removed while hot, under vacuum. of.

   After recrystallization of the crystalline residue using methanol and
 EMI10.4
 chloroform, 7-monoethylenedithioacetal is obtained from L122s233ma.cetoxy 7,11-diketo-ergostene melting at 224 - 225 o In a suspension of Raney nickel, freshly prepared from 5 parts by weight of Raney alloy in 20 parts by volume of dioxane, 0.1 part by weight of the above 7-mono-ethylene-dithioacetal, dissolved in 5 parts by volume of dioxane, is added and the mixture is heated under reflux for 3 hours. The Raney nickel is then filtered off and washed well with benzene. The filtrate is concentrated under video by dissolving the residue in a mixture of methanol and water,
 EMI10.5
 3macetoxy 11 ketomergostane with a melting point of 135-136 is obtained; (! "') 2 = +320 (c = 0.905 in chloroform).



  Using a less active Raney nickel catalyst, 7-mono-ethylenedithioacetal is obtained from A22,233macetoxymll = eetomergostene with a melting point of 125-126.0.



  Exe1nî> the 'o; :, On'.disso1; it 1 part by weight of A7 '$' '11 3.20 diactoxyma.ïlo-prem gnadiene in 20 parts by volume of ether and add 5 parts by volume of an ethereal solution of mono-peracid phthalic acid containing 1.1 equivalents of active oxygen. The reaction solution is left for some time at room temperature and is then washed with an aqueous solution of sodium bicarbonate, then with water, dried and concentrated, the residue is recrystallized.
 EMI10.6
 dried in acetone. The A9 $ m3s20diacetoxy 9, llêpoxymallopregnéne thus obtained does not exhibit characteristic absorption at the absorption spectrum in the ultraviolet and gives with tetranitromethane a colored reaction of a pure yellow.
 EMI10.7
 



  1 part by weight of 1 '$ m3', 20 diaoetoxy 9,11 epoxy allopregnem is dissolved in 150 parts by volume of dioxane and the solution is mixed, at room temperature, with 40 parts by volume of an aqueous solution. 0.3 normal sulfuric acid. After 10 minutes, the reaction mixture is poured into a stopcock funnel containing 1000 parts by volume of ether and 500 parts by volume of a saturated aqueous solution of sodium bicarbonate, the mixture is stirred well and the mixture is stirred. then wash the ethereal solution again with water o Concentrating the dried ethereal solution, the # 8,9-
 EMI10.8
 , 20mdiacetoxy'7.11 = dioxy = crystallized allopregnene; it is pure enough to be suitable for further processing.
 EMI10.9
 



  For the purpose of the oxidation, 1 part by weight of A '-3r} 20-diacetoxy-7,11-dihydroxy-allo-pregnene is dissolved in 100 parts by volume of glacial acetic acid and the mixture is mixed. solution, at room temperature, over 15 minutes, in portions, with 0.3 part by weight of chromium trioxide

 <Desc / Clms Page number 11>

 in 5 parts by volume of a 90% aqueous solution of acetic acid. The solution is left to itself for several hours at the same temperature, then the unused oxidizing agent is destroyed by adding methanol and the reaction solution is poured into 500 parts by volume of water. The oxidation product is taken up in ether and the ethereal solution is washed several times with saturated sodium bicarbonate solution, then with water.



  The neutral oxidation product is advantageously recrystallized from al-
 EMI11.1
 cool diluéo We thus obtain the, 20mdiaoétoxymg, époxymi, lldiketoallom prégnane, whose absorption spectrum in the ultraviolet has a wide absorption band at 280 - 290 mp (loge = 1.9) and whose reaction with tetranitromethane shows that it is saturated.



   By treatment in a boiling water bath of a solution of one part
 EMI11.2
 tie by weight of, 0diacetoxy, 9epoxy 7,11diketoallopregnan, in 100 parts by volume of glacial acetic acid, per 5 parts by weight of zinc powder, we obtain 3PJ, (, d3.acetoxym7,11-diketoallopregnane, which one can recrystallize from methanol.



  0nAnd also obtain the, 20diacetoxym7, llmdiketomallopregzam ne, by o, datlôZpÉf "the chromatic aciÉe, 'in solution in acetic acetic acid, of Ln99110,0 diacetoxy allomprégnadine, in Q', 20mdiacetoxy (maximum absorption 7,11dicne for 273 ml in ultra-violet, loge- = 3.95), and by subsequent reduction of this product with zinc in solution in glacial acetic acid.



   For 1, selective elimination of the keto group in position 7,
 EMI11.3
 1 part by weight of 3 (, Odiacetoxym ", llmdiketomaZlopregnane is dissolved in 5 parts by volume of ethylene dithioglycol and the solution is treated at 0 for 1 hour with a strong stream of dry hydrochloric gas. then, ethylenedithioglycol is removed under high vacuum and crystallized.
 EMI11.4
 read in methanol the 7-mono-ethylene-dithioacetal obtained For the reductive desulfurization, 1 part by weight of this product is dissolved in 50 parts by volume of absolute dioxane and the solution is heated for a certain time with a nickel catalyst freshly made from 10 parts by weight of Raney nickel.

   When the treatment is finished, we get the
 EMI11.5
 3, 0diacétoxymllmcétomallompégnaneo By saponification of this keto-diacetate with a 0.5 n solution of potassium hydroxide in methyl alcohol and oxidation of the crude product of saponification with chromic acid dissolved in glacial acetic acid (3 oxygen atoms), the known 3,11,20-triketo-allo-pregnane is prepared
Example 10
 EMI11.6
 -1 part by weight of ô '' '- 3h-acé) oxy-stigmastatriene (obtained by selective hydrogenation of 5,6; 7,8,22,23 Known paoetoxy-stigmastatriene, using Raney nickel , in alcoholic solution, 7.8;

  22,2J-J-acetoxy-stigmastadiene, then by subsequent dehydrogenation of this diene with mercuric acetate dissolved in chloroform and glacial acetic acid, at room temperature), is dissolved in 50 parts by volume d The ether and the solution is mixed with 5 parts by volume of an ether solution of phthalic monoperacid containing 1.1 equivalents of active oxygen.

   The oxidation mixture is left on its own for 7 days at room temperature, the reaction product is isolated in the usual manner and re
 EMI11.7
 crystallizes in acetone the â7.8; 22.2J = 3-acetoXY-9, ll-epoxy = stigmas = tadiene obtained
By treating, at room temperature, a solution of 1 part
 EMI11.8
 by weight of 'sacetoxy, 11 = epox stigmastadine in 200 parts by volume of dioxane, per 40 parts by volume of 0.3 normal aqueous sulfuric acid, it forms at 99s 2.acetoxy7, .ldihydroxy stigmastadié only l' it is purified by crystallization from acetone.



  To transform this  8.9; 22 23 = J = acetoXY = 7.11-dihydroxy-stig = mastadiene into Qz ,, acetmxyg, 9epocy 'i, llmdikétomstigma.stene, 1 part by weight of the triol mono-acetate is dissolved in 100 parts by volume of glacial acetic acid and add to the solution at room temperature 0.4 per-

 <Desc / Clms Page number 12>

 1% by weight of chromium trioxide dissolved in 10 parts by volume of a 90% aqueous solution of acetic acid.

   After 5 hours, the reaction product is isolated in the usual manner and the neutral oxidation product is recrystallized from a mixture of methanol and water or acetone and water.
By treating in a water bath a solution of 1 part by weight of
 EMI12.1
 4 zz923 3 'acetox3r, 9epoxym7,11 = diketo: gmastne in 50 parts by volume of glacial acetic acid per 5 parts by weight of zinc powder, in a boiling water bath, Q 22233acetoxy, lld.cétostigmas is obtained = tene, which is purified by recrystallization from a mixture of ether and methanol or ether and hexane.
 EMI12.2
 



  1 part by weight of A "-3P-acetoxy-7,11-diketo-stigmastene is heated for a short time in a water bath with 100 parts by volume of triethyleneglycol, 100 parts by volume of methanol and 5 parts by volume of Hydrazine hydrate. A further 5 parts by volume of hydrazine hydrate, together with 10 parts by weight of sodium hydroxide and 20 parts by volume of water, are added to the mixture, the mixture is heated to water. oil bath, in one hour, at 180, and then maintained for two hours at this temperature., After having isolated the reaction product, acetylated with 15 parts by volume of acetic anhydride and 15 parts by volume of pyridine It is advantageous to chromatograph the reaction mixture on an alpha-oxide column.
 EMI12.3
 activated luminium, The A22,

  23 = 3 = acetoXY = 11-keto = stigmastene can be recrystallized from a mixture of methanol and water.



   Example 11.



   8; 9.11 5 parts by weight of the methyl ester of the acid are dissolved
 EMI12.4
 9 pplle3acetoxymcholadiene in 300 parts by volume of absolute ether and the solution is mixed with 50 parts by volume of a phthalic monoperacid solution containing 2 parts by weight of active oxygen per part by volume 0 ;;

  After having stored the solution for 3 days at 0 and for 7 days at room temperature, the reaction mixture is washed successively with a solution of sodium bicarbonate and water by recrystallizing the product from oxidation in a mixture of acetone
 EMI12.5
 and mineral spirits, we obtain the methyl ester of steel 4 s = 3xaceous = toxy-9,11-epoxy-cholene with a melting point of 154. = 15 9 a 0 = '<' 121 (G 0.850 in chloroform) o This product gives a yellow color with tetranitromethanec
By chromatographic purification of the stock solution on aluminum oxide, an isomeric compound with a melting point of 179-181 is obtained.
 EMI12.6
 



  2.9 parts by weight of the methyl ester of the acid Asg3ct, macem toxy-9,11-epoxy-cholene are dissolved in 375 parts by volume of absolute dioxane and the solution is stirred for about 5 minutes at the room temperature, with -66 part by volume of 2N sulfuric acid. The solution is then immediately introduced into a funnel with a stopcock containing ether and a solution of sodium bicarbonate and stirred intensely.

   After washing, drying and evaporation of the ether, the ester is obtained in the form of an oil.
 EMI12.7
 methyl acid .g99 = 3macetoxyï, ll d.ioxy cholenico This product, without being purified, is mixed, while cooling with ice, with 730 parts by volume of a solution of chromium trioxide in glacial acetic acid (containing 0.00113 part by weight of oxygen per part by volume) and left to stand overnight at room temperature. After having isolated the reaction product in the usual manner, 2.6 parts are obtained
 EMI12.8
 by weight of Q acid methyl ester g9 = 3acetoxy 7.11 = diketocholén. that, which, after recrystallization, melts at 137 - 139 ea. ¯ z (c = 0.87 in chlorafome). The absorption spectrum of this product in ultraviolet shows IÎ1axpnum at 70 mf1 (log 3.90) o;

     @
1.8 parts by weight of 8.9- acid methyl ester are dissolved.
 EMI12.9
 3oe-acetoxy-7, llrdiketo-cholenic in 400 parts by volume of glacial acetic acid and add, at room temperature, 2 parts by weight of zinc powder. The solution is then heated to the boiling point and added, in portions

 <Desc / Clms Page number 13>

 
 EMI13.1
 about 1.5 parts by weight, over about 30 minutes, a total of 9 parts by weight of zinc. The reaction product is isolated in the usual manner and the methyl ester of 3 a.macetoxym7,11diketomcholanic acid is obtained which, after having been purified by chromatography and having been recrystallized from a mixture of ether and hexane, melts at 159 - 160; [[alpha]] D = +16.5 (c = 0.885 in chloroform).

   In ethanol, this product has an absorption maximum in ultra-violet at 290 mp (log = 2.0) 0
To eliminate the ketone group in position 7, we dissolve 1.2
 EMI13.2
 part by weight of 3a-acetoxy-7,11-diketo-choianic acid methyl ester in 20 parts by volume of ethylenedithioglycol and the solution is passed through the solution for one hour with seco hydrochloric gas After operating as indicated in Example 8, 7-mono-ethylenedithioacetal is obtained which, after recrystallization from methanol, melts at 161 - 162. 1 part by weight of this product is dissolved in 200 parts by volume of dioxane, added Raney nickel (freshly prepared from 50 parts by weight of alloy) and the solution heated to reflux for about three hours.

   We isolate the pro-
 EMI13.3
 reaction product and obtains the methyl ester of 3a <-aoetoxy-ll-oetoocholanic acid which, after chromatography with aluminum oxide and crystallization from a mixture of hexane and pentane, melts at 127 - 1280 ; 10-) D = +68 (c = 1.49 in acetone).



   For example, the methyl ester of the acid is obtained as follows:
 EMI13.4
 A?, 8s', llm3acoacétoxr choladien3que used as starting material in the example above: The methyl ester of 3aG, 7diacetoxy-12-keto-cholanic acid is oxidized with the aid of selenious anhydride, in 99113c acid methyl ester,? acmdia.cetoxy7 = ketocholéniqua which, treated with a 10% solution of potassium hydroxide in methanol provides the acid / 7 $ 31 3oxy 1ketomcholadienic, melting point 184 - 1870 (recrystallized in a mixture of methanol and water).

   The methyl ester of the acid A7,8; 9> 1l- $ succ- cinoxy-12-keto-choladienic, melting at 123 - 124, prepared from this acid, gives by reduction according to the method of Wolff-Kishner , subsequent etherification with diazomethane and acetylation with acetic anhydride
 EMI13.5
 and pyridine, the methyl ester of Z $ 11m3 acetoxyclaoladienic acid. The latter compound can also be obtained by reducing by means of
 EMI13.6
 Wolff-Kishner method 9,11-3r-, 7diacem toxy-12-keto-cholenic acid methyl ester, esterifying the transformation product with diazomethane and acetylating with acetic anhydride and pyridine Example 12.



   To a solution of 0.5 part by weight of acid methyl ester
 EMI13.7
 of 0 7n 3s113, acetoxymchflladiene in 10 parts by volume of glacial acne- tic acid, is added over about 20 minutes at room temperature, 0.5
 EMI13.8
 part by weight of chromium antioxidant dissolved in 5 parts by volume of 90% acetic acid; the solution is then changed to 500;

   after which it is left to stand for 14 hours at room temperature After having isolated the reaction product in the usual way and having purified it, the ester is obtained
 EMI13.9
 Q $ 99m3amacetOxy'7,11diketomcholenic acid methyl ester with a melting point of 137 - 13m, which can be converted into the methyl ester of 3a-acetoxy-11-keto-eholanic acid, according to the indications of Example 110 Example 1 4.36 parts by weight of acetoxy androstadiene 47 $ e11o3491Z with a melting point of 131 - 132.5 ([&] D = 0 in chloroform) are dissolved in 40 parts by volume of absolute ether, cooled to 0 and added 35 parts by volume of an ethereal solution of phthalic monoperacid (containing 0.00355 mol of active oxygen per part by volume). After allowing to stand for 5 days at f3,

   active oxygen is almost completely used up.



  The reaction mixture is diluted with 300 parts by volume of ether, washed twice with 100 parts by volume of a 0.5 n solution of sodium bicarbonate and washed twice with 100 parts by volume of water o The aqueous extracts are stirred once with 150 parts by volume of ether The ethereal solutions are combined and dried over sodium sulfate, adding a little carbohydrate.
 EMI13.10
 ;: 3 - - .. ";

  .., f

 <Desc / Clms Page number 14>

 potassium nate, filtered and concentrated, first in a 40 - 50 bath, and then in a vacuum. There remains 4.32 parts by weight of a colorless oil by crystallization from ether and a mixture of ether and hexane,
 EMI14.1
 we obtain the A 7.8 = 9.11 = epoXY = JP, 17P = diacetoxy = androstene in the form of well-formed crystals, with a melting point of 152 - 153.5 [[alpha]] D = -66 in chloroform.
 EMI14.2
 1.2 part by weight of 0? Eg 9.11 3i ', 1? Epoxy is dissolved. crude toxy-androstene diacean in 300 parts by volume of pure dioxane, add 50 parts by volume of 2n sulfuric acid;

   After 5 minutes the reaction product is poured into a separating funnel containing 300 parts by volume of a saturated solution of sodium bicarbonate and 500 parts by volume of ether, and immediately stirred well. The organic solution is washed twice, each time with 100 parts by volume of a saturated solution of sedium bicarbonate and then, three times, each time with 100 parts by volume of water. All the aqueous extracts are extracted twice, each time with 500 parts by volume of ethero. The combined ethereal solutions are dried and concentrated in a bath at 50.



  In this way, 1.37 parts by weight of a solid residue are obtained. By recrystallization from acetone, one obtains in the form of long needles
 EMI14.3
 felted, d49R ?, 11 dioxym3,1? i'diacetory androstene sparingly soluble in ether, melting point 208-2100; a-p = -55 in chloroform.



  0.22 part by weight of 0 9R ?, 11dioxym, 3.1? 'Is dissolved. crude toxy-androstene diacean in 2.5 parts by volume of carbon tetrachloride; while cooling with ice and stirring, 0.5 part by volume of a solution of tertiary butyl chromate in carbon tetrachloride, prepared from 0.093 part by weight of chromium trioxide, is added and tertiary butanol-free; Stirring is then continued for half an hour at 0, then 4 1/2 hours at room temperature. To decompose the excess oxidizing agent, a solution of 1 part by weight of oxalic acid in 10 parts by volume of water and 2 parts by volume is introduced dropwise while cooling with ice. 2 n sulfuric acid, and vigorous stirring for 30 minutes.

   The reaction mixture is then diluted with 60 parts by volume of ether, washed twice, each time with 15 parts by volume of water, two more times, each time with 15 parts by volume of a saturated solution. sodium bicarbonate and then washed further with 15 parts by volume of water; the aqueous extracts each are subsequently extracted with 30 parts by volume of ether. The combined organic solutions are dried and concentrated. As residue, 0.233 part by weight of a light yellow oil is obtained, which is easily removed by crystallization from
 EMI14.4
 methanol, d? 3 ', 1? diacetoxy? keta 11 hydroxy = ostene a.ndx with a melting point of 190.5 - 192.

   It presents in the ultra-violet a maximum at 248
 EMI14.5
 me (logi - 3.9) .., In an analogous manner, the sR; 22,23 3r acetoxy = ?, 11 dioxy = ergos tadiene described 14ens = in example 8 can, for example, be partially dehydrated by 0 g92z92. 3 acetoxy? ketoQll oxy ergostadiene - L can also be further oxidized as follows! g '9 3.1? p dia = ketoXY-7, 11 = diQ,;, Androstene described above:' - '' -, "¯" ¯ .. t- ...



   0.2 part by weight of diol is mixed with a cooled solution of 0.25 part by weight of chromium trioxide in 50 parts by volume of glacial acetic acid and 0.1 part by volume of sulfuric acid 2 n and left to stand overnight at about 15. Then, 2 parts by volume of methanol and 5 parts by volume of water are added, left to stand for 2 hours at room temperature, and the reaction product is isolated as usual.



  0.17 part by weight of a neutral oxidation product is obtained from which,
 EMI14.6
 after crystallization in methanol, the 3 = 17 = di = aceto: xy = 8.9..epoXY-7, ll = diketo = androstane with a melting point of 171 - po The stock solution colored in yellow contains the A 9R 3r'91? I 'diacetoxy = ?, 11 diketo androstane, exhibiting in the absorption spectra in the ultraviolet, at 272 mp, a strong absorption maximum.

 <Desc / Clms Page number 15>

 
 EMI15.1
 



  For the reduction, 0.5 part by weight of [, l7diacea toxr, 9epoxy = "%, lldiketomandrostane is dissolved in 60 parts by volume of glacial acetic acid and 1.8 parts by weight of zinc powder are added. The mixture is then heated slowly and maintained for 1 hour at reflux, then it is cooled, filtered to remove the excess zinc, diluted with ether, the ice acetic acid is removed by washing with water and the mixture is concentrated. the ethereal solution o We obtain
 EMI15.2
 0.5 part by weight of ', 1? diacetoay 7.11 = diketomandrostane which, after recrystallization from ether, melts at 214-215.



   The same end product is obtained by reducing in an analogous manner
 EMI15.3
 logue, with zinc and glacial acetic acid, the Â8.9¯3.17 p-diacetoxy = 7.11-diketo-androstene mentioned above.



  2.07 parts by weight of d.acetoxy7, Zlmdiketoandrostane are dissolved in 40 parts by volume of freshly distilled ethylene-dithioglycol. While stirring, a strong stream of dry hydrochloric gas is then passed to 0 for one hour over the solution. After having removed under vacuum, at room temperature, the hydrochloric gas, it is distilled under vacuum.
 EMI15.4
 ethyl% ene-dithioglycol in excess.

   From the crystallized residue, one obtains by recrystallization in methanol, the 7-monoethylene-dithioacetal of 3r, 17F-diacetoxy-7,11-diketo-androstane with a melting point of 203 - 204 (a.JD ::: - 33 (in chloroform) o 1.55 parts by weight of 7-mono-dithioacetal are dissolved in 50 parts by volume of dioxane, a suspension of nickel catalyst is added, prepared from 100 parts by weight of Raney alloy in 150 parts by volume of dioxane and heated for one hour at reflux. Then, it is filtered and concentrated under video By recrystallization from a mixture
 EMI15.5
 of ether and pentane, 9,17p-diacetoxy-l1-keto-androstane with a melting point of 153 - 15 ± z 9 tpc bzz (in chloroform) is obtained. It is also possible to isomerize as follows 6 7 , 8¯3e, 17p-diacetoxy-9,11- epoxy = androstene described above:

   
0.1 part by weight of the epoxy compound is dissolved in 2.5 parts by volume of absolute benzene and a drop of a complex of ether and freshly distilled boron trifluoride is added. After leaving to stand for 72 hours at room temperature , diluted with 50 parts by volume of ether, washed with sodium bicarbonate solution and with water, dried and concentrated under video The crude crystalline product is recrystallized from a mixture of ether and hexane or methanol, which makes it possible to obtain the
 EMI15.6
 0g9,1'idiacetoxyllketomandrostane pure, with a melting point of 177.5 - 1? 9m at D = + 93 (in chloroform), which shows in the ultraviolet absorption spectrum a characteristic maximum at 252 mp ( house 3.96).



  As follows, the A '' 9'Zlm ,, 17Pmdiacetoxymandrostam diene used., In this example, as the starting substance is obtained.
10 parts by weight of
 EMI15.7
 79, 17diacetoxyandrostene in 200 parts by volume of 95% alcohol and this solution is added to a solution of 20 parts by weight of mercuric acetate in 200 parts by volume of glacial acetic acid in a flask. nitrogen the air above the solution and stir the flask 65 hours in the dark at room temperature.

   The weak yellow colored solution is then filtered, the precipitate is washed with ether and the filtrate is concentrated in vacuo on a 35-40 bath until about 170-200 parts. volume of the solvent are removed by distillation. The reaction mixture is taken up in 500 parts by volume of ether, and stirred once with 300 parts by volume of water, and then nine times with 100 parts by volume of water each time. water. All the aqueous extracts are subsequently extracted twice, each time with 200 parts by volume of ethero. The combined ether extracts are dried and concentrated on a 60 bath.

   The oily residue, light yellow, is dried under high vacuum. This residue (11.39 parts by weight) is dissolved in 20 parts by volume of methanol and held for a certain time at -10 for the purpose of crystal.
 EMI15.8
 lisationo It crystallizes 4.9 parts by weight of crude Q7, g; 9,11,171-diacetoxym androstadiene. The stock solutions also still contain a little diene. By crystallization in methanol, we obtain 799911j ', 1'7m

 <Desc / Clms Page number 16>

   pure diacetoxy-androstadiene, melting point 131 - 132.5 [[alpha]] D = C
 EMI16.1
 (in chloroform), \ max $ 235; 242; 250 mm; (log = 4 '7..E, .ç 4.18; 4.00) 0' Example 14.



  1 part by volume of absolute ether is dissolved in 35 parts by volume.
 EMI16.2
 wt of 1? 9 s9.13 (maeetoxymcholestaaiene (melting point 115), cooled to 0 and added 5.75 parts by volume of an ethereal solution of phthalic monoperacid (containing 0.00712 part by weight of active oxygen per part in The solution is stored 1 day at 0 and then 3 days at 20, after which the active oxygen is almost completely used up. The reaction mixture is diluted with 100 parts by volume of ether, washed twice with 100 parts by volume of a half-normal solution of sodium bicarbonate and twice with 100 parts by volume of water. The aqueous extracts are stirred with 80 parts by volume of ether.

   The combined ethereal solutions are dried over sodium sulfate, filtered and concentrated in a bath at 40 -
 EMI16.3
 50o There remains 1.05 part by weight of 67,8-3fi-acetoxy-9,11-epoxy-choles- tene in the form of a colorless oil, which crystallizes after dissolution in a mixture of ether and hexaneo
 EMI16.4
 1 part by weight of this crude A 7, 8 = 3-acetoXY-9, ll-epoxycholestene is dissolved in 210 parts by volume of pure dioxane, 40 parts by volume of 2 n sulfuric acid are added and the mixture is stirred well for About 5 minutes;

  The solution is then poured into a funnel with tap containing 300 parts by volume of a saturated solution of sodium bicarbonate and 500 parts by volume of ether and immediately stirred well. The ethereal solution is washed twice, each time with 100 parts by volume of a saturated solution of sodium bicarbonate, then three times, each time with 100 parts by volume of water; it is then dried, filtered and concentrated in a bath at 50.

   1.05 part by weight of a solid residue is obtained, which is recrystallized from acetone and then from methanol, melting at 228 - 230 This product is
 EMI16.5
 A 8,9-3f-acetoxy-7,11-dioxy-cholestenev 1 part by weight of 6 8.9-3f. LacetoXY-7,11-dioxy-cholestene is mixed at 0 while stirring well with 240 parts by volume of a solution of chromic acid in glacial acetic acid (containing 0.0011 parts by weight: of active oxygen per part by volumejo Further added to the solution, after allowing it to stand shortly, 1 part by volume of 2% sulphuric acid and the reaction mixture is then left for 16 hours at 20.

   By isolating the reaction product in the usual way, 1 part by weight of an amorphous product is obtained, exhibiting in the ultraviolet absorption spectrum only absorption at the end of the spectrum, at
 EMI16.6
 220 mU This product is 3acetoxTmB, j epoxy = ?, 11 crude diketomcholestane ,, 1 part by weight of 3 acetocy, mepoxy = ?, 11 = d.cet cholestane is dissolved in 130 parts by volume of glacial acetic acid and add at room temperature 1 part by weight of zinc powder. The solution is then heated to the boiling point and thereto is added, over the course of 30 minutes, in portions of 1 part by weight each, a total of 5 parts by weight of zinc powder.

   After having isolated the reaction product in the usual manner,
 EMI16.7
 1 part by weight of crude 3-acetoxy ™, 11-diketocholestane is obtained which, after chromatographic purification and recrystallization from a mixture of acetone and water, melts at 168-169.
 EMI16.8
 If instead of A7,8; 9,11-3-acetoxy = cholestadiene with a melting point of 115, the corresponding 3-benzoate with a melting point of 132 is used as the starting material, the product is obtained final of this
 EMI16.9
 series of reactions 3benzoxym ™, lidiketocholestane with a melting point of 198.



  To prepare 3-oxy-11-keto-cholestane, 1 part by weight of 3-acetoxy-7,11-diketo-cholestane with a melting point of 169 is mixed or 1 part by weight of the corresponding benzoate of a melting point of 198 with
 EMI16.10
 100 parts by volume of triethylenemglycolo To the suspension formed is added, while heating in a water bath, sufficient methanol so that everything is dissolved. Then, the 2 parts by weight solution of hydra- hydrate is added.

 <Desc / Clms Page number 17>

 zine and heat in a water bath for about 15 minutes. Then 1 part by weight of hydrazine hydrate together with 10 parts by weight of sodium hydroxide and 20 parts by volume of water are again added to the solution and the solution is heated for about one hour at 180, the easily volatile components are thus removed by distillation.

   Then heated for another 2 hours at 180. After having isolated the reaction product in the usual manner, the crude product is purified by adsorption on aluminum oxide. Along with a little cholestanol, the main product of the reaction is obtained.
 EMI17.1
 duction 3p-hydroxy-11-keto-cholestane with a melting point of 152 0 Example 15.



  Suspended in 100 parts by volume of tetrachloride
 EMI17.2
 of carbon 1 part by weight of A8,9; 22,23-3-acetoxy-7,11-diketo-ergostadiene finely pulverized, prepared according to the indications of Example 9, and added to - 10, 30 parts by volume a solution of tertiary butyl chromate in carbon tetrachloride (corresponding to 0.035 part by weight of chromic acid per part by volume). The reaction mixture is left for 8 hours at -10 and then worked up as described in Example 13.

   The crude product obtained is, with a view to its purification, chromatographed with aluminum oxide, the average fractions yielding, after recrystallization from
 EMI17.3
 a mixture of methanol and water, 0.5 part by weight of A, 93222331-macetoxym 7mcétolloxyergostadiéne which melts at 235 and which, in ethanolic solution, gives an absorption spectrum in the ultra-violet which exhibits a maximum at 252 mp (log # = 3.98).

   
 EMI17.4
 It is also possible to prepare A g'93229z3m3acétoxy7cétomllmhydroxy ergostadiene in the following manner o Is dissolved in a mixture of 200 parts by volume of dioxane and 40 parts by volume of water, 1 part by weight of
 EMI17.5
 Finely pulverized to 8,9,922,23-3p-acetoxy-7,11-dihydroxy-ergostadiene, melting point 269 - 2700 and 50 parts by weight of bromosuccinimideo are added thereto. The reaction mixture is allowed to stand for 20 hours to 20 hours, then add 400 parts by volume of water, then an extraction is carried out with 400 parts by volume of ethero The ethereal solution is washed with water, with a solution of sodium bicarbonate and again a times with water, then dried and concentrated:

  , After chromatographic purification of
 EMI17.6
 crude product, one obtains the Qs9; 2z, 233aetoxy? kétomllhydroxyergosta diene described above, with a melting point of 235 o
If we oxidize with chromic acid in acetic acid
 EMI17.7
 glacial, under the conditions indicated in Example 8, the α8,9; 22,23-3fi-acetoxy-? -keto = 11h dro er ostadiene, the sole reaction product is then A 8 s' = 3acetoxy? , lldicetomergostad.ene described in Example 1, melting at 132-135 and which, in alcoholic solution, exhibits in the ultraviolet an absorption maximum at 272 my (log # = 3.95).



   Example 16.



   2.5 parts by weight of
 EMI17.8
 a, s 22.23m3 ('macetoxy ?, l.md.hydroxy ergostadine finely ground, melting point 269-270, prepared as described in Example 8, with 200 parts by volume of acetic acid Glacial While continuing to cool, 16.08 parts by volume of a solution of chromic acid in glacial acetic acid, containing per part by volume of 0.0106 parts by weight of active oxygen are added to the suspension.

   The reaction mixture is allowed to stand for 15 minutes at 0 and then 4 hours at 20, after which the oxidizing agent has reacted and all the substance has gone into solution. The reaction mixture is worked up as described in Example 8 and the crude product is separated into its components by fractional crystallization or better still by chromatography on aluminum oxide. The following three compounds can be isolated: -
The first eluates of the chromatogram provide 0.6 part
 EMI17.9
 by weight of s22923m3 (acetoxym?, lldicetoergostad3.ene already described in Example 1, with a melting point of 132 - 135 # max Cl in alcohol = 272
 EMI17.10
 J !!. R; .- 1pg f "" 3.91).



  The other fractions provide after dissolution in a mixture

 <Desc / Clms Page number 18>

 
 EMI18.1
 methanol and water 0.4 part by weight of Â22.23 = 3 = a.cetoXY = 7 = keto = 8.9 = epoxy = ll = hydroxy-ergostene, which melts at 152 - 1540 and whose spectrum d absorption in the ultraviolet only shows an absorption at the end of the spectrum, but on the other hand presents in the absorption spectrum in the infrared, for 3300 cm-1, a band characteristic of hydroxyl groups free.



   Finally, the last fractions give, on recrystallization from a mixture of methanol and water, 0.7 part by weight of # 22,23-
 EMI18.2
 3macetoacym8, '9 epoxy ?, 11 = dihydrox ergostne which melts at 145 - m7 oo One can also prepare A' - = '3-aoetoxy = 8,9-epoxy = 7, ll-dihy-droxy-ergostene by dissolving, to 0, 1.5 parts by weight of to S, 922,23 acetoxy-7,11-dihydroxy-ergostadiene in 300 parts by volume of dioxane and adding 15 parts by volume of an ethereal solution of phthalic monoperacid containing 0.007 part by weight of active oxygen per part by volume.



  The solution is left to stand for 24 hours at 0 and then 5 days at 20. The reaction mixture is then treated as described in Example 2. The crude product gives, on recrystallization from a mixture of methanol and water, the mixture.
 EMI18.3
 n.3acetoxy $, 9mepo.y 7, llmaihydroxy ergosténe described above, with a melting point of 145 - l ± 7 o Both:

  '3 = acetox, = epoxym, lld, ir.ydroxr ergostne that the z9j = aCetO.y, 9epoxy = 7cétollmhydroxyergosténe provide, when they continue to oxidize with chromic acid in glacial acid, under the conditions described in Example 8, by a unit reaction, the
 EMI18.4
 to, 3m3acetoxy8, epoxy '7, lldiketoergostene with a melting point of 130 - 131 To transform the z, 3 3macetoxym $, epoxym7 = keto llmhydxoxym ergostene in J3,23 = 3macetoxy 7meetomllhydroxyergostne, 1.5 parts are dissolved by weight of , d 92macêtoxy, epoxy? = kétomllhydrocy ergostène in 150 parts by volume of glacial acetic acid and 2 parts by weight of zinc powder are added ,, The mixture is heated to 80 and 3 portions are added over the course of 30 minutes zinc powder, each 1 part by weight, After cooling,

   the zinc is separated by filtration, the residue is taken up in ether and the ethereal solution is treated as indicated in Example 80 The crude product obtained by recrystallization from a mixture of methanol and
 EMI18.5
 of water, p32, o3 a.cétox: y ïcétoll = hydroxy ergostadiéne already described in Example 5, with a melting point of 235 o
Example 17.
 EMI18.6
 



  6 parts by weight of '' 91'9'3 (acetoxy = ergosm tatriene) are dissolved in 500 parts by volume of glacial acetic acid and a solution of 3 parts by weight of chromic acid in 100 parts by volume of 90% acetic acid.



  The solution is continued to stir vigorously for a further 1 hour, after which all the oxidizing agent is used up. The reaction mixture is then diluted with water, extracted with ether and the ethereal solution is treated with water. usual way. The crude product provides, from its solution in the metha-
 EMI18.7
 nol, crystals melting at 176 - 1781>.

   This product is 11, 11; 22,23-3 = acé = toxy-7-keto-ergostadiene whose absorption spectrum in the ultra = violet shows no characteristic absorption. This compound can also be prepared by putting suspended in 300 parts by volume of acetic acid gla-
 EMI18.8
 cial, 1.7 parts by weight of 8,922,23 acetoxy-7, ll-dihydroxy-ergostadiene and adding 20 parts by volume of an aqueous solution of hydrogen peroxide, containing 0.012 part by weight of oxygen active per part in volume.



  The mixture is shaken for 12 hours at 20 and then treated as indicated in Example 8. The crude product gives, after crystallization in a mixture.
 EMI18.9
 ge of methanol and water, 1.1 part by weight of A9,1122,23-3-.acetoxy = .7-keto-ergostadiene, with a melting point of 176 - 1785a One part is dissolved in weight of '11'22''m, acetoxy ketom ergostadiene in 100 parts by volume of absolute ether and add 6 parts
 EMI18.10
 by volume of an ethereal solution of phthalic monoperacid containing 0.007 - part by weight of active oxygen per part by volume. -0n-.aisse = tepose the reaction mixture 2 days at 0, then 2 weeks at 20 and then it is treated

 <Desc / Clms Page number 19>

 as indicated in Example 2o The crude product melts at 205 after recrystallization
 EMI19.1
 sation in methanol.

   The compound obtained is A22,23 = 3t '= acetoxy-7-keto = il-epoxy-ergostene showing no characteristic absorption in the absorption spectrum in the ultra-violeta 1 part by weight of A zZ92 acetoxy is dissolved Aceto 9.11m epoxy-ergostene in 100 parts by volume of absolute benzene and 1 part by volume of a complex of ether and boron trifluoride is added. The reaction mixture is left to stand for 3 days at 20 and then heated for 2 hours to the boil. The treatment then takes place as indicated in Example 2. The crude product gives, after purification by chromatography and recrystallization from a mixture of acetone and water, needles which melt at
 EMI19.2
 196 - 19'i o The compound obtained is (, macétoxym7,11 = dieétoergostne already described in Example 1.



   If we treat with potassium carbonate in methane solution
 EMI19.3
 eliminates Z., aeétox3r keto 9911 epoxy = ea gosténep it forms L1 g, 9zz, 2! acetoxy ketomll hdroxyergostadiene9 which melts at 235 ° C. and whose absorption spectrum in the ultra-violet shows a maximum at 252 m #
 EMI19.4
 (housed "'", 94) Example 18 ..
 EMI19.5
 3.5 parts by weight of A s9? 1122.23 acetoxy-ergostatriene in 500 parts by volume of glacial acetic acid and 66 parts by volume of an aqueous solution of hydrogen peroxide containing 0.012 part by weight of active oxygen per part by volume are added.

   The reaction mixture is stirred well for 5 days, after which a clear solution is obtained. To this is added 1000 parts by volume of water and extracted with ether. The ethereal solution is washed with water, with sodium bicarbonate solution and once again with water, then dried and concentrated. The crude product gives, on recrystallization from methanol, crystals which melt at 2050 and whose absorbp spectrum =
 EMI19.6
 tion in leultra-violet, shows no characteristic absorption. The compound obtained is the, A, acetoxy keto 9911 epox ergostne already described in Example 17.



   If the stock solution of the crystallization described above is treated, as indicated in Example 17, in absolute benzene, with a complex of ether and boron trifluoride, one obtains after recrystallization =
 EMI19.7
 sation of the crude product in methanol, d 9329. 3 acetoxy eeto = erm gostadiene pure, with a melting point of 210 - 212.



   Example 19.
 EMI19.8
 



  1 part by weight of to g99ns acetoxr 11 keto-ergostadiene, with a melting point of 122-1230, is boiled with a solution of 125 parts by volume of acetic anhydride and 0.1 part by weight of acid p -toluenesulfonic acid., so that in 6 hours 20 parts by volume of the solvent are separated by distillation, Then the solution is concentrated, in vacuo, to 100, until dryness, the amorphous crude product is dissolved in 50 parts by volume of absolute ether and to 0.6 parts by volume of an ethereal solution of phthalic monoperacid (containing 0.008 part by weight of active oxygen per part by volume) is added thereto. The solution is stored for 24 hours at 0 then 6 days to 20.

   Then the reaction mixture is treated as indicated in Example 2o This gives 1 part by weight of 48.9; 22.23-3ss-
 EMI19.9
 crude aeeto hydox 11 keto e gostadine with a maximum absorption spectrum in the ultraviolet. 252 miJ (109 e G 3.97). In the absorption spectrum in the infra = red appears at 3400 cm-1 the characteristic band of an unesterified hydroxyl, at 1730 cm-1 that of group 3 = acetoxy = and at 1660 cm-1 that of 11 -ketone unsaturated in [alpha], ss.
 EMI19.10
 



  For the oxidation, 1 part by weight of 9.9'2.23, acetoxy = 7 hy-d ox .. keto ergostadiene, is mixed while cooling with ice, arc 200 parts by volume of a solution of chromic acid. in glacial acetic acid, containing 0.001 part by weight of active oxygen per part by volume o The reaction mixture is left to stand for 10 hours at room temperature

 <Desc / Clms Page number 20>

 and it is then treated as indicated in Example 8.

   After chicmatographic purification of the crude product, 0.6 part by weight of # 8.9; 22.23- is obtained.
 EMI20.1
 3-acetoxy-7,11-diketo-ergostadiene with a melting point of 132 - 135 (fi = 272 mp: logs = 3.95) o max If we submit the: $ '992z, f3 3 acetoxy' 7mhydroxy = 11 = keto = crude ergos tadiene to a gentle reduction by the method of Clemmensen, one then obtains, by elimination of the double bond in 8,9 and the hydroxyl group in
 EMI20.2
 position 7, L1 22.23 3acetoxy = 11 keto ergostne, with a melting point of 124 - 126 124 - We also succeed, in A, 9922.2 3 'acetoxy =' l hydroxy 11 keto ergostadiene, to eliminate by degrees the double bond in the ring and the hydroxyl group in position 7, first saturating, catalytically, the double bond # 8;

  9, by then oxidizing the hydroxyl attached to the carbon atom 7 to ketone and converting, according to the indications of Example 1, into
 EMI20.3
 At 22.23 = 3 = acetoxy-ll = keto = ergostene with a melting point of 124 - 126, the A 2z9z3 = 3ma.cetoxy = ?, 11 diketo = ergostene obtained, with a melting point of 195, 5 - 196.



   Example 20.
 EMI20.4
 1 part by weight of 99 $ '9 3 pmnitrobenoxy = cholesm tadiene is dissolved in 100 parts by volume of carbon tetrachloride and added to 0.30 parts by volume of a solution of tertiary butyl chromate in carbon tetrachloride (corresponding to 0.035 part by weight of chromic acid per part by volume) and 30 parts by volume of glacial acetic acid The mixture is stored for 6 days at room temperature and then treated as described in Example 13, The crude product obtained is, with a view to its purification, chromatography on aluminum oxide and it is obtained.
 EMI20.5
 holds it at $ 699 9 3p nitro'benoxy 11 keto cholestadiene which is saponified by boiling it for 3 hours, in a nitrogen atmosphere,

   with 50 parts by volume of a half-normal solution of potassium hydroxide in methanolo.For the following reactions, it is advantageous to convert the 3-hydroxy compound formed into the corresponding acetate, the absorption spectrum of which in ultra-violet exhibits a characteristic maximum at 285 m # (log. = 4.0) and whose absorption spectrum in the infrared shows at 1732, 1664, 1620 and 970 cm-1 the bands of the group acetate, from the group-
 EMI20.6
 ment A 8g9-11-eeto and the double bond A 6.7.



  1 part by weight of 3 acetor ll keto = cholestadiene is dissolved in 30 parts by volume of absolute ether, cooled to 0 and added 6 parts by volume of an ethereal solution of phthalic monoperacid (containing 0.007 part by weight of active oxygen per part by volume) The solution is stored for 7 days at 0, after which the oxidizing agent is completely used. The reaction mixture is treated as indicated in Example 14 and the crude oxidation product is isomerized in a benzene solution, with a complex of ether and boron trifluoride and the reaction product isolated according to the indications of Example 17.

   We obtain in this way
 EMI20.7
 Lesson 0.6 part by weight of $ 9g 3macetoxy ?, 11 diketo cholestne which can, without special purification, be reduced to 3 acetoxy 7.11 = diketo eholes tane, with a melting point of 168 - 169, at zinc aid in glacial acetic acid, as described in Example 1.

   
 EMI20.8
 1 part by weight of A '' "-3r-aeetoxy-ll-keto-cho-lestadiene is dissolved in 150 parts by volume of ethanol, 0.001 part by weight of eosin is added and passed through the solution under a strong lighting, for 6 to 8 hours, a strong draft, The solution is concentrated under vacuum at the
 EMI20.9
 room temperature dissolves the 6,9-peroxide of 9'9 9 3Y acetoxy 11 eeto-cholestad6énàzfçrmé in 100 parts by volume = at? acetic glacial acetic and adds to the solution, at room temperature, 5 parts by weight of powder of zinc.

   The mixture is heated for a short time to 80, then it is treated
 EMI20.10
 as described in Example 140 This gives 3 acetoxy ?, 11 = diketo cholestane with a melting point of 168 - 169 o

 <Desc / Clms Page number 21>

 
 EMI21.1
 Example 210 r "D.



  Ex = 2-1 -.- one part by weight of ± 7.8; 22.23-3ibac'toxy-9.11- One part by weight of '' '' -acetoxy-.9, ll- epoxy is dissolved -ergostadiene, described in example 2, in 100 parts by volume of absolute benzene, add 0.3 part by weight of freshly sublimated ferric chloride and leave the whole for 2 hours at room temperature. The mixture is then diluted. reaction mixture with ether, the ethereal solution washed with water, sodium bicarbonate solution and water, dried and the ether evaporated ;, The crude product obtained is recrystallized from methanol; ,
 EMI21.2
 A g99322z3 3r acetoxy llmeeto ergostadiene is thus obtained, melting at 122 - 123;

   (read ") D = +90 (c = 0.951 in chloroform), the absorption spectrum of which in the ultra-violet shows a maximum of 252 mali log E = .0) and the spectrum of which absorption in the infrared present, next to the band at 1730 cm-1 due to the acetate group, a strong characteristic absorption at 1660 cm-lo
 EMI21.3
 A'-3'17diacetoxy-9,11-epoxy-androstene, described in Example 13, can be converted in a similar manner by treatment with ferric chloride, in benzene solution, into A 819-30,17ê-diacetoxy- 11-keto-androsteneo This compound can be recrystallized from a mixture of ether and hexane or from methanol, it melts at 177.5 - 179, has a specific optical rotation.


    

Claims (1)

EMI21.4 cifiqüea. D = +930 (in chloroform) and its absorption spectrum in cifique (a. D = presents a chloroform) m its absorption spectrum in the ultra-violet has a maximum of 5 mp (log ± = 3.96 ) 0 REV END ICA T ION 80 ============================= 1. - A process for preparing compounds of the steroid series with oxygen in position 11, remarkable, in particular, by the following characteristics considered separately or in combination: a) It consists of treating with agents allowing the introduction of EMI21.5 re oxygen, unsaturated 7-keto-steroids in 8,9, their enol derivatives or the corresponding diene compounds, unsubstituted in position 7, to cause hydrolysing or isomerizing agents to act on the epoxides formed , in reacting the 7,11-dihydroxy compounds with dehydrogenating agents, in treating compounds having a double bond or an epoxy group in the ring B with reducing agents, if appropriate after introduction of oxygen in position 7, and finally, in the compounds having a substituent in position 7, to replace the latter by hydrogenated b) After the action of the dehydrogenation agents according to 1, one eliminates by reduction, in the 11-ketones obtained , a double bond or an epoxy group in position 8,9, if necessary after introduction of a ketone group in position 7, and finally the oxo groups present in the B ring are replaced by hydrogen. ) As starting substances, 8,9 unsaturated 7-keto-steroids, their enol derivatives or the corresponding diene compounds unsubstituted in position 7, and having in position 3 a free or functionally modified hydroxyl or oxo group are used. d) The starting substances are treated in successive stages with the agents allowing the introduction of oxygen. EMI21.6 e) A 7'g9'll terodes are transformed by means of agents permitting the introduction of oxygen into A 9 -7-keto-steroids and the latter are further treated with agents permitting the introduction of oxygen. oxygen., 'f) Dehydrogenating agents are made to act in stages on EMI21.7 7,11-dihydroxy compounds. g) The 8,9-epoxy-compounds are acted in stages of reduction, h) A 7'g11; 22,233 acetoxy-ergostatriene is used as starting material i) 7 '$' is used as starting material 'llm3macetoxym cholestadieneo <Desc / Clms Page number 22> dry j) 1-alpha methyl ester is used as starting material. EMI22.1 cide A 'l, 8J9, 1l-3O Exacetoxy-choladieno k) A' g'11m20 = diacetic toxy-allo-pregnadiene, o 1) is used as starting substance y'g''ll '= 3 acem toxy = stigmastatrieneo m) A 7,8 is used as starting substance; 9.11¯3.17 = diaceous = toxy-androstadiene 2. - A variant of the process defined under 1.), characterized in that one starts with a compound which can be obtained as an intermediate product at a stage of the process and that all the remaining stages of the product are carried out. ceded or part thereof. 3. - As new industrial products and in so far as they are not used in human therapy, the compounds prepared according to 1) and 2.). 4. - As new industrial products, the compounds used as starting substances for the process according to 1a) and 2). 5. - As new industrial products and in so far as they are not used in human therapy, the compounds obtained according to 1a) and 20) as intermediate products or as final products. 60 - As new industrial products and in so far as they are not used in human therapy, the new compounds described in the examples