BE509837A - - Google Patents

Description

       

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  CYCLOPENTANOPOLYHYDROPHENANTHRENE SERIES COMPOUNDS AND PROCESS
FOR THEIR PREPARATION.



   The invention relates more particularly to new chemical compounds of the cyclopentanopolyhydrophenanthrene series and to the methods for preparing them. The invention relates more particularly to new compounds of cyclopentanopolyhydrophenanthrene having functional substituents in the carbon nucleus and specifically to novel compounds having a hydroxy or keto substituent in the 11-position, and to methods of preparing such compounds.



   It has been found that compounds of the adrenal cortical substance, for example Kendall's compound E (Cortisone) have great value in the treatment of various diseases. In addition, it is likely that Kendall's compound E and / or other closely related 11-hydroxysteroids will find increasing therapeutic uses in the future. Unfortunately, the only method of preparing such compounds presently available uses deoxycholic or cholic acids as a starting material. Cholic and deoxycholic acids have hydroxy substituents in the carbon ring at position 12, thus providing a means of introducing a functional substituent at position 11.

   However, cholic and deoxycholic acids, which are obtained from animal bile, are only available in limited quantities. Until now, there has been no practical method by which a functional group could be introduced into the carboneg nucleus allowing the use of more abundant steroids such as sterols, ergosterol, cholesterol, stigmasterol, or sapogenins. plants such as diosgenin, tigogenin and the like.



   An object of the present invention is to provide a method of introducing a functional group into the carbon nucleus at position 11.



  Another object is to provide a process for converting compounds of cyclopentanopolyhydrophenanthrene having a double bond at the 7: 8 position to the corresponding compound of cyclopentanopolyhydrophenanthrene having a - group.

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 Hydroxy or keto compound at the 7 and 11 positions. Another object is to provide new compounds of the steroid series having functional groups in the carbon ring suitable for the preparation of other cyclopentanopolyhydrophenanthrene compounds. Other objects will be made apparent by the detailed description given below.



   In accordance with the present invention, it has been found that compounds of the cyclopentanopolyhydrophenanthrene series having a keto substituent can be synthesized by the reactions given below.
 EMI2.1
 
These reactions are carried out as follows:
A cyclopentanopolyhydrophenanthrene compound having a 7: 8 double bond (1) is reacted with mercuric acetate, yielding the corresponding compound having conjugated de-double bonds in the 7: 8 and 9:11 positions (11). which is treated with a peracid, thereby forming an epoxide represented by either of formulas III A and III B.

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  (The exact structure of the epoxide is not currently known and is represented by one or the other of forms III A and IIIB. Or, the product obtained may be a mixture of these 2 forms. ). This epoxide is then treated with an adsorbent to form the corresponding # 8-7,11-dihydro-xy compound (IV) o
Compound A 8-7,11-dihydroxy (IV) is reacted with an oxidizing agent to convert the hydroxy substituents to keto groups thereby obtaining the corresponding 8-7, 11-diketo derivatives of cyclopentano-polyhydrophenanthrene (V).

   These diketo compounds are then reduced to saturate the # 8 double bond and form the corresponding 7,11-diketo compound (VI) o The saturated diketo compound is then reduced to remove the 7-keto substituent, thereby producing the corresponding 11-keto compound. (VII). These latter compounds are useful intermediates for the preparation of 11-keto compounds having desirable therapeutic properties.



   Compounds # 7,9 (11) of the cyclopentanopolyhydrophenanthrene series are conveniently prepared by reacting the corresponding compound # 7 with mercuric acetate. This reaction has been found to be preferably effected by reacting Compound # 7 with mercuric acetate and glacial acetic acid in the presence of a suitable solvent medium such as chloroform. The reaction is conveniently carried out by stirring the reaction mixture for 16-24 hours. When the reaction is complete, the compound # 7.9 (11) is recovered from the reaction mixture by removing the precipitated mercury acetate and concentrating the solution under reduced pressure.

   If desired, the residue can be further purified by crystallization from suitable solvents. Thus, this process can be used to prepare 7,9 (11) - pregnadiene-3-ol-20- 3-acetate. one, and # 7.9 (11) -dehydrotigogenin acetate from # 7-pregnolone acetate and # -dehydrotigogenin acetate respectively. In an alternative process, other acylated derivatives of these starting materials or the 3-hydroxy compounds can be used as starting materials in the present process to prepare the corresponding compounds # 7,9 (11).



   In addition, 3-hydroxy- # 7,9 (11) -choladienic acid, which is also a useful starting material for the processes according to the invention, is readily prepared by reduction of 3-hydroxy acid. -12-keto # 7.9 (11) -choladienic. This is conveniently accomplished by reacting the ketoacid with hydrazine hydrate and an alkali metal hydroxide in the presence of a suitable high boiling solvent, for example diethylene glycol.



   According to a feature of the invention, it has been found that cyclopentanopolyhydrophenanthrene compounds having double bonds at the 7: 8 and 9:11 positions are readily oxidized to the corresponding epoxy derivatives. By carrying out the process according to the invention the compound # 7,9 (11) is reacted with an organic peracid such as perbenzoic acid, perphthalic acid, performic acid, peracetic acid and other compounds. - similar ones.

   It is preferred to carry out this reaction by bringing the peracid at room temperature or lower in intimate contact with a solution or a suspension of the starting material in an inert solvent medium such as benzene, toluene, xylene, etc. a petroleum hydrocarbon, ether and the like. It has been found that the organic peracides: perbenzoic acid and perphthalic acid, give particular satisfaction in the process of the invention in that they allow maximum yields to be obtained under the best conditions. .



   If desired, the epoxy derivative can be easily recovered from the resulting reaction product by extracting the acidic reaction by-products with an aqueous solution of an alkali and by evaporation.

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 The residue thus obtained can be further purified by conventional crystallization methods in order to recover the epoxide in pure form to dryness.



   However, when it is desired to convert the epoxy compound to the compound
 EMI4.1
 If the corresponding 9 -'l, 11-dihydroxy se is not necessary to isolate the epoxy compound and the reaction product, obtained by oxidation with the peracid, can be reacted directly with the adsorbent to form the
 EMI4.2
 desired Li "-7,11-dihydroxy-cyclopentanopolyhydrophenanthrene compound.



   Thus, by the process described above, compounds of cyclopentanopolyhydrophenanthrene having double bonds in position 7: 8 and 9: 11 are converted into corresponding epoxy derivatives; example, compounds such as ergosterol D, acylated derivatives of ergosterol D, 3-hy- acid
 EMI4.3
 droxy- '9 (' ') - bisnorallochloladiene or its esters, 3-acyloxy- 1). 7.9 (11) -bisnorallochloladienic acid or its esters, 3-hydroxy- 14 7.9 (11) -cholad.enic acid, or its esters, 3-acyloxy- L1 7 '9 (11) - choledienic or its esters, 7,9 (II) -dehYdrotigogenin or its acyl derivatives, A '9 (11) -allopregnadiene-3-ol-20-one or its acyl derivatives, and other similar compounds are converted into their corresponding epoxy compounds.



   According to another feature of the present invention it has been found that the epoxy compound can be reacted with an adsorbent.
 EMI4.4
 acid to produce the compound: 8: 9-7,11-dihydroxy. In carrying out this reaction, it is found preferable to react the epoxide and the adsorbent material in an inert solvent medium such as benzene or ether. Although various acidic adsorbents can be used for this purpose, such as silica or acid washed alumina, it has been found particularly suitable to employ an acid washed adsorbent, such as washed alumina. acid, since these substances are more active and carry out the desired reaction in a very short period of time.

   Carrying out this reaction in accordance with the preferred method of the invention, a solution of the oxide in an inert solvent medium is passed through a chromatography column containing acid washed alumina or acid washed alumina. silica. Alternatively, the reaction is carried out by mixing the adsorbent with the epoxide, preferably a suitable mixture of the adsorbent, and the epoxide is allowed to stand for a period sufficient to convert substantially all of it.
 EMI4.5
 the epoxy in compound A '9''ll-dihydroxy corresponding. The time required for the reaction to complete varies somewhat depending on both the structure of the epoxy being treated and the particular adsorbent that is used.

   In general, with an acid washed adsorbent such as alumina, the reaction proceeds in about 3 to 5 hours for compounds of the cholic acid series, while the corresponding compounds of the series of l ergosterol may take 1 to 4 days to complete the reaction.



   After the reaction is complete, the adsorbent is first eluted with a non-polar solvent such as petroleum ether, benzene, or ethyl ether to remove the epoxide which has not reacted. - gi, or any other impurity, and then with a polar solvent such as a lower aliphatic alcohol or mixtures consisting of a lower aliphatic alcohol and a non-polar solvent, in order to elute the compound
 EMI4.6
 The desired '9 7'f'-dihydroxy. Generally, it is found that methanol, or mixtures of chloroform and methanol are particularly suitable for eluting the # 8-7,11-dihydroxy compound. The product is then recovered from the polar solvent eluting by evaporation to dryness.

   The residue thus obtained can be purified by recrystallization from organic solvents according to the conventional practice of chemistry.

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 Thus by the process described above, various epoxides of com-
 EMI5.1
 containing Ó 7.9 (11) -cyclopentanopolyhydrophenanthrene, such as the epoxides of ergosterol D, acyl derivatives of ergosterol D, 3-hydro- xy- A 799 (11) -bisnorallocholadienic acid or its esters , 3-acyloxy- Q 7,9 (11) -bisnorallocholadienic acid or its esters, 3-hydroxy- j 7'9 (11) -choladienic acid or its esters, 3-acyloxy acid - d 7'9 (11) - choladienic or its esters, of acylated 7'9 (11) y g .., of '7 9 (11), or its acylated derivatives, and other similar compounds are converted to the corresponding # 8- 7,11-dihydroxy derivatives.



   According to another feature of the invention, it has been found that
 EMI5.2
 8-7,11-dihydroxy compounds are easily oxidized to give a new series of compounds having a double bond at the 8: 9 position and keto substitutes at the 7 and 11 positions. This oxidation is easily accomplished.
 EMI5.3
 for example by treating the 8-7,11-dihydroxy compounds with chromic acid, in the presence of an acid such as acetic or sulfuric acid.



  It has been found that an oxidizing mixture consisting of chromic acid, acetone and sulfuric acid is particularly suitable for this oxidation and makes it possible to obtain maximum yields of the desired diketo compound under optimum conditions. When carrying out this process, it is necessary to protect any other hydroxyl substituent, for example a 3-hydroxy group, by converting that group to an acyloxy substituent. After the oxidation, such acyloxy substitutes can be readily hydrolyzed to prepare the corresponding hydroxy compounds.
 EMI5.4
 



  These novel compounds of A $ -7,11-d.ceto-cyalopentanopolyhydrophenanthrene are reduced to saturate the 8: 9 double bonds and produce the corresponding saturated 7,11-diketo compound. This reduction is conveniently accomplished by, for example, reacting compound # 8 with zinc in the presence of acetic acid.



   According to the methods described above, cyclopentanopolyhydrophenanthrene compounds having 7,11-diketo substituents, such as
 EMI5.5
 3-acyloxy-7,11-diketo-8,22-ergostadiene, 3-acyloxy-7,11-diketo-# 8 -bisnorallocholenic acid and its esters, 3-acyloxy-7,11-diketo acid - # 8
 EMI5.6
 cholenic and its esters, 3-acyloxy-7,11-diketo-8¯tigogenin, La $ -allopregnene-3-ol-7,11,20-trione and its acyl derivatives and other similar compounds, can be obtained by the oxidation of the corresponding 7,11-dihydroxy compounds. In addition, these diketo compounds can be reduced to corresponding compounds having a saturated bond at the 8: 9 position.



   In addition, it has been found that the compounds of 7,11-diketo-cyclopenta-
 EMI5.7
 nopolyhydrophenanthrene can be reduced to the corresponding 11-keto compounds. It is preferred to effect this reduction by reacting the 7,11-diketo compound with hydrazine hydrate and an alkali metal hydroxide at elevated temperatures in a high boiling solvent medium, for example, diethylene glycol. It is surprising that under these reaction conditions the 11-keto group is not simultaneously reduced with the 7-keto group. On the contrary, it has been found that the desired 11-keto compounds are obtained under optimum conditions in excellent yields by this reduction process.



   Thus, following the processes described above we can prepare
 EMI5.8
 3-hydroxy-11-keto-22-ergostene, 3-hydroxy-11-ketobisnorallocholanic acid, 3-hydroxy-11-ketotigogenin, as well as the corresponding esters, acyl derivatives or derivatives esterified acyls, from corresponding 7,11-diketo compounds. If desired, these 3-hydroxy-11- compounds

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 keto can be oxidized to give the 3,11-diketo-compounds by known methods of chemistry.



   The 11-keto cyclopentanopolyhydrophenanthrene compounds obtained by the methods of the invention can be used as starting materials in the preparation of other steroid compounds such as compound E or Kendall's compound F.



   Thus, the processes of the invention provide a convenient and practical method by which one can convert compounds of the cyclopentanopolyhydrophenanthrene series, which do not contain a functional group in the carbon ring, into corresponding 11-hydroxy or 11-keto compounds. - laying. Therefore, as previously indicated, the production of Kendall's Compound E and similar compounds containing an 11-keto or hydroxy group is no longer limited by the availability of relatively scarce and expensive raw materials such as cholic acid. or deoxycholic, and these therapeutically important compounds can be prepared from the more abundant plant sterols, sapogenins and their degradation products.



   The following examples are presented for the purpose of explaining the specific features of the invention.



  Example 1.



   Preparation of ergosterol D acetate epoxide from ergosterol D acetate.



   One gram (2.27 millimoles) of ergosterol D acetates is dissolved in 30 cm3 of benzene and 10 cm3 of a solution of perbenzoic acid equivalent to 1.21 millimoles of oxygen (O2) is added. . After 5 minutes the perbenzoic acid is consumed and the reaction mixture is transferred to a separating funnel with 50 cm3 of benzene. The solution was washed 4 times with 25 cc of a 1% solution of caustic potassium hydroxide and then with water until the washings were neutral. The benzene solution is dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo under a nitrogen atmosphere. The yield of crude product is 950 mg.



  Crude ergosterol D acetate epoxide by recrystallization from acetone melts at 208-210 ° C.
 EMI6.1
 analysis calculated for C30H46OC: C = 79.25; H = 10.20 Found: C = 78.83; H = 9.85 Example 2.



   Preparation of ergosterol D acetate epoxide from ergosterol D acetate.



   In an operating variant, the process of Example 1 is carried out as follows:
5 grams (11.4 millimoles) of ergosterol D acetate are dissolved in 32 cm3 of benzene and 12.5 millimoles of monoperphthalic acid in 176 cm3 of ether are added. After overnight rest, the monoperphthalic acid is completely consumed.



   The reaction mixture is filtered off a small amount of precipitated crystalline material and the filtrate is concentrated to dryness.



   The crude product on recrystallization from acetone melts at 198-204 C. The mixed melting point with an authentic sample of o-

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 EMI7.1
 xyde is 201-206950C.
 EMI7.2
 



  Example 3.



   Preparation of ergosterol D epoxide from ergosterol D.



   4 g of ergosterol D (9.9 millimoles) are suspended in 65 cm3 of benzene and slowly added at 5 ° C. while stirring 10.9 millimoles of perbenzoic acid in 27.5 cm3 of benzene. The reaction mixture is allowed to warm to room temperature and after 4 3/4 hours all of the perbenzoic acid is consumed as indicated by the negative reaction with iodine-starched paper.



   The insoluble crystalline material, which is ergosterol D epoxide, is filtered off. The epoxide melts at 182-186 ° C.
 EMI7.3
 



  Recrystallized from benzene, the melting point is 185-188 C.
 EMI7.4
 analysis calculated for G2SH4402: C = 81.50; H = 10.75 Found: C = 81.25; H = 10.79 Example 4.
 EMI7.5
 



  Preparation of 3-acetoxY-7.ll-dihydroxY-8,22-ergostadiene from ergosterol acetate epoxide D.



   8.6 g of ergosterol acetate epoxide D is dissolved in 100 cm3 of benzene and 220 cm3 of petroleum ether is added. This solution is chromatographed in a column containing alumina washed with acid (172 g Al2O3).



   The column is prepared in acetone and washed with 1000 cm3 of petroleum ether before passing the compound through it.



   The column is then eluted successively with the following solvents:
 EMI7.6
 
<tb> ether <SEP> from <SEP> petroleum
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> petroleum / benzene <SEP> <SEP> <SEP> 4 <SEP>: <SEP> 1
<tb>
 
 EMI7.7
 n r8 AB 11 3; 2 fi fi .t fi fi "" t) 1: 4
 EMI7.8
 
<tb> benzene
<tb>
<tb> ether
<tb>
<tb>
<tb> Methanol
<tb>
<tb>
ethyl <tb> acetate <SEP>
<tb>
<tb>
<tb> chloroform
<tb>
   From the elution with methanol, a fraction (535 mg) melting between 232-234 C. By recrystallization from chloroform-acetone, the fraction is obtained.
 EMI7.9
 substance, which is 3-acetoxy-7,11-dLhydrozy-Ô '22 -ergostadiene, melts at 24.0-242 oc.
 EMI7.10
 

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 EMI8.1
 Analysis hold. for C30H0.

   C, 76.22; H = la, 24
 EMI8.2
 
<tb> found <SEP> C <SEP> = <SEP> 76.04 <SEP>; <SEP> H <SEP> = <SEP> 10.29 <SEP>
<tb>
 Example 5.
 EMI8.3
 Preparation of 3-acetox.Y-7,11-dihydroxy-8,22 -ergostadiene from ergosterol acetate epoxide D.



   13 g of the ergosterol acetate epoxide D are dissolved in 200 cm3 of benzene and chromatographed on 390 g of alumina washed with acid. The chromatographic column is prepared in acetone and washed with benzene before passing the compound.



   The chromatogram is developed with the following solvents:
 EMI8.4
 
<tb> petroleum / benzene <SEP> <SEP> <SEP> 4 <SEP>: <SEP> 1 <SEP> 1500 <SEP> cm3
<tb>
<tb>
<tb> "<SEP> fi <SEP> fi <SEP>" <SEP> 3 <SEP>: <SEP> 2 <SEP> 2000 <SEP> cm3
<tb>
<tb>
<tb>
<tb> "<SEP>" <SEP> "<SEP>" <SEP> 2 <SEP>: <SEP> 3 <SEP> 2500 <SEP> cm3
<tb>
 
 EMI8.5
 if Il fa n 1: 4 2000 cm3
 EMI8.6
 
<tb> ether <SEP> 4500 <SEP> cm3
<tb>
<tb> methanol <SEP> 1500 <SEP> cm3
<tb>
<tb> <SEP> ethyl acetate <SEP> 4500 <SEP> cm3
<tb>
<tb> acetone <SEP> 1500 <SEP> cm3
<tb>
<tb> chloroform <SEP> 1500 <SEP> cm3
<tb>
 
From the methanol fraction, 2.7 g of a substance melting at 244 C.



   From the ethyl acetate, acetone and chloroform fractions
 EMI8.7
 5.3 g of 37-acetoxy-7,11-dihydroxy-8,22-ergostadiene are obtained which, by recrystallization from acetone, melts at 245-247 C. Mixed with a sample
 EMI8.8
 As a result of the product of Example 4, a melting point of 21, .- 2/6 C (0 ..) 3 = + 80 Calc. for C30H4804: C = 76.22; H = 10.24 Found: C = 76.28; H = 10.19
The 3,7,11-triacetate derivative is obtained by treating the 7,11dihydroxy compound with acetic acid and pyridine. Melting point: 171-173 C.
 EMI8.9
 



  Calc analysis. for C30H5206: C = 73.34; H = 9.41 Found: C = 73.35; H = 9.03 Example 6.
 EMI8.10
 



  Preparation of 3-acetox.y-7.11-dihydroxy-g'zz-erostadiene from ergosterol acetate D.



   309 g of ergosterol acetate D are dissolved in 1876 cm3 of benzen and oxidized at 10-15 C with 107.6 g of perbenzoic acid in 1775 cm3 of benzene. The reaction mixture is allowed to stand overnight. It is washed twice with 630 cm3 of a 5% solution of caustic potassium hydroxide, 3 times with 1000 cm3 of water and dried over anhydrous magnesium sulfate.



   70 cm3 of the above solution are diluted with 50 cm3 of benzene and 100 g of acid washed alumina are added. After standing for 4 days, the alumina is separated by filtration and washed as follows:
1000 cm3 of benzene at room temperature
6 x 300 cm3 of methanol at room temperature
500 cm3 of boiling metahanol
500 cm3 of boiling chloroform.

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   The product resulting from the washings with cold methanol is taken up in hot methanol-chloroform and the insoluble material is removed by filtration. By concentrating the filtrate until a small volume is obtained and seeding, 820 mg of 3-acetoxy-7,11-dihydroxy # 8 (9) 22 are obtained.
 EMI9.1
 ergostadiene (melting point 238.5-240.5oC) a
 EMI9.2
 Example 70
 EMI9.3
 Hydrolysis of 3-acetoy-7911-dihydroxr- to 8'22-ergostadiene to 3.7911-trihpdror-1 '2-ergostadiene.



   200 mg of 3-acetoxy-7,11-dihydroxy- # 8,22 ergostadiene are distilled under reflux with 15 cm3 of 1N caustic potassium hydroxide in methanol. A crystalline precipitate is obtained after a short period of reflux and the mixture is treated under reflux for one hour. After dilution with water
 EMI9.4
 3,7-trihydroxy A 8,22-ergostdiene precipitates; it is recovered by filtration. After crystallization from metahanol, the compound has a point of 273-274 C.
 EMI9.5
 Analysis hold. for C 28 H4603 C = 78.13; H = 10.77 Found C = 77.99; H = 10.91 Example 8.
 EMI9.6
 



  Preparation of 3-acetoxy-7.11-diketo-8,22 -ergostadiene from 3-aceto-7.11-dihydroxy-4'zz-erostadiene.



  200 mg of 3-acetoxy-7,11-dihydroxy-8 (9) ¯, 22 -ergostadiene, suspended in 10 cm3 of acetic acid, are treated with 100 mg of sodium dichromate. After gentle agitation, the product dissolves rapidly; the resulting green solution is diluted with water and a gummy product is separated off which is extracted with benzene. The residue obtained after removing the benzene under vacuum readily crystallizes from methanol in the form of compact rosettes of fine needles. Yield: 40 mg, mp 121-123 C; # max. 2650, #, E% 147.



   Further purification by chromatography on aluminum
 EMI9.7
 mine gives pure 3-aceto-'7,11-diketo-$ '22 -ergostadiene; melting point 135-136 C.



  Cal analysis. for c 3 E 44 o: 4 C = 76.88; H = 9.46 Found: C = 76.91; H = 9.58 max. 2660 A (E 200 - isooctane) max. 2700 A (E 186 - ethanol)
 EMI9.8
 D = + 18 ô 2 (1% CHG13) a Example 9.



  Preparation of 3-acetoxY-7911-diketo-8,22-ergostadiene from α-acetoM-7,11-diMdroxv-4i '-ergostadienea To a stirred suspension of 2.36 g of 3-acetoxy-7, 11-dihydroxy- $ 'z2ergostadiene in 50 cm3 of purified acetone - a solution of 6.65 millimoles of chromic oxide in 5 cm3 of 3.6 N sulfuric acid is added.



  The mixture is stirred at 10 C for 10 minutes, after which 2 cm3 is added.

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 of water, and the mixture was stirred for 25 minutes at room temperature.



  The green inorganic material which separates is removed by filtration. The filtrate is stirred while adding 50 cm3 of water. The product is collected on a filter and washed with water. After drying under vacuum over pentoxide
 EMI10.1
 phosphorus, the product, 3-acetoxy-7,11-di.ceto-8, 22-ergostadiene is obtained in the form of a light yellow powder. Yield: 2.26 g melting point
 EMI10.2
 range 103-1140C; max. 2660 (E% 121 -ethanol).



  Example 10.
 EMI10.3
 



  Preparation of 3-aceto 7 11-diketo-22-ergostene from 3-acetox. Y-7911-cU.ceto, -er, ostadiene.



  A hot solution of 100 mg of 3-acetoxy-7,11-diketo is treated.
 EMI10.4
 Â 8.22-ergostadiene in 5cm3 of acetic acid and 0.1cm3 of water with 250 mg of zinc. The initially yellow solution is rapidly discolored and the mixture is heated in a steam bath for 3 hours. Water is then added to precipitate the diketone, which is dissolved in benzene. After elimination of the benzene, a residue is obtained which is recrystallized from
 EMI10.5
 methanol shot. Yield: 70 mg; melting point: 196-198OC; LC D = -25 (1.0% CHCl3).



  Calc analysis. for C30H46O4: C = 76.55; H = 9.85 Found: C = 76.68; H = 9.59
 EMI10.6
 Alkaline hydrolysis of 3-acetox3r-7,11-diketozz -ergostene gives 3-hydroxy-7,11-diketo-lL22-ergostene, melting point 198-199 C. Calc. Analysis. for C28H44O3: C = 78.46; H = 10.37 Found: C = 78.28; H = 10.09 Example 11.
 EMI10.7
 



  Preparation of 3-h droxy-11-keto-zz-erostene from 3-acetoxy-7,11-diketo-to -ergostene
A mixture of 1 g of 3-acetoxy-7,11-diketo-# 22-ergostene, 5 cm3 of diethylene glycol, 0.455 g of powdered caustic potash and 0, is heated at a temperature of 132 ° C. for 1 hour. 5 cm3 of 85% hydrazine hydrate. The temperature is then raised to 190-200 C and the reaction mixture is maintained at this temperature for 2 hours. Water is separated by distillation during the heating period.



   15 cm3 of water are added to the cooled reaction mixture and the dark brown suspension is acidified with hydrochloric acid and then filtered.



  The brown product is dissolved in hot acetone, filtered and then treated with charcoal (Darcoà and filtered. The solvent is evaporated off in a stream of nitrogen and the residue is dissolved in 25 cm3 of benzene and chromatography is carried out. on 20 g of acid washed alumina.



   The column is developed with the following solvents: benzene ether methanol ethyl acetate chloroform acetone
The benzene fractions provide a brown amorphous solid. All the other fractions are empty or give brown tars. The brown amorphous material is dissolved in 30 cm3 of benzene and 10 cm3 of petroleum ether is added and the solution is then chromatographed on 20 g of alumina washed with a-.

 <Desc / Clms Page number 11>

 cide. The chromatogram is developed with the following solvents:
Petroleum ether / benzene 1: 3
Benzene
Ether
Methanol
From the ether fractions, 150 mg of 3-hydroxy-
 EMI11.1
 Crystallized 11-keto-A -ergostene which on recrystallization from methanol melts at 173-174 C.



    [#] 23 = +26.6 [alpha] = 0.485 C = 0.91% CHCl3.



   Analysis hold. for C28H46O2: C = 81.10; H = 11.17 Found: C = 81.72; H = 11.29
3.175 g of 3-hydroxy-11-keto-# 22 ergostene are refluxed for 1 hour with 20 cm3 of acetic anhydride. On cooling to room temperature the 3-acetoxy compound crystallizes out. It is filtered and washed with a little cold methanol. Yield: 2.685; point
 EMI11.2
 of fusion 122-124 C. A small achenatillon of 3-acetoxy¯ ,, ¯Kétō 22 -ergostene recrystallized from methanol melts at 129.5-131.5 C.



  Analysis hold. for C30H48O3 C = 78.90; H = 10.59 Found C = 78.95; H, 10.82.



  Example 12.
 EMI11.3
 



  Degradation of 3-acetoxy-11-keto-22-ergostene to methyl 3-acetoxy-11-ketobisnorallocholanate.



  2.36 g of 3-acetoxy-11-keto-z2-ergostene are dissolved in 75 cm3 of chloroform and treated with ozone at 0 C. The reaction mixture is diluted with 100 cm3 of glacial acetic acid and oxide. at room temperature with 1 g of chromic acid dissolved in 1 cm3 of water and 50 cm3 of glacial acetic acid. 5 cc of methanol is added to destroy excess chromic acid and the solvent is removed in vacuo to almost dryness. The residue in the container is dissolved by shaking twice with a mixture of 100 cm3 of benzene and 50 cm3 of 5% sulfuric acid. The combined acidic aqueous solution was extracted again with 50 cm3 of benzene. The combined benzene extracts were washed with 50 cm3 of water and dried over anhydrous magnesium sulfate. The benzene is removed in vacuo and the residue dissolved in 250 cm3 of ether.



   The ethereal solution is stirred with 5 g of anhydrous sodium carbonate and 10 cc of water for 45 minutes. The ethereal layer is removed by decantation and the aqueous layer is washed twice by decantation with ether,
The aqueous layer is acidified with 50% sulfuric acid and the liberated 3-acetoxy-11-keto-bisnorallocholanic acid is extracted into ether and separated from the aqueous layer.



   The ethereal solution of the acid is treated with an ethereal solution of diazomethane and the ether evaporated on a steam bath until a small volume is obtained after which the methyl ester crystallizes out. . Yield: 750 mg.



  Recrystallized from methanol, the substance, which is methyl 3-acetoxy-ll-ketobisnorallocholanate, melts at 191-194 C.



  Analysis hold. for C25H38O5: C = 71.73; H = 8.91 Found C = 71.89; H = 9.15

 <Desc / Clms Page number 12>

 
 EMI12.1
 Preparation of methyl 3,11-diketobisnorallocholanate from methyl 3-acetoxy-ll-ketobisnorallocholanate.



   750 mg of methyl 3-acetoxy-11-ketobisnorallocholanate (prepared as indicated in Example 12) are distilled under reflux with 30 cm3 of 5% caustic potassium hydroxide for 1/2 hour. 50 cc of water are added, the precipitated product is filtered off and washed with water. The produces methyl 3-hydroxy-11-ketobisnorallocholanate, melts at 176-178.5 C.



   The 3-hydroxy compound is dissolved in about 30 cm3 of acetone and oxidized at room temperature by the addition of 200 mg of chromium trioxide in 5 cm3 of 1N sulfuric acid. The oxidizing agent is added dropwise. with stirring for a period of 1/2 hour. The reaction mixture is stirred for a further 10 minutes, 1 cm3 of methanol is added and the precipitated chromium salts are filtered off.



   The acetone solution is diluted with approximately 100 cm3 of water which precipitates the product. After cooling, the product is filtered off and washed with water. Recrystallized from acetone, the substance, methyl 3,11-diketobisnorallocholanate, melts at 201-204 C. The mixed melting point with an authentic sample is 201-204 C. The mixed melting point with the cis isomer is 171-193 C. Yield 250 mg.



  37% yield. [a] D = + 63 Calc. for C23H3304: C = 73.96; H = 8.90 Found: C = 74.18; H, 9.20.



  Example 14.
 EMI12.2
 Methyl 3-hydroxy-11-keto-bisnorallocholanate.
 EMI12.3
 

 <Desc / Clms Page number 13>

 



   One gram of 3-acetoxy-7,11-diketo-# 22-ergostene (I) obtained as described in Example 10 is dissolved in 100 cm 3 of chloroform and ozone is passed through it to the temperature of the ice bath until the approximate theoretical quantity of ozone is absorbed. The reaction mixture is diluted with 100 cm3 of glacial acetic acid, cooled to 5 ° C. and then oxidized with 0.5 g of chromic acid dissolved in 0.75 cm3 of water and 50 cm3 of glacial acetic acid. After standing overnight, 5 cm3 of methanol are added and the solvent is removed in vacuo until almost completely dry. The residue in the vessel is dissolved by shaking 2 times with a mixture of 25 cm3 of 5% sulfuric acid and 50 cm3 of benzene.

   The combined benzene solutions are dried over anhydrous magnesium sulfate, and the benzene is evaporated on a steam bath in a stream of nitrogen.



   The residue is dissolved in 200 cm3 of ether and stirred with 5 g of sodium carbonate and 2 cm3 of water for 21 hours. The sodium salt of 3-acetoxy-7,11-diketo-bisnorallocholanic acid (II) is separated by filtration and dried in a vacuum desiccator.



   The sodium salt is suspended in 25 cm3 of ether and 25 cm3 of 50% sulfuric acid are added in small portions until the mixture becomes distinctly acidic. 100 cm3 of ether are added to bring about the complete dissolution of all the solids. The aqueous layer is separated and extracted once with 50 cm3 of ether. The combined ethereal solutions are dried over anhydrous magnesium sulfate and then evaporated in a steam bath until a small volume is obtained, which causes crystallization of the 3-acetoxy-7 acid. 11-diketo-bisnorallocholanic (II). The product is recrystallized from ether; mp 235-238 C.
 EMI13.1
 



  Calc analysis. for C24H34O6: C = 68.87; H = 8.19 Found: C = 68.67; H, 8.04.



   125 mg of 3-acetoxy-7-11-diketo-bisnorallocholanic acid are suspended in 25 cm3 of ether and esterified with diazomethane. All the solid material dissolves and on evaporation of the ether to a small volume the methyl ester (III) crystallizes. Melting point 226.5-229 C. The mixed melting point with an authentic sample of the ester is 227-2300C.



   5 g of methyl 3-acetoxy-7,11-diketobisnorallocholanate (III) and 2.07 g of powdered caustic potassium hydroxide are introduced into a round-bottomed flask. 25 cc of diethylene glycol and 2.3 cc of 85% hydrazine hydrate are added, and the temperature is raised to 130-140 ° C and maintained for one hour. The temperature was then raised to 195-200 C and held for 2 hours. The temperature was then raised to 195-200 C and held for 2 hours. After cooling, the reaction mixture is dissolved in benzene and water and 50% sulfuric acid added until acidic reaction. The benzene layer is separated and the aqueous layer is extracted 3 times with 50 cm3 of benzene. The combined benzene solutions were washed with water and dried over anhydrous magnesium sulfate.



   Benzene is treated with Darco. The benzene solution is concentrated in vacuo to dryness, the residue dissolved in ether and esterified with an ethereal solution of diazomethane. The ether is evaporated off and the methyl 3-hydroxy-11-ketobisnorallocholanate (IV) recrystallized from methanol, melting point 177.5-180.5 C ..



   The mixed melting point with an authentic sample is 177-179 C. [[alpha]] D 23 = + 41.

 <Desc / Clms Page number 14>

 



  Example 15.



   Preparation of methyl 3-acetoxy- # 7,9 (11) -bisnorallocholadienate from methyl 3-acetoxy- # 7-bisnorallocholénate.
 EMI14.1
 



   To a stirred solution of 16.75 g of methyl 3-acetoxy- # 7-bisnorallocholenate in 235 cm3 of chloroform is added a solution of 31.8 g of mercuric acetate in 525 cm3 of acetic acid, in l. within 30 minutes. After stirring the mixture overnight, the precipitated mercury acetate is filtered off. The filtrate is shaken with 2 liters of water, and the 2 layers are separated. The aqueous layer is extracted with chloroform. The combined chloroform extracts are washed with water and then dried over anhydrous sodium sulfate. The chloroform is removed by vacuum distillation.

   The residual oily mass is triturated with methanol and filtered to give 11.03 g of crystalline methyl 3-acetoxy- # 7.9 (11) -bisnorallocholadienate, melting point 132-148 C. After several re-examinations. crystallizations from methanol and from acetone, the melting point is 162.5-165.5 C.



   Analysis of the product indicates that it is solvated with one mole of acetone.



  Analysis hold. for C25H36O4.C3H6O: C = 73.32; H = 9.23 Found C = 73.33; H = 9.08 [[alpha]] D 24 = + 54.7 (C = 1.077 in CHCl3) ultraviolet absorption: # max. 2500 # 2425, 2350; E% 310, 471, 424 (solvent: ethanol).



  Example 16.



    Preparation of methyl 3-acetoxy- # 7.9 (11) -bisnorallocholadienate epoxide from methyl 3-acetoxy # 7.9 (11) -bisnorallocholadienate.



   To a solution of 2.60 g of methyl 3-acetoxy- # 7.9 (11) -bisnorallocholadienate in 25 cm3 of benzene is added a benzenic solution containing 0.0072 moles of perbenzoic acid. After 7 minutes, a test with sodium iodide solution indicates that perbenzoic acid is consumed. The mixture is shaken with a cold 1N solution of caustic soda, and the benzene layer is washed with water. After drying over anhydrous sodium sulfate, the benzene is removed by vacuum distillation.



  The residue is washed on a filter with acetone. The crude product weighs 2.12 g; melting point 174-190 C. After 2 recrystallizations from acetone, 1.07 g of fine needles are obtained, melting at 196-200 C. A final recrystallization from acetone raises the melting point to 198 -201 C. After drying for 8 hours under vacuum at 100 C., analysis indicates that the epoxide is still solvated with one mole of acetone.



  Calc analysis. for C25H36O5.C3H6O: C = 70.85; H = 8.92 Found C = 70.73; H = 8.48

 <Desc / Clms Page number 15>

 
 EMI15.1
 M; 4 = -21 (C = 0.817 in CHCl3).



  Example 17.



  Preparation of methyl-aceto 11-dih, 8-bisnorallocholénate from 3-acetozy- Ô7.9 (11) - methyl bisnorallocholadienateea 1 gOde is dissolved in 3-acetoxy- lk, 7 $ 9 (11) Methyl bisnorallo- choladienate in 10 cm3 of benzene. This solution is placed on a column of 30 g of acid washed alumina which has previously been washed with acetone and benzene. After standing for 5 days, the column is eluted successively with 200 cm3 of ether, a mixture of 45 cm3 of acetone and 105 cm3 of ether, a mixture of 120 cm3 of acetone and 80 cm3. cm3 of ether, 200 cm3 of acetone and 250 cm3 of methanol. The fractions eluted with the acetone-ether mixtures are combined, and recrystallized from various solvents.

   It can be seen that the melting points are very variable and are a function of the heating rate.



   Recrystallization.
 EMI15.2
 
<tb>



  Solvent <SEP> Melting point <SEP> of <SEP>.
<tb>
<tb> acetone <SEP> 225 <SEP> - <SEP> 251 C
<tb>
<tb> <SEP> ethyl acetate <SEP> 237 <SEP> - <SEP> 248 C
<tb>
<tb> methanol <SEP> 218 <SEP> - <SEP> 230 C
<tb>
 Despite these variations, a satisfactory analysis is obtained for the
 EMI15.3
 product, methyl 3-acetoxy-'7,11-dihydroxy- ,, 8-bisnorallocholénate, recrystallized from methanol and dried at 100 ° C. under vacuum for 3 hours.



  Analysis hold. for C25H38O6: C = 69.09; H = 8.81 Found: C = 69.13; H = 9.02
 EMI15.4
 (..) 4 = + 92.4 (CHCl3) 'Example 18.



  Preparation of methyl 3-acetox-7.11-diketo -bisnorallocholénate from methyl 3-aceiox-7.11-dihvdror-4 -bisnorallocholénate.



  To a stirred solution of 1.60 g of methyl 3-acetoXY-7,11-dihydroxy-8-bisnorallooholenate in 30 cm3 of glacial acetic acid is added a solution of 0.730 g of sodium dichromate dihydrate in 30 cm3 of glacial acetic acid within 15 minutes. After stirring at 25 ° C. for 2 hours, the mixture is concentrated in vacuo to reduce it to a low volume. The residue is shaken with 50 cm3 of benzene and 50 cm3 of water. The aqueous layer was extracted twice with 25 cc portions of benzene. The combined benzene extracts were washed with 50 cc of water, dried over anhydrous sodium sulfate and the benzene removed by vacuum distillation. The residual oil was triturated with 3 cc of cold methanol and the resulting crystalline product collected and washed with cold methanol.



  Yield: 550 mg; melting point: 183-185 C. After two recrystallizations from methanol, the melting point of the diketo compound rises to 186.5-
 EMI15.5
 187.5 Co [o.) 4 = + 38.7 (C = 1.04, mal;). max. = 2700; Eg = 212. Analysis calculated for C25H34O6: C = 69.74; H 7, 96 Found: C = 70.00; H, 8.12.

 <Desc / Clms Page number 16>

 



  Example 19.
 EMI16.1
 



  Preparation of meth-aceto -7 11-diketo-bisnorallocholanate from 3-acetoX, methyl V-7.11-diketo-9-bisnorallocholenate.



  A mixture of 400 mg of methyl 3-acetoxy-7,11-diketo -bisnorallocholénate, 20 cm3 of glacial acetic acid, 0.4 cm3 of water, and 1 hour on a steam bath is heated for 1 hour. , 5 g of zinc powder. 1 g of zinc is added and the mixture is heated for an additional 2 hours. After cooling to room temperature, 50 cc of water is added to the mixture. The precipitated product is collected on filter as well as the residual zinc. The dried mixture is extracted with benzene. After removal of the benzene by vacuum distillation, the product, methyl 3-acetoxy-7,11-diketo-bisnorallocholanate, is recrystallized from methanol. Yield: 270 mg Melting point: 230-231.5 C.

   The analytical sample is recrystallized from methanol, melting point: 230.5-231.5 C.
 EMI16.2
 
 EMI16.3
 analysis hold. for Cz5H3606 G = 69.41? H = 8.39 Found: C = 69.70; H = 8.40 Example 20.
 EMI16.4
 



  Preparation of 3-hydroxsy-11-eetobisnorallocholanic acid and its methyl ester from 3-acetoxy-79ll-diketobisnorallocholanic acid.



  2 g of 3-acetoxy-7,11-diketobisnorallocholanic acid (prepared as described in Example 14) are stirred in a 50 cm3 round-bottomed flask with 15 cm3 of diethylene glycol, 1.5 g of powdered caustic potash and 1.5 cc of 85% hydrazine hydrate, then the temperature is slowly raised to 135-140 ° C and held there for 45 minutes. The temperature is then raised to 190-195 ° C. and maintained there for 1 hour.



   After cooling, the reaction mixture is acidified with 2N sulfuric acid, diluted with 30 cm3 of distilled water and filtered. The dried cake is tan in color and weighs 1.57 g. The product is dissolved in a benzene-ethanol mixture, treated with Darco, filtered through Supercell and the filtrate concentrated until crystallization begins. Recrystallization from benzene gives 0.60 g of a product melting at 258-261.4 C.



  Analysis hold. for C22H34O4: C = 72.89; H = 9.45 Found: C = 72.82; H = 9.34 In addition 0.60 g of lower melting point acid (melting point 252-258 C) is recovered from the mother liquors of the above product.



   A sample of the acid is esterified with diazomethane in ethereal solution to obtain methyl 3-hydroxy-11-keto-bisnorallocholanate (III) mp 175-177.5 C;
 EMI16.5
 (0. J 3 = + 42930. The melting point of mixing this compound with an authentic sample is 175-178 C.



  Example 21 - Preparation of 3-hydroxy-d 99 (11) -choladienic acid.
 EMI16.6
 

 <Desc / Clms Page number 17>

 



  A mixture of 77.6 g of 3-hydroxy-12-keto-# 7,9-choladienic acid, 600 cm3 of diethylene glycol, 116 cm3 is heated in a nitrogen atmosphere for 1/2 hour at 135-140 C. of hydrazine hydrate (85% solution) and 80 g of anhydrous caustic potash. During this time 130 cm3 of solvent (Glycol + ether) separated by distillation. Total reflux is maintained, the temperature is raised to 195-200 C and maintained for 6 hours. After cooling, the reaction mixture is diluted with 800 cm3 of water, cooled to 10 ° C. and acidified with 2.5N hydrochloric acid. The crude product is filtered off, washed until the mineral acid has completely disappeared. and dry. Yield 73 g.

   By recrystallization from acetone, 47 g of 3-hydroxy-7.9 (11) - choladienic acid are obtained, melting at 204-206 C.
 EMI17.1
 u. v. in ethanol: x .. max. E% 2450 410 2375 366 Methyl 3-hydroxy- # 7.9 (11) -choladienate.



   In order to obtain a more soluble compound for subsequent reactions, 3-hydroxy # 7.9 (11) -choladienic acid is esterified using diazomethane. The methyl ester melts at 122-124 C # max. 2380 - E% 366
2440 .- E% 411 [[alpha]] D 20 = 122 (dioxane) Calc. for C25H38O3: C = 77.65; H = 9.91 Found C = 77.02; = 9.72.



  Example 22.



   Preparation of methyl 3-acetoxy- # 7.9 (11) -choladienate from methyl 3-hydroxy- # 7.9 (11) -choladienate.



   A solution of 8 g of methyl 3-hydroxy- # 7.9 (11) -choladienate and 8 g of acetic anhydride in 50 cm3 of pyridine is stored overnight at room temperature. The solution is added to 300 cm3 of ice-water while stirring, the solid is filtered off, washed with water and dried in vacuo. Yield (crude product) 8.7 g; mp 143-147 C.



  A portion of the 3-acetoxy derivative purified by recrystallization from acetone melts at 153-154 ° C. and gives the following analysis: Wedge analysis. for C27H40O4: C = 75.66; H = 9.41 Found: C = 75.80; H = 9.18 Example 23.



   Preparation of Methyl 3-Acetoxy- # 7.9 (11) -choladienate Epoxide from Methyl 3-Acetoxy- # 7.9 (11) -choladienate.



   5 C 26 cm3 of a benzene solution of perbenzoic acid (0.011 mole) is added over the course of one hour while stirring to a solution containing 4.28 g (0.01 mole). of methyl 3-acetoxy # 7.9 (11) -choladienate in 100 cm3 of benzene. When the addition is complete, the solution is stirred for 1/2 hour at 5 ° C and then for 3 hours at room temperature. One molar equivalent of perbenzoic acid is consumed. The benzene solution is washed with 3 portions of 30 cm3 of a

 <Desc / Clms Page number 18>

 5% cold solution of caustic potash to remove residual perbenzoic acid and other acidic materials, followed by washing with ice water until neutral. The neutral benzene solution is dried over anhydrous sodium sulfate and concentrated in vacuo.

   A yield of 4.3 g of crude methyl 3-acetoxy- # 7.9 (11) -choladienate oxide, melting point 142.6 C. A sample purified by recrystallization from The acetone melts at 162-163 C and gives the following analysis:
 EMI18.1
 Analysis hold. for CZ7I105: C = 72.94; H = 9507 molecular weight. 444.6) Found: C = 73.03; H, 9.08.



     [[alpha]] D 23 = + 117 (in CHCl3) Example 24.
 EMI18.2
 



  Preparation of methyl 3-hydroxy-7.9 (II) -choladienate epoxide from methyl 3-hydroxy-Q 7'g (11) -choladienate.



   A solution containing 0.033 moles of perbenzoic acid in 100 cm 3 of benzene is added with stirring at 5 ° C. over the course of one hour.
 EMI18.3
 a solution of 11.6 (0.03 mol) of methyl 3-hydroxy-4a 799 (11) -choladienate in 300 cm3 of benzene. After the addition is complete, stirring is continued for 1/2 hour at 5 ° C., then for 3 hours at room temperature.



   One molar equivalent of perbenzoic acid is consumed in the reaction.



   The benzene solution was washed with 3 portions of 100 cm3 of a cold 5% caustic potassium hydroxide solution, then with ice water and dried over sodium sulfate. By concentration of the benzene solution
 EMI18.4
 When dried, the epoxide of methyl 3-hydroxy-7'9 (11) -choladienate is obtained.



  Example 25.



  Preparation of methyl 3-acetoy-7.11-dihydroxy-A -cholenate from the epoxy of methyl 3-aeetoxg-7.9 (11) -choladienate.



  A solution of 2 g of 3-acetoxy-Q 7'9 (11) -choladienate epoxide in 50 cm3 of benzene in contact with 40 g of washed alumina is kept for 4 days at room temperature. acid, stirring occasionally.



   The alumina is separated by filtration, washed until complete disappearance of the unchanged oxide using 6 portions of 50 cm 3 of benzene and then elution is carried out in a column with methanol (250 cm 3). The re-
 EMI18.5
 The solid of methyl 3-acetoxy-7,1L-d3.hydroxy-Q 8cholenate (1 g), obtained by removal of methanol, is purified by recrystallization from acetone; mp 193-197 C.



    Analysis calculated for C27H42O6: C = 70.10; = 9.15 Found: C = 70.20; H = 9.29 Example 26.
 EMI18.6
 



  Preparation of methyl 3-acetoxy-7.11-dihydroy- -cholenate from methyl 3-acetoxy-7.9 (11) -choladienate epoxide.



   A solution of 16 g of 3-acetoxy epoxide is kept for 5 hours at room temperature and with occasional stirring.
 EMI18.7
 to 7.9 -methylcholadienate in 400 cm3 of benzene in contact with 320 g of acid washed alumina.

 <Desc / Clms Page number 19>

 



   The alumina is separated by filtration, washed until complete disappearance of unchanged oxide using 6 portions of 300 cm3 of benzene, then the elution is carried out in a column with 3200 cm3 of methanol.



   By evaporating off the methanol, 7.2 g of methyl 3-acetoxy-7,11-dihydroxy-A 8-cholenate are obtained. The purification is carried out by tripping with a small volume of petroleum ether followed by recrystallization from acetone. The purified sample (2.5) melts at 194.8 C.



   The above transformation also proceeds well when the reaction time is reduced to a period of 3 hours.
 EMI19.1
 



  Example 27. Preparation of methyl 3-acetoxy-7.11-diketo-$ -cholenate from methyl 3-acetox.y-7-11, -didro, γ-0 $ -cholenate.



   To a stirred suspension of 1.7 g of methyl 3-acetoxy-7,11-dihydroxy- # 8 cholenate in 100 cm3 of acetone is added at 20 ° C. while stirring a solution of 0.5 g of chromium trioxide. in 4 cm3 of 10% sulfuric acid over 10 minutes.



   When the addition is complete, the mixture is stirred for 1 1/2 hours. The inorganic residue is filtered off and washed with 3 10 cc portions of acetone. The acetone solution is added with stirring to 66 cm3 of water and the precipitated 7,11-diketo compound is filtered off, washed with water until it is free of acid and then it is dried. Yield 1.57 g; melting point 112.5-113.5 C. After recrystallization from ethanol,
 EMI19.2
 the product, methyl 3-acetoxy-7,11-diketo-8-eholenate, melts at 114-115 C.



  Analysis hold. for C27H40O6 C = 70.40; H = 8.75 Found C = 70.93; H = 8.30
 EMI19.3
 ale. max. 2715 bzz $ 1 7 Example 28.
 EMI19.4
 



  Preparation of methyl 3-acetox.y-7,11-diketo-cholenate from methyl 3-acetoZY-7,11-diketo-8-cholenate.



  A mixture of 1.57 g of methyl 3-acetoxy-7,11-diketo-$ -cholenate, 17 cm3 of acetic acid, 1.7 cm3 of water and 3 is heated on a steam bath for 1 hour. , 4 g of powdered zinc.



   The reaction mixture is diluted with 80 cm3 of benzene and the zinc residue is separated by filtration. The benzene solution is washed with water to make it acid-free, dried over anhydrous sodium sulfate and concentrated to dryness. Yield 1.57 g. The product is purified by recrystallization from ethanol. Yield 1.17 g; of fusion 162--163 C.



  Calc analysis. for C27H42O6: C = 70.10; E = 9.15 Found: C = 70.52; H = 8.65 Example 29.
 EMI19.5
 



  Preparation of 7 <9 (II) -dehydrotisosenine acetate from 7-dehydrotioenine acetate.

 <Desc / Clms Page number 20>

 
 EMI20.1
 



   To a solution of 2.62 g (5.74 millimoles) of 7-dehydro-tigogenin acetate in 32 cm3 of chloroform is added a solution of 4.40 g of mercuric acetate in 70 cm3 of acetic acid. glacial. The mixture is stirred overnight after which the precipitated mercury acetate is filtered off.



   The filtrate is shaken twice with 200 cm3 portions of water. The chloroform layer is separated and dried over anhydrous sodium sulfate. After removing the chloroform by vacuum distillation, the syrupy residue is triturated with methanol. The crystalline product obtained in this way weighs 2.22 g. The compound has a double melting point. If placed in a bath below 150 C, the compound partially melts at 160-190 C, then resolidifies and remelt at 212-216 C. Recrystallization from hexane yields crystals showing the same behavior at Fusion point; however, recrystallization from absolute ethanol with slow cooling gives sheets melting at 214-219 ° C without prior melting.
 EMI20.2
 max.

   (in ethanol) 2350, 2425, 2500. 1% 249, 279, 181. max. (in ethanol) 2350, z4z5, 2500. E: - 249th z79, 181.



  Example 30.
 EMI20.3
 Preparation of 7.9 (11) -dehydrotigogenin acetate epoxide.



   To a solution of 1960 g (3.5 millimoles) of 7.9 (11) -dehydrotigogenin acetate in 25 cm3 of benzene is added 10 cm3 of a benzene solution containing 3.67 millimoles of perbenzoic acid. After standing at room temperature for 20 minutes, substantially all of the perbenzoic acid is consumed. The mixture is washed with 1N sodium hydroxide solution and with water. After drying with anhydrous sodium sulfate, the solvent is removed in vacuo, and the crystalline epoxide is digested in 10 cm3 of acetone. Yield 0.82 g; mp 263-270 C. with decomposition. (the bath is preheated to 250 C).



     ([alpha]) D 24 = - 73.



  Example 31.
 EMI20.4
 



  Preparation of 3-acetoT-'7911-dihydroy-8¯tigogenin from the epoxy of A 7.9 (11) -dehydrotigogenin acetate.



   A solution of 0.78 g of the epoxide in 20 cm3 of benzene is thickened with 25 g of alumina washed with 1-acid. After standing for 5 days at room temperature, the mixture is filtered and the alumina washed with 75 cm3 of benzene in several portions. The alumina is washed with 50 cc of hot methanol in several portions then with 75 cc of hot chloroform per portion. The combined washes of methanol and chloroform are distilled off in vacuo and crystallization of the residue is initiated with a little methanol.

 <Desc / Clms Page number 21>

 
 EMI21.1
 The product, 3-acetoxy-7,11-clihydroxy-8¯tigogenin, which crystallizes in fine needles, is collected on a filter and washed with methanol.



  Yield: 0.28 g; melting point: 250-254 C.
 EMI21.2
 



  Additional material was collected from the methanol washes: 0.08 g; mp 245-251 C.



  Example 32.
 EMI21.3
 



  Preparation of 3-acetoxy-7.ll-diketo-8-dehydrotigogenin from 3-acetoxy-7,11-dihydroxy-8-dehydrotixofienin.



   To a suspension of 0.346 g (0.71 millimoles) of 3-acetoxy-7,11-dihydroxy-8-dehydrotigogenin in 10 cm3 of acetone is added 0.8 cm3 of a solution of 1.06 millimoles of sodium trioxide. chromium in 3.6N sulfuric acid. After stirring for 15 minutes, the chromium salts which have formed are removed by filtration and washed with 5 cm3 of acetone. The filtrate is treated with 50-60 cm3 of water to precipitate the product which, after drying, weighs 0.283 g and melts at 190-200 C. After 2 recrystallizations from methanol, 3-acetoxy-7 is obtained. , 11-diketo-8-dehydrotigogenin in the state
 EMI21.4
 needles pale yellow, melting point 226-227 C. ['n ,, 24 = -14 (C = 0.813, CHCl3). # max. (in ethanol) 2700, E1% 180. D Example 33.
 EMI21.5
 



  Preparation of 3-acetoxy-7,11-diketotiRofienin from 3-acetoxy-7,11-diketo-8-dehydrotiaogenin.



   A mixture of 130 mg of 3-acetoxy-7,11-diketo-8-dehydrotigogenin, 4 cm3 of glacial acetic acid, a drop of water and 400 mg of powdered zinc is heated in a steam bath for 1 hour. The mixture is cooled and 30 cm3 of water and 20 cm3 of chloroform are added. After shaking well and filtering, the layers are separated and the aqueous layer extracted twice with 5 cc portions of chloroform. The combined chloroform extracts are dried over sodium sulfate, and concentrated in vacuo.



  Recrystallization of the residue gives small rectangular premiums. Return-
 EMI21.6
 ment 75 mg, melting point 241-243 0, f \ 1 24 = -72 (C = p, g27 'CHCl3).



  Example 34.
 EMI21.7
 Preparation of 11-ketotigogenin from 3-acetoxy-7.ll-diketotigenin.



   A mixture of 0.42 g is heated in an oil bath while stirring.
 EMI21.8
 of 3-acetox, p-7,11-diketotigogenin, 2.1 cm3 of diethylene glycol, 0.20 g of powdered caustic potash and 0.21 cm3 of hydrazine hydrate (85%). The temperature is raised to 120-130 C, and maintained there for 15 minutes. The temperature is then brought to 195-200 C for 45 minutes. After cooling, the mixture is poured into 25 cm3 of a mixture of water and ice and the resulting mixture is neutralized with dilute sulfuric acid. The solid part is removed by filtration and washed well with water. The dried crude product is dissolved in 20 cc of methanol and boiled for 5 minutes with a small amount of activated carbon. After removal of the carbon by filtration, the methyl solution is concentrated to 10 cm3.

   Water is added to the hot solution until crystallization begins. On cooling, 0.22 g of 11-ketotigogenin is obtained in the form of needles, melting at 220-226 C. Recrystallized from an ethyl acetate-petroleum ether mixture, the product melts at 222-226. vs.



  Cal analysis. for C27H42O4: C = 75.31 H = 9.83 Found C = 75.40; H = 10.20

 <Desc / Clms Page number 22>

 11-Ketotigogenin acetate is prepared by distillation under reflux with acetic anhydride, recrystallized from methanol, the acetate melts at 224-229 C.



  Example 35.



   Preparation of -acetate of # 7,9 (11) -allopregnadiene-3-01-20- one from 7-allopregnenolone acetate.
 EMI22.1
 



  To a solution of 6.4 g (0.0178 mol) of # 7-allopregnenolone acetate in 100 cm3 of chloroform is added a solution of 13.6 g (0.0427 mole) of mercuric acetate in 200 cm3 of glacial acetic acid and stir the mixture overnight.



   The mercury acetate formed is filtered off and the filtrate is shaken twice with 400 cc portions of water. The chloroform layer is separated and dried over sodium sulfate. After removing the solvent by vacuum distillation, the syrupy residue was triturated with methanol to give a crystalline product, wt 4.88 g, mp 130-159 C. Recrystallization from ethanol (abs.) 3.45 g of elongated prisms are obtained; melting point 155-159 C.
 EMI22.2
 



  1.) 4 = - 4.3, 6 i C = 1.09 in THIS).



  \ max. 2350, 2420, 2500; El cm 356, 396, 273.



  Example 360
Preparation of # 7,9 (11) -allopregnadiene-3-ol-20-oneo 3-acetate epoxide
To 58 cm3 of a benzene solution containing 0.0106 mole of perbenzoic acid is added 3.45 g (0.0097 mole) of # 7,9 -allopregnadiene -3-ol-20-one 3-acetate . The mixture is stirred for a few seconds to dissolve the crystalline material. After standing for 15 minutes, practically all of the perbenzoic acid is consumed. The mixture is washed with a 1N solution of caustic soda and then with water. After drying and removing the solvent in vacuo, the epoxide is recrystallized from acetone in the form of small prisms.

   Yield: 1.43 g, mp 186-192 C [a] 24 = 8.2 (C = 0.550 in CHCl3). @ Example 37.



  Preparation of # 8-allopregnene-3,7,11-triol-20-one 3-acetate from # 7,9 (11) -allopregnadiene-3-ol-20-one 3-acetate epoxide .



   To a solution of 1.43 g of # 7,9-allopregnadiene-3-ol-20-one 3-acetate epoxide in 35 cm3 of benzene is added 50 g of acid-washed alumina. After standing for 5 days at room temperature, the mixture is filtered and the alumina washed with 120 cc of benzene. The alumina is then extracted with 120 cm3 of hot methanol and 120 cm3 of hot chloroform. The extracts

 <Desc / Clms Page number 23>

 combined methanol and chloroform are concentrated to dryness and the residue is recrystallized from methanol to obtain 0.85 g of taken.
 EMI23.1
 my sand color, melting point 188-200oC C, 14 = 14.1 (C = 0.336 CHCl3) [a] D Example 38.
 EMI23.2
 



  Preparation of 11 -allopresnene-3-ol-7tll <20-trione 3-acetate from -allopresnene-3-7.11-triol-20-one 3-acetate.



  780 mg of g (9) -allopregnene-3,7-, 11-triol-20-one 3-acetate are oxidized in 20 cm3 of acetone using 2.66 millimoles of chromium trioxide in 2 cm3 10% aqueous sulfuric acid. After isolation of the product in the usual manner, it is recrystallized from methanol, which
 EMI23.3
 which gives 260 mg of pale yellow prisms, melting point 177-179 0. ["") 4 = 710 (C 1.12 CHCL \ max. 1% 226.



  + 71 (C - 1.12 CHCl3) o max. 2690, icm 226.



  Example 39.



  Preparation of allopregnan-3-01-7.11.20-trione 3-acetate from -allopregnene-3-ol-7.11.20-trione 3-acetate.



  A mixture of 210 mg of A-3-allopregnene-3-ol-7,11,20-trione 10 cm3 of glacial acetic acid, 2 drops of water, and 1 hour is heated in a steam bath for one hour. , 0 g of zinc powder. The product is isolated in the usual manner and recrystallized from methanol to give 140 mg of hexagonal prisms, mp 214-215 ° C.



  Example 40.
 EMI23.4
 



  Preparation of 3-acetoXY-7.ll-dihydroxy-0 '22 -erostadiene from ergosterol acetate epoxide D on silica gel.



   6.5 g of ergosterol acetate epoxide D are dissolved in 100 cm3 of benzene and chromatographed on a mixture of 159 g of silica gel and 120 g of sea sand. The chromatographic column is prepared in acetone and washed with benzene before passing the compound through. After washing the solution in the column with 75 cm3 of benzene, the chromatogram is developed with the following solvents:
 EMI23.5
 
<tb> petroleum / benzene <SEP> <SEP> <SEP> 2 <SEP>: <SEP> 3 <SEP> 1250 <SEP> cm3
<tb>
 
 EMI23.6
 tc He rr "1;

   1000 cm3
 EMI23.7
 
<tb> "<SEP> ethyl <SEP> 1000 <SEP> cm3
<tb>
<tb>
<tb>
<tb> methanol <SEP> 1000 <SEP> cm3
<tb>
<tb>
<tb>
<tb> <SEP> ethyl acetate <SEP> 1000 <SEP> cm3
<tb>
<tb>
<tb>
<tb> acetone <SEP> 1000 <SEP> cm3
<tb>
<tb>
<tb>
<tb>
<tb> ethyl <SEP> ether <SEP> 800 <SEP> cm3
<tb>
<tb>
<tb>
<tb>
<tb> methanol <SEP> hot <SEP> 600 <SEP> cm3
<tb>
<tb>
<tb>
<tb>
<tb> chloroform <SEP> 500 <SEP> cm3
<tb>
 From the first fraction of ethyl ether, 0.15 g of the 7,11-dihydroxy compound is obtained, melting at 235-238.5 C. From the methyl fractions, 0.18 g of the 7,11- compound is obtained. dihydroxy which, after recrystallizations from methanol and acetone, melts at 238-241 C.



   A mixed melting point with the product obtained by the process
 EMI23.8
 alumina (melting at 24l-244 C) gives 238-240 C 1a) 23 = + '79 Analysis ch. for C30H48O4: C = 76.22; H = 10.24 Found: C = 76.41; H = 10.40.



   Various changes and modifications can be made in carrying out the method according to the invention without departing from the spirit and object of the invention. So far as these changes and modifications are within the scope of the appended claims, they are to be regarded as constituting


    

Claims (1)

part of the invention. EMI24.1 RJLIJL! L5JL2JLTJL9JLS 1. Process using a steroid containing conjugated double bonds in the 7: 8 and 9:11 positions, characterized in that this system with conjugated double bonds is monoepoxidized. 2. Method according to claim 1, characterized in that the monoepoxidation is obtained by the use of an organic peracid. 3. Process for preparing an epoxide of a compound of # 7,9 cyclopentanopolyhydrophenanthrene, characterized in that the compound of cyclopentanopolyhydrophenanthrene is reacted with an organic peracid. 4. Method characterized in that catalytically rearranges a EMI24.2 epoxide of a compound of 11 7,9 -cyclopentanopolyhydrophenanthene to form a compound of -7,11-cU.hydroxyphenanthrene. 5. Method according to claim 4, characterized in that the catalyst is an acidic substance. 6. Process according to Claim 4, characterized in that the catalyst is an acidic solid adsorbent material. EMI24.3 7. Process for the preparation of an 11-keto-steroid characterized in that the conjugated double bonds located in the 7: 8 and 9:11 positions of the steroid nucleus are mono-epoxidized, in that the catalytically rearranged. resultant unsaturated epoxide to form a / \ 8-7,11-dihydroxy- steroid, in that this dihydroxysteroid is oxidized to form an # 8-7,11-clicketosteroid, in that the diketosteroid is reduced to a 7 , 11-diketoste- EMI24.4 stiff and that this 7,11di ketosteroid is selectively reduced to form an 11-ketosteroid. 8. Method according to claim 7, characterized in that the monoepoxidation is carried out using an organic peracid. 9. A method characterized in that an acyl derivative of ergosterol D is reacted with an organic peracid to obtain the corresponding epoxide. 10. Process characterized in that ergosterol D is reacted with an organic peracid to obtain ergosterol D epoxide. 11. A method characterized in that reacting an ester of a- EMI24.5 3-acyloxy-9g (11) -bisnorallocholadienic acid with an organic peracid to obtain the corresponding epoxide. 12. A method characterized in that reacting an ester of acid EMI24.6 of 3-acyloxy- / J. 7.9 (11) -choladienic with an organic peracid to obtain the corresponding epoxide. 13. A method characterized in that reacting an acyl derivative of 7,9 (11) -dehydro-ligogenin with an organic peracid to obtain the corresponding epoxide. 14. A method characterized in that reacts an acyl derivative of EMI24.7 A 99Cllmallopregnadiene 30l-20one with an organic peracid to obtain the corresponding epoxide. 15. A method characterized in that catalytically rearranges a EMI24.8 epoxide of a compound of A 7,9¯cyclopentanopolyhydrophenanthrene to form a compound of 8-7,11-dihydroxy-cyclopentanopolyhydrophenanthrene. 16. Process for preparing a compound of -711-dihydro- xycyc10pentanopolyhydrophenanthrene, characterized in that a <Desc / Clms Page number 25> EMI25.1 epoxy of a compound of A 7 j 9 -cyclopentanopolyhydrophenanthene with an acidic adsorbent material. 17. Process for the preparation of 3-acyloxy - ?, 11-dihydroxy- $ '22 - ergostadiene, characterized in that an epoxide of ergosterol D acylate is reacted with alumina washed with acid. EMI25.2 18. Process for the preparation of methyl 3-acetoxy-7,11-dihydrozy 1l8-bis-norallocholénate, characterized in that the epoxide of 3-acetoxy-A, 7'9 (11) -bisnorallocholedienate of methyl with acid washed aluminum. 19. Process for preparing 3-acetoy-7,11-dihydroxy- $ - methyl cholenate, characterized in that the epoxide of 3-acetoxy-! J is reacted. 7.9 (11) -methylcholadienate with acid washed alumina. 20. Process for the preparation of 3-aéetozy-7,11-dihydroxy-8-dehy- drotigogenin, characterized in that the epoxide of the acetate of 7,9 (11) -dehydrotigogenin is reacted with acid washed alumina. 21. Process for preparing # 8 -allopregnene-3- 7,11-triol-20-one 3-acetate, characterized in that the epoxide of 3-acetate is reacted EMI25.3 of A '-allopregnadiene-3-ol-20-one with acid washed alumina. 22. a) Process for the preparation of a # 8-7,11-diketo compound of the cyclopentanopolyhydrophenanthene series, characterized in that one oxidizes EMI25.4 a compound of -7,11-dihydroxycyclopentanopolyhydrophenanthrene. 22. b) The method of claim 22 a), characterized in that the oxidation is carried out with chromic acid. 23 a). Process for the preparation of a 7,11-diketocyclopen- compound EMI25.5 tanopolyhydr ophénantr sne, characterized in that one reduces a compound of $ - '7,11-diketo-cyclopentanopolyhydrophenanthrene < 23 b) A method according to claim 23 a), characterized in that the reduction is carried out using a metallic reducing agent in the presence of an acid. 23 c). Process according to Claim 23 b), characterized in that the reduction is carried out using zinc in the presence of an acid. 24 a). Process for the preparation of an 11-keto-cyclopentanopolyhydrophenanthrene compound characterized in that a 7,11-diketo-cyclopentanopolyhydrophenanthrene compound is selectively reduced. 24 b). Process according to Claim 24 a), characterized in that the compound of 7,11-diketo-cyclopentanopolyhydrophenanthrene is reduced using a hydrazine. 24 c). Process according to Claim 24 a), characterized in that EMI25.6 reducing the compound of ', 11-diketo-cyclopentanopolyhydrophenanthene using hydrazine hydrate and an alkali metal hydroxide in a suitable high boiling solvent. EMI25.7 25. Methods of preparing Q, 7'9 (11) -steroids, 7.9 (11) steroid epoxides, $ -7,11-dihydroxysteroids, '$ -', 11 diketosteroids, 7.11 -diketosteroids and 11-ketosterofids. and'the compounds thus obtained substantially as described and claimed. 26. As a new compound, an epoxide of a cyclopentanopolyhydrophenanthrene compound having double bonds at positions 7: 8 and 9:11. 27. Ergosterol acetate epoxide D. 28. Ergosterol epoxide D. EMI25.8 29. 3-Acetoxy- '9 (' l ') -bi snorallo methyl choladienate epoxide. <Desc / Clms Page number 26> EMI26.1 30. 3-Acetoxy-! ::: epoxide,. 79 (11) -methylcholadienate. 31. Methyl 3-hydroxy T 9 (11) -choladaenate epoxide. 32. Ag (11) -dehydrotigogenin acetate epoxide. 33. 7,9 (11) -allopregnadiene-3-ol-20-one 3-acetate epoxide. EMI26.2 34. A compound of cyclopentanopolyhydrophenanthrene having a double bond at the 8: 9 position and hydroxy substituents at the 7 and 11 positions. EMI26.3 35. 3-Acetoxy-7g11-dihydroxy- /.18.22 -ergostadiene. 36. 3,7,11-triacetoxy- to 8,22-ergostadiene. 37. 3,7,11-trihydroxy-A 8'j22-ergostadiene. 38. 8-Allopregnene-3,711-triol-20-one 3-acetate. 39. 3-aceto-7yll-dihydroxy- A 8 -bi snorallo methyl cholenate EMI26.4 the. EMI26.5 40. Methyl 3-acetoxy-7,11-dihydroxy-0 -cholenate. 41. 3-Acetoxy-ï, 11-dihydroxy-8-dehydrotigogenin. EMI26.6 42. A cyclopentanopolyhydrophenanthrene compound having keto substituents at positions 7 and 11. 43. A compound of cyclopentanopolyhydrophenanthrene having a double bond at the 8: 9 position and keto substituents at the 7 and 11 positions. EMI26.7 44. 3-acetoxy-7,11-diketo-Á 8,22-ergostadiene .. Methyl 45. 3-acetoxy-7,11-diketom tA -bisnorallocholenate. 46. Methyl 3-acetoy-7,11-diketo-A -cholenate. 47. 3-Acetoxy-7,11-diketo-8-dehydrotigogenin. 48. 6-Alloprene 3-acetate 3-ol-i, 11,20-trione. 49. Allopregnan-3-ol-7,11-20-trioneo 3-acetate 50. 3-acetoXY-7,11-diketo-Il 22 -ergostene. 51. 3-hydroxy-7,11-diketo-22 -ergostene. 52. Methyl 3-acetoxy-7,11-diketotigogeninea 53a-3-acetoxy-7,11-diketocholanate. 54. 3-Acetoxy-7 ., 11-diketobisnorallocholanic acid. 55. Methyl 3-acetoxy-7,11-diketobisnorallocholanate. 56. Methyl 3-hydroxy-7,11-diketobisnorallocholanate. EMI26.8 56 a). Composed of 11-keto-allocyclopentanopolyhydrophenanthrene. having a substituent at 17 which contains more than 2 carbon atoms. EMI26.9 57. Compound of 11-keto-cyclopentanopolyhydrophenanthrene having EMI26.10 the formula: <Desc / Clms Page number 27> EMI27.1 wherein R is a radical selected from the group consisting of hydroxy, acyloxy and keto and R1 is a substituent selected from the group consisting of EMI27.2 wherein R2 is a substituent selected from the group consisting of carboxy and esterified carboxy. EMI27.3 58. 3-hydroxy-11-c'to- a Z2-ergostene. 59. 3-acetoxy-11-keto -ergostene. 60. Methyl 3-acetoxy-11-ketobisnorallocholanate. 61. Methyl 3-hydrozy-11-ketobisnorallocholanate. b2. Methyl 3,11-diketobisnorallocholanate. 63. 3-Acetoxy-11-ketobisnorallocholanic acid. 64. 3-Hydroxy-11-ketobisnorallocholanic acid. EMI27.4 65. 11-Ketotigogenin. 66. 3-acetoxy-11-ketotigogenin. <Desc / Clms Page number 28> N. R. EMI28.1 5'70 - Compound of 11-keto-cyclopentanopolyhydrophenanthrene having the form: EMI28.2 wherein R is a radical selected from the group consisting of hydroxy, acyloxy and keto and R1 is a substituent selected from the group consisting of: EMI28.3 Claim 57 contains formulaic errors: the first formula on page 27 is incorrect, as can be seen from the explanations which follow: "in which R is a radical ... and R1 'is a substituent 0'0 It . Indeed, the letters R and R 'do not appear in the preceding formula. This first formula should have been the one on page 28. This is only a clarification, given the explanations given in the preamble of description and formula VII at the bottom of page 2. On the other hand, as appears from page 28, the formula which appears at the head of claim 57 as filed must replace the third formula of this claim,