US2844601A - 3-oxygenated bisnor-17(20)-cholen-22-ols - Google Patents

Description

United States Patent I 3-OXYGENATED BISNOR-17(20)-CHOLEN-22-OLS Raymond L. Pederson and Erik H. Jensen, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application October 10, 1955 Serial No. 539,673

16 Claims. (Cl. 260-3973) H CH3 wherein R is selected from the group consisting of hydrogen and acyl, the acyl group being of an organic carhoXyli-c acid containing from one to eight carbon atoms, inclusive, and wherein R is selected from the group consisting of hydroxy, acyloxy, the acyl group of which is definedas above, and keto. In the preferred embodiment of the invention the acyl radical is of ahydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

The term bisnor-l7(20)cholene is used generically in the description and claims and includes those bisnorl 7(20).-cholenes having additional double bonds, such as .in positions 4, (6), and the like. These compounds are preferably, but not necessarily, oxygenated in the 3-positionthat is substituted by hydroxy and acyloxy, wherein the acyl group is of an organic carboxylic, preferably a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, or keto group.

The term l'7-ketoandrostane is used in its generic sense and refers throughout the description and claims to 17- ketoandrostanes with or without double bonds in positions 4 or 5 or in additional positions and preferably oxygenated in the 3-position, that issubstituted by hydroxy and acyloxy, defined as shown above, or a keto group.

Similarly, the termv l7-ketoetiocholane is used generical free ly and includes 17-ket-oetiocholanes which may have double bonds in positions 6(7), 9(11), or the like, and which are preferably oxygenated in position 3, having a 3-hydroxy, acyloxy, as defined above, or a keto group.

The process of the present. invention comprises selectively reducing the 22-aldehyde group of a bisnor-17(20)- cholen-22-al (I) with a metal borohydride to obtain the corresponding bisnor-17(20)-cholen-22-ol and thereafter subjecting the thus obtained bisnor -17-(20)-cholen- 22-01 (II) or the 22-ester thereof, produced by esterification of the obtained bisnor-17(20)-cholen-22-ol, to ozonolysis to obtain the corresponding 17-ketoandrostane or 17-ketoetiocholane (III);

.It is an object of the present invention to provide a method for the production of 17-ketosteroids of the androstane and etiocholane series from the corresponding 17(20)-bisnorcholene aldehydes through selective reduction of the aldehyde group to the alcohol group with or without esterification of the thus obtained l7(20)-bisnorcholen-22-ol and selective ozonolysis of the 17(20)- double bond. It is another object of the instant invention to produce new and useful steroid intermediates belonging to the class of bisnor-17(20)-cholen-22-o1s and 22- esters thereof through selective reduction of the bisnor- 17(20)-cholen-22-ols in the presence of double bonds and/or keto groups and esterification ofthe 22-alcohol group by conventional methods. A particular object of the instant invention is the provision of a process for the production of bisnor-17(20)-cholen-22-ols such as especially the 3-ketobisnor-4,17(20)-choladien-22-ol, 3-ketobisnor 17(20) cholen 22 01, 3 ketoallobisnor- 17(20) cholen 22 ol, 3 acyloxybisnor 5,17 (20)- choladien-2201 wherein the acyl groups is defined as before, bisnor-5,17 (20)-choladiene-3,22-diol and the respective 6- and ll-hydroxy, acyloxy, keto derivatives thereof and the corresponding 22-organic carboxyl-ic and preferably hydrocarbon carboxylic acids there-of. Other objects of the present invention will be apparent to those skilled in the art to which this invention pertains.

The intermediates and the process of the present invention are useful for the production of physiologically active compounds and key-intermediates for the production of such physiologically active compounds belonging to the androstane and etiocholane series. Thus through reduction of 3 ketobisnor 4,17 (20) choladien 22 a1 is obtained 3 ketobisnor 4,17(20) choladien 22 01 which by ozonolysis yields 4-androstene-3,l7-dione possessing androgenic properties andbeing an intermediate in the production of testosterone. In a similar manner 3- ketobisnor 4,17 (20) choladien 22 01 22 acylate, such as the acetate propionates, benzoates, and the like, are useful to give by ozonolysis or chromic acid oxidation, 4 androstene 3,17 dione; 3,11 diketobisnor 4,17(20) choladien 22 01 and 22 esters thereof, obtained by reduction of 3,11 diketobisnor 4,17(20) choladien 22 ols are useful for the production of androgenically and anabolically active adrenosterone; 3a-

or 3,8 hydroxybisnor 17-(20) cholen 22 01 and 22-acylates thereof give anesthetically active 30:- or 3,3- hydroxyetiocholan l7 one; 3,11-diketobisnor-17(20)- cholen 22 01 gives etiocholane e 3,11,20 trione (genera1 anesthetic activity), 3-hydroxyor 3-acyloXy-6-ketobisnor-17(20)-cholen-22-ol provide the corresponding 3-hydroxyetiocholane-G,17-dione and 3-esters thereof which can be oxidized, after hydrolysis, in the case of a 3-ester, to the corresponding etiocholane-3,6,17-trione which may be brominated to 4-bromoetiocholane-3,6,l7-trione and dehydrobrominate-d to give 4-androstene-3,6,17-trione of estrogenic activity. Similarly the etiocholane-3,6,17-trione from which 4-androstene-3,6,l7-trione is prepared, may also be prepared by the method of the present invention from 3,6-diketobisnor-l7(20)-cholen-22-ol. 3,11--

bisnorallo-17(20)-cholen-22-ol yields androgenically active androstane-3,l1,17-trine by the method of the present invention.

The starting compounds of the present invention are bisnor-1 7(20)-cholen-22-als, such as illustratively: bisnor 17(20) cholen 22 al, bisnor 4,17(20) choladien 22 al, 3 ketobisnor 17(20) cholen 22 a1, 3 keto'bisnor 4,17(20) -choladien 22 al, 3 hydroxybisnor 17(20) cholen 22 al, 3a and 3 3 acetoxybisnor 17(20) cholen 22 als, 3aand 3B hydroxybisnor 5,17(20) choladien 22 als, 3aand 3pacetoxybisnor 5,17(20) choladien 22 al, 3,11 diketobisnor 4,l7(20) choladien 22 al, 3 ketoallobisnor 17(20) cholen 22 al, 3,11 diketoallobisnor- 17(20) cholen 22 al, 3,6 diketobisnor 17(20)- cholen 22 al, 3 ketobisnor 11cc hydroxyand 3- ketobisnor 115 hydroxy 4,17(20) choladien 22- als, 3/3 hydroxyand 3,8 acetoxy 6 ketobisnor- 17(20) cholen 22 als, 3- acetoxyallobisnor 17(20)- cholen 22 al, 3,11 dihydroxybisnor 17(20) cholen- 22 al, 3,12 dihydroxybisnor 7 17(20) cholen 22- al, 3 acyloxybisnor 17(20) cholen 22 a1, 3 acyloxybisnor 5,1?(20) choladien 22 -al, 3 acyloxy- 6 ketobisnor 17(20) cholen 22 al, 3 acyloxybisnorallo 17(20) cholen 22 al, 3 ketobisnor 110cacyloxy 4,17(20) choladien 22 al, 3,11 diacyloxybisnor- 17(20) cholen 22 al, 3,12 diacyloxybisnor- 17(20) cholen 22 al, and the like, wherein the acyloxy groups are of an organic carboxylic acid containing from one to eight carbon atoms, inclusive, preferably of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive. Representative acyloxy groups illustratively comprise: formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoyloxy, B-cyclopentylpropionyloxy, dimethylacetoxy, trimethylacetoxy, phenylacetoxy, toluyloxy, anisoyloxy, gallyloxy, salicyloyloxy, cinnamyloxy, hemisuccinyloxy, hemitartaryloxy, dihydrogencitryloxy, hemimaleyloxy, hemifumaryloxy, crotonyloxy, acrylyloxy, B-methylcrotonyloxy, cyclohexanecarbonyloxy, chloroacetoxy, di chloroacetoxy, trichloroacetoxy, bromoacetoxy, hemiquinolinoyloxy, nicotinyloxy, piperonyloxy, 2-furoyloxy, thioglycollyloxy, para-chlorobenzoyloxy, para-bromobenzoyloxy, meta-nitrobenzoyloxy, 3,5-dinitrobenzoyloxy, benzenesulfonyloxy, para chlorobenzenesulfonyloxy, para-toluenesulfonyloxy, para-nitrobenzenesulfonyloxy, 3, -dinitrobenzenesulfonyloxy, benzenephosphonyloxy, and the like. I

The preparation of the starting compounds belonging to the new class of bisnor-17(20)-cholen-22-als is described in detail in copending application Serial No. 539,671, filed October 10, 1955, and comprises: reacting a bisnorcholan aldehyde either available or produced by reduction of the carboxyl group of the known bisnorcholanic acid to an aldeyde group by methods known in the art iRosenmund, McFayden-Stevens and the more recent method by Weygand et al., Angew. Chem. 65, 525 (1953)] with a secondary amine, preferably a cyclic secondary amine such as piperidine, morpholine, pyrrolidine, homomorpholine, oxazolidine, and the like, to obtain the corresponding 22-(N-tertiaryamino)-bisnor- (22)-cholen, brominating the thus obtained 22-(N- tertiaryamino)-bisnor-20(22)-cholene at a temperature between about minus thirty and plus twenty degrees centigrade to obtain a 20-bromobisnorcholan-22-al and dehydrobrominating with pyridine or other tertiary amines to obtain the corresponding bisnor-17(20)-cholen-22-al.

In carrying out the process of the present invention the selected bisnor-17(20)-cholen-22-al, dissolved in an organic solvent, is treated with a metal borohydride. Solvents used in this reduction are aqueous solutions of dioxane, methanol, ethanol, tetrahydrofuran, isopropyl alcohol, tertiary butyl alcohol, and the like. The metal a borohydrides used are essentially the alkali-metal borohydride such as lithium, sodium or potassium borohydride. However, other metal hydrides such as calcium, zinc, cadmium, aluminum and ammonium borohydride, are operative. The reduction reaction is performed at a temperature between minus ten degrees centigrade and the boiling temperature of the solvents, up to degrees centigrade, but is preferably conducted at room temperature, that is, between twenty to thirty degrees centigrade. The time of reaction is between fifteen minutes and four hours preferably between one and two hours and at the end of this time the reaction is stopped by the decomposition of the metal borohydride, for example, by adding a dilute mineral acid such as hydrochloric orsulfuric acid. The amount of metal borohydride used is generally in a ratio of stoichiometric proportions of each to an excess of the borohydride ranging up to five equivalents. One fourth mole of borohydride to one mole of steroids is commonly used. Larger or smaller amounts of metal borohydride can be used but no advantages are obtained. Larger amounts of borohydride may reduce the carbonyl groups on other positions than the 22-aldehyde group. The' reaction product is separated from the mixture by conventional means such as chromatography or extraction with a water-immiscible solvent, for example, ether, benzene, chloroform, carbon tetrachloride, methylene dichloride, ethylene dichloride, or the like, followed by drying and evaporating the solvent to obtain the solid reaction product. Recrystallization from convenient organic solvents such as methanol, ethanol, acetone Skellysolve B hexanes, ethyl acetate, mixtures of these, or the like, and/ or chromatography are used to obtain the pure reaction product. I

The ozonolysis of the reaction product, a bisnor-17- (20)-cholen-22-ol, is carried out in conventional manner, by dissolving the product in a convenient solvent such as methylene chloride, chloroform, ethyl acetate, cyclohexane, or the like, and letting a stream of ozone-oxygen pass through the cooled solution. Temperatures be tween minus 75 degrees and plus 25 degrees centigrade are operative, with the preferred range between minus thirty and about minus seventy degrees centigrade. The solution containing the ozonide of the 17(20)-cholen-22 01 is then decomposed by the addition of acetic acid and zinc dust, in the preferred embodiment under continuous stirring. The decomposition of the ozonide by zinc and acetic acid is performed at room temperature and requires a reaction period between fifteen minutes and several hours. The reaction product is separated by conventional means such as filtering the solution to remove the zinc dust, washing and evaporating the solvent, and

recrystallization or chromatography as deemed necessary to obtain a pure 17 -ketosteroid.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting.

EXAMPLE 1 3-ket0bisn0r-4J 7(20 -ch0ladien-22-0l A solution containing 4.90 grams of 3-ketobisnor- 4,l7(20)-choladien22-al in a mixture of fifty milliliters of dioxane and twenty milliliters of water, was reacted with 100 milliliters of 0.5 N sodium borohydride in 1 N aqueous sodium hydroxide solution. One mole of sodium borohydride (NaBH by reaction with water is capable of giving eight hydrogen equivalents; therefore a 0.5 normal sodium borohydride solution corresponds to one sixteenth molar sodium borohydride solution. After a period of ninety minutes the mixture was stopped by adding 100 milliliters of 4 N sulfuric acid. The reaction mixture was then extracted with benzene, the extract was washed with dilute alkali and thereafter with water. The :benzene layer was separated from the water layer and evaporated to give 4.91 grams of residue which was chromatographed over 400 grams of Florisil with petroleum ether of boiling TABLE I Fraction Solvent petroleum ether-acetone 97:3. petroleum ether-acetone 96:4. petroleum ether-acetone 92:8. petroleum ether-acetone 85:15.

Fractions 42 thru 48, inclusive, were combined and evaporated to yield 1.32 grams of 3-ketobisnor-4,l7(20)- choladien-ZZ-ol. The thus obtained crude 3-ketobisnor- 4,l7(20)-choladien-22-ol of melting point 160 to 170 degrees centigrade was recrystallized from acetone to give a pure sample of 3-ketobisnor-4,17(20)-choladien-22-ol of melting point 166 to 168 degrees centigrade, rotation [al plus 109 degrees (in chloroform) Egg- 242 mmu, 16,700

Analysis.--Calcd. for (2221 13202: C, 80.44; H, 9.82. Found: C, 80.05; H, 9.94.

EXAMPLE 2 3-ket0bisn0r-4J 7(20) -choladien-22-0l ZZ-acetate A solution containing 500 milligrams of 3-ketobisnor- 4,17(20)-choladien-22-ol in a mixture of eight milliliters of pyridine and four milliliters of acetic anhydride was allowed to stand at room temperature (22-25 degrees centigrade) over a period of sixteen hours. Thereafter the solution was poured into 75 milliliters of ice-water and thus-formed precipitate collected on filter. Recrystallization of the precipitate from ethyl acetate and Skellysolve B hexanes yielded pure 3-ketobisnor-4,17(-20)- choladien-22-ol 22-acetate.

EXAMPLE 3 3-ketobisn0r-4,1 7(20) -chladien-22-0l 22-benz0ate In the manner shown in Example 2, reacting B-ketobisnor 4,17(20)-choladien-22-ol with benzoylchloride in pyridine solution results in 3-ketobisnor-4,17(20)-choladien-22-ol 22-benzoate.

EXAMPLE 4 3-ket0bisn0r-4,17(20) -ch0ladien-22-0l 22-pr0pionate In the manner shown in Example 2, reacting 3-ketobisnor-4,l7( 20) -choladien-22-ol with propionic anhydride in pyridine solution results in 3-ketob'isnor-4,17(20)- choladien-22-ol 2.2-propionate.

EXAMPLE 5 3-ket0bisnor-4,1 7 20 -choladi'en'-22-ol 22-valerate In the manner shown in Example v2, reacting 3-ketobisnor-4,17(20)-choladien-22-ol with Valerie anhydride in pyridine solution results in 3-ketobisnor-4,17(20)-choladien=22 ol '2 2' -valerate. i

EXAMPLE 6 3-ket0bisn0r-4,17(20) '-cholddien-"2 2-ol Z Z -phehyIdc-'zate In the manner shown in Example 2, reacting S-ketobisnor-4,17 (20)-clroladien-22-ol with phenylacetyl bromide in pyridine solution results in 3-ketobisnor-4,17(20)- choladien-ZZ-ol 22-phenyl'acetat'e;

EXAMP E 7 ates are obtained by reacting 3-kt'etobisnor-4,17 (20)-chola* dien-22-ol with an acylating reagent such as an organic carboxylic acid halide or anhydride and preferably a hydrocarbon carboxylic acid halide or anhydride having from one to eight carbon atoms, inclusive. Representative 3- ketobisnor-4,17(20)-choladien-22-ol 22-acylates thus obtained comprise the 3-ketobisn or-4,17(20)-choladien-22-ol 22-butyrate, isobutyrate, isovalerate, hexanoate, heptanoate, octanoate, toluate, trimethylacetate, 2-furoate, nicotinate, cinnamate, salicylate, trichoroacetate, bromoacetate, o, p, m-bromobenzoate, 0-, p-, m-nitrobenzoate, 3,5- dinitrobenzoate, piperonate, p-toluenesulfonate, benzenesulfonate, methanesulfonate and the like.

EXAMPLE 8 4-andr0sten'e-3J 7-di0ne A solution containing 82 milligrams of S-ketobisnor- 4,17(20)-choladien-22-ol, 0.5 milliliter of pyridine, and fifty milliliters of methylene chloride was cooled in a Dry- Ice acetone bath. An ozone-oxygen stream containing 0.0275 millimole of ozone per minute of flow (in 200 milliliters of oxygen) was added for a period of 13.6 minutes. The reaction mass was thereupon poured onto 0.5 gram of zinc dust and stirring started; twenty milliliters of acetic acid was added and stirring continued for a period of two hours. The reaction mixture was then filtered, washed with water and the solvent was evaporated to leave 79 milligrams of a white solid. The thus obtained crude 4-androstene-3,17-dione was chromatographed over Florisil taking the following fifty-milliliter.

fractions:

TABLE II Fraction Solvent 1-5 .l Skellysolve B-acetone 96:4. 6-15 Skellysolve B-aeetone :5.

Fractions 7 to 11 were combined and recrystallized from methylene chloride Skellysolve B hexanes giving pure 4-androstene-3,l7-dione of melting point 175 to 176 degrees centigrade. Infrared spectrum was compared to that of a known sample and found to be identical.

Analysis-Calm. for C H O C, 79.68; H, 9.15. Found: C, 79.36; H, 9.12.

EXAMPLE 9 4-androStene-3,1 7-dione from 3-ket0bisn0r-4,I 7(20) choladien-22-ol 22-acetate A solution containing 100 milligrams of 3-ketobisnor- 4,17 (20)-choladien-22-ol 22-ace'tate, 0.5 milliliter of pyridine and fifty milliliters of methylene chloride was cooled in a Dry Ice acetone bath. An ozone-oxygen stream containing 0.02.75 millimole of ozone per minute of flow was added over a period of twelve minutes. The reaction mass was thereupon poured onto 0.5 gram of zinc dust. Thereto was added under continuous stirring twenty milliliters of acetic acid. The reaction mixture was filtered, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give as a white crystalline solid crude 4-androstene-3,17-dione, which is purified in the manner shown in Example 8. In the same manner as given in Example 9, other 3-ketobisnor 4,17(20)-choladien 22-ol 22-acylates such as shown in Examples 3 through 7, inclusive, can be ozonolyzed to give 4-androstene-3,l7-dionc. Alternatively 3-ketobisnor-4,l7(20)-choladien-22-ol 22-acylates can be converted to 4-androstene-3,-17-dione through oxidation with chromic anhydride in acetic acid solution at temperatures between zero and fifty degrees Centigrade.

- EXAMPLE l0 3a-acetoxybisnor-1 7 (20 -ch0len-22-0l Otherwise like Example 1, 3u-acetoXybisno r-7(20)- eholen-22-al, dissolved in ethanol, was treated with .7 potassium borohydride in the presence of' an aqueous solution of potassium hydroxide. The mixture thereafter wasextracted with chloroform, the chloroform'solution was'dried over anhydrous sodium sulfate and evaporated to give white crystals which were purified by recrystallization from ethyl acetate-Skellysolve B hexanes to give pure 3u-acetoxybisnor- 17 (20) -cholen-22-ol.

In the same manner as given in Example 2, 22-acylates of 3a-acetoxybisnor-17(20)-eholen-22-ol, such as 3a,22- diacetoxy-bisnor-17(20)cholen may be prepared.

EXAMPLE 1 1 3u-acet0xyeti0ch0len-1 7-0ne In the manner given in Example 2, 3a-acetoxybisnor- 17(20)-cholen-22-ol was subjected to ozonolysis while dissolved in methylene dichloride to give 3a-acetoxyetiocholan-17-one.

In the same manner as shown in Example 9, 22-acylates of 3a-acetoxybisnor-17(20)-cholen-22-ol, illustratively 3a,22-diacetoxybisnor-17(20)cholen is converted to 3ot-acetoxyetiocholan-17-one thru ozonolysis.

EXAMPLE 12 3,1 1 -diketobisnr-4,I 7 (20 -ch0ladien-22-0l EXAMPLE 13 4-andr0stene-3J1 ,1 7-tri0ne (adrenosterone) Ozonolyzing (i. e. ozonizing and decomposing the ozonide) in the manner shown in Example 2, 3,11-diketobisnor-4,17(20)-choladien-22-ol produced 4-androstene- 3,1 1,17-trione (adrenosterone).

In the same manner as shown in Example 9, 22-acylates of 3,11-diketobisnor-4,17(20)-choladien-22-ol when subjected to ozonolysis give adrenosterone.

EXAMPLE 14 3 fl-acetoxy-fi -keto-bisnor-1 7 20 -ch0len-22-0l In the manner given in Example 1, reacting 3 B-acetoxy- 6-ketobisnor-17(20)-cholen-22-al, dissolved in dioxane and water, with sodium borohydride, dissolved in one Normal sodium hydroxide solution, yielded the Bfl-acetoxy-6-ketobisnor-17 (20) -cholen-22-ol.

EXAMPLE 15 3 8-acet0xyeti0ch0lane-6J 7-di0ne Ozonolyzing in the manner shown in Example 2, Sfl-acetoXy-6-ketobisnor-17,20-cholen-22-ol produced SB-acetoXyetiocholane-6,17-dione. Hydrolysis of 313 acetoxyetiocholane-6,l7-dione with sodium hydroxide produced 3 B-hydroxyetiocholane-6, l7-dione.

EXAMPLE 16 3 ,6 -diketobisn0r-1 7 (20 )-ch0len-22-ol In the manner given in Example 1, reacting 3,6-diketobisnor-17(20)-ch0len-22-al, dissolved in dioxane and water, with sodium borohydride, dissolved in one Normal sodium hydroxide solution, yielded the 3,6-diketobisnor- 17 (20) cho1en-22-ol.

EXAMPLE 17.

Eti0ch0lane-3,6,1 7-trione Ozonolyzing in the manner shown in Example 2, 3,6-diketobisnor-17(20)-ch.olen-22-ol produced etiocholane-3,6,17-trione.

7 EXAMPLE 18 3-ket0bisnorall0-1 7 (20 -ch0len-2Z-ol In the manner given in Example 1, reacting 3-ketobisnoraIlo-17(20)-cholen-22-al, dissolved in dioxane and water, with sodium borohydride dissolved in one Normal sodium hydroxide solution, yielded the 3-ketiobisnorallo- 17(20)-cholen-22-ol.

EXAMPLE 19 A ndr0stane-3,1 7-dione Ozonolyzing in the manner shown in Example 2, 3-ketoallobisnor-17(20)-cholen-22-ol produced androstane-3,17-dione.

EXAMPLE 2O 3a-hydr0xybisn0r-5J 7(20)-choladien-22-0l In the manner given in Example 1, reacting 3m-hydroxybisnor-5,17(20)-choladien-22-al, dissolved in dioxane and water, with potassium borohydride, dissolved in one Normal potassium hydroxide solution, yielded the 3a-hydroxybisnor-5, 17 (20) -choladien-22-ol.

EXAMPLE 21 3a-hydr0xy-5 -androsten-1 7-0ne Ozonolyzing in the manner shown in Example 2, 3a-hydroxybisnor-5,l7(20) choladien 22 01 produced 3a-hydroxy-5-androsten-17-one.

EXAMPLE 22 3u-hydr0xyall0bisn0r-1 7(20 -ch0len-22-0l Inthe manner given in Example 1, reacting 30L-hYdl'OXY- allobisnor-17(20)-cholen22-ol, dissolved in dioxane and water, with sodium borohydride, dissolved in one Normal sodium hydroxide solution, yielded the 3et-hydroxyallobisnor-17 (20) -cholen-22-ol.

EXAMPLE 23 3a-hydr0xyahdr0stan-17-0ne Oz onolyzing in the manner shown in Example 2, 3a hydroxyallobisnor 17 (20) cholen 22 01 produced 3u-hydroxyandrostan-17-one.

EXAMPLE 24 3a-acet0xyall0bisn0r-1 7 (20 -ch0len-22-0l In the manner given in Example 1, reacting 3a-acetoxyallobisnor-17(20)-cholen-22-al, dissolved in dioxane and water, with sodium borohydride, dissolved in one Normal sodium hydroxide solution, yielded the Soc-acetoxyallobisnor:17(20)-cholen-22-ol.

EXAMPLE 25 3u-ace t0xyandr0stan-1 7-0ne Ozonolyzing in the manner shown in Example 2, 3oz acetoxyallobisnor 17 (20) cholen 22 01 produced 3a-acetoxyandrostan-17-one.

EXAMPLE 26 3,11-diketobisn0r-17(20l-cholen-22-ol In the manner given in Example 1, reacting 3,11-diketobisnor-17(20)-cholen-22-al, dissolved in dioxane and water, with sodium borohydride dissolved in one Normal sodium hydroxide solution, yielded the 3,11-diketobisnor- 17 (2 0) -cholen-22-ol., 1 A

9 EXAMPLE 2,7

Etich0lane-3,11,17-iri0ne Ozonolyzing in the manner shown in-Example 2, 3 ,1 1-diketobisnor-17 (20 -cholen-22-ol produced etiocholane-3,11,17-trione.

EXAMPLE 28 3-keti0bisnor-17(20)-ch0len-11a,22-diol In the manner givenin'Example 1, reacting 3-ketobisnor-l1a-hydroxy-1'7(20) cholen 22 al, dissolved in dioxane and water, with sodium borohydride, dissolved in one Normal Sodium hydroxide solution, yielded the 3-k6t0bl81101-17(20)-ChO16I1-110:,22-di01.

EXAMPLE 29 1 Iu-hydrOxyeticiuOIane-SJ 7-ai0ne Ozonolyzing in the manner shown in Example 2, 3-

ketobisnor- 17 20) -cholen-1 100,22-di01 produced 1 la-hydroxyeticholane-3,17-dione.

EXAMPLE 30 3-ketobisnor-17:(20)-ch0len-11;8,22-di0l In the manner given in Example 1, reacting 3-ketobisnor 11,8 hydroxy 17(20) cholen 22- a1, dissolved in dioxane and water, with sodium borohydride, dissolved in one Normal sodium hydroxide solution, yielded the 3- ketobisnor-17(20)-cholen-1113,22-diol.

Ozonolyzing in the manner shown in Example 2, 3,11- diketoallobisnor 17(20) cholen 22-01 produced androstane-3,l1,17-trione.

EXAMPLE 34 Bisnar-l 7 (20 -ch=0 len-3 0:,22 -di0l In the manner given in Example 1, reacting 3a-hydroxybisnor-17(20)-cholen-22-a1, dissolved in dioxane and water, With sodium borohydride, dissolved in one Normal sodium hydroxide solution, yielded the bisnor- 17(20)-cholen-3a,22-diol.

EXAMPLE 35 3a-hydroxyeti0ch0lan-1 7-0ne Ozonolyzing in the manner shown in Example 2, bisnor- 17(20)cholen-3a,22-diol produced 3OL-hYdIOXYfitiOChO1E1I1- 17-one.

EXAMPLE 36 Bisn0r-5,7,17(20)-cholatrien-3B,22-diol 5,8-muleic anhydride adduct In the manner given in Example 1, reacting 3 9-hydroxybisnor-5,7,17(20) 'cholatrien 22 al 5,8 maleic anhydride adduct, dissolved in dioxane and water, with sodium borohydride, dissolved in one Normal sodium hydroxide solution, yielded the bisnor-5,7,l7(20)-cholatriene-3fl-22-diol 5,8-maleic anhydride adduct.

10 V k EXAMPLE 37 33-hydroxy-5,7-androstadien-I7-one 5,8-maleic aci'd anhydriae adduct Ozonolyzing in the manner shown in Example 2, bisnor- 5,7,17(20) cholatrien 3B,22-diol 5,8 maleic anhydride adduct produced 3/3-hydroxy 5,7-androstadien-17-one 5,8- maleic acid anhydride adduct.

In the same manner as Example 1, other bisnor-17(20)- cholen-22-ols may be produced be reducing the corresponding bisnor-17(20)-cholen-22-al, dissolved in a suitable organic solvent in the presence of water, with sodium, potassium or lithium borohydride. Representative bisnor- 17(20)-cholen-22-ols thus obtained comprise: S-ketobisnor 11oz hydroxy 4,17(20) choladien 22 ol, 3- ketobisnor 6,8,l1a dihydroxy 4,17(20) choladien- 22 01, 3,6 diketoallobisnor 11a acetoxy 17(20)- cholen 22 ol, 3 keto bisnoral'lo 11B hydroxy- 17(20) cholen 22 ol, 3- ketobisnor 613,110; dipropionyloxy 4,17(20) choladien 22 01, 3,12 diketobisnor 7 4,17(20) choladien 2 01, 3,7 diketoallobisnor-l7(20)-cholen-22-ol, and the like.

These bisnor-17(20)cholen-22-ols can be subjected to ozonolysis in the manner shown in Example 2 to give respectively 11a-hydroxy-4-androstene-3,l7-dione, 65,110:- dihydroxy 4 androstene 3,17 dione, llu-acetoxyandrostane 3,6,17 trione, 11B hydroxyandrostane- 3,17 dione, 6 3,110; dipropionyloxy 4 androstene- 3,17 dione, 4 androstene 3,12,17- trione, androstane- 3,7,l7-trione, and the like.

In the same manner as shown in Examples 2 through 7, inclusive, 22-acylates of the obtained bisnor-17(20)- cholen-22-ols can be produced by esterification of these 22-alcohols in conventional manner such as, for example, with acid halides and anhydrides. 22-acylates thus produced include the 22 -acetates, benzoates, phenylacetates, phenylpropionates, toluates, propionates, butyrates, valer-. ates, hexanoates, heptanoates, and the like, of 3,6-diketobisnor 17(20) cholen 22 01, 3 ketoallobisnor- 17(20) cholen 22 01, 3oz hydroxybisnor 5,17(20)- choladien 22 01, 3a hydroxyallobisnor 17(20)- cholen 22 01, 3a acetoxyallobisnor 17(20) cholen- 22 01, 3,11 diketobisnor 17-(20) cholen 22 ol, 3 ketobisnor 17(20) cholen 11a,22 diol, 3,11 diketoallobisnor 17(20) cholen 22 ol, bisnorl7-(20)- cholen 301,22- diol, 3 ketobisnor 6B,1ladihydroxy 4,17(20)'- choladien 22 01; 3,6 diketoallobisnor -11a acetoxy 17(20) cholen a 22 01, and thelike.

These compounds by oxidation with chromic acid or by ozonolysis as described previously split ofl? the 17(20)- side chain, attached by a double bond, and give the correresponding 17 ketoandrostane, respectively 17 ketoetiocholane compound.

It isto be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of 3-oxygenated bisnor-l7(20)-cholen-22 ol and 3-oxygenated bisnor-17(20)-cholen-22-ol 22-acylates and the corresponding nuclearly unsaturated compounds having a double bond at a position of the nucleus selected from 4(5) and 5(6), wherein the acyl group is that of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, and wherein the 3-oxygenated group is selected from the class consisting of acyloxy, wherein the acyl group is defined as above.

2. 3-ketobisnor-4,17(20)-choladien-22-ol.

3. 3-ketobisnor-4,l7(20)-choladien-22-ol 22-acetate.

4. 3 ,l l-diketobisnor-4, 17 20 -choladien-22-ol.

5. 3-ketobisnorallo-17(20) -cholen-22-ol.

keto, hydroxy and 6. 3a-acetoxybisnor-17(20)+cholen-22-ol.

7. A process for the production of a 3-oxygenated bisnor-17(20)-cholen-22-ol, which comprises: reacting a Bl-oxygenated bisnor-17(20)-cholen-22-a1 wherein the 3-oxygenated group is selected from the class consisting of hydroxy, acyloxy, wherein the acyl radical is of an organic carboxylic acid, containing from one to eight carbon atoms, and keto, with a metal borohydride to reduce the 22-aldehyde group and to obtain the corresponding 3-oxygenated bisnor-17(20)-cholen-22-ol.

8. A process for the production of a 3-ketobisnor-l7- (20)-cholen-22-ol which comprises: reacting a 3-ketobisnor-l7(20)-cholen-22-al in an organic solvent containing water with a metal borohydride, dissolved in an aqueous solution of alkali metal hydroxide, to obtain the corresponding 3-ketobisnor-17 (20)-cholen-22-ol.

9. A process for the production of 3-ketobisnor-4,17- (20)-choladien-22-ol which comprises: reacting at a temperature between about minus ten and about plus 100 degrees centigrade 3-ketobisnor-4,l7(20)-choladien-22-al, dissolved in a mixture of an organic solvent and water, with a solution of sodium borohydride and sodium hydroxide to obtain 3-ketobisnor-4,17(20)-choladien-22-ol.

10. A process for the production of 3,11-diketobisnor- 4,17(20)-choladien-22-ol which comprises: reacting at a temperature between about minus ten and about plus 100 degrees centigrade 3,11-diketobisnor-4,17(20)-choladien-22-al, dissolved in a mixture of an organic solvent and water, with a solution of sodium borohydride and sodium hydroxide to obtain 3,11-diketobisnor-4,l7(20)- choladien-22-ol.

11. A process for the production of 3-ketobisnorallo- 17(20)-cholen-22-ol which comprises: reacting at a temperature between about minus ten and about plus 100 degrees centigrade 3-ketobisnorallo-l7(20)-cholen-22-al, dissolved in a mixture of an organic solvent and water, with a solution of sodium borohydride and sodium hydroxide to obtain 3-ketobisnora1lo-17(20)-cholen-22-ol.

12. A process for the production of 3a-acetoxy-bisnor- 17(20)-cholen-22-ol which comprises: reacting at a temperature between about minus ten and about plus 100 degrees centigrade 3a-acetoxy-bisnor-l7(20)-cholen-22-al, dissolved in a mixture of an organic solvent and water, with a solution of sodium borohydride and sodium hydroxide to obtain 3a-acetoxy-bisnor-17(20)-cholen-22-ol.

13. A process for the production of a 17-ketosteroid selected from the group consisting of 3-oxygenated 17- ketoandrostanes and 17-ketoetiocholanes which comprises: reacting a 3-oxygenated bisnor-17(20)-cholen-22- a1 wherein the 3-oxygenated group is selected from the 12 class consisting of hydroxy, acyloxy, wherein the acyl radical is of an organic carboxylic acid, containing from one to eight carbon atoms, and keto with a metal borohydride to reduce the 22-aldehyde group and to obtain the corre sponding 3-oxygenated bisnor-17(20)-cholen-22-ol and subjecting the thus obtained 3-oxygenated bisnor-17(20)- cholen-22-ol to ozonolysis to obtain the corresponding 3- oxygenated 17-ketosteroid.

14. A process for the production of a 17-ketosteroid selected from the group consisting of 3-oxygenated 17- ketoandrostanes and 17-ketoetiocholanes which comprises: reacting a 3-oxygenated bisnor-17 (20)-cholen-22-al wherein the 3-0xygenated group is selected from the class consisting of hydroxy, acyloxy, wherein the acyl radical is of an organic carboxylic acid, containing from one to eight carbon atoms, and keto, dissolved in an aqueous organic solvent, with a metalborohydride, dissolved in an aqueous solution of alkali metal hydroxide, to obtain the corresponding 3-oxygenated bisnor-17(20)-cholen-22-ol, esterifying the thus obtained 3-oxygenated17(20)-cholen- 22-01 with an acylating agent'selected from halides and anhydrides of an organic carboxylic acid containing from one to eight carbon atoms, inclusive, and subjecting the thus obtained 3-oxygenated bisnor-17(20)-cl1olen-22-ol 22-acylate to ozonolysis to obtain the corresponding 3- oxygenated 17-ketosteroid.

15. A process for the production of 4-androstene-3,17- dione which comprises: reacting at a temperature between about minus ten and about plus degrees centigrade, 3-ketobisnor-4,17(20)-choladien-22-al, dissolved in a mixture of an organic solvent and water, with a solution of sodium borohydride and sodium hydroxide to obtain 3- ketobisnor-4,17(20)-choladien-22-ol and subjecting the thus obtained 3ketobisnor-4,17(20)-choladien-22-ol to ozonolysis to obtain 4-androstene-3,17-dione.

16. A process for the production of adrenosterone which comprises: reacting at a temperature between about minus ten and about plus 100 degrees centigrade, 3,11- diketobisnor-4,17(20)-choladien-22-al, dissolved in a mixture of an organic solvent and water, with a solution of borohydride and sodium hydroxide to obtain 3,11-diketobisnor-4,17(20)-choladien-22-ol and subjecting the thus obtained 3,11-diketobisnor-4,17(20)-choladien-22-ol to ozonolysis to obtain adrenosterone.

References Cited in the file of this patent UNITED STATES PATENTS I UNITED STATES PATENT omcc CERTIFICATE OF CORRECTION Patent N 2,844,601 k July 22', 1958 Raymond L. Pe'derson et all It .is hereby certified that error appear-sh in the printed specification of the above numbered patent requiring correction andthet the acid Letters Patent should read as corrected below.

Column 6, line '74, for "-'7(2'O)-'" read -l'7(20)- column 7, line 25, for "3-ll-" read 3,11- line 32, for -4,-l'7(20) read -4,l'7(20)- column 8, line 12, for "-ketiobisnorallo-" read -ketobisnoralloline 41,. for "-22-ol," read -22-al, column 9, line 9, for "-ketiobisnorin italics, read -ketobisnorin italics; lines 16 and 31, for "-hy ilro cyet:1' c1r1olane-- in italics, each occurrence, read -hydroxyetiocholanein italics; same column 9, lines 19 and 20, for "-hydroxyeticholane read -hydroxyetiocholanecolumn 10, line 10, for "be reducing" read by reducing line 21, for "-2-01," read -22-ol, R

Signed and sealed this 12th day of May 1959.

(SEAL) Attest:

KARL H. AXLINE y, ROBERT C. WATSON Attesting Officer Commissioner of Patents UNITED STATES PATENT OFFICE I a CERTIFICATE OF CORRECTION Patent No. 2,844,601 July 22', 1958 Raymond L. Pederson et a1 It is hereby certified that error eppears in the printed specification of the above numbered patent requiring correction nndthet the acid Letters Patent should read as corrected below.

Column 6, line '74, for "-'7(20)" read -l'7(20)- column '7, line 25, for "3-ll-" read 3,11- line 32, for "-4,-l'7(20) read -4,l'7(20)- column 8, line 12, for "-ketiobisnorallo-" read -ketobisnoralloline 41,. for "-22-ol," read -22-al, column 9, line 9, for --'ketiomLsnor-" in italics, re'ad -ketobisnorin italics; lines 16 and 31, for "-hydroxyeticholane in italics, each occurrence, read -hydroxyetiocholane-' in italics; same column 9, lines 19 and 20, for "-hydroeq eticholane read -hydroxyetiocholanecolumn 10, line 10, for '"be reducing" read by reducing line 21, for --.2-ol," read -22-ol,

Signed and sealed this 12th day of May 1959.

(SEAL) Attest:

KARL H. AXLINE A I ROBERT C. WATSON Attesting Officer Commissioner of Patents

Claims (2)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-OXYGENERATED BISNOR-17(20)-CHOLEN-22-OL AND 3-OXYGENATED BISNOR-17(20)-CHOLEN-22-OL 22-ACYLATES AND THE CORRESPONDING NUCLEARLY UNSATURATED COMPOUNDS HAVING A DOUBLE BOND AT A POSITION OF THE NUCLEUS SELECTED FROM 4(5) AND 5(6), WHEREIN THE ACYL GROUP IS THAT OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, AND WHEREIN THE 3-OXYGENATED GROUP IS SELECTED FROM THE CLASS CONSISTING OF KETO, HYDROXY AND ACYLOXY, WHEREIN THE ACYL GROUP IS DEFINED AS ABOVE.

13. A PROCESS FOR THE PRODUCTION OF A 17-KETOSTEROID SELECTED FROM THE GROUP CONSISTING OF 3-OXYGENATED 17KETOANDROSTANES AND 17-KETOETIOCHOLANES WHICH COMPRISES: REACTING A 3-OXYGENATED BISNOR-17(20)-CHOLEN-22AL WHERE THE 3-OXYGENATED GROUP IS SELECTED FROM THE CLASS CONSISTING OF HYDROXY, ACYLOXY, WHEREIN THE ACYL RADICAL IS OF AN ORGANIC CARBOXYLIC ACID, CONTAINING FROM ONE TO EIGHT CARBON ATOMS, AND KETO WITH A METAL BOROHYDRIDE TO REDUCE THE 22-ALDEHYDE GROUP AND TO OBTAIN THE CORRESPONDING 3-OXYGENATED BISNOR-17(20)-CHOLEN-22-OL AND SUBJECTING THE THUS OBTAINED 3-OXYGENATED BISNOR-17(20)CHOLEN-22-OL TO OZONOLYSIS TO OBTAIN THE CORRESPONDING 3OXYGENATED 17-KETOSTEROID.