2,940,991 Paterated Jj Line 4, 1960

United States Patent Office 2 provide easy access to other biologically active steroid compounds. 2,940,991 These and other objects of this invention will become apparent on reading the following description in con METHOD OF EPIMERIZING 11-BROMO junction with the drawings in which: STERODS Figure 1 is a schematic representation of the process Percy L. Juliana, Oak Park, and Arthur Magnani, Wi in accordance with this invention. w X mette, Ill., assignors to The Julian Laboratories, ne, With respect to the following description, it is desired Frankin Park, I., a corporation of Illinois to point out that reduction providing an OH group in the O 12-position results in a mixture of compounds, some Filed Mar. 1, 1957, Ser. No. 643,353 having the OH bonded by a bond in the or position and 7 Claims. (C. 260-397.45) some by a bond in the 6 position. In the starting mate rial triols either the 12c ol or 126 ol compounds or a Rixture thereof may be employed. The structural formu This invention relates to novel steroid compounds and 15 las herein and in the claims are intended to cover both to processes for their preparation. The compounds of the 12c, ols and 12p ols where discussed and/or claimed. this invention are particularly useful as intermediates in It is also desired to point out that the steroid com the preparation of cortical hormones which have useful pounds discussed and claimed exist in either the 3ox,56 therapeutic activity. or 36,5a form. The structural formulas in the descrip The cortical hormones, particularly cortisone, hydro 20 tion and claims are intended to cover both of these cortisone and various derivatives thereof, have found forms. widespread utilization in the treatment of rheumatoid The starting materials are either well known or obvious arthritis and related conditions. At present, these cortical to those skilled in the art. The desired pregnane-3c, 12c, hormones are obtained from raw material sources, name 2,3-triol starting material is produced from the known ly, bile acids and vegetal sterols. In both instances, the pregnarne-3cz, 12c-diol-20-one diacetate which can be ob problem of converting the starting material, e.g., desoxy tained from desoxycholic acid, by reduction of the 20 cholic acid from bile acids, and stigmasterol, similagenin, keto group using either a chemical reducing agent, such diosgenin or hecogenin from vegetal sterols, into a desired as a bimetallic anhydride, for instance sodium borohydride intermediate which contains an oxygen function attached in an aqueous organic, solvent, such as aqueous methanol to the 11-position of the steroid nucleus has provided a 30 or lithium aluminum hydride in a dry organic solvent, major obstacle due to the complex nature of the Syn such as ethyl ether or tetrahydrofuran, or catalytically, thetic methods involved. The bile acid synthesis of for instance with hydrogen in the presence of a hydro &endall as well as the microbiological oxidation pro genation catalyst, such as Raney nickel in alcoholic solu cedures currently known to the art are laborious and ex tion. The resulting diacetate is hydrolyzed to the 3oz, pensive methods for the introduction of the 11 oxygen 3. 5 12c,203 triol with an alkaline solution, for instance with function. The process of this invention solves this im potassium hydroxide or sodium hydroxide in aqueous portant problem in employing a synthetic route for intro methanol. ducing an oxygen function into the 11-position which The known allopregnane-38-ol-12,20-dione acetate, ob employs steps that are carried out in excellent yields. tained from hecogenin by typical genin degradative oxida Similarly, the 17-side chain of the natural products : tion of the acetate with chromium oxide, is similarly mentioned herebefore, containing a 12-oxygen function, reduced to give the allopregnane-3,6,12a, (6)20-triol start e.g., desoxycholic acid and/or hecogenin, also may be ing materia?. The testane starting material, testane degraded to a 17-oxygen function by methods described 3c, 12c, 178-triol, is produced from pregnane-3oz,12o-diol in the prior art. The resulting compounds, of course, 20-one diacetate by perbenzoic acid oxidation, followed Would be 12-oxygenated testane and androstane deriva by hydrolysis of the acetate groups. Androstane-3,3,12, tives which also could be submitted to the process of this 45 17-triol is similarly prepared from allopregnane-3,6-ol invention (after converting the 17-oxygen to a hydroxy 12,20-dione acetate. -group), thereby converting the 12-oxygen function to the As illustrated in Figure 1, the pregnane, allopregnane, 11-position, and thereby obtaining 3,11,17-triones of value testane or androstane-triol (I) selected, depending upon as intermediates. the end product trione desired, is preferentially oxidized More specifically, it is a prime object of our invention 50 at position 12. Blocking the hydroxyl groups in the 3 to provide an improved method for the production of and 17 or 20 positions is essential in order to accomplish pregnane - 3,11,20-trione, allopregnane-3,1120 - trione, a clean-cut reaction (to facilitate the following descrip androstane-3,11,17-trione and testane-3,11,17-trione from tion, “Y” will be used hereinafter to indicate the “17” 12-oxygenated sterols in which the side chain.attached or "20" position). This is accomplished by blocking to ring D has been degraded to a simple substituent in 55 íhese positions with a suitable acyl group, for example, the 17-position. This substituent, which can be, for ex either an aromatic acyl group such as benzoyl, hemi ample, the Ox-hydroxyethylene moiety or a hydroxyl radi phthalyl or toluyl or by a lower alkanoyl group such as propionyl, butyryl or preferably by an acetyl or hemi cal, does not have the disadvantages of the more complex Succinyl group. Acylation is accomplished by acylating 17-substituents utilized by the processes of the prior art 60 with the appropriate acyl anhydride or acyl chloride in since it does not react under the various steps of the basic solution such as in an excess of a tertiary amine, process to form undesirable side products. Furthermore, for instance pyridine, collidine, or picoline or in an inert the degradation of the complex side chain in ring D, for solvent such as dimethylformamide, acetone or dimethyl instance the 17-0-carboxyalkylene moiety of desoxycholic acetamide with about one equivalent of an acid binding - acid or the typical genin moiety of hecogenin, as an 65 agent, for instance pyridine, tributylamine or picoline. early step in the procedure results in an economical ad The resulting 3, 12, Y3-triol-3,Y-diacylate (II) then is oxi vantage over degradation after the 12 to 11 oxygen shift. dized with a suitable oxidizing agent, for example, chromic It is a further object of our invention to provide novel acid in aqueous acid solution, for example, aqueous acetic intermediates and valuable processes useful in the syn acid or chromic oxide in basic solution, for example, in thesis of cortisone and related compounds from bile acids pyridine solution, to form the corresponding 3,YB-diol and hecogenin. Another object of our invention is to 12-one diacylate (III). 2,940,991 3 When the 3-Y-blocking acyl groups contain centers such as silver oxide-pyridine. Since only the 12a-hydroxy reactive under the bromination conditions later employed form of the triol VII is converted to the epoxy compound in the process, it is necessary to hydrolyze the blocking - VIII, this form, if desired, can first be separated from the groups after the oxidation step and reacylate to introduce 12a-hydroxy and 126-hydroxy mixture (VII) by, for nonreactive blocking groups, preferably acetate. As an example, fractional crystallization. example of a blocking group reactive to bromine, the The thus formed 118,128-epoxide (VIII) then is re hemidibasic esters are mentioned, for instance the hemi acted with an aqueous - hydrohalic acid, for example, succinyl and the hemiphthalyl moieties. By way of spe hydrobromic, hydrochloric or hydrofluoric acid, in a cific example, the procedure where the hemisuccinyl water-miscible organic solvent, for example, acetone, moiety is employed is as follows: Diacylation with, for O dioxane or methanol at moderate temperatures, prefer example, succinyl anhydride in an excess of tertiary ably from about 15° C. to about 40° C., to give the 12 amine, such as pyridine, or in an inert solvent, such as halo-3,116,YB-triol (IX). Similarly, anhydrous hydro dimethylformamide, acetone or dioxane with an equiva gen halides can also be used in anhydrous organic solvents lent of acid binding agent, for example, pyridine, tri such as, for example, chloroform, -ethylene dichloride, butylamine or picoline, normally first produces a mixture s glacial acetic acid and the like to form these compounds. of the mono- and dihemisuccinates. The monohemisuc The halohydrin (IX) is treated with a suitable oxidiz cinate, upon retreatment, produces a further quantity of ing agent as described above, for example, chromic acid the dihemisuccinate (IV). The thus formed 3,Y-dihemi in an organic solvent acid medium such as chloroform succinate (IV) then is oxidized with an oxidizing agent, acetic acid or ethylene dichloride-acetic acid at moderate as described above, preferably with chromic acid in 20 temperature, preferably from about 15° C. to about 40 aqueous acetic acid solution or with chromic oxide in C., to give the 12-halo-3,11,Y-trione (X). Exemplary of pyridine solution to the desired 3,YB-diol-12-one dihemi other oxidizing agents are aluminum isopropoxide or succinate. The protective groups in the 3 and Y-posi alkaline permanganate. . . tions then are hydrolyzed by alkali, for example, potas The 12-halo-3,11,Y-trione (X) then is reacted with a sium or sodium hydroxide in alcohol, for example, dehalogenating agent, for example, zinc in acetic acid, methanol or isopropanol or in an aqueous alcohol mix chromous chloride, aluminum amalgam, hydrogen in the ture, for example, aqueous methanol, ethanol, isopropanol presence of a catalyst such as a palladium catalyst at or butanol. The resulting 3,YB-diol-12-one (V) can moderate temperatures, preferably from about 15° C. then be diacylated with nonreactive acyl groups inert to to about 40° C. to give the desired 3, 11,Y-trione (XI). bromine (using the same procedure as described above 30 It is apparent to one skilled in the art that with certain in connection with the 3,Y acylation of 3,12YB-triol (I). of these dehalogenating agents, reduction of the oxo - to the diacylate (III) to produce the corresponding 3,Y8 moieties will occur simultaneously. In such examples diol-12-one diacylate (III) in which i there are no acyl the alcohol can be oxidized under conditions described groups reactive during the bromination step. The better above to the trione. The preferred dehalogenating agent yields obtained by using this alternative procedure are 8 is zinc in acetic acid. due to the favorable solubility characteristics of the hemi succinate derivatives...... EPIMERIZATION . The diacylate (III)- containing the inert to bromine In practicing the process of this invention, the 11oz 3,Y blocking agents is brominated in an inert organic bromo isomer is necessary as previously noted for forma solvent, for example, chloroform, chloroform-acetic acid 40 tion of the 11,12-epoxide. This isomer may be isolated or ethylene dichloride by treatment with bromine at mod by fractional crystallization, however, in this case the erate temperature, from about 15 C. to about 40 C., 11,3-bromo isomer must be either reworked chemically preferably at about 25. C. The bromination can be or discarded. A simple method of converting the 116 catalyzed by and hence is preferably carried out in the bromo isomer to the necessary 11oz. isomer is, therefore, presence of HBr. A mixture of 11oz (VI) and 116-bromo 45 of great value. isomers results. The 11oz. isomer is required for the It has been found possible to epimerize the 116-bromo ... formation of the 11,12-epoxide; preferably, therefore, the pregnane-3,20,8-diol-12-one diacylate congeners of the organic extract from the bromination reaction may be 11ac compounds of Formula VI either by treating a mix concentrated and the isomers separated by fractional ture of the 11a and 116 bromo compounds or by treating crystallization from, for example, methanol or ethanol. 50 the particular 116 isomer obtained by the previously The resulting 11a-bromo-3,YB-diol-12-one diacylate (VI) discussed fractional crystallization with a strong acid then is reduced with a bimetallic hydride in an organic such as a mineral acid, for example, sulfuric, phosphoric, solvent such as sodium borohydride in an aqueous or preferably a hydrohalic acid, for example, hydro ... organic -solvent inert to reduction, such as aqueous chloric or hydrobromic, or an organic acid, such as phenyl - methanol or - ethanol, or lithium aluminum hydride in a 55 sulfonic acid, p-toluene sulfonic acid or acetic acid. The dry organic solvent, such as diethyl ether, dibutyl ether epimerization is carried out at moderate temperature of , or tetrahydrofuran at moderate temperatures, preferably about 15° C. to 40°C., preferably at below about 25 C. from about 15°C. to about 40. C. to form a mixture of in an organic solvent, for example, methanol, ethanol, the 11a-bromo-3,12YB-triol (VII) and its 3,Y acylate. . isopropanol, dioxane, dimethylformamide, benzene, chlo If desired, the mixture of the acylated and free triol can roform, methylene chloride or tetrahydrofuran. Up to be reacylated using the appropriate acyl anhydride or about 85% of the desired 11o isomer is obtained by this ;acyl chloride, for example, those set forth above in con procedure. The 11o isomer is isolated and purified, if ...nection with the formation of the diacylate compound necessary, by conventional techniques, for example, by - III in a tertiary base such as pyridine or in an inert precipitation or fractional crystallization. When hydro -solvent such as dimethylformamide, acetone or dioxane 65 lytic solvents such as alcoholic solvents or aqueous mix employing about one equivalent of an acid binding agent, ...ture of solvents, for instance aqueous dioxane or aqueous for example, pyridine, tributylamine or picoline. If de dimethylformamide are used, the 3.20 protective groups sired, the acyl groups can be removed by hydrolysis be- h : are also hydrolyzed during the epimerization steps in fore the reduction step. - which event 11oz-bromopregnane-3,20,8-diol-12-one is re ... The triol (VII) alone, its 3,Y acylate or a mixture covered. If a non-hydrolytic organic solvent: such as ...thereof then is converted to the 116,123-epoxy-3,YB-diol dry benzene, chloroform, methylene chloride or tetra (VIII) with a strong - dehydrohalogenating agent such as hydrofuran is used, the acyl groups remain intact and a strong base such as caustic alkali, for example, potas 11a-bromopregnane-3,20,3-diol-12-one diacylate is recov sium-hydroxide or sodium hydroxide, in aqueous ered. Irrespective of whether a hydrolytic or non-hydro méthanól, isopropanol or ethanol or such as collidine or 75 lytic solvent is used, the resulting product can now be re

2,940,991 7 s - 8 on a steam bath for three hours. Thereafter, the excess balance of the bromination charge (1,243 g) is added acetic anhydride is decomposed by the addition of water. over a 50-minute period. After the completion of the The oil which appears is redissolved in the hot mixture addition of bromine, the mass is permitted to stand for which upon cooling, deposits a crystalline solid. The about 10 to 20 minutes. ? ? ? ? & ? ? ...... ?? mixture is extracted with ether. The ether extracts are 5 Two such bromination masses are combined and washed washed with dilute hydrochloric acid, water, dilute caustic with water. After the addition of approximately-1500 soda and finally with water. The washed extract is dried cc. of saturated aqueous sodium bicarbonate, the resultant over anhydrous sodium sulfate and then concentrated to slightly alkaline mass is decolored by the addition of 1200 a low volume. Upon the addition of petroleum ether, ml. of 10% aqueous sodium sulfite. The mixture is the product crystallizes. The slurry is filtered to give the O washed with water until the aqueous wash liquid is ° solid, pregnane-3oz,208-diol-12-one ? diacetate, . 720. mg., neutral to litmus. . . . - M.P. 135-7 C. A further quantity is obtained from the The neutral aqueous chloroform solution is concen mother liquor. - - - - - trated to incipient crystallization. Then 22 1. of methanol (b) Using perchloric acid.--To a solution of 15 g. of are added to the syrup. The mixture is distilled to re pregnane-3a,20ß-diol-12-one prepared as in Example II move about 5 1. of distillate. The distilland is agitated above, in 15 cc. acetic anhydride and 30 cc. of glacial and cooled to 30° C. A solution of 1590 g of hydrogen acetic acid, 2 drops of perchloric acidis added. The mix chloride dissolved in 8,550 ml. of methanol is added to ture is cooled to control the exothermic reaction and per the mass. The mixture almost immediately sets to a mitted to stand at about 25 C. for about 45 minutes. crystalline mush which, upon being agitated, gradually . After the addition of water, the product is extracted with 20 dissolves. The temperature of the resultant solution rises ether and the extract washed with water, aqueous sodium to 35 C. The mass is cooled to below 10 C. and held at bicarbonate, and finally with water. After drying the this temperature for at least 24 hours. The resultant washed extract, the mass is concentrated and the product slurry is filtered and the filter cake washed with methanol. crystallizes from a mixture of ether-petroleum ether. The washed cake is dried in a circulating hot air drier. Thereby pregnane-3a,203-diol-12-one diacetate, M.P. The product, 11oz-bromopregnane-3a,206-diol-12-one, M.P., 175° C. (dec.), together with a second crop ob 135-7°C. is obtained. - - - - tained by concentration of the mother liquor to 12 l. - EXAMPLE IV . . . . . volume, 4,744 g. of product is obtained. -- 12-KETO DLACETATE VILA: TRIOL DLACETATE The mother liquor, after the separation of the second A mixture consisting of 50 g. of pregnane-3a,12a208 30 crop material, contains essentially all of the 11.f3-bromo triol, prepared as described in Example II. above, 125 cc. isomer together with unchanged starting material and 11a of pyridine and 40 cc. of acetic anhydride is agitated for . . . bromo compound. Treatment of these mother liquors ten minutes and then 10 cc. additional of acetic anhy with zinc and acetic acid debrominates the mixture of, dride added. The agitation is continued for one-half giving pregnane-3a,203-diol-12-one in a form suitable for hour, or until the dissolution of the solid is completed. 3. 5 recycling in this process. - : The solution is permitted to stand for one-half hour This example illustrates the process step whereby the and 5 cc. of acetic anhydride is added, followed one-half mixture of 11-bromo compounds is epimerized, in the hour later by a further addition of 5 cc. of acetic an presence of halogen acid to a mixture comprising a pre hydride. The mass is permitted to stand for about 16 ponderance of the 11a-bromo derivative, and simultane hours, then the mixture is diluted with water to a volume 40 ously hydrolyzes the 3,20-diacetoxy groups. By using of about 2 liters. The-crystalline slurry is filtered and the instead of methanol, a solvent such as glacial acetic acid, filter cake is redissolved in ether. The ether solution is anhydrous ether or acetone, the hydrolysis of the acetate washed with dilute hydrochloric acid, water, dilute moietus can be prevented and the product isolated as the aqueous caustic soda and finally with water. The washed 11a bromopregnane-3a,208-diol-12-one diacetate. . . ether solution is evaporated to dryness and the residue We find it possible to isolate up to 85% yield of 11a recrystallized from 80% methanol. A first crop of 30.5 bromo compound from such an epimerization reaction. g. of pregnane-3oz,120,206-triol. 3,20 diacetate, M.P. 125 Initially on bromination, the ratio of isomers produced is 130 C. is obtained. - - - - about 60% or and 40% (8 isomers. This epimerization is A solution prepared by warming 45 g. of the pregnane demonstrated by reaction of either epimer in the pure 3a,120,206-triol 3,20 diacetate, prepared as above, in 180 50 state with halogen acid to yield a mixture from which cc. of acetic acid is permitted to cool. A mixture of 15 up to 85% of the 11o-bromo epimer can be isolated. g. of chromic acid in 20 cc. of water and 40 cc. of acetic acid is added to this slurry in portions over a 20-minute EXAMPLE VI period. The mass is agitated for three hours at ambient REDUCTION OF 11a-BROMOPREGNANE-3a,208-DIOL-12 temperature and then diluted with water. The mixture is ONE AND CLOSURE TO 1112-EPOXIDE - extracted with ether. The ethereal extract is washed with A slurry of 10 g. of finely ground 11a-bromopregnane water, aqueous sodium bicarbonate and finally with water. 3a,203-diol-12-one, prepared as in Example V above, in The washed solution is evaporated to dryness and the 100 cc. of methanol is warmed to 35 C., and 0.5 g. of residue redissolved in anhydrous ether. The solution is sodium borohydride in 5 cc. of water is added. The heat concentrated to a low volume. The addition of petroleum of reaction causes the temperature to rise to 45 C. at ether causes the crystallization of 35.3 g of pregnane 60 which temperature complete solution occurs. After 3a,208-diol-12-one diacetate, M.P., 125-130 C. several minutes, the product begins to crystallize. The The crude product after recrystallization from hexan mixture is agitated for one-half hour and then 140 cc. of gives material crystallizing in the form of needles, M.P., water is slowly added. The slurry is filtered and the filter 130-136° C... . , - - - - - 65 cake is washed with water. The product, 11a-bromo ... " . . . - EXAMPLE V ...... pregnane-30,126,203-triol after drying, weighs 9.7 g., BROMINATION OF PREGNANIE-3a,20g-DIOL. 12-ONE. DI M.P., 203-4 C. ? ? ? ? ? ? ...... ? , '" . '.' :'...... : ...... - ACETATE FOLLOWED BY EPIMERIZATION-HYDROL This material is suspended in 80 cc. of methanol con YSIS TO GIVE 11a-BROMOPREGNANE-3a,206-DIOL-12 taining 4 g. of potassium hydroxide. The mixture is ONE 70 heated at reflux for one-half hour. The solution is con To a solution of 3,188 g. of pregnane-30,206-diol-12 centrated to a low volume and 125 cc. of water added. one diacetate, prepared as in Examples III or IV above, The slurry is cooled and filtered. The filter cake is -in-14,750 I. of dry chloroform, 5 cc. of bromine and 80 washed with water and dried to give 7.8 g. of 116,126 ml of 20% hydrogen bromide in glacial acetic acid is epoxypregnane-3a,206-diol, M.P., 188-192 C. This (added to initiate the bromination reaction. Thereafter the epoxide can be oxidized with chromic acid to 116,12p ?940991 O epoxypregnane-3,20-dione, M.P., 139-142 C., or treated to obtain 2.05 g, of prisms, M.P., 157-161 C, the 11a with halogen acids to form the corresponding halohydrins. epimer and 1.80 g. of needles, M.P., 151-153° C., es EXAMPLE VII sentially the 116-epimer. The lio-bromopregnane 2-BROMOPREGNANE-3a, 11 B,20E-TRIOL 30,203-diol-12-one 3,20-diacetate is recrystallized from 5 five parts of methanol to yield the pure compound, M.P., An aqueous slurry of 40 g. of the epoxide, produced as 163-5 C. in Example Wii, in 700 cc. of acetone is stirred while 250 (b) Reduction.--A solution of 1 g of 11oz-bromo cc. of 4 N hydrobromic acid is added. The temperature pregnane-3o,206-diol-12-one-3,20-diacetate, in 15 cc. of rose to 42 C. A small amount 3.6 g. of insoluble start methanol is agitated, as a solution of 300 mg. of sodi ing material is filtered from the solution and washed um bicarbonate in 1.5 cc. of water is added. The result with 300 cc. of acetone. The clarified solution is diluted O ant crystalline slurry is cooled to about 27 C. and 100 with 1400 cc. of water slowly, for about two hours. The mg. of sodium borohydride dissolved in 0.75 cc. of water resultant slurry is filtered. The filter cake is dried in air. is added. The mixture is agitated for two hours during The dried product, 12-bromopregnane-3oz,11B,20,8-triol, which the crystalline solid goes into solution and shortly melts at 187-9 C. A further quantity is obtained by 5 thereafter a precipitate forms. The mixture is diluted extraction of the aqueous mother liquor with methylene with water and extracted with ether. The extract is chloride. Total yield is 45 g. The corresponding washed with water and then evaporated to dryness. The chlorohydrin is obtained in an analogous manner using crude residue, about 1 g of a white fluffy material, is 4 N hydrochloric acid. By treatment of the epoxy dissolved in 5 cc. of acetic anhydride and 1 cc. of pyri pregnane diol with aqueous hydrogen fluoride in dioxane 20 dine. The solution is warmed on a steam bath for one the fluorohydrin results. hour, permitted to stand for one hour, and then the EXAMPLE VIII excess acetic anhydride is decomposed with water. The mixture is extracted with ether. The extract is washed OXOATION OF TE BROMOHYDRIN FOOWED BY with dilute hydrochloric acid, water, aqueous sodium bi DEBROMINATION carbonate, and finally with water. The washed extract A solution of 81 g. of 12 bromopregnane-3c, 11.3,206 25 is concentrated and the product is crystallized from ether triol, the product of Example VII, in 240 cc. of methyl petroleum ether, yielding 600 mg. of 11oz-bromopreg ene chloride is mixed with 320 cc. of glacial acetic acid. nane-3c, 12,3,206-triol-3,20-diacetate, M.P., 147-150 C. The mixture is cooled and maintained at 20-25 C. dur Upon recrystallization from 90% aqueous methanol, the ing the addition of a solution of 60 g. of chronic acid 30 product meits at 154-6. C. in 80 cc. of water and 80 cc. of acetic acid (20 minutes). The bromohydrin so obtained is converted by treat The mixture is agitated for two hours and then diluted ment with alcoholic KOH into the 116,126-epoxypreg with water. The mass is extracted with three portions nane-3c.,20,8-diol. of methylene chloride. The combined extracts are EXAMPLE X washed with water. The solvent solution is debromi nated by the addition of 60 cc. of glacial acetic acid fol 35 A Solution of 50 g. of allopregnane-3,6-ol-12,20-dione lowed by the portionwise addition of 32 g. of zinc. Dur acetate, cbtained from hecogenin according to known ing the latter addition the temperature is permitted to procedures, namely, isomerization, chromic oxide oxida rise to 40° C. The mixture is agitated for 40 minutes, tion of the genin side chain and selective hydrogenation, decanted from the spent zinc residue and the solvent 40 in 400 cc. of methanol is reacted with 7 g. of sodium solution washed with water. The washed solution is con borohydride in water following the procedure of Ex centrated to about 150 cc, and diluted with 500 cc. of ample I(b) to give allopregnane-3,6,12a,208-triol. ether. The resultant crystalline slurry is distilled to re A mixture of 30 g. of the solid triol and 30 g. of suc move 425 cc. of distiliate. The residue is cooled and cinic anhydride in 75 cc. of pyridine and 150 cc. of filtered. The filter cake is washed with ether and dried. methylene chloride is heated at reflux for five hours. In this manner, 42.2 g of pregnane-3,11,20-trione, M.P., 45 The solvent is removed and the residue is worked tap ti 157-160° C., is obtained. give the mcno and dihemisuccinates as in Example II. The resultant trione, by reduction with sodium boro The monosuccinate is reworked to give additional di hydride by the method of Gallagher et al. J. Am. Chem. Succinate. Soc., 75, 2356 (1953) yields pregnane-3c-ol-11,20 A solution of 30 g. of the crude diester in 125 cc. of dione. This product is then converted by the method of 50 glacial acetic acid is oxidized with a solution of 6 g. of Gallagher (U.S. Patent No. 2,562,030) to pregnane chronic oxide in 12 cc. of Water at room temperature. 3c, 17g-diol-1120-dione-3-acetate which is thereafter After quenching with water and extraction of the 12 converted to cortisone acetate as disclosed in U.S. Patent ketoester with ether the residue obtained by evaporating No. 2,752,339. m the ether is heated at reflux with 18 g. of potassium hy EXAMPLE X 55 droxide in aqueous methanol. The methanol is evapo rated and the resulting solid is water washed, taken REDUCTION OF 1a-BROMOPREGNANE-3a,203-DIOL-12 through ether and recrystallized to give allopregnane ONE 3,20-DACETATE 36,206-diol-12-one. (a) Bromination.--Pregnane-3cz,203-diol - 12 - one di A solution of 20 g. of the ketone in 20 cc. of acetic acetate (5 g.), made as in Example IV, is dissolved in 25 60 anhydride and 30 cc. of acetic acid with 2 drops of per cc. of chloroform and a portion of the requisite amount, chloric acid is allowed to stand at about room tempera 2.1 g., of bromine dissolved in 5 cc. of chloroform is ture for two hours. After working up as in Example added, followed by the addition of two drops of meth III(b), allopregnane-3ß,20ß-diol-12-one diacetate is ob anol. In about five minutes the solution becomes dis tained. Sixteen grams of this ester in 160 cc. of chloro colored, indicating the reaction of the bromine. The 65 form are brominated with 6 g. of bromine following the balance of the bromine is added dropwise over a ten procedure of Example V. The crude product thereof is minute interval and the mass is permitted to stand for used to react with methanolic hydrochloric acid at 30 to ten minutes. The mixture is concentrated in vacuo to a 35 C. The solid product after recrystallization from low volume. The residue is dissolved in ether. The at LeCl3 methanol is 1a-bromoallopregnane-36,208-diol ether solution is washed with water, aqueous sodium bi 70 12-one. carbonate, and a final water Wash. The washed solu A mixture of 5 g. of the ox-bromo compound in 75 tion is dried over anhydrous sodium sulfate. The dried cc. of methanol is mixed with a solution of 0.5 g. of solution is evaporated to a yellow oily residue which is Sodium borohydride in 5 cc. of water. The mixture is dissolved in 20 cc. of methanol. This solution is per warmed until the reaction is completed. After two mitted to stand and the product fractionally crystallized 75 hours at room temperature, the mixture is diluted with

2,940,991 3. 14 the reaction is carried out in a hydrolytic solvent and References Cited in the file of this patent the ester groups are hydrolyzed. r 3. The method in accordance with claim 1 in which UNITED STATES PATENTS the acid is acetic acid. 2,447,325 Gallagher S SS SS SSSSLS S LSL S SSSS SS S Aug. 17, 1948 4. The method in accordance with claim 1 in which 5 2-534882 Reichstein ------May 29, 1951 the acid is a mineral acid. 2,782,211 Wettstein ------Feb. 19, 1957 5. The method in accordance with claim 4 in which 2,810,734 Herzog et al. ------Oct. 22, 1957 the mineral acid is a hydrohalic acid. 6. The method in accordance with claim 5 in which OTHER REFERENCES the hydrohalic acid is hydrochloric acid. 0 Meystre et al., Helv. Chim. Acta., vol. 32 (1949), 7. The method in accordance with claim 5 in which pages 1978-1992. (Pages 1982, 1988, and 1989 neces the hydrohalic acid is hydrobromic acid. sary.)