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.