US2701808A - Process for the production of 3alpha-hydroxypregnane-11, 20-dione - Google Patents

Description

PROCESSFOR THE PRODUCTION OF Soc-HY- DROXYPREGNANE-ILZO-DIONE John A. Hogg, Alan H. Nathan, Douglas A. Lyttle, and Arthur R. Hanze, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application August 28, 1952, Serial No. 306,943:

9 Claims. (Cl. 260-397.3)

The present invention relates to a novel process for the production of steroid compounds and is more particularly concerned with a process for the production of 3a-hydroxypregnane-l1,20-dione from 1la-hydroxyprogester one.

It is an object of the present invention to provide a novel process for the production of 3a-hydroxypregnane- 11,20-dione. Another object of the present invention is to provide a methodwhereby 3a-hydroxypregnane-ll,20- dione is prepared from lla-hydroxyprogesterone through the intermediate compounds 1lot-hydroxypregnane-3,2(ldione and pregnane-3,11,20-trione. A further object of the presentinvention is the provision ofa method for the production of the useful 3a-hydroxypregnane-11,20-dione from llu-hydroxyprogesterone which proceeds through 11ot-hydroxypregnane-3,20-dione. and pregnane-3,1l,20'- trione and in which all of the steps cooperate, or integrate for. the attainment of the production of 3u-hydroxypreg nane-l1,20-dione. Other objects of the present invention willbe apparent to those skilled in the art to which thisinvention pertains.

According to the novel sequence of the present. invention, 11a.-hydroxyprogesterone is hydrogenated with hydrogen in the presence of a palladium catalyst to cause saturation of the 4(5) -double bond and yield Ila-hydroxy pregnane-3,20-dione. lla-hydroxypregnane-3,20-dione. is oxidized with an oxidizing agent to produce pregnanc- 3,11,20-trione which is then selectively reduced to 30- hydroxypregnane-l1,20-dione. The reaction sequence is illustrated graphically by the formula below:

We have found that the above sequence of steps operates cooperatively and conveniently. to produce 3a-hydroxypregnane-11,20-dione in high yields from 110:- hydroxyprogesterone. We have also found that variations in the sequence from that shown above lead to complications and consequently result in lower yield, if

any yield is obtained, of 3rx-hydroxypregnane-l1,20-dione. For example, if llot-hydroxyprogesterone is oxidized first, in addition to oxidation of the lla-hydroxy group to a keto group, the double bond at the 4(5)-position is attacked by the oxidizing agent to an appreciable extent, thereby. reducing the yield of the: oxidation product.

2,701,808 Patented Feb. 8, 1955 Furthermore, hydrogenation of the resulting l1-keto'-progesterone at the 4(S)-position results mainlyin the formation of hydrogenation product having the allo configuration of hydrogen at carbon atom five. fully stated hereinafter, the normal configuration is the desired form. According to the present invention, hydrogenation of llot-hydroxyprogesterone yields predominantly the normal hydrogenation product, which can then be oxidized without difficulty since the molecule no longer contains a double bond. We have further found that selective reduction of pregnane-3,1l,20-trione is accomplished smoothly and in good yield whereas selective oxidation of ,1lu-dihydrOXypIegnane-ZO-one is hard to control and generally results in low yields. Consequently, the yields of 3a-hydroxypregnane-l1,20-dione obtained by oxidation of 1lwhydroxypregnane-S,20-dione followed by selective reduction of the 3-keto group, are.

much higher than could be obtained if lloq-hydroxpreg nane-3,20-dione was selectively reduced first to produce.

tive reduction, undesirable complications are avoided and the useful 3tx-hydroxypregnane-l1,20-dione is produced.

from lla-hydroxyprogesterone in good yield.

The 3a-hydroxypregnane-11,ZO-dione produced according to the method of the present invention, and usually in high yield, is an important and useful compound for the synthesis of adrenal steroids such as, for example, cortisone and cortisone acetate. workers, in a recent publication [Kritschevsky, Garmaise and Gallagher, 1. Am. Chem. Soc., 74, 483 (1952)], have utilized 3whydroxypregnanel1,20-dione as starting material and have shown its conversion to cortisone acetate. Such a conversion is accomplished, for example, by reacting 3a-hydroxypregnane-l1,20-dione with an acid anhydride in the presence of an acid catalyst to cause acylation of the 3a-hydroxyl group and enol acylation of the ketones at the 11* and 20-positions and thereby yield 3a,l 1,20- triacyloxy-9 1 l 17 (20 -pregnadiene. Treatment of the acyl-ated compound thus-formed with an epoxidizing agent, such as a peracid, results in the formation of the 17(20)-epoxide compound which on treatment with dilute base yields 3a,17a-dihydroxypregnane-l1,20-dione. Thus the Hot-hydroxyl has been introduced into the molecule. This procedure is then followed by the introduction of the oxygen function at the 2l-position which consists of.

bromination, with bromine, of 3a,l7a-dihydroxypregnane- 11,20-dione to yield the 21-bromo derivative which is. then treated first with an oxidizing agent to oxidize the:

3-hydroxyl to a 3-ketone followed by reaction with dilute base to replace the 21-bromine with a hydroxy group and give 17a,2l-dihydroxypregnane-3,11,20-trione. Acylation of the'thus-produced trione yields 17x-hydroxy-21-acyloxypregnane-3,l1,20-trione.

Variations in the sequence of reactions in the production of l7a-hydroxy-2l-acyloxypregnane-3,11,20-trione from 30:,17oL-dihYdI0XY 21 bromopregnane-l1,20-dione may also be employed. For example, 3a,17a-dihydroxy- ZI-bmmopregnane-l1,20-dione can be treated with dilute base first to replace the 21-bromine with a hydroxyl which is then followed with oxidation of the 3-hydroxyl and acylation of the 2l-hydroxyl to give 17ahydroxy-21 acyloxypregnane-3,l1,20-trione, or the 21-bromine may be directly replaced with an acylate by reaction withametal acylate, such as potassium acetate, according to the method of Inhoffen (U. S. Patent 2,409,043, issued October 8, 1946) to give the 2l-acyloxy derivative which on oxidation of the 3-hydroxyl yields l7a-hydroxy-2l-acyloxypregnane-3 ,1 1,20-trione.

17a-hydroxy-2l-acyloxypregnane-3,ll,20-trione to form the 4-bromo product, which on treatment with a nitrogen carbonyl reagent such as semicarbazide, forms the carbonyl derivative at the 3-position with elimination of hydrogen halide from the 4(5 )-position. Removal of the nitrogen carbonyl derivative with an exchange reagent such as pyruvic acid yields cortisone acetate.

As previously stated, according to the method of the present invention, the first step in the production of 3d- As more Gallagher and co- The 4(5)-double bond is finally introduced into the molecule by bromination of t hydroxypregnane-l1,20-dione from lla-hydroxyprogesterone is the hydrogenation of the 4(5)-doub1e bond of llot-hydroxyprogesterone. Thishydrogenation results in the formation of two isomeric products, one having the normal and the other having the allo configuration of hydrogen at the 5-position, i. e., llu-hydroxypregnane- 3,20-dione and 1la-hydroxyallopregnane-3,20-dione. Of the two isomers, the one having the normal configuration is the most desirable product and a hydrogenation process, to be of any practical value, must produce wholly or predominantly the normal isomer. The importance of the normal isomer over the allo isomer arises from the fact that, as previously shown, in the synthesis of adrenal steroids the 4(5)-double bond must be reestablished in the molecule in the final stages of the synthesis. This step of reestablishing the double bond is dependent on the configuration of the molecule at position five. Compounds with the allo configuration can be converted to the 4(5)-unsaturated compounds only with difficulty and in low yields, whereas in compounds with the normal configuration the double bond at the 4(5)-position can be formed easily and in good yields.

The hydrogenation step, when carried out according to the method of the present invention, results predominantly in the formation of the normal stereochemical configuration of hydrogen at carbon atom five in the steroid nucleus. The normal isomer can be consistantly obtained as the predominant isomer, and yields of 65 per cent and better are frequently attained. Production of the normal isomer, and in such high yields, is wholly unexpected in view of the prior art experience which shows that hydrogenation of the double bond in the 4-position generally results in formation of the allo configuration at carbon atom five or a mixture of the allo and normal configurations with the allo form predominating. EButenandt, Tscherning and Hanisch, Berichte, 68, 2097 (1935); Butenandt and Fleischer, Berichte, 68, 2094 (1935)]. A recent report by Pataki, et al., J. Biol. Chem., 195, 751 (1952) showed that the catalytic hydrogenation of ll-oxygenated A -3-keto-steroids leads chiefly to the allo isomer. It was found that hydrogenation of corticosterone acetate l 1B-hydroxy-2 l-acetoxy-progesterone) with a ten per cent palladium-barium sulfate catalyst gave seventy per cent of the allo isomer; hydrogenation of ll-keto-progesterone in a similar manner gave 68 per cent of the pure allo isomer; hydrogenation of Kendalls Compound F acetate (1 1 ,B,17 x-dihydroxy 21 acetoxyprogesterone) gave 82 per cent allo isomer. Hydrogenation of cortisone acetate (ll-keto-l7m-hydroxy-2l-acetoxyprogesterone) with a ten per cent palladium-barium sulfate catalyst gave seventy per cent of the allo isomer [Djerassi, et al., J. Biol. Chem, 194, 115 (1952)]. Similarly, Mason, et al., J. Biol. Chem., 120, 733 (1937), report a yield of eighty per cent of the allo isomer when hydrogenating dehydrocorticosterone droxyprogesterone) with hydrogen in the presence of palladium black catalyst.

According to the hydrogenation step of the present invention, llot-hydroxyprogesterone is hydrogenated'with hydrogen in the presence of a palladium catalyst such as, for example, palladium black, palladium or charcoal, palladium on an ion exchange resin, palladium on barium sulfate, palladium on magnesium oxide, palladium on calcium carbonate, or the like, to produce lla-hYClt'OXY- pregnane-3,20-dione. The preferred order of hydrogenation is first to subject the palladium catalyst to hydrogen in conventional hydrogenation apparatus to reduce the catalyst prior to the introduction of the starting steroid material. It is not essential that the catalyst be in a solvent medium, but methanol, hexane, acetone, methyl ethyl ketone, ethanol, or like organic solvent may be advantageously employed. Preferably, an alcohol solvent is used. Alternatively, the catalyst and starting steroid to be hydrogenated can be contacted together in a solvent medium prior to introduction of the hydrogen. It is not necessary to conduct the reaction under pressure, although, when pressure is utilized, a hydrogen pressure of about one to 100 pounds or more is operative. Any suitable temperature between about zero and 100 degrees centigrade may be employed, with room temperature being satisfactory. Sometimes a small amount of a base such as, for example, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, or the like, is added to the reaction mixture in order to enhance the yield of the normal isomer. In the preferred embodiment of the present invention, the starting steroid material is added to the already reduced catalyst and hydrogenation with hydrogen at atmospheric pressure continued until approximately one molar equivalent of hydrogen has been absorbed. The use of substantially less than one molar equivalent of hydrogen results in the incomplete saturation of the double bond in the 4(5)-position of the steroid nucleus, whereas the use of substantially more than one molar equivalent of hydrogen does not appear to increase the yield of hydrogenated product. The spent catalyst is then separated from the solution containing the hydrogenated products by conventional procedure, such as by filtration, centrifugation or decantation. Filtration is preferred. Conventional separation or extraction procedures can be used in obtaining the hydrogenated product from the solution. Preferably, the hydrogenated productis separated into its normal and allo fractions chromatographically by passage through a column packed with a mixture of diatomaceous material, colloidal clays, activated carbons, or other conventional adsorbents, followed by development of the adsorbed reaction products with organic solvents, such as acetone, ethyl acetate, carbon tetrachloride, hexane, methylene chloride, chloroform, methyl ethyl ketone, or mixtures of such solvents. In some instances, elution of the adsorbed hydrogenated products with selective solvents is desirable, as in the chromatographing of 1lu-hydroxypregnane-3,20-dione, wherein acetone is preferred, and lla-hydroxypregnane- 3,20-dione, wherein methylene chloride is preferred. The eluted fractions may be evaporated to dryness leaving the crystalline residue of the desired hydrogenated prodnot which can then be further purified by crystallization from ordinary organic solvents. Alternatively, separation may be achieved by other conventional procedures such as, for example, fractional crystallization. In some instances, as in the separation of lla-hydroxypregnane- 3,20-dione and 11(x-hydroxyallopregnane-Za,ZO-dione, fractional crystallization does not result in a true representation of the amounts of normal and allo isomers present in the hydrogenation mixture. The normal isomer is more difficulty isolated and consequently the yields of the normal isomer are usually low. In such cases it is preferred to use chromatography for the separation.

In the second step of the method of the present invention, lla-hydroxypregnane-3,20-dione is oxidized to produce pregnane-3,11,20-trione. The oxidation may be accomplished either in a homogeneous reaction system with chromic acid or more preferably in a heterogeneous sys tem. When oxidation is carried out homogeneously, 11u-hydrOXypregnane-B,ZO-dione is dissolved in an organic solvent, preferably acetic acid, and to this solution is added a solution of chromium trioxide in acetic acid containing a small amount of water (chromium trioxide in the presence of water results in the formation of chromic acid which acts as the oxidizing agent). When oxidation is carried out heterogeneously, llct-hydroxypregnane-3,20-dione is dissolved in an organic solvent which is substantially water-immiscible. Solvents such as benzene, toluene, chloroform, ethyl acetate, normal hexane, ortho-chlorotoluene, carbon tetrachloride, and chlorobenzene may be advantageously employed, the latter solvent being preferred. The proper solvent is one which readily dissolves the steroid, is substantially nonreactive with the reactants and reaction products, and is substantially immiscible with water. The oxidizing media is prepared by dissolving an alkali metal dichromate salt in water, the hydrated sodium dichromate being the preferred dichromate salt, although other dichromate or even chromate salts can be used. To the resulting aqueous alkali metal dichromate solution is added an acid, for example, a mineral acid such as sulfuric acid, or a sulfonic acid, such as para-toluenesulfonic acid. Such an oxidizing media results in the formation of chromic acid in the solution which acts as the oxidizing agent. The function of the acid is merely to furnish hydrogen ions in the oxidizing media and, therefore, acids such as sulfuric, phosphoric, and the like, may be employed. The solution of the starting steroid in the organic solvent is then admixed with the aqueous oxidizing media, formed by reaction of the alkali metal dichromate solution with the acid, at a temperature below about thirty degrees centigrade, the temperature range of from'about minus thirty degrees centigrade to about thirty degrees centigrade being entirely satisfactory with about minus ten to plus ten degrees centigrade being the preferred temperature range. The order of mixing the reactants IS not critical and admixing of the solutions is generally conducted by adding small portions of one solution to the other at the indicated temperatures, accompanied by continual stirring or other agitation. The entire mixture is usually stirred for an additional period of from about one-half to about five hours, during which time the oxidation of the ll-hydroxy group to the keto group is effected. Upon completion of the oxidation, usually in from about one-half to eight hours, with about two hours being preferred, the organic layer is separated from the aqueous layer by conventional separation procedures. The aqueous layer may then be extracted with successive portions of benzene or other organic solvent which is substantially water-irnmiscible and in which the product is soluble. The organic extractions are separated and combined with the first organic layer and the combined organic solutions are then washed with successive portions of water and sodium bicarbonate or other weakly basic solution to remove any acidic material. The oxidized product may then be recovered from the organic layer by conventional procedure, such as drying over anhydrous sodium sulfate, filtering and concentrating to give the desired pregnane-3,ll,20-trione.

1n the final step of the method of the present invention, pregnane-3,l1,20-trione is selectively reduced to 3a-hydroxypregnane-l1,20-dione. The selective reduction is preferably accomplished with a metal borohydride, which procedure affords a simple and effective means of converting the carbonyl group at the 3-position of pregnane- 3,11,20-trione to a hydroxyl group. Confinement of the reduction to the carbonyl group at the 3-position is controlled most conveniently by limiting the amount of borohydride employed, although temperature and duration of the reaction can also be used as controlling factors. The reduction permits considerable latitude in the selection and range of operating conditions. Concentrations of the steroid and the borohydride can vary from stoichiometric amounts of each to an excess of the borohydride ranging up to 300 per cent (four equivalents). However, when an excess of borohydride is used, the duration of the reaction and/or the temperature should be decreased in order to prevent reduction of carbonyl groups at the 11- and 20-positions. Therefore, in order to minimize the possibility of reduction of the carbonyl groups in the 11- and 20-positions in addition to that at the 3-position, the preferred amount of borohydride is from about 1 to about 1.25 equivalents (based on the amount required for the reduction of one carbonyl rou g Tli e period during which pregnane-3,11,20-trione is subjected to the action of the borohydride can vary from about two minutes to about two hours, depending upon the relative concentrations of the two reactants and the temperature at which the reduction is conducted. Periods longer than two hours do not appear to be necessary. Temperatures can range from the boiling point of the solvent to well below room temperature providing the solvent does not freeze or the steroid separate from solution. A convenient and preferred range is from about twenty degrees centigrade to about fifty degrees centigrade. Among the solvents which can be used for the reaction are methanol, ethanol, isopropanol, dioxane, tetrahydrofuran and the like. These can be used in the anhydrous state or admixed with a small amount of water. A preferred solvent is a mixture of isopropanol and water. The steroid is dissolved in isopropanol and to this solution is added sodium borohydride dissolved in a volume of water amounting to about 5-10 per cent of the volume of isopropanol. The borohydride does not need to be 100 per cent pure. Sodium borohydride having a purity of 83-88 per cent and lithium borohydride having a purity of 55 per cent have been used successfully in this step of the invention and compensatingly larger amounts were employed.

Because of the ease of operation, and of the high yields of reduction product obtained, a metal borohydride is preferred for the selective reduction, although other selective reduction procedures may be employed such as, for example, hydrogenation with one molar equivalent of hydrogen in the presence of a platinum oxide catalyst, and the like.

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

Example 1.-IIa-hydroxypregnane-3,20-di0ne and 11a.- hydroxyallopregnane-3 ,ZO-dione A solution of 250 milligrams (0.75 millimole) of llahydroxyprogesterone [Peterson and Murray, J. Am. Chem. Soc.', 74, 1871 (1952)] in milliliters of ethanol containing six drops of triethylamine was subjected to hydrogenation at room temperature under a pressure of about ten pounds of'hydrogen in the presence of 45 milligrams of a thirty per cent palladium-charcoal catalyst in a Parr apparatus with an auxiliary mercury manometer. The time required for the hydrogenation was about twenty minutes. The reaction mixture was filtered and the solvent was evaporated to yield 265 milligrams of material melting at -185 degrees centigrade. This product was extracted with a mixture of one mililiter of ether and nine milliliters of Skellysolve B (petroleum ether, boiling range 60-70 degrees centigrade). On standing, the extract deposited eighty milligrams (32 per cent) of llahydroxypregnane-3,20-dione as feathery needles which melted at 85-90 degrees centigrade. Recrystallization from a mixture of about six drops of ethyl acetate and five milliliters of Skellysolve B did not change the melting point.

Analysis.-Calculated for C21H32O32 C, 75.86; H, 9.70. Found: C, 76.13; H, 9.63.

The residue from the above extraction weighed 146 milligrams (58 per cent) and melted at -185 degrees centigrade. Recrystallization from ethyl acetate gave 85 milligrams (34 per cent) of lle-hydroxyallopregnane- 3,20-dione melting at 193-196 degrees centigrade with softening about degrees. A purified sample melted at 1985-1995 degrees centigrade.

Analysis.-Calculated for C21H3203Z C, 75.86; H, 9.70. Found: C, 75.59; H, 9.98.

The separation of the normal and allo pregnanes was also accomplished by chromatography. An intimate mixture of 16.7 grams of Celite S-545 and 8.3 grams of Darco G-60 was wet packed with about 150 milliliters of methanol into a column three centimeters wide. (The ratio of fifty grams of adsorbent to one gram of the reaction mixture, as used here, was satisfactory in cases where the normal form predominated. When the allo form was the major component or when the composition of the mixture was not known, a ratio of 100:1 was used.) About two pounds of air pressure was applied until the liquid had dropped to the level of the adsorbent. A plug of cotton was packed on top of the adsorbent and the column was washed with one 200-milliliter fraction of methanol and two 200-milliliter fractions of acetone. The reaction mixture from the hydrogenation in methanol of 500 milligrams of 1la-hydroxyprogesterone, according to the procedure above described, was dissolved in 200 milliliters of acetone and added to the column. This fraction, after passing through the column, was termed the first eluate fraction. It was followed by eight 200-milliliter fractions of acetone and four 200-milliliter fractions of methylene chloride. (For the elutions about eight milliliters of solvent per gram of adsorbent wassatisfactory.) Each new fraction was added when the level of the preceding one reached the cotton plug. The 11a-hydroxypregnane-3,20-dione was usually obtained by evaporation of fractions 2-6 while the lla-hydroxyallopregnane-3,20-dione was obtained by evaporation of fractions 10-12. Following are the results of a typical separation:

Fraction No. Solvent Wt. in milligrams 43 J. ormal 323 mg., 64

22 percent A 0.55 gram sample of the normal form as obtained above was dissolved in ten milliliters of acetone, twenty milliliters of warm water was added, and the solution was allowed to cool gradually at room temperature and finally was placed in a refrigerator. Crystallization occurred and 0.38 gram (69 per cent recovery) of Ila-hydroxypregnane-3,20-dione was obtained which melted at 55-70 degrees centigrade. The melting point of the normal form was extremely variable, ranging from that given above to 115-120 degrees centigrade. The variability in melting point did not affect the utility of the various batches as the same results were obtained when these batches were employed in further operations.

Example 2.--Hydragenation of Ila-hydroxyprogesterone Following the procedure of Example 1, a series of experiments were conducted wherein llu-hydroxyprogesterone was hydrogenated in the presence of different palladium catalyst. The reactions were conducted in methanol as solvent. The reduction product was separated into the normal (11a-hydroxypregnane-3,20dione) and allo (11a-hydroxyallopregnane-3,20-dione) isomers by chromatography as described in Example 1. Table I shows the catalyst and the per cent yield of normal and allo isomers.

TABLE I Percent Percent catalyst Normal A110 4 percent Pd-polyvinylalcohoL- '1 percent Pd-Charcoal 57-62 32-35 percent Pd-BaSO4. 42 39 5 percent Pd-SiO: 44 32 4 percent Pd-Celite (magnesium silicate)--- 54 45 5 percent Pd-MgO 49 51 Pd- 47 45 5 percent Pd-AhO:. 63 37 30 percent Pd-Chareoa 55 38 5 percent Pd-MgCOz-.- 52 48 percent Pd-Cl1COz 63 31 Example 3.Hydrogenati0n of Ila-hydroxyprogesterone Following the procedure of Example 1, a series of experiments were conducted wherein l1a-hydroxyprogesterone was hydrogenated in different solvents. The catalyst was one per cent palladium on charcoal. The prodnot was separated into the normal (llwhydroxypregnane- 3,20-dione) and allo (l1a-hydroxyallopregnane-3,20- dione) isomers by chromatography as described in Ex ample 1. Table II shows the solvent and the per cent yield of the normal and allo isomers.

Example 4.Hydrogenation of lla-hydroxyprogesterone Following the procedure of Example 1, a series of experiments were conducted wherein lla-hydroxyprogesterone was hydrogenated under diiferent pressures. catalyst was one per cent palladium on charcoal and the solvent was methanol. The product was separated into the normal (l1a-hydroxypregnane-3,20-dione) and allo (lliz-hydroxyallopregnane-3,ZO-dione) isomers bychromatography as described in Example 1. Table III shows the pressure and the per cent yield of normal and allo isomers.

TABLE III Hi Pressure (lbs.) 233 ig m Example 5.Pregnane-3,.11,20-trione Four hundred fifty milligrams of lla-hydroxypregnane- 3,20-dione, obtained according to the procedure of Example 1, was mixed with 5.3 milliliters of chlorobenzene and the resulting chlorobenzene solution added, in small portions, with continual stirring, to a mixture obtained by dissolving 707 milligrams of hydrated sodium dichromate (NazCrzOmZHzO) in 3.1 milliliters of water and 0.93 milliliter of concentrated sulfuric acid maintained in an ice-bath, and the resulting reaction mixture stirred for an additional two hours in an ice-bath. The chlorobenzene and aqueous layers were separated, and the aqueous layer extracted with two successive portions of benzene. The combined chlorobenzene and benzene layers were separated from the aqueous layer and washed successively with two -milliliter portions of water, one IOO-milliliter portion of saturated sodium bicarbonate solution, and two 50-milliliter portions of water. The organic layer was separated from the aqueous washings, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crystalline residue of 367.2 milligrams (81.6 per cent) of pregnane-3,1l,20-trione, melting at 150-153 degrees centigrade.

Similar results were obtained when lla-hydroxypregna r(11e-3,20'dione was oxidized with chromic acid in acetic acr Example 6.-3ot-hydr0xypregnane-I1,20di0ne v A solution of 1.085 grams (3.29 millimoles) of pregnane-3,1l,20-trione in 35 milliliters of dioxane (freshly distilled from sodium borohydride) was cooled to thirteen degrees centrigrade and to it was added as rapidly as possible with vigorous stirring a solution of 39.8 milligrams (0.927 millimole based on pure reagent) of sodium borohydride (assay 88.2 per cent) in 3.5 milliliters of water. The reaction mixture was stirred for thirty minutes at fifteen degrees centigrade and acidified by the addition of three milliliters of glacial acetic acid. Water was added and the mixture was extracted three times with ether. The extracts were combined, washed with water, dried over magnesium sulfate and the solvent was removed. Twice benzene was added to the residue and removed by distillation to remove the dioxane. The residual oil crystallized when it was dissolved in ether and the ether was removed on a steam bath. Removal of last traces of ether under reduced pressure and recrystallization of the crude product from acetone and Skellysolve B gave 795 milligrams (73 per cent) of 3u-hydroxypregnane-l1,20-dione melting at 1695-1725 degrees centigrade. A second recrystallization gave 675 milligrans (63 per cent) melting at 173.5-'174.5 degrees centigra e.

Reduction of pregnane-3,11,20-trione in isopropyl alcohol gave like results.

Example 7.-3a-hydroxypregnane-I1,20-dione A solution of 0.867 grams (2.63 millimoles) of pregnane-3,11,20-trione in twenty milliliters of tetrahydrofuran (freshly distilled from sodium borohydride) was cooled in ice water and to it was added rapidly with vigorous stirring a solution of 26.0 milligrams (0.655 millimole based on pure reagent) of lithium borohydride (assay per cent) in twelve milliliters of water. The reaction mixture was stirred for fifteen minutes at zero degrees centigrade and acidified by the addition of glacial acetic acid. Solvents were removed under reduced pres sure and the residue was dissolved in the minimum amount of hot isopropanol. To this solution hot water was added until a faint turbidity was present'and isopropanol was added dropwise until the turbidity was discharged. The mixture was seeded and allowed to cool slowly to room temperature. After two hours, the crystalline product which had separated was collected by filtration, washed thoroughly with dilute isopropanol and dried. Recrystallization from ethyl acetate-Skellysolve B gave 546.5 milligrams (63 per cent) of pregnane-Iauo]'11,20-dione melting at 177.5-179 degrees centigrade. A second crop of 66 milligrams melting at 170-172 degrees Centigrade was obtained from the mother liquors; the total yield was 612.5 milligrams (70.6 per cent).

It is to 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 process which consists of the steps of (1) hydrogenating lla-hydroxyprogesterone with hydrogen in the presence of a palladium hydrogenation catalyst to produce a high proportion of 11a-hydroxypregnane-3,20- dione having the normal stereochemical configuration of hydrogen at carbon atom five of the steroid molecule, and (2) oxidizing the resulting l1a-hydroxypregnane- 3,20-dione with an oxidizing agent to produce pregnane- 3 ,l 1,20-trione.

2. The process of claim 1 wherein the oxidizing agent is chromic acid.

3. In a process for the production of 3a-hydroxypregnane-ILZO-dione from llu-hydroxyprogesterone, the steps of (1) hydrogenating lla-hydroxyprogesterone with hydrogen in the presence of a palladium hydrogenation catalyst to produce 1la-hydroxypregnane-3,ZO-dione, (2) oxidizing the 11ct-hydroxypregnane-3,20-dione with an oxidizing agent to convert the Ila-hydroxy group to an ll-keto group and produce pregnane-3,11,20-trione, and (3) selectively reducing the 3-keto group of the resulting pregnane-3,1l,20-trione to a hydroxy group to produce 3a-hydroxypregnane4 1,20-dione.

4. In a process for the production of 3-a-hydroxypregnane-l1,20-dione from llu-hydroxyprogesterone, the steps of (1) hydrogenating llu-hydroxyprogesterone with hydrogen in the presence of a palladium hydrogenation catalyst to produce 11m-hydroxypregnane-3,ZO-dione, (2) oxidizing the 11a-hydroxypregnane-3,20-dione with an oxidizing agent to convert the Ila-hydroxy group to an ll-keto group and produce pregnane-3,1l,20-trione, and (3) selectively reducing the 3-keto group of the resulting pregnane-3,ll,20-trione to a hydroxy group with a metal borohydride to produce 3a-hydroxypregnane-l1,20-dione.

5. The process of claim 4 wherein the oxidizing agent is chromic acid, and wherein the metal borohydride is an alkali metal borohydride.

6. In a process for the production of 3a-hydroxypregnane-11,20-dione, the steps of (l) oxidizing Ila-hydroxypregnane-3,20-dione with an oxidizing agent to convert the lla-hydroxy group to an ll-keto group and produce pregnane-3,ll,20-trione, and (2) selectively reducing the 3-keto group of the resulting pregnane-3,1'l,20-trione to a gydroxy group to produce 3a-hydroxypregnane-l1,20-

tone.

7. In a process for the production of 3m-hydroxypregname-11,20-dione, the steps of (1) oxidizing Ila-hydroxypregnane-3,20-dione with an oxidizing agent to convert the Ila-hYdIOXY group to an ll-keto group and produce pregnane-3,11,20-trione, and (2) selectively reducing the 3-keto group of the resulting prcgnane3,ll,20-trione to a hydroxy group with a metal borohydride to produce 3 a-hydroxypregnane-l 1,20-dione.

8. The process of claim 7 wherein the oxidizing agent is chromic acid and wherein the metal borohydride is an alkali metal borohydride.

9. In a process for the production of ia-hydroxypregnane-1l,20-dione from lla-hydroxyprogesterone, the steps of (l) hydrogenating llu-hydroxyprogesterone with hydrogen in the presence of a palladium hydrogenation catalyst to produce 11a-hydroxypregnane-3,20-dione, (2) oxidizing the thus-produced 1la-hydroxypregnane-3,20- dione with chromic acid to convert the lloc-hYdlOXY group to an ll-keto group and produce pregnane-3,l1,20-trione, and 3) selectively reducing the thus-produced pregnanc- 3,11,20-trione with sodium borohydride to produce 3mhydroxypregnane-l1,20-dione; the steps of hydrogenating, oxidizing, and reducing being conducted in the presence of an organic solvent.

References Cited in the file of this patent Fieser et al., Natural Products Related to Phenanthrene, 3rd ed., pp. 417-422 (1949).

Claims (1)

1. A PROCESS WHICH CONSISTS OF THE STEPS OF (1) HYDROGENATING 11A-HYDROXYPROGESTERONE WITH HYDROGEN IN THE PRESENCE OF PALLADIUM HYDROGENATION CATALYST TO PRODUCE A HIGH PROPORTION OF 11A-HYDROXYPREGNANE-3,20DIONE HAVING THE NORMAL STEREOCHEMICAL CONFIGURATION OF HYDROGEN AT CARBON ATOM FIVE OF THE STEROID MOLEUULE, AND (2) OXIDZING THE RESULTING 11A-HYDROXPREGNANE3,20-DIONE WITH AN OXIDIZING AGENT TO PRODUCE PREGNANE3,11-20-TRIONE.