3,531,475 United States Patent Office Patented Sept. 29, 1970 2 3,531,475 SUMMARY OF INVENTION PROCESS FOR THE OXEDATION OF ALCOHOLS AND OXDZING AGENT UTILIZED THEREN The invention sought to be patented in its process aspect Marcel Fetizon, Leflageolet, and Michael Golfier, Paris, resides in the concept of an oxidation process in which France, assignors to Société de Recherches Biologiques an alcohol, preferably a steroidal alcohol, having a hy d'Asnieres, a limited-liability company, Levallois, 5 droxyl function selected from the group consisting of a France primary and a secondary hydroxyl, is oxidized to a non No Drawing. Filed Aug. 13, 1968, Ser. No. 752,184 carboxy carbonyl steroidal compound in an organic sol Claims priority, application France, Aug. 21, 1967, vent utilizing an oxidizing agent comprising silver car 118,383 bonate and a diatomaceous earth (preferably Celite). Int. CI. C07e 169/08, 169/10 O The invention sought to be patented in its composition U.S. C. 260-239.55 18 Claims of matter aspect resides in the concept of an oxidizing agent comprising silver carbonate and a diatomaceous earth (preferably Celite) which is useful as an oxidizing ABSTRACT OF THE DISCLOSURE agent in the oxidation of primary and secondary alcohols A process for oxidizing primary and secondary alco 5 to aldehydes and ketones. The composition of matter hols to aldehydes and ketones in neutral media and in sought to be patented is particularly useful in oxidizing excellent yields comprises reacting a primary or secondary non-activated steroidal hydroxy functions in a neutral alcohol with an oxidizing agent comprising silver car medium, which function heretofore could only be oxidized bonate on an inert carrier, a preferred carrier being di in acidic or basic media. atomaceous earth, particularly Celite. This process is ex 20 tremely useful when applied to steroidal alcohols, par GENERAL DESCRIPTION OF THE INVENTION ticularly in the oxidation of saturated-A-ring-3-hydroxy The process aspect steroids to saturated-A-ring-3-keto-steroids. According to one of its aspects, this invention provides a process for oxidizing steroidal hydroxy compounds in the liquid phase which involves using as the oxidizing FIELD OF INVENTION agent a composition of matter which comprises silver carbonate and an inert carrier on which the salt is dis This invention relates to a process for oxidizing pri persed, specifically a diatomaceous earth, with Celite be mary and secondary alcohols in a neutral medium and 30 ing preferred. to the oxidizing agent utilized therein. To facilitate complete oxidation of the steroidal hy More particularly, this invention relates to the process droxy starting compound, it is preferred that the compo of oxidizing primary and secondary steroidal alcohols in sition should provide between 2 and 30, advantageously a neutral medium by the action of an oxidizing agent between 8 and 15 molar equivalents of silver carbonate comprising silver carbonate and a diatomaceous earth 3 5 therein per mole of the starting steroidal alcohol. (preferably Celite) whereby is obtained the correspond The process of this invention is conveniently effected ing aldehyde or ketone, respectively, in excellent yield. in an organic solvent which preferably is substantially Also included in this invention are compositions of matter anhydrous, since water even in quite small quantities, for comprising silver carbonate on a diatomaceous earth example, 1%, can deleteriously affect the reaction leading (preferably Celite) useful as oxidizing agents in neutral 40 to poor yields. The solvent should be one which is inert media. in the sense that it does not adversely affect the oxidizing agent nor the starting compound nor the oxidized prod DESCRIPTION OF THE PRIOR ART uct. The solvent of choice often depends upon the nature of the steroidal hydroxy starting compound, though other Heretofore, compositions of matter comprising silver factors such as price, ease of recovery, temperature condi carbonate on a diatomaceous earth useful as oxidizing tions, also influence this. Particularly useful as solvents in agents have been unknown. Also, the process of this in our process are aromatic hydrocarbons such as benzene, vention has been heretofore unknown. toluene and xylene. In many instances, benzene is the Prior art processes for oxidizing steroidal primary and preferred solvent because (a) it is readily available at a secondary alcohols to steroidal aldehydes and ketones all reasonable cost; (b) it has a high solubility power for a require the use of either a basic medium (e.g. the Op great number of organic hydroxy compounds including penauer oxidation utilizing aluminum isopropoxide and steroidal hydroxy compounds; (c) under standard, at cyclohexanone in toluene) or an acid medium (e.g. mospheric conditions it has a convenient boiling point chromic acid in sulfuric acid) or the presence of an acti (80° C.); and also (d) it can be readily stripped from vated hydroxy group, e.g. the oxidation of an allylic hy 5 5 the reaction mixture upon completion of the reaction. droxyl group such as in a A-3-hydroxyl moiety by the use Other suitable solvents include, for instance, chlorinated of manganese dioxide, which process requires long reaction hydrocarbons such as chloroform, aliphatic alcohols and times. On the other hand, the process of the present in preferably methanol which is found particularly satis vention whereby a steroidal primary or secondary hy factory in the oxidation of allylic alcohols and ketones droxyl function is oxidized to a steroidal non-carboxy 60 such as methyl, ethyl, ketone and tetrahydrofuran. carbonyl derivative by reaction with silver carbonate on The temperature at which the oxidation process is car a diatomaceous earth advantageously is carried out in a ried out can vary over a wide range. The selection of an neutral media and, thus, is useful when oxidizing steroidal appropriate temperature for a particular case will depend compounds containing groups sensitive to acid or base. upon such factors as the nature of the steroidal hydroxy Additionally, the process of this invention will quickly compound, the solvent in which the oxidation is being per oxidize in good yields non-activated steroidal hydroxyl formed, and the desired rate of oxidation. Generally groups such as those present in a 3-hydroxy-saturated-A- speaking, lower temperatures will reduce the rate of oxi steroidal system such as in 36-hydroxy-166-methyl-5oz dation whilst higher temperatures give rise to side reac pregnane-17a,21-diol-20-one 21-acetate, a known inter tions. In certain instances, especially when the starting mediate in the preparation of betamethasone (i.e. 9oz 70 steroid is an allylic alcohol, the oxidation proceeds satis fluoro-166-methyl-1,4-pregnadiene-1118, 17 c.21 - triol-3,20 factorily at ambient temperature. More usually, however, dione). it is desirable to operate at a temperature of between 3,531,475 3 4 about 40° C. and about 150° C., and the preferred range responding homo and nor derivatives. Many naturally is often from about 50° C. to about 100° C. Sometimes, occurring steroids commonly used as the starting point as for example, when the solvent is benzene, it is con for the synthesis of important therapeutically active Ste venient to operate at the reflux temperature of the solvent. roids contain a 3-hydroxy-saturated-A-ring System, and The reaction mixture is preferably agitated vigorously their conversion into the final product often involves the through the oxidation period. oxidation of the hydroxy group at the 3-position to a keto The time needed to effect the oxidation depends pri group. Accordingly, the process of this invention affords a marily upon the nature of the organic hydroxy starting simple yet effective means of effecting this conversion, so compound and also the temperature at which the process that an especially valuable application of the process is to is conducted. In some instances, the oxidation is substan such 3-hydroxy-saturated-A-ring steroids. tially complete within a period of between about 30 min O By way of example, included in known procedures for utes and about 2 hours, but in other cases longer periods, the preparation of known therapeutically valuable com say 10-20 hours, may be required. The course of the pounds such as 160-methylprednisone, 16.6-methylpred oxidation can be readily followed by thin-layer chroma nisone, 9a-fluoro-166-methylprednisolone 21-acetate, is a tography, with the disappearance of the spot due to the 5 step involving the oxidation of a 3-hydroxy intermediate hydroxy compound indicating complete oxidation to the to the corresponding 3-keto compound, i.e. the oxidation corresponding carbonyl compound. Preferably, the water of 3c - hydroxy - 160-methylpregnane-17o,21-diol-11,20 formed during the oxidation is continuously eliminated, dione 21-acetate, 3c - hydroxy - 166 - methylpregnane for otherwise the accumulation of water may deleterious 170,21 - diol - 11,20 - dione 21-acetate, 3c-hydroxy-16,3- ly affect the reaction resulting in poor yields. When the 20 methylpregnane - 110,17a,21 - triol - 20-one 21 acetate process is conducted in benzene as the Solvent, then by and 313 - hydroxy - 16oz - methyl - 5o-pregnane-17 oz,21 operating at the reflux temperature and in an apparatus diol-20-one 21-acetate, respectively to the corresponding such as the Dean-Stark apparatus, the water formed in the 3-keto derivatives, which oxidations car now be advan reaction may be continuously eliminated. tageously carried out in good yield according to the Alternatively, water may be removed from the conden 25 process of this invention. sate, prior to its return to the reaction, by passage over a With certain steroidal alcohols containing two or more molecular sieve (e.g. Soxhlet apparatus). hydroxy groups, steric factors operate which make for The process according to this invention is of particular differences in the reactivity of the hydroxy groups so en value in that it provides a new and simple method of dowing the process with a certain selectivity in that the converting an organic hydroxy compound into the cor 30 more reactive hydroxy groups are preferentially oxidized. responding carbonyl compound. Whilst the process is of For instance, it has been found that in steroidal alcohols, general application, the organic hydroxy compound is hydroxy groups at the 3oz-, 36- and 176-positions are more typically a primary or secondary steroidal alcohol which readily oxidized than hydroxy groups at the 60-, 7c- and are converted by the process, often in virtually quantita 12a-positions. This feature of the process is advantageous, tive yields, to the corresponding aldehyde and ketone re for it provides for the possibility of selective oxidation. spectively. The primary or secondary alcohol grouping Thus, 4,4-dimethyl-5o-androstane-6a, 17,3-diol may, using may be present in, for instance, an aliphatic, alicyclic, the process of this invention, be converted in good yield aromatic, heterocyclic, or carbohydrate compound and into the corresponding 6oz-hydroxy-17-keto compound for examples of alcohols which are oxidized successfully to the 176-hydroxy group is more reactive than that at the the corresponding aldehyde and ketone using the process 40 6oz-position. Again, methyl cholate which contains hy of this invention include, methanol, ethanol, propanol, droxy groups at the 3oz-, and 7 oz- and 12a-positions may butanol, hexanol, benzyl alcohol, catechol, hydroquinone, be selectively oxidized at the 3oz-position. 14 - naphthaquinol, 2,6 - naphthaquinol, geraniol, nerol, Aside from the observed preferential oxidation of phytol and farnesol. hydroxy groups dependent upon their location in a par The process of this invention is very well suited to, and 45 ticular steroidal alcohol, the reactivity of the hydroxy accordingly is particularly valuable for, the oxidation of groups and, therefore, the speed of the reaction often steroidal compounds containing one or more primary or appears to be dependent upon the structure of the com secondary hydroxy groups. Many steroid compounds, for pound. For example, in allylic alcohols, the double bond instance, sapogenins such as Smilagenin and corticoids enhances the reactivity of the hydroxy group so that these such as various pregnane compounds, are extremely sensi 50 alcohols are generally more readily oxidized than the tive and are very liable to undergo degradation or rear corresponding saturated alcohols. Accordingly, steroid rangement on contact with acid or base. Thus, the spiro molecules containing both an allylic hydroxy group and ketal side chain in sapogenins is readily cleaved upon ex a saturated hydroxy group can, using the process of this posure to acid, and the side chain at the 17-position in invention, be selectively oxidized. For instance, when steroids of the pregnane series is susceptible to attack by 55 4-androstene-3,6,17B-diol is used as the starting compound acid or base, and is very easily degraded. Now, the and the reaction is done at room temperature, the process of this invention, when, as is preferred, it is con 3-hydroxy group is preferentially oxidized, and testos ducted in an organic solvent, is effected under neutral terone can be isolated in excellent yields. conditions. Sensitive steroidal compounds, therefore, are Composition of matter aspect less likely to be adversely affected by the oxidation proc 60 ess than they would be were the oxidation to involve According to the invention, in its composition of acidic or basic media. For example, employing the process matter aspect, there is provided a composition of matter of this invention, smillagenin is converted into the corre suitable for use as an oxidizing agent, which comprises sponding 3-keto compound without any appreciable cleav silver carbonate and an inert carrier, preferably diato age of the spiroketal side chain, and a pregnane steroid, 65 maceous earth, on which the salt is dispersed. Other sub such as 16 (c. or 6)-methyl-5a-pregnane-3,6,170,21 - triol stances, for example, binders and lubricants, may be 20-one 21-acetate is oxidized at the 3-position without any present in these compositions. degradation of the cortical side chain at the 17-position. The composition according to this invention is an The process according to the invention is, therefore, a advantageous oxidizing agent because the silver carbonate highly useful method for the oxidation of hydroxy groups O is dispersed over, and combined with, a matrix provided located at various positions in a steroid molecule and is by the inert carrier, preferably diatomaceous earth, so applicable to pregnanes, spirostanes, Oestranes, andro ensuring good contact between the silver carbonate and stanes, cholestanes, ergostanes, lanostanes and Stigmas the organic hydroxy compound which it is desired to tanes together with their various unsaturated derivatives, oxidize. Further, the composition is in a convenient form for example, pregnenes, pregnadienes, etc. and the cor for use, for instance, it can be readily stored, it mixes 3,531,475 5 6 readily with the organic hydroxy compound during the with water until neutral. It is then dried on a water bath oxidation process, and can be easily recovered, say by under vacuum to give a fine yellowish-brown powder filtration, from the aldehyde or ketone end product of which is not affected by light, and which can be stored the oxidation process. for some weeks without any significant diminution of The proportion of the silver carbonate required in these activity, though best results are often obtained in the compositions can vary considerably depending upon such 5 process when the composition is prepared immediately, factors as, for example, the nature of the organic hydroxy or just shortly before use. compound which it is desired to oxidize. Generally, how The method outlined in the foregoing can be varied ever, it is preferred that the silver carbonate be present considerably without essentially departing from the prop in an amount such that when a given composition is erties of he composition so obtained and, it will be appre utilized in the oxidation process, there are between 2 O ciated, that the initial reactants can be mixed together in and 30, usually between 2 and 15, equivalents of silver various amounts. carbonate per mole of the compound undergoing the oxidation. DESCRIPTION OF THE PREFERRED Suitable inert carriers for the oxidizing agent com EMBODIMENTS position include materials such, for example, as alumina, Composition of mater aspect silica-alumina, siliceous earths, clays, kieselguhr, carbon Preferred oxidizing agents of this invention are com black, and preferably diatomaceous earths. These carriers positions of matter comprising silver carbonate on a di are generally characterized by having a large surface atomaceous earth wherein the diatomaceous earth com area which makes, in the oxidation process, for good 20 prises from about 40% to about 60% by weight of said contact between the salt dispersed thereon, and the organic compositions. For use in the foregoing compositions, the hydroxy compound. A particularly convenient material preferred diatomaceous earth is Celite. for use as the carrier is diatomaceous earth which is Specifically, the oxidizing agent of this invention most commercially available under such trade names as Dicalite advantageously employed in the preferred embodiment and Celite. Preferred is the diatomaceous earth known by 25 the trade name Celite. Prior to incorporating this Celite of the process aspect of our invention is a composition in the composition it may be desirable to wash it, for comprising silver carbonate on Celite which contains one instance, first with an acid and then with distilled Water millimole of silver carbonate per 0.57 gm. of said com until the washings are neutral. position. These preferred compositions are made accord The amount of carrier, e.g. Celite, present in these ing to the procedure set forth hereinbelow in Example 1. compositions can vary considerably, and the optimal quan 30 tity is dependent upon variables such as the content of Process aspect the carrier, the nature of the organic hydroxy compound When carrying out the oxidation process of this in and the amount thereof which is to be oxidized. However, vention, there is preferably utilized a quantity of oxidizing for convenience of use in the process, especially removal agent sufficient to supply from about 8 to about 15 molar of the oxidizing agent composition from the oxidized equivalents of silver carbonate per mole of steroid to be product, it is often desirable that the carrier content oxidized. We find it most convenient to utilize the pre should not be much less than 1 gm. for lesser amounts ferred oxidizing agent of this invention as defined here can present recovery problems. In typical compositions inabove as our source of silver carbonate; thus a pre provided by this invention the carrier, e.g. Celite, forms 40 ferred mode of our process is that wherein for each milli 30-70 percent by weight of the composition, and usually mole of steroid there is used about 4.57 gms. to about 40-60 percent, although the proportion of carrier, e.g. 8.55 gms. of an oxidizing composition comprising silver Celite, relative to silver carbonate may be higher or carbonate and Celite which contains one millimole of lower according to the circumstances. silver carbonate per 0.57 gram of said composition. The oxidizing agent compositions of matter according When the starting steroid contains a non-reactive hy to this invention may be made in a number of different droxyl function, e.g. such as in 166-methylpregnane-3,6, ways. For example, an appropriate quantity of the inert 17a,21-triol-20-one 21-acetate, the solvent of choice is carrier may be added to a dispersion of the silver carbon anhydrous benzene maintained at from about 50° C. to ate, and effective distribution of the latter over the carrier about 80 C., preferably at reflux temperature (around surface accomplished simply by stirring together. Alter 80° C.). natively, the oxidizing agent may be made by mixing the When the starting steroid has an allylic (therefore silver carbonate in powder form, conveniently in the more reactive) hydroxyl function, e.g. 4 - androstene-36, presence of water, with the carrier and any other Sub 175-diol, a solvent of choice is anhydrous methanol main stances which are to be present. The resulting mixture tained at room temperature or at reflux temperatures for may then, if desired, be formed into shaped pieces, for a short time, e.g. 10 minutes. example, by compression or extrusion. In another, and As set forth hereinabove, our process is particularly preferred mode of making the compositions, the silver valuable when applied to the oxidation of 3-hydroxy carbonate may be precipitated onto the inert carrier, pref Saturated-A-ring steroids, particularly of the pregnane erably Celite, by reacting together in the presence of the series whereby are formed 3-keto-saturated-A-ring ste inert carrier, e.g. Celite, a soluble silver salt, e.g. silver roids. Thus, in particular, a preferred species of the proc nitrate, and a salt, e.g. sodium carbonate or bicarbonate, 60 ess aspect of our invention is the process which com which undergoes a double decomposition reaction with prises reacting a 3-hydroxy-A-ring-saturated pregnane in the silver salt, to form the desired insoluble silver anhydrous benzene with an oxidizing agent comprising carbonate. silver carbonate and Celite, said oxidizing agent con A convenient method for producing the preferred Com taining from about 8 to about 15 molar equivalents of position of matter comprising silver carbonate and Celite, silver carbonate per mole of said 3-hydroxy-A-ring-satu is outlined below: rated pregnane, whereby is formed a 3-keto-A-ring-satu A commercially available grade of Celite is washed rated pregnane. with an alcohol containing some hydrochloric acid, then Most specifically, the preferred species of the process with water until there is no chloride reaction with silver aspect of our invention is the foregoing process when nitrate. An appropriate quantity of this washed Celite is there is utilized the preferred oxidizing agent of our in added to a solution of silver nitrate in water, and the vention, i.e. the process of reacting a 3-hydroxy-saturated mixture stirred until a slurry is formed. A solution of A-ring-pregnane in anhydrous benzene at reflux tempera sodium carbonate in water is then added slowly, and ture with an oxidizing composition comprising silver car with constant stirring to this slurry. The solid yellow bonate and Celite which has one millimole of silver phase so obtained is separated by filtration, and washed carbonate per 0.57 gm. of said composition, the amount 3,531,475 7 8 of said composition being from about 4.57 grams to about 8.55 grams of oxidizing composition per mole of EXAMPLE 4 3-hydroxy-saturated-A-ring-pregnane. Oxidation of methyl 2-napthoquinol to methyl Another preferred species of the process aspect of our 2-napthoquinone invention is that wherein the starting steroid contains an Following the procedure of Example 3, using 174 mg. allylic hydroxyl at C-3 and less reactive hydroxyl groups 5 (1 millimole) of methyl 2-napthoquinol and refluxing for at other positions of the steroid molecule such as is 3 hours, there is obtained 170 mg. of the corresponding present in 4-androstene-3,6,17,3-diol, wherein, by utilizing methyl 2-napthoquinone in the form of yellow crystals anhydrous methanol at room temperature and by utilizing the preferred oxidizing composition of our invention, oxi (M.P. 103-106° C.; lit. 104-106 C.). dation at C-3 is effected in almost quantitative yields IO EXAMPLE 5 without oxidation occurring at the less reactive groups, Oxidation of abietic alcohol to abietaldehyde e.g. at C-17, elsewhere, thus providing a method for se 411 mg. of abietic alcohol dissolved in 30 ml. an lective oxidation of steroidal hydroxy groups in good hydrous benzene are added to 10 g. of the silver carbonate yields of pure product. containing composition of Example 1 and the mixture re In order that the invention may be well understood fluxed for 3 hours at the end of which period the oxida the following examples are given by way of illustration tion of the alcohol to the corresponding aldehyde, abieti only. The first two of these examples show the prepara nol is complete (as evidenced by thin-layer chromatogra tion of typical compositions of matter provided by this phy). The aldehyde (abietaldehyde), which is obtained invention, whilst the remainder illustrate the use of the 20 in almost quantitative yield, is recovered by filtration to re compositions of matter in the oxidation of various or move the oxidizing agent and evaporation to remove the ganic hydroxy compounds. benzene solvent. EXAMPLE 1. EXAMPLE 6 A quantity of a commercially available grade of Celite 25 (No. 535) is washed with methanol containing 10 per Oxidation of phytol to 3, 7, 11, 15-tetramethyl-2- cent by volume of hydrochloric acid, filtered and then hexadecene-1-al washed with distilled water until the washings show no 5 g. phytol (3, 7, 11, 15-tetramethyl-2-hexadecene-1-ol) chloride reaction when tested with silver nitrate. are added to a suspension containing 57 g. (10 milli 30 gms. of this washed Celite are added to a stirred 30 moles) of the silver carbonate-containing composition of solution comprising 34 gms. of silver nitrate in 200 ml. Example 1 in 500 cc. benzene. The mixture is refluxed for distilled water. To the resulting slurry is then slowly 1% hr., and the water formed continuously eliminated. added a stirred solution comprising 30 gms. of sodium The reaction mixture is then filtered to remove the oxidiz carbonate (decahydrate) in 300 ml. water. A solid yellow ing agent and the aldehyde product recovered from the phase is formed which, after about 10 minutes, is sepa 35 filtrate by evaporation of the benzene solvent. The alde rated by filtration. It is then washed with distilled water hyde (3, 7, 11, 15-tetramethyl-2-hexadecene-1-al) of which until the washings are neutral, then dried on a water 4 g. are obtained, is substantially pure as there is only one bath under vacuum. The composition so-obtained is in spot on the chromatogram. the form of a fine brownish-yellow powder which is not EXAMPLE 7 affected by light and which can be stored, without any 40 appreciable diminution of activity, for some weeks. It Oxidation of lithocholic acid methyl ester to contains 1 millimole of silver carbonate per 0.57 gm. of 3-ketolithocholic acid methyl ester the composition. 196 mg. of the methyl ester of lithocholic acid are EXAMPLE 2 added to 4.5 g. (8 millimoles) of the composition of Ex 30 gms. of “prepared Celite washed in the same way ample 1 in 60 ml. of benzene. The mixture is refluxed for as that employed in the procedure of Example 1 are 22 hours, at the end of which period the oxidation is com added to a stirred solution comprising 32.5 gms. of mer plete and the corresponding 3-keto-lithocholic acid methyl curic nitrate dissolved in 500 ml. distilled water. To the ester is recovered in an amount of 187 mg. (96 percent resulting slurry, there is added a solution comprising 40 yield). It had a M.P. of 112-116° C. (lit. 116-120° C.). gms. of potassium bicarbonate dissolved in 200 ml. dist EXAMPLE 8 tilled water. The solution is stirred for 10 minutes after the addition, and during this time carbon dioxide is 3.6 g. (8.6 millimoles) of the methyl ester of cholic acid evolved. The solid material is recovered by filtration, then (3.cx, 7 oz, 12c-trihydroxycholanic acid methyl ester) are taken up twice in distilled water, and the suspension fil oxidized following the general procedure of the previous tered on each occasion after which the material is washed example using 48 g. of the silver carbonate-containing until neutral. It is then dried on a water-bath under vac composition in 500 ml. of benzene and refluxing for 48 uum to yield 51.2 gms, of the composition in the form of hours. At the end of this period, 3.4 g. of oxidized prod uct are recovered by filtration and evaporation. It is then a reddish-brown powder which is believed to contain mer recrystallized from ethyl acetate to yield 2.4 g. of 3-keto curic carbonate. 7o, 12a-dihydroxycholanic acid methyl ester (M.P. 175 EXAMPLE 3 60 176 C.; lit. 171-173. C.) showing that the hydroxy Oxidation of hydroquinone to quinone group at the 3-position is preferentially oxidized. EXAMPLE 9 110 mgs. (1 millimole) of hydroquinone are added to a Dean-Stark apparatus containing 2.25 gms. (4 millimole) Oxidation of similagenin to the 3-keto analog; 22E, 25D of the silver carbonate-containing composition of Example spirostan-3-one 1 as the oxidizing agent in 80 ml. benzene. This mixture 35 g. of the composition of Example 1 are heated in a is heated for 2 hours at the reflux temperature of benzene, Dean-Stark apparatus with 120 ml. of benzene until the and during this heating the water formed as a consequence residual water in the composition is eliminated. There of the oxidation is continuously eliminated from the sys 70 after, 1.250 g. (3 millimoles) of smillagenin are added, and tem. The reaction mixture is then filtered to remove the the mixture refluxed for 1% hour. At the end of this peri oxidizing agent, and the benzene removed from the filtrate od, the starting compound, as evidenced by thin layer by evaporation to leave 94 mg. of quinone crystals (identi chromatography, has been entirely transformed into the fied by the I.R. spectra which was superposable upon corresponding 3-keto compound without cleavage of the that of an authentic sample of quinone). spiroketal side chain. The reaction mixture is then filtered

3,531,475 12 7. The process of claim 1 wherein said diatomaceous Starting compound, 3-hydroxy earth is Celite and said inert organic liquid medium is Steroid Product, 3-ketosteroid (1) methanol. 8. The process of claim 1 wherein said diatomaceous (67) 5a-androstan-38-ol-17-one------(67) 5a-androstane-3,17-dione. (68) 56-androstan-3a-ol-17-one------(68) 53-androstane-3,17-dione. 5 earth is Celite, said inert organic liquid medium is benzene, (69)(70) 5a-Androstan-3a-ol-17-one------17a-methyl-5a-androstane-36, (69)(70) 17a-methyl-5a-androstan-17,3-53-androstane-3,17-dione. and wherein said oxidizing agent provides from about 17,3-diol. ol-3-one. 2 to about 15 molar equivalents of silver carbonate per (71) 17a-ethinyl-5a-androstane-36, (71) 17a-ethinyl-5a-androstan-176 mole of steroidal alcohol. (72)17B-diol. Desoxycholic acid ethyl ester--- (72)ol-3-one. 3-keto-12a-hydroxycholanic 9. The process of claim 1 wherein said diatomaceous acid ethyl ester. earth is Celite, said inert organic liquid medium is benzene, (78) 5a-cholestan-33-ol------(73) 5a-cholestan-3-one. and wherein said oxidizing agent comprises one millimole (75)(74) 33,19-dihydroxy-5a-cholestan.--58-cholestan-36-ol------(75)(74) 19-hydroxy-5a-cholestan-3-58-cholestan-3-one. of silver carbonate per 0.57 gram of said oxidizing agent, (76) 5 a-stigmastan-36-ol------(76)O3. 5a-stigmastan-3-one. there being Sufficient oxidizing agent to provide from (78)(77) Solandianol-----Diosgenin------(78)8 5-22e,25D-spirosten-3-one.Solanidanone. about 2 to about 15 molar equivalents of silver carbonate (79) Yanogenin------(79) 5-22e,25L-spirosten-3-one. per mole of steroidal alcohol. (80) 11-keto-ticogenill------(s) 5a,226,25D-spirostane-3,11 10. The process of claim 1 wherein said steroidal (81) Ticogenin------(81) 5a,226,25D-spirostan-3-one.Olle. alcohol is a member selected from the group consisting of -- (82) 5a,226,25L-spirostan-3-one. (82) Neoticogenin ---- (83) 226,25L-spirostan-3-one. a 3-hydroxy steroid and a 176-hydroxy steroid and wherein (83)(84) Sarasapogenin.Hecogenin------(3. 5a,22e,25D-spirostane-3,12 said diatomaceous earth is Celite. (85) Neohecogenin------(83.lOle. 5a,226,25L-spirostane-3,12 11. The process of claim 1 wherein said steroidal Ole. alcohol is a 3-hydroxy steroid, said diatomaceous earth (86) Botogenin.------(86) 5-226,25D-spirostene-3,12 dione. is Celite, and wherein said oxidizing agent provides from (87) Neobotogenin -- (87) 5-226,25L-spirostene-3,12-dioline. about 2 to about 15 molar equivalents of silver carbonate (88) Digitoxigenin-- -- (88) 17g-(2-butemolid)-58-androstan 143-ol-3-one. per mole of said 3-hydroxy steroid, and whereby said (89) Tomatidine- -- (89) 3-keto analog. steroid obtained is a 3-keto steroid. 12. The process of claim 1 wherein said steroidal alcohol is a 3-hydroxy-Saturated-A-ring steroid of the pregnane series, said diatomaceous earth is Celite, said non-reactive liquid medium is benzene at reflux tempera EXAMPLE 1.4 ture, and wherein said oxidizing agent provides about 8 In a manner similar to that described in Examples 9, molar equivalents of silver carbonate per mole of said 3 10-12, each of the following steroidal alcohols were hydroxy-saturated-A-ring steroid and whereby there is reacted in refluxing benzene with the composition com obtained a 3-keto-saturated-A-ring steroid of the pregnane prising silver carbonate and Celite prepared as described SeleS. in Example 1, and there were obtained the following non 13. The process of claim 12 wherein said oxidizing carboxy carbonyl steroidal derivatives, respectively. agent comprises one millimole silver carbonate per 0.57

Moles silver Reaction Percent Starting steroidal alcohol Oxidized steroid carbonate time, hrs. yield

Androstan-176-ol------Androstan-17-one.------7.5 5 98.5 5-Androsterl-78-0------5-androsten-17-one- 7.5 ... 5 95 Androstan-36-01------Androstan-3-one------8 5 87 4,4-dimethylandrostane- 4,4-dimethylandrostan- S 2 87.5 6a, 176-diol. 6a-ol-17-one. Methylcholate Methyl 3-keto-7a, 12a-di- 30 5 91 hydroxy cholanate. Cholan-25-01------Cholan-25-al------20 33 9.5

We claim: gram of oxidizing agent, there being sufficient oxidizing agent to provide about 8 molar equivalents of silver 1. The process which comprises reacting a steroidal carbonate per mole of said 3-hydroxy-Saturated-A-ring alcohol having a hydroxyl function selected from the Steroid of the pregnane series. group consisting of a primary and a secondary hydroxyl 14. The process of claim 1 wherein said steroidal with an oxidizing agent comprising silver carbonate and alcohol is a 3-hydroxy-saturated-A-ring-steroid of the diatomaceous earth in an essentially anhydrous inert pregnane series, said diatomaceous earth is Celite, said organic liquid medium whereby is obtained a steroid hav non-reactive liquid medium is benzene at reflux tempera ing a non-carboxy carbonyl function. ture, and wherein for each millimole of said 3-hydroxy 2. The process of claim 1 wherein said diatomaceous Saturated-A-ring steroid of the pregnane series there is earth is Celite. used from about 4.57 grams to about 8.55 grams of 3. The process of claim wherein said inert organic Oxidizing agent comprising one millimole of silver liquid medium is an aromatic hydrocarbon. carbonate per 0.57 gram of said oxidizing agent whereby 4. The process of claim 3 wherein said aromatic hydro is obtained a 3-keto-saturated-A-ring steroid of the carbon is benzene. pregnane series. 5. The process of claim 1 wherein said diatomaceous 15. The process of claim 1 wherein said steroidal earth is Celite and said inert organic liquid medium is alcohol is an allylic 3-hydroxy-steroid, said diatomaceous benzene. 6. The process of claim 1 wherein said inert organic earth is Celite, said non-reactive liquid medium is liquid medium is an aliphatic alcohol. 7 5 methanol, said oxidizing agent provides from about 2 to 3,531,475 13 14 about 15 molar equivalents of silver carbonate per mole 18. A process according to claim 1 wherein said of said allylic 3-hydroxy-steroid, whereby is obtained an steroidal alcohol is a 3-hydroxy-saturated-A-ring steroid allylic 3-keto-steroid. of the pregnane series. 16. The process of claim 15 wherein for each mole of said allylic 3-hydroxy-steroid there is sufficient 5 No references cited. oxidizing agent to provide about 15 moles of silver carbonate. ELBERT L. ROBERTS, Primary Examiner 17. A process according to claim 1 wherein said l R steroidal alcohol is a member selected from the group U.S. Cl. X.R. consisting of a 3-hydroxy steroid and a 176-hydroxy 260-239.57, 397.1, 397.2, 397.3, 397.4, 397.45, 397.47 steroid. PO - 050 UNITED STATES PATENT OFFICE (5/69) CERTIFICATE OF CORRECTION Patent No. 3, 551,475 Dated September 29, lSTO Inventor(s) M. Fetizon and M. Golfier It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: - - Column l, lines 5 - 7, "as signors to Société . . . Lev allois, France" should read - - - as signors, by roe sne as signments, to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey - - - . Column l, line 55, "hydroxy" should read - - - hydroxyl - - - . Column l, line 67, "saturated-A-steroidal" should read - - - saturated-A-ring-steroidal ---. Column 5, line 6, "through the oxidation" should read - - - throughout the oxidation - - - . Column 4, line 20, "20- one 2l acetate" should read - - - 20- one 2l-acetate ---. Column 6, line lS, "mater a spect" should read - - - matter a spect ---. Column 8, lines 3 and 6, "2-napthoqui nol" should read - - - 2-naphthoquinol - - -. Column 8, lines l and 7, "2-naptho quinone" should read - - - 2-naphthoquinone - - - . Column 9, line 5, "solver" should read - - - silver - - - . Column 9, line 75, second row, "ol-3, 26-dione" should read - - - ol-3, 20 dione ---. Column 9, line 72, first row, "56-pregnane" should read . . . 58-pregnan - - -. Column 9, line 74, second row "léo. methyl" should read - - - l6O-methyl - - - - Column lo, line 7, first row, "3C-ol-one" should read - - - 3C-ol-2O-one - - - . Column lo, line 38, second row, "ol-5, 20-2Ordione" should read - - - ol-5, 20-dione - - - - Column lo, line l. 5, first row, "2l troil-2O-one" should read - - - 21-triol-2O - one - - - - Column lo, line 5, second row "pregnene-pregnene-3, 20-dione" should read - - - pregnene -5, 2 O-dione - - - - Column lo, line 5O, second row l6O-methyl-5C" should read - - - l60-methyl-5p - - - - Column lo, line 55, first row, "l 73-methyl-5C-9 (ll -pregnene -5B, 18O-diol 20-one" should read - - - 16B-methyl-5C-9 (ll)-pregnene-3 p, lTO diol-20- one - - - . Column lo, line 75, first row "2l-troil-2O" should read - - - 2l-triol-2O - - - - Column ll, line 5, second row, "5 B-andro stane" should read - - - 5O-androstane - - - . Signed and sealed this 29th day of December 1970 (SEAL) Attest : EDWARD. M. FLETCHER, JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents