United States Patent Office Patented Sept
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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.