3,338,926 United States Patent Office Patented Aug. 29, 1967 1. 2 3,338,926 Sult in an appreciable amount of by-product formation PROCESS FOR THE HYDROLYSIS OF CYCLIC through esterification of free hydroxyl groups on the ACETALS AND KETALS nucleus or in the side chains (producing, for example, 21 Francisco Alvarez, John B. Siddall, and Augusto Ruiz, formoxy steroids which, if they also contain a 17a-hy Palo Alto, Calif., assignors to Syntex Corporation, droxyl group and are later hydrolyzed, will in part un Panamaa, Panama, a corporation of Panama dergo D-homo rearrangement no matter how mild the No Drawing. Filled May 2, 1966, Ser. No. 546,602 base used, or 116-formoxy steroids, which can only be 10 Claims. (C. 260-397.4) hydrolyzed back to the free alcohols under relatively drastic conditions, thus giving rise, again in the case of the This is a continuation-in-part of copending application O 17a-hydroxypregnanes, to an even greater amount of D Ser. No. 460,462, filed June 1, 1965, now abandoned. homo rearrangement), degradation of a dihydroxy-ace This invention relates to a process for the preparation tone side chain, if present, or destruction of acid-sensi of cyclopentanophenanthrene derivatives. tive groups elsewhere in the steroid molecule, or all of More particularly, this invention relates to a novel these, leading to poor yields of free dihydroxy final prod method for the conversion, in good yields and with a 5 uct contaminated with relatively large amounts of un minimum of by-product formation, of cyclic acetal and wanted by-products. ketal derivatives of dihydroxy steroids of the androstane, The present invention affords a practical solution to estrane, pregnane, 19-norpregnane, cholestane and Sapo these difficulties by providing a novel and efficient method genin series, wherein the hydroxyl groups are on adjacent for the conversion of steroidal cyclic acetal and ketal de or nonadjacent carbon atoms in the steroid nucleus or side 20 rivatives to the corresponding dihydroxy steroids. More chains, to the corresponding free dihydroxy steroids. particularly, we have now discovered, quite unexpectedly, The cyclic acetal and ketal derivatives which can be that by treating cyclic acetal and ketal derivatives of di converted to the corresponding dihydroxy steroids by the hydroxy steroids of the androstane, estrane, pregnane, 19 novel process of the present invention can be represented norpregnane, cholestane and sapogenin series with aque by the general formula: - 25 ous solutions of hydrogen halides at relatively low tem peratures, the corresponding dihydroxy steroids are ob R1 ~o R tained in greater yields and with less by-product contami / o, nation than had hitherto generally been possible using avO R3 I the known methods of hydrolyzing cyclic acetal and ketal wherein R represents the steroid nucleus, including the 30 derivatives. side chains and the carbon atoms to which the cyclic A further advantage of the novel process of the present acetal or ketal group is attached; the symbol a repre invention is that many acid-sensitive groupings elsewhere sents either the o- or the 3-configuration; R and R3, taken in the steroid molecule, such as hydroxyl groups, cyclo alone, can each represent hydrogen, a lower alkyl (includ propyl groups, and the like, are stable under the conditions ing substituted and unsubstituted lower alkyl and cyclo 35 employed. alkyl) group, an aryl (including substituted and unsubsti It is to be understood that by the term "aqueous solu tuted aryl, alkaryl and aralkyl) group or a monocyclic tions of hydrogen halides' is intended conventional hy heterocyclic (including substituted and unsubstituted het drohalic acids, particularly hydrofluoric and hydrochloric erocyclic) group; and R2 and R3, taken together with the acid. carbon atoms to which they are attached, can also repre 40 The novel process of the present invention is carried sent a cycloalkyl, or monocyclic heterocyclic group. out by adding the steroidal cyclic acetal or ketal deriva It has been known for some time that the reaction of tive to aqueous hydrohalic acid containing between 20% a dihydroxy steroid, wherein the hydroxyl groups are not and 90% by weight of hydrogen halide, preferably from too widely separated, with an aldehyde or ketone in the about 35% to about 55%. Generally the maximum con presence of a strong acid catalyst produces the corre 45 centration of hydrochloric acid is limited to 37% to 38% sponding cyclic acetal or ketal. by Weight at room temperature and at atmospheric pres In many cases, the formation of a cyclic acetal or ketal Sure. By increasing the pressure, the concentration of grouping produces steroid derivatives having enhanced hydrochloric acid can be increased, but the 37% to 38% therapeutic activity, and frequently such groupings will concentration is normally satisfactory. With hydrofluoric be introduced after various transformations have been 50 acid, aqueous solutions containing about 48% to 70% carried out elsewhere in the steroid molecule. However, of hydrogen fluoride are generally employed. Hydro these groupings also have potentially great value in the chloric and hydrofluoric acid are conveniently employed preparation of other steroid derivatives using reactions at reagent grade concentrations of about 38% and about which would normally affect unprotected hydroxyl groups. 48%, respectively. The amount of acid employed may For example, cyclic acetal and ketal groupings, and par 55 range from 10 mols or less to about 600 mois, prefer ticularly those which themselves contain no reactive ably from about 20 to about 60 mols of hydrochloric groupings, e.g., an isopropylidenedioxy grouping, are not acid and from about 20 to about 160 mols of hydrofluoric affected by submitting compounds containing them to acid, per mol of cyclic acetal or ketal. Generally the alkylation, acylation, ketalization, epoxidation, bromina process is executed at a temperature in the range of from tion, oxidation, reduction or certain acid-catalyzed rear 60 -30° C. to about 25 C. or higher, and preferably from rangements. about -5° C. to about 5 C. The reactants are stirred Nevertheless, up to the present time the difficulties en for a period of from about 30 minutes to about 30 hours countered in removing cyclic acetal and ketal groupings or longer with hydrofluoric acid and for 1 to 5 minutes following transformations elsewhere in the steroid mole after a solution is obtained with hydrochloric acid, gen cule constitute a serious drawback to their use as protec 65 erally from about 10 to 20 minutes. tive groups, especially in commercial production of ste If desired, inert organic solvents can be added to the roids. reaction mixture ranging in amounts up to 50% by vol The reported conditions for the removal of cyclic acetal ume, and more often ranging in amounts from about 25% and ketal groupings call for refluxing for prolonged peri 70 to 35% by volume, based on the total volume of the ods of time in concentrated aqueous formic acid of up reaction mixture. Among the solvents which may be to 90% strength. These conditions almost invariably re employed are Water-soluble ethers such as dioxane, tetra 3,838,926 3. 4. hydrofuran, tetrahydropyran, ethyleneglycol monoethyl 6a-methyl-116,16cy, 17c,21-tetrahydroxypregn-4-ene ether acetate, higher polyethylene and polypropylene 3,20-dione; glycol ethers, ether esters and the like, as well as mixtures 60-methyl-113,160,17a,21-tetrahydroxypregna-1,4-diene thereof. 3,20-dione; At the end of the reaction period, the dihydroxy steroid 60-methyl-160,170,21-trihydroxypregna-1,4-diene can be isolated in a conventional manner. For example, 3,11,20-trione; the reaction mixture is added to an ice cooled aqueous 6a-fluoro-119,160,170,21-tetrahydroxypregn-4-ene alkali solution, such as sodium or potassium carbonate 3,20-dione; or bicarbonate, containing an excess of alkali. As equally 6a-fluoro-11p,160,17a,21-tetrahydroxypregna-1,4-diene practical, the ice cooled aqueous alkali solution can be 10 3,20-dione; added to the reaction mixture. The product may be iso 6cy-fluoro-160,17a,21-trihydroxyphegn-4-ene lated by extracting it from the mixture with an organic 3,11,20-trione; solvent such as methylene chloride, diethyl ether, hexane 6cy-fluoro-160,170,21-trihydroxypregna-1,4-diene and the like. Additional purification can be effected 3,11,20-trione; through recrystallization and/or chromatography, if 5 9o-fluoro-11p,160,17a,21-tetrahydroxypregn-4-ene necessary. 3,20-dione; One class of cyclic acetals and ketals which can be 9cy-fluoro-11p,160,170,21-tetrahydroxypregna-1,4-diene hydrolyzed to the corresponding dihydroxy steroids by 3,20-dione; the novel process of the present invention encompasses 9oz-fluoro-160,17o,21-trihydroxypregna-1,4-diene the 160,17a-cyclic acetals and ketals of the pregnane and 20 3,11,20-trione; 19-nor pregnane series represented by the general formula: 60-methyl-9oz-fluoro-118,16a, 17o,21-tetrahydroxypregn 60-methyl-9a-fluoro-11p,16oz,17a,21-tetrahydroxypregna4-ene-3,20-dione; (H.R. 1,4-diene-3,20-dione; g=o 25 60-methyl-9a-chloro-116,160,17a,21-tetrahydroxy pregna-1,4-diene-3,20-dione; 6a,9o-difluoro-11p,160,17a,21-tetrahydroxypregn-4-ene 3,20-dione, and the like. Other classes of 160,17a-cyclic acetal and ketal-con 30 taining steroids besides that described hereinabove can also be efficiently hdyrolyzed by the novel process of the present invention. These include 96-steroids, such as 16a, II 17 or - isopropylidenedioxy - 96-A-pregnen-21-ol-3,11,20 35 trione or the