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 like, retro steroids, i.e., those having the In this formula R, R3 and the symbol - have the 96,10c-steric configuration, such as 160,17a-isopropyli Same meanings as set forth hereinabove for Formula I; denedioxy-93-10oz-Al-pregnene-11g,21-diol-3,20 - dione or R4 and R6 represent hydrogen or methyl; R5 represents the like, 19-nor retro steroids, such as 16a,17a-isoprop hydrogen, 6-hydroxyl or a keto group; R represents hy ylidenedioxy - 19 - nor - 98,10oz - A - pregnen-21-ol-3, drogen, halogen, i.e., fluoro, chloro, bromo or iodo, 40 11,20-trione, oxa and aza steroids wherein oxygen or hydroxyl or acyloxy; X represents hydrogen, methyl, nitrogen is present in the ring structure, such as 160,17a fluoro or chloro; Y and Y represent hydrogen, methyl, isopropylidenedioxy - 4 - oxapregnane-116,21-diol-3,20 halogen, hydroxyl or acyloxy, with at least one of Y and dione or the like, B-homo steroids, such as B-homo-16o, Y being hydrogen and with both Y and Y being hydro 17 or - isopropylidenedioxy - 19 - nor-A5(10)-pregnen - 21 gen when R5 is hydrogen; and Z1 and Z represent either ol-3,20-dione or the like, 16,17-cyclic acetals and ketals a saturated linkage or a double bond between the carbon 45 of the androstane and estrane series, such as 160,17a atoms at the 1 and 2 and 6 and 7 positions, respectively. isopropylidenedioxy-A85-estratrien-3-ol or the like, and Typical 160,17c-cyclic acetals and ketals coming within steroids having substituents elsewhere in the steroid nu the Scope of this general formula include the 160,17a cleus and side chains, e.g., keto groups or derivatives isopropylidenedioxy; 16oz,17a-(2-butylidenedioxy); 160,- thereof, such as enolized or ketalized keto groups (which 17a-(3'-pentylidenedioxy); and 160,17a-(4-methyl-2'- will be hydrolyzed to free keto groups during the reac pentylidenedioxy) derivatives of: tion), hydroxyl groups or derivatives thereof, such as es 60-methyl-160,17a-dihydroxypregn-4-ene-3,20-dione; terified or etherified hydroxyl groups, alkyl groups, such 6a-fluoro-160,17a-dihydroxypregn-4-ene-3,20-dione; as methyl, ethyl or propyl groups, halogen atoms, such 6a-chloro-160,17a-dihydroxypregn-4-ene-3,20-dione; as fluorine or chlorine, nitro groups, amino groups, double 6a-chloro-160,17a-dihydroxy-19-norpregn-4-ene 55 bonds, and the like. Furthermore, as previously indicated, cyclic acetal and 6-chloro-160,17a-dihydroxypregna-4,6-diene-320-dione;3,20-dione; ketal-containing steroids which can be variously substituted 6a-chloro-160,17a-dihydroxy-19-norpregna-4,6-diene in the manner described hereinabove wherein the cyclic 3,20-dione; 60 acetal or ketal group is attached to positions other than 60-methyl-116,160,17a-trihydroxypregn-4-ene the 16,17-positions of the steroid nucleus can also be hy 3,20-dione; drolyzed by the novel process of the present invention. 6a-chloro-115,160,17a-trihydroxypregn-4-ene These include, for example, the 1a,2a-cyclic acetal and 3,20-dione; ketal-containing steroids such as 10,2a-isopropylidenedi 60-methyl-160,17a-dihydrozypregn-4-ene-3,11,20-trione; 65 oxy - 9a-fluoro - 160,21-bisacetoxy-17a-hydroxypregn-4- 60-fluoro-160,17a-dihydroxypregn-4-ene-3,11,20-trione; ene-3,11,20-trione; the 26,36-cyclic acetal and ketal-con 9oz-fluoro-116,160,17a-trihydroxypregna-1,4-diene taining steroids such as 26,36-isopropylidenedioxy - 17a 3,20-dione; methylestran-176-ol; the 6a,7a-cyclic acetal and ketal 9oz-fluoro-160,17a-dihydroxypregn-4-ene-3,11,20-trione; containing steroids such as 6cy,7oz - cyclohexylidenedioxy 21-chloro-116-16cy, 17 ca-trihydroxypregn-4-ene-3,20-dione; 70 116,160,170,21-tetrahydroxypregn-4-ene-3,20-dione; 116,17a,21 - trihydroxypregn-4-ene-3,20-dione; the 116, 160,170,21-trihydroxypregn-4-ene-3,11,20-trione; 12(3-cyclic acetal and ketal-containing steroids such as 160,17a,21-trihydroxypregna-1,4-diene-3,11,20-trione; 116,12,3-isopropylidenedioxy-17o - hydroxy - 21-acetoxy 2-methyl-11g,160,17a,21-tetrahydroxypregna-1,4-diene pregna - 1,4-diene - 3,20-dione; the 170,21-cyclic acetal 3,20-dione; 75 and ketal-containing steroids such as 17ox,21-cyclopentyli 3,338,926 5 6 denedioxy - 11 g - hydroxypregna-1,4-diene-3,20 - dione; and then was stirred for one additional minute. The reac and the like. tion mixture was poured into a mixture of ice and 10% In order that those skilled in the art can more fully aqueous sodium bicarbonate solution. The steroid was understand the present invention, the following examples extracted with diethyl ether. The ether layer was washed are set forth. These examples are given solely for the pur with water until neutral, dried over anhydrous magnesium pose of illustrating the invention, and should not be con sulfate and evaporated at reduced pressure. The residue sidered as expressing limitations. All parts and percent was then chromatographed on a silica gel column yield ages are by weight unless otherwise stated. ing 60 - methyl - 9a - fluoro - 116,160,17a,21 - tetrahy EXAMPLE 1. droxypregna - 1,4-diene - 3,20 - dione, which was re Two hundred fifty mg. 0.60 mmol (millimol) of 10 crystallized from acetone:hexane. 16a, 17 or - isopropylidenedioxy - 116,21-dihydroxypregna EXAMPLE 5 1,4-diene-3,20-dione were suspended in 2.5 cc. (60 mmols) Five hundred milligrams (1.45 mmols) of 160,17a-iso of aqueous 48% hydrofluoric acid (thus giving approxi propylidenedioxyestr-4-en-3-one were suspended in 10.5 mately 100 mols of hydrofluoric acid per mol of steroid g. (87.0 mmols) of aqueous 30% hydrochloric acid. The starting material), maintained at 0° C. in a polyethylene mixture was stirred while maintaining the temperature be reaction vessel, and the resulting reaction mixture was tween -5 C. and 5° C. until a solution was obtained stirred at 0° C. for 20 hours. Following this reaction pe and then stirred for an additional two minutes. The reac riod, the reaction mixture was neutralized by the addition tion mixture was neutralized by the addition of an excess of aqueous 5% potassium bicarbonate solution and then of ice-aqueous 10% sodium carbonate solution mixture. extracted with ethyl acetate. The thus-obtained extract 20 The organic layer was extracted with methylene chloride, was evaporated to dryness under reduced pressure to give washed with water until neutral, dried over sodium sulfate, a crude product which was then filtered through a silica and then evaporated to dryness at reduced pressure. The gel column, eluting with 35% ethyl acetate in hexane and then with ethyl acetate alone. Evaporation of the final residue160,17a-dihydroxyestr-4-en-3-one. was crystallized from acetone:hexane to yield product-containing fractions of the eluate to dryness un 25 der reduced pressure, followed by recrystallization from EXAMPLE 6 acetone:hexane, gave 118,160,17a,21 - tetrahydroxy Two and one-half grams (6.8 mmols) of 2a,3oz-iso pregna-1,4-diene-3,20-dione. propylidenedioxy - 17 oz-ethynyl-17 (3-hydroxyandrost-4-ene were added to 14.0 g. (144 mmols) of an aqueous solu EXAMPLE 2 30 tion containing 37.6% by weight of hydrogen chloride. The procedure of Example 1 hereinabove was repeated The mixture was stirred until a complete solution was ob in every detail except for the following. The steroid start tained and then stirred for one additional minute. An ing material employed was 116,12,6-isopropylidenedioxy excess of ice cooled aqueous 25% potassium carbonate 17a. - hydroxy - 21 - acetoxypregna-1,4-diene-3,20-dione, 35 solution was added to neutralize the acid. The mixture was and it was added to a mixture of 2.5 cc. of aqueous 48% extracted with methylene chloride. The extract was washed hydrofluoric acid and 1.2 cc. of tetrahydrofuran, which with water to neutrality, dried over sodium sulfate and gave a single phase reaction solution immediately. After evaporated to dryness to yield the 20,30,176-trihydroxy working up the reaction mixture, 116,126,17a-trihydroxy 17a-ethynylandrost-4-ene. 21-acetoxypregna-1,4-diene-3,20-dione was obtained. 40 EXAMPLE 7 EXAMPLE 3 Six grams of 6a-fluoro-160-hydroxyhydrocortisone 16oz, Fifty-seven grams (0.132 mol) of 6oz - fluoro - 96,116 17a-acetonide were added to 150 cc. of concentrated hy oxido - 160,17a - isopropylidenedioxy - 21 - hydroxy drochloric acid (37.6%) at 0-5 C. This mixture was pregna - 1,4 - diene - 3,20-dione were suspended in 570 45 stirred at the same temperature for 13 minutes. At the cc. (19.95 mols) of aqueous 70% hydrofluoric acid (thus end of this time the reaction mixture was neutralized with giving approximately 151 mols of hydrofluoric acid per cold 10% sodium carbonate solution and extracted with mol of steroid starting material), maintained at -20° C. methylene chloride. These extracts were washed with in a polyethylene reaction vessel, and the resulting reac water to neutrality, dried over sodium sulfate and evapo tion mixture was stirred at -20° C. for 15 hours. Fol 50 rated to dryness to yield 6oz-fluoro-160-hydroxyhydrocorti lowing this reaction period, the reaction mixture was Sone, which was recrystallized from acetone:hexane. slowly poured into 5 liters of water, and 4 kilograms of The above procedure was repeated, using 38 g. of potassium carbonate were then added in portions, thus steroidal starting material in 750 cc. of concentrated hy giving a slightly alkaline solution from which the product drochloric acid, the reaction period being extended to 17 precipitated. This precipitate was collected by filtration, 55 minutes. In both instances yields of approximately 60% washed with water until neutral and dried, thus giving were obtained. a 90% yield of 60,9oz - difluoro - 116,160,17a,21-tetrahy What is claimed is: droxypregna-1,4-diene-3,20-dione, melting point 260 1. The process for hydrolyzing a steroidal cyclic acetal 264 C. - or ketal, which is represented by the formula: This procedure was then repeated in every detail but one, namely, 60,90 - difluoro - 160,17ox - isopropylidene 60 ra. O R2 dioxy - 116,21 - dihydroxypregna - 1,4 - diene - 3,20 Ri dione was used as the steroid starting material, and 6oz, 9oz - difluoro - 11 (8,160,17a,21 - tetrahydroxypregna-1,4- wherein R is the steroid nucleus; R2 and R3 taken alone diene-3,20-dione, identical to that prepared as described 65 are selected from a group consisting of hydrogen, a lower hereinabove, was obtained. alkyl group, an aryl group and a monocyclic heterocyclic EXAMPLE 4 group; and R and R3 taken together with the carbon atom to which they are attached are selected from the group One gram (2.3 mmol) of 160,17ox - isopropylidenedi consisting of a cycloalkyl group and a monocyclic hetero oxy- 6oz - methyl- 9a fluoro - 116,21-dihydroxypregna 70 cyclic group, to give the corresponding free dihydroxy 1,4-diene - 3,20-dione was added to 8.75 g. (90 mmols) Steroidal compound, which comprises treating the steroidal of aqueous hydrochloric acid (giving approximately 40 cyclic acetal or ketal at a temperature from about -30° C. mmols of hydrochloric acid per mol of starting material). to about 25 C. with at least a 10-fold molar excess of an The reaction mixture was maintained at 0° C. with con aqueous solution of from about 20% to about 90% by tinuous stirring until a homogeneous solution was obtained 75 weight of hydrogen fluoride or hydrogen chloride. 3,338,926 7 3. 2. The process according to claim wherein the steroi fold to about 60-fold molar excess of an aqueous solution dal cyclic acetal or ketal is treated with from about 10 of about 48% by weight of hydrogen fluoride at a temper fold to about 160-fold molar excess of an aqueous solu ature ranging from about -5° C. to about 5 C. tion of about 20% to about 38% by weight of hydro 7. The process according to claim 6 wherein the treat chloric acid at a temperature of from about -5° C. to ment is conducted in the presence of a water-miscible about 5 C. ether. 3. The process according to claim 1 wherein the steroi 8. The process according to claim 1 wherein the steroi dal cyclic acetal or ketal is treated with from about 20 dal cyclic acetal or ketal is derived from the 16a,17a-di fold to about 160-fold molar excess of an aqueous solu hydroxy pregnane series. tion of about 37% to 38% by weight of hydrogen chlo 9. The process according to claim 8 wherein the steroi ride at a temperature ranging from about -5° C. to dal cyclic acetal or ketal is treated with from about 20 about 5° C. - - - fold to 160-fold molar excess of an aqueous solution of 4. The process according to claim 1 wherein the steroi about 37% to 38% by weight of hydrogen chloride at a dal cyclic acetal or ketal is treated with from about 20 temperature ranging from about -5° C. to about 5° C. fold to about 250-fold molar excess of an aqueous solu 15 10. The process according to claim 8 wherein the steroi tion of about 48% to about 70% by weight of hydrogen dal cyclic acetal or ketal is treated with from about 20 fluoride at a temperature ranging from about -5° C. to fold to about 60-fold molar excess of an aqueous solution about 5° C. of about 48% by weight of hydrogen fluoride at a temper 5. The process according to claim 1 wherein the steroi ature ranging from about -5° C. to about 5 C. dal cyclic acetal or ketal is treated with from about 20 20 fold to about 60-fold molar excess of an aqueous solu No references cited. tion of about 48% to about 70% by weight of hydrogen fluoride at a temperature ranging from about -5° C. to LEWIS GOTTS, Primary Examiner. about 5° C. 6. The process according to claim 1 wherein the steroi 25 ELBERT L. ROBERTS, Examiner. dal cyclic acetal or ketal is treated with from about 20