United States Patent Office 3,350,427 Patented Oct. 31, 1967 1. 2 3,358,427 By lower alkyl is contemplated hydrocarbon radicals PROCESS FOR THE DEHYDROHALOGENATION having preferably up to four carbon atoms including CF SEROADS methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and WilliamOrange, H. N.J., Gebert, assignors Morris to ScheringPaias, and Corporation, Nathaniel Murrill, Bloom tertiary butyl. field, N.Y., a corporation of New Jersey Our process is particularly valuable when it is desired No Drawing. Fied Jan. 28, 1966, Ser. No. 523,573 to dehydrobrominate a 17-bromo-20-keto-steroid having 10 Claims. (C. 260-397.4) at least one hydrogen at C-16, e.g. 16oz - methyl - 17 oz bromo-5-pregnen-3,6-ol-20-one or the 3-acetate thereof to This invention relates to a novel improved process for the corresponding 16-dehydro-20-keto-steroid, e.g. 5, 16 dehydrohalogenating organic compounds. O pregnadien-36-ol-20-one or the 3-acetate thereof, which In general, the invention sought to be patented is de are known, valuable intermediates in the preparation of scribed as residing in the concept of treating an o-bromo other known therapeutically valuable compounds. For ketone having a hydrogen on the beta carbon with a example, 16-methyl - 5, 16 - pregnadien-3 (3-ol-20-one may dehydrchalogenating agent selected from the group con be catalytically hydrogenated to provide 166-methyl-5- sisting of an alkaline earth oxide, an alkaline earth hy 5 pregnen-36 - ol - 20-one which may be oxidized to 16,3- droxide, and mixtures thereof in a solvent Selected from methylprogesterone. 16 - methyl-5, 16 - pregnadien - 3 3 the group consisting of an N,N-dillower alkyl amide of ol-20-one may also be epoxidized by well-known pro a hydrocarbon carboxylic acid having up to 18 carbon cedures to the valuable 166-methyl - 16a, 17a- Oxido de atoms and an N-lower alkyl-2-pyrrollidone whereby de rivative which, in turn, upon addition of hydrogen bro hydrobromination occurs and there is formed an c.f3-un 20 mide will yield 16-methylene-17 cy-hydroxypregnenolone, saturated ketone. a valuable precursor in the preparation of 16-methylene More specifically, the invention sought to be patented 17 c. - alkanoyloxy-progesterones and 16 - methylene-corti is described as residing in the concept of treating an ox coids. bromo-keto steroid having a hydrogen on the carbon atom Heretofore, a-bromo-keto steroids and, in particular, positioned beta to the keto group, with a dehydrobro 17-bromo steroids such as 16 oz - methyl - 17cc - bromo-5- minating agent selected from the group consisting of pregnen-36-ol-20-one 3-acetate have been dehydrohalo an alkaline earth oxide, an alkaline earth hydroxide, and genated to the corresponding a (3)-unsaturated keto ste mixtures thereof in a solvent selected from the group roid, e.g. 16 - dehydro - 20 - keto - steroids such as 16 consisting of an N,N-dillower alkyl amide of a hydro methyl - 5, 16 - pregnadien - 33 - ol - 20 - one 3-acetate carbon carboxylic acid having up to 18 carbon atoms and 30 by the action of the carbonates of alkali and alkali earth an N-lower alkyl 2-pyrrollidone whereby dehydrobromi metals of groups IA and IIA of the periodic table either nation occurs and there is formed an ox (B)-unsaturated alone or coupled with lithium halide. Lithium carbonate keto-steroid. and lithium bromide in dimethylformamide or dimethyl Included within the dehydrohalogenating agents con acetamide is a well-known reagent mixture used for de templated by this invention are alkaline earth oxides such hydrobrominations of cy-bromo-keto steroids. By our in as magnesium oxide, strontium oxide, barium oxide, and vention, we have found that suspension of the oxides calcium oxide; alkaline earth hydroxides, Such as magne and/or hydroxides of magnesium, barium, strontium, cal sium hydroxide, strontium hydroxide, barium hydroxide, cium, and other alkaline earth metals of group IIA and calcium hydroxide; and mixtures of the foregoing, of the periodic table, in a solvent selected from the group in particular, a mixture of magnesium oxide and mag 4) consisting of N,N-dillower alkyl amides of hydrocarbon nesium hydroxide, said mixture preferably containing carboxylic acids and N-lower alkyl - 2 - pyrrollidones are about 70% magnesium oxide and about 30% magnesiulin excellent dehydrohalogenating agents and are particularly hydroxide (by weight). The aforementioned alkaline earth useful for dehydrohalogenating an ox-bromo-keto steroid oxides and/or hydroxides may be used alone or, if it Such as 16 oz - methyl - 17a - bromo - 5 - pregnen-3,3-ol-20 is desired to increase the speed of the dehydrohalogena one 3-acetate, whereby there is obtained the corresponding tion, they may be used together with a lithium halide, ck (g)-unsaturated keto steroid, e.g. 16-methyl-5, 16-preg e.g., lithium bromide. nadien - 3 3-ol - 17 - one 3-acetate, of high purity and The approximately 70/30 weight mixture of magne in yields at least equal to the yields produced when uti sium oxide and magnesium hydroxide is a preferred de 50 lizing prior art reagents such as the lithium carbonate/ hydrohalogenating agent of this invention. This reagent lithium bromide couple. The alkaline earth metal oxides mixture may be prepared by mixing weighed portions and/or hydroxides of our invention are advantageously of magnesium oxide and magnesium hydroxide. Alterna less expensive and more readily available than the prior tively, this reagent mixture is contained in a readily avail art alkali metal carbonate/lithium bromide couple. Our able commercial product called Sea Sorb (registered novel process thus represents an improvement over known trademark of FMC Corporation, New York City), one processes for dehydrohalogenating an o-bromo-keto ste form of which, Sea Sorb 53, is particularly effective when roid to an cz (3)-unsaturated steroid. used in our process. Included among the ox-bromo-keto steroids having a included within the N,N-disubstituted amides useful hydrogen on the carbon positioned beta to the keto group as solvents in our process are N,N-dillower alkyl amides 60 which are dehydrobrominated by our process are par of hydrocarbon carboxylic acids having up to 18 carbon ticularly those of the cholestane, spirostane, androstane, atoms such as N,N-dimethylformamide, N,N- diethyl estrane and pregnane series, having ox-bromo-keto systems formamide,caproamide, N.NN,N-dimethylcaprylamide, - dimethylacetamide, N,N N,N-dimethyl - dimethyl such as the 2-bromo-1-keto-, 3-bromo-2-keto-, 2-bromo capramide, N,N-dimethylauramide, N,N-dimethyl 3-keto-, 3-bromo-4-keto-, 4-bromo-3-keto-, 2,4-dibromo-3- myristamide, N,N-dimethylpalmitamide, N,N-dimethyl 85 keto-, 6-bromo-7-keto-, 7-bromo-6-keto-, 8-bromo-7-keto-, stearamide, and N,N-dimethyloleamide, as well as N 9-bromo-11-keto-, 18-nor-12-bromo-11-keto-, 14-bromo lower alkyl substituted cyclic amides such as N-methyl 15-keto-, 16-bromo-17-keto-, and 17-bromo-20-keto Sys 2-pyrrolidone and N-ethyl 2-pyrrolidone. Preferred sol tems which, upon dehydrobromination, will yield steroids vents for use in the process of this invention are N,N- having the corresponding C(S)-unsaturated-keto Systems, dimethylacetamide and, in particular, N,N-dimethylform 0. i.e. the 2-dehydro-1-keto-, 3-dehydro-2-keto-, 1-dehydro amide. 3-keto-, 2-dehydro-4-keto-, 4-dehydro-3-keto-, 1,4-bis-de hydro-3-keto-, 5-dehydro-7-keto-, 7-dehydro-6-keto-, 8 3,350,427 4. ar Our process finds its greatest usefulness in dehydro dehydro-7-keto-, 8-dehydro-11-keto-, 18-nor-12-dehydro brominating ca-bromo-keto-steroids of the pregnane series 11-keto-, 8-dehydro-15-keto-, 15-dehydro-17-keto-, and 16 to obtain c. (3)-unsaturated-keto steroids of the pregnane dehydro-20-keto-systems. series which are useful as intermediates in preparing Thus, a-bromo-keto steroids of the cholestane series 5 therapeutically valuable progestins and corticoids. Thus, such as for example, 1-keto-2a-bromocholestane, 2a-bromo-pregnane-3,11,20-trione,2a-bromo-17 oz-acetoxy-pregnane-3,20-dione, 2-keto-3oz-bromocholestane,3-keto-2,4-dibromocholestane, 2,2-dibromo-5a-pregnan-36-ol-20-one, 3-keto-2-bromocholestane, O 2,2-dibromo-168-methyl-5oz-pregnane-17a,21-diol 36-acetoxy-7-keto-86-bromocholestane,36-acetoxy-9a-bromo-11-keto-cholestane, 2,2-dibromo-16c-methyl-5-ox-pregnane-173,20-dione 21-acetate, oz,21-diol 3,3-acetoxy-5cy-bromo-6-ketocholestane,3,3-acetoxy-6-keto-7c-bromocholestane, and 40-bromo-17a-hydroxypregnane-3,20-dione,3,20-dione 21-acetate, upon treatment with an alkaline earth metal oxide and/or 5 4-bromopregnane-17 oz,21-diol-3,20-dione 21-acetate, hydroxide, e.g. magnesium hydroxide and/or magnesium 48,17a-dibromopregnan-11,3-ol-3,20-dione 11-acetate, oxide (7:3) (with or without lithium bromide) in reflux 2cy,46-dibromopregnane-170,21-diol-3,20-dione ing dimethylformamide, will undergo dehydrobromination 20,43,21-tribromopregnane-3,20-dione,21-acetate, to give ox (B)-unsaturated-ketocholestanes known in the 20 art, e.g. 2c,46,17o,21-tetrabromopregnane-3,20-dione, 1-keto-2-dehydrocholestane, 17a-bromo-5-pregnen-36-ol-20-one 3-acetate 2-keto-3-dehydrocholestane, 176-bromo-17-iso-5-pregnen-36-ol-20-one(17a-bromopregnenolone acetate), 3-acetate, 3-keto-1,4-bis-dehydrocholestane, 17 oz,21-dibromopregnan-3,6-ol-20-one 3-acetate, and 3-keto-1-dehydrocholestane, 25 17a-bromo-56-pregnan-36-ol-11,20-dione 3-acetate, 3.8-acetoxy-7-keto-8-dehydrocholestane, upon treatment in refluxing dimethylformamide with a 36-acetoxy-11-keto-8-dehydrocholestane, mixture of magnesium oxide and magnesium hydroxide 36-acetoxy-6-keto-4-dehydrocholestane, and (7:3) (with or without the presence of lithium bromide) 36-acetoxy-6-keto-7-dehydrocholestane, respectively. yields the corresponding c.6-unsaturated keto steroid, all Similarly, typical a-bromo-keto steroids of the spiro 30 of which are known, useful compounds of the art: i.e. stane, androstane, and estrane series which are dehydro brominated by means of alkaline earth metal oxides and/ 1-pregnene-3,11,20-trione, or hydroxides in dimethylformamide to yield cy((3)-un 17c-acetoxy-1-pregnene-3,20-dione, saturated steroids known in the art, are spirostanes such as 2-bromo-5c-1-pregnen-36-ol-20-one, 11,23-dibromo-5-ox,22a-spirostan-12-one-3-ol 3-acetate 35 2-bromo-166-methyl-5a-1-pregnene-170,21-diol-3,20 (11,23-dibromo-hecogenin acetate), 2-bromo-16a-methyl-5a-1-pregnene-17dione 21-acetate, oz,21-diol-3,20 2-bromo-5a,22c-spirostan-3-one,2,4,23-tribromo-5a,22ox-spirostan-3-one, 17a-hydroxy-4-pregnene-3,20-dionedione 21-acetate, (17a-hydroxyproges 40 which dehydrobrominate to yield 4-pregnene-17a,21-diol-3,20-dioneterone), - 21-acetate, 23-bromo-5a,22c-9(11)-spirosten-3,6-ol-12-one 3-acetate, 4, 16-pregnadien-116-ol-3,20-dione 11-acetate, 5a,22c-1-Spirosten-3-one,23-bromo-5o,22a-1,4-spirostadien-3-one, and 1,4-pregnadiene-17a,21-diol-3,20-dione 21-acetate, 45 21-brono-1,4-pregnadiene-3,20-dione, respectively; androstanes such as: 5,21-brono-1,4,16-pregnatriene-3,20-dione, 16-pregnadien-36-ol-20-one 3-acetate (16-dehydro 4,12-dibromo-3,11-diketo-17.6-carbomethoxy-56 pregnenolone acetate), androstane, 5, 16-pregnadien-3,6-ol-20-one 3-acetate, 2c,4oz-dibromo-3-keto-androstan-17B-ol, 21-bromo-16-pregnen-33-ol-20-one 3-acetate, and 2c-bromo-4cy-methyl-androstan-176-ol-3-one 17-acetate, 50 56-16-pregnen-3,6-ol-11,20-dione 3-acetate, respectively. 4-bromo-androstan-17f8-ol-3-one, and As exemplified by some of the starting steroids appear 2,4-dibromo-androstane-3,17-dione, ing in the above lists, substituents other than the necessary which upon dehydrobromination as outlined above, yields c-bromo-keto moiety may be present in the molecule, such oz(3)-unsaturated-keto steroids of the androstane series, e.g. as free or esterified hydroxyl groups and free or substi 55 tuted carbonyl groups. Fluorine is usually not affected 3,11-diketo-12-bromo-176-carbomethoxy-4-androstene, under the conditions of our reaction; additionally, bromine 4-cy-methyl-1-androsten-171,4-androstadien-17 3-ol-3-one, 3-ol-3-one 17-acetate, atoms present in the steroidal molecule may remain un touched during our dehydrohalogenating process if there 4-androsten-176-ol-3-one (testosterone) and is no activating or reactive groups (e.g. a keto group) on 1,4-androstadiene-3,17-dione, respectively; 60 the carbon alpha to the bromine bearing carbon and/or no and estranes such as available hydrogen on the carbon beta to the activating group. Thus, when dehydrohalogenating 2c,43,21-tribro 16-bromo-1,3,5(10)-estratrien-3-ol-17-one mopregnane-17a-ol-3,11,20-trione with an excess of alka (16-bromoestrone); line earth oxide and/or hydroxide, e.g. 6 moles of Sea 4-bromo-19-nor-androstan-176-ol-3-one; 65 Sorb 53 per mole of steroid in refluxing dimethylform 4-bromo-19-nor-5,3-androstane-3,17-dione; amide, dehydrobromination occurs at C-2, and C-4, but 4,3-bromo-40-methyl-19-nor-androstan-176-ol-3-one not at C-21 (where there is no available p-hydrogen) and 17-acetate, there is obtained 21-bromo-1,4-pregnadien-17a-ol-3,11,20 which upon dehydrobromination yield trione. In general, any cc-bromo-keto steroid derivative 1,3,5(10), 15-estratetraen-3-ol-17-one 70 having a hydrogen on the beta carbon will dehydro (15-dehydroestrone); brominate to an c. (3)-unsaturated keto-steroid when heated with an alkaline earth oxide and/or hydroxide in 19-nor-4-androsten-176-ol-3-one (19-nor-testosterone); a solvent selected from the group consisting of an N,N- 40-methyl-19-nor-4-androsten-1719-nor-4-androstene-3,17-dione, and 3-ol-3-one 17-acetate (40-methyl-19-nor-testosterone acetate), respectively. 75 dilower alkyl amide of a carboxylic acid and an N-lower 3,350,427 5 6 alkyl 2-pyrrolidone. Thus, six-membered D-ring steroidal drolysis of the ester function. The hydrolysis is usually derivatives, e.g., 2a-methyl-2,4-dibromo-4,5-dihydro-allo less than 10% when the oxides or hydroxides of magnesi testolactone, and 5-membered A-ring steroidal deriva um and calcium are used, but approaches completion when tives such as 1,3-dibromo-2-keto-A-nor spiroStane upon the oxides or hydroxides of strontium or barium are em treatment with magnesium oxide and/or hydroxide in re ployed. When the product desired is an ester, acylation of fluxing dimethylformamide will dehydrobrominate to the resulting product before isolation and purification yield the corresponding c. (B)-unsaturated keto steroid, thereof will yield the desired product. When a hydroxy A-nor-3-Spirostene,i.e. 2-methyl-1-dehydro-testolactone respectively. and 1-bromo-2-keto compound is desired, use of strontium or barium oxides In a preferred mode of this invention, a mixture of 16oz and/or hydroxides as dehydrobrominating agent is pref methyl-17 oz-bromo-5-pregnen-36-ol-20-one 3-acetate (e.g. O erable. 16a-methyl-17 cy-bromopregnenolone acetate) and approxi We have described in detail the dehydrobromination of mately a 70:30 mixture by weight of magnesium oxide 16cz-methyl-17 ca-bromopregnenolone acetate to obtain 16 and magnesium hydroxide (usually about 6.5 moles of methyl-1,6-dehydropregnenolone acetate. An isomer of the reagent per mole of steroid is used) in dimethylform foregoing, i.e. 16cy-methyl-17 3-bromo-17-iso-pregnenolone amide is heated at reflux temperature for 16 hours under 5 acetate, or mixtures thereof with 160-methyl-17 oz-bromo an atmosphere of nitrogen. After filtering the inorganic pregnenolone acetate are also dehydrobrominated by salts, the dimethylformamide solution containing the 16 means of alkaline earth oxides and/or hydroxides to ob methyl-5, 16-pregnadien-33-ol-20-one 3-acetate (e.g. 16 tain 16-methyl-16-dehydropregnenolone or the acetate methyl-16-dehydropregnenolone acetate) thereby formed thereof. is concentrated and treated with acetic anhydride and 20 Additionally, by our process, there is conveniently ef pyridine according to known procedures to reacetylate fected the dehydrobromination of 2,4-dibromo-166-meth any hydrolyzed ester groups. The 16-methyl-5, 16-pregna yl-5a-pregnane-17a,21-diol-3,20-dione 21-acetate to the dien-36-ol-20-one 3-acetate is then isolated by precipita corresponding c.f3-unsaturated keto steroid, e.g. 16.3-meth tion in a mineral acid-water medium whereby is obtained yl-1,4-pregnadiene-17a,21-diol - 3.20 - dione 21-acetate, a almost a theoretical yield of 16-methyl-1,6-dehydro 25 known, valuable intermediate in the preparation of thera pregnenolone acetate (M.P. 160° C.) which upon re peutically valuable 11-oxygenated-166-methyl-1,4-pregna crystallization from methanol yields pure 16-methyl-5, 16 dienes. Thus, treatment of 2,4-dibromo-163-methyl-5a pregnadien-36-ol-20-one 3-acetate (M.P. 170° C.). pregnane-17a,21-diol-3,20-dione 21-acetate with usually 8 For complete dehydrobromination, there is used at molar excess of Sea Sorb 53 (to which lithium bromide least a half mole (one equivalent weight) of alkaline may be added) under nitrogen at 100° C. for 24 hours earth metal oxide or hydroxide, or mixture thereof per according to our process, yields the resulting dehydro mole of bromide to be dehydrobrominated. By this We brominated product, i.e. 16.3-methyl-1,4-pregnadiene-17a, mean that if the steroid to be dehydrohaiogenated 21-diol-3,20-dione 21-acetate into which can be introduced possesses but one c-bromo-keto function having a 3 an 110-hydroxyl function by means of a micro-organism hydrogen, such as in 17 cc-bromo-5-pregnen-33-ol-20-one, 35 of the genus Glomerella (e.g. Glomerella cingulata, ATCC the theoretical quantity of alkaline earth oxide and/or 10534) according to known procedures. The 11 a-hydroxy hydroxide needed to completely dehydrobrominate a intermediate thereby formed, i.e. 16{3-methyl-1,4-pregna mole of said steroid would be a half mole (which is one diene-11a, 17a,21-triol-3,20-dione, can be readily converted equivalent weight); whereas, to completely dehydrobro 40 to the corresponding 11 (3-hydroxy or 11-keto-analogs minate a mole of steroid possessing two ox-bromo-keto which are therapeutically active anti-inflammatory com functions having available (3-hydrogens, e.g. 2,4-dibromo pounds useful in the treatment of arthritis and like dis 163-methyl-5a-pregnane-17 ca,21-diol - 3,20 - dione, there CaSCS should be used at least a mole (i.e. two equivalents) of The best mode contemplated by the inventors for carry said alkaline earth oxide and/or hydroxide. ing out their invention will now be set forth as follows. We find it convenient when practicing our invention to It is to be understood that the examples are merely illus use a substantial excess of alkaline earth metal oxide trative of the process of this invention and are not to be and/or hydroxide, and usually use about 6 to 7 moles of construed as limiting the invention. reagent per mole of cz-bromo-keto steroid being dehydro brominated. EXAMPLE 1. Our process is carried out at temperatures in the range 50 of 50-165 C., usually between about 100 and 165 C. and preferably at the reflux temperature of N,N-dimethyl Dehydrobromination of 16 cy-methyl-17c-bromopregneno formamide, which is about 153 C. lone acetate ittilizing a magnesium oxide/magnesium The time required for complete dehydrobromination hydroxide mixture is dependent upon the temperature of the reaction mix 55 ture and upon the particular alkaline earth base used. It (A) Prepare an anhydrous mixture of 40 g. of 16cy is therefore desirable to monitor the reaction by obtaining methyl-17 cy-bromopregnenolone acetate in 800 ml. of di ultraviolet absorption or thin layer chromatographic data methylformamide and 27.4 g. of Sea Sorb No. 53 (a mix on aliquots of the reaction mixture at given intervals un ture of about 70% magnesium oxide and 30% magnesium til there is no further evidence of any starting bromo 60 hydroxide). Heat the reaction mixture at reflux tempera steroid. ture (150-155 C.) in a nitrogen atmosphere for 16 hours. A lithium halide, e.g. lithium bromide may be used in Cool the reaction mixture to 40° C. and filter. Distill the conjunction with the alkaline earth oxide and/or hy filtrate in vacuo to a concentrated solution having a vol droxide reagent in which case the dehydrobromination une of about 270 ml. comprising 16-methyl-16-dehydro reaction will usually proceed at a faster rate. For example, pregnenolone acetate together with a small amount (usual if about an equimolar weight of lithium bromide per mole ly at most 5% total weight) of the corresponding 3-hy of steroid is added to the Sea Sorb 53 reagent mixture droxy analog thereof in dimethylformamide. when dehydrobrominating 16cy-methyl-17 cy-bromo-5-preg (B) Add 800 mi. of dry pyridine and 40 ml. of acetic nen-36-ol-17-one 3-acetate as described hereinabove, the anhydride to the concentrated dimethylformamide solu dehydrobrominating time will be shortened to less than 70 tion of Example 1A and stir the reaction mixture at 90° half the original reaction time. C. for two hours. Cool to 40-50° C. and pour into 8 liters When dehydrohalogenating a steroid containing an ester of 10% aqueous hydrochloric acid with vigorous stirring. group such as in 16 cc-methyl-17 cy-bromopregnenolone ace When the pH of the mixture is above 0.8, add concen tate according to our process, there may occur some hy trated hydrochloric acid dropwise until the mixture is at 75 pH=0.8 or below. Filter the resultant precipitate, wash 3,350,427 8 7 stirring the mixture at 90° C. for two hours. Cool the with water, and dry at 60° C. to obtain substantially 16 mixture to 40-50° C. and isolate the resultant 3-acetate methyl-16-dehydropregnenolone acetate. M.P. 160° C.; in the manner described in Example 1B to obtain sub stantially 16-methyl-16-dehydropregnenolone acetate. M.P. 160-161 C.; c.25 -77.3 (1% dioxane); 250-251 mu (e=7900); yield=32 g. Purify by crystallization from methanol after first ACH3OHtax. clarifying the methanol solution by means of activated carbon to yield 16-methyl-16-dehydropregnenolone ace 250-25 mu (e=7550); yield=8.4 g. (80% theory). tate. M.P. 170 C.; a 25's -80 (1% dioxane); Ama. Purify by crystallization from methanol to give 16 250-251 mu, (e=8600). Yield=25.4 g. (77.2% theory). 10 methyl-16-dehydropregnenolone acetate. M.P. 172-174 Similarly, in the manner described hereinabove, treat C. Lo D = -80.3 (1% dioxane); an anhydrous mixture of 16a-methyl-17a-bromopregneno lone acetate and from 5 to 10% (by weight) of the cor SEOHax. responding 17,3-bromo-17-iso derivative, i.e. 160-methyl 250-251 mu, (e=8900); yield=6.3 g (73% theory). 176-bromo-17-isopregnenolone 3-acetate (mixture pre pared as in Preparation I) with Sea Sorb 53 in dimethyl EXAMPLE 3 formamide. Isolate the resultant product in the described In each of the following examples, 1 g. of 160-methyl manner, then reacetylate to esterify any 3-hydroxy group 17a-bromopregnenolone acetate in dimethylformamide is which may be present to obtain 16-methyl-16-dehydro 20 dehydrobrominated in the manner similar to that de pregnenolone acetate. scribed in Example 1A, except there is utilized in place of EXAMPLE 2 Sea Sorb No. 53 the reagent listed in the chart below. In each example listed below, the reaction mixture 1s Dehydrobromination utilizing a magnesium oxide/mag heated for the time indicated, then cooled, filtered, and nesium hydroxide mixture and lithium bromide 25 concentrated in vacuo to a residue comprising a product (A) Prepare an anhydrous mixture of 10.5 g. of 16oz mixture whose components are determined by thin layer methyl-17 cy-bromopregnenolone acetate, 10.6 g. of lithium chromatography utilizing a benzene/methanol solvent bromide, 210 ml. of dimethylformamide, and 7.17 g. of System (99:1, v./v., i.e. by taking the chromatogram of Sea Sorb No. 53. Heat at reflux temperature (150-155 5-y of a 5% solution of the product. C.) for six hours under an atmosphere of nitrogen. Cool 30 In each of the following examples, reacetylation of the the reaction mixture to 40 C., filter, and distill the filtrate product mixture obtained and purification thereof accord in vacuo to a concentrated solution (about 70 ml.) com ing to the procedure of Example 1B yields 16-dehydro prising 16-methyl-1,6-dehydropregnenolone 3-acetate in pregnenolone acetate. In those examples wherein the prod admixture with a small amount (usually at most 5% by uct comprises 16-dehydropregnenolone acetate, the re weight) of the corresponding 3-hydroxy analog thereof in acetylation procedure may be omitted. dimethylformamide. All melting points are taken on a Kofler Hot Bench, (B) Reacetylate by adding 21 ml. of pyridine and 10.5 and all rotations taken were of a 1% dioxane solution. ml. of acetic anhydride to the concentrated solution and

Reagent Reaction Time and Temperature Yield and PropertiesReacetylation of Crude Product Prior to

(A) Strontium oxide, 1.77g------17hrs. F100° C------M.P.Yield=0.65 224-228° g. comprisingC.; (alp?s=-79.4°; 6-methyl-16-dehydropreg ASE 250-251 m.a. renolone. (B) Barium oxide, 2.61 g------17hrs. F100 C------M.P.136-1469Yield=0.72 g. comprisingC.; alp?s=–71.6°; 16-methyl-6-dehydropreg ASE 250-251 m.a. nenolone16-methyl-16-dehydropregnenolone. acetate, together with a small amount of

(C) Barium hydroxide, 2.91 g------16 hrs. 100 C------M.P.Yield=0.75 170-180° g. comprisingC.; alo's--78.69;ASE 16-methyl-16-dehydropreg 250-251 m.a. nenolone. (D) Strontium hydroxide, 2.07 g------16 hrs. F100° C------M.P.Yield=0.65 190-205 g. comprisingC.; (alos--87.3°, 16-methyl-6-dehydropreg ASE 250-251 m.a. M.P.nenolone. 158-166° C.; (alp?s=-75°; ASE 250-251 m.a. (E) Magnesium oxide, 0.685g------6 hrs. at reflux (150-155 C.).------Yield=0.803 g. comprising 16-methyl-16-dehydropreg menolone acetate with trace, amounts of 6-methyl-6- dehydropregnenolone. (F) Magnesium oxide, 0.685g------16 hrs. = 100° C------M.P.150–158°Yield=0.69 g. comprisingC.; (old?s=-67.9°; 16-methyl-16-dehydropreg ASE 250-251 m.a. nenolone acetate with trace quantities of 16-methyl-6- M.P.dehydropregnenolone. 156–160° C.; alp?s=-61'; SE 250-251 m.a. (G) Magnesium hydroxide, 0.992 g------16 hrs. Fi00 C------Yield=0.75 g. comprising 16-methyl-16-dehydropreg M.P.nenolone 153° C.; acetate. (alp?s=-649; ASE 250-251 m. (H) Magnesium oxidelmagnesium hydroxide 6 hrs. at reflux (150-155° C.)------Yield=0.78 g. comprising 16-methyl-16-dehydropreg (7:3, w.fw.), Sea, Sorb 53, 0.684 g. M.P.nenolone 154-160° acetate. C.; folp?s=-5S°; ASE 250-251 m. I) Magnesium oxidelmagnesium hydroxide 16 hrs. F100 C------Yield=0.88 g. comprising 16-methyl-16-dehydropreg (7:3, w.fw.), Sea Sorb 53, 0.684 g. M.P.nenolone 96-100° acetate. C.; alp?s=-769; x 9250-251 m. (J) Calcium oxide, 0.952g------15hrs. -100 C------Yield=0.55g. comprising a mixture8x. of 16-methyl-6- dehydropregnenolone and acetate thereof, together with a polar inpurity. (K) Calcium oxide, 0.952 g------6hrs. at reflux (50-155 C.).------M.P.Yield=0.684 168-174° g. C.; comprising (alp?s=-79.9°; 16-methyl-16-dehydropreg ASE 250-251 m.a. nenolone. 3,350,427 10 Reagent Reaction Time and Temperature Yield and PropertiesReacetylation of Crude Product Prior to (L) Calcium hydroxide, 1.26 g------16 hrs.=100 C------M.P. 95-115° C.; alp25= -75°; Anas. 250-251 m. Yield=0.65 g. connprising a product mixture comprising 16-methyl-16-dehydropregnenolone and the 3-acetate (M) Calcium hydroxide, 1.26 g------6 hrs. at reflux (150-155° C.).------M.P.ester 170-180° thereof C.;together op?S= with -70.4; a polar x. impurity. 250-251 m. Yieldmenolone. = 0.71 g. comprising 16-methyl-16-dehydropreg

Dehydrobromination ofEXAMPLE 2,4-dibromo-168-methyl-5a-preg 4 plete, and there is formed 36-acetoxy-160-methyl-5,17 nane-17,21-diol-3,20-dione 21-acetate utilizing a mag tetrahydrofuran.(20)-pregnadien-20-ol. 20-magnesium bromide salt in nesium oxide/magnesium hydroxide mixture (B) In situ bromination of the 20-magnesium bromide To an anhydrous mixture of 1.8 g. of Sea Sorb No. 53 enolate.-Continue to vigorously agitate the reaction mix. and 1 g. of lithium bromide in 30 ml. of dimethylform ture of Preparation 1A containing 36-acetoxy-16cz amide at 100° C., add 1 g of 2,4-dibromo-16(3-methyl 20 methyl-5, 17 (20)-pregnadien - 20 - ol. 20-magnesium bro 5a-pregnane-17a,21-diol-3,20-dione 21-acetate over a 30 mide Salt in tetrahydrofuran under a blanket of nitrogen minute period with stirring. Stir the reaction mixture un and add over a 10 to 15 minute period about 14 g. of dry der a blanket of nitrogen for about 20 hours at 100 C. bromine at Such a rate as to maintain the reaction temper Cool the reaction mixture to 30° C. Filter, and concen ature at 0-5 C. Then continue cautious addition of small trate the filtrate in vacuo to a residue of about 10 ml. 25 quantities of bromine until a total of about 0.10 mole Pour the residue into dilute hydrochloric acid (1.2 ml. of bromine has been added as determined by obtaining of concentrated hydrochloric acid to 200 ml. of water). a positive test of the reaction mixture with starch-iodide Filter and wash to neutrality with water with the result test paper. Pour the reaction mixture into 10 liters of ant precipitate comprising 16.3-methyl-1,4-pregnadiene distilled water, and collect the precipitate thereby formed 17a,21-diol-3,20-dione 21-acetate. 30 by filtration, and wash with water and dry to obtain sub stantially 160-methyl-17a-bromopregnenolone acetate in EXAMPLE 5 admixture with a small quantity (usually about 5%) of Dehydrobromination of 2,4-dibromo-166-methyl-5c.-preg 160-methyl-17,3-bromo-iso-pregnenolone acetate. Yield= nane-17 oz,21-diol-3,20-dione 21-acetate using magnesi 47 g. um oxide This product may be used without further purifica Treat 2,4-dibromo-168-methyl-5a-pregnane-17a,21-diol tion for dehydrohalogenation according to the pro 3,20-dione 21-acetate in a manner similar to that described pregnenolonecedure of Example acetate. 1 to produce 16-methyl-16-dehydro in Example 4 using powdered magnesium oxide instead of We claim: Sea Sorb No. 53, and there is obtained 16.3-methyl-1,4- 40 pregnadiene-17 ca,21-diol-3,20-dione 21-acetate. 1. In the process wherein an cc-bromo-keto-steroid hav Alternatively, treat 2,4-dibromo-168-methyl-5oz-preg ing a hydrogen on the beta carbon is treated with a de nane-17 oz,21-diol-3,20-dione 21-acetate with magnesium hydrohalogenating agent and there is formed an a (6)- oxide in the manner described above with the exception unsaturated-keto-steroid, the improvement which com that the reaction mixture is kept at 105 C. rather than prises treating said oc-bromo-keto-steroid with a dehydro 100° C., whereby complete dehydrobromination is 45 halogenating agent selected from the group consisting of achieved after four hours. Isolate the resultant product in an alkaline earth oxide, an alkaline earth hydroxide, and mixtures thereof, in a solvent selected from the group the manner similar to that described in Example 4 to ob consisting of an N-lower alkyl 2-pyrrolidone and an N,N- 2-acetate.tain 168 - methyl-1,4-pregnadiene-17a,21-diol-3,20-dione dillower alkyl amide of a hydrocarbon carboxylic acid 50 having up to 18 carbon atoms. PREPARATION I 2. The process of claim 1 when carried out at tem Preparation of 16a-methyl-17a-bromopregnenolone ace peratures in the range of from about 100 to about tate in admixture with 16a-methyl-17 3-bromo-17-iso 165 C. and wherein said a-bromo-keto steroid is a 17 pregnenolone acetate from 16-dehydropregnenolone 55 bromo-20-keto-steroid of the pregnane series and wherein acetate Said16-dehydro-20-keto-steroid C. (3)-unsaturated-keto-steroid of the pregnanethereby formedseries. is a (A) Grignard reaction to form 5,3-acetoxy-16c-methyl 3. The process of claim 2 wherein the dehydrohalo 5,17(20)-pregnadien-20-ol 20-magnesium bromide Salt genating agent is a mixture of about 70% magnesium To a solution of 35.65 g. (0.10 mole) of 16-dehydro oxide and about 30% magnesium hydroxide by weight. pregnenolone acetate in 356.5 ml. of dry tetrahydro 60 4. The process of claim 2 wherein the solvent is an furan, add 1.1 g. of cuprous chloride (0.011 mole), and N,N-dillower alkyl amide of a hydrocarbon carboxylic cool the mixture to 0-5 C. Vigorously stir this cooled acid having up to 18 carbon atoms. solution under a blanket of nitrogen and add dropwise a 5. The process of claim 2 wherein the solvent is di 0.5 N. solution of methyl magnesium bromide in dry methylformamide. tetrahydrofuran until slightly less than 0.10 mole of the 65 6. The process of claim 2 wherein the dehydrohalo Grignard reagent is added; continue the addition of Gri genating agent is a mixture of about 70% magnesium gnard reagent and determine the ultraviolet absorption at oxide and about 30% magnesium hydroxide by weight 237 mu (conjugated A16-20-carbonyl) of samples removed and wherein the solvent is refluxing dimethylformamide. from the reaction mixture. When the absorption at 70 7. The process of claim 2 wherein said c-bromo-20 237 mu, becomes negligible, discontinue addition of the keto-steroid is 160-methyl-17 cy-bromo-5-pregnen-3 (3-ol-20 methyl magnesium bromide solution. Add the methyl one 3-acetate, wherein the dehydrohalogenating agent is magnesium bromide solution at such a rate So as to a mixture of about 70% magnesium oxide and about 30% maintain the reaction temperature between 0 and 5 C. magnesium hydroxide by weight, wherein the solvent is Normally within 15 to 20 minutes, the addition is com 75 refluxing dimethylformamide, and wherein said 16-dehy 3,350,427 12 11 ol 3-acetate and the dehydrohalogenating agent is a mix dro-20-keto steroid thereby produced is 16-methyl-5, 16 ture of about 70% magnesium oxide and about 30% mag pregnadien-36-ol-20-one 3-acetate. nesium hydroxide by weight, together with lithium bro 8. The process of claim 1 wherein said o-bromo-keto mide, and the solvent is refluxing dimethylformamide, steroid is a 17-bromo-20-keto-steroid of the pregnanese 5 said 16-dehydro-20-keto-steroid thereby formed being ries and wherein said ox (6)-unsaturated steroid thereby 16-methyl-5, 16-pregnadien-36-ol-20-one 3-acetate. formed is a 16-dehydro-20-keto steroid of the pregnane series, when carried out at temperatures in the range of References Cited from about 100° C. to about 165 C. and wherein lithium UNITED STATES PATENTS bromide is added to said dehydrohalogenating agent. 9. The process of claim 8 wherein the dehydrohalo l0 3,018,285 1/1962 Ringold et al. --- 260-239.55 genating agent is a mixture of about 70% magnesium OTHER REFERENCES oxide and about 30% magnesium hydroxide by weight, together with lithium bromide, and wherein the solvent Holysz: J. Amer. Chem. Soc., 75. 4432-4437 (1953). is refluxing10. The dimethylformamide.process of claim 8 wherein said 17-bromo- 15 LEWIS GOTTS, Primary Examiner. 20-keto steroid is 160-methyl-17a-bromo-5-pregnen-36 T. M. MESHBESHER, Assistant Examiner.