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United States Patent Office 3,350,427 Patented Oct 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.
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