2,986,560 United States Patent Office Patented May 30, 1961 2. free or functionally converted carboxyl groups, such as 2,986,560 nitrile groups or esterified carboxyl groups or by a lactone PROCESS FOR THE MANUFACTURE OF 11-OXY group, for example butenolide group. The starting ma GENATED STEROIDS AND INTERMEDIATES terials can have any configurations and may also contain THEREFOR double bonds, as for example in 4:5-, 5:6- or 20:22 position. Albert Wettstein and Julius Schmidlin, Basel, Switzerland, For the reduction of the oxo group there are suitable assignors to Ciba Pharmaceutical Products, Inc., Sum primarily complex hydrides of boron, such as sodium, mit, N.J. lithium borohydride, or alkali-alkoxy borohydrides, for No Drawing. Filed Nov. 18, 1953, Ser. No. 392,982 example, sodium trimethoxy borohydride. As agents for 0. splitting off hydrohalic acid there are preferably used Claims priority, application Switzerland Nov. 19, 1952 hydroxides or oxides of metals of the first and second 38 Claims. (CI. 260-239.55) group of the periodic system, for example silver oxide and further tertiary bases such as pyridine or collidine. This invention relates to a new process for the manu In this case it is often of advantage in order to obtain facture of compounds of the steroid series which are 15 high yields of 11:126-oxides, to use tertiary bases in unsubstituted in 12-position and have an oxygen atom combination with one of the specified mono- or divalent in 11-position. More particularly, the invention relates metal hydroxides or oxides. to a process for the manufacture of 119-hydroxy- and The 11-halogen-126-hydroxy-steroids, and also in some 11-keto-steroids from 11-halogen-12-oxo-compounds by cases the 11:123-oxido-steroids produced therefrom, for way of the 11:128-oxides. 20 example 11:126-oxido-spirostanes, and the 116-hydroxy In general, the process comprises reacting a 11-halogen 12a-halogen-spirostanes which compounds are obtainable 12-oxo-steroid with a complex hydride of an amphoteric according to the present process, are new, and are also metal so as to produce the corresponding 11:12 halogen embraced within the scope of the present invention. hydrin, dehydrohalogenating the latter to form the cor 25 To produce the 12-unsubstituted compounds of the responding 11:123-oxide, reacting the latter with a hydro steroid series, which comprise another aspect. of the in halic acid to form the corresponding 116-hydroxy 12-halo vention, the 11:123-oxido-steroids are converted into gen steroid, oxidizing the 11g-hydroxy-12-halogen steroid 11(3-hydroxy-12-halogen compounds with the aid of hy so as to convert the 11-hydroxy group into a keto group, drohalic acids, the 12-halogen atom is removed and, if and replacing the halogen by hydrogen, the last two steps 30 desired, the hydroxy group in 11-position is oxidized to being carried out in optional sequence. the keto group, the last two steps being carried out in 11:126-oxides of the steroid series were hitherto only optional sequence, For the cleavage of the 11:12,3-epox difficultly available. Starting from 12-hydroxy-steroids, ides hydrohalic acids, for example, hydrogen chloride, these had first to be esterified and then the esterified hydrogen bromide, or hydrogen iodide, are employed. hydroxyl group split off with formation of a double 35 The said hydrohalic acids are used for this purpose in bond in 11:12-position. By adding on hypohalous acid aqueous or anhydrous diluents, for example in aqueous to the unsaturated compounds thus produced, they were dioxane. The halogen atom in 12-position can be elim first converted into 11-hydroxy-12-halogen steroids and nated by means of nascent or catalytically activated hy these then treated with dehydrohalogenating agents to drogen. It is of advantage to use Raney nickel charged obtain the 11:123-oxides. This process gives poor yields. 40 with hydrogen or zinc in the presence of a weak acid or it therefore constitutes a considerable advance that an alcohol, for example, glacial acetic acid or 2-ethoxy one aspect of the present invention also provides a ethanol. It is possible to apply especially mild conditions process that makes it possible to produce the 11:126-oxides to remove the iodine from the 12-iodo derivatives. in a simple manner and in excellent yield. In this process The products are intended for use as intermediate prod there are used as starting materials 11-halogen-12-oxo 45 ucts for the production of midicaments especially for the steroids, which are obtainable for example by halogena manufacture of cortisone, Kendall's Compound F tion of 12-oxo-steroids, especially 110-halogen-12-oxo-, (A-3:20-diketo-1 16:17 cy:21 - trihydroxy - pregnene) and such as 11c-bromc-12-oxo-steroids. The process com related hormones. Thus the 11-oxygenated 5-allo- and prises reacting the 11-halogen-12-oxo-steroids with com 5-normal spirostane compounds obtained according to the plex hydrides of amphoteric metals and dehydrohalo 50 process of the invention on treatment with acetic anhy genating the 11:12-halogen hydrins thus obtained to form dride at elevated temperature are converted into the the 11:128-oxides. In view of the facility with which corresponding pseudo derivatives which by careful oxida the halogen, for example in 11c-bromo-12-ketones, is tion with chromic acid can be transformed into 20-keto removed by various reducing agents, it is surprising that compounds of the pregnane series. The reactions by a smooth selective reduction to the halogen hydrins should 55 which the 11-oxygenated compounds of the pregnane be possible. It was further not to be expected that by series are converted into the above mentioned hormones this means, for example starting from 110-halogen-12-ke are well known and consist in hydroxylations at positions tones, practically exclusively the 12,3-hydroxy-compounds 17 and 21 and introduction of a double bond at position would be obtained which are suitable for cyclization to the 4:5 by a halogenation-dehydrohalogenation procedure. 11:126-oxides. The starting materials belong to the cyclopentanopoly 60 11-oxygenated compounds of the pregnane series are also hydrophenanthrene or polyhydrochrysene series. Especial obtained from correspondingly substituted cholanic acid importance is attached to the derivatives of Spirostane, esters by converting the ester group by reaction with allospirostane, furostane, allofurostane, cholane, allocho phenylmagnesiumbromide into a diphenylcarbinol group, lane, pregnane, allopregnane, androstane and testane. splitting off water therefrom, allylic bromination followed The starting materials may also be substituted in the 65 by dehydrohalogenation to produce a A20:23-24:24-di nucleus or in the side chain, for example in 3, 5, 6, 17, 20 phenyl-choladiene which is oxidized to a 20-keto-preg and/or 21-position by free or functionally converted nane compound. The above mentioned hormones may hydroxyl or oxo groups, such as acyloxy groups, for ex also be prepared by elaboration of the dihydroxy-acetone ample acetoxy, propionyloxy or benzoyloxy groups, by side chain starting from a 17-ketone of the androstane alkoxy groups, for example methoxy or ethoxy groups, by 70 and testane series. For this purpose it is of especial ad halogen atoms, by acetalized oxo groups and further by vantage to use the well known method which consists in 2,986,560 3 4. tht reaction of the 17-ketone with acetylene followed by Example 2 partial hydrogenation of the acetylene grouping. By 0.2108 part by weight of pure 36-acetoxy-11f8: 128 allylic rearrangement of the 17-hydroxy-compound ob oxido-23:-bromo-5:22a-spirostane is dissolved in 19.1 tained a A17:20-21-hydroxy-pregnane is formed which by parts by volume of pure dioxane, the solution is mixed treatment with hydrogen peroxide in the presence of os with 4.77 parts by volume of aqueous 2.5 N-hydrochloric mium tetroxide is converted in to a 17o:21-dihydroxy acid and allowed to stand at room temperature for 1 20-keto-pregnane. hour. To the solution there are then added while shak The following examples illustrate the invention, the re ing in the course of 10 minutes 14.3 parts by volume of lation between parts by weight and parts by volume being water. 15 minutes later, the crystals which have sepa the same as that between the gram and the cubic centi 0. rated are removed by suction-filtering, washed with aque meter: ous dioxane of 40% strength and water, and then dried Example 1 over phosphorus pentoxide and potassium hydroxide in To a solution, cooled to 0° C., of 1.261 parts by weight vacuo. By recrystallization once from ether with the use of 11a:23-dibromo-hecogenin acetate in 10 parts by of methylene chloride as additional solvent there can be volume of anhydrous tetrahydrofurane, there are added obtained 0.1972 part by weight (88.0% of the theoretical dropwise with stirring within 12 hours 5 parts by volume quantity) of pure 38-acetoxy-11g-hydroxy-12a-chloro of a 2-molar solution of lithium borohydride in tetrahy 23:-bromo-5o:22a-spirostane in the form of fine colour drofurane. After the reaction mixture has been further less prisms of melting point 240-242 C. (with decom stirred for 10% hours at 0° C., the excess of hydride is position), c.28=-31:2 (c.-1.000 in chloroform). destroyed by careful addition of 10 parts by volume of 10 20 A solution of 0.1313 part by weight of 3{3-acetoxy percent acetic acid and the tetrahydrofurane then re 116-hydroxy-12a-chloro-233-bromo - 5o:22a - spirostane moved by evaporation under vacuum.