Patent GB-478583-A (GB)
Title: Manufacture of sterol derivatives
IPC: C07J75/00
Filed: 1936-07-20
Abstract: Physiologically active sterol derivatives having the character of sex hormones are prepared by degradation of hydroxy bisnorallocholanic acid by a process which is characterized in that the special configuration of the hydroxyl group at position-3 is changed to convert it into its sterio isomeric form of epi-hydroxybisnorallocholanic acid.  The epimerization process comprises the oxidation of the hydroxybisnorallocholanic acid in the form of an ester to the corresponding keto compound, followed by catalytic reduction in an acid solution to the epi-hydroxy compound. The degradation of this epi-hydroxy compound may be done by subjecting it twice to the action of Grignard reagent with subsequent splitting off of water and oxidation in each operation, to yield 3-epi-acetoxy-ethio-allo-cholanone.  Alternatively, the degradation may be accomplished by subjecting the epi-hydroxy-bisnorallocholanic acid to one Grignard degradation, oxidizing the carbinol or the ethylene compound so obtained so as to produce epi-acyloxy-ethio-allo-cholanic acid, and subjecting this acid in the form of its ester again to the action of Grignard reagent and then oxidizing the carbinol.  A third alternative method of degradation comprises subjecting the epi-acyloxy-ethio - allo - cholanone obtained as described above to the Curtius transformation via the acid chloride, the azide, the isocyanate and the amine to the corresponding alcohol which may then, if desired, be oxidized.  The various modifications described above are illustrated by examples. The preparation of 3-epi-acetoxy-bisnorallo-cholanic acid.--The starting material for the preparation of this compound is acetoxy-bisnorcholenic acid obtained by an oxidation degradation from the sterols, which is first reduced by hydrogen in the presence of a palladium catalyst to acetoxy-bisnorcholanic acid. The corresponding hydroxy compound is then oxidized by means of chromic anhydride to the 3-keto-bisnorallocholanic acid which is in turn reduced again by means of hydrogen in the presence of palladium in glacial acetic acid solution to the required 3-epi-acetoxy-bisnorallocholanic acid. Instead of the acetoxy compound, other acyloxy compounds may be used, for example, from propionic acid or butyric acid.  The degradation of 3-epi-acetoxy-bisnorallo-cholanic acid.--(1) The methyl ester prepared by the action of diazomethane on the parent acid is reacted with a Grignard reagent prepared from magnesium and bromobenzene. The tertiary alcohol so produced is dehydrated by heating the reaction mixture for 5 hours and the resulting ethylene compound distilled off.  This is then oxidized in chloroform solution with ozone to give an isomer of allo-pregnanol-(3)-one-(20).  This compound is then subjected to a similar Grignard degradation to give 3 - epi - acetoxy - ethio - allocholanone.  (2) The tertiary carbinol or the ethylene compound obtained from the first Grignard reaction is oxidized with chromic acid to produce 3-epi-ethio - allocholanic acid. This acid which forms a sparingly soluble silver salt, by means of which it may be purified, is converted into its methyl ester by means of diazomethane, and then subjected to a Grignard reaction as described in (1) above.  The product after the ozone oxidation is 3-epi-acetoxy-ethio-allocholanone identical with that obtained in (1) above.  (3) The 3 - epi - acetoxy - ethio-allocholanic acid obtained as described in (2) above is converted into its acid chloride by thionyl chloride.  This is then transformed into the corresponding azide by treatment with sodium azide.  The azide is at once dissolved in toluene and heated slowly in a paraffin bath to convert it into the isocyanate.  Treatment of the isocyanate with acetic anhydride, followed by saponification with alcoholic alkali yields 3-epi-hydroxy-17-amino-androstane.  The hydrochloride of this amine is converted with an acid solution of sodium nitrite or with silver nitrite into dihydroandrosterone.  A sample has been furnished under Sect. 2 (5) of dihydro androsterone made as follows: The epi-acetoxy-ethio-allo-cholanyl-isocyanate-(17) prepared as described in (3) above is dissolved in a mixture of ether and benzene.  An approximately equal volume of 60 per cent sulphuric acid is then added, and the two layers well mixed by stirring. The amine sulphate which separates is centrifuged, treated with caustic potash to liberate the amine, and then transformed into dihydro-androsterone as described in (3) above.