Patent GB-486854-A (GB)
Title: Process for the manufacture of compounds of the androstane and pregnane series
Filed: 1936-12-05
Abstract: Oxygen is introduced into the molecule of unsaturated compounds of the androstane and pregnane series by subjecting compounds of these series which possess in the adjacent position to the carbon to carbon double bond a methylene group, to the action of oxidizing-agents under energetic conditions, without protection of the double bond. The preferred oxidizing-agents are compounds of hexavalent chromium such as chromium trioxide, also selenium dioxide.  In the latter case the oxidation preferably takes place in the presence of catalysts such as iodine.  The action of the oxidizing-agents is rendered particularly energetic by prolonged action at elevated temperatures, with the oxidizing-agent in excess.  As starting materials for the present invention there are mentioned dehydroandrosterone, androstendiols, and pregnenolones. Starting materials which contain oxygen can either be employed as such in the form of free alcohols or ketones, but they are preferably employed in the form of derivatives as this procedure results in better yields.  In the case of alcohols the derivatives employed are the esters ethers or halogen derivatives.  The reaction products obtained after the oxidation are worked up so that the acid portion is first separated from the neutral portion, and from the latter there is isolated the desired oxidation products by fractional crystallization or fractional distillation or sublimation in vacuo.  Ketones may also be isolated with the aid of the usual ketone reagents.  The compounds produced according to the present invention contain three oxygen atoms directly connected to the carbon atoms of the androstane or pregnane system and also contain a keto group in the adjacent position to the carbon-carbon double bond.  Reduction products of the oxygenated products prepared as above described are also made according to the present invention.  As starting materials for the reduction process there may be used 7-oxo- and 7-hydroxy-androstenolones, 7-oxo- and 7-hydroxy-androstendione, the isomeric 7-oxo- and 7-hydroxy-androstendiols and the corresponding unsaturated 7-oxo- and 7-hydroxy-pregnane compounds.  The reduction process may be such that either complete reduction takes place with the production of saturated alcohols or a partial reduction may be obtained with the production either of saturated keto bodies or unsaturated alcohols according to the reduction conditions.  If the keto groups are required to remain unaltered and the double bonds reduced, a reducing agent of the type of aluminium isopropylate is used, or the substance is treated with such Grignard reagents as incline to the formation of unsaturated hydrocarbons such as isopropyl magnesium halogenide.  If both the carbon double bond and the keto groups are to be reduced then the material is hydrogenated in the presence of a noble metal catalyst such as platinum, platinum oxide or palladium, or nickel, or an alloy skeleton catalyst such as the Raney catalyst.  There may also be used the nacent hydrogen obtained by the action of alkali metals on alcohols.  The above class of reducing-agents may also be used under mild conditions to effect a reduction of the carbon double bond without reducing the keto group.  In examples: (1) a glacial acetic acid solution of androstendiol diacetate is treated with an aqueous solution of chromium trioxide for two hours at 50-55 DEG  C. to give D 5-7-oxo-androstendiol diacetate.  Instead of the diacetate other esters may be used such as the dibenzoate or the acetate-benzoate; (2) 7-oxo-androstendiol diacetate is treated with aluminium isopropylate in absolute isopropyl alcohol solution for 7 hours to give 7-hydroxy androstendiol diacetate; (3) 7-oxo-androstendiol diacetate is shaken in alcohol solution with hydrogen in the presence of Raney catalyst to give 7-oxo-androstandiol diacetate; (4) 7-oxo-androstendiol diacetate is shaken in glacial acetic acid solution with hydrogen in the presence of previously reduced platinum oxide catalyst to give 7-hydroxy androstandiol diacetate.  Specifications 445,189 and 448,183 are referred to.  Samples have been furnished under Sect. 2 (5) of (1) D 5-androstentriol tribenzoate prepared by the reduction of D 5-7-oxo-androstendioldiacetate-3 : 17 with aluminium isopropylate in isopropyl alcohol solution; (2) 7-oxo-pregnendiol diacetate prepared by the oxidation of pregnendiol diacetate with chromium trioxide in glacial acetic acid solution.