Patent GB-517133-A (GB)
Title: Manufacture of cyclic ketones of the cyclopentanopolyhydrophenanthrene series
IPC: C07J75/00
Filed: 1938-07-19
Abstract: 517,133. Cyclopentanophenanthrene ketones. SOC. OF CHEMICAL INDUSTRY IN BASLE. July 19, 1938, Nos. 21404, 21405, 21406 and 21407. Convention dates, July 22, 1937, March 15, 1938, April 6, 1938, and May 12, 1938. [Class 2 (iii)] Ketones of the cyclopentanopolyhydrophenanthrene series which have in the 17- position an unsaturated side chain containing a multiple carbon-carbon linkage in alpha:#-position with respect to the nucleus are prepared by the oxidation or dehydrogenation of the corresponding secondary carbinol compound. Such oxidation may be carried out by means of any oxidizing agent known to be applicable for this reaction, such as chromic acid in glacial acetic acid or with a permanganate. Alternatively a dehydrogenating agent may be used such as a carbonyl compound for example acetone or cyclohexanone in the presence of a metal alcoholate such as for example aluminium butylate, or propylate, or a magnesium halogen alcoholate. Other dehydrogenating agents include a metal or a metal oxide of the copper, iron or platinium group, if required under reduced pressure in the presence of an inert gas and/or in combination with a hydrogen acceptor. It has been found unnecessary to protect the side chain unsaturated bond, but in the case of compound containing nuclear double bands, protection is preferred, using halogen or halogen hydride and regenerating the bond after the oxidation by means of zinc dust and acetic acid or an alcohol, or a tertiary base such as pyridine or dimethylaniline, or an alkali iodide-benzene, or an alkali or a salt of an organic acid. If the nuclear double link is in #-gamma position to the newly produced keto group, the halogen may be split off in neutral solution by means of zinc dust and an alcohol. Protection of the nuclear double bond is unnecessary when using dehydrogenation or delicate methods of oxidation such as by means of mercury salts, or formaldehyde and a tertiary base. The unsaturated linkage may be either an ethylenic or an acetylenic linkage. If the parent material contains an acetylenic linkage and it is desired to obtain a cyclic ketone with an ethylenic side chain the reduction of the side chain may precede the oxidation of the carbinol group. Such reduction may be carried out by treatment with a metal such as an alkali metal or zinc in an acid such as acetic acid, or in an alcohol or in a moist ether, or in the form of an amalgam. The reduction may also be electrolytic or by means of hydrogen in the presence of a catalyst such as nickel cobalt, copper, iron, platinum, palladium, or a chromium salt. In examples: (1) An acetone solution of #<5>.<6>-17-ethinylandrostendiol-3:17 is refluxed for 21 hours with a toluene solution of tertiary aluminium butylate. The reaction product is washed with dilute mineral acid to give #<4>.<5>-17-ethinylandrostene-3-one-17-ol. (2) An alcohol solution of # <5>.<6>-17-ethinyl-androstenediol-3:17 is reduced by hydrogen at ordinary temperature in the presence of a Raney nickel catalyst until one mol. of hydrogen has been adsorbed to give #<5>.<6>-17-ethenyl androstendiol-3:17. This is then dissolved in acetone and refluxed with a benzene solution of tertiary aluminium butylate for 20 hours. The reaction product is purified by adsorption. on aluminium oxide to give 17-ethenyl testosterone. In place of the free #<5>.<6>-17-ethenyl-androstendiol-3:17, there may be used for the dehydrogenation' process the 17-mono-esters such as the acetate propionate or benzoate. (3) #<5>.<6>-17-ethinyl-androstendiol is oxidized by chromium trioxide in glacial acetic acid solution with intermediate protection of the nuclear double bond by bromine, to #<4>.<5>-17-ethinyl testosterone. Instead of the chromic acid as oxidizing agent, a dehydrogenation by copper powder may be used, and 17- ethinyl-androstandiol may be uaed as the starting material to give the corresponding ethinyl-dihydrotestosterone. (4) #<5>.<6>-17-ethenyl androstendiol-3:17 is oxidized by chromic acid in glacial acetic acid solution with intermediate protection of the nuclear double bond by bromine to #<4>.<5>-17-ethenyl-testosterone if the regeneration of the double bond is by zinc dust in acetic acid solution and to the #<5>.<6>-compound if zinc dust in methanol is used. Specifications 487,360 and 500,186 are referred to. The Specification as open to inspection under Sect. 91 includes also as starting materials for the process of the invention compounds of the cyclopentanopolyhydrophenanthrene series with the carbinol group in 3, 11, 12, and/or 17 positions, or also partially substituted by acyloxy-, alkoxy-, or keto-groups and by halogen. The unsaturated side chain may be in any desired position on the cyclopentanopolyhydrophenanthrene nucleus and there are specified side chains of the following constitutions :- where R, R<1> and R<11> represent hydrogen, a substituted or unsubstituted hydrocarbon residue or an acid residue. This subject-matter does not appear in the Specification as accepted.