Patent GB-464396-A (GB)
Title: Process for the manufacture of androstenol-(17)-ones-(3) and derivatives thereof
IPC: C07J1/00
Filed: 1935-09-09
Abstract: 17-Hydroxy-3-keto compounds of the cyclopentanopolyhydrophenanthrene series are prepared by subjecting saturated or unsaturated 3 : 17-dihydroxy compounds of the androstane series to the action of agents capable of transforming a secondary alcohol group into a keto group.  As starting materials there are used both saturated and unsaturated compounds of the androstane series, and particularly those compounds which possess a hydrocarbon radical on position 17, such as alkyl-androstandiols and androstendiols-3-17.  The oxidation may be performed directly on the free diols, especially when the carbon atom 17 is substituted by a hydrocarbon radical, or the 17-hydroxy group may be protected by convertion into a group which on hydrolysis can be re-converted into a hydroxy group such as an ether, ester or halogen group.  In the case of unsaturated starting materials it is preferred to protect the nuclear double bond by the addition of halogen or halogen hydride.  The 17-hydroxy-3-keto compounds may be isolated from the reaction mixture by the usual methods of fractional crystallization, distillation or sublimation. Use may also be made of keto reagents and acylating agents capable of yielding difficultly soluble esters.  Saponines such as digitonine are particularly useful for separation of nonreacted diol compounds. If desired, the 17-derivatives of the 17-hydroxy-3-keto compounds prepared according to the invention may be converted into the free hydroxy compounds or alternatively if the free hydroxy body has been produced it may be subsequently esterified, etherified or halogenated.  In examples: (1) a glacial acetic acid solution of androstendiolmonoacetate-17 is brominated, oxidized with chromium trioxide, and debrominated with sodium iodide to yield an ester which on saponification gives a hydroxy-ketone identical with the natural material extracted from the testicles of bulls; (2) androstendiol-monoacetate-17 brominated and oxidized as in example (1) is debrominated by zinc dust to give on saponification the same keto-alcohol.  Reaction of this keto-alcohol with benzoyl chloride produces the 17-benzoic acid ester which is of particular physiological value; (3) 17-methyl-androstandiol-3-17 is oxidized in glacial acetic acid solution with chromium trioxide at room temperature for 12 hours, to give 17-methyl-androstanol-17-one-3; (4) 17-methyl androstendiol-3-17 is brominated and then oxidized as in example 3.  After debromination with zinc dust, a hydroxy ketone is obtained; (5) 3-hydroxy-17-chlorandrostene is brominated, oxidized, and debrominated as in example (4) to give 17-chlorandrostenone - 3; (6) androstendiol - 3 - 17 is brominated, oxidized and debrominated as in example (4).  The product is then treated with digitonine and the digitonide of the dehydroandrosternone formed in the oxidation is obtained.  This is removed and the residue treated with phthalic acid anhydride to isolate androstenol-17-one-3 (testosterone); (7) isoandrostandiol-mono-acetate-17 obtained from iso-androstandiol-diacetate by partial hydrolysis, is oxidized with chromium trioxide and the androstanol-17-one-3 isolated by its semicarbazide; (8) iso-androstandiol-monoacetate-17-is treated as in example (7) except that use is not made of semicarbazone; (9) iso androstandiol-monobenzoate-17 is treated as in example (8); (10) 17-ethyl-androstendiol-3 : 17 is brominated, oxidized, and debrominated as described in example (4) to give D 5 : 6-17-ethyl-androstenol-17-one-3; (11) D 5 : 6-17-ethyl-androstendiol-3 : 17 is brominated, oxidized and debrominated as described in example (4) to give D 4 : 5-17-ethyl-androstenol-17-one-3; (12) 17-methyl-androstandiol-3 : 17-monoacetate-17 is oxidized with chromium trioxide to 17-methyl-androstanol - 17 - one - 3; (13) androstendiol-monobenzoate-17 is brominated, oxidized and debrominated as described in example (4) to give androstenol-17-one-3-benzoate-17, which on hydrolysis with dilute methyl alcoholic potash gives testosterone; (14) the 17-triphenylmethyl-ether of androstendiol-3-17 is brominated in pyridine solution and chromium trioxide in a small amount of water added.  The reaction proceeds at room temperature for 2 days when it is debrominated with zinc dust to give androstenol-17-one-3.