Patent GB-888165-A (GB)
Title: Improvements in or relating to 4-methyl-3-oxo-í~-steroids
Inventor: KIRK DAVID NEVILLE
IPC: C07J1/00
Filed: 1958-11-19
Abstract: The invention comprises (1) a process for the preparation of 4-methyl-3-oxo-D 4-steroids by reacting a 4-organo-thiomethyl-3-oxo-D 4-steroid with a reducing agent; and (2) as new steroids, 2a  : 4- and 4 : 6a -dimethyltestosterones and their acyl esters; 17a -acetoxy-4 : 6a -dimethylprogesterone; 4 : 16a -dimethylprogesterone; 4-methyl-17a  - acetoxy - 16 - methylene - progesterone; 4 : 17a -dimethyl-9a -fluoro-11b  : 17b -dihydroxyandrost-4-en-3-one; 4-methyl-11a - and -11b -hydroxy - 17b  - hydroxyandrost - 4 - en - 3 - ones; 4-methylandrost-4-ene-3 : 11 : 17-trione; and 11b -hydroxy-17a  : 20 : 20 : 21-bis-methylenedioxy - 4 - methylpregn - 4 - en - 3 - one.  The preferred reducing agent is Raney nickel, which is desirably deactivated by a preliminary heating in a ketonic solvent, the organothiomethyl steroid then being added to the resulting suspension.  Alternatively, zinc dust and an alkali metal hydroxide may be used as reducing agent. Readily oxidizable hydroxy groups may be protected prior to the desulphurization reaction by esterification, and subsequently regenerated by hydrolysis; and a 17-ketol side-chain may be protected by 20-ketalization or conversion of the side-chain into the bis-methylenedioxy derivative, the protecting groups subsequently being removed.  The process may be applied to any of the organothiomethyl steroids described in Specification 862,621. In examples the preparation of all the above-mentioned steroids and of 4-methyl-testosterone acetate and other esters, 4 : 17a -dimethyl-testosterone, 17a -ethyl-4-methyltestosterone, 4-methyl- and 4 : 6a -dimethylandrost-4-ene-3 : 17-diones, 4-methyl-progesterone, 4-methylpregna-4 : 9(11)-diene-3 : 20-dione, 17a -acetoxy-4-methylprogesterone and other esters, 17a  : 20 : 20 : 21-bismethylenedioxy-4-methylpregna-4-ene-3 : 11-dione, 4-methyl-25D - spirost - 4 - en - 3 - one, 17b  - acetoxy - 4 - methylandrosta-4 : 6-dien-3-one, 4-methyl-D-homotestosterone acetate, 4 : 6-dimethyl-androsta-4 : 6-diene-3 : 17-dione, 4-methyl-cholest-4-en-3-one, 4-methyl-stigmasta-4 : 22-dien-3-one, 4-methylergosta-4 : 7 : 22-trien-3-one, methyl 3-oxo-4-methylchol-4-en-24-oate, 4 : 7b -dimethyltestosterone acetate, 4-methyl-16a  : 17a -dimethylmethylenedioxy-progesterone, 4-methypregna-4 : 11-diene-3 : 20-dione, 4-methyl- and 1 : 4-dimethyl-19-nor-testosterone acetates, 9a -fluoro-17a  : 20 : 20 : 21-bis methylenedioxy-4-methylpregn-4-ene-3 : 11-dione, 4 : 14a -dimethyl-17a  : 20 : 20 : 21-bismethylenedioxypregn-4-ene-3 : 11-dione, 4 : 14a -dimethylcortisone acetate, 20#x-acetoxy-4-methylpregn-4-en-3-one, 21-acetoxy-4-methylpregna-4 : 17(20)-dien-3-one, 3-oxo-4-methylpregna-4 : 17(20)-dien-21-oic acid and its ethyl ester, 14a -hydroxy-4-methylprogesterone, 17a  : 20 : 20 : 21-bismethylenedioxy-4-methylpregna-4 : 14-diene-3 : 11-dione, 11b -hydroxy-4 : 11a -dimethyltestosterone-17-acetate, 20 : 20-ethylenedioxy - 4 - methylpregn - 4 - en - 3 - one, 11a  - hydroxy - 4 - methyl - progesterone, 4 - methyl-pregn-4-ene-3 : 11 : 20-trione, 16a  : 17b -diacetoxy-4-methylandrost-4-en-3-one, 16a  : 17a -benzylidenedioxy-4-methylprogesterone, 20 : 20-ethylenedioxy - 17a  - hydroxy - 4 - methylpregn - 4-en-3-one, 4 : 7 : 7-trimethylcholest-4-en-3-one and 21-acetoxy-20 : 20-ethylenedioxy-4-methylpregn-4-en-3-one by the process of the invention is described.  The hydrolysis of the last named compound to the 21-hydroxy compound and then to 21-hydroxy-4-methylpregn-4-ene-3 : 20-dione. and the reacetylation of this also is described, as is the hydrolysis of many of the other acyloxy and alkylenedioxy products.  4-Phenylthiomethyltestosterone b -phenyl propionate, phenoxyacetate and p-chlorophenoxyacetate are all prepared from the free ol and the appropriate acid chloride.  The Provisional Specification refers also to reduction with Raney cobalt and to the preparation of 6a -fluoro-4-methyl-testosterone acetate, 16a  : 17a -dihydroxy - 4 - methyl - progesterone and 11a -acetoxy-4-methylprogesterone.