Patent GB-789065-A (GB)
Title: 17-alkyl-19-nortestosterones and their preparation
IPC: C07J75/00
Filed: 1955-08-25
Abstract: The invention comprises compounds of the formula <FORM:0789065/IV (b)/1> wherein R is alkyl containing 2-8 carbon atoms and a process for their preparation by isomerizing the corresponding 3-oxo-17a -alkyl-5(10)-estren-17-ol using an acidic or basic isomerization agent, e.g. hydrochloric acid, p-toluene sulphonic acid, or sodium hydroxide in aqueous methanol.  The 5(10)-estrenol compound is obtained (normally without isolation) by strong acid hydrolysis of the corresponding 3 - alkoxy - 2,5(10) - estradien - 17 - ol, which in turn is prepared by a Birch reduction of 17a -alkylestradiol 3-monoalkyl ether with lithium and ammonia followed by mild acid hydrolysis.  Alternative methods of preparation of the 19-nortestosterone derivatives are described: (a) by hydrogenation of the corresponding 17a -unsaturated hydrocarbon derivatives which may be of olefinic or acetylenic type, and which are themselves obtained by the addition of an acetylene or an organic metallic compound to the steroidal 17-ketone; (b) by acid cleavage in an hydroxylic medium of a nuclearly unsaturated derivative of 17a  - alkyl - 19 - norandrostan - 17b  - ol containing in position 3 a group convertible to keto by such treatment, e.g. alkoxyl, alkylthio, benzylthio, ethylenedioxy, ethylenedithio, ethylenethio-oxy and N-pyrrolidyl. The hydrolysis is effected with mineral or organic acids or with mixtures of compounds which generate acid, e.g. a mixture of acetone, cadmium carbonate and mercuric chloride.  In examples: (1) 3 - methoxy - 13 - methyl - 17b  - ethynyl - 1,4,6,7,8,9,11,12,13,14,16,17 - dodecahydro - 15H - cyclopenta[a]phenanthrene - 17 - ol is refluxed with aqueous-methanolic HCl, 17-ethynyl-19-nortestosterone then precipitated by dilution of the mixture, and hydrogenated in dioxan over palladium charcoal to yield 17-ethyl-19-nortestosterone; (2) estrone methyl ether is treated with allyl magnesium bromide and the resulting 17a -allyl-3-methoxy-1,3,5(10)-estratrien-17-ol hydrogenated in ethanol over palladium charcoal to 17a -propyl-3-methoxy-1,3,5(10)-estratrien-17-ol, which is then treated with lithium in liquid ammonia and the resulting 17# - propyl - 3 - methoxy - 2,5(10) - estradien-17-ol refluxed with aqueous-methanolic HCl, yielding 17 - propyl - 19 - nortestosterone; (3) and (4) as in (2), but using butyl and octyl lithium respectively as the organo-metal reagent and omitting the hydrogenation, when 17-butyl- and 17-octyl-19-nortestosterone are obtained; (5) 17a -ethynyl-3-methoxy-1,3,5(10)-estratrien-17-ol is hydrogenated to the corresponding 17-ethyl compound, reduced with lithium to the 2,5(10)-estradien-ol, refluxed with acetic acid and methanol giving 17a -ethyl-3-oxo-5(10)-estren-17-ol and hydrolysed to 17-ethyl-19-nortestosterone, also prepared (6) from the corresponding 3-ethoxyestratrienol; (7) 17-allyl-19-nortestosterone is hydrogenated to 17-propyl-19-nortestosterone; (8) 17-ethynyl19-nortestosterone is hydrogenated using palladium-calcium carbonate to the 17-vinyl analogue and then using palladium-charcoal to the 17-ethyl derivative; (9) as in (2), using 1-octyne and potassium in tert.-amyl alcohol as the organo-metal reagent, giving 17-octyl-19-nortestosterone; (10) 3-ethoxy-19-nor-3,5-androstadien-17-one is treated with ethyl or propyl magnesium bromide and the product hydrolysed with HCl giving 17-ethyl- or propyl-19-nortestosterone; (11) 19-nor-4-androstene-3,17-dione is converted to a 3-N-pyrrolidyl-19-norandrostadien-17-one which is treated with ethyl magnesium bromide and then hydrolysed to 17-ethyl - 19 - nortestosterone; (12) 19 - nortestosterone is converted to its ethylene ketal, which is oxidized with chromic acid and the resulting 17-one reacted with ethyl magnesium bromide and hydrolysed as in (11); (13) and (14) as in (11), protecting the 3-keto group by reaction with 2-methyl-2-ethyl-1,3-dioxolane and b -mercaptoethanol respectively.  Specification 789,066, and U.S.A.  Specifications 2,655,518, 2,666,769, 2,691,028, 2,702,811 and 2,704,768 are referred to.