Patent GB-928411-A (GB)
Title: 17ª -substituted steroids and process for their manufacture
IPC: C07J75/00
Filed: 1959-11-20
Abstract: The invention comprises steroids of the formula <FORM:0928411/IV(a)/1> and their 1,2-dehydro analogues (wherein X is H, F, Cl or Br and Y is O or (H, OH), or X and Y together represent a 9b ,11b -oxido group; and R is alkyl or 1-alkynyl); and their preparation by alkylating or alkynylating, by means of a metal organic reaction, if desired after protection of the 3-keto group, a corresponding 17-keto androstane compound and, as necessary to obtain the desired end product, submitting the thus obtained 17a -substituted-17b -hydroxy compound in any order of succession to D 1-dehydrogenation, hydrolysis of the protecting group in the 3-position, oxidation of the 11-hydroxy group to 11-keto and/or hydrohalogenation of the 9b ,11b -oxido group to 9a -halo-11b -hydroxy substituents.  Dehydrogenation may be effected with an organism such as Cornynebacterium simplex or chemically, e.g. using chloranil or selenium dioxide.  The metal organic reaction may be conducted wth an alkyl alkali metal, e.g. an alkyl lithium, or a Grignard reagent, or with alkyl metal alkynylides, the keto group being protected for example by conversion to a ketal, an enol ether or a pyrrolidyl enamine.  In examples (1) 9b ,11b -oxido-16a -methyl-4-pregnene-17a 21-diol-3,20-dione (obtained by hydrolysis of the corresponding 21-acetate) is reacted with sodium bismuthate to give 9b ,11b -oxido- 16a -methyl- 4-androstene-3,17-dione, this is converted to 3-pyrrolidino-9b ,11b -oxido- 16a -methyl-3,5-androstadien-17-one, this with methyl magnesium iodide and hydrolysis gives 9b ,11b -oxido- 16a ,17a -dimethyl-4-androsten-17b -ol-3-one, and this with hydrogen fluoride gives 9a -fluoro-11b -hydroxy-16a ,17a -dimethyl-testosterone; (2) the final product of (1) is oxidized to the 11-ketone; (3)-(5) the oxido product of (1) is converted to the 9a -chloro-11b -hydroxy- and 9a -bromo-11b -hydroxy-compounds and the latter is oxidized to the 11-ketone; and reference is also made to similar oxidation of the corresponding 16b -methyl compound; (6) 16a -ethyl-hydrocortisone is converted to the 21-acetate, this is dehydrated to the corresponding 4,9(11)-pregnadiene, this is brominated to give 9a -bromo-16a -ethyl-hydrocortisone 21-acetate, this is converted to 9b ,11b -oxido-16a -ethyl- 4-pregnene- 17a ,21-diol-3,20-dione, this with sodium bismuthate gives 9b ,11b -oxido- 16a -ethyl- 4-androstene- 3,17-dione, this is converted to 3-pyrrolidino-9b ,11b -oxido- 16a -ethyl-3,5-androstadiene-17-one, and this by the method of (1) gives 9b ,11b -oxido- 16a -ethyl-17a - methyl-4-androsten-17b -ol-3-one; (7) the product of (6) is converted to the 9a -fluoro-11b -hydroxy-compound and this is dehydrogenated to the D 1,4-compound; (8) ethyl magnesium iodide replaces the methyl compound of (1) to give the appropriate 17a -ethyl compound (the corresponding 16b -methyl compound is prepared similar) and this and the 16b -methyl compound are converted to the corresponding 9a -chloro- 11b -hydroxy-compounds; (9) the final products of (8) are oxidized to the corresponding 11-ketones; (10) 16a -methyl-17a ,21-dihydroxy- 4-pregnene- 3,20-dione is converted to 16a -methyl- 4-androstene-3,17-dione, this to 3-pyrrolidino-16a -methyl-3,5-androstadien-17-one, this with methyl magnesium iodide gives 16a ,17a -dimethyltestosterone, this with the organism Rhizopus nigricans gives 11a -hydroxy-16a ,17a -dimethyltestosterone, this is converted to the 11-tosylate, this to 16a ,17a -dimethyl-4,9(11)-androstadien-17b -ol-3-one, and this to the 9a -bromo-11b -hydroxy-compound; (11) the product of (10) is converted to 9b ,11b -oxido-16a ,17a -dimethyl-testosterone, and this to the 9a -fluoro- 11b -hydroxy-compound; (12) the enamine of (1) or the corresponding D 4-3-ketone is converted to 16a -methyl-17a -ethynyl-9b , 11b -oxido- 4-androsten- 17b -ol-3-one, and the corresponding 16b -methyl compound is prepared similarly; (13) 16a -methyl-hydrocortisone is reacted with sodium bismuthate to give 16a -methyl-4-androsten-11b -ol-3,17-dione and this is converted to 16a -methyl-17a -ethynyl-4-androstene- 11b -17b -diol-3-one, and the corresponding 16b -methyl compound and the 11-ketones corresponding to these products are prepared similarly; (14) 16a -methyl-prednisolone 21-acetate by the methods of (1) and (12) gives 16a -methyl-17a -ethynyl- 9b ,11b -oxido- 1, 4-androstadien-17b -ol-3-one, and the 16b -methyl compound is prepared similarly (or they may be prepared by D 1-dehydrogenation procedures); and 9a -bromo-16a -methyl-hydrocortisone 21-acetate is dehydrogenated to 9a -bromo-16a -methyl-prednisolone 21-acetate which, by the methods of (1) and (12) is converted to 16a -methyl-17a -ethynyl- 9b ,11b -oxido- 1, 4-androstadien-17b -ol-3-one; (15) and (16) some of the products of (12) and (14) are converted to the corresponding 9a -fluoro-11b -hydroxy-compounds and thence to the corresponding 11-ketones, and these may also be prepared by D 1-dehydrogenation of the corresponding D 4-compounds; and reference is also made to the oxidation of other previously described 11-ols to the corresponding 11-ketones; (17) 16b -n-butyl-cortisone with sodium bismuthate gives 16b -n-butyl-4-androstene-3,11,17-trione, and this is converted to the corresponding 17a -ethynyl-17b -ol and this to the corresponding D 1,4-compound, which may also be prepared by dehydrogenating 16b -n-butyl-cortisone to give 16b -n-butyl-prednisone, oxidizing this to 16b -n-butyl-1,4-androstadiene-3,11,17-trione and reacting this with acetylene; and (18) to (23) further steroids of the invention are prepared by similar processes.  The 11-keto and 11b -hydroxy-steroids of the invention, some of which are stated to possess anabolic and androgenic activity and others of which are stated to possess antiinflammatory and anti-anabolic activity, may be formulated as pharmaceutical compositions, e.g. tablets, solutions or elixirs, with suitable carriers.  Specifications 807,227, 901,092, and 923,904 are referred to.