Patent GB-1014656-A (GB)
Title: New oxido-steroids and a process for their manufacture
IPC: C07J75/00
Filed: 1962-09-24
Abstract: The invention comprises 4b ,19-oxido-steroids of the partial formula <FORM:1014656/C2/1> (wherein R1 is two hydrogen atoms, a hydrogen atom together with a free, esterified or etherified hydroxyl group, or a free or ketalized oxo group, and R2 is a hydrogen or halogen atom or a free, esterified or etherified hydroxyl group, or R1 and R2 together represent a 3-hydrogen atom and the bivalent radical of a dibasic mineral acid, of carbonic acid or of an alkylene diol of at most 7 carbon atoms; and X is two hydrogen atoms, a hydrogen together with a free or esterified hydroxyl group, or an oxo group) and the preparation thereof by treating a 4b -hydroxy-steroid of the partial formula <FORM:1014656/C2/2> (wherein R1 and R2 have the above meanings except for free hydroxyl groups and a free keto group) with a compound capable of generating monovalent positive iodine and, if desired, oxidizing a resulting 19-unsubstituted or free or esterified 19-hydroxy-steroid to the 4b ,19-lactone of a 4b -hydroxy-19-acid, and/or, if desired, hydrolysing any acyloxy group present, and/or, if desired, oxidizing any hydroxyl group to an oxo group.  The steroids may be of the androstane, pregnane, cholane, cholestane, stigmastane, spirostane or cardanolide series and may contain free, ketalized or enolized oxo groups, esterified or etherified hydroxyl groups, alkyl, alkenyl or alkynyl groups and/or halogen atoms in the nucleus or 17-side chain, or double bonds or oxido groups, e.g. in positions 9 (11) or 16 (17).  Iodine containing reagents are N-iodo-carboxylic acid amides or imides, iodine halides, alkyl hypoiodites prepared, for example, from iodine and alcohols with heavy metal oxides, and acyl hypoiodites, prepared, for example, from iodine and heavy metal salts of carboxylic acids, e.g. iodine and lead tetraacylates. The 4b ,19-oxido-steroids obtained contain as a rule one of the aforesaid substituents in the 19-position, but under certain conditions. 19-Iodo-compounds are formed, which are then partially converted into 19-hydroxy and 19-acyloxy compounds or which may be converted into 19-unsubstituted 4b ,19-oxido-steroids by treatment with bases, and there on drastic oxidation yield 4b ,19-lactones of 4b -hydroxy-steroid 19-acids.  Other transformations which may be effected in the products of the present process are as follows: 5a -halogeno-4b ,19-oxido -17-oxo-androstanes may be reacted with hydrocarbon metal compounds to give the corresponding 17b -hydroxy-17a -hydrocarbyl compounds; a 17a - and/or 21-hydroxyl group may be introduced into a 4b ,19-oxido-20-oxo-pregnane by known methods, e.g. by enol-acetylation to form the D 17(20)-20-acetate followed by peroxidation and hydrolysis to the 17a -hydroxy-20-ketone; 4b ,19-oxides containing no halogen in position 5 may be opened hydrolytically or acylolytically, e.g. with an acylating agent in the presence of an acid catalyst to give 4b ,19-diacyloxy compounds or D 4-19-acyloxy steroids; 4b ,19-oxides may be converted into 4a ,halogeno-19-acyloxy-steroids with acid halides, and the products may be converted into 4-unsubstituted D 4-compounds, particularly the 3-oxo compounds formed by hydrolysis and oxidation of 3-acyloxy compounds or by reaction of 3-unsubstituted D 4-19-hydroxy-steroids with chromium trioxide in glacial acetic acid or acetone and sulphuric acid; 5a -halogeno-4b ,19-oxides may be opened under reducing conditions, e.g. with metals and liquid ammonia or amines or with zinc in alcohol or an acid, to give D 4-19-hydroxy-steroids, and, similarly, the 19-hydroxy-compounds and 4b ,19-lactones give D 4-19-oxo-steroids or D 4-steroid-19-acids, and the latter may be esterified or decarboxylated to D 5(10)-19-nor-steroids; 4b ,19-oxido-19-hydroxy-steroids unsubstituted in positions 3 and 5 may be reacted with hydroxylamine to give 4b -hydroxy-19-oximino-steroids, and these on dehydration yield D 4 - 10b  - cyano - 19 - nor - steroids, which with sodium in alcohol give 3-unsubstituted-D 5(10) - 19 - nor - steroids.  Examples are given, a by-product in one process being the anhydro product formed from 2 molecules of 4b ,19-oxido -17b  - propionyloxy - 19 - hydroxy - androstane.  4b  - Hydroxy - 5a  - androstane starting materials and the corresponding 4-oxo-compounds, from which they are prepared and into which they may be oxidized in the process of the invention, which are stated also to be new compounds, are prepared, for example, from 3-unsubstituted D 4-androstenes by nitration and reduction of the resulting D 4-4-nitro-androstenes, or by epoxidation of the D 4-double bond and isomerization of the resulting epoxide in the 4-ketone; or from D 4-3-oxo-androstenes by epoxidation and hydrolysis to D 4-3-oxo-4-hydroxy -androstenes, the 3-thioketals of which on desulphurization give 3,4-dioxo-androstane compounds.  4b  - Hydroxy - 5a  - halogen - steroids are prepared by addition of hypohalogenous acid to the corresponding D 4-compounds.  D 4 - 3b ,17b  - diacetoxy - androstene is prepared by acetylation of the corresponding diol.  D 4 - 17b  - Propionyloxy - androstene is prepared by reacting testosterone propionate with ethylenedithioglycol to give the 3-ethylenethioketal of testosterone propionate, and refluxing this with Raney nickel in dioxan.  D 4-20b -acetoxypregnene is prepared similarly.  4b ,17b ,19-Trihydroxy-5a -androstane is prepared by lithium aluminium hydride reduction of the 4b ,19-lactone of 4b -hydroxy-17b -propionyloxy - 5a  - androstane - 19 - acid, and on reaction with propionic acid and concentrated sulphuric acid at 20 DEG  C. gives 4b ,19-oxido-17b -propionyloxy -5a -androstane.  D 4 - 17b ,19 - Dihydroxy - androstene is prepared by lithium aluminium hydride reduction of D 4 - 19 - acetoxy - 17b  - propionyloxy - androstene, and on oxidation yields D 4-17-oxo-androstene-19-acid.  D 4-17-Oxo-androstene is prepared by oxidation of D 4-17b -hydroxy-androstene, prepared in turn by hydrolysis of the 17-propionate.