Patent GB-968206-A (GB)
Title: 17-oxygenated-2-oxa-3-oxosteroids
IPC: C07J73/00
Filed: 1961-05-16
Abstract: The invention comprises lactones of the general formula: <FORM:0968206/C1/1> and the corresponding 4-dehydro and 5-dehydro derivatives, R represents a hydrogen atom or a methyl group and X represents a carbonyl, hydroxymethylene, alkanoyloxymethylene, a -alkyl-b -hydroxymethylene or a -alkyl-b -alkanoyloxymethylene group. Equivalent to the lactones of the general formula are the hydroxy acids with which they are in equilibrium in aqueous solution and the alkali metal salts derived therefrom.  These relationships are illustrated in the formulae: <FORM:0968206/C1/2> wherein R and X have the above significance, M represents an alkali metal and the dotted line represents the optional presence of a double bond. In the case of the presence of D 4-unsaturation, treatment with the base MOH or with acid forms a mixture of the D 4 and D 5 acids and their salts. The D 5-acids can be converted to the D 5-lactones since there is an equilibrium the D 4-dehydrolactones can be obtained by treatment of the 5-dehydrolactones with an acid or base.  The lactones of the first formula above may be prepared by reducing an aldehyde acid of the 1,2-seco-A-nor series or its salt and having the general formula: <FORM:0968206/C1/3> wherein A represents -CH2COOM or =CH-COOM, R represents hydrogen or a methyl group, M represents a hydrogen atom or an ammonium, alkali metal or alkaline earth metal cation, and X has the above significance (a carbonyl group at the 17-positions can be reduced simultaneously with the reduction of the formyl group). The reduction may be effected with conventional reagents suitable for the reduction of formyl radicals to carbinol radicals. Especially useful reducing agents are of the type (alkali metal) YZ3 wherein Y represents boron or aluminium and Z represents a hydrogen atom or an alkoxide group, or alkali metals and alcohols, or magnesium and alcohol, or zinc and hydrochloric acid, or formaldehyde and sodium hydroxide, or catalytic hydrogenation agents such as Raney nickel and the noble metals. When using a noble metal such as palladium-on-charcoal, a starting compound of the above general formula in which A represents =CHCOOM yields a product having a saturated A ring, and when using other reducing agents referred to above a 4-dehydro-2-oxa-3-oxo-steroid type of compound is formed. The lactones of the above general formula may also be prepared by treating 6b , 19-epoxy-5a -androstane-3b , 17b -diol 3, 17-diacetate with methanolic aqueous sodium hydroxide to form the corresponding free 3b , 17b -diol, oxidizing this diol with chromic acid to form 6b , 19-epoxy-5a -androstane-3, 17-dione, brominating this compound and then dehydrobrominating the product by heating with magnesium oxide in dimethylformamide to form 6b , 19-epoxy-5a -androst-1-ene-3, 17-dione, oxidizing this compound and treating the resulting 6b -hydroxy-10-carboxy lactone with methanolic aqueous potassium carbonate to form 6b -hydroxy-5a -ester-1-ene-3,17-dione acetylating this compound to form the corresponding 6-acetate, treating the acetate with osmium tetroxide and lead tetracetate to form 6b -hydroxy-1, 17-dioxo-1, 2-seco-A-nor-5a -estran-2-oic acid 6-acetate, reducing this acetate with sodium borohydride and oxidizing the resulting 6b  - acetoxy - 17b  - hydroxy -2-oxa-5a -estran-3-one with chromic acid forms 6b -hydroxy-2-oxa-5a -estrane-3, 17 - dione 6-acetate, hydrolyzing the 6-acetate with aqueous alkali to form the free 6b -hydroxy-2-oxa-5a -estrane-3, 17-dione, dehydrolizing this compound either with phosphorus oxychloride in pyridine or by forming the 6b -methane sulphonate and then heating with pyridine to form 2-oxaestr-4-ene-3,17-dione and, when required, reducing this compound with sodium borohydride to form 17b -hydroxy-2-oxaestr-4-en-3-one. The corresponding 17a -alkyl-17b -hydroxy-2-oxaestr-4-en-3-one is prepared by a method similar to the previous method using 6b , 19-epoxy-17b -hydroxy-17a -alkyl-5a -androstan-3-one as the starting compound (obtainable by treating 6b , 19-epoxy-5a -androstane-3, 17-dione with methanol in the presence of p-toluenesulphonic acid to form the corresponding 3-dimethyl ketal, and treating the ketal with an alkyl Grignard reagent and then aqueous hydrochloric acid).  A compound of the first general formula above having at the 17-position a b -hydroxy group and a hydrogen atom may be acylated with an alkanoic acid anhydride in pyridine to form the 17b -alkanoates or having an a -alkyl group and a b -hydroxy group are present at the 17-position may be acylated with an isopropenyl-alkanoate to form a 17a -alkyl-17b -alkanoate; a compound of the above general formula having a b -hydroxy group and a hydrogen atom at the 17-position may be oxidized to the corresponding 17-keto compound; and a compound of the above general formula having D 4-unsaturation may be reduced to the corresponding saturated compounds, for example with hydrogen in the presence of a hydrogenation catalyst.  Hydroxy-esters of the general formula: <FORM:0968206/C1/4> wherein R has the above significance and R1 represents a lower alkyl group, are prepared by treating the lactones of the first general formula above with a lower alkanol in the presence of an acid catalyst.  1,2-Seco-A-norsteroids of the general formula: <FORM:0968206/C1/5> wherein R, X and A have the above significance, are prepared by treating the corresponding 1,2-dehydro-3-keto-steroids with osmium tetroxide and lead tetracetate or a similar reagent such as sodium periodate.  This process may be modified in that the 1,2-dehydro-3-keto-steroids are first hydroxylated to form the 1,2-glycol, for example, with osmium tetroxide followed by hydrolysis of the osmate ester, and then treating the 1,2-glycol which may be contain the isomeric 4,5-glycol with lead tetracetate, sodium periodate or similar reagent as above. 17b -Hydroxy-1-oxo-1, 2-seco-A-norandrost-3-en-2-oic acid is prepared by reducing the corresponding 17-oxo compound with lithium tri-(tertiary butoxy) aluminium hydride.