Patent GB-948268-A (GB)
Title: Improvements in or relating to 11, 18-epoxy steroid compounds
IPC: C07J71/00
Filed: 1960-08-23
Abstract: The invention comprises steroids of the general formula: <FORM:0948268/C2/1> wherein Y represents ethylene or vinylene, the values of Y being chosen so that the ring containing Y is 5a - or 5b - saturated or D 4- or D 1,4-unsaturated; R4 represents keto, R5 represents hydrogen, methyl, chloro or fluoro; R6 represents hydrogen or methyl; R7 represents methyl or, when at least one Y is ethylene, hydrogen; R8 represents hydrogen, chloro, bromo, or fluoro; and R9 represents a group of the formula <FORM:0948268/C2/2> or <FORM:0948268/C2/3> in which Ac represents alkanoyl containing 2 to 7 carbon atoms; the preparation of the pregnanes and allopregnanes of the first general formula above by treating 18-quaternary-amino-steroids of premane or allopregnane series having the general formula: <FORM:0948268/C2/4> with an alkaline reagent such as an alkali metal alkoxide, amide, hydride or hydroxide, in a polar strongly ionising solvent such as the simple liquid formamides and acetamides and the N-alkyl derivatives thereof, acetonitrile and lower alkyl alcohols, to form steroids of the general formula: <FORM:0948268/C2/5> (in these formulae R1, R2 and R3 represent alkyl groups containing 1 to 4 carbon atoms, R4 represents a hydroxy, acyloxy or keto group-an acyloxy group is usually hydrolysed by the alkaline treatment, R5 represents hydrogen, chlorine, fluorine or a methyl group, R6 and R7 each represent hydrogen or a methyl group and R8 represents hydrogen, chlorine, bromine or fluorine, and X represents an anion, oxidising the steroids of the previous general formula (this step is only necessary when R4 represents a hydroxy or acyloxy group), oxygenating the resulting steroids of the general formula: <FORM:0948268/C2/6> to form desired pregnanes or allopregnanes of the general formula: <FORM:0948268/C2/7> wherein R5, R6, R7 and R8 have the above significance, with osmium tetroxide, with osmium tetroxide and organic iodose compounds, with potassium permanganate and pyridine or with osmium tetroxide and potassium perchlorate and, if necessary, decomposing an osmate ester formed, diacylating the steroids of the previous general formula to form the desired 20, 21 - diacyloxy-pregnanes or allopregnanes of the general formula: <FORM:0948268/C2/8> wherein R5, R6, R7 and R8 have the above significance (the desired 21-monoacyloxy-20-hydroxy-pregnanes or allopregnanes are obtained by using about one equivalent of the acylating agent and may then be oxidised to the corresponding desired 21-acyloxy -20- keto-pregnanes or allopregnanes and hydrolysed to the corresponding desired 21-hydroxy -20- keto-pregnanes or allopregnanes); the preparation of the D  4-steroids of the first general formula above by brominating the 20, 21-diacyloxy pregnanes or allopregnanes to form the corresponding 2, 4-dibromo 21-diacyloxy-steroids (in the allopregnane series) or the corresponding 4-bromo-20, 21-diacyloxy steroids (in the pregnane series), dehydrobrominating the bromo-steroids by consecutive reaction with sodium iodide and hydriodic acid or with collidine to form desired D  4-steroids of the general formula: <FORM:0948268/C2/9> hydrolysing these steroids to form desired D 4-steroids of the general formula: <FORM:0948268/C2/100> wherein R5, R6, R7 and R8 have the above significance and Y represents ethylene, 21-monoacylating the steroids of the previous general formula, oxidising the resulting desired 20-hydroxy -21-acyloxy D  4-steroids to form the corresponding desired 20-keto-21-acyloxy D 4-steroids, and hydrolysing the 20-keto -21-acyloxy-steroids to form the corresponding desired 20-keto -21-hydroxy D  4-steroids; and the preparation of the D  1,4-steroids of the first general formula above by dehydrohalogenating the 2, 4-dibromo-20, 21-diacyloxy-steroids of the allopregnane series referred to above using an excess of collidine or by treating the saturated 20, 21-diacyloxy steroids of the sixth general formula above with selenium dioxide in acetic acid-t-butanol to form desired D  1,4-steroids corresponding to the D 4-steroids of the seventh general formula above (the D 1,4-19-nor-compounds cannot be prepared because of aromatisation), hydrolysing these steroids to form desired D  1,4-steroids corresponding to the D  4-steroids of the previous general formula and 21-monoacylating, oxidising the resulting desired 20-hydroxy-21-acyloxy-D  1,4-steroids to form the corresponding desired 20-keto-21-acyloxy- D  1,4-steroids, and hydrolysing the 20-keto-21-acyloxy-steroids to form the corresponding desired 20-keto-21-hydroxy- D  1,4-steroids.  18-Quaternary - amino - steroids of the second general formula above wherein R1 to R8 and X have the above significance are prepared by the method described in Specification 933,156.  3b , 11b -Dihydroxy-conanine is prepared by reducing 3b -acetoxy-11-keto-conanine with lithium aluminium hydride. 3b , 11b -Dihydroxy -6a - fluoro - conanine is prepared by reducing 3b -hydroxy-6a -fluoro-11-keto-conanine with lithium aluminium hydride.