Patent GB-768648-A (GB)
Title: Cyclopentanopolyhydrophenanthrene compounds
IPC: C07J75/00
Filed: 1952-08-01
Abstract: The invention comprises D 8(9)-7-keto-11-hydroxy-cyclopentanophenanthrene compounds having at rings B and C the formula <FORM:0768648/IV(b)/1> and the preparation thereof by hydrolysing a D 7 - 7 - acyloxy - 9,11 - epoxy - cyclopentanophenanthrene compound having at rings B and C the formula <FORM:0768648/IV(b)/2> wherein R1 represents an acyloxy radical.  The process may be extended in that the resulting 7-keto-11-hydroxy compound may be acylated to form a 7-keto-11-acyloxy compound or may be oxidized, e.g. with chromic acid, to form a 7,11-diketo compound. The above process may be modified in that the D 7-7-acyloxy-9,11-epoxy - cyclopentanophenanthrene reactant is obtained by acylating a D 8(9)- or a D 9(11)-7-keto-cyclopentanophenanthrene compound or a mixture of such compounds to produce a D 7,9(11) - 7 - acyloxy - cyclopentanophenanthrene compound which is then treated with an organic per-acid.  The hydrolysis of the 9,11-epoxy compound may be carried out with an alcoholic solution of an alkali metal hydroxide such as methanolic sodium or potassium hydroxide or ethanolic potassium hydroxide, in which case other hydrolysable substituents present are also hydrolysed, or may be carried out with a mild hydrolysing agent whereby other hydrolysable substituents, e.g. other ester substituents such as a 3-acyloxy group, are not affected.  In the latter case, suitable mild hydrolysing agents are water, or an aqueous solution of a water-miscible solvent such as an aqueous solution of acetone or an aqueous solution of a lower aliphatic alcohol, particularly methanol or ethanol. D 8(9)-7-Keto-11-hydroxycyclopentanophenanthrene compounds obtainable by the above process are D 8(9),22-7-keto-11 - hydroxy - ergostadiene, D 8(9) - 7 - keto - 11-hydroxy-substituted cholestene and dehydrotigogenin, D 8(9),22 - 3,11 - dihydroxy - 7 - keto - substituted ergostadiene and stigmastadiene, and D 8(9) - 3,11 - dihydroxy - 7 - keto - substituted cholenic, allocholenic, bisnorcholenic, bisnorallocholenic, etiocholenic and etioallocholenic acids, pregnene and allopregnene.  The 3-acyloxy - 7 - keto - 11 - hydroxy -, 11 - acyloxy - 7 - keto -, 3,11 - diacyloxy - 7 - keto -, 7,11 - diketo-and 3 - acyloxy - 7,11 - diketo compounds corresponding to the D 8(9)-7-keto-11-hydroxy compounds detailed above are obtainable using the processes referred to above, the specific compounds mentioned having an acetoxy group in the 11-position or acetoxy groups in the 3-and 11 - positions.  The D 7 - 7 - acyloxy - 9,11 - epoxy compounds from which the above specific 7-keto-11-hydroxy compounds may be obtained are also detailed.  A number of detailed examples are given illustrating the above processes, and, in addition, D 8(9),22 - 3,11 - dihydroxy - 7 - keto - ergostadiene is prepared by hydrolysing D 8(9),22 - 3 - acetoxy - 7 - keto - 11 - hydroxy - ergostadiene with methanolic sodium hydroxide, and D 8(9) - 7 - keto - 11 - hydroxy-dehydrotigogenin is prepared from D 8(9) - 7 - keto - 11 - hydroxy - dehydrotigigenin acetate by a similar method.  Derivatives of the above D 8(9)-7-keto-11-hydroxy - cyclopentanophenanthrene compounds. Cortisone acetate is obtained by the following synthesis in which the first step involves treating a D 8(9)-3, 11-dihydroxy-7-keto-cyclopentanopolyhydrophenanthrene compound with zinc and acetic acid to form the corresponding 3,11 - dihydroxy - 7 - keto - cyclopentanonehydrophenanthrene compound, which is heated with a diethylene glycol solution of hydrazine and potassium hydroxide to form the corresponding 3,11 - dihydroxy - cyclopentanonehydrophenanthrene compound.  The next step involves the conversion of the organic substituent attached to the 20-carbon atom to a keto radical to form a 3,11 - dihydroxy - 20 - keto pregnane, the method of treatment depends upon the side chain attached to the 17-carbon atom, e.g. in the case of 3,11-dihydroxy-bisnorallocholanic acid, the acid is esterified to form methyl 3,11-dihydroxy - bisnorallocholanate, reaction with phenyl magnesium iodide then forms 3,11-dihydroxy - 20 - allopregnanyl - diphenyl carbinol, reaction with acetic anhydride forms 3,11-diacetoxy - alloetiocholanyl - methyl - diphenyl - ethylene which on treatment with ozone forms 3,11 - diacetoxy - 20 - keto - allopregnane.  This 20-keto-compound is reacted with acetic anhydride in the presence of p-toluene-sulphonic acid to form D 17-3,11,20-triacetoxy-pregnene, treatment with perbenzoic acid forms 3,11-diacetoxy - 17 - hydroxy - 20 - keto - allopregnane, treatment with bromine followed by sodium acetate forms 3,11,21-triacetoxy-17-hydroxy-20-keto-allopregnane which is then hydrolysed and partially esterified to form 3,11,17-trihydroxy-20-keto-21-acetoxy-allopregnane.  This 21-acetoxy compound is then reacted with chromic acid to form 3,11,20-triketo-17-hydroxy-21-acetoxyallopregnane, treatment with two molecular equivalents of bromine followed by rearrangement forms 2,4 - dibromo - 3,11,20 - triketo - 17 - hydroxy - 21 - acetoxy - allopregnane which is then treated with a dehydrohalogenating agent and a reducing agent to form the required cortisone acetate.