Patent GB-764321-A (GB)
Title: Processes for preparing compounds of the cyclopentanopolyhydrophenanthrene series
IPC: C07J75/00
Filed: 1952-03-03
Abstract: A process for the preparation of a monoepoxide of a cyclopentanopolyhydrophenanthrene compounds comprises reacting a D 7,9(11)-cyclopentanopolyhydrophanthrene compound containing the structure <FORM:0764321/IV(b)/1> with an organic peroxide.  The process may be extended to any stage of the following synthesis: the monoepoxide prepared as above is catalytically rearranged with an acid activated solid inorganic adsorbent to form a D 8(9)-7,11-dihydroxy - cyclopentanopolyhydrophenanthrene compound which contains the structure <FORM:0764321/IV(b)/2> the 7,11-dihydroxy compound is oxidized with chromic acid to form a D 8(9)-7,11-diketo-cyclopentanopolyhydrophenanthrene compound which contains the structure <FORM:0764321/IV(b)/3> the D 8(9)-unsaturated bond is saturated by hydrogen formed in situ by the reaction of a metal and an acid, and the 7-keto radical is reduced by means of hydrazine hydrate and an alkali metal hydroxide in an inert high boiling organic solvent at an elevated temperature to form an 11-keto-cyclopentanopolyhydrophenanthrene compound which contains the structure <FORM:0764321/IV(b)/4> The monoepoxide may be a compound having the structure <FORM:0764321/IV(b)/5> or the structure <FORM:0764321/IV(b)/6> or may be a mixture of compounds containing both these structures. Suitable organic peracids which may be used to form the monoepoxide are perbenzoic, perphthalic, performic and peracetic acid.  This reaction is preferably carried out at room temperature or at lower temperatures with a solution or suspension of the starting cyclopentanopolyhydrophenanthrene compound in an inert solvent, e.g. benzene, toluene, xylene, petroleum hydrocarbon or ether.  The monoepoxide product can be recovered by extracting the acidic by-products of the reaction with an aqueous solution of alkali and evaporating the resulting solution to dryness.  The reaction to form the D 8(9)-7,11 -dihydroxy compound is preferably carried out by reacting the epoxide and the adsorbent material in an inert solvent such as benzene or ether, e.g. by passing a solution of the epoxide through a chromatographic column containing the adsorbent, or by mixing the solution and adsorbent, the resulting D 8(9)-7,11-dihydroxy compound may be recovered by eluting the adsorbent material with a non-polar solvent such as petroleum ether, benzene or ethyl ether to remove impurities and then with a polar solvent such as a lower aliphatic alcohol or a mixture of a lower aliphatic alcohol and a non-polar solvent such as methanol or mixtures of chloroform and methanol. Suitable acid activated solid inorganic adsorbents are acid washed silica or acid washed alumina. The oxidation step to form the D 8(9) - 7,11 - diketo - cyclopentanopolyhydro - phenanthrene compounds from the corresponding 7,11-dihydroxy compounds may be carried out with chromic acid in the presence of an acid such as acetic or sulphuric acid or with chromic acid in the presence of acetone and sulphuric acid.  In this step it is preferable to protect any other hydroxyl groups present, e.g. a 3-hydroxy group, by conversion to acyloxy groups which may be hydrolysed back to hydroxyl groups after the oxidation.  The reduction of the D 8(9) double bond of the D 8(9)-7,11-diketo-cyclopentanopolyhydrophenanthrene compound is preferably carried out with zinc and an acid such as acetic acid. The 7-keto group of the resulting 7,11-diketo compound with hydrazine hydrate and an alkali metal hydroxide at an elevated temperature in a high boiling inert organic solvent is preferably carried out in diethylene glycol.  Suitable D 7,9(11)-cyclopentanopolyhydrophenanthrene reactants for the epoxide formation are ergosterol D and acyl derivatives thereof, 3-hydroxy (and acyloxy)-D 79(11)-bisnorallocholadienic acid and esters thereof, 3 - hydroxy (and acyloxy) - D 7(9)(11)-choladienic acid and esters thereof, D 7,9(11)-bisdehydrotigogenin and acyl derivatives thereof, D 7,9(11) - pregnadiene - 3 - ol - 20 - one - 3 - acetate, and D 7,9(11)-allopregnadiene - 3 - ol - 20-one and acyl derivatives thereof, and the epoxide derivatives of these D 7,9(11)-compounds may be converted to the corresponding D 8(9)-7,11-dihydroxy compounds and then to the corresponding D 8(9) - 7,11 - diketo compounds. D 8(9)-7, 11-diketo-compounds which may be prepared are 3-acyloxy-7,11-diketo-D 8(9),22-ergostadiene, 3 - acyloxy - 7,11-diketo - D 8(9) - bisnorallocholenic acid and esters thereof, 3-acyloxy - 7,11 - diketo - D 8(9) - chloric acid and esters thereof, 3-acyloxy-7,11-diketo-D 8(9)-tigogenin and D 8(9) - allopregnene - 3 - ol - 7,11,20-trione and acyl derivatives thereof.  These D 8(9)-7,11-diketo compounds may be reduced to the corresponding compounds having a saturated bond in the 8 : 9 position in which the 7-keto group may then be reduced to form compounds such as 3-hydroxy-11-keto-D 22-ergostene and 3-hydroxy-11-keto-tigogenin.  In the examples the following compounds are prepared: the monoepoxide derivatives of ergosterol D, ergosterol D acetate, methyl 3-acetoxy-D 7,9(11)-bimorallocholadienate methyl 3-hydroxy (and acetoxy) - D 7,9(11) - choladienate, 7,9(11) - disdehydrotigogenin acetate, and D 7,9(11) - allopregnadiene - 3 - ol - 20 - one - 3 - acetate; the D 8(9)-7,11-dihydroxy compounds 3 - acetoxy - 7,11 - dihydroxy - D 8(9),22 - ergostadiene which may then be hydrolysed to 3,7,11 - trihydroxy - D 8(9),22 - ergostadiene with methanolic potassium hydroxide or acetylated with acetic acid and pyridine to form 3,7,11-triacetoxy - D 8(9),22 - ergostadiene, methyl 3-acetoxy - 7,11 - dihydroxy - D 8(9) - bisnorallo - cholenate, methyl 3-acetoxy-7,11-dihydroxy-D 8(9) - cholenate, 3 - acetoxy - 7,11 - dihydroxy-D 8(9) - dehydrotigogenin, and D 8(9) - allopregnene - 3,7,11 - triol - 20 - one - 3 - acetate; the D 8(9)-7,11-diketo compounds 3-acetoxy-7,11-diketo - D 8(9),22 - ergostadiene, methyl 3-acetoxy - 7,11 - diketo - D 8(9) - bisnorallocholenate, methyl 3 - acetoxy - 7,11 - diketo - D 8(9)-cholenate, 3 - acetoxy - 7,11 - diketo - 8(9) - dehydro - tigogenin and D 8(9) - allopregnene - 3 - ol - 7,11, 20-trione-3-acetate; the 7,11-diketo compounds having a saturated bond in the 8 : 9 position 3 - acetoxy - 7,11 - diketo - D 22 - ergostene which may be hydrolysed to 3-hydroxy-7,11-keto-D 22-ergostene, methyl 3-acetoxy-7,11-diketo-bisnorallocholonate, methyl 3 - acetoxy - 7,11 - diketo - cholanate, 3 - acetoxy - 7,11 - diketo - tigogenin and allopregnon - 3 - ol - 7,11,20 - trione-3-acetate; the 7-keto compounds prepared by reduction with hydrazine hydrate from the corresponding 7,11-diketo compounds having a saturated 8 : 9 bond 3-hydroxy-11-keto-D 22-ergostene (prepared from 3-acetoxy-7,11-keto-D 22-ergostene the reduction process hydrolysing the 3-acetoxy group) which may be reacetylated with acetic anhydride to form 3 - acetoxy - 11 - keto - D 22 - ergostene, 11-keto-tigogeni (prepared from 3-acetoxy-7,11-keto-tigogenin the reduction process hydrolysing the 3-acetoxy group) which may be reacetylated with acetic anhydride to form 11-keto-tigogenin acetate. D 7,9(11) - Cyclopentanopolyhydrophenanthrene compounds having the structure <FORM:0764321/IV(b)/7> are prepared by reacting the corresponding D 7-compounds with mercuric acetate, e.g. by reaction with mercuric acetate and glacial acetic acid in the presence of a suitable solvent medium such as chloroform.  The process can be utilized to prepare D 7,9(11)-pregnadiene - 3 - ol - 20 - one-3-acetate from D 7-pregnenolone acetate, and D 7,9(11)-dehydrotigogenin acetate from D 7-dehydrotigogenin acetate as well as other acyloxy derivatives of these compounds and the 3-hydroxy derivatives of these compounds.  The preparations of D 7,9(11) - dehydrotigogenin acetate from D 7-dehydrotigogenin acetate, methyl 3 - acetoxy - D 7,9(11) - bisnorallocholadienate from methyl 3-acetoxy-D 7-bisnorallocholenate, and D 7,9(11)-allopregnadiene-3-ol-20-one-3-acetate from D 7-allopregnenolone acetate are detailed.  3-Hydroxy-D 7,9(11)-choladienic acid is prepared by reducing 3-hydroxy-12-keto-D 7,9(11)-choladienic acid, e.g. by heating with hydrazine hydrate and an alkali metal hydroxide such as potassium hydroxide in the presence of a high boiling solvent such as diethylene glycol.