Process for the manufacture of ª‡-substituted, side chain ketones of the cyclopentanopolyhydrophenanthrene series

Реферат: a -Substituted side chain ketones of the cyclopentanopolyhydrophenanthrene series are prepared from a carboxylic acid halide of this series which contains in the 3-position a group which is convertible to a hydroxyl group by hydrolysis and which in the 11- and/or 12-position contains a keto group, a group convertible into hydroxyl by hydrolysis or a double bond extending from the 11-position, and if desired further substituents, by treatment with an aliphatic diazo compound followed by regeneration of the 3-hydroxyl group and the oxidation thereof to a keto group, and finally treatment of the product with an organic or inorganic acid, an alkali or a carboxylic acid salt to form a free or esterified ketol group in place of the diazo or halogen ketone group originally formed by the action of the aliphatic diazo compound. If desired the oxidation of the 3-hydroxy group to a keto group may be carried out after the formation of the free or esterified ketol group. The factor which determines whether the action of the aliphatic diazo compound will produce a diazo ketone <FORM:0573786/IV/1> or a halogen ketone <FORM:0573786/IV/2> Halogen is the speed with which the aliphatic diazo compound is added. Also, an excess tends towards the formation of the diazo ketone. The product produced by the above series of reactions may be further treated if desired to introduce a double bond into the a -position to the 3-keto group by halogenation followed by elimination of hydrogen halide, and also subjected to the action of a hydrolysing agent and/or an esterifying agent. During the oxidation of the 3-hydroxyl group to a keto group any double bonds present may be protected in known manner. In addition to the presence of the substituents named above there may also be present other nuclear substituents such as substituted hydroxyl or carbinol groups, carbonyl groups. Starting materials mentioned include saturated or unsaturated, esterified or etherified 3-oxy-, 3 : 7- or 3 : 17-dioxy-, 3 : 7 : 17-trioxy-, or 3-oxy-7-keto-etio-cholanic, -cholanic, -norcholanic, or -bisnorcholanic acids which are substituted as above. Suitable aliphatic diazo compounds mentioned include diazo-methane or mono-substituted diazo-methanes such as diazo ethane, diazo-butane, diazo-propylene, phenyl-diazo-methane, or diazo-acetophenone, also diazo-carboxylic acid derivatives such as diazo-acetic acid ester, amide and nitrile. The regeneration of the 3-hydroxyl group is carried out preferably by hydrolysing agents although when a benzyl group is present, a reducing agent may be used. The oxidation of the 3-hydroxyl group may be carried out by chromic acid or by dehydrogenating agents such as copper powder, or by the action of metal alcoholates or phenolates in the presence of ketones. Agents mentioned which may be used to convert the diazo ketone group into a free or esterified ketal group include anhydrous or dilute organic or inorganic acids such as acetic, propionic, butyric, crotonic, palmitic, benzoic, phenyl-acetic, sulphuric, methane-sulphonic, toluene-sulphonic, hydrohalic, phosphoric or boric acids. Agents mentioned to convert a halogen ketone group into a free or esterified ketol group include alkaline agents such as bicarbonates and salts of carboxylic acids. In examples: (1) etio-desoxycholic acid diacetate is converted into its acid chloride with thionyl chloride and treated with an ether solution of diazomethane to form 21-diazo pregnane-3a -12b -diol 20-one diacetate. This compound is saponified with potassium hydroxide-bicarbonate mixture, and the diol heated in glacial acetic acid to split off nitrogen and form pregnane-3a -12b -21-triol-20-one-21-monoacetate. Oxidation with chromic acid forms pregnane-21-ol-3 : 12 : 20-trione acetate. Treatment of this compound with bromine and elimination of hydrogen bromide gives D 4-pregnane-21-ol-3 : 12 : 20-trione-acetate, which may be saponified with alcoholic bicarbonate; (2) pregnane-3a -12b -21-triol-20-one-21-monoacetate prepared as in example (1) is oxidized with aluminium phenolate in the presence of acetone to form pregnane-12b : 21-diol-3 : 20-dione-21-monoacetate. Bromination and elimination of hydrobromic acid produce from this compound D 4-pregnane-12b : 21-diol-3 : 20-dione-21-monoacetate, which may be hydrolysed with alcoholic bicarbonate; (3) 21-diazopregnane-3a : 12b -diol-20-one-diacetate, prepared as in example (1) is partially saponified with alcoholic bicarbonate to 21-diazo-pregnane-3a : 12b -diol-20-one-12-monoacetate, and heated in glacial acetic acid to eliminate nitrogen and form pregnane-3a : 12b : 21-triol-20-one-12 : 21-diacetate. Oxidation of this compound with chromic acid forms pregnane-12b : 21-diol-3 : 20-dione-diacetate. Bromination and elimination of hydrobromic acid produces D 4-pregnane - 12b : 21 - diol - 3 : 20 - dione - di - acetate, which may be partially saponified with alcoholic bicarbonate to D 4-pregnane-12b : 21-diol-3 : 20-dione-12-monoacetate; (4) D 9,11-3-acetoxy-etio-cholenic acid chloride is treated with diazomethane in benzene solution, hydrolysed with alcoholic bicarbonate-hydroxide solution, oxidized with aluminium phenolate in the presence of acetone, heated in glacial acetic acid solution to remove nitrogen and form D 9,11 - 21 - acetoxy - pregnane - 3 : 20 - dione. Bromination and removal of hydrobromic acid results in the formation of D 4,5, 9,11-21-acetoxypregnadiene-3 : 20-dione. By starting from D 11,12-3a - (or -3b -) acetoxy etio-cholenic acid chloride there is obtained in a similar manner D 4,5, 11,12-21-acetoxy-pregnadiene-3 : 20-dione; (5) 3b - acetoxy - 11 - keto - etiocholanic acid is treated with thionyl chloride to form the acid chloride and then with diazomethane to form 21-diazo-pregnane-3b -ol-11 : 20-dione acetate. This is hydrolysed and heated in glacial acetic acid to remove nitrogen and form pregnane-3b : 21 - diol - 11 : 20 - dione - 21 - monoacetate. Oxidation with chromic acid produces pregnane-3 : 11 : 20-trione-20-ol-acetate. Bromination and removal of hydrobromic acid gives D 4-pregnane-3 : 11 : 20-trione-21-ol-acetate (dehydrocorticosterone acetate). This may be saponified with methyl alcoholic hydrochloric acid. If as starting material in this example there is used a 3 : 11-diacyloxy-etiocholanic acid there is obtained the corresponding cort costerone. D 9,11-3-acetoxy-etiocholenic acid chloride is obtained from 3 : 11-diketo-etiocholenic acid methyl ester by hydrogenation in the presence of platinum oxide to a mixture of 3a - and 3b : 11 -dioxy-etiocholanic acids, partial acetylation with acetic anhydride and glacial acetic acid to form a mixture of 3a - and 3b -acetoxy-11-oxyetiocholanic acids, which on treatment with thionyl chloride yields the desired product. Specifications 500,767, 516,828, 544,484 and 561,566 are referred to.