Patent GB-512954-A (GB)
Title: Manufacture of ketones or secondary alcohols of the cyclopentanopolyhydrophenanthrene series
IPC: C07J5/00
Filed: 1938-03-23
Abstract: 512,954. Sex hormones. SOC. OF CHEMICAL INDUSTRY IN BASLE. March 23, 1938, Nos. 8913, 8914 and 8915. Convention dates, March 29, 1937, March 29, 1937, and Feb. 28, 1938. Sample furnished. [Class 2 (iii)] Ketones or secondary alcohols of the cyclopentano-polyhydrophenanthrene series are prepared by reducing a compound which has the general formula where R is a residue containing the cyclopentano-polyhydrophenanthrene nucleus. R1 is hydrogen or a monovalent residue containing carbon such as an alkyl, aralkyl, aryl or acyl group, a substituted carboxyl group such as an acid ester or an acid amide group, 'or a cyanogen group. R2 is halogen or a monovalent residue containing carbon. The two substituents other than R1 may also be combined to constitute a diazo group. The side chain may be linked directly to the cyclic nucleus at positions 3 or 17, or it may be separated from the nucleus by one or more carbon atoms. Parent materials mentioned include saturated or unsaturated 3-oxy- or 3-keto-21-halogen pregnanones-20, such as 21- halogen-progesterones, 3-oxy- or 3-keto-21- halogen pregnane-20-one-21-carboxyl acid esters, 3 oxy- or 3-keto-21 dihalogen-pregnanones- 20, 3-dihalogen-acetyl actio-allo-cholanols-17 or allo-cholanones-17, 3-oxy- or 3-keto-21- diazo-pregnanones-20 such as 21-diazo-progesterone, 3-oxy- or 3-keto-21-diazo-21. acetyl pregnanones-20 or their sterio-isomerides. Derivatives of these compounds, particularly enol derivatives and dihalogen substitution products such as the 5 : 6-dibromo- or 5 : 6- dichloro-compounds may also be used. The parent materials may also contain additional substituents particularly substituted or non- substituted hydroxyl-, carbinol-, amino-, carboxyl-, or hydrocarbon groups, as well as ring keto groups or their enol derivatives such as enol esters or enol ethers. Reducing agents mentioned include metals such-as zinc, copper, magnesium, or their alloys in the presence of solvents such as alcohols, aqueous alcohols, acetic acid, mixtures of acetic acid and hydrogen halides, alkalis. The reduction may also be electrolytic or by means of catalytically activated hydrogen in the presence of nickel, palladium or platinum. Finally there may be used amalgams such as aluminium-, sodiumamalgam, zinc-palladium, alkali iodide and glacial acetic acid, sodium and alcohol, a disubstituted aniline, or with a combination of these reducing agents. The reduction is particularly easy in the case of products iodinated in the 21-position, and therefore hydrogen iodide or salts thereof act on the other 21- halogen-ketones as reducing agents. Hydriodic acid, or iodides in the presence of acids react with the diazo group to cause direct replacement with hydrogen. Hydrazones are frequently obtained as by-products when reducing diazoketones. It frequently happens that other reducible atomic groupings present in the molecule are reduced simultaneously with the halogen or diazo groups of the ,side chains. Thus, for example, nuclear halogen is replaced by hydrogen, keto groups are reduced to secondary alcohol groups, alpha-# unsaturated ketones to saturated ketones or alcohols, as well as nuclear dihalogen substitution products to either saturated or unsaturated products. In the case of the production of unsaturated products, the nuclear double bonds may be isomerized during or after the reduction by treatment with acids, or alkalis, In cases where the reduction products still contain substituted or non-substituted carboxyl groups or cyanogen groups these may be subsequently saponified and/or decarboxylated. The products of the invention may be separated and purified by recrystallization, sublimation in a vacuum, selective adsorption, or through their derivatives such as esters, condensation products with ketone reagents, or by a combination of such methods. The diazo ketones for use in the process of this invention are obtainable by reaction of the corresponding acid halides with aliphatic diazo-compounds. From the diazo-ketones there are obtained by the action of hydrogen halide or halogen the alpha-mono- or -dihalogen ketones, whereby simultaneously or subsequently nuclear double bonds may also become saturated, and finally any nuclear hydroxyl groups present oxidized to keto groups. Since compounds of the latter type are generally easily decomposed it is preferred not to isolate them but to reduce them in the crude condition in the presence or absence of a solvent. In examples (1) a glacial acetic acid solution of #-<5>-21-chloro-pregnene- 3-ol-20-one-acetate is shaken with zinc dust for 10 minutes and then heated to 100‹ C. for 20 minutes to give A <5>-pregnene-3-ol-20-oneacetate. The acetate may also be obtained by heating the acetylated chloro-ketone with alkali iodide in glacial acetic acid. (2) A dioxane solution of # <5>-21-chloro-pregnen-3-ol- 20-one is treated with zinc dust in the presence of a small amount of hydrochloric acid to give #<5>-pregnene-3-ol-20-one. (3) A glacial acetic acid solution of #<5>-21-dibromo-pregnanol-3- one-20 is treated with a zinc-copper alloy in the presence of 5 per cent. solution of hydrogen bromide at 90‹ C. for ¢ hour to give A <5>-pregnenol-3-one-20. Instead the free dibromopregnendone, there may be used its esters or ethers such as the acetate or the trityl ether, and the resulting compound hydrolyzed to give the free pregnenolone. If the reduction is by catalytically activated hydrogen in neutral medium such as hydrogen in presence of nickel or platinum in alcohol a mixture of two isomeric # <5>-pregnene-diols-(3 : 20) is obtained which are isomeric at carbon atom.20. By subsequent oxidation with temporary protection of the double.bonds, both yield the same progesterone. If one starts from compounds, hydroxylated at carbon atom 17, there are obtained 17: 20 glycols. In the above particular case, there would be produced #<5>-3-17-20-pregnene triols. By elimination of water with potassium bisulphate or phosphorus pentoxide in toluene or with sulphuric acid there is obtained #<5>- pregnenol-3-one-20. (4) A glacial acetic acid solution of 21-chloro-pregnane-3:20 dione is treated with zinc dust for 15 minutes to give pregnane-(3 : 20) dione. (5) The 3-enol acetate of 21-chloro-progesterone (obtained by reaction of #<3À4>-#<5À6> -3-acetoxy-aetio-cholane-dione acid chloride with diazo methane and subsequent action of hydrogen chloride) is treated with zinc in glacial acetic acid solution to give the 3-enol acetate of progesterone which may be saponified with alcoholic potash to the free progesterone. If the 21-bromo-, or the 21-iodo-compound is used the reaction proceeds similarly. There may also be used as the parent material a 3-enol ester of a 21-halogen-progesterone-21-carboxylic acid ester in which case a 21-carboxylic acid ester of progesterone is formed which by subsequent saponification and decarboxylation is converted into progesterone. (6) An alcoholic solution of # <5>-21 diazo-pregnene-3-ol-20-one is treated with sodium iodide in the presence of a small amount of concentrated hydrochloric acid. The solution is decolourized with bisulphate or thiosulphate and worked up to give #<5>-pregnene-3-ol-20-one. (7) 3-Epi-oxy-21- diazo-allopregnanone-20 is reduced with hydrogen in the presence of palladium in alcohol solution to give epi-allo-pregnanol-3-one-20. Instead of the free 3-oxy-diazo compound an ether or ester thereof may be used such as the acetate or the trityl ether. (8) A chloroform solution of # <5>-21-chloro-pregnene-3-ol-20-one is treated with bromine in chloroform and the bromo-compound so produced is oxidized with chromium trioxide in glacial acetic acid solution. The oxidation product is taken up in ether and the 5 : 6 : 21-trihalogen-pregnane- 3: 30-dione so formed is debrominated with zinc dust. The double link is shifted by a further treatment with boiling glacial acetic acid for five minutes to give #-pregnene-3: 20- dione. Instead of zinc dust there may be used as reducing agent, sodium iodide in glacial acetic acid. Instead of 5: 6: 21-trihalogenpregnane-3: 20-dione there may be used as parent material 5 : 6 : 21 : 21-tetrahalogen-pregnane-dione-(3: 20). This material is obtained by treating #<5>-21-diazo-pregnane-3-ol-20-one with four atoms of halogen and oxidizing the 5-6: 21: 21 tetrahalogen-pregnane-3-ol-20-one thus obtained. A sample has been furnished under Sect. 2 (5) of a product prepared by treatment of #<5>- 21-carbethoxy-21-chloro-pregnane-3-ol-20-one in glacial acetic.acid with zinc dust followed by ether extraction and washing of the product with alkali after which a saponification with alcoholic sodium hydroxide yields #<5>-pregnene-3-ol-20. The Specification as open to inspection under Sect. 91 includes also the treatment of compounds of the cyclopentanopolyhydrophenanthrene series in which the side chain is attached to positions on the nucleus other than position 17, particularly at position -3. The nucleus may contain in addition to the side chain also hydroxyl, carbinol, amino, carboxyl, hydrocarbon or halogen atoms. In the case where the keto group in the side chain is reduced to a secondary alcohol group, and there is present in the alpha-position a free or esterified hydroxyl group, the latter may be eliminated by an agent which splits off water or acid, and the glycol so obtained converted through the unstable intermediate enol compound to the ketone thus :- where R, is as defined above and R4 is hydrogen or an acid residue. Reagents mentioned as suitable for this purpose include mineral acids, phosphorus oxychloride, bisulpbates, formic acid, oxalic acid, acid anhydrides or catalysts such as iodine on the one hand or a basic agent for instance on alkali or alkaline earth ,metal or their hydroxides or carbonates, or tertiary amines on the other hand. The reaction may be conducted at raised temperature or particularly in an indifferent gas or under reduc