DE722943C - Process for the preparation of 3-ketocyclopentanopolyhydrophenanthrene compounds doubly unsaturated in ring A - Google Patents

Description

Process for the preparation of 3-ketocyclopentanopolyhydrophenanthrene compounds which are doubly unsaturated in ring A It has been found that valuable ones which are doubly unsaturated in ring A of the sterol ring system 3-ketones of the cyclopentanopolyhydrophenanthrene series or their enol derivatives, if from those saturated derivatives which are dihalogenated in the 2,2- or 2,4-position these compounds by heating with hydrogen halide agents in as is known, 2 moles of hydrogen halide are split off in one go or in two stages. The following reactions can occur: i. Elimination of hydrogen halide and formation of one or more double bonds: 2. Replacement of halogen by Ester or ether residues a) with subsequent saponification and formation of a double bond by elimination of water or 1 »with subsequent thermal elimination of the ester or ether group with formation of double bonds.

3. Replacement of the halogen by a substituted or unsubstituted one Amino group with subsequent cleavage of the bases in question.

4. Combination of these different methods.

To carry out these reactions one uses itself known per se Methods. The treatment of the dihalogenated ketones mentioned with has proven itself Salts of organic acids, such as. B. Kaliumbenzoa "Sodium acetate and other more. The reaction in the presence of such solvents is expedient for this Salts carried out that boil at a higher temperature, especially of B.utanol or also the acids themselves, such as acetic acid, benzoic acid, isovaleric acid and the like can especially use the treatment with organic bases and thereby get directly to the doubly unsaturated ketones in ring A or the obtained ones Subject nitrogenous compounds to thermal decomposition. Enol derivatives these doubly unsaturated 3-ketones, like the inorganic and organic esters or ether, are obtained in a known manner, by doing this Connections e.g. B. with acylating agents such as acid anhydrides or acid halides or mixtures thereof, optionally with heating, treated.

They are not used as starting materials for these processes only those in the 2,2- or 2,4-position (lilialogeierten ketones of the sterol series, but also those of the Prehnan and Androstan series. You can also use the appropriate ini ring A (halogenated 3-osocholanic acids or their lower homologues, bile acids and in general all ketones hzw. their enol derivatives use which have a cyclopentanopolyhydroplienanthrene ring With a methyl group on the carbon atom 1o, a keto group on the carbon atom 3 and halogen atoms in =, 2- or a,: f-position.

The reaction is explained, for example, on the basis of the conversion of the 2,1-dibronicholestanone into the / 91, z: 4, s-cliolestadienone-3: It is true that the attempt been assumed to be substances of this type reach. According to Journal pharmac. Society Japan, vol. 56, p.102 ff Bromination of 5-Clilorandrostandions-3,1; (read 2-bromo-5-cliloratidrostandion-3,1i and from it by 1-Ialogeiiiwasserstoifal) Spalttui ;; the d 1, 2- Dehv (lro -d 4,;, - androstenedione-3, 1 7 arise. In fact, however, there is no doubly unsaturated compound in thing A. Neither are such compounds according to Helvetica chimica acta, B (1. 19 (1936), pp. So6 ff. The invention is explained in more detail below using examples.

Example i 2, 2-dibromocholestanone-3 with a melting point of 1.1 l °, obtained e.g. B. after Doree, Journ. Chem. Soc. 95, 648 (19o9), 6 g of potassium benzoate and a mixture of 20 cc toluene and 50 cc butyl alcohol are added and the mixture is refluxed for 1 hour. Then it is diluted with water and shaken out with ether. The ether solution is evaporated to dryness in vacuo and the residue is recrystallized from chloroformal alcohol. Magnificent needles are obtained which melt together at 176 'to form an opaque liquid (the melt becomes clear at 216 °) and the A1, 2-cholestenone-3-olbenzoate-q. of the composition C34 H48 03 represent. Yield 0.6 ".

o, 5- of this benzoate are retorted under a pressure of 2 mm H-2 hours heated to about 220 °, whereby benzoic acid is split off, which in the original sublimates. When this cleavage has ended, the mixture is distilled under a pressure of 0.05 mm Hg for another hour. The distillate thus obtained is taken up in ether, washed the ethereal solution with soda solution and water and thoroughly Freed from solvent by evaporation. The Gholestadienon h. Remains as a weak yellow oil that can be further purified. Example 2 2 g of 2, q.-Dibromocholestanone-3 melting point 197 ° with 3 g of potassium benzoate and 2o ccm of isovaleric acid Heated to the boil for 20 minutes, during which potassium bromide precipitates quickly. Thereon is absorbed in ether and the ethereal solution is shaken out with dilute potassium hydroxide solution. After washing with water, the ether is evaporated and the residue is taken up in alcohol. After a while, crystallization occurs. The resulting Isovalerianate is suctioned off and recrystallized several times from alcohol. It has the composition C3.2 H ,, = O3. When heated in the melting point tube, it sinters at ioz °, falls between 118 to 127 'together and delivers a clear melt at 144 " 127 to 1 ¢ 4 ° the known color appearance of the sterol esters was observed. Yield 0.2 G.

The conversion of this ester into a ketone which is doubly unsaturated in ring A takes place according to example i. Example 3 250- 2, .l-Dibronicholestanon-3 (Schmelzl) nrikt R97 °) are dissolved in 1 r "uluol. The 1-dissolution is 3-1-butanol and 25o g Ka.-littinbenzoat added. The mixture is in Cinem The glycerine bath is boiled under reflux for 2 1/2 hours at a bath temperature of 130 to 14 degrees. A solution and washed three times with water. The solution, which has been clarified with sodium silicate, is then strongly concentrated in vacuo at 80 ° until abundant crystallization has occurred. After cooling, the crystals are filtered off with suction and washed with alcohol; yield 10 5 g, crude melting point 135 to 145 °. after five fractional recrystallization from Chloroformallzoliöl the constant melts at 176-1 77 ° (clearing of the melt at his 2i6 2i7 °) can be one- sparingly soluble fraction in fine, silky needles separated, and @: 1i , Represents 2-cholestenone-3-olbenzoate-4; Yield 35g.

This product is identical to that according to Example i from 2,2-dibromocholestanone-3 unsaturated benzoate of the composition C34 shown at the melting point 141 ° H48 03.

A more easily soluble crystal fraction can be separated from the combined mother liquors of the product with a melting point of 176 to 177 ° by dilution with water, which, after recrystallization from a chloroform-alcohol mixture, melts at 137 to 138 ° (color appearance when melting), yield 50 g.

This product represents the isomeric A4, s-cholestenone-3-olbenzoate-2 of the formula C34 H48 03.

The acid residue is split off from the unsaturated benzoates in the same way, "as described in example i.

Instead of the monoesters of the unsaturated oxyketones, e.g. B. instead of A 4, s-cholestenone-3-olbenzoate-2, as it is, for. B. is available as an intermediate product in the treatment of 2,4-dibromocliolestanone-3 with potassium benzoate in toluene and butyl alcohol according to Example 3, the enol derivatives, such as the esters, ethers or halides of these substances, can also be used for the further reactions , by subjecting these enolic derivatives, for example, to the action of such agents, by means of which further double bonds are placed in ring A. This can take place, for example, in the way that the secondary ester or EXAMPLE 4 46 g of dibromo androstandione, as obtained when a solution of 31.7 androstandione in a mixture of 11 cc of chloroform and zoo cc of glacial acetic acid is mixed with a solution of 1 cc of bromine (= 11ol ) in 100 ccm of glacial acetic acid and after washing with water and drying the reaction solution evaporated in vacuo at 50 °, 500 cc of dry PVC are poured over the mixture Boiled under reflux for 4 hours at 135 to 14o ° bath temperature. The pyridine is then evaporated off in vacuo at So 'and the reaction product obtained is treated with ether and water.

The ethereal solution is washed with water and leaves after Evaporation of 5 g of an oil from which the d 1, 2: 4, s-androstadiendione-3, I7 is expedient is isolated by vacuum distillation and chromatographic purification.

Those contained in the aqueous layer, too, during the reaction formed pyridine compounds are, after addition of sodium bicarbonate for the purpose Binding of hydrobromic acid in one. Soxleth extracted with chloroform. Included i i g of a pyridine ketone are still obtained. Example s 600 g of 2,4-dibromocholestanone-3 are dissolved in 1 pyridine, and the solution is in a glycerol bath at a bath temperature refluxed for 8 hours from 135 '. Then the pvridine is in a vacuum on the Water bath evaporated and the residue treated with ether and water. While the formed cholestadienone-3 goes into the ether, a large amount remains more water-soluble Pyridine bodies in the aqueous layer; - these latter are after the addition of excess sodium carbonate to neutralize the hydrobromic acid extracted in a Soxleth with chloroform. It also separates as an intermediate layer cholestenonylpyridine hydrobromide, which is insoluble in ether and water, in crystals away.

After separating the aqueous layer, filtering off the crystalline intermediate layer and washing the ethereal solution, the latter is evaporated. The ether-soluble part represents a dark OI; Yield 120g.

If you stand for a long time with the addition of a little alcohol, it separates Crystals were usually produced from the oil. When this no longer multiplies, it is suctioned off and washed with methanol; Raw booty io g.

After repeated recrystallization from: alcohol water, once with addition before. Animal charcoal, the resulting crystal melts 11e1 110 to I II '.

Since the product obtained in this way gave a slightly positive Beilstein test, 6.2 - of this material are heated to boiling with ig potassium acetate in 70 cc of isovaleric acid for 15 minutes in order to remove the remaining halogen. After being taken up in ether and washing with dilute potassium hydroxide solution and water, the crystals obtained after evaporation of the ether are first recrystallized from dilute alcohol and then from acetone water. The d 1.2: 4, s-cholestadienone-3 of the general formula CIIHq = O is obtained in white, star-shaped or crosswise arranged leaflets which melt -constantly at ii I to 112 '; the optical rotation is [x) 1) = + 32.5 ° (in chloroform). Yield 3.5g. Further amounts of the same substance can be recovered from the mother liquors.

If the cholestadienone described is to be obtained rapidly in crystallized form, it is advisable to distill the ether-soluble dark oil obtained in the pyridine treatment of the dibromocholestanone in a high vacuum; .4 g of the oil are distilled in a retort at 170 to 180 ° and 0.0003 mm Hg. The distillate is dissolved out with ether and recrystallized from dilute alcohol, whereby the cholestadienone is also obtained in beautiful crystals. Example 16 A solution of doo g of 2,4-dibromocholestanone (melting point 192 °) in 1.61 dry pyridine (standing over caustic potash) was refluxed in a glycerine bath for 6 hours at a bath temperature of 135 °, the solution quickly turning dark. Then the pyridine was completely evaporated on the water bath in vacuo and the residue treated with a lot of ether and water. While the cholestadienone formed went into the ether, a large part of the water-soluble reaction products remained in the aqueous layer; cholestenonylpyridine hydrobromide, which is sparingly soluble in water and ether, also deposited on the intermediate layer. The aqueous layer was drained off and extracted twice more with ether. The combined ether extracts, after being filtered off from the test intermediate layer, were washed three times with 5% potassium hydroxide solution and then several times with finite water and finally evaporated to dryness. The dark product obtained (yield 82 g) was distilled in two portions with the addition of C g of sodium acetate each in a high vacuum at 0.06 μm Hg and: 2.2%. The wine-red distillate, which had already crystallized in the receiver, was dissolved out using chloroform (about 25o ccm) and the solution was largely evaporated after adding about z 1 alcohol. The concentrated alcoholic solution (about 25o ccm) quickly crystallized when standing in ice after being rubbed. The crystal slurry was filtered off with suction and washed with cold alcohol; Crude yield 51 g. A second crystallization was achieved from the mother liquor. The product was recrystallized first from a little alcohol, then several times from methanol, once with the addition of animal charcoal. The pure cholestadienone melts at III to 112 'MD - [- 30.8 ° (in chloroform). Yield 35g. The dienone crystallizes from methanol in magnificent, long, flat prisms; it is readily soluble in the usual solvents, slightly soluble in cold alcohol, sparingly soluble in cold methanol.

Example 7 i, 1 g of the z. B. cholestenonylpyridine hydrobromide obtained according to Examples 5 and 6 are heated in a retort at 6 mm Hg for 2 hours to 180 to 100 °, the pyridine component subliming into the template. Then: 2 hours at 0.005 min Hg and zoo to 220 ° distilled, a light oil passing over. The distilled oil is taken up in ether and the ethereal solution is washed several times with 5% potassium hydroxide solution to remove acidic components. After further washing with water, evaporation of the ether gives the CholestadienOn-3 as pale 01, which can be further purified. Example 8 2 g of 2,4-dibromoandrostanol-17-one-3 are dissolved in 2o ccm of toluene. 60 cc of butanol and 3 g of potassium benzoate are then added to the solution. The reaction mixture is then refluxed for 2 hours and, after cooling, washed in a separating funnel with soda solution and water. After evaporation in vacuo, the unsaturated benzoate of the formula CIGH3 = 04 is obtained in the form of an oil.

0.8 g of this benzoate of androstenediolone-3 are in a retort heated to 220 ° to 230 ° at 0.5 mm H- il /, hours, benzoic acid being split off. Then it is distilled in a high vacuum at o, ooo4nunHg and 170 to igo °. The distillate is taken up in ether and the solution washed with soda and water. After evaporation of the ether. one obtains about 0.4. g 1.2; 4., 5-alldrostadienol-17-on-3 in the form of a Oil that can be cleaned even further.

Instead of the dillalogenated androstanol-17-one-3, one can use a similar method Also the esters or ethers of this substance or the 17-alkyl-substituted compounds or use their esters or ethers.

Furthermore, instead of the 2-monoester, the unsaturated 2-oxyandrostanol-i7-one-3 or their 17-alkyl compounds or the 17-esters or ethers of these compounds, how they z. B. according to the above example as, intermediate products in the treatment of 2, 2- or 2, 4-dibromoandrostanol-17-one-3 with potassium benzoate in toluene and butanol are available, including the enol derivatives of these esters or other 2-compounds, such as the free oxy compounds or their ethers, use for further reactions find by these enolic derivatives z. B. subject to the action of such agents through which further double bonds are placed in ring A. this can e.g. B. be done in such a way that the secondary ester or ether group or the free oxy group on carbon atom 2 is split off.

EXAMPLE 9 3 g of 2,4-dibromocholestanone are refluxed with 50 ccm of 2,4,6-trimethylpyridine (collidine) for 21/2 hours. The cooled reaction solution is then poured into excess dilute hydrochloric acid and the acidic solution is extracted with ether.

The one after you wash out the essential solution to neutral Reaction and evaporation of the ether residue obtained is stirred with petroleum ether and sucked off the crystal powder. One obtains 0.6 g of A 1.2; 4, 5-Chalestadienon-3 from the melting point fog to ifo °; Further amounts can be obtained from the mother liquor isolate this substance. A, y-lutidine can also be used in place of the collidine and use the y-picoline with equal success.

Example fo 11,49 2,4-dibromoandrostanone-3-olacetate-17 of melting point 19.I °, obtained by breadnating androstanolone acetate in glacial acetic acid in the presence of a few drops of broin hydrogen vinegar at room temperature, will be in 125 ccm COllidln cooked for 3/4 hour. After cooling, the brown solution becomes with ether diluted, decanted from the collidine salt and treated with diluted Schwc: -felsällre, -Soda solution and guard water. The neutral, ethereal solution is dried over sodium sulfate and evaporated. The brown residue is obtained from a solution in a mixture of benzene and gasoline i: i kn aluminum oxide (lferck stand. after Brockmann) absorbed. From the eluate succeeds it, using the same mixture after rclamping the solvent, the d 1 # 4-Aridrostadienolacetat-17-011-3 in light yellow needles with a melting point of 151 to 152 ° to receive. The absorption spectrum shows a high 'maximum at 235 m. the Yield is 5.3 g. This substance proved to be more effective in the capon test than the testosterone acetate.

3 ,; g androstadienolone acetate are in 50% strength methyl alcohol in so cc Alkali boiled for 1 1/2 hours on reflux. Obtained after spraying with water the d 1, 4-androstadienol-17-one-3 in fine needles, which are recrystallized from methanol water melting at 16.9 to 169 '.

The d 1,4-androstadienol-i #: -one-3 propionate can be prepared by reacting this dienolone with propionic anhydride in pyridine. After this mixture has stood for 24 hours, the propionate is precipitated with water and recrystallized from methanol. This gives colorless flakes which melt at 138 to 139 '. Example ii A solution of .4 g of 2,4-dibromocholestanone in dry oil is added to a suspension of 4 g of naphthol potassium in oil. After refluxing for 2 hours, the solution is filtered off from the potassium bromide, the solvent is evaporated and the residue is heated in a retort under a pressure of 2 mm for 2 hours at about 220 to -24o °. The distillation is then continued for another hour at 0.05 mm. A pale oil passes over, from which the cholestadienone is isolated by chromatographic separation and purification.

The compounds obtained are either themselves physiologically active or are intended to be used for the production of physiologically active compounds Find.

Claims (3)

PATENT CLAIMS: i. Method of making in ring A twice unsaturated 3-ketocyclopentanopolyhydrophenanthrene compounds or their enol derivatives, characterized in that dillalogpnated from in the 2,: 2 or 2, 4-position saturated derivatives of these compounds by heating with hydrogen halide-releasing agents Averaging in a known manner 2 moles of hydrogen halide in one go or in two stages splits off. 2. The method according to claim 1, characterized in that one in the Starting materials initially the halogen through the remainder of an ester, ether or one replaces organic base and then splits off the ester, ether or organic base. 3. The method according to claim i and z, characterized in that after the first or second cleavage carries out an enolization in a known manner.