DE1035130B - Process for the production of hecogenin and its acyl derivatives from crude hecogenin - Google Patents

Description

Process for the preparation of hecogenin and its acyl derivatives Crude hecogenin The present invention relates to a process for the preparation of Hecogenin and its acyl derivatives from raw lecogenin.

Hecogenin is a steroid compound obtained from various plant species, especially from the sisal plant and can be used as a raw material for the synthesis of various steroid compounds, especially cortisone and related ones Connections, is suitable. The production of hecogenin in practically pure form in technical Scale is therefore of considerable importance, but it has been shown to be has been associated with difficulties.

Hecogenin is found in the sap of the plant in the form of the corresponding saponin before, whose glycosidic bond must first be hydrolyzed, which for example by autolysis of the sap and acid hydrolysis of the resulting slurry is effected. The hydrolysis product of the natural material is colored and contains in addition to the desired hecogenin, many impurities, such as other steroid compounds, Waxes or gums.

In the known process for the production of hecogenin from Heconinhydrolysateii ether, isopropyl ether, ethyl acetate, benzene, carbon tetrachloride or Trichloräthvlen used as an extractant. These procedures are cumbersome and time consuming as either a large volume is processed or the sapogenin is pre-processed extraction must be removed from the hydrolyzate with the aid of an adsorbent. In addition, the hydrolysis product, the crude hecogenin residue, is mostly in shape a waxy press cake, which is difficult to achieve satisfactorily Way to pulverize. To get good results in a solvent extraction However, a: Material in a finely divided state is required. Such a one Fine distribution cannot be achieved with the solvents previously used.

Surprisingly, it has now been found that in the treatment of Raw hecogenin is rapidly dispersed with a lower alcohol, whereby the hecogenin goes into solution and the impurities remain suspended, so that they can be separated easily.

In the process according to the invention for the production of hecogenin this is achieved by hydrolysis of the corresponding naturally occurring plant saponin raw hecogenin obtained used as starting material; for simplicity should the term "raw hecogenin" means hecogenin-containing material, how it is obtained directly during hydrolysis and that normally after hydrolysis of naturally occurring saponin present. That directly Crude hecogenin obtained from the hydrolysis stage usually contains up to 30% and mostly between 5 and 25% hecogenin.

This raw hecogenin is dissolved in a lower alcohol and the solution obtained freed from the undissolved impurities. The lower alcohol can contain 1 to 5 carbon atoms, preferred alcohols are ethanol and methanol.

The higher purity hecogenin can either be left directly from the obtained Crystallize the solution, or it can be obtained by evaporation of the alcoholic Solution practically to dryness, dewaxing the residue. Dissolving the purified Material in a lower alcohol and allowing the hecogenin to crystallize from this solution.

The solubility of hecogenin in low molecular weight alcohols is proportionate large, whereby smaller amounts of solvent are required than with the known Procedure.

The alcoholic solution can also be treated with activated charcoal be subjected.

This either by crystallization or by evaporation to dryness obtained solid material can then advantageously with a cold Hydrocarbon solvents, in particular an aliphatic hydrocarbon, for example petroleum ether, extracted. This procedure removes the waxes. It goes without saying possible to mix the crude hecogenin with the cold hydrocarbon solvent before Treat alcohol extraction, however, as stated above, is the nature of solid Crude hecogenin contained waxes such that extraction with such solvents causes certain difficulties. It is therefore better to use the distributive effect to use the lower molecular weight alcohol on the waxy raw material, before trying to remove the waxes with the cold hydrocarbon solvent.

If you first mix the raw hecogenin with a low molecular weight alcohol extracted, then evaporated to dryness and finally with a cold hydrocarbon solvent has extracted, it is then expedient to extract the material obtained from a lower Bringing alcohol to crystallization. This level is not absolutely necessary if you crystallize the material from the first alcohol extraction directly leaves, but further purification is generally often achieved when doing this Stage recrystallization from alcohol is switched on, even if the first alcohol extraction included such a crystallization stage. In the application This second treatment with alcohol can of course also be a treatment be enclosed with activated charcoal; this may be unnecessary if the first alcohol extraction included treatment with activated charcoal.

The hecogenin-containing obtained in the above-mentioned procedures Material is then expediently acvated in a manner known per se, preferably with an aliphatic acid. like acetic acid. By subsequent crystallization A further noticeable purification of the acetate from acetic acid is achieved.

The following is an explanation of the method according to the invention a general description of the preferred embodiments of the present invention Invention given.

The raw hecogenin residue can either be in the heat or in the cold can be extracted with the low molecular weight alcohols as solvents. Make sure to use enough solvent to dissolve the whole existing hecogenins at the extraction temperature used. The extraction is preferably carried out in the heat, in particular at the boiling point of the Solvent, and methanol was used as the extraction solvent. About 90 parts by volume of methanol per part by weight of isosapogenins are expedient The amount of isosapogenin in the raw residues can be can of course be determined by prior extraction on a small scale. Preferably, the solid residues are washed thoroughly with the extraction solvent stirred, creating a thorough dispersion of the solid substance in the liquid thus ensuring maximum extraction of the hecogenin present in solution will.

The solids contained in the suspension can easily be separated off by any conventional method, for example by allowing the suspension to settle and decanting off the supernatant liquid, by centrifugation or preferably by filtration, expediently in a filter press. The separation of the solid substance full of liquid can take place in the heat or in the cold, provided that the crude residues solvent was applied in carrying out the extraction in the heat sufficiently to precipitation of hecogenin from the solution upon cooling prior to separation to prevent the solid substance.

Treatment of the alcoholic extract with decolorization activated charcoal has proven to be particularly good at this level, as it changes the color of the extract is improved to a great extent and the subsequent process steps are easier to carry out are. The treatment with animal charcoal is preferably carried out in the heat, which is advantageous at the same time as the extraction of the raw residues, as the activated carbon then removed at the same time as the solids remaining in the extraction can. The amount of activated carbon to be used is best determined by preliminary tests: In general, such an amount of activated carbon is preferably used that the The amount of isosapogenins present is practically the same.

The obtained alcoholic and solids-free extract contains in addition to hecogenin, other isosapogenies as well as waxy substances and other impurities and must therefore be cleaned further. Significant cleaning is required, however achieved by the alcohol extraction, and these extracts show in particular if decolorizing activated carbon had been used, only a relatively light one Coloring.

The next stage is the concentration of the alcoholic Extract, preferably by evaporating on heat to the appropriate volume is carried out, the hecogenin crystallizing out. When using -Iethanol and the use of 90 parts by volume of solvent in the extraction it is expedient. the extract to about a quarter of the original volume evaporate, after which the raw hecogenin crystallizes out on cooling and, for example can be separated by filtration; further amounts of hecogenin become more common Way obtained from the mother liquors. Can the alcoholic extract be natural? even evaporated to dryness, but the solid substance obtained is below In some cases quite pasty, which is less for the treatment in the subsequent stage is useful as a crystalline material.

The next step is the separation of the waxy impurities of the raw hecogenin-containing solids from the alcoholic extracts. this can conveniently by extracting these solids with a cold hydrocarbon solvent, in particular aliphatic hydrocarbon solvents can be achieved. Petrol fractions are very suitable for these substances, and use one in the range of 100 The fraction boiling up to 120 ° C has proven to be useful. The extraction will preferably carried out by mixing the solid substance in the cold with the hydrocarbon solvent stirred, the amount of solvent used -.lein, d. H. straight to Sufficient extraction of the existing waxy contamination is maintained. The solvent can then in any convenient manner, preferably through Filtration can be removed and the remaining crude hecogenin is preferred washed with further amounts of the solvent. It should be mentioned that in the way of working where in the previous stage the hecogenin material crystallize left and not just by evaporating the alcoholic extract to dryness leaching with the hydrocarbon solvent and filtering is more easily feasible from the same.

That obtained by cold extraction with hydrocarbon solvents Material will vary depending on the origin of the original raw hecogenin residues in purity, but such material generally contains 50 to 85% Hecogenin. Usually desirable in cases where the degree of purity is below 80 °! further purification can appear by recrystallizing from a lower molecular alcohol, such as methanol, preferably in the presence of a small amount, expediently 5 to 25% decolorization activated carbon can be achieved. The obtained recrystallized Material generally has a purity of 60 to 100 "/ 0. This stage of recrystallization is of course essential if the first extract is evaporated to dryness and was not caused to crystallize.

In the synthesis of other steroids such as cortisone and the sex hormones a hecogenin ester, especially the acetate, is usually used as the starting material. used. It has been found that the hecogeninacviation step is often simultaneous brings about further purification.

That in the above-described steps of the invention Method obtained hecogenin material can preferably with an aliphatic Acid, such as acetic acid, can be acylated. Such acylation is preferred using a mixture of the appropriate acid anhydride and the acid even performed as an acylating agent. For example, the hecogenin-containing Material using a mixture of acetic anhydride and acetic acid, preferably in proportions of 2 to 3 parts by volume of acetic acid to 1 part by volume Acetic anhydride, can be acetylated particularly well. The use of acetic acid is advantageous in that it firstly results in the deposition of the hecogenin acetate before completion of the acetylation avoided and secondly the crystallization through Decomposition of any excess anhydride to acetic acid by adding a suitable amount of water and letting the acetate crystallize out can be easily obtained from the acetic acid solution obtained. The crystallization of hecogenin acetate from acetic acid generally has the advantage that it is undesirable steroid-like impurities, such as other sapogenins, as well as remaining traces of color removed, causing the product after washing with water for most synthetic purposes.

If desired, further purification can be carried out by recrystallization of the hecogenin ester from a suitable solvent, such as ethyl acetate, Acetic acid or petroleum ether (preferably one boiling in the range from 100 to 120 ° C Fraction), if necessary, in the presence of a small amount, e.g. B. about 511 / o Activated carbon can be achieved.

The procedure described above may lead to lead to a material that is not quite as pure as appears desirable. Such illaterial, for example, often looks good, but shows a slightly lower melting point than pure hecogenin. For example, according to the above-described crystallization process when using hecogenin acetate such an impure material obtained from the mother liquors, its melting point is about 10 ° C below that of pure hecogenin acetate. The cleaning of one Experience has shown that such material, which does not meet the requirements, has difficulties prepared, but it was found that by rehydrolysis it to hecogenin with a solution of an alkali in a lower molecular weight alcohol and then purified again acylation and treatment according to the procedure described above can be.

The following examples explain the process according to the invention without to restrict them. Example 1 14 kg of sisal residues (Tanganyika) were added with stirring heated under reflux with 225 l of methyl alcohol for 11/2 hours. After sitting down The clear methanol extract was decanted off the suspended solids. The remaining ones Solids were further boiled with 225 l of fresh methanol with stirring for 1 hour heated to reflux. After the suspended solids were allowed to settle, the Methanol extract was again decanted and the combined extracts were dried to dryness evaporated, the last traces of methanol being removed under reduced pressure became. The viscous residue was with 18 l of petroleum ether (boiling range 100 to 120 ° C) stirred and filtered off. The cake was washed with 6 l of petroleum ether and dried at 80 ° C. 4.3 kg of the pale green crude hecogenin were used for 2 hours 73 1? @Lethyl alcohol, 1.1 kg of activated carbon and 0.5 kg of kieselguhr to boil under reflux heated. The mixture was filtered through a heated stainless steel filter, the residue is washed with 61 methyl alcohol and the filtrate and washing liquids were allowed to cool; the next day the purified hecogenin was filtered off, washed with 4 l of methanol and dried in an oven at 80 ° C .; it was 1.76 kg of a white solid substance obtained. From the mother liquors were after Evaporation to a quarter of its volume gained another 0.5 kg.

1.67 kg of the purified hecogenin were heated with 1.7 l of acetic anhydride and 3.41 of acetic acid until completely dissolved and a vigorous reaction began. After refluxing for 2 hours, 226 ml of water were carefully added to decompose the excess acetic anhydride and the solution was allowed to cool overnight, during which time hecogenin acetate crystallized out. After filtering off, this was washed with a little acetic acid and then with water. After drying in an oven at 100 ° C., 1.435 kg of substance with a mp = 243 to 248 ° C. were obtained from the acetic acid mother liquors on evaporation to a quarter of their volume, a second yield of 125 g with a mp = 237 to 243 ° C received. Example 2 15 kg of sisal residues (Jamaica) were heated with 280 l of 1-lethanol for 1 hour with stirring and reflux. The mixture was cooled to room temperature and filtered through a filter press, the filter cake being washed with 22 liters of methanol. The filtrate and washing liquids were combined and refluxed for 1 / 2h hour with 2.25 kg of activated charcoal and 1.6 kg of kieselguhr. After cooling to room temperature, the mixture was filtered through a filter press and the cake washed with 22 liters of methanol. The filtrate and washings were concentrated together to a volume of 701 and allowed to cool. The crystallized product was filtered, washed with 6 l of methanol and dried at 80 ° C., whereby 2.26 kg were obtained. After the mother liquors had been concentrated to 6 liters and allowed to cool, the crystallized product was filtered off, washed and dried at 80 ° C., which gave a further 0.89 kg.

2.94 kg of the crude hecogenin thus obtained were converted from 38 liters of methyl alcohol with 0.29 kg of activated carbon (18%), as described in Example 1, recrystallized. Included a first crop of 1.57 kg and a second crop of 0.49 kg were obtained.

1.57 kg of the purified hecogenin were acetyiated as described in Example 1 using 1.6 l of acetic anhydride and 3.2 l of acetic acid, 212 ml of water being added at the end of the reaction. 1.14 kg of acetate with a melting point of 225 to 235 ° C. were obtained. Purification was carried out by dissolving 44 liters of petroleum ether (boiling range 100 to 120 ° C.) and treating with 100 g of activated charcoal. After the solution had been filtered off in the heat, the filtrate was allowed to cool and then obtained as a first crop 810 g of hecogenin acetate with a mp = 240 to 246 ° C. and as a second crop 98 g with a mp = 229 to 236 ° C. Example 3 25 kg of sisal residues (Tanganyika) were heated for 1 hour with 270 l of methanol and 3 kg of activated charcoal with stirring and reflux and then filtered off while hot through a filter press. After washing the filter cake with 22 liters of methanol, the combined filtrate and washings were evaporated to about 50 liters and allowed to cool overnight. The crystallized solid substance was filtered off and washed with 5 l of methanol. The filter cake was slurried with 151 petroleum ether (boiling range 100 to 120 ° C.), filtered off, washed with a further 5 liters of petroleum ether and dried at 80 ° C., which gave -1.82 kg of brownish-yellow colored crude hecogenin.

The methanol mother liquors were concentrated to 71 and allowed to cool. The crystalline product was filtered off and washed with 2 l of methanol. The filter cake was stirred with 11 petroleum ether (boiling range 100 to 120 ° Cl, filtered off, with Washed 200 ml of petroleum ether and then dried at 80 ° C; 0.26 kg was obtained.

The crude hecogenin was purified by recrystallization from methanol and acetylated according to Examples 1 and 2. Example 4 20 g of the one used in earlier Experiments obtained mother liquors obtained raw hecogenin acetate from F. = 230 to 235 ° C were 1/2 hour with 450 ml of methanol and 20 ml of 40% sodium hydroxide under Heated to reflux. After cooling, the crystalline solid substance was filtered off, washed with a little methanol and dried. It was made by heating with 16.5 ml Acetic anhydride and 33 ml of acetic acid are acetylated under reflux for one hour. The mixture was allowed to cool, and the crystalline precipitate was filtered off and washed with a little acetic acid and then with water. The dry solid substance was recrystallized using 0.7g (5%) activated charcoal from 560m1 petroleum ether. The isolated hecogenin acetate (9.7 g) had a melting point of 242 to 246 ° C.

Example s 100 g of sisal residue (Tanganyika) were used for 1 hour 800 ml of ethanol denatured with methanol are heated with stirring and reflux. After adding of 30 g of kieselguhr, the solution was filtered hot and the filter cake with 50 ml Alcohol washed. The filter cake was left with 800 ml of alcohol for an additional hour extracted again and the mixture filtered hot. The filter cake was 50 ml of alcohol and the filtrates combined with the washes were evaporated to dryness. The viscous residue was washed with 30 ml of petroleum ether (boiling range 100 to 120 ° C), and the crystals were washed with 30 ml of petroleum ether dried at 100 ° C. 25.9 g of pale green crude hecogenin were obtained, which test showed 17% sapogenins.

Claims (5)

PATEN TANSPRÜCHF-1. Process for the preparation of hecogenin and its acyl derivatives from crude hecogenin, characterized in that the crude hecogenin is dissolved in a lower alcohol, the undissolved impurities are separated from the solution obtained and the higher purity hecogenin either crystallizes out directly from the solution obtained or through Evaporation of the resulting solution to practically dryness, dewaxing of the residue, dissolving the purified material in a lower alcohol and letting the hecogenin crystallize out of the resulting solution and optionally acvated with an acid anhydride in a manner known per se. 2. The method according to claim 1, characterized. that the lower alcohol used is methanol or ethanol. 3. The method according to claim 1 or 2, characterized in that about 90 parts by volume of hot alcohol per Part by weight of the isosapogenins present in the raw material is used. 4. Procedure according to claims 1 to 3, characterized in that the solution of crude hecogenin is also used treated in the lower alcohol with decolorizing activated carbon. 5. The method according to claim 1, characterized. that dewaxing can be done with a cold hydrocarbon solvent, especially with an aliphatic hydrocarbon solvent, in particular Petroleum ether, Performed-Pamphlets Considered Journ. Cupid. Cliem. Soc., 65, 1943, p. 1199; 64, 1942, p. 1283: British Patent Specification 722186, 702072.