METHOD TO PREPARE (El-OXIMA OF 4-ri7B-METOXY-17a-METOXIMETHYL-3-OXOESTRA- 4.9-DIEN-11 ß-IUBENZALDEHÍDO (ASOPRISNIL)
FIELD OF THE INVENTION The present invention relates to a method for the reliable and reproducible preparation of (E) -oxime of 4- [17P-methoxy-17a-methoxymethyl-3-oxostra-4,9-dien-1 ip-iljbenzaldehyde (asoprisnil) on a pilot and manufacturing scale. The asoprisnil that is prepared with this method is distinguished by a very good physical stability, making it particularly suitable for the manufacture of solid pharmaceutical forms (tablets, coated tablets, etc.), and can even withstand accelerated ICH conditions (40 ° C) , 75% of HR).
BACKGROUND OF THE INVENTION The preparation of asoprisnil on a laboratory scale is described, for example, in DE 43 32 283 A1; Further details on asoprisnil can be found in EP 0571 15, DE 35 04 42, DE 100 56 675 A1 and DE 100 56 676 A1. Intermediates have been described for preparing asoprisnil, for example, the preparation of 3,3-dimethoxyestra-5 (10), 9 (11) -dien-17-one (nordiendione ketal) is described in French patent 151 4 086 and the publication "Pharmazie 39, No. 7 (1984)" (B. Menzenbach, M. Hiibner, R. Sahm, K. Ponsold: "Synthese potentieller Metaboliten der STS 557 (Dienogest)"), the preparation of 3,3,173 -trimethoxy-17a-methoxymethyl-tetra-5 (10): 9 (11) -diene (trimethoxydiene) from nordienedione ketal is described in EP 0 648 779, EP 0 648 778, EP 0 411733, DD 289539, DE 100 56675 , and the preparation of the dienone aldehyde and asoprisnil is described in DE 43 32 283. In EP 129 26 07 new solid forms of asoprisnil are described, in particular, a highly pure, amorphous and stable, or highly crystalline form (ansolvate / anhydrate), a method for its preparation, and its use in pharmaceutical compositions. The solid forms are distinguished in particular by their high stability. In these preparation methods the principle of the preparation of the various intermediates and the white product, the active ingredient (E) -oxime of 4- [17-methoxy-17a-methoxymethyl-3-oxostrae-4.9, is described. -dien-1 i p-il] benzaldehyde (asoprisnil), on a laboratory scale. The literature does not describe details on the reaction conditions for preparing asoprisnil on a pilot scale, or even on a manufacturing scale. According to the details described in the literature, it is not possible to prepare the individual intermediaries at the manufacturing scale in such a way that it is possible to obtain the asoprisnil with medicinal activity and its precursors from said intermediates in a reliable and reproducible way, or with the analytical parameters required by authorities or legislation, in accordance with the ICH Q6A, 2000 guidance, such as by-product profile, active ingredient content, chemical and physical purity, and stability. Accordingly, although the amorphous solid form described in EP 129 26 07 exhibits good stability as an active ingredient, in the solid dosage form there is partial to complete crystallization under accelerated ICH conditions (40 ° C, 75% r.h.). Consequently, the suitability of asoprisnil that can be obtained with this method for a solid dosage form is low.
SUMMARY OF THE INVENTION Thus, an object of the present invention is to provide a productive and reliable method for preparing asoprisnil, with which it is possible to prepare the active ingredient in a reproducible manner, with a high purity and high yield, at a pilot and manufacturing scale. . Purity refers to the physical and chemical purity of the active ingredient.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 describes the preparation of asoprisinil. Figure 2 describes the synthesis of 3,3-dimethoxy-tetra-5 (10), 9 (11) -dien-17-one (nordiendione ketal) from 17 -? G? ß8? G3-4, 9 ?? ß? -3- ?? 3 (hydroxyestradienone). Figure 3 shows the enthalpy of fusion (DSC at 5 K / minute): 4.1 J / g.
DETAILED DESCRIPTION OF THE INVENTION The object is met with the present multi-step method for preparing asoprisnil.
It consists of the following stages (see Figure 1): 17 -hydroxyestra-4,9-dien-3-one (hydroxyestradienone)
I 3,3-dimethoxyestra-5 (10), 9 (11) -dien-l7-one (nordiendione ketal)
i 3,3,17 -trimethoxy-17a-methoxymethyl-tetra-5 (10), 9 (11) -diene (trimethoxydiene)
i 4- [17p-methoxy-17a (methoxymethyl) -3-oxoestra-4,9-dien-1 ^ -yl] -benzaldehyde (dienone aldehyde)
l 11 - [4- (hydroxyiminomethyl) -phenyl-17p-methoxy-l7a-methoxymethyltra-4,9-dien-3-one (asoprisnil) In the first step of the method (see Figure 2), the synthesis of 3, 3-dimethoxy-tetra-5 (10), 9 (11) -dien-17-one (nordiendione ketal) from 17 -hydroxyestra-4,9-dien-3-one (hydroxyestradienone), the ketal resin is obtained by the following means: - by oxidation of 17 -hydroxyestra-4,9-dien-3-one (hydroxyestradienone) in estra-4,9-dien-3,17-diene (nordiendione) and the subsequent selective ketalization to obtain 3,3-dimethoxyestra-5 (10), 9 (11) -dien-17-one (nordiendione ketal), or - > by ketalization of hydroxyestradienone in 170-hydroxy-3,3-dimethoxy-tetra-5 (10), 9 (11) -diene (hydroxy ketal) and the subsequent oxidation to obtain nordiendione ketal. The second stage of the method, the preparation of 3,3,17-trimethoxy-17a-methoxymethyltranstra-5 (10), 9 (11) -diene (trimethoxydiene) from nordiendione ketal, takes place in three steps, through of the stages of 3,3-dimethoxyestra-5 (10), 9 (11) -dien-17 [3-spiro-1 ', 2'-oxirane (nordienepirano) and 3,3-dimethoxyestra-5 (10), 9 (11) -dien-17ß- ?? (ether of nordieno). In a third step, trimethoxydiene is converted to 5a, 10a-epoxide (enpoxide), and in a subsequent Grignard reaction with dimethyl ketal of 4-bromobenzaldehyde and catalyzed with Cu (l), it is converted to the so-called dimethoxy acetal of (3,3,17p-trimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17a-methoxy-methyl-tr-9-en-5a-ol). The reaction of dimethoxy acetal with acids such as, for example, acetic acid with a strength of between 85 and 95%, makes it possible to obtain 4- [17-methoxy-17a-methoxymethyl-3-oxostra-4,9-dien-1 i -yl] benzaldehyde (dienone aldehyde). The procedure allows to reduce the formation of by-products, so it ensures the possibility of reproducing and validating each individual step in this stage of the method. The resulting product has a purity that can be checked with individual specific analytical evaluations (HPLC purity, UV content), the preparation has a reliability and reproducibility that allows to reduce the amount of impurities, such as, for example, by-products of the Grignard reaction (Wurtz products), 11a-aldehyde and 5a-OH aldehyde. For the final stage, the synthesis of (E) -oxime of 4- [17-p-methoxy-17a-methoxymethyl-3-oxostra-4,9-dien-11-yl] benzaldehyde, that is, asoprisnil, the aldehyde of dienone is reacted with hydroxyamine hydrochloride in organic solvents such as, for example, pyridine or methylene chloride, as described in DE 43 32 283. Next, the product is processed and purified by methods known to those trained in the art. techniques, such as chromatography, fractional filtration or crystallization, and subjected to spray drying. In this regard, it is particularly important to prepare amorphous asoprisnil microparticles with high physical purity and stability, and in particular, reproducible, in the solid dosage form. It is known that there is an elevated risk of recrystallization in the preparation of pure amorphous forms of active ingredients when performing spray drying, so that recrystallization can occur in the active ingredient alone or due to contact with the excipients of the pharmaceutical form ( Nurnberg, Acta Pharmaceutica Technologica, 26, 1980). Both the crystalline form and the amorphous form of asoprisnil described in EP 129 26 07 satisfy the stability requirements as active ingredients and for pharmaceutical processing. However, the asoprisnil microparticles must also have sufficient stability as active ingredients (drug substance) in the solid dosage form itself under accelerated ICH conditions. This imposes special requirements on physical purity, which in amorphous structures has a direct effect on its stability in relation to recrystallization. Then, it is indispensable that a non-detectable recrystallization of these microparticles occurs during the storage of the solid dosage form under normal conditions (25 ° C, 60% r.h.) and accelerated conditions (40 ° C, 75% r.h.). The reliable and particularly reproducible preparation of these microparticles imposes special requirements on the purification and drying of asoprisnil. Therefore, in the method according to the invention there is also included a step to dry the asoprisnil where the contamination of the microparticles with seed centers is greatly reduced by means of an appropriate procedure. In all spray drying systems, the dried particles are deposited to a greater or lesser extent on the hot internal surfaces of the apparatus, for example, the wall of the tower. Surprisingly, it has been discovered that the wetting processes that occur as a result of incomplete evaporation of the droplets, which is associated with a brief and localized increase in the concentration of ethanol in the particle layer, result in the formation of so-called Seed crystals in a few seconds. The seed crystals are crystals or groups of microscopic or submicroscopic crystals that are stable from the thermodynamic point of view and constitute the starting point for the recrystallization process (I. Gutzow, J. Schnelzer, "The Vitreous State", Springer Verlag 1995, Chapter 9, page 221). In the present method according to the invention, the spray drying process is characterized in that the larger drops in the spray cone produced by the atomizing device evaporate so rapidly that even the wetting processes isolated on the surfaces of the apparatus with which the product comes in contact with are reduced very substantially, or better, they are avoided. This wetting effect is reduced or even prevented to a degree distinctly greater than that conventional in conventional spray drying. The distribution of droplet sizes generated in the atomization unit depends on the atomizing device (pressure nozzle, rotating disk, double flow nozzle), its geometry and the atomization parameters. For example, in comparison with other atomizing devices, the double flow nozzle generates a very fine but very wide range of droplet sizes. In contrast, the rotating disk produces a more irregular, but narrower range. The particle size distribution of the dry particles is determined from the range of droplet sizes. In order to use asoprisnil as a drug substance, for example, in forms intended for oral use in low doses, it is crucial to generate a particular particle size distribution. On the one hand, the uniformity of content (CUT - content uniformity), and on the other, especially for hydrophobic substances of low solubility, such as asprrisnil, it is necessary to ensure the kinetics of the dissolution of the active ingredient from the form pharmaceutical In general, a technology is commonly used with which the active ingredient is subsequently micronized. This preferably takes place in spray mills, and constitutes an additional step of the method which is associated with high risks for the stability of the solids and the purity of the phases. The entrance of high energies frequently results in phase transformations or in the generation of planting centers for phase transformations. It is known that amorphous substances such as asprrisnil are commonly dried from the solutions to form a solid film on the surface of the drops. The liquid contents of the globule are subsequently evaporated and in a distinctly slower manner from a blow orifice or by diffusion. Thus, the measured particle sizes are insubstantially smaller than the droplets from which said particles are formed. This second drying phase makes it possible to further delay the kinetics of the drying of the drops. The possibility of completely evaporating and drying a drop to obtain a particle during spray drying depends not only on the size, but also on the geometrical and aerodynamic conditions in the drying tower, for example, on the length of the flight path and speed (Nurnberg, Acta Pharmaceutica Technologica, 26, 1980; Bauckhage, Chem. Ing. Technik 62 (1990), No. 8; Zbicinski, Chemical Engineering Journal 86, 2002, pp. 207-216). Then, another advantageous configuration of the method according to the invention consists in obtaining the active ingredient asoprisnil after spray drying to obtain amorphous microparticles with a particular particle size distribution in one step of the method, without a subsequent micronization. The following describes particularly preferred embodiments of the method according to the invention, which consists of the following steps: hydroxyestradienone - > nordiendiona ketal - > trimethoxydiene - > dienone aldehyde - > asoprisnil (see Figure 1). The hydroxyestradienone starting material of the method according to the invention can be obtained by methods known to those skilled in the art (Menzenbach, Bernd, Huebner, Michael, Zeitschrift für Chemie (1986), 26 (10), 371ff). 1. Nonalignal Cetal 1.1. Nordiendione ketal via nordiendione (hydroxyestradienone - &nt; nordiendione - nordiendione acetal) Oxidation of hydroxyestradienone with chromic acid Performing oxidations with chromic acid during the synthesis of steroid active ingredients is a synthesis stage that is widely used and has been described in detail in the specialized literature. The spheroidal alcohols are oxidized to ketones using a mixture of chromic acid and sulfuric acid (Reagent Jones, J. Chem. Soc. 1946, 39 and J. Chem. Soc. 1953, 2548). This oxidation with chromic acid is carried out in various solvents, such as acetone, DMF, dichloromethane and chloroform. In some cases, DMF and chloroform can be replaced by acetone, which is less problematic in physiological and ecological terms. The disadvantages of this replacement of DMF and chloroform by acetone are the incomplete and non-reproducible conversion of the starting material. For example, the unreacted hydroxyestradienone can only be removed with greater difficulty, whereby it "carries" as an impurity throughout the synthesis of the active ingredient, which generally alters the quality of the synthesized product. According to the invention, the complete and reproducible oxidation of the hydroxyestradienone with chromic acid is carried out in acetone, carrying out the reaction as a two-phase reaction between liquid phases. For this purpose, a certain amount of water is added to a solution of hydroxyestradienone in acetone, so that the water content of the organic phase passes through a minimum in the balance of water distribution between the organic phase and the aqueous phase in chromic acid. This minimum arises due to the surprising occurrence of a phase change of the inorganic phase of chromic acid, whereby water is extracted from the inorganic phase, despite an increase in the total water content of the reaction solution. This has the following results: 1. the solubility of the organic phase for the steroid is improved, 2. the chromium suspension can not trap any starting material because it is possible to instantly reduce the viscosity, and 3. an area can be created of very large mass transfer with the agitator. This minimum is influenced by the conditions of temperature and concentration in the chromic / sulfuric acid. The optimum of these parameters can be determined experimentally by those trained in the art. The complete and particularly reproducible reaction is carried out by adding water, preferably 2-10% by weight based on acetone, to a solution of hydroxyestradienone in acetone, so that a defined systemic concentration of water is obtained (added water plus water). of chromic / sulfuric acid), preferably 10-15% by weight, so that the concentration of spheroids does not exceed 8 g / l of acetone. According to the invention, the subsequent selective monoketalization of the nordiendione diketone is carried out with Lewis acids, according to the following variants: 1. selective ketalization with silicon tetrachloride and methanol: a) the silicon tetrachloride is placed in a mixture of methanol and n-hexane as solvent, and the addition takes place at a temperature in a range between -5 and 15 ° C, preferably between 2 and 10 ° C; b) rapid addition of nordiendione is carried out in the aforementioned temperature range, that is, between -5 and 15 ° C, preferably between 2 and 10 ° C; c) is stirred during crystallization, that is, the solution obtained in b) is preferably stirred at a temperature between 5 ° C and 15 ° C, particularly preferably 10 ° C, for between 60 and 100 minutes, and then at a temperature of temperature between -8 ° C and 0 ° C to complete the crystallization;
d) the resulting crystals are isolated using a solids / liquids separating device, and then washed alternately with methanol and hexane, or methanol / aqueous ammonia; e) the resulting core ketal is dried; or 2. selective ketalization with acetyl chloride and methanol, by using a solution of the crude product of chromic acid oxidation. The variants described for a specific procedure for the selective ketalization of nordiendione are distinguished by a marked reduction in the formation of by-products. These methods result in a product that allows to perform specific individual analyzes in a reliable and reproducible manner, and satisfies the quality requirements. 1.2. Nitiandione ketal via hydroxy ketal In this variant, 17p-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) is first ketalized to obtain the intermediate 17p-hydroxy-3,3-dimethoxystra-5 (10), 9 ( 11) -diene (hydroxy ketal). This is followed by an oxidation in a nordiendione ketal according to an Oppenhauer oxidation: hydroxyestradienone-hydroxy ketal keto-nordiendione. The purification is carried out according to the usual methods known to those trained in the art, for example, by chromatography or fractional filtration. Examples of solvents that may be mentioned include methanol, heptane, cyclohexane, methyl tert-butyl ether, and also combinations thereof, and mixtures of solvents, such as, for example, methyl tert-butyl ether / heptane, cyclohexane / methyl tert. Butyl ether, isopropanol / water. The cyclohexane / methyl tert-butyl ether mixture is particularly suitable. The support material used for a purification by chromatography is, for example, aluminum oxide. Cetalization with trialkyl ortho-methoxides in methanol is described in detail for steroid active ingredients in the literature (Byer, Walter, Lehrbuch der organischen Chemie, 21st edition, S. Hirzel Verlag Stuttgart, p.216). Steroids having a keto function at position 3 are converted to the corresponding dimethyl ketals using trimethyl orthoformate in solvent mixtures containing methanol. In conventional ketalization methods, sulfuric acid or sulfuric acid derivatives, such as, for example, p-toluenesulfonic acid, are added as a catalyst. A disadvantage of the mentioned method is that these catalysts must be subsequently removed by extraction. The ketals are unstable under these acidic aqueous conditions. Therefore, according to the invention, the ketalization is carried out in an ion exchanger activated by acid. The ion exchanger can be placed directly in the reaction solution. The advantage of this is that the ion exchanger can be easily removed by filtration. According to the invention, another variant of the ketalization configuration consists in passing the reaction solution over the ion exchanger activated by acid in what is called the derivation method. This means that it is no longer necessary to remove the ion exchanger. Similarly, Oppenhauer's oxidation of spheroids is described in detail in the literature (Byer, Walter, Lehrbuch der organischen Chemie, 21st edition, S. Hirzel Verlag Stuttgart, page 216). The spheroids with a 17-hydroxyl function are oxidized to obtain the corresponding 17-ketones using aluminum alcoholates and cyclohexanone. However, it is not possible to carry out the reaction of the nordienedione hydroxy ketal in a quantitative manner using conventional aluminum alcoholates, such as, for example, aluminum triisopropoxide. For this reason, according to the invention, the reaction is carried out with aluminum trifluoroacetate diisopropoxide (DIPAT) as catalyst, in the presence of cyclohexanone. The hydroxy ketal is reacted virtually completely by the use of DIPAT. The product of the reaction, the nordiendiona ketal, is obtained as a raw product. However, with conventional methods, such as, for example, recrystallization, it is only possible to obtain a purity of less than 90%. For this reason, according to the invention, the prepared nordienedione ketal is dissolved in tertiary methyl butyl ether, filtered through aluminum oxide, and then eluted with a mixture of cyclohexane and methyl tertiary butyl ether. The product is obtained with a purity greater than 95%. 2. Trimetoxidiene via nordienpyrene and nordien ether According to DE 100 56 675, the nordienepirano is prepared from nordiendione ketal, with trimethylsulfonium iodide and tertiary potassium butoxide in DMF. Then, the nordienepirano is converted with sodium methanolate into methanol in nordien ether. A precondition for this conversion to trimethoxydiene according to the following sequence: nordiendione ketal - >; nordienespirano - > nordien ether - trimethoxydiene comprises the isolation and purification of the ether ether, which is carried out in a complicated manner. When processing is continued in solution, for the conversion to be as quantitative as possible, it is necessary to remove the water and methanol residues originating in the precursors of the nordien ether solution as much as possible. According to the invention, the virtually complete conversion to trimethoxydiene is carried out in the following manner: a) in the nordienespirane stage, carrying out the reaction in DMF in an initial phase, with the addition of the reactants at a temperature in the range between 0 and 25 ° C, preferably between 0 and 20 ° C, and in a phase subsequent to the reaction, at a temperature between 20 and 40 ° C, preferably between 30 and 35 ° C; b) not isolating the reaction product obtained in step a), but rather using it as a buffer solution in solvents, preferably hexane, DMF or THF; c) for the conversion of the nordienepirano from step b) into nordien ether, changing the solvent, preferably during the reaction with sodium methanolate, in particular preferably by azeotropic distillation, whereby the required reaction temperatures of 70 ° C are achieved or more; d) in the trimethoxydiene step, crystallizing from methanol by cooling a solution of spheroids, preferably a solution with 40-50% by weight of steroids, at 20-35 ° C, preferably 25 ° C, for approximately between 1 and 2 hours, and then performing an additional cooling at a temperature between -5 ° C and -15 ° C, preferably -10 ° C. Since the water and solvent contents in the starting material for the conversion of nordiendone ketal to nordienepirano have a substantial participation, in this stage a virtually complete conversion is obtained by limiting the amounts of methanol and water in the core ketal, which are considerable as a result of the preparation. This is ensured when the water content in the core ketal is less than 1%, preferably less than 0.6%, and the methanol content is less than 1%, preferably less than 0.8%. The change of the solvent in the conversion of the nordienespirano in nordien ether, for example, hexane by methanol, preferably by azeotropic distillation, allows to continue the synthesis without great losses and without complicating the isolation of the intermediate from the nordienespirano. As the water and solvent contents in the starting material for the conversion of nordien ether to trimethoxydiene have an equally important participation to that which they have in the conversion of the pendant of nordiendione to nordienepirano mentioned above, in this case the complete conversion is also guaranteed. in trimethoxydiene by reducing the amounts of water and methanol derived from the ether ether stage, preferably by azeotropic distillation, to less than 0.8% water, particularly preferably less than 0.4% water. The removal of the unreacted ether is not possible later. The specific control of the temperature has the effect of distinctly reducing the formation of by-products, while allowing a virtually complete and rapid conversion. In particular, the formation of the nordienespyran epimer 17a and the formation of 16-methyltrimethoxydiene are greatly minimized. The specific handling of the crystallization guarantees a very good reduction of the amount of by-products in the crystals. In particular, the unreacted nordien ether and the by-products, such as, for example, the 17-oxetane compound of the nordiene ketal, remain in solution. The resulting product can be filtered, washed and dried easily. 3. Dienone aldehyde via enepoxide and dimethoxy acetal Trimethoxydiene is dissolved in dichloromethane and pyridine. Hexafluoroacetone is added as a catalyst for the subsequent epoxidation. A hydrogen peroxide solution is placed at a temperature between 25 and 35 ° C. Once the conversion has occurred, the phases are separated. After removing the peroxides by means of washing with water, sodium bicarbonate solution and sodium thiosulfate solution, the organic phase is changed to THF by distillation. The dimethoxy acetal is prepared by means of a Grignard reaction, from enepoxide and magnesium in THF, with dimethyl acetal bromobenzaldehyde. The bromobenzaldehyde of dimethyl acetal is obtained by the acetalization of 4-bromo-benzaldehyde with trimethyl orthoformate in an organic solvent, such as, for example, methanol and THF, in the presence of an acid catalyst, for example, sulfuric acid derivatives ( for example, p-toluenesulfonic acid). For this reason, in a variant of the method, the reaction is carried out as described in 1.2., With an ion exchanger activated with acid, where the ketalization takes place with a derivation method according to the invention. As those skilled in the art should know, in some circumstances it may be necessary to activate the magnesium for the Grignard reaction, for example, with dibromoethane or DIBAH. A catalytic amount of copper chloride (l) is added to the Grignard solution, which amount can be controlled before addition, for example, using a temperature between 10 and 20 ° C, under inert conditions and with agitation. Then, preferably in less than 60 minutes, a solution of 17a- (methoxymethyl) -3,3-17P-dimethoxy-5a, IOa-epoxystr-9 (11) -nene and THF is added to the stirred Grignard solution, a temperature between -10 ° C and 55 ° C, with a maximum of 45 ° C, after which a subsequent reaction is carried out at the same maximum temperature. The processing is carried out according to methods known to those trained in the art. 4; Asoprisnil 4.1. Synthesis According to the invention, the step for preparing asoprisnil as crude product is composed of the following individual steps: a) a suspension or a solution of dienone aldehyde, for example, in pyridine or methylene chloride, is mixed with a solution of hydroxyamine hydrochloride in pyridine; b) the reaction solution obtained in step a) is placed at a temperature of 0-30 ° C, preferably 20-25 ° C, in a solvent, preferably ethyl acetate, methylene chloride or toluene, which is controlled at a temperature of 5-15 ° C, with stirring, and acidified with hydrochloric acid or sulfuric acid; c) the processing is carried out according to the following methods: - > crystallization by the addition of tertiary methyl butyl ether to the solution, whereby a tertiary methyl butyl ether solvate with 12-20% tertiary methyl butyl ether is obtained, followed by drying, or - > filtration, preferably through silica gel, change by methanol by distillation, precipitation with water and drying of the solid obtained in this way. 4.2. Processing The processing of the asoprisnil obtained with the synthesis method described above takes place by means of an HPLC purification and a subsequent spray drying, processes which will be described below. Purification by HPLC can be carried out according to methods known to those skilled in the art. A solution of asoprisnil in alcohol, preferably lower alcohols, such as ethanol, methanol and isopropanol, is atomized at a specific temperature regime in a spray drying system as described in WO 01/90137. This regime is such that the outlet temperature of the drying gas is maintained between 40 ° C and 90 ° C, preferably between 75 ° C and 90 ° C. Moreover, the mass ratio between the atomization gas used and the atomization solution is between 1, 5 and 10, preferably between 2.5 and 5, and the mass ratio between the atomization gas used and the solution of The atomization employed is at least 10, preferably at least 20. Moreover, the dry asoprisnil particles are separated from the drying gas in a filter for the product, and are deposited virtually completely in a collection vessel. It has been discovered that the otherwise unusual deposition of spray-dried particles results in distinctly more unstable products in the case of asoprisnil. Then, the deposition of spray-dried asoprisnil particles in a filter for the product is a particularly advantageous embodiment of the invention. The use of fresh, unused filter surfaces for each production process is another advantageous embodiment of the invention, since a product with the desired stability properties can be prepared in this way. Even a few ppm of crystalline asoprisnil particles can result in significant destabilization of the amorphous product. It has been observed that, in spite of performing a thorough purification with the usual solvents, such as ethanol or methanol, surprisingly small residues of crystalline substances remain in the material in the filter, residues that contaminate the amorphous product with seed crystals. The spray drying is followed by a subsequent drying. In this process, the microparticles are treated under a vacuum < 100 mbar, preferably less than 10 mbar, and at a temperature lower than 90 ° C, preferably lower than 50 ° C, and / or with an application of a solvent-free drying gas, for a prolonged period, until the content of alcohol is less than preferably less than 0.5%, in order to further stabilize the amorphous structure. The procedure described results in physically pure and stable amorphous asoprisnil microparticles. In the present documentation, the term "physical purity" has a definition consistent with that provided in the literature (A. Burger, Pharmazie in unserer Zeit 26, 1997, 93), that is, it refers to a chemically pure substance that essentially comprises impurities of the same chemical substance, but in a different solid state (polymorphic, amorphous, pseudopolymorphic) and only in small amounts . Depending on the type of substance, these physical impurities can be measured quantitatively by thermomicroscopy, differential scanning calorimetry (DSC), powder X-ray diffractometry or other methods. Accordingly, the present invention relates to a method for the preparation, processing and reliable and reproducible purification of amorphous asoprisyl, which can be practiced at the manufacturing scale. The method according to the invention makes it possible to prepare asoprisnil on a pilot scale and / or of manufacture with high purity and a high overall yield of crude asoprisnil, that is, not yet purified, of 58% (crude). Taking into account the content of active ingredient in the final product of asoprisnil, a yield of 47% (net) is obtained. For the methods described above for preparing asoprisnil on a laboratory scale, published in DE 433 2283, WO 02/38582 and WO 02/38581, yields of between 5 and 23% are reported. The comparison of the obtained yields is only possible under certain conditions, since the synthesis starts with different initial materials and / or takes place through different routes. In comparison with the methods described in DE 433 2283 and WO 02/38582, where starting at a substantially later point, namely, 3,3-dimethoxy-5a, IOa-epoxystr-9 (11) -in-17- ona, and in comparison with the method described in WO 02/38581, where starting with a subsequent starting material, 3,3-dimethoxy-tetra-5 (10), 9 (11) -dien-17-one, the method according to the invention, where it is started with 17R-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) and is followed with the following steps: 3,3-dimethoxystra-5 (10), 9 (11) -dien-l7-one (nordiendiona ketal)
i 3,3,17 -trimethoxy-l7a-methoxymethyl-tetra-5 (10), 9 (11) -diene (trimethoxydiene)
i 4- [17β-methoxy-17a (methoxymethyl) -3-oxostra-4,9-dien-11β-yl] -benzaldehyde (dienone aldehyde)
i 11 - [4- (hydroxyiminomethyl) -phenyl-17p-methoxy-17a-methoxymethyl-tetra-4,9-dien-3-one (asoprisnil), allows to obtain an increase in the distinguishable yield, of 47 or 58%. Surprisingly, with the method according to the invention, an improvement in performance is obtained despite the conversion of much larger quantities, ie, to a pilot or manufacturing scale, than those described in previously published laboratory methods. Another advantage of the method according to the invention is that each individual stage of the method can be implemented reliably and reproducibly on a pilot scale and at a manufacturing scale. The method for preparing asoprisnil according to the invention can be practiced in accordance with the following examples, which serve to provide a detailed explanation without restricting the invention. The method can be implemented using agitated reactors, distillation apparatus, crystallizers, centrifuges and conventional dryers in the chemical practice oriented to the production of batches. 1. Nonalignal Cetal 1.1. Nordiendione ketal via nordiendione Variant A 12 kg of hydroxyestradienone are dissolved in 180 l of acetone, and then 7.5 l of water are added. Chromic / sulfuric acid for oxidation is prepared from 50 I of water, 18 kg of chromium trioxide and 12 I of sulfuric acid. At 15 ° C, 17.5 I of this chromic / sulfuric acid are added with 260-270 mg of chromium trioxide / ml over a period of one hour, and then the reaction is continued at 22-25 ° C for 1 hour. . The processing is carried out according to the usual methods known to those trained in the art (reduction of Cr6 + with bisulfite, concentration and crystallization from mixtures of acetone / water). 33 I of methanol and 46 I of n-hexane are controlled at a temperature of 2-10 ° C. They are first added 1.2 kg of SiCI4, and then 10 kg of nordiendione with agitation. Once the crystallization is started, the mixture is stirred at 5-15 ° C for between 1 hour and 1.5 hours, then cooled to a temperature between 0 and -8 ° C, and filtered with suction. If the crystallization does not start without help, it is also possible to carry out the sowing in a conventional manner. The crystals are washed on a frit with hexane and methanol in ammonia. Drying results in 80-109% expected yield. The quantities that can be obtained reliably are detailed in the specification, and according to the method according to the invention, a purity of 95% of the area (HPLC), an unreacted ratio of zero of 0, are obtained. 2% of the area, and a proportion of the most important unspecified byproduct of 1.0% of the area. Variant B 100 g of hydroxyestradienone are introduced into 400 ml of acetone and 20 ml of water. A solution of chromic / sulfuric acid, prepared from 101 ml of water, 35.6 g of chromium trioxide and 32 ml of sulfuric acid, is added, with an internal temperature of 12 ° C, so that they are introduced 3/4 of said solution in two hours, and the rest is introduced in another 2 hours. After stirring for 30 minutes, the excess chromic acid is decomposed by adding 26 ml of isopropanol. The change is then carried out by water, by means of a vacuum distillation at an internal temperature of 60 ° C. For this, approximately 400 ml of water is needed. The precipitated intermediate (nordiendione) is removed by suction filtration and washed with water until neutral. Then, the nordienedione is dissolved in 170 ml of methylene chloride and stirred with 3.6 g of diatomaceous earths for 20 minutes. The diatomaceous earths are removed by filtration, and the filtrate is washed twice, each with 50 ml of water, to remove the chromium salts. The organic phase is changed to methanol by vacuum distillation and concentrated to 300 ml. 440 ml of hexane are added at an internal temperature of 20 ° C. The suspension is cooled to 5 ° C. 26 ml of acetyl chloride are added in a period of one minute, and then washed with 37 ml of methanol. The starting material is dissolved, after which the product precipitates. If necessary, sowing with stainless steel is done after 3 minutes. Once the crystallization is started, the mixture is stirred for 80 minutes, then the temperature is adjusted to 5 ° C and it is made alkaline by adding 37 ml of a sodium hydroxide solution with a force of 50%. The product (nordiendione ketal) is isolated and washed first with a mixture of 320 ml of methanol and 13 ml of aqueous ammonia, and then with 35 ml of hexane. It is suctioned under a nitrogen atmosphere and dried under vacuum. Yield: 82.4 g of nordiendione ketal. 1.2. Nordienedione ketal via hydroxy ketal 66.7 kg of hydroxyestradienone are dissolved in 500 l of toluene and 400 ml of methanol. If appropriate, filtration is carried out through 3.4 kg of activated carbon. The addition of 51 I of trimethyl orthoformate and another 70 I methanol is followed by a circulation with the aid of a pump over 33.4 kg of an ion exchanger activated at 30 ° C until the conversion to hydroxy ketal is completed. The addition of 20 I of pyridine and 400 I of a sodium carbonate solution is followed by stirring and separation of the phases. The aqueous phase is extracted again several times with 135 I of toluene. The combined organic phases are concentrated to 300 I, and a change is made to 300 I of toluene by distillation. 40 kg of aluminum isopropoxide and 180 l of heptane are introduced into a second reaction vessel. 14.7 I of trifluoroacetic acid are introduced at a temperature of 50 ° C. The addition of 6.7 I of pyridine is followed by the removal of the heptane by distillation to obtain 95 I. After cooling to 25 ° C, the organic hydroxy ketal solution is added with stirring. The addition of a total of 76 I of cyclohexanone, introduced in part, is followed by stirring for at most 6 hours, until the conversion is complete. The addition of 570 I of a sodium hydroxide solution is followed by stirring and phase separation. The aqueous phase is extracted several times with 70 l of toluene. The combined organic phases are washed several times with 70 l of water. The mixture is concentrated to about 270 I, and a change is made by water by distillation. This results in 270 I of a suspension of crude product and water. The crude product is isolated and dissolved in 270 I of methyl tert-butyl ether. The solution is washed with 70 I of water. The aqueous phase is extracted with 70 l of methyl tert-butyl ether. The combined organic phases are filtered and concentrated to 135 I. After adding 540 I of cyclohexane, the solution is filtered through 134 kg of aluminum oxide. The aluminum oxide is washed with a mixture of a total of 270 I of cyclohexane and 100 I of methyl tert-butyl ether. The fractions containing the product are concentrated and a change is made by 200 I of heptane by distillation. The heptane solution is cooled to -15 ° C, whereupon the product crystallizes. The product is isolated and washed with 35 l of heptane and 35 l of water. The product of nordiendione ketal is dried at a maximum of 40 ° C until the loss during drying is <0.5%. 2. Trimetoxidiene via nordienpyrene and nordien ether 65.6 kg of nordienedione ketal and 50 kg of trimethylsulfonium iodide are suspended in 150 l of dimethylformamide (DMF), and cooled to 15 ° C. A solution of 30 kg of potassium tert-butoxide in 65 I of DMF at 20 ° C is introduced. The mixture is stirred at 30 ° C for 30 minutes, and the conversion is verified by TLC. 200 I of water and 410 I of hexane are added at a temperature between 30 and 40 ° C to transfer the reaction product to the hexane phase. The aqueous phase in DMF is extracted four times, each with 50 I of hexane. The combined organic phase is washed twice with 85 I of water. The aqueous phase is extracted with 50 l of hexane. It is then concentrated in vacuo to a volume of 150 I and mixed with 130 I of methanol. Approximately 250 I of a solution of sodium methanolate (30%) is added to the solution in methanol, and the distillate is removed at atmospheric pressure until a temperature of at least 70 ° C is reached. Subsequently, the mixture is heated to reflux for 1.5 hours until the conversion is complete. The vacuum distillation is continued with the continuous addition of 215 I of water. The ether thus obtained is taken up in 330 I of methyl tertiary butyl ether (MtBE), the organic phase is separated off and the aqueous phase is extracted twice, each with 100 l of methyl tertiary butyl ether. The combined organic phases were extracted twice 100 I of water. The aqueous phase was extracted again with 60 I of MtBE. This is followed by the concentration in vacuo, and when a volume of 165 I is reached, the water and methanol are removed by azeotropic means from the organic phase with the addition of 165 I of methyl tertiary butyl ether to maintain this volume. 27.2 I of methyl iodide and 10 I of MtBE are added. Then 70.5 kg of tertiary butyl ether of potassium are introduced into 300 I of MtBE at 35 ° C. The reaction continues between 1 and 2 hours, and the conversion is verified. After adding 245 I of water, the organic phase is separated and washed with 65 l of water. The aqueous phase is extracted with 65 I of MtBE. This is followed by the concentration to approximately 80 I in vacuo. The distillation to change by methanol and the concentration to a volume of 140 I are followed by stirring at 25 ° C for between 1 and 2 hours. Afterwards, the mixture is cooled to below -10 ° C and stirred for another 2 hours. Subsequently, the product is isolated and washed with 15 I of cold methanol. The trimethoxydiene is dried under vacuum at 40 ° C. 3. Dienone aldehyde via enepoxide and dimethoxy acetal 3.1. Enepoxide 10.6 I of hexafluoroacetone are added to a solution of 80.6 kg of trimethoxydiene, 755 l of methylene chloride and 11 l of pyridine. To this solution is added gradually 81 I of a hydrogen peroxide solution with a force of 35% at a temperature between 30 and 40 ° C. After the addition, the mixture is stirred at a temperature between 30 and 40 ° C for 30 minutes, and then the conversion is verified. The organic phase is separated and washed twice with 175 I of an aqueous solution of sodium bicarbonate. Subsequently, the organic phase is washed with 250 I of sodium thiosulfate solution. Finally, the organic phase is washed three or four times with 160 I of water. The organic phase washed in this way is concentrated under vacuum and at a temperature of 30 ° C, and is changed to THF by distillation, so that the final volume is 170 I. 3.2. Dimethoxy acetal The Grignard reagent is prepared from 13 kg of magnesium reagent, 280 I of THF, 7.3 kg of DIBAH and 106 I of bromobenzaldehyde of dimethyl acetal. The bromobenzaldehyde of dimethyl acetal is prepared by the acetalization of 4-bromo-benzaldehyde with trimethyl orthoformate in methanol in the presence of acid catalysts, preferably an acid ion exchanger, preferably in a derivatization method. After adding approximately 0.5 kg of copper chloride (1), the enepoxide solution is added and the mixture is stirred at 40 ° C until the conversion is complete. The excess Grignard reagent is destroyed by introducing 490 I of an ammonium chloride solution at a maximum temperature of 10 ° C. After adding 142 I of diluted acetic acid, the organic phase is washed 3 or 4 times with 122 I of ammonium chloride solution. The aqueous phases are extracted again three or four times with 90 I of ethyl acetate. The combined organic phases are washed with 170 I of sodium chloride solution and concentrated to 220 I in vacuo at 40 ° C. 3.3. Dienone Aldehyde The dimethoxy acetal solution is mixed with 312 I of concentrated acetic acid and 35 I of water, and heated to 90 ° C for about 30 minutes. After cooling, 680 I of water are introduced. The crude product is isolated, stirred and washed several times with 170 I, 170 I and 110 I, and 340 I of MtB ether, at temperatures up to 50 ° C. The dienone aldehyde is dried under vacuum at a temperature between 30 ° C and 40 ° C. 4. Asoprisnil 4.1. Synthesis Variant A 15 kg of dienone aldehyde in 38 I of pyridine are suspended. To this is added 42 I of a prepared solution of hydroxyamine hydrochloride / pyridine. After successfully verifying the conversion and taking the mixture in 88 I of ethyl acetate, 6 N HCl is added while monitoring the pH (2-4). After separating the phases and extracting the organic phase with water, concentrate the organic phase of ethyl acetate, distill with toluene and then mix with 50 l of methyl tertiary butyl ether. The crystallization results in the desired product. Then it dries. After the HPL examination, the following impurities were observed with the method according to the invention: Oxime = 92.9% of the Aldehyde area = 0.08% of the Z-Oxime area = 3.1% of the A Dioxime = 3, 1% of A Variant B 50 kg of dienone aldehyde are dissolved in 250 I of methylene chloride. A solution of 8.86 kg of hydroxyamine hydrochloride in 130 I of pyridine is added at 20 ° C in a period of between 1 and 2 hours. After successfully verifying the conversion, approximately 280 I of sulfuric acid are introduced at a temperature <lt.10 ° C. At 10 ° C, the phases are separated and the aqueous phase is extracted twice with 120 I of methylene chloride. The organic phase is washed three times with 200 l of water, and extracted again with 110 l of methylene chloride. The organic phase is concentrated to 200 I in vacuo and filtered through silica gel. The organic phase is washed with approximately 100 l of a sodium bicarbonate solution. Vacuum distillation is carried out to obtain a final volume of 200 I of methanol. The product solution in methanol is added to 510 I of water, whereupon the product precipitates. Asoprisnil (crude) is isolated and dried under vacuum at a temperature between 30 and 40 ° C. The crude product is purified by preparative high performance liquid chromatography (HPLC). For this purpose, asoprisnil (crude) is dissolved in dichloromethane and applied to a silica gel. Then, the substance is eluted with a toluene / acetone mixture. In addition to the pure fraction, a mixed fraction is obtained, which can be subjected again to a chromatography to increase the yield. The pure fraction is concentrated and isolated in the next step of the process. 4.2. Processing and purification Example 1 5.1 kg of asoprisnil in 57 I of ethanol (DAB) are dissolved with heating at 60 ° C. The transparent solution is pumped with a minimum pulsation, using a pump that operates at a rate of 6 l / hour, towards the double flow nozzle (d = 0.8 mm) of a spray dryer, which has a cylinder with a diameter of 800 x 620 mm, a basal cone at 60 ° and a heating operation and atomization with gas in favor of the current. The asoprisnil solution is maintained at a temperature of 65 ° C during the process. The atomization gas is adjusted in the nozzle to obtain 12 Nm3 of N2 / hour. The heating gas flow is 85 m3 / hour. The heating gas inlet temperature is adjusted so that the outlet temperature in the dryer is between 78 ° C and 85 ° C. The dried microparticles are deposited on fresh textile filters with a PTFE membrane of 1 m2. For this purpose, the surface of the filter is treated with periodic pulses of nitrogen in a direction opposite to the current. After the spray drying process, the asoprisnil powder is subjected to a subsequent drying process. For this purpose, the drying chamber is alternatively subjected to a vacuum of 5 mbar and an application of nitrogen heated to 45 ° C. Each of the phases of vacuum and nitrogen application is extended for 45 minutes. The drying period is 12 hours, and the temperature reached by the final product is 35 ° C. The asoprisnil microparticles obtained in this way are analyzed and present the following characteristics: Residual solvent content: 0.36% ethanol Particle distribution: d50 = 2.1 μ? T ?, d100 = 21 μ? T? Fusion enthalpy (DSC at 5 K / minute): 4.1 J / g (see Figure 3) Number of crystals at 170 ° C: 1187 crystals per mg XRPD: amorphous, no crystalline reflections Example 2 Coated tablets are stored 25 mg film in packages with PVC-AI ampoules with excipients of usual pharmaceutical use and 16% active ingredient according to example 1, which, according to a DSC with a heating rate of 5 K / minute, present a fusion enthalpy of 4.1 J / g, and according to a thermomicroscopy, have a quantity of crystals of 1187 per mg, at 40 ° C, with 75% of hr, as indicated in the ICH guidelines. Analysis of the stability by XRPD After 9 months at 40 ° C, 75% r.r .: amorphous