BRPI0710517A2 - method for preparing 4- [17 beta-methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-diean-11beta-yl] benzaldehyde (e) -oxime (asoprisnyl) - Google Patents

Abstract

<B> METHOD FOR PREPARING 4- [17BETA-METOXY-ALPHA-METOXIMETHYL-3-OXOESTRA-4,9-DIE N-11-BETA-ILIBENZALDEIDE (E) -OXYME (ASOPRISNIL). <D> The present invention relates to refer to a method for reliable and reproducible preparation of 4- [17beta-methoxy-17alpha-methoxymethyl-3-oxoestra4,9-dien-11beta-yl] be nzaldehyde (E) -oxime (asoprisnil) on a pilot and industrial scale. Asoprisnil, which is prepared by this method, is distinguished by very good physical stability and is therefore particularly suitable for the manufacture of solid dosage forms (tablets, coated tablets, etc.).

Description

Patent Descriptive Report for "METHOD FOR PREPARING 4- [17BETA-METHYXY-17ALFA-METOXYMETHYL-3-OXOESTRA-4,9-DIEN-11 BETA-IL] BENZALDEHYDE (E) -OXYM (ASOPRIS-NIL)".

The present invention relates to a reliable and reproducible method for the preparation of 4- [17β-methoxy-17βδ-methoxymethyl-3-oxoestra-4,9-dien-11β-yl] benzaldehyde (E) -oxime (asoprisnil) at scale. -pilot and industrial.

Visnil, which is prepared by this method, is distinguished by very good physical stability and is therefore particularly suitable for the manufacture of solid pharmaceutical forms (tablets, coated tablets, etc.) that withstand even accelerated ICH conditions ( 40 ° C, 75% rh).

The laboratory scale preparation of asoprisnil is described, for example, in DE 43 32 283 A1; Further details on the structure can be found in EP 0571 15, DE 35 04 42, DE 100 56 675 A1 and DE100 56 676 A1.

Intermediates for preparing asprisnil, for example, the preparation of 3,3-dimethoxystra-5 (10), 9 (11) -diene-17-one (nordienedione ketal), are described in French Patent 151,486 and in a publication in "Pharmazie 39, No. 7 (1984)" (B. Menzenbach, M. Hubner, R. Sahm, K.Ponsold: "Synthese Potentieller Metaboliten der STS 557 (Dienogest)"), preparation of 3,3, 17β-trimethoxy-17α-methoxymethyl-estra-5 (10): 9 (11) -diene (trimethoxyidiene) from nordienedione ketal in EP 0 648 779, EP 0 648 778, EP 0 411 733, DD 289539, DE 100 No. 56675 and the preparation of dienone and asoprisnil aldehyde in DE 43 32 283. EP 129 26 07 describes solid new forms of asoprisnil, in particular a high purity, stable amorphous or highly crystalline form (unsolvate / anhydrate), a method for preparation and use in pharmaceutical compositions. Solid forms are distinguished in particular by their high stability.

These preparation methods describe the principle of preparation of the various intermediates and the target product, the active ingredient 4- [17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl] benzaldehyde (E ) -oxime (asoprisnil) on a laboratory scale. Details of reaction conditions for preparing asprrisnil on pilot scale or industrial scale are not described in the literature.

According to details described in the literature, it is not possible to prepare individual intermediates on an industrial scale in such a way that medicinally active asoprisnil and its precursors can be obtained from this with confidence and reproducibility and have the analytical parameters required by the authorities. or by legislation in accordance with the ICH Q6A, 2000 Guidelines, such as by-product profile, active ingredient content, chemical and physical purity and stability. Thus, while the amorphous solid form described in EP 129 26 07 shows good stability as a pure active ingredient, in solid pharmaceutical form there is partial to complete recrystallization under accelerated ICH conditions (40 ° C, 75% r.h.). The suitability of asoprisnil obtainable by this method for a solid pharmaceutical form is therefore low.

Therefore, it is an object of the present invention to provide a productive and reliable method for preparing asprisnil with which the active ingredient can be reproducibly prepared with high purity and pilot and industrial scale yield. Purity means the physical and chemical purity of the active ingredient.

This objective is achieved by the present multistage method for preparing asoprisnil. It consists of the following stages (see Figure 1):

17p-Hydroxystra-4,9-dien-3-one (hydroxyestradienone)

3,3-Dimethoxiestra-5 (10), 9 (11) -dien-17-one (nordienodi-one ketal)

3,3,17p-Trimetoxy-17α-methoxymethyl-estra-5 (10), 9 (11) -diene (tri-methoxydien)

4- [17β-Μείόχί-17cc (methoxymethyl) -3-oxoestra-4,9-dien-11 β-yl] benzaldehyde (dienone aldehyde)

11 - [4- (Hydroxyiminomethyl) phenyl-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one (asoprisnyl)

In the first stage of the method (see Figure 2), the synthesis of 3,3-dimethoxystra-5 (10), 9 (11) -dien-17-one (nordienedione ketal) from 17β-hydroxiestra-4,9 -dien-3-one (hydroxyestradienone), the nordienodi-one ketal is obtained

• by the oxidation of 17β-hydroxiestras-4,9-dien-3-one (hydroxiestras-dienone) to estra-4,9-diene-3,17-dione (nordienedione) and subsequent selective ketalisation to 3,3- dimethoxystra-5 (10), 9 (11) -dien-17-one (nor-dienedione ketal) or

• by ketalizing hydroxyestradienone to 17β-hydroxy-3,3-dimethoxystra-5 (10), 9 (11) -diene (ketal hydroxy) and subsequent paracetal oxidation of nordienedione.

The second stage of the method, the preparation of 3,3,17-trimethoxy-17α-methoxymethyl-estra-5 (10), 9 (11) -diene (trimethoxyidiene) from denordienedione ketal occurs in three steps through stages 3. , 3-dimethoxystra-5 (10), 9 (11) -diene-17β-spiro-1 ', 2'-oxirane (nordienespiran) and 3,3-dimethoxystra-5 (10), 9 (11) -dien- 17β-οΙ (nordiene ether).

In a third stage trimethoxyidiene is converted to the corresponding 5a, 10a-epoxide (enepoxide) and, in a subsequent Cu (I) catalyzed Grignard reaction with 4-bromobenzaldehyde dimethyl ketal, converted to the so-called acetal dimethoxy ( 3,3,17p-trimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17a-methoxy-methylestr-9-en-5a-ol). Reaction of dimethoxyacetal with acids such as, for example, with 85 to 95% strong acetic acid, provides 4- [17p-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl] benzaldehyde (aldehyde dienone).

The procedure reduces the formation of by-products and thus ensures the reproducibility and validity of each individual step at this stage of the method. The resulting product has a purity which is proved by the specified individual analytical evaluations (HPLC purity, UV content) and whose preparation reliably and reproducibly reduces the amounts of impurities, such as, for example, Grignard reaction by-products. Wurtz), 11 α-aldehyde and 5α-OH-aldehyde.

For the final stage, synthesis of dienone 4- [17beta-methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-dien-11beta-yl] benzaldehyde (E) oxime - asospris-nyl aldehyde is reacted with hydrochloride hydroxyamine in organic solvents such as, for example, pyridine or methylene chloride as described in DE 43 32 283.

The product is subsequently processed and purified by methods known to one of ordinary skill in the art, such as chromatography, crystallization or fractional filtration, and subjected to spray drying. In this connection, it is particularly important to prepare asoprisnil amorphous microparticles which have a high and in particular reproducible physical purity and stability in solid pharmaceutical form. It is known that there is a high risk of recrystallization in the preparation of pure amorphous forms of spray drying active ingredients, the recrystallization of which may occur in the active ingredient alone or by contact with excipients of the pharmaceutical form Nürnberg, Acta Pharmaceutica Technological, 26.1980).

Both the crystalline and amorphous asoprisnil form described in EP 129 26 07 satisfy the requirements to be met by stability as an active ingredient and for pharmaceutical processing. However, asoprisnil microparticles may additionally show sufficient stability as an active ingredient (Pharmacological Substance) in solid pharmaceutical form itself under accelerated ICH conditions. This creates special demands on physical purity, which in amorphous structures has a direct effect on their stability in relation to recrystallization. Therefore, it is essential that no detectable recrystallization of these microparticles occur during storage of the solid pharmaceutical form under normal conditions (25 ° C, 60% r.h.) and under accelerated conditions (40eC, 75% r.h.). The reliable and in particular reproducible preparation of these microparticles brings special needs in the purification and drying of aso-prisnil.

The method according to the invention therefore also includes an asprisil drying step in which contamination of the microparticles with seed cores is considerably reduced by a suitable procedure.

In any spray drying system, dry particles are deposited to a greater or lesser extent on the hot internal surfaces of the equipment, for example on the tower wall. Surprisingly, it has been found that humidification events resulting from incompletely vaporized drops, which are associated with only a slight and localized increase in the concentration of ethanol in the particle layer cause the formation of the so-called seed crystals within seconds. By seed crystals are meant microscopic or submicroscopic crystalline crystallites or clusters that are thermo-dynamically stable and are the starting point for recruitment processes (I. Gutzow, J. Schnelzer1. 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 largest spray droplets produced by the spraying equipment are vaporized so rapidly that even isolated humidification events on equipment surfaces with which the product is sprayed. comes in contact with are greatly diminished or better eliminated. This humidifying effect is reduced or even eliminated to a significantly higher degree than usual in conventional spray drying.

The size distribution of the droplets generated in the atomization unit depends on the atomization equipment (pressure nozzle, disc nozzle, double fluid nozzle), their geometry and the atomization parameters. The double fluid nozzle generates, for example, by comparison with other atomizing equipment, a very thin range, but very large droplet sizes. The rotating disc, in contrast, a thicker but otherwise narrower range of droplet sizes. The particle size distribution of dry particles is determined by the variation of droplet sizes.

For the use of asoprisnil as a pharmacological substance, for example in low dose oral forms, it is crucial to generate a particular particle size distribution. On the one hand, content uniformity (CUT) and, on the other hand, especially low solubility hydrophobic substances such as asoprisnil, the dissolution kinetics of the active ingredient in the pharmaceutical form must be ensured. Traditionally, a technology with which the dry active ingredient is subsequently micronized is generally common. This happens in jet mills and signifies an additional step in the method associated with high risks to solid stability and phase purity. This high energy input often leads to phase transformations or seed center generation for phase transformations.

Amorphous substances such as asoprisnil are often known to dry out from solutions to form a solid film on the surface of the droplets. Only subsequently and distinctly slower, the liquid contents of the globule vaporize through a ruptured or diffusion orifice. The measured particle sizes are therefore substantially smaller than the droplets from which they are formed. This second drying phase further delays the kinetics of large drop drying. Whether or not a droplet can be completely vaporized and dried to a particle during spray drying will depend not only on its size, but also on the geometry and aerodynamic conditions in the drying tower, for example the length of the spray path. available flight and speed (Nuremberg, Acta Pharmaceutical Technology, 26, 1980; Bauckhage, Chem. Ing. Technik 62 (1990), No. 8; Zbicinski, Chemical Engineering Journal 86, 2002, pp. 207-216).

A more advantageous embodiment of the method according to the invention is therefore to obtain the active ingredient after spray drying in the form of amorphous microparticles with a particular particle size distribution in a subsequent micronization method step.

Particularly preferred embodiments of the method according to the invention are described below, consisting of the following stages: nordienedione -> trimethoxyidene dienone aldehyde aldehyde (see Figure 1) hydroxyestradienone.

The hydroxyestradienone starting material of the method according to the invention may be obtained by methods known to one skilled in the art (Menzenbach, Bernd; Huebner, Michael Zeitschrift fur Chemie (1986), 26 (10), 371ff).

1. Nordienedione ketal1.1. Nordienedione ketal via nordienedione (hydroxyestradienone-> nordienedione -> nordienedione ketal)

Hydroxyestradienone oxidation with chromic acid

Performing chromic acid oxidations on the synthesis of steroid active ingredients is a synthesis stage that is widely used and described in detail in the specialized literature. Steroidal alcohols are oxidized to ketones using a mixture of chromic acid and sulfuric acid (Jones reagent, J. Chem. SOC. 1946, 39 and J. Chem. Soc. 1953,2548). This chromic acid oxidation is performed in various solvents such as acetone, DMF, dichloromethane and chloroform. DMF and chloroform can in many cases be replaced by acetone, which is less physiologically and ecologically reprehensible. The disadvantages of replacing DMF and chloroform with acetone are incomplete and non-reproducible conversion of the starting material. For example, unreacted hydroxyestradienone can be removed only with great difficulty and is therefore "transferred" as impurity during synthesis of the active ingredient, thereby greatly impairing the quality of the synthesized product.

Complete and reproducible oxidation with chromic hydroxyestradienone is carried out according to the invention in acetone by controlling the reaction as a two-phase reaction between liquid phases. To this end, a certain amount of water is added to a solution of hydroxyestradienone in acetone such that the water content of the organic phase passes a minimum in the water distribution equilibrium between the organic phase and the aqueous phase of chromic acid. This minimum arises through the surprising occurrence of a phase change in the inorganic phase of chromic acid, which extracts water from the inorganic phase despite an increase in the total water content of the reaction solution. The result is that

1. solubility of organic phase for steroid is improved,

2. chrome sediment cannot capture any broken material because its viscosity can be instantly reduced and

3. thus a very large mass transfer area can be created by the stirrer.

This minimum is influenced by temperature and deconcentration conditions in chromic / sulfuric acid. The best of these parameters can be determined experimentally by someone skilled in the art.

The complete and particularly reproducible reaction is obtained by the addition of water, preferably 2 to 10% by weight based on acetone, to a solution of hydroxyestradienone in acetone, such that a defined concentration of water in the system (water added plus acidic water sulfuric acid), preferably from 10 to 15% by weight, is adjusted with the steroid concentration not exceeding 8 g / l acetone. Subsequent selective monoketetalization of nordienedione diketone is carried out according to the invention with Lewis acids according to the following variants:

1. Selective ketalization with silicon tetrachloride and methanol

(a) Silicon tetrachloride is placed in a mixture of methanol and n-hexane solvents, with the addition occurring within a temperature range of -5 to 15 ° C, preferably 2 to 10 ° C;

b) the rapid addition of nordienedione occurs within the aforementioned temperature range between -5 to 15 ° C, preferably 2 ° C to 10 ° C;

c) stirring during crystallization, where the solution obtained in b) is preferably stirred from 5 ° C to 15 ° C, particularly preferably 10 ° C, for 60 to 100 minutes, and then at -8 ° C to 0 ° C to complete. crystallization;

d) the resulting crystals are isolated using a solid / liquid separation device and are then washed alternately with methanol and hexane or methanol / aqueous ammonia.

e) drying the resulting nordienedione ketal or

2. Selective ketalization with acetyl chloride and methanol using a crude product solution from chromic acid oxidation.

The described variants of a specific procedure for selective nordienedione acetalization are distinguished by the fact that byproduct formation is greatly reduced. Said methods provide a product that makes specified individual analytical assessments reliably and reproducibly possible and meets the demands of high quality.

1.2. Nordienedione ketal via ketal hydroxy

In this variant, first 17p-hydroxystra-4,9-dien-3-one (hydroxyestradienone) is ketalized to give intermediate 17p-hydroxy-3,3-dimethoxystra-5 (10), 9 (11) -diene (hydroxy ketal). ). This is followed by oxidation to a nordienedione ketal by Oppenhauer oxidation:

hydroxyestradienone -> nordienedione ketal hydroxy ketal

Purification occurs by the usual methods known to one of ordinary skill in the art, for example by chromatography or fractional filtration. Examples of which may be mentioned are the following solvents such as methanol, heptane, cyclohexane, methyl tert-butyl ether as well as combinations thereof and solvent mixtures such as, for example, methyl tert-butyl ether / heptane, cyclohexane / methyl tert-butyl ether, isopropanol / water. Cyclohexane / methyl tert-butyl ether are particularly suitable.

The support material used for chromatographic purification is, for example, aluminum oxide.

Ketalization with trialkyl orthoformates in methanol is described in detail for steroidal active ingredients in the literature (Byer, Walter, Lehrbuch der organischen Chemie, 2nd Edition, S. HirzelVerlag Stuttgart1 ρ. 216).

Steroids having a keto function at position 3 are converted to the corresponding dimethyl ketals by the use of trimethyl orthoformate in methanol-containing solvent mixtures. In conventional ketalization methods, sulfuric acid or sulfuric acid derivatives such as, for example, p-toluenesulfonic acids are added as catalysts. A disadvantage of the mentioned procedure is that these catalysts must subsequently be removed by extraction. Ketassains are unstable under these aqueous acid conditions.

Ketalization is therefore performed according to the invention on an acid activated ion switch. The ion switch can be placed directly into the reaction solution. The advantage of this is that the ion exchanger can be easily removed again by filtration. A further variant of the ketalization configuration is, according to the invention, to pass the reaction solution through an acid-ionized switch in the so-called bypass method. This means that the removal of the ion switch will no longer be necessary.

Oppenhauer steroid oxidation is also described in detail in the specialized literature (Byer, Walter, Lehrbuch der organischen Chemie, 2nd Edition, S. Hirzel Verlag Stuttgart, p. 216). Steroids with a 17-hydroxy function are oxidized to the corresponding 17-ketones by the use of aluminum alcoholates and cyclohexanone. However, it is not possible to perform the nordienedione hydroxy ketal -> ketal reaction quantitatively using conventional aluminum alcoholates such as, for example, aluminum triisopropoxide. For this reason, the reaction is carried out according to the invention with aluminum diisopropoxide trifluoroacetate (DIPAT) as catalyst in the presence of cyclohexanone. Ketal hydroxy is virtually completely reacted through the use of DIPAT.

The product of the nordienedione ketal reaction results in a crude product. However, it is possible with conventional methods such as, for example, recrystallization, to obtain a purity of just under 90%. Therefore, the prepared nordinedione ketal is dissolved according to the invention in tertiary methyl butyl ether, filtered through aluminum oxide and then eluted with a mixture of cyclohexane and methyl butyl tertiary ether. The product is obtained with a purity of more than 95% .2. Trimethoxidiene through nordiene spirane and nordiene ether

Nordienespiran is prepared from nordienedio ketal according to DE 100 56 675 with trimethylsulfonium iodide and potassium butoxide in DMF. Nordienespiran is then converted using sodium methanolate in methanol to nordiene ether. A precondition for its further conversion to trimethoxydiene according to the following

nordienedione ketal nordienespiran nordiene trimethoxy diene ether

is that the nordiene ether is isolated and purified in a complicated manner.

In further processing in solution, for as quantitative conversion as possible, it is necessary to remove water and methanol residues originating from the precursors of the nordienoton ether solution as completely as possible.

Virtually complete conversion to trimethoxyidiene is obtained according to the invention by

(a) carry out in the nordienespiran stage the DMF reaction at an early stage with the addition of reagents in a temperature range of 0 to 25 ° C, preferably 0 to 20 ° C and in a post-reaction phase between 20 at 40 ° C, preferably 30 to 35 ° C;

b) the reaction product obtained in step a) not being isolated, but being employed as a nordienespiran solution in solvents, preferably in hexane, DMF or THF;

c) for converting the nordienespiran from step b) to denordiene ether, exchanging the solvent, preferably during the reaction with sodium methanolate, particularly preferably by azeotropic distillation and thereby obtaining the required reaction temperatures of 70 ° C or higher;

d) at the trimethoxyidene stage, crystallize from methanol by cooling a steroid solution, preferably a 40 to 50 wt% steroid solution, to 20 to 35 ° C, preferably 25 ° C, for about 1 to 2 hours and then cool further to -5 ° C to -15 ° C, preferably -10 ° C.

Since the water and solvent contents in the starting material for the conversion of nordienedione ketal to nordienespiran have a substantial function, a virtually complete conversion is obtained at this stage by limiting the amounts of methanol and water, which are considerable as a result of the preparation. in the nordienedione ketal. This is guaranteed when the water content is less than 1%, preferably less than 0.6% and the methanol content is less than 1%, preferably less than 0.8% in the nordienedione ketal.

Exchanging the solvent in the conversion of nordienespiran to denordiene ether, for example from hexane to methanol, preferably by azeotropic distillation, allows synthesis to continue without large losses and complicated intermediate isolation of nordienespiran.

Since the water and solvent content in the starting material for the conversion of nordiene ether to trimethoxyidene has an equally important function as in the above mentioned conversion of nordienedione ketal to nordienoespiran, in this case also complete conversion to trimethoxyidene is guaranteed. by reducing the amounts of water and methanol derived from the nordiene ether stage, preferably by azeotropic distillation, to less than 0.8% water, particularly preferably less than 0.4% water. Removal of unreacted denordiene ether is not possible later.

Controlling the specific temperature has the effect of clearly reducing the formation of by-products although, at the same time, conversion is virtually complete and rapid. In particular, the formation of nordienespiran epimers 17a and the formation of 16-methyltrimethoxyidiene is greatly minimized.

Specific crystallization control ensures a very good reduction in the amount of by-products in the crystals. In particular, unreacted nor-diene ether and by-products such as, for example, the nordiene ketal 17-oxetane compound remain in solution. The resulting product can be easily filtered, washed and dried.

3. Dienone aldehyde through enepoxide and dimethoxy acetal

Trimethoxidiene is dissolved in dichloromethane and pyridine. Hexa-fluoroacetone is added as a catalyst to subsequent epoxidation. A hydrogen peroxide solution is added in a controlled manner at 25 to 35 ° C. After the conversion has taken place, the phases are separated. The organic phase, after removal of the peroxides by washing with water, sodium bicarbonate solution and sodium thiosulfate solution, is exchanged for THF by distillation. Dimethoxy acetal is prepared by a Grig-nard reaction from enepoxide and magnesium in THF with bromobenzaldehyde dimethyl acetal. Bromobenzaldehyde dimethyl acetal is obtained by acetalizing 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 (eg, p-toluenesulfonic acid) . For this, the reaction is performed as described in 1.2.com with an acid-activated ion switch, with ketalization occurring by a bypass method according to the invention in a preferred variant of the method. As one skilled in the art is aware, activation of magnesium chips for the Grignard reaction, for example with dibromoethane or DIBAH, may be required in some circumstances. A catalytic amount of copper (I) chloride is added to the Grignard solution, which can be controlled prior to use, for example a temperature of 10 to 20 ° C under inert and shaking conditions. Subsequently, preferably within less than 60 minutes, a solution of 17α- (methoxymethyl) -3,3-17β-trimethoxy-5α, 10α-epoxyestr-9 (11) -ene and THF is added to the solution of Grignard is stirred at -10 ° C to 55 ° C, maximum 45 ° C, subsequently a post-reaction is carried out at the same maximum temperature. Processing takes place by methods known to the person skilled in the art. Asoprisnil4.1. Synthesis

The stage for preparing asoprisnil as a crude product is, according to the invention, the following individual steps:

(a) a suspension or solution of dienone aldehyde, for example in pyridine or methylene chloride, is mixed with a solution of hydroxyamine hydroxychloride in pyridine;

b) the reaction solution obtained in step a) is placed at a temperature of 0 to 30 ° C, preferably 20 to 25 ° C, in a solvent, preferably ethyl acetate, methylene chloride or toluene, which is controlled by a 5 to 15 ° C, with stirring, and acidified with hydrochloric acid or sulfuric acid;

c) processing takes place by

Crystallization by the addition of tertiary methyl butyl ether to the solution thereby obtaining a tertiary methyl butyl ether solvate with 12 to 20% tertiary methyl butyl ether and subsequent drying or

Filtration, preferably through silica gel, exchanging paramethanol for distillation, precipitation with water and drying of the solid obtained in this manner.

4.2. Processing

Processing of asoprisnil obtained from the synthetic method described above occurs by HPLC purification and subsequent spray drying, the procedure of which is described below.

HPLC purification may be performed by methods known to the person skilled in the art.

A solution of asopropyl alcohol, preferably lower alcohols such as ethanol, methanol and isopropanol, is sprayed with a specific temperature regime in a spray drying system as described in WO 01/90137. Such a regime is such that the drying gas outlet temperature is maintained at 40 ° C to 90 ° C, preferably 75 ° C to 90 ° C. In addition, the mass ratio of the atomizer gas employed to the atomized solution is 1.5 to 10, preferably 2.5 to 5, and the excess ratio of the drying gas employed to the atomized solution employed is at least at least 10, preferably at least 20. In addition, the dried asoprisnil particles are separated from the drying gas on a filter and deposited virtually completely in a collection flask. It has been found that the deposition of otherwise atomically dried particles through a cyclone surprisingly leads to clearly more unstable products in the case of asoprisnil. The deposition of spray dried spray particles on a filter is therefore a particularly advantageous fashion of the invention. The use of unused new filter surfaces for each production run is an additional advantageous embodiment of the invention as a product with the desired stability properties is prepared in this way. Even a few ppm crystalline asoprisnil departments lead to significant destabilization of the amorphous product. It has been found that despite intense purification with usual solvents such as ethanol or methanol, surprisingly little residues of crystalline substances remain in the filter material, which contaminates the amorphous product with crystallization seeds. Spray drying is followed by post drying. In this procedure, the microparticles are vacuum treated at <10 kPa (100 mbar), preferably less than 1 kPa (10 mbar) and at a temperature lower than 90 ° C, preferably below 50 ° C and / or with flux. with a solvent free drying gas for an extended period until the alcohol content is less than 1%, preferably less than 0.5%, in order to further stabilize the amorphous structure. The described procedure results in physically pure and stable microparticles.

The term "physical purity" here refers, according to the literature (A. Burger, Pharmazie in unserer Zeit 26, 1997, 93), to a chemically pure substance which comprises essentially impurities of the same chemical substance, but in a different solid state (polymorph, amorphous, pseudopolymorph) only in small quantities. Depending on the type of substance, these physical impurities can be quantitatively measured by thermomicroscopy, differential scanning calorimetry (DSC), powder X-ray diffractometry and other methods.

Accordingly, the present invention relates to a method for the reliable and reproducible preparation, processing and purification of amorphous sterile, which can be performed on an industrial scale. The method according to the invention makes it possible to prepare high purity pilot and / or industrial scale asprisnil with an overall unpurified yield of 58% (crude). Taking into account the active ingredient content in the final product, a yield of 47% (net) is obtained.

Previously described methods for preparing asprisnil in laboratory scale, as published in DE 433 2283, WO 02/38582 and WO02 / 38581, describe yields of between 5 and 23%. Comparison of the yields obtained is possible only with caveats, because the synthesis begins with different starting materials and / or takes place in different ways. Compared to the methods described in DE 433 2283 and WO 02/38582, which start at a substantially later point, ie 3,3-dimethoxy-5cc, 10a-epoxyester-9 (11) -en- 17-one, and compared to the method described in WO 02/38581, which starts from a starting material also maystardium-3,3-dimethoxystra-5 (10), 9 (11) -dien-17-ona-, the method according to the invention, starting from 17β-hydroxystra-4,9-dien-3-one (hydroxy estradienone) through the following stages

3,3-Dimethoxiestra-5 (10), 9 (11) -diene-17-one (nordiene dione ketal)

3,3,17β-βrimethoxy-17α-methoxymethyl-estra-5 (10), 9 (11) -diene (tri-methoxyidiene)

4- [17p-Methoxy-17a (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde (dienone aldehyde)

11 β- [4- (Hydroxyiminomethyl) phenyl-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one (asoprisnyl)

obtain a distinct increase in yield to 47 to 58%. The method according to the invention surprisingly achieves an improvement in yield despite the conversion of larger quantities, ie on a pilot or industrial scale, than described in previously published laboratory methods. An additional advantage of the method according to the invention is that the individual stage of the method can be reliably executed and reproducible on a pilot and industrial scale.

The method according to the invention for preparing the invention may be performed according to the following examples, which serve for detailed explanation without restricting the invention.

The method can be performed by employing the usual stirred reactors, distillation apparatus, crystallizers, centrifuges and dryers in the practice of batch oriented chemistry.

1. Ketal

1.1. Nordienedione ketal through nordienedione

Variant A

12 kg of hydroxyestradienone is dissolved in 180 l of acetone and then 7.5 l of water is added. Chromic / sulfuric acid for oxidation is prepared from 50 l of water, 18 kg of chromium trioxide and 12 l of sulfuric acid. At 15 ° C, 17.5 l of this chromic / sulfuric acid with 260 to 270 mg of chromium trioxide / ml is added over one hour and then the reaction is continued at 22 to 25 ° C for 1 hour. Processing is carried out by the usual methods known in the art (reduction of Cr6 + with bisulfite, concentration and crystallization from acetone / water mixtures).

33 I methanol and 46 I n-hexane are controlled at a temperature of 2 to 10 ° C. To this are first added 1.2 kg of SiCl4 and then 10 kg of nordienedione with stirring. After crystallization begins, the mixture is stirred at 5 to 15 ° C for 1 hour to 1.5 hours and then cooled to 0 to -8 ° C and filtered with suction. If crystallization does not start spontaneously, it is also possible to sow in a traditional way. The crystals are washed in a frit with hexane and ammoniacal methanol. Drying results in 80-109% of the expected. Reliably obtainable qualities are described in the specification and are obtained with the method according to the invention including 95% purity (HPLC), unreacted nordienedione ratio = 0.2%, largest non-specific by-product = 1.0 A%.

Variant B

100 g of hydroxyestradienone is introduced into 400 ml of α-ketone and 20 ml of water. A chromic / sulfuric acid solution prepared from 101 ml of water, 35.6 g of chromium trioxide and 32 ml of sulfuric acid is added in a controlled manner at an internal temperature of 12 ° C such that% is added. in two hours and the rest in another 2 hours. After stirring for 30 minutes, excess chromic acid is decomposed by adding 26 ml of isopropanol. The switch to water is then carried out by vacuum distillation at an internal temperature of 60 ° C. About 400 ml of water is required for this. The precipitated intermediate (nor dienedione) is suction filtered and washed with water until neutral.

The nordienedione is then dissolved in 170 ml methylene chloride and stirred with 3.6 g kieselguhr for 20 minutes. Kieselguhr is filtered and the filtrate is washed 2 x 50 ml of water each time to remove 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. After one minute, 26 ml of acetyl chloride is added and then washed with 37 ml of methanol. The starting material dissolves, and the product precipitates. If necessary, seeding with nordienedione ketal occurred after 3 minutes.

After crystallization has begun, the mixture is stirred for 80 minutes, then controlled to 5 ° C and made alkaline by adding 37 ml of 50% strength sodium hydroxide solution. The product (nor-dienedione ketal) is isolated and washed with a mixture of 320 ml methanol and 13 ml aqueous ammonia and then 35 ml hexane. It is suction dried under nitrogen atmosphere and vacuum dried. Yield: 82.4 g of nor dienedione ketal.

1.2. Nordienedione ketal via hydroxy ketal66.7 kg of hydroxyestradienone are dissolved in 500 l of toluene and 400 ml of methanol. Filtration through 3.4 kg of activated carbon is performed where appropriate. Addition of 51 I trimethyl orthoformate plus 70 I methanol is followed by pump circulation by 33.4 kg of ion co-mutator at 30 ° C until conversion to ketal hydroxy is complete. The addition of 20 l of pyridine and 400 l of sodium carbonate solution is followed by stirring and phase separation. The aqueous phase is reextracted several times with 135 l of toluene. The combined organic phases are concentrated to 300 l and exchanged to 300 l of toluene by distillation.

40 kg of aluminum isopropoxide and 180 l of heptane are introduced into a second reaction flask. 14.7 l of trifluoroacetic acid are added in a controlled manner at a temperature of 50 ° C. Addition of 6.7 l of pyridine is followed by distillation of heptane to 95 1. After cooling <25 ° C, the organic hydroxy ketal solution is added during stirring. Addition of a total of 76 l of cyclohexanone, measured in part, is followed by stirring for up to 6 hours until conversion is complete. The addition of 570 l of sodium hydroxide solution is followed by stirring and phase separation. The organic phase is reextracted 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 270 l and distilled into water. This results in 270 l of a product and water suspension. The crude product is isolated and dissolved in 270 l of methyl tert-butyl ether. The solution is washed with 70 l of water. The aqueous phase is reextracted with 70 l of tert-butyl methyl ether. The combined organic phases are filtered and concentrated to 135 I. After addition of 540 l 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 l of cyclohexane and 100 l of tert-butyl methyl ether. Product containing fractions are concentrated and exchanged to 200 l of heptane by distillation. The heptane solution is cooled to -15 ° C, to which it crystallizes. The product is isolated and washed with 35 I deheptane and 35 I water. The nordienedione ketal product is dried at a maximum of 40 ° C until the loss on drying is ≤ 0.5% .2. Trimethoxidiene through nordiene spirane and nordiene 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 l of DMF is added in a controlled manner at 20 ° C. The mixture is stirred at 30 ° C for 30 minutes and the conversion is checked by TLC. 200 l of water and 410 l of hexanes are added at 30 to 40 ° C to transfer this reaction product into the hexane phase. The aqueous phase of DMF is reextracted four times with 50 l of hexane each time. The combined organic phase is washed twice with 85 l of water. The aqueous phase is reextracted with 50 l of hexane. Subsequently concentrated in vacuo to a volume of 150 l and mixed with 130 l of methanol. About 250 l of sodium methanolate solution (30%) is added to the methanolic solution, the distillate is removed under atmospheric pressure until at least 70 ° C is reached. The mixture is then heated under reflux for 1.5 hours until conversion is complete. Distillation is maintained under vacuum with continuous addition of 215 l of water. The nor-diene ether thus obtained is placed in 330 l tertiary methyl butyl ether (MtBE), the organic phase is separated and the aqueous phase is extracted twice with 100 l of tertiary methyl butyl ether each time. The combined organic phases are extracted twice with 100 l of water. The aqueous phases were reextracted with 60 l of MtBE. This is followed by vacuum concentration, and in a volume of 165 l, water and methanol are azeotropically removed from the organic phase with the addition of 165 l of tertiary methyl butyl ether to maintain this volume. 27.2 l of methyl iodide and 10 l of MtBE are added to this. Thereafter, 70.5 kg of potassium tertiary butyl ether in 300 l of MtBE is added in a controlled manner at 35 ° C. The reaction is continued for 1 to 2 hours, and conversion is verified. After addition of 245 l of water, the organic phase is separated and washed with 65 l of water. The aqueous phase is re-extracted with 65 l of MtBE. This is followed by concentration to about 80 I under vacuum. Distillation to change to methanol and concentration to a volume of 140 l are followed by stirring at 25 ° C for 1 to 2 hours. The mixture is then cooled to below -10 ° C and stirred for a further 2 hours. The product is subsequently isolated and washed with 15 l of cold methanol. The trimethoxyidene is vacuum dried at 40 ° C.

3. Dienone aldehyde through enepoxide and dimethoxy acetal3.1. Epoxide

10.6 l of hexafluoroacetone is added to a solution of 80.6 kg of trimethoxy diene, 755 l of methylene chloride and 11 l of pyridine. A 35% strength hydrogen peroxide solution is gradually added to this solution while stirring at a temperature of 30 to 40 ° C. After addition, the mixture is stirred at 30 to 40 ° C for 30 min and then a conversion check is performed. The organic phase is separated and washed twice with 175 l of aqueous sodium bicarbonate solution. The organic phase is subsequently washed with 250 l of sodium thiosulfate solution. Finally, the organic phase is washed three to four times with 160 l of water. The organic phase washed in this manner is concentrated in vacuo at a temperature of 30 ° C and exchanged for THF by distillation so that the final volume is 170 l.

3.2. Dimethoxy acetal

Grignard reagent is prepared from 13 kg of magnesium chips, 280 l of THF, 7.3 kg of DIBAH and 106 l of bromobenzaldehyde dimethyl acetal. Bromobenzaldehyde dimethyl acetal is prepared by acetalizing 4-bromo-benzaldehyde with trimethyl orthoformate in methanol in the presence of acid catalysts, preferably acid ion switch, preferably in a bypass method. After the addition of about 0.5 kg of copper (I) chloride, the enepoxide solution is added, the mixture is stirred at 40 ° C until conversion is complete. Excess Grignard reagent is destroyed by adding in 490 l of ammonium chloride solution at a maximum of 10 ° C. After addition of 142 l of dilute acetic acid, the organic phase is washed 3 to 4 times with 122 l of ammonium chloride solution. The fasesaques are re-extracted three to four times with 90 l of ethyl acetate. The combined organic phases are washed with 170 l of sodium chloride solution and concentrated at 220 l in vacuo at 40 ° C.

3.3. Dienone Aldehyde

The acetal dimethoxy solution is mixed with 312 l of concentrated a-skeptic acid and 35 l of water and heated to 90 ° C for about 30 minutes. After cooling, 680 l of water is added in a controlled manner. The crude product is isolated, stirred and washed several times with 170 l, 170 l and 110 l and 340 l of MtB ether at temperatures up to 50 ° C. Dienone aldehyde is vacuum dried from 30 ° C to 40 ° C.

4. Asoprisnil

4.1. Synthesis

Variant A

15 kg of dienone aldehyde is suspended in 38 l of pyridine. To this is added 42 l of a prepared hydroxyamine / pyridine hydrochloride solution. After successful verification of conversion and addition to 88 l of ethyl acetate, 6N HCl is added while pH (2 to 4) is monitored. After phase separation and extraction of the organic phase with water, the organic phase of ethyl acetate is concentrated, distilled with toluene and subsequently mixed with 50 l of tertiary methyl butyl ether. Crystallization results in the target product. Then it is dry.

The following purities were obtained with the method according to the invention after HPLC examination: Oxime = 92.9 area% Aldehyde = 0.08 area% 25 Z-Oxima = 3.1 A%

Dioxime = 3.1 A%

Variant B

50 kg of dienone aldehyde is dissolved in 250 l of methylene chloride. A solution of 8.86 kg of hydroxyamine hydrochloride in 130 l of pyridine is added at 20 ° C over 1 to 2 h. After a successful conversion check, about 280 l of sulfuric acid is added in a controlled manner at <10 ° C. At 10 ° C, the phases are separated, and the phase is reextracted twice with 120 l of methylene chloride. The organic phase is washed three times with 200 l of water, which is reextracted with 110 l of methylene chloride. The organic phase is concentrated at 200 l under vacuum and filtered through silica gel. The organic phase is washed with about 100 l of a sodium bicarbonate solution. Distillation is performed under vacuum to change to a final volume of 200 l of methanol. The solution of the methanolic product is added to 510 l of water, where the crude product precipitates. Aspirisil (crude) is isolated and vacuum dried at 30 to 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 silica gel. The substance is then eluted with a toluene / acetone mixture. A mixed fraction is obtained in addition to the pure fraction and can be rechromatographed to increase yield. Pure affraction is concentrated and isolated in the next step of the process.4.2. Processing and PurificationExample 1

5.1 kg of asoprisnil are dissolved in 57 l of ethanol (DAB) by heating to 60 ° C. The clear solution is pumped with minimum pulsation by a 6 l / h measuring pump to the double fluid nozzle (d = 0.8 mm) of a spray drier, d = 800 χ 620 mm cylinder, 60 ° base cone , in co-current gas heating and spraying operation. The solution of asoprisnil is maintained at a temperature of 65 ° C during this process. The atomizing gas is set at the nozzle to 12 Nm3 N2 / h. The heating gas flow is 85 m3 / h. The inlet temperature of the heating dog is adjusted so that the inlet temperature in the dryer is 78 ° C to 85 ° C. The dried microparticles are deposited on new textile fabrics with 1 m2 PTFE membrane. For this purpose, the filter surface is periodically pulsed freely with countercurrent nitrogen. After the spray drying process, the asprisil powder is subjected to a post drying process. For this purpose, the drying chamber is alternatively subjected to a vacuum of 0.5 kPa (5mbar) and fluxing with heated nitrogen at 45 ° C. The vacuum and flow phases last every 45 minutes. The drying time is 12 h and the final product temperature reached is 35 ° C. Asoprisnil microparticles obtained in this way are analyzed and show the following characteristics:

<table> table see original document page 25 </column> </row> <table>

Example 2

25 mg film-coated tablets in blister packs with usual pharmaceutically excipients and 16% active ingredient according to example 1, which shows by DSC with a warming rate of 5 K / min a melt enthalpy of 4.1 J / g and by thermomicroscopy a crystallite number of 1187 per mg is stored at 40 ° C, 75% relative humidity (rh) as specified in the DOICH guidelines.

Stability analysis with XRPD

After 9 months at 40 ° C, 75% r.h .: amorphous

Claims (26)

1. Method for preparing the pilot and industrial scale through stages 17β-Hydroxiestra-4,9-dien-3-οna (hydroxyestradienone) -3,3-Dimethoxiestra-5 (10), 9 (11) -dien- 17-one (nordienodi-one ketal) -3,3,17β-trimethoxy-17a-methoxymethyl-estra-5 (10), 9 (11) -diene (tri-methoxyidiene) -4- [17β-methoxy-17a (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde (dienone aldehyde) -11- [4- (Hydroxyiminomethyl) phenyl-17β-methoxy-17α-methoxymethyl-estra-4, 9-dien-3-one (asoprisnyl) comprising the following steps: a) synthesis of nordienedione ketal from hydroxyestradenone. by oxidation of 17β-hydroxystra-4,9-dien-3-one (hydroxiestras-dienone) to estrra-4,9-diene-3,17-dione (nordienedione) and subsequent selective ketalisation to 3,3-dimethoxystra -5 (10), 9 (11) -dien-17-one (nor-dienedione ketal) or • by hydroxyestradienone ketalization to 17β-hydroxy-3,3-dimethoxystra-5 (10), 9 (11) - diene (hydroxy ketal) and subsequent paracetal oxidation of nordienedione. -diene-17β-spiro-1 ', 2'-oxirane (nordienespiran) and 3,3-dimethoxystra-5 (10), 9 (11) -dien-17β-ol (nordiene ether), not isolating nordi enoespiran and nordiene ether, c) synthesis of 3,3,17β-trimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17a-methoxymethylestr-9-en-5a-ol) (dimethoxy acetal) from trimethoxyidene through via 17a- (methoxymethyl) -3,3,17p-trimethoxy-5a, 10a-epoxyestr-9 (11) -ene (enepoxide) in a Grignard reaction catalysed by Cu (I) with bromobenzaldehyde dimethyl acetald) synthesis of dienone aldehyde by reaction with acidosis) synthesis of asoprisnil from dienone aldehyde with a solution of hydroxyamine hydrochloride, f) purification by chromatography, g) drying. The method according to claim 1, wherein the hydroxystra-dienone is converted to nordienedione ketal by Lewis acid ketalization and chromic acid oxidation or Oppenauer oxidation. The method according to Claim 2, wherein the hydroxy tradienone is first oxidized and then ketalized or first ketalized and then oxidized. A method according to Claim 3, wherein the chromic acid oxidation first and subsequently a selective ketalization or first and subsequently an Oppe-nauer oxidation. A method according to Claim 3, wherein chromic acid oxidation is carried out as a two phase reaction between two liquid phases. A method according to Claim 5, wherein water, preferably 2 to 10% by weight, based on acetone, is added to a solution of hydroxyestradienone in acetone such that a concentration of water defined in the system, preferably from 10 to 15% by weight, is adjusted, with the steroid concentration not exceeding 8 g / l acetone A method according to Claims 3 and 4, wherein the ketalisation is performed first, preferably on an acid ion switch. A method according to Claim 7, wherein the ketalization occurs in a bypass method. A method according to Claims 3 and 4, wherein the oxidation of Oppenauer occurs with aluminum diisopropoxide trifluoroacetate (DIPAT) catalysis. The method according to Claim 1, the nordie-nodione ketal is completely converted to trimethoxyidiene via the three-stage nordienespiran and nordiene ether stages, characterized in that) performing the DMF1 reaction at an early stage in the nordienespiran stage adding the reactants in a temperature range of 0 to 25 ° C, preferably 0 to 20 ° C and in a post-reaction phase of 20 to 40 ° C, preferably 30 to 35 ° C; reaction product obtained in step a) not being isolated, but being employed as a solution of nordienespiran in solvents, preferably hexane, DMF or THF c) for converting the nordienespiran of step b) to denordiene ether, changing the solvent, preferably during the reaction with sodium methanolate, particularly preferably by azeotropic distillation and thus obtaining the required reaction temperatures of 70 ° C or more; d) in the trimethoxyidene stage crystallize from of the methanol by cooling a steroid solution, preferably a 40 to 50 wt% steroid solution, at 20 to 35 ° C, preferably 25 ° C, for about -1 to 2 hours and then further cooling to -5 ° C to -15 ° C, preferably -10 ° C. The method according to Claim 1, wherein the drying in step g) occurs such that contamination of the dried seed-free microparticles with seed cores in the drying equipment is greatly reduced. A method according to Claim 11, wherein the drying preferably takes place by spray drying, characterized in that a narrow range of particle sizes is obtained by the geometrical and aerodynamic conditions in the atomization equipment, and by spray-drop humidification events. Equipment surfaces with which the product comes into contact are avoided. A method according to any one of the preceding claims 11 to 12, wherein the narrow particle size range is generated by a high atomization efficiency of the atomization unit by maintaining a mass ratio between the atomizer gas employed and the solution. atomization range from 1.5 to 10, preferably from 2.5 to 5, and an excessive ratio of the drying gas employed to the spray solution employed of at least 10, preferably at least 20 and having a temperature of drying at 40 ° C to 90 ° C, preferably 75 ° C to 90 ° C. A method according to claim 13, wherein a high atomization efficiency of the spray unit is produced by a high rotational speed of a rotating disc or high flow of deaerization gas through a double fluid nozzle. A method according to any one of the preceding claims 11 to 14 such that the spray-dried asoprisnil microparticles are subjected to a vacuum drying and / or post-drying of the asoprisnil microparticles with a free drying desolvent gas below 90 ° C, preferably below 50 ° C for at least 12h. A method according to any one of claims 11 to 15, wherein depositing the asprisnil microparticles after spray drying onto a product filter, preferably using new, unused filter surfaces. Physically pure, amorphous asoprisnil microparticles obtainable by a method as defined in any one of the preceding claims 1 to 16. Asoprisnil microparticles according to Claim-17 having an average particle size dso of less than 2.5 μιτι, preferably 2.1 μιτι, and a maximum dioo particle size of less than 25 μηι, preferably 11 μηη. Asoprisnil microparticles according to any one of the preceding claims 17 and 18, characterized in that the melt enthalpy at 194.7 ° C ± 2 ° C, determined by DSC with a heating rate of 5 K / min, is less than 20 J / g, preferably smaller than 5 J / g, preferably less than 1 J / g. Asoprisnil microparticles according to any one of the preceding claims 17 to 19, characterized in that when they are heated to 20 K / min at 170 ° C and then cooled to 20K / min to 90 ° C, the number of crystallites visible by thermomicroscopy is less than 10,000 per mg, preferably less than 4000 per mg, particularly preferably less than 1000 per mg. Asoprisnil microparticles according to any one of the preceding claims 17 to 20, for the manufacture of medicaments. Use of asoprisnil microparticles as defined in claim 21 for the manufacture of a medicament for treating hormone dependent gynecological disorders, especially for the treatment of endometriosis, fibroid or other gynecological dysfunctions. Use of asoprisnil microparticles as defined in any one of the preceding claims 17 to 20, in hormone replacement therapy (HRT) and for female fertility control. A pharmaceutical composition comprising aspartisible microparticles as defined in any one of the preceding claims 17 to 20, together with pharmaceutically acceptable excipients and / or vehicles. Pharmaceutical composition according to Claim 24, characterized in that the composition is a solid pharmaceutical form. Solid pharmaceutical form as defined in claim 25, characterized in that the administration takes place orally.