DE102006018888A1 - Process for the preparation of 4- [17beta-methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-diene-11beta-yl] benzaldehyde (E) -oxime (asoprisnil) - Google Patents

Abstract

The present invention relates to a process for the safe and reproducible preparation of 4- [17beta-methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-dien-11beta-yl] benzaldehyde (E) oxime (asoprisnil) in the pilot and production scale. Asoprisnil, which is produced by this process, is characterized by very good physical stability and is therefore particularly suitable for the production of solid dosage forms (tablets, coated tablets, etc.).

Description

object The present invention is a method for safe and reproducible Preparation of 4- [17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl] benzaldehyde (E) oxime (Asoprisnil) in pilot and production scale.

asoprisnil, which is produced by this method is characterized a very good physical stability and is therefore special suitable for the preparation of solid dosage forms (tablets, dragees, etc.) which also exist under ICH-Accelerated-Conditions (40 ° C, 75% rh).

The production of Asoprisnil on a laboratory scale is, for example, in DE 43 32 283 A1 described; more information on Asoprisnil can EP 0571 15 . DE 350 442 . DE 100 56 675 A1 and DE 100 56 676 A1 be removed.

Intermediates for the production of asoprisnil, bsplw. the preparation of 3,3-dimethoxy-estra-5 (10), 9 (11) -diene-17-dione (Nordiendionketal) are described in French Patent 151 4 086 and in a publication in "Pharmazie 39, H. 7 (1984) "(B. Menzenbach, M. Huebner, R. Sahm, K. Ponsold:" Synthesis of potential metabolites of STS 557 (dienogest) ", the production of 3,3,17β-trimethoxy-17α-methoxymethyl-estra- 5 (10), 9 (11) -diene (trimethoxydiene) from nordiendione ketal in EP 0 648 779 . EP 0 648 778 . EP 0 411 733 . DD 289539 . DE 100 56 675 and the production of dienoaldehyde and asoprisnil in DE 43 32 283 ,

EP 129 26 07 describes new solid forms of asoprisnil, in particular a highly pure and stable amorphous or highly crystalline form (ansolvate / anhydrate), a process for the preparation and the use in pharmaceutical compositions. These solid forms are characterized in particular by a high stability.

These Manufacturing processes describe the principle of production 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. Information about Reaction conditions for the production of asoprisnil in pilot or even production scale not known from the literature.

To the information known from the literature, it is not possible, the produce individual intermediate products on a production scale such that from it the pharmaceutically effective Asoprisnil and its precursors with that of authorities or by the legislator according to ICH Q6A Guidance, 2000 required analytical parameters, such as by-product profile, Content of active ingredient, chemical and physical purity as well Stability sure and can be reproducibly obtained.

So shows the in EP 129 26 07 Although the described amorphous solid form a good stability as a pure active ingredient in the solid dosage form but it comes to partial to complete recrystallization under ICH-Accelerated-Conditions (40 ° C, 75% rh) Obtainable by this method Asoprisnil is therefore for a solid dosage form little suitable.

task The present invention is therefore a productive and safe To provide a method for the production of Asoprisnil, with which the Active ingredient in pilot and production scale in high purity and Yield can be reproducibly produced.

Under Purity is the physical and chemical purity of the active ingredient Understood.

This object is achieved by the present multistage process for producing asoprisnil. It consists of the following stages (s. 1 ):

• – durch Oxidation von 17β-Hydroxy-estra-4,9-dien-3-on (Hydroxyestradienon) zu Estra-4,9-dien-3,17-dion (Nordiendion) und anschließende selektive Ketalisierung zu 3,3 Dimethoxy-estra-5(10),9(11)-dien-17-dion (Nordiendionketal) oder
• – durch Ketalisierung von Hydroxyestradienon zu 17β-Hydroxy-3,3-dimethoxy-estra-5(10),9(11)-dien (Hydroxyketal) und anschließende Oxidation zu Nordiendionketal erhalten.

In the first stage of the process (s. 2 ), the synthesis of 3,3-dimethoxy-estra-5 (10), 9 (11) -dien-17-one (nordienedione ketal) from 17β-hydroxy-estra-4,9-dien-3-one (hydroxyestradienone) becomes the Nordiendionketal either

• - by oxidation of 17β-hydroxy-estra-4,9-dien-3-one (hydroxyestradienone) to Estra-4,9-diene-3,17-dione (Nordiendion) followed by selective ketalization to 3,3-dimethoxy-estra -5 (10), 9 (11) -dien-17-dione (Nordiendione ketal) or
• - obtained by ketalization of hydroxyestradienone to 17β-hydroxy-3,3-dimethoxy-estra-5 (10), 9 (11) -diene (hydroxyketal) and subsequent oxidation to Nordiendionketal.

The second stage of the process, the preparation of 3,3,17-trimethoxy-17α-methoxymethyl-estra-5 (10), 9 (11) -diene (Trimethoxydien) from Nordiendionketal, takes place in three steps over the Levels 3,3-Dimethoxy-estra-5 (10), 9 (11) -diene-17β-spiro-1 ', 2'-oxirane (Northern Spain) and 3,3-dimethoxy-estra-5 (10), 9 (11) -diene-17β-ol (Nordienether).

In In a third step trimethoxydiene is converted into the corresponding 5α, 10α-epoxide (enepoxide) and in a subsequent Cu (I) -catalyzed Grignard reaction with 4-Bromobenzaldehyddimethylketal to so-called dimethoxyacetal (3,3,17β-trimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17α-methoxymethyl-estr-9-en-5α-ol) reacted.

The Reaction of Dimethoxyacetals with acids such. B. with 85 to 95% acetic acid provides 4- [17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl] benzaldehyde (dienoic aldehyde).

By the procedure, in which the formation of by-products is reduced, is the Reproducibility and validation of every single step given this stage of the process. It will receive a product whose Purity by specified individual analytical ratings (HPLC purity, UV content) is occupied, and in its production impurities such as B. By-products of the Grignard reaction (Wurtzprodukte), 11α-aldehyde and 5α-OH-aldehyde be safely and reproducibly depleted.

For the final step, the synthesis of 4- [17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl] benzaldehyde (E) -oxime - asoprisnil - is dienoaldehyde with hydroxylamine hydrochloride in organic Solvents such. For example, pyridine or methylene chloride as in DE 43 32 283 described implemented.

Subsequently, will the product with methods known to those skilled in the art, such as chromatography, Fractionated filtration or crystallization worked up, purified and a spray-drying subjected. It all depends on amorphous asoprisnil microparticles produce a high and above all reproducible physical Purity and stability in the solid dosage form.

It is known that in the production of pure amorphous active substance forms by spray drying there is a high risk for recrystallization, which in the active ingredient alone or by contact with excipients of the drug may occur (Nuremberg, Acta Pharmaceutica Technologica, 26, 1980.

The in the EP 129 26 07 described crystalline as well as the amorphous form of asoprisnil meet the requirements that are placed on the stability as an active ingredient or for pharmaceutical processing.

The Asoprisnil microparticles need however about it In addition, sufficient stability as an active substance (Drug Substance) in the solid dosage form even under ICH accelerated conditions demonstrate. This places special demands on the physical Purity, which has an immediate impact on amorphous structures their stability against recrystallization has. Therefore, it is imperative that both when the solid dosage form is stored under normal conditions (25 ° C., 60% rh) and under Accelerated Conditions (40 ° C, 75% rh) no detectable Recrystallization of these microparticles occurs. The safe and especially reproducible production of these microparticles special requirements for the cleaning and drying of Asoprisnil.

The inventive method therefore also includes a process step for drying asoprisnil, in which by appropriate litigation contamination of the Microparticles with germinal centers is greatly reduced.

In every spray-drying plant there are more or less deposits of dried particles on hot Apparatuses inner surfaces, z. B. on the tower wall. Surprisingly was found to wetting events as a result of incomplete vaporization Drops that increase with only a brief and punctual increase Ethanol concentration in the particle layer are connected, the Formation of so-called "seed Crystals "within of seconds. Under "Seed Crystals" are microscopic or submicroscopic crystallites or crystalline clusters, the thermodynamically stable and starting point of recrystallization processes are understood (I. Gutzow, J. Schmelzer, 'The Vitreous State', Springer Verlag 1995, chapter 9, page 221).

According to the present inventive method is the spray drying process characterized in that generated in the sputtering device spray cones the biggest drops evaporated so quickly that even isolated wetting events on the product contact equipment surfaces pushed back as far as possible or are better excluded. This wetting effect is in one significantly higher Dimensions, as conventional, sprayed or pushed back conventional even excluded.

The in the atomizer generated drop size distribution depends on the sputtering device (Pressure nozzle, Rotating disk, two-fluid nozzle), their geometry, as well as from the Zerstäubungsparametern. The two-fluid nozzle generates For example, compared to other sputtering a very fine, but also wide drop size spectrum. The rotation disk a coarser, but for that narrower drop size spectrum. About the Droplet size spectrum becomes the particle size distribution the dried particle.

For the use of asoprisnil as a drug substance, for example, in oral low-dose forms is the Generation of a specific particle size distribution crucial. On the one hand, salary uniformity (CUT Content Unifomity) and on the other hand, especially in poorly soluble, hydrophobic substances such as Asoprisnil, the dissolution kinetics of the drug from the drug form guaranteed be. Generally common traditionally a technology where the dried active ingredient later is micronized. This is preferably done in jet mills and means an extra Process step, with high risks for solid state stability and the Phase purity is afflicted. Due to the high energy input comes it often leads to phase transformations or to the production of germinal centers for phase transformations

It It is known that amorphous substances such as asoprisnil often come from solutions drying to form a solid film on the surface of the drop. Only then evaporates, much slower, the liquid ball contents from a blow-out opening or by diffusion. The measured particle sizes are therefore not essential smaller than the drops from which they are formed. This second Phase of drying delayed the drying kinetics at large Drop even further. Whether a drop during spray drying Completely evaporated or dried to a particle, hang next his size too from the geometric and aerodynamic conditions in the dry tower, z. B. from the available standing flight path length and speed (Nuremberg, Acta Pharmaceutica Technologica, 26, 1980; Bauckhage, Chem. Ing. Technik 62 (1990), No. 8; Zbicinski, Chemical Engineering Journal 86, 2002, pp. 207-216).

Therefore there is a further advantageous embodiment of the method according to the invention in that the active ingredient asoprisnil after spray drying in the form of amorphous microparticles with a certain particle size distribution obtained in a process step without subsequent micronization becomes.

In the following, particularly preferred embodiments of the method according to the invention are comprised of the following stages:
Hydroxyestradienone → nordienedione ketal → trimethoxydiene → dienoaldehyde → asoprisnil (s. 1 ).

The Starting product hydroxyestradienone of the process according to the invention, is accessible by methods known to those skilled in the art (Menzenbach, Bernd; Huebner, Michael, Journal for Chemistry (1986), 26 (10), 371ff).

1. Nordiendion ketal

1.1. Nordiendion ketal via Nordiendion (Hydroxyestradienone → Nordiendion → Nordiendionketal)

Chromic acid oxidation of hydroxyestradienone

The execution of chromic acid oxidations in the synthesis of steroidal drugs is a common and in the literature in detail described synthesis step. Using a chromic acid and sulfuric acid mixture (Jones Reagent, J. Chem. SOC. 1946, 39 and J. Chem. Soc. 1953, 2548), steroidal alcohols are oxidized to ketones.

These Chromic acid oxidation is in different solvents, such as acetone, DMF, dichloromethane and chloroform. DMF and chloroform in many cases by the physiologically and ecologically harmless acetone be replaced.

disadvantage this substitution of DMF and chloroform by acetone are the incomplete and non-reproducible conversion of the starting material.

For example let yourself unreacted Hydroxyestradienon very difficult to separate and is therefore "dragged" as an impurity throughout the synthesis of the active ingredient, thereby increasing the quality of the synthesis product massively impaired becomes.

According to the invention full and reproducible chromic acid oxidation of hydroxyestradienone in acetone by the reaction as Two-phase reaction between liquid Phases is performed.

• 1. die Löslichkeit der organischen Phase für das Steroid verbessert wird,
• 2. der Chromschlamm kein Ausgangsprodukt einschließen kann, da sich seine Viskosität sprunghaft erniedrigt und
• 3. damit eine sehr große Stoffaustauschfläche über das Rührwerk geschaffen werden kann.

For this purpose, a certain amount of water is added to a solution of hydroxyestradienone in acetone in such a way that in the distribution equilibrium of the water between the organic phase and the aqueous chromic acid phase, the water content of the organic phase passes through a minimum. This minimum is caused by a surprisingly occurring phase change in the inorganic chromic acid phase, which extracts water from the organic phase despite increasing total water content of the reaction solution. This ensures that

• 1. the solubility of the organic phase for the steroid is improved,
• 2. The chromium sludge can not include any starting material, as its viscosity suddenly decreases and
• 3. So that a very large mass transfer area can be created via the agitator.

This Minimum is temperature and concentration ratios influenced in the chromic acid. The optimum of these parameters can be determined experimentally by the person skilled in the art become.

The full and above all reproducible implementation is achieved by: to a solution of hydroxyestradienone in acetone water, preferably 2-10% by weight based on acetone, be added such that a defined systemic water concentration (water addition plus water from the chromosulfuric acid), preferred from 10-15 Wt .-%, with the steroid concentration at most 8 g / l acetone.

• 1. Selektive Ketalisierung mit Siliziumtetrachlorid und Methanol a) Siliziumtetrachlorid wird in ein Lösungsmittelgemisch aus Methanol und n-Hexan gegeben, wobei die Zugabe in einem Temperaturbereich von –5 bis 15°C, bevorzugt 2 bis 10°C erfolgt; b) zügige Zugabe von Nordiendion wird im vorgenannten Temperaturbereich von –5 bis 15°C, bevorzugt 2°C bis 10°C; c) Rühren unter Kristallisation, wobei die unter b) erhaltene Lösung vorzugsweise 60 bis 100 Minuten bei 5°C bis 15°C, besonders bevorzugt 10°C, und anschließend zur Vervollständigung der Kristallisation bei –8°C bis 0°C gerührt wird; d) die erhaltenen Kristalle werden mit einer Fest-Flüssig-Trennvorrichtung isoliert und anschließend abwechselnd mit Methanol und Hexan oder Methanol/Ammoniakwasser gewaschen e) Trocknen des erhaltenen Nordiendionketals

oder

• 2. selektive Ketalisierung mit Acetylchlorid und Methanol unter Verwendung einer Lösung des Rohprodukts aus der Chromsäureoxidation.

According to the invention, the subsequent selective monoketalization of the diketone Nordiendions with Lewis acids are carried out according to the following variants:

• 1. Selective Ketalisierung with silicon tetrachloride and methanol a) silicon tetrachloride is added to a solvent mixture of methanol and n-hexane, wherein the addition takes place in a temperature range of -5 to 15 ° C, preferably 2 to 10 ° C; b) rapid addition of Nordiendion is in the aforementioned temperature range of -5 to 15 ° C, preferably 2 ° C to 10 ° C; c) stirring under crystallization, wherein the solution obtained under b) is preferably 60 to 100 minutes at 5 ° C to 15 ° C, more preferably 10 ° C, and then to complete the crystallization at -8 ° C to 0 ° C is stirred ; d) the crystals obtained are isolated with a solid-liquid separation apparatus and then washed alternately with methanol and hexane or methanol / ammonia water e) drying of the Nordiendionketals obtained

or

• 2. selective ketalization with acetyl chloride and methanol using a solution of the crude product from the chromic acid oxidation.

The described variants of a special procedure for Selective ketalization of the northern dynasty is characterized by this that the formation of by-products is greatly reduced. The above methods provide a product, the specified analytical Single evaluations safely and reproducibly makes possible and high quality requirements enough.

1.2. Nordiendionketal on hydroxyketal

In this variant, first 17β-hydroxy-estra-4,9-dien-3-one (hydroxyestradienone) to the intermediate 17β-hydroxy-3,3-dimethoxy-estra-5 (10), 9 (11) -diene (hydroxyketal ) ketalized. Thereafter, the oxidation takes place to Nordiendionketal means Oppenhauer oxidation:
Hydroxyestradienone → hydroxyketal → nordiendione ketal

The Purification takes place with usual, the methods known to the person skilled in the art, bsplw. by chromatography or fractionated filtration. Illustrative of this are the following solvents such as methanol, heptane, cyclohexane, methyl tert-butyl ether as well Combinations thereof or solvent mixtures such as methyl tert-butyl ether / heptane, Cyclohexane / methyl tert-butyl ether, called isopropanol / water. Especially suitable are cyclohexane / methyl tert-butyl ether.

When support material for one chromatographic purification is, for example, alumina used.

The Ketalization with trialkyl orthoformates in methanol is for steroidal drugs in the literature in detail (Byer, Walter, Lehrbuch der organischen Chemie, 21. Aufl., S. Hirzel Verlag Stuttgart, p. 216).

By Use of trimethyl orthoformate in solvent mixtures containing methanol Contain steroids that are in the 3-position a keto function have converted to the corresponding dimethoxyketals. at common Ketalisierungsverfahren be as catalysts sulfuric acid or sulfuric acid derivatives such as B. p-toluenesulfonic acid added. A disadvantage of the mentioned procedure is that these Followed by catalysts must be removed by extraction. Under these watery sour Conditions are not stable ketals.

According to the invention Ketalisierung therefore on an acid-activated ion exchanger carried out. The ion exchanger can be added directly to the reaction solution become. Advantageous for this is that the ion exchanger easily by filtration again can be removed.

A further embodiment variant of the ketalization according to the invention consists in that the reaction solution over the acid-activated ion exchanger in a so-called bypass process to be led. Thus, a separation of the ion exchanger is no longer necessary.

The Oppenhauer oxidation of steroids is also described in detail in the literature (Byer, Walter, Lehrbuch der organischen Chemie, 21st ed., S. Hirzel Verlag Stuttgart, p 216). Using aluminum alcoholates and cyclohexanone, steroids having a 17-hydroxy function are the equivalent oxidized 17-ketones.

With common Aluminum alcoholates such. For example, aluminum triisopropylate is the reaction Hydroxyketal → Nordiendione ketal but not quantitatively feasible. For this reason, the reaction according to the invention with aluminum diisopropylate trifluoroacetate (DIPAT) as a catalyst in the presence of cyclohexanone.

By the use of DIPAT, the hydroxyketal is almost completely implemented.

The Reaction product Nordiendionketal is obtained as crude product. With common However, processes such as recrystallization can only be one purity reach less than 90%. Therefore, the produced Nordiendionketal becomes according to the invention in methyl tert-butyl ether dissolved, over alumina filtered and then eluted with a mixture of cyclohexane and methyl tert-butyl ether.

The Product is obtained with a purity greater than 95%.

2. Trimethoxydiene over Northern Spain and northern ethers

Northern Iranian pirate is made from Nordiendionketal according to DE 100 56 675 with trimethylsulfonium iodide and potassium tertiary butylate in DMF. Nordienspiran is then reacted with sodium methoxide in methanol to Nordienether. Prerequisite for its further conversion to Trimethoxydien according to the following sequence
Nordiendionketal → Northern Spain → Nordienether → Trimethoxydiene
is that the Nordienether is consuming isolated and purified.

at a further processing in solution have to for one preferably quantitative implementation of the precursor water and methanol residues from the Nordienether solution as completely as possible become.

• a) dass in der Stufe Nordienspiran die Reaktion in DMF in einer Startphase bei Zugabe der Reaktanten in einem Temperaturbereich von 0 und 25°C, vorzugsweise zwischen 0 und 20°C und in einer Nachreaktionsphase zwischen 20 und 40°C, vorzugsweise zwischen 30 und 35°C, durchgeführt wird;
• b) dass das in Schritt a) erhaltene Reaktionsprodukt nicht isoliert wird, sondern als Lösung aus Nordienspiran in Lösungsmitteln, bevorzugt in Hexan, DMF oder in THF eingesetzt wird;
• c) dass bei der Umsetzung des Nordienspirans aus Schritt b) zum Nordienether ein Wechsel des Lösungsmittels erfolgt, bevorzugt während der Umsetzung mit Natriummethanolat, besonders bevorzugt durch azeotrope Destillation, und so die erforderlichen Reaktionstemperaturen von 70°C oder mehr erreicht werden;
• d) dass in der Stufe Trimethoxydien die Kristallisation aus Methanol erfolgt, indem eine Steroidlösung, bevorzugt eine Lösung mit 40–50 Gew.-% Steroid, etwa 1 bis 2 Stunden auf 20–35°C, bevorzugt 25°C, gekühlt und anschließend weiter auf –5°C bis –15°C, bevorzugt –10°C, gekühlt wird.

According to the invention, an almost complete conversion to trimethoxydiene is achieved by

• a) that in the stage Nordienspiran the reaction in DMF in a starting phase with the addition of the reactants in a temperature range of 0 and 25 ° C, preferably between 0 and 20 ° C and in a post-reaction phase between 20 and 40 ° C, preferably between 30 and 35 ° C, is carried out;
• b) that the reaction product obtained in step a) is not isolated, but is used as a solution of Nordienspiran in solvents, preferably in hexane, DMF or in THF;
• c) that in the conversion of Nordienspirans from step b) to Nordienether a change of the solvent takes place, preferably during the reaction with sodium methoxide, more preferably by azeotropic distillation, and so the required reaction temperatures of 70 ° C or more can be achieved;
• d) that in the step trimethoxydia, the crystallization from methanol, by a steroid solution, preferably a solution with 40-50 wt .-% steroid, about 1 to 2 hours to 20-35 ° C, preferably 25 ° C, cooled and then further to -5 ° C to -15 ° C, preferably -10 ° C, is cooled.

There the water and solvent content in the use product for the implementation of Nordiendionketal to the Northern Spain is an essential one The role is played by the limitation of manufacturing considerable Amounts of methanol and water in Nordiendionketal a nearly complete conversion reached in this stage. This is guaranteed when the water content less than 1%, preferably less than 0.6% and the methanol content less than 1%, preferably less than 0.8% in Nordiendionketal.

Of the Change of solvent in the implementation of Nordienspiran to Nordienether, for example from hexane to methanol, preferably by azeotropic distillation a continuation the synthesis without lossy and expensive intermediate isolation of Northern Spain.

There the water and solvent content in the starting product for the conversion of nordienether to trimethoxydiene is just as important like the one mentioned above The conversion of Nordiendionketal to the Northern Iranian Piran will also take place here by reducing the coming out of the stage Nordienether Amounts of water and methanol, preferably by azeotropic distillation below 0.8% water, more preferably below 0.4% water, a complete reaction guaranteed to Trimethoxydien. Unreacted nordienether can later no longer be removed.

The special temperature control causes a significant reduction in the formation of by-products at the same time almost complete and fast turnover. In particular, the formation of the 17α-epimers of Northern Spain and the formation of 16-methyl-trimethoxydiene are greatly minimized.

The special leadership The crystallization guarantees a very good depletion of the by-products in the crystals. In particular, unreacted nordienether remains as well By-products such as the 17-Oxetanverbindung the Nordienketals in solution.

It A product is formed which filters very well, washing and let it dry.

3. dienoaldehyde via enepoxide and dimethoxyacetal

Trimethoxydien is dissolved in dichloromethane and pyridine. For the upcoming epoxidation hexafluoroacetone is added as catalyst. At 25 to 35 ° C is a hydrogen peroxide solution added. After the conversion, the phases are separated. The organic phase is after removal of the peroxides by washing with water, sodium hydroxide solution and sodium thiosulfate solution Redistilled THF.

The Preparation of the dimethoxyacetal takes place via a Grignard reaction Enepoxide and magnesium in THF with bromobenzaldehyde dimethyl acetal. Bromobenzaldehyde dimethyl acetal is prepared by acetalization of 4-bromobenzaldehyde with trimethyl orthoformate in organic solvents such. For example methanol and THF in the presence of an acidic catalyst, for example sulfuric acid derivatives (eg, p-toluenesulfonic acid). This is the reaction as in 1.2. described with a sour activated ion exchanger, wherein according to the invention in a preferred variant of the method, the ketalization via a bypass method he follows.

As the person skilled in the art can possibly activate the magnesium chips for the Grignard reaction, for example with dibromoethane or DIBAH, be necessary.

to Grignard solution the before use z. B. can be tempered at 10 to 20 ° C is under inert conditions and stirring added a catalytic amount of cuprous chloride. Subsequently, will preferably within less than 60 minutes of a solution 17α- (methoxymethyl) -en -3,3,17β-trimethoxy-5α, 10α-epoxy-estr-9 (11) and THF to the stirred Grignard solution at -10 ° C to 55 ° C, maximum 45 ° C given and subsequently an after-reaction at the same maximum temperature carried out. The workup is carried out by methods known to those skilled in the art.

4. Asoprisnil

4.1. synthesis

• a) eine Suspension bzw. Lösung aus Dienonaldehyd, bsplw. in Pyridin oder Methylenchlorid wird mit einer Lösung aus Hydroxylamin-Hydrochlorid in Pyridin vermischt
• b) die Reaktionslösung, die nach Schritt a) erhalten wurde, wird bei einer Temperatur von 0 –30 °C, bevorzugt 20–25°C in ein auf eine Temperatur von 5–15°C temperiertes Lösungsmittel, bevorzugt Essigester, Methylenchlorid oder Toluol, unter Rühren gegeben und mit Salzsäure oder Schwefelsäure angesäuert;
• c) die Aufarbeitung erfolgt durch – Kristallisation, indem der Lösung Methyltertiärbutylether zugesetzt und dadurch ein Methyltertiärbutylether-Solvat mit 12–20% Methyltertiärbutylether erhalten und anschließend getrocknet wird, oder – Filtration, bevorzugt über Kieselgel, Umdestillieren auf Methanol, Ausfällen mit Wasser und Trocknen des so erhaltenen Feststoffes.

The stage for the production of asoprisnil as a crude product according to the invention consists of the following individual steps:

• a) a suspension or solution of dienoaldehyde, bsplw. in pyridine or methylene chloride is mixed with a solution of hydroxylamine hydrochloride in pyridine
• b) the reaction solution obtained after step a), at a temperature of 0 -30 ° C, preferably 20-25 ° C in a tempered to a temperature of 5-15 ° C solvent, preferably ethyl acetate, methylene chloride or toluene , added with stirring and acidified with hydrochloric acid or sulfuric acid;
• c) the work-up is carried out by - crystallization by adding methyltertiary-butyl ether to the solution and obtaining a methyl tert-butyl ether solvate with 12-20% methyl tertiary butyl ether and then drying it, or filtration, preferably over silica gel, redistilling to methanol, precipitation with water and drying the thus obtained solid.

4.2. workup

The Working up of the Synthesevefahren described above Asoprisnil obtained via HPLC purification and subsequent Spray drying, their execution will be described below.

The HPLC purification can be carried out by methods known to those skilled in the art.

In a spray drying plant As described in WO 01/90137, a solution of asoprisnil in alcohol, preferably in lower alcohols such as ethanol, methanol and isopropanol, sprayed under a special temperature regime. This is designed that a drying gas outlet temperature of 40 ° C to 90 ° C, preferably 75 ° C to 90 ° C, complied with becomes. It is the mass ratio of inserted spray gas to the spray solution 1.5 to 10, preferably from 2.5 to 5, and the mass ratio of used drying gas to the spray solution used at least 10, preferably at least 20.

there The dried asoprisnil particles are removed via a product filter from the Drying gas separated and almost completely deposited in a collecting vessel. It was found that the otherwise usual deposition of spray-dried Particles over a cyclone in Asoprisnil surprisingly leads to much more unstable products. Therefore, the deposition the spray-dried Asoprisnil particles over a product filter a particularly advantageous embodiment of Invention. The use of fresh unused filter surfaces at Each production campaign is a further advantageous embodiment the invention, as a result of a product with the desired stability properties will be produced. Even a few ppm of crystalline particles on asoprisnil to lead to a significant destabilization of the amorphous product. It has been shown that, surprisingly despite thorough Cleaning with the usual Solvents like Ethanol or methanol always low crystalline substance residues in the Filter material remain that the amorphous product with crystal nuclei contaminate.

To the spray drying a subsequent drying takes place. In this procedure, the microparticles are under Vacuum of <100 mbar, preferably less than 10 mbar and at a temperature of less than 90 ° C, preferably less than 50 ° C, and / or under rinsing with a solvent-free Drying gas longer Time treated until the alcohol content is less than 1%, preferably less than 0.5% to further stabilize the amorphous structure.

According to the described Procedure receives one physically pure and stable amorphous asoprisnil microparticles.

Of the Term "physical Purity "refers Here according to the literature (A. Burger, Pharmacy in our Zeit 26, 1997, 93) on a chemically pure substance, essentially Admixtures of the same chemical substance, but in another Solid state (polymorphs, amorphous, pseudopolymorphs) only in small Contains quantities. Dependent on of the substance type these physical contaminants by thermomicroscopy, differential scanning calorimetry (DSC), X-ray powder diffractometry or other methods.

object Accordingly, the present invention is a method for safe and reproducible production, processing and purification of amorphous asoprisnil, which are carried out on a production scale can.

By the inventive method is the production of asoprisnil in pilot and / or production scale in high purity with an overall yield of crude, d. H. not yet purified asoprisnil of 58% (gross) possible. Considering the active ingredient content in the final product asoprisnil becomes a yield of 47% (net).

Previously known methods for the production of asoprisnil on a laboratory scale, as in DE 43 32 283 , WO 02/38582 and WO 02/38581 disclose yields between 5 and 23%. The comparison of the yields obtained is only possible to a limited extent since the syntheses start from different starting materials and / or take place in different ways.

eine deutliche Steigerung der Ausbeute auf 47 bzw. 58% erzielt. Durch das erfindungsgemäße Verfahren wird überraschenderweise eine Verbesserung der Aus beute trotz Umsatz weitaus größerer Mengen, d.h. im Pilot- bzw. Produktionsmaßstab, erreicht als in den bereits publizierten Laborverfahren beschrieben. Ein weiterer Vorteil des erfindungsgemäßen Verfahrens besteht darin, dass jede einzelne Verfahrensstufe sicher und reproduzierbar im Pilot- bzw. Produktionsmaßstab ausgeführt werden kann.Opposite the in DE 43 32 283 or WO 02/38582 starting from a much later point, namely 3,3-dimethoxy-5α, 10α-epoxyestr-9 (11) -en-17-one, as well as compared to that described in WO 02/38581 Process which starts from an also later starting material - 3,3-dimethoxy-estra-5 (10), 9 (11) -dien-17-one - is obtained by the process according to the invention starting from 17β-hydroxy-estra-4 , 9-dien-3-one (hydroxyestradienone) via the subsequent steps

achieved a significant increase in yield to 47 or 58%. The process of the invention is surprisingly an improvement in the prey despite sales of much larger amounts, ie in pilot or production scale, achieved as described in the already published laboratory method. Another advantage of the method according to the invention is that each individual process stage can be carried out safely and reproducibly on a pilot or production scale.

The inventive method for the production of Asoprisnil according to the following Execute examples, these being closer explanation serve, without limiting the invention.

to execution of the method the stirred reactors, distillers, Crystallizers, centrifuges and dryers are used.

1. Nordiendion ketal

1.1. Nordiendion ketal via Nordiendion

option A

12 kg of hydroxyestradienone are dissolved in 180 l of acetone and then 7.5 l of water are added. Chromosulfuric acid for oxidation is prepared from 50 liters of water, 18 kg of chromium trioxide and 12 liters of sulfuric acid. At 15 ° C 17.5 l of this chromic acid with 260-270 mg chromium trioxide / ml are added within one hour and then post-reacted at 22-25 ° C for 1 hour. The workup is carried out by the customary methods known to the person skilled in the art (Cr ⁶⁺ reduction with bisulfite, concentration and crystallization from acetone / water mixtures).

33 l of methanol and 46 l of n-hexane are heated to 2-10 ° C. For this purpose, first 1.2 kg SiCl ₄ and then 10 kg Nordiendion be added with stirring. After incipient crystallization is stirred for 1 hour to 1.5 hours at 5-15 ° C, then cooled to 0 to -8 ° C and filtered with suction. If the crystallization does not start by itself, it can also be inoculated in the usual way. The crystals are washed on frit with hexane and ammoniacal methanol. After drying, 80-109% by volume

The safely achievable qualities are written down in the specification and are with the inventive method reached, i.a. Purity ≥ 95 F% (HPLC), unreacted nordiendione content ≤ 0.2 F%, largest non-specific by-product ≤ 1.0 F%.

Variant B

100 g of hydroxyestradienone is initially charged in 400 ml of acetone and 20 ml of water. A chromosulphuric acid solution, prepared from 101 ml of water, 35.6 g of chromium trioxide and 32 ml of sulfuric acid, is metered in at an internal temperature of 12 ° C in such a way that the remainder is added in two hours and in another 2 hours. After stirring for 30 minutes, excess chromic acid is decomposed by addition of 26 ml of isopropanol. It is then redistilled in vacuo at an internal temperature of 60 ° C to water. For this purpose, about 400 ml of water are needed. The precipitated intermediate (Nordiendion) is aspirated and with Washed water neutral.

Subsequently, will Nordiendion dissolved in 170 ml of methylene chloride and 20 minutes with 3.6 g Diatomaceous earth stirred. Diatomaceous earth is filtered off and the filtrate to remove chromium salts 2 × with washed 50 ml of water. The organic phase is grown in vacuo Methanol distilled and concentrated to 300 ml. At an internal temperature from 20 ° C will add 440 ml of hexane. The suspension is cooled to 5 ° C. Within 1 minute 26 ml of acetyl chloride are added and then with Rinsed 37 ml of methanol. The starting material dissolves yourself and the product falls subsequently out. If necessary, after 3 minutes with Nordiendionketal inoculated.

After crystallization has begun, the mixture is stirred for a further 80 minutes, then heated to 5 ° C. and rendered 50% alkaline by the addition of 37 ml of sodium hydroxide solution. The product (Nordiendionketal) is isolated and washed first with a mixture of 320 ml of methanol and 13 ml of ammonia water, then with 35 ml of hexane. It is sucked dry under a nitrogen atmosphere and dried in vacuo.
Yield: 82.4 g Nordiendionketal

1.2. Nordiendionketal on hydroxyketal

66.7 kg of hydroxyestradienone is dissolved in 500 l of toluene and 400 l of methanol. Possibly will be over 3.4 kg activated carbon filtered. After addition of 51 liters of trimethyl orthoformate and another 70 l of methanol is about 33.4 kg of activated ion exchanger at 30 ° C pumped in a circle until the conversion to hydroxyketal is complete. After addition of 20 l of pyridine and 400 l of a sodium carbonate solution is stirred and the phases separated. The watery Phase is nachextrahiert several times with 135 l of toluene. The United organic phases are concentrated to 300 l and to 300 l of toluene redistilled.

In a second reaction vessel 40 kg of aluminum isopropoxide and 180 l of heptane submitted. At a Temperature of 50 ° C becomes 14.7 l of trifluoroacetic acid added. After adding 6.7 l of pyridine, heptane is reduced to 95 distilled off.

To cooling down to ≤ 25 ° C is under stir the organic hydroxyketal solution added. After addition of a total of 76 l of cyclohexanone, partial dosed, stirring is continued for up to 6 hours until the sales are complete is. After adding 570 l of a sodium hydroxide solution stirred and the phases separated. The watery Phase is nachextraiert several times with 70 l of toluene. The United organic phases are washed several times with 70 l of water. It is concentrated to 270 l and redistilled on water. It forms 270 l of a suspension of crude product and water. 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 water phase is back-extracted with 70 l of methyl tert-butyl ether. The combined organic phases are filtered and adjusted to 135 l concentrated. After addition of 540 l of cyclohexane, the solution over 134 kg of alumina filtered. The alumina is mixed with a mixture from a total of 270 l of cyclohexane and 100 l of methyl tert-butyl ether rewashed. The product-containing fractions are concentrated and distilled to 200 l of heptane. The heptane solution is cooled to -15 ° C, where the product crystallizes out. The product is isolated and with Washed 35 l of heptane and 35 l of water. The product Nordiendion ketal is at max. 40 ° C dried to a drying loss of ≤ 0.5%.

2. Trimethoxydiene over Northern Spain and northern ethers

65.6 kg Nordiendionketal and 50 kg of trimethylsulfonium iodide are 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 at 20 ° C. It will be 30 minutes at 30 ° C stirred and sales are controlled by DC.

The Reaction product is at 30 to 40 ° C by adding 200 l of water and 410 l of hexane converted to the hexane phase. The aqueous DMF phase is washed four times with 50 l of hexane extracted. The combined organic phase is washed twice with 85 l of water. The aqueous phase is washed with 50 l Hexane extracted. Subsequently concentrated under vacuum to a volume of 115 l and in 130 l of methanol mixed. About 250 l of sodium methoxide solution (30%) to the methanolic solution given and removed under normal pressure distillate until at least 70 ° C reached become. After that will be for 1.5 hours under reflux heated until the conversion is complete is. Under vacuum and continuous addition of 215 l of water is distilled off further.

The Nordienether thus obtained is taken up in 330 l of methyl tert-butyl ether (MtBE), the organi phase is separated and the aqueous phase with 100 l. Methyltertiärbutylether extracted twice. The combined organic phases were extracted twice with 100 l of water. The aqueous phases are back-extracted with 60 l of MTBE. It is then concentrated under vacuum and azeotropically removed from the organic phase at a volume of 165 l while maintaining this volume with the addition of 165 l of methyl tert-butyl ether of water and methanol.

To 27.2 l of methyl iodide and 10 l of MtBE are added. Then be 70.5 kg of potassium tertiary butyl ether in 300 l MTBE at 35 ° C added. It is post-reacted for 1 to 2 hours and the sales checked. To Addition of 245 l of water, the organic phase is separated and washed with 65 l of water. The watery Phase is back-extracted with 65 l of MTBE. Thereafter, the narrowing occurs to about 80 liters in a vacuum. It is redistilled to methanol and concentrated to a volume of 140 l and stirred at 25 ° C for 1 to 2 hours. After that is cooled to less than -10 ° C and stirred for a further 2 hours. Subsequently the product is isolated and washed with 15 l of cold methanol. Trimethoxydiene is dried in vacuo at 40 ° C.

3. dienoaldehyde via enepoxide and dimethoxyacetal

3.1. Enepoxid

To a solution from 80.6 kg of trimethoxydiene, 755 l of methylene chloride and 11 l of pyridine 10.6 liters of hexafluoroacetone are added. To be this solution 81 l of a 35% hydrogen peroxide solution at a temperature of 30 to 40 ° C gradually with stirring added. After addition, the batch is stirred for 30 min at 30 to 40 ° C and then a sales control carried out. The organic phase becomes separated and washed twice with 175 l of aqueous sodium bicarbonate solution. The organic phase is then 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 thus washed is dried under vacuum and at a Temperature of 30 ° C concentrated and redistilled to THF, so that the final volume 170 l is.

3.2. dimethoxy

The Grignard reagent is made up of 13 kg of magnesium turnings, 280 l of THF, and 7.3 kg of DIBAH and 106 L of bromobenzaldehyde dimethyl acetal. bromobenzaldehyde is prepared by acetalization of 4-bromobenzaldehyde with trimethyl orthoformate in methanol in the presence of acidic catalysts, preferably acidic Ion exchanger, preferably produced by the bypass method. to Add about 0.5 kg of copper (I) chloride becomes the eneoxide solution added and at 40 ° C stirred to complete sales. Excess Grignard reagent is added by adding 490 l of ammonium chloride solution Max. 10 ° C destroyed. After adding 142 l of dilute acetic acid the organic phase washed 3 to 4 times to 122 l of ammonium chloride solution. The watery Phases are back-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 in vacuo at 40 ° C concentrated to 220 l.

3.3. Dienonaldehyd

The Dimethoxy solution is concentrated with 312 l. acetic acid and 35 l of water and heated to 90 ° C for about 30 min. After cooling, be 680 l of water added. The crude product is isolated and several times with 170 l, 170 l and 110 l and 340 l of MtB ether at temperatures up to to 50 ° C stirred or washed. Diene aldehyde is dried at 30 ° C to 40 ° C in a vacuum.

4. Asoprisnil

4.1. synthesis

option A

15 kg of dienoaldehyde are suspended in 38 l of pyridine. To do this 42 l of a prepared hydroxylamine hydrochloride-pyridine solution. After successful sales control is taken up in 88 l of ethyl acetate and under pH control (2-4) mixed with 6N HCl. After phase separation and extraction of the organic Phase with water, the organic ethyl acetate phase is concentrated, distilled off with toluene and subsequently with 50 l of methyl tert-butyl ether added. Crystallization leads to the target product. Subsequently is dried.

The following purities were achieved by the method according to the invention after HPLC testing:
Oxime = 92.9 area%,
Aldehyde = 0.08 area%,
Z oxime = 3.1 F%,
Dioxime = 3.1 F%

Variant B

50 kg of dienoaldehyde are dissolved in 250 l of methylene chloride. In 1 until 2 h at 20 ° C a solution Add 8.86 kg of hydroxylamine hydrochloride in 130 l of pyridine. To successful sales control, about 280 l of sulfuric acid at <10 ° C are added. At 10 ° C The phases are separated and the aqueous phase twice with 120 After-extracted with methylene chloride. The organic phase becomes three Washed with 200 l of water, which with 110 l of methylene chloride be extracted. The organic phase is heated to 200 l in vacuo narrowed and over Silica gel filtered. The organic phase is about 100 l sodium bicarbonate washed. The mixture is distilled off in vacuo to methanol, final volume 200 l. The methanolic product solution is dosed to 510 l of water, the crude product precipitates. asoprisnil (crude) is isolated and dried at 30 to 40 ° C in a vacuum.

The Crude product is prepared by preparative High performance liquid chromatography (HPLC). For this purpose, the asoprisnil (crude) in dichloromethane solved and applied on silica gel. Subsequently, the substance with eluted a mixture of toluene / acetone. Next to the value fraction a mixed fraction is recovered, which is rechromatographed to increase the yield can be. The value fraction is concentrated and in the next process step isolated.

4.2. Work-up and cleaning

example 1

5.1 kg of asoprisnil in 57 L ethanol (DAB) with heating until 60 ° C dissolved. The clear solution is about one Dosing pump with 6 l / h to the two-fluid nozzle (d = 0.8 mm) of a spray dryer, Cylinder d = 800 × 620 mm, ground cone 60 °, DC operation of heating and spraying gas, pumped with as little pulsation as possible. The Asoprisnil solution is at 65 ° C annealed.

The atomizing gas at the nozzle is adjusted to 12 Nm ³ N ₂ / h. The heating gas throughput is 85 m ³ / h. The heating gas inlet temperature is adjusted so that the outlet temperature at the dryer is 78 ° C to 85 ° C. The dried microparticles are deposited over fresh textile filters with PTFE membrane of 1 m ² . For this purpose, the filter surface is pulsed periodically with nitrogen in countercurrent. After the spray-drying process, the asoprisil powder is subjected to a post-drying process. For this purpose, the drying chamber is alternately applied with a vacuum of 5 mbar and heated purge nitrogen of 45 ° C. The vacuum and rinse phases last 45 min. The drying time is 12 h, and the product end temperature reached is 35 ° C.

The asoprisnil microparticles thus obtained are analyzed and have the following quality: Restlösmittelgehalt: 0.36% ethanol Grain distribution: d ₅₀ = 2.1 μm, d ₁₀₀ = 21 μm Enthalpy of fusion (DSC at 5K / min) 4.1 J / g (see Figure 3) Crystal number at 170 ° C 1187 crystallites per mg XRPD amorphous, no crystalline reflexes

Example 2

25 mg film-coated tablets in PVC-Al blisters with pharmaceutically customary excipients and with 16% active ingredient according to Example 1, which has a melting enthalpy of 4.1 J / g according to DSC at a heating rate of 5 K / min and a crystallite number of 1187 per mg according to thermomicroscopy , are stored according to ICH guideline at 40 ° C, 75% rh Stability analysis with XRPD
After 9 months 40 ° C, 75% rh: amorphous

Claims (26)

Process for the production of asoprisnil on a pilot or production scale across the stages

comprising the following steps: a) Synthesis of nordienedione ketal from hydroxyestradienone either - by oxidation of 17β-hydroxy-estra-4,9-dien-3-one (hydroxyestradienone) to estra-4,9-diene-3,17-dione ( Nordiendion) and subsequent selective ketalization to 3,3-dimethoxy-estra-5 (10), 9 (11) -diene-17-dione (Nordiendionketal) or - by ketalization of hydroxyestradienone to 17β-hydroxy-3,3-dimethoxy-estra -5 (10), 9 (11) -diene (hydroxyketal) and subsequent oxidation to Nordiendionketal obtained. b) Synthesis of trimethoxydiene from nordienedione ketal in three steps via the stages 3,3-dimethoxy-estra-5 (10), 9 (11) -diene-17β-spiro-1 ', 2'-oxirane (Nordiaspiran) and 3, 3-Dimethoxy-17α-methoxymethyl-estra-5 (10), 9 (11) -diene-17β-ol (nordic ether), with northern spirits and nordien ethers not being isolated, c) synthesis of 3,3,17β-trimethoxy-11β - [4- (dimethoxymethyl) -phenyl-17α-methoxymethyl-estr-9-en-5α-ol (dimethoxyacetal) from trimethoxydiene via the 17α- (methoxymethyl) -3,3,17β-trimethoxy-5α, 10α-epoxy- estr-9 (11) -enes (enepoxide) in a Cu (I) -catalyzed Grignard reaction with bromobenzaldehyde dimethylacetal d) synthesis of dienoaldehyde by reaction with acids e) synthesis of asoprisnil from dienonaldehyde with a hydroxylamine hydrochloride solution, f) purification by Chromatography, g) drying. Method according to claim 1, wherein hydroxyestradienone is prepared by ketalization with Lewis acids and either by chromic acid oxidation or Oppenauer oxidation is transferred to the Nordiendionketal. Method according to claim 2, either oxidizing the hydroxyestradienone first and then ketalizing it is first ketalized and then oxidized. Method according to claim 3, wherein first the chromic acid oxidation and subsequently a selective ketalization or first the ketalization and then a Oppenauer oxidation performed become. Method according to claim 3, wherein the chromic acid oxidation is carried out as a two-phase reaction between two liquid phases. Method according to claim 5, being a solution of hydroxyestradienone in acetone water, preferably 2-10% by weight based on acetone, be added such that a defined systemic water concentration, preferably from 10-15% by weight wherein the steroid concentration is at most 8 g / l acetone. Process according to claims 3 and 4, the first being the ketalization, preferably on an acidic ion exchanger carried out becomes. Method according to claim 7, wherein the ketalization takes place in a bypass process. Process according to claims 3 and 4, wherein the Oppenauer oxidation with catalysis of aluminum diisopropylate trifluoroacetate (DIPAT). Method according to claim 1, wherein Nordiendionketal about the steps Nordienspiran and Nordienether in three steps, marked as a result of that a) in the Nordienspiran stage, the reaction in DMF in a start phase with the addition of the reactants in a temperature range from 0 to 25 ° C, preferably between 0 and 20 ° C and in a post-reaction phase between 20 and 40 ° C, preferably between 30 and 35 ° C, carried out becomes; b) the reaction product obtained in step a) not is isolated, but as a solution from Northern Spain in solvents, is preferably used in hexane, DMF or in THF; c) at the implementation of the Northern Spain from step b) to the Nordienether a change of the solvent takes place, preferred during the reaction with sodium methoxide, particularly preferably by azeotropic Distillation, and so the required reaction temperatures of 70 ° C or more can be achieved; d) crystallization in the trimethoxy stage from methanol by a steroid solution, preferably a solution with 40-50 Wt .-% steroid, about 1 to 2 hours at 20-35 ° C, preferably 25 ° C, cooled and subsequently is further cooled to -5 ° C to -15 ° C, preferably -10 ° C, completely closed Trimethoxydiene is implemented. Method according to claim 1, wherein in step g) the drying takes place in such a way that a contamination of the dried asoprisnil microparticles with germinal centers in the drying device is greatly reduced. Method according to claim 11, wherein the drying preferably via a spray drying takes place, characterized in that by the geometric and aerodynamic conditions the sputtering device a narrow drop spectrum is achieved and wetting events on the product contact equipment surfaces by spray drops be avoided. Method according to one of the preceding claims 11 to 12, in which the narrow drop spectrum through high atomization performance of the spray unit is generated by a mass ratio of used spray gas to Spray solution of From 1.5 to 10, preferably from 2.5 to 5, and a mass ratio of used drying gas to the spray solution used of at least 10, preferably at least 20 and maintained at a drying temperature of 40 ° C to 90 ° C, preferably 75 ° C to 90 ° C. becomes. Method according to claim 13, the high atomization power of the spray unit by high disk speed of a rotary disk or by high Zerstäubungsgasdurchsatz through a two-fluid nozzle is produced. Method according to one of the preceding claims 11 to 14 such that the spray-dried Asoprisnil microparticles subjected to a post-drying procedure which are in the vacuum and / or with rinsing the asoprisnil microparticles with a solvent-free Drying gas for at least 12 h below 90 ° C, preferably below 50 ° C, takes place. Method according to one of the preceding claims 11 to 15, wherein the deposition of Asoprisnil microparticles after the spray drying over a Product filter, preferably using fresh unused filter surfaces he follows Amorphous, physically pure asoprisnil microparticles obtainable after a method according to one of previous claims 1 to 16. Asoprisnil microparticles according to claim 17 having an average particle size d ₅₀ smaller than 2.5 μm, preferably 2.1 μm, and a maximum particle size d ₁₀₀ smaller than 25 μm, preferably 11 μm. Asoprisnil microparticles according to one of the preceding claims 17 and characterized in that the means of DSC at a heating rate melting enthalpy determined at 5K / min at 194.7 ° C ± 2 ° C less than 20 J / g, preferably is less than 5 J / g, preferably less than 1 J / g. Asoprisnil microparticles according to one of the preceding claims 17-19 characterized in that when heated at 20 K / min to 170 ° C and subsequently at 20 K / min to 90 ° C chilled are, the thermo-microscopically visible number of crystals less than 10,000 per mg, preferably less than 4,000 per mg, especially preferably less than 1000 per mg. Asoprisnil microparticles according to one of the preceding claims 17 to 20 for the preparation of medicaments. Use of asoprisnil microparticles according to claim 21 for the preparation a drug for the treatment of women's hormone-dependent disorders, especially for the treatment of endometriosis, fibroids or other gynecological Dysfunctions. Use of asoprisnil microparticles according to one of the preceding claims 17 to 20 in hormone replacement therapy (HRT) as well as for the female Fertility control. Pharmaceutical composition containing asoprisnil microparticles according to one of the preceding claims 17 to 20 together with pharmaceutically acceptable excipients and / or carriers. Pharmaceutical composition according to claim 24, characterized that the composition is a solid dosage form. Solid dosage form according to claim 25, characterized in that the application is carried out orally.