EP2010555A2 - Method for preparing 4-[17beta -methoxy-17 -alpha methoxymethyl-3-oxoestra-4,9-dien-11beta -yl]benzaldehyde (e)-oxime (asoprisnil) - Google Patents

Method for preparing 4-[17beta -methoxy-17 -alpha methoxymethyl-3-oxoestra-4,9-dien-11beta -yl]benzaldehyde (e)-oxime (asoprisnil)

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Publication number
EP2010555A2
EP2010555A2 EP07724653A EP07724653A EP2010555A2 EP 2010555 A2 EP2010555 A2 EP 2010555A2 EP 07724653 A EP07724653 A EP 07724653A EP 07724653 A EP07724653 A EP 07724653A EP 2010555 A2 EP2010555 A2 EP 2010555A2
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EP
European Patent Office
Prior art keywords
asoprisnil
drying
solution
reaction
nordienedione
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07724653A
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German (de)
English (en)
French (fr)
Inventor
Detlef Grawe
Sabine Gliesing
Hagen Gerecke
Peter Hoesel
Uwe Mueller
Thomas Michel
Robert Eilers
Uwe Knabe
Bernd Erhart
Michael Mosebach
David Voigtlaender
Ulf Tilstam
Juergen Jacke
Klaus Bahl
Ulf Bohlmann
Dieter Wehmeier
Michael Sander
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
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Bayer Schering Pharma AG
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Publication date
Application filed by Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Publication of EP2010555A2 publication Critical patent/EP2010555A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes

Definitions

  • the present invention relates to a method for the reliable and reproducible preparation of 4-[17 ⁇ -methoxy-17 ⁇ -methoxymethyl-3-oxoestra-4,9-dien-l l ⁇ - yl]benzaldehyde (E)-oxime (asoprisnil) on the pilot and manufacturing scale.
  • Asoprisnil which is prepared by this method, is distinguished by a very good physical stability and is therefore particularly suitable for the manufacture of solid pharmaceutical forms (tablets, coated tablets, etc.) which even withstand ICH accelerated conditions (40°C, 75% r.h.).
  • EP 129 26 07 describes novel solid forms of asoprisnil, in particular a high-purity and stable amorphous or highly crystalline form (ansolvate/anhydrate), a method for the preparation, and the use in pharmaceutical compositions.
  • the solid forms are distinguished in particular by high stability.
  • the second stage of the method the preparation of 3,3,17-trimethoxy-17 ⁇ - methoxymethylestra-5(10),9(l l)-diene (trimethoxydiene) from nordienedione ketal takes place in three steps via the stages 3,3-dimethoxyestra-5(10),9(l l)-diene-17 ⁇ - spiro-l',2'-oxirane (nordienespirane) and 3,3-dimethoxyestra-5(10),9(l l)-dien- 17 ⁇ -ol (nordiene ether).
  • trimethoxydiene is converted into the corresponding 5 ⁇ ,10 ⁇ - epoxide (enepoxide) and, in a subsequent Cu(I)-catalyzed Grignard reaction with 4-bromobenzaldehyde dimethyl ketal, converted into the so-called dimethoxy acetal (3,3,17 ⁇ -trimethoxy-l 1 ⁇ -[4-(dimethoxymethyl)phenyl]-l 7 ⁇ -methoxy- methylestr-9-en-5 ⁇ -ol).
  • the procedure reduces the formation of byproducts and thus ensures the reproducibility and validatability of each individual step in this stage of the method.
  • the resulting product has a purity which is proved by specified individual analytical assessments (HPLC purity, UV content), and whose preparation reliably and reproducibly reduces the amounts of impurities such as, for example, byproducts of the Grignard reaction (Wurtz products), l l ⁇ -aldehyde and 5 ⁇ -0H aldehyde.
  • the product is subsequently worked up and purified by methods known to the skilled person, such as, chromatography, fractional filtration or crystallization, and subjected to a spray drying. It is particularly important in this connection to prepare amorphous asoprisnil microparticles which have a high and, in particular, reproducible physical purity and stability in the solid pharmaceutical form. It is known that there is a high risk of recrystallization in the preparation of pure amorphous forms of active ingredients by spray drying, which recrystallization may occur in the active ingredient alone or through contact with excipients of the pharmaceutical form (N ⁇ rnberg, Acta Pharmaceutica Technologica, 26, 1980).
  • the method according to the invention therefore also includes a step for drying asoprisnil in which a contamination of the microparticles with seed centres is greatly reduced through a suitable procedure.
  • dried particles are deposited to a greater or lesser extent on hot inner surfaces of the apparatus, e.g. on the tower wall.
  • wetting events resulting from incompletely vaporized drops which are associated with an only brief and localized increase in the ethanol concentration in the particle layer cause the formation of so-called seed crystals within a few seconds.
  • seed crystals are meant microscopic or submicroscopic crystallites or crystalline clusters which are thermodynamically stable and are the starting point for recrystallization processes (I. Gutzow, J. Schnelzer, 'The Vitreous State', Springer Verlag 1995, Chapter 9, page 221).
  • the spray-drying process is characterized in that the largest drops in the spray cone produced by the atomizing device are vaporized so rapidly that even isolated wetting events on surfaces of the apparatus with which the product makes contact are very substantially decreased or, better, precluded. This wetting effect is reduced or even precluded to a distinctly higher degree than usual in conventional spray drying.
  • the size distribution of the drops generated in the atomizing unit depends on the atomizing device (pressure nozzle, rotating disc, twin fluid nozzle), the geometry thereof, and on the atomization parameters.
  • the twin fluid nozzle generates, for example by comparison with other atomizing devices, a very fine but very broad range of drop sizes.
  • the rotating disc by contrast a coarser but, on the other hand, narrower range of drop sizes.
  • the particle size distribution of the dried particles is determined by the range of drop sizes.
  • amorphous substances like asoprisnil often dry from solutions to form a solid film on the surface of drops. Only subsequently and distinctly more slowly do the liquid contents of the globule vaporize from a blow-out orifice or by diffusion. The measured particle sizes are therefore insubstantially smaller than the drops from which they are formed.
  • This second phase of drying delays the kinetics of drying of large drops even further. Whether a drop can be completely vaporized and dried to a particle during the spray drying depends not only on its size but also on the geometric and aerodynamic conditions in the drying tower, e.g. on the length of the flight path available and the velocity (N ⁇ rnberg, Acta Pharmaceutica Technologica, 26, 1980; Bauckhage, Chem. Ing.technik 62 (1990), No. 8; Zbicinski, Chemical Engineering Journal 86, 2002, pp. 207-216).
  • a further advantageous configuration of the method according to the invention therefore consists of obtaining the active ingredient asoprisnil after the spray drying in the form of amorphous microparticles with a particular particle size distribution in one method step without subsequent micronization.
  • hydroxyestradienone starting material of the method according to the invention can be obtained by methods known to the skilled person (Menzenbach, Bernd; Huebner, Michael, Zeitschrift fur Chemie (1986), 26(10), 371ff). 1. Nordienedione ketal
  • Complete and reproducible chromic acid oxidation of hydroxyestradienone is carried out according to the invention in acetone by managing the reaction as two- phase reaction between liquid phases.
  • a certain amount of water is added to a solution of hydroxyestradieneone in acetone in such a way that the water content of the organic phase passes through a minimum in the distribution equilibrium of the water between organic phase and the aqueous chromic acid phase.
  • This minimum arises through the surprising occurrence of a phase change in the inorganic chromic acid phase, which extracts water from the inorganic phase despite an increase in total water content of the reaction solution. The result of this is that
  • the complete and, in particular, reproducible reaction is achieved by adding water, preferably 2-10% by weight based on acetone, to a solution of hydroxyestradienone in acetone in such a way that a defined systemic water concentration (added water plus water from the chromic/sulphuric acid), preferably of 10-15% by weight, is adjusted, with the steroid concentration not exceeding 8 g/1 of acetone.
  • a defined systemic water concentration added water plus water from the chromic/sulphuric acid
  • the subsequent selective monoketalization of the diketone nordienedione is carried out according to the invention with Lewis acids according to the following variants:
  • 17 ⁇ -hydroxyestra-4,9-dien-3-one (hydroxyestradienone) is ketalized to give the intermediate 17 ⁇ -hydroxy-3,3-dimethoxyestra-5(10),9(l l)- diene (hydroxy ketal).
  • This is followed by oxidation to a nordienedione ketal by Oppenhauer oxidation:
  • Purification takes place by usual methods known to the skilled person, for example by chromatography or fractional filtration.
  • solvents such as methanol, heptane, cyclohexane, methyl tert-butyl ether as well as combinations thereof, and mixtures of solvents 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 a purification by chromatography is for example aluminium oxide.
  • Steroids which have a keto function in position 3 are converted into the corresponding dimethyl ketals by using trimethyl orthoformate in mixtures of solvents containing methanol.
  • sulphuric acid or sulphuric acid derivatives such as, for example, p-toluenesulphonic acids are added as catalysts.
  • catalysts must subsequently be removed by extraction. Ketals are unstable under these aqueously acidic conditions.
  • the ketalization is therefore carried out according to the invention on an acid- activated ion exchanger.
  • the ion exchanger can be put directly into the reaction solution.
  • the advantage of this is that the ion exchanger can easily be removed again by filtration.
  • a further variant of the configuration of the ketalization consists according to the invention of passing the reaction solution over the acid- activated ion exchanger in a so-called bypass method. This means that removal of the ion exchanger is no longer necessary.
  • the nordienedione ketal product of the reaction results as crude product.
  • the prepared nordienedione ketal is dissolved according to the invention in methyl tertiary butyl ether, filtered through aluminium oxide and then eluted with a mixture of cyclohexane and methyl tertiary butyl ether.
  • the product is obtained with a purity of more than 95%.
  • Nordienespirane is prepared from nordienedione ketal according to DE 100 56 675 with trimethylsulphonium iodide and potassium tertiary butoxide in DMF. Nordienespirane is then converted with sodium methanolate in methanol into nordiene ether. A precondition for its further conversion to trimethoxydiene according to the following sequence
  • Virtually complete conversion to trimethoxydiene is achieved according to the invention by a) carrying out at the nordienespirane stage the reaction in DMF in an initial phase with addition of the reactants in a temperature range from 0 to 25 °C, preferably between 0 to 20 0 C and in an after-reaction phase between 20 to
  • step b) the reaction product obtained in step a) not being isolated but being employed as solution of nordienespirane in solvents, preferably in hexane, DMF or in THF; c) for conversion of the nordienespirane from step b) into the nordiene ether changing the solvent, preferably during the reaction with sodium methanolate, particularly preferably by azeotropic distillation, and thus reaching the required reaction temperatures of 70°C or more; d) at the trimethoxydiene stage crystallizing from methanol by cooling a steroid solution, preferably a solution with 40-50% by weight steroid, to
  • Changing the solvent in the conversion of nordienespirane to nordiene ether allows the synthesis to be continued without high-loss and complicated intermediate isolation of the nordienespirane.
  • the specific temperature control has the effect of distinctly reducing the formation of byproducts while, at the same time, conversion is virtually complete and rapid.
  • the formation of the 17 ⁇ epimers of nordienespirane and the formation of 16-methyltrimethoxydiene are greatly minimized.
  • Trimethoxydiene is dissolved in dichloromethane and pyridine. Hexafluoroacetone is added as catalyst for the subsequent epoxidation. A hydrogen peroxide solution is metered in at 25 to 35°C. After conversion has taken place, the phases are separated. The organic phase is, after removal of the peroxides by washing with water, sodium bicarbonate solution and sodium thiosulphate solution, changed to THF by distillation.
  • the dimethoxy acetal is prepared by a Grignard reaction from enepoxide and magnesium in THF with bromobenzaldehyde dimethyl acetal.
  • Bromobenzaldehyde dimethyl acetal is obtained by acetalization of 4-bromo- benzaldehyde with trimethyl orthoformate in organic solvent such as, for example, methanol and THF in the presence of an acidic catalyst, for example sulphuric acid derivatives (e.g. p-toluenesulphonic acid).
  • organic solvent such as, for example, methanol and THF
  • an acidic catalyst for example sulphuric acid derivatives (e.g. p-toluenesulphonic acid).
  • the reaction is carried out as described under 1.2. with an acid-activated ion exchanger, with the ketalization taking place by a bypass method according to the invention in a preferred variant of the method.
  • activation of the magnesium turnings for the Grignard reaction for example with dibromoethane or DIBAH, may be necessary in some circumstances.
  • a catalytic amount of copper(I) chloride is added to the Grignard solution, which can be controlled before use for example to a temperature of 10 to 20°C, under inert conditions and with stirring. Subsequently, preferably within less than 60 minutes, a solution of 17 ⁇ - (methoxymethyl)-3,3-17 ⁇ -trimethoxy-5 ⁇ ,10 ⁇ -epoxyestr-9(l l)-ene and THF is added to the stirred Grignard solution at -10°C to 55°C, maximally 45 °C, and subsequently an after-reaction is carried out at the same maximum temperature. Working up takes place by methods known to the skilled person.
  • the stage for preparing asoprisnil as crude product is composed according to the invention of 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- hydrochloride in pyridine b) the reaction solution obtained in step a) is put at a temperature of 0-30°C, preferably 20-25°C, into a solvent, preferably ethyl acetate, methylene chloride or toluene, which is controlled at a temperature of 5-15°C, with stirring, and acidified with hydrochloric acid or sulphuric acid; c) working up takes place by
  • HPLC purification can be carried out by methods known to the skilled person.
  • a solution of asoprisnil in alcohol preferably in lower alcohols such as ethanol, methanol and isopropanol, is sprayed with a specific temperature regime into a spray-drying system as described in WO 01/90137.
  • This regime is such that the outlet temperature of the drying gas is kept at 40°C to 90°C, preferably 75°C to 90°C.
  • the mass ratio of spraying gas employed to sprayed solution is 1.5 to 10, preferably from 2.5 to 5, and the mass ratio of drying gas employed to sprayed solution employed is at least 10, preferably at least 20.
  • the dried asoprisnil particles are separated from the drying gas on a product filter and deposited virtually completely in a collecting vessel.
  • the spray drying is followed by an after- drying.
  • the microparticles are treated 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 with flushing with a solvent-free drying gas for a lengthy period until the alcohol content is less than 1%, preferably less than 0.5%, in order to stabilize the amorphous structure further.
  • the present invention accordingly relates to a method for the reliable and reproducible preparation, working up and purification of amorphous asoprisnil, which can be carried out on the manufacturing scale.
  • the method according to the invention makes it possible to prepare asoprisnil on the pilot and/or manufacturing scale in high purity with an overall yield of crude, i.e. not yet purified, asoprisnil of
  • the method according to the invention surprisingly achieves an improvement in the yield despite conversion of far larger quantities, i.e. on the pilot or manufacturing scale, than described in the laboratory methods previously published.
  • a further advantage of the method according to the invention is that each individual stage of the method can be carried out reliably and reproducibly on the pilot and manufacturing scale.
  • the method according to the invention for preparing asoprisnil can be carried out in accordance with the following examples, these serving for detailed explanation without restricting the invention.
  • the method can be carried out by employing the agitated reactors, distilling apparatuses, crystallizers, centrifuges and dryers customary in batch-oriented chemical practice.
  • 33 1 of methanol and 46 1 of n-hexane are controlled at a temperature of 2-10°C. To them are added firstly 1.2 kg of SiCl 4 and then 10 kg of nordienedione with stirring. After crystallization starts, the mixture is stirred at 5-15°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 unaided, seeding is also possible in a conventional way. The crystals are washed on a frit with hexane and ammoniacal methanol. Drying results in 80- 109% of expected.
  • Variant B 100 g of hydroxyestradienone are introduced into 400 ml of acetone and 20 ml of water.
  • a chromic/sulphuric acid solution prepared from 101 ml of water, 35.6 g of chromium trioxide and 32 ml of sulphuric acid is metered in at an internal temperature of 12°C in such a way that 3 A is metered in in two hours and the remainder in a further 2 hours.
  • excess chromic acid is decomposed by adding 26 ml of isopropanol.
  • the change to water is then effected by distillation in vacuo at an internal temperature of 60°C. About 400 ml of water are required for this.
  • the precipitated intermediate (nordienedione) is filtered off with suction and washed with water until neutral.
  • Nordienedione is then dissolved in 170 ml of methylene chloride and stirred with 3.6 g of kieselguhr for 20 minutes. Kieselguhr is filtered off and the filtrate is washed 2 x with 50 ml of water each time to remove chromium salts. The organic phase is changed to methanol by distillation in vacuo 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. Over the course of one minute, 26 ml of acetyl chloride are added and then washed with 37 ml of methanol. The starting material dissolves, and the product then precipitates. If necessary, seeding with nordienedione ketal takes place after 3 minutes.
  • the combined organic phases are concentrated to 300 1 and changed to 300 1 of toluene by distillation.
  • 40 kg of aluminium isopropoxide and 180 1 of heptane are introduced into a second reaction vessel.
  • 14.7 1 of trifluoroacetic acid are metered in at a temperature of 50°C.
  • Addition of 6.7 1 of pyridine is followed by removal of heptane by distillation down to 95 1.
  • the organic hydroxy ketal solution is added while stirring.
  • Addition of a total of 76 1 of cyclohexanone, metered in part, is followed by stirring for up to 6 hours until conversion is complete.
  • Addition of 570 1 of a sodium hydroxide solution is followed by stirring and separation of the phases.
  • the aqueous phase is back-extracted several times with 70 1 of toluene.
  • the combined organic phases are washed several times with 70 1 of water.
  • the mixture is concentrated to 270 1 and changed to water by distillation. This results in 270 1 of a suspension of crude product and water.
  • the crude product is isolated and dissolved in 270 1 of methyl tert-butyl ether.
  • the solution is washed with 70 1 of water.
  • the aqueous phase is back-extracted with 70 1 of methyl tert-butyl ether.
  • the combined organic phases are filtered and concentrated to 135 1. After addition of 540 1 of cyclohexane, the solution is filtered through 134 kg of aluminium oxide.
  • the aluminium oxide is washed with a mixture of a total of 270 1 of cyclohexane and 100 1 of methyl tert-butyl ether.
  • the product-containing fractions are concentrated and changed to 200 1 of heptane by distillation.
  • the heptane solution is cooled to -15°C, whereupon the product crystallizes.
  • the product is isolated and washed with 35 1 of heptane and 35 1 of water.
  • the nordienedione ketal product is dried at max. 40°C until the loss on drying is ⁇ 0.5%.
  • the aqueous phase is back-extracted with 50 1 of hexane. Subsequently concentrated in vacuo to a volume of 150 1 and mixed with 130 1 of methanol. About 250 1 of sodium methanolate solution (30%) are added to the methanolic solution, and distillate is taken off under atmospheric pressure until at least 70°C is reached. The mixture is then heated under reflux for 1.5 hours until the conversion is complete. Distillation is continued in vacuo with continuous addition of 215 1 of water. The nordiene ether obtained in this way is taken up in 330 1 of methyl tertiary butyl ether (MtBE), the organic phase is separated off and the aqueous phase is extracted twice with 100 1 of methyl tertiary butyl ether each time.
  • MtBE methyl tertiary butyl ether
  • the combined organic phases were extracted twice with 100 1 of water.
  • the aqueous phases were back-extracted with 60 1 of MtBE. This is followed by concentration in vacuo and, at a volume of 165 1, water and methanol are removed azeotropically from the organic phase with the addition of 165 1 of methyl tertiary butyl ether to maintain this volume.
  • 27.2 1 of methyl iodide and 10 1 of MtBE are added thereto.
  • 70.5 kg of potassium tertiary butyl ether in 300 1 of MtBE are metered in at 35°C. Reaction is continued for 1 to 2 hours, and the conversion is checked.
  • the organic phase is separated off and washed with 65 1 of water.
  • the aqueous phase is back-extracted with 65 1 of MtBE. This is followed by concentration to about 80 1 in vacuo. Distillation to change to methanol and concentration to a volume of 140 1 are followed by stirring at 25°C for 1 to 2 hours. The mixture is then cooled to below -1O 0 C and stirred for a further 2 hours. The product is subsequently isolated and washed with 15 1 of cold methanol. Trimethoxydiene is dried in vacuo at 40°C.
  • the Grignard reagent is prepared from 13 kg of magnesium turnings, 280 1 of THF, 7.3 kg of DIBAH and 106 1 of bromobenzaldehyde dimethyl acetal.
  • Bromobenzaldehyde dimethyl acetal is prepared by acetalization of 4-bromo- benzaldehyde with trimethyl orthoformate in methanol in the presence of acidic catalysts, preferably acidic ion exchanger, preferably in a bypass method.
  • acidic catalysts preferably acidic ion exchanger
  • Dienone aldehyde The dimethoxy acetal solution is mixed with 312 1 of cone, acetic acid and 35 1 of water and heated at 90°C for about 30 min. After cooling, 680 1 of water are metered in. The crude product is isolated and stirred and washed several times with 170 1, 170 1 and 1 10 1 and 340 1 of MtB ether at temperatures up to 50°C. Dienone aldehyde is dried in vacuo at 30°C to 40°C.
  • the organic phase is washed with about 100 1 of a sodium bicarbonate solution. Distillation is carried out in vacuo to change to a final volume of 200 1 of methanol. The methanolic product solution is added to 510 1 of water, whereupon the crude product precipitates. Asoprisnil (crude) is isolated and dried in vacuo at 30 to 40°C.
  • the crude product is purified by preparative high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the 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 the yield.
  • the pure fraction is concentrated and isolated in the next process step.
  • HPLC high performance liquid chromatography
  • the dried microparticles are deposited on fresh textile filters with PTFE membrane of 1 m 2 .
  • the surface of the filter is periodically pulsed free with counter-current nitrogen.
  • the asoprisnil powder is subjected to an after-drying process.
  • the drying chamber is alternately subjected to a vacuum of 5 mbar and flushing nitrogen heated to 45°C. The vacuum and flushing phases each last 45 min.
  • the drying time is 12 h, and the final product temperature reached is 35°C.
  • the asoprisnil microparticles obtained in this way are analyzed and show the following characteristics:
  • Residual solvent content 0.36% ethanol

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EP07724653A 2006-04-18 2007-04-17 Method for preparing 4-[17beta -methoxy-17 -alpha methoxymethyl-3-oxoestra-4,9-dien-11beta -yl]benzaldehyde (e)-oxime (asoprisnil) Withdrawn EP2010555A2 (en)

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DE102006018888A DE102006018888A1 (de) 2006-04-18 2006-04-18 Verfahren zur Herstellung von 4-[17beta-Methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-dien-11beta-yl]benzaldehyd-(E)-oxims (Asoprisnil)
PCT/EP2007/003723 WO2007118717A2 (en) 2006-04-18 2007-04-17 METHOD FOR PREPARING 4-[17β-METHOXY-17α-METHOXYMETHYL-3-OXOESTRA-4,9-DIEN-11β-YL]BENZALDEHYDE (E)-OXIME (ASOPRISNIL)

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CN (1) CN101466724A (pt)
AU (1) AU2007237457A1 (pt)
BR (1) BRPI0710517A2 (pt)
CA (2) CA2839228A1 (pt)
DE (1) DE102006018888A1 (pt)
MX (2) MX2007000450A (pt)
RU (1) RU2008145098A (pt)
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ZA (1) ZA200809787B (pt)

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CN108003210A (zh) * 2018-01-24 2018-05-08 四川理工学院 一种雌甾-4,9-二烯-3,17-二酮的制备方法

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FR5183M (pt) * 1966-03-04 1967-06-19
ZA8231B (en) * 1981-01-09 1982-11-24 Roussel Uclaf New 11 -substituted steroid derivatives, their preparation, their use as medicaments, the compositions containing them and the new intermediates thus obtained
DD296931A5 (de) * 1987-08-28 1991-12-19 Jenapharm Gmbh Jena,De Verfahren zur herstellung von 13 beta-alkyl-5(10),9(11)-gonadienderivaten
US4910191A (en) * 1988-06-28 1990-03-20 Merrell Dow Pharmaceuticals Inc. 19-substituted progesterone derivatives useful as 19-hydroxylase inhibitors
DE4332283A1 (de) * 1993-09-20 1995-04-13 Jenapharm Gmbh Neue 11-Benzaldoximestradien-Derivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
EP1157996A1 (de) * 2000-05-23 2001-11-28 JENAPHARM GmbH Neue Festkörperformen des Mesoprogestins 11Beta-[4E-(Hydroxyiminomethyl)-phenyl]-17Alpha-methoxymethyl-17Beta-methoxy-estra-4,9-dien-3-on
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DE10056676A1 (de) * 2000-11-10 2002-05-16 Jenapharm Gmbh Verfahren zur Herstellung von 4-/17alpha-substituierten-3-oxoestra-4,9-dien-11beta-yl)benzaldehyd-(1E oder 1Z)-oximen
JP4197890B2 (ja) * 2001-05-24 2008-12-17 興和創薬株式会社 第一級アリルアルコール類の酸化方法
DE10311092A1 (de) * 2003-03-07 2004-10-07 Schering Ag Verfahren zur Oxidation der 17-Hydroxylfunktion in Steroiden und die Verwendung von Trifluoressigsäure und Cyclohexanon zur Herstellung von steroidalen 17-Ketonen mittels Oppenauer Oxidation
DE102004021060A1 (de) * 2004-04-29 2005-11-24 Schering Ag Wiederfindung von Arzneistoffen im ppm-Bereich in Produktionsanlagen

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WO2007118717A2 (en) 2007-10-25
CN101466724A (zh) 2009-06-24
MX2007000450A (es) 2009-02-11
AU2007237457A1 (en) 2007-10-25
ZA200809787B (en) 2010-01-27
RU2008145098A (ru) 2010-05-27
CA2839228A1 (en) 2007-10-25
MX2008013336A (es) 2008-10-31
WO2007118717A3 (en) 2008-04-24
CA2648537C (en) 2014-09-23
JP2009534345A (ja) 2009-09-24
KR20080110629A (ko) 2008-12-18
CA2648537A1 (en) 2007-10-25
BRPI0710517A2 (pt) 2011-08-16
DE102006018888A1 (de) 2007-10-25

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