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

Abstract

The present invention relates to a method for the reliable and reproducible preparation of 4-[17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-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.).

1 ) Method for preparing asoprisnil on the pilot or manufacturing scale via the stages 
       
         
           
           
               
               
           
         
         comprising the following steps: 
         a) synthesis of nordienedione ketal from hydroxyestradienone either 
         by oxidation of 17β-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) to estra-4,9-diene-3,17-dione (nordienedione) and subsequent selective ketalization to 3,3 dimethoxyestra-5(10),9(11)-diene-17-one (nordienedione ketal) or 
         by ketalization of hydroxyestradienone to 17β-hydroxy-3,3-dimethoxyestra-5(10),9(11)-diene (hydroxy ketal) and subsequent oxidation to nordienedione ketal.
 b) synthesis of trimethoxydiene from nordienedione ketal in three steps via the stages 3,3-dimethoxyestra-5(10),9(11)-diene-17β-spiro-1′,2′-oxirane (nordienespirane) and 3,3-dimethoxy-17α-methoxymethylestra-5(10),9(11)-dien-17β-ol (nordiene ether), not isolating nordienespirane and nordiene ether, 
 c) synthesis of 3,3,17β-trimethoxy-11β-[4-(dimethoxymethyl)phenyl]-17α-methoxymethylestr-9-en-5α-ol (dimethoxy acetal) from trimethoxydiene via 17α-(methoxymethyl)-3,3,17β-trimethoxy-5α, 10α-epoxyestr-9(11)-ene (enepoxide) in a Cu(I)-catalyzed Grignard reaction with bromobenzaldehyde dimethyl acetal 
 d) synthesis of the dienone aldehyde by reaction with acids 
 e) synthesis of asoprisnil from dienone aldehyde with a hydroxyamine hydrochloride solution, 
 f) purification by chromatography, 
 g) drying. 
 
       
     
     
         2 ) Method according to  claim 1 , where hydroxyestradienone is converted into nordienedione ketal by ketalization with Lewis acids and either by chromic acid oxidation or Oppenauer oxidation. 
     
     
         3 ) Method according to  claim 2 , where either the hydroxyestradienone is first oxidized and then ketalized or is first ketalized and then oxidized. 
     
     
         4 ) Method according to  claim 3 , carrying out the chromic acid oxidation first and a selective ketalization subsequently or the ketalization first and an Oppenauer oxidation subsequently. 
     
     
         5 ) Method according to  claim 3 , where the chromic acid oxidation is carried out as two-phase reaction between two liquid phases. 
     
     
         6 ) Method according to  claim 5 , where water, preferably 2-10% by weight based on acetone, are added to a solution of hydroxyestradienone in acetone in such a way that a defined systemic water concentration, preferably of 10-15% by weight, is set up, with the steroid concentration not exceeding 8 g/l of acetone. 
     
     
         7 ) Method according to  claim 3 , where the ketalization is carried out first, preferably on an acidic ion exchanger. 
     
     
         8 ) Method according to  claim 7 , where the ketalization takes place in a bypass method. 
     
     
         9 ) Method according to  claim 3 , where the Oppenauer oxidation takes place with catalysis by aluminium diisopropoxide trifluoroacetate (DIPAT). 
     
     
         10 ) Method according to  claim 1 , where nordienedione ketal is converted completely to trimethoxydiene via the stages of nordienespirane and nordiene ether in three steps, characterized 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° C. and in an after-reaction phase between 20 to 40° C., preferably between 30 to 35° C.;   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 20-35° C., preferably 25° C., for about 1 to 2 hours, and then cooling further to −5° C. to −15° C., preferably −10° C.   
     
     
         11 ) Method according to  claim 1 , where the drying in step g) takes place in such a way that contamination of the dried asoprisnil microparticles with seed centres in the drying device is greatly reduced. 
     
     
         12 ) Method according to  claim 11 , where the drying preferably takes place by a spray drying, characterized in that a narrow particle size range is achieved through the geometrical and aerodynamic conditions in the atomizing device, and wetting events by spray drops on surfaces of the apparatus with which the product makes contact are avoided. 
     
     
         13 ) Method according to  claim 11 , in which the narrow drop size range is generated by a high atomizing efficiency of the spraying unit by maintaining a mass ratio of spraying gas employed to sprayed solution of from 1.5 to 10, preferably from 2.5 to 5, and a mass ratio of drying gas employed to sprayed solution employed of at least 10, preferably at least 20 and with a drying temperature of from 40° C. to 90° C., preferably 75° C. to 90° C. 
     
     
         14 ) Method according to  claim 13 , where the high atomizing efficiency of the spraying unit is produced by a high speed of rotation of a rotating disc or by a high atomizing gas throughput through a twin-fluid nozzle. 
     
     
         15 ) Method according to  claim 11  such that the spray-dried asoprisnil microparticles are subjected to an after-drying procedure which takes place in vacuo and/or with flushing of the asoprisnil microparticles with a solvent-free drying gas below 90° C., preferably below 50° C., for at least 12 h. 
     
     
         16 ) Method according to  claim 11 , where the deposition of the asoprisnil microparticles after the spray drying takes place on a product filter, preferably using fresh unused filter surfaces. 
     
     
         17 ) Amorphous, physically pure asoprisnil microparticles obtainable by a method according to  claim 1 . 
     
     
         18 ) Asoprisnil microparticles according to  claim 17  having an average particle size d 50  of less than 2.5 μm, preferably 2.1 μm, and a maximum particle size d 100  of less than 25 μm, preferably 11 μm. 
     
     
         19 ) Asoprisnil microparticles according to  claim 17 , characterized in that the enthalpy of fusion at 194.7° C.±2° C., determined by DSC with a heating rate of 5 K/min, is less than 20 J/g, preferably less than 5 J/g, preferably less than 1 J/g. 
     
     
         20 ) Asoprisnil microparticles according to  claim 17 , characterized in that, when they are heated at 20 K/min to 170° C. and then cooled at 20 K/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. 
     
     
         21 ) Asoprisnil microparticles according to  claim 17  for the manufacture of medicaments. 
     
     
         22 ) Use of asoprisnil microparticles according to  claim 21  for the manufacture of a medicament for the treatment of hormone-dependent gynaecological disorders, especially for the treatment of endometriosis, fibroids or other gynaecological dysfunctions. 
     
     
         23 ) Use of asoprisnil microparticles according to  claim 17  in hormone replacement therapy (HRT) and for female fertility control. 
     
     
         24 ) Pharmaceutical composition comprising asoprisnil microparticles according to  claim 17  together with pharmaceutically acceptable excipients and/or carriers. 
     
     
         25 ) Pharmaceutical composition according to  claim 24  characterized in that the composition is a solid pharmaceutical form. 
     
     
         26 ) Solid pharmaceutical form according to  claim 25 , characterized in that administration takes place orally.