4-[17beta-methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-dien-11-beta-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 . Amorphous, physically pure asoprisnil microparticles obtainable by a method comprising reacting on the pilot or manufacturing scale 
       
         
           
           
               
               
           
         
         by a process comprising: 
         a) synthesizing 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 
 ketalizing hydroxyestradienone to 17β-hydroxy-3,3-dimethoxyestra-5(10),9(11)-diene (hydroxy ketal) and subsequent oxidation subsequently oxidizing to nordienedione ketal, 
 
         b) synthesizing 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) synthesizing 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) synthesizing the dienone aldehyde by reaction with acids, 
         e) synthesizing asoprisnil from dienone aldehyde with a hydroxyamine hydrochloride solution, 
         f) purifying by chromatography, 
         g) drying. 
       
     
     
         2 . The microparticles according to  claim 1 , where in the process hydroxyestradienone is converted into nordienedione ketal by ketalization with Lewis acids and either by chromic acid oxidation or Oppenauer oxidation. 
     
     
         3 . The microparticles according to  claim 2 , where in the process either the hydroxyestradienone is first oxidized and then ketalized or is first ketalized and then oxidized. 
     
     
         4 . The microparticles according to  claim 3 , where the process comprises carrying out the chromic acid oxidation first and a selective ketalization subsequently or the ketalization first and an Oppenauer oxidation subsequently. 
     
     
         5 . The microparticles according to  claim 3 , where in the process the chromic acid oxidation is carried out as two-phase reaction between two liquid phases. 
     
     
         6 . The microparticles according to  claim 5 , where in the process water, is 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 . The microparticles according to  claims 3  and  4 , where the ketalization is carried out first. 
     
     
         8 . The microparticles according to  claim 7 , where in the process the ketalization takes place in a bypass method. 
     
     
         9 . The microparticles according to  claim 3 , where in the process the Oppenauer oxidation takes place with catalysis by aluminium diisopropoxide trifluoroacetate (DIPAT). 
     
     
         10 . The microparticles according to  claim 1 , where in the process nordienedione ketal is converted completely to trimethoxydiene via the stages of nordienespirane and nordiene ether in three steps, comprising
 a) producing nordienespirane in DMF in an initial phase with addition of the reactants in a temperature range from 0 to 25° C., and in an after-reaction phase between 20 to 40° C.;   b) the reaction product obtained in a) not being isolated but being employed as solution of nordienespirane in solvents;   c) for conversion of the converting nordienespirane from b) into the nordiene ether changing the solvent, optionally during the reaction with sodium methanolate, or by azeotropic distillation, and thus reaching reaction temperatures of 70° C. or more;   d) crystallizing trimethoxydiene from methanol by cooling the solution, to 20-35° C., for about 1 to 2 hours, and then cooling further to −5° C. to −15° C.   
     
     
         11 . The microparticles according to  claim 1 , where in the process the drying in g) takes place in such a way that contamination of the dried asoprisnil microparticles with seed centers in the drying device is greatly reduced. 
     
     
         12 . The microparticles according to  claim 11 , where in the process the drying takes place by a spray drying, a narrow particle size range is achieved through 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 . The microparticles according to  claim 12 , 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, and a mass ratio of drying gas employed to sprayed solution employed of at least 10, and with a drying temperature of from 40° C. to 90° C. 
     
     
         14 . The microparticles according to  claim 13 , where in the process 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 . The microparticles according to  claim 11  wherein 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. for at least 12 h. 
     
     
         16 . The microparticles according to  claim 11 , where in the process the deposition of the asoprisnil microparticles after the spray drying takes place on a product filter. 
     
     
         17 . (canceled) 
     
     
         18 . The microparticles according to  claim 1  having an average particle size d 50  of less than 2.5 μm, and a maximum particle size d 100  of less than 25 μm. 
     
     
         19 . The microparticles according to  claim 1 , having enthalpy of fusion at 194.7° C.±2° C., determined by DSC with a heating rate of 5 K/min, is of less than 20 J/g. 
     
     
         20 . The microparticles according to  claim 1 , when heated at 20 K/min to 170° C. and then cooled at 20 K/min to 90° C., having a number of crystallites visible by thermomicroscopy is less than 10 000 per mg. 
     
     
         21 . The microparticles according to  claim 1 , in the form of medicaments. 
     
     
         22 . In a medicament for the treatment of hormone-dependent gynaecological disorders, endometriosis, fibroids or other gynaecological dysfunctions, the improvement wherein the medicament comprises microparticles of  claim 21 . 
     
     
         23 . In a medicament for hormone replacement therapy (HRT) or for female fertility control, the improvement wherein the medicament comprises microparticles of  claim 21 . 
     
     
         24 . A pharmaceutical composition comprising asoprisnil microparticles according to  claim 1  together with a pharmaceutically acceptable excipient and/or carrier. 
     
     
         25 . The pharmaceutical composition according to  claim 24 , in a solid pharmaceutical form. 
     
     
         26 . The pharmaceutical composition according to  claim 25 , formulated for oral administration.