Method for producing 5-hydroxyalkyl-substituted 1-phenyl-1,2,4- triazole derivatives

Abstract

The present application relates to a novel and improved process for preparing 5-(hydroxyalkyl)-1-phenyl-1,2,4-triazole derivatives of the formula (I) in which R 1A and R 1B are independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxy, difluoromethoxy and trifluoromethoxy, to novel precursors for preparation thereof, and to the preparation and use of the crystalline polymorph I of (5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one of the formula (I-A-1).

1 . A compound which is (5-(4-Chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one of the formula (I-A-1) in crystalline form of the polymorph I 
       
         
           
           
               
               
           
         
         wherein the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 7.0, 8.9, 16.8, 17.7, 17.9, 18.1, 21.6, 21.8, 22.4 and 24.6. 
       
     
     
         2 . A pharmaceutical composition comprising the crystalline form of the polymorph I according to  claim 1  of any other form of the compound of the formula (I-A-1). 
     
     
         3 . A pharmaceutical composition comprising the crystalline form of the polymorph I according to  claim 1  in more than 90% by weight based on the total amount of the compound of the formula (I-A-1) present. 
     
     
         4 . A method for producing a pharmaceutical composition for treatment of cardiovascular disorders or renal disorders, the method comprising the step of mixing the crystalline form of the polymorph I of  claim 1  with at least one pharmaceutically acceptable carrier. 
     
     
         5 . A method of treating a cardiovascular disorder or a renal disorder comprising administering an effective amount of a crystalline form of the polymorph I according to  claim 1 . 
     
     
         6 . A process for preparing the compound (5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one of the formula (I-A-1) in crystalline form of polymorph I, the process comprising
 stirring the compound of the formula (I-A-1), in a mixture of methyl tert-butyl ether/diisopropyl ether or of methyl tert-butyl ether/n-heptane at a temperature of 20° C. to 80° C., wherein the compounds is optionally present in one or more polymorphs or in solvate form   filtering the compound;   washing the compound;   drying the compound under reduced pressure.   
     
     
         7 . A compound of the general formula (X) 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound of the general formula (XI) 
       
         
           
           
               
               
           
         
         where 
         R 2  is (C 1 -C 4 )-alkyl. 
       
     
     
         9 . The compound of  claim 8  wherein R 2  is methyl.