Process for preparing epothilone derivatives by selective catalytic epoxidation

Abstract

The present invention describes a novel process for preparing an epothilone derivative using substituted pyridines and methyltrioxorhenium as catalyst.

1 . Process for preparing the epothilone derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       characterized in that the dialkene of the formula (II) 
       
         
           
           
               
               
           
         
       
       is epoxidized using methyltrioxorhenium with an epoxidizing agent in an aprotic solvent at −60° C. to −20° C. 
     
     
         2 . Process according to  claim 1 , in which the epoxidizing agent is aqueous hydrogen peroxide solution. 
     
     
         3 . Process according to  claim 1 , in which there is further addition of a substituted pyridine derivative. 
     
     
         4 . Process according to  claim 3 , characterized in that the dialkene of the formula (II) is reacted at −60 to −20° C. in chlorinated hydrocarbons or mixtures thereof with low-boiling alkanes or toluene or trifluorotoluene as solvent 
       using 6-36 mol % of a substituted pyridine, 
       and 1-7 mol % methyltrioxorhenium 
       and 2-5 equivalents 10-60% strength aqueous hydrogen peroxide solution. 
     
     
         5 . Process according to  claim 1 , where the reaction times are between 20-120 h. 
     
     
         6 . Process according to  claim 1 , where the concentration of the compound of the formula II is in the range from 1 g in 5 ml of solvent to 1 g in 50 ml of solvent. 
     
     
         7 . Process according to  claim 1 , characterized in that the solvent is selected from the group of dichloromethane, 1,2-dichloroethane, chloroform, and mixtures thereof with pentane, hexane, heptane, cyclohexane, toluene or trifluorotoluene, or toluene or trifluorotoluene on their own. 
     
     
         8 . Process according to  claim 3 , characterized in that the substituted pyridine is selected from the group 
       
         
           
           
               
               
           
         
       
     
     
         9 . Process according to  claim 3 , characterized in that the substituted pyridine is an electron-poor pyridine derivative which is substituted in position 4 by CN, Br, Cl, F, CF 3 , SO 2 (C 1 -C 4 )alkyl, SO 2 NH 2 , SO 2 N[(C 1 -C 4 )alkyl] 2 , COOH, COO(C 1 -C 4 )alkyl. 
     
     
         10 . Epothilone derivative of the formula I prepared by the process according to  claim 1  containing rhenium. 
     
     
         11 . Epothilone derivative according to  claim 10 , containing 0.01 to 30 ppm rhenium. 
     
     
         12 . Process according to  claim 1 , characterized in that the crude product obtained is crystallized.