Method for producing epothilone B and derivatives, and intermediate products for this method

Abstract

This invention relates to a process for the production of epothilone B and derivatives as well as intermediate products for this process. In the new process, epothilone B or the derivatives are built up in high yields from the C1-C6, C7-C10 and C11-C20 fragments (2, 3 and 4) that can be obtained at a reasonable price and free of diastereomers (the variable radicals have the meanings that are indicated in the description).

1 . Process for the production of epothilone B and derivatives of general formula  
       
         
           
           
               
               
           
         
       
       in which 
 R means a methyl group, and  
 R 6  means a straight-chain or branched-chain alkyl group with up to 6 carbon atoms, a cycloalkylalkyl group with up to 10 carbon atoms, a phenyl group, 1- or 2-naphthyl group, heteroaryl group, benzyl group or methylheteroaryl group,  
 characterized in that a compound of general formula 3  
                     
 in which  
 PG 3  means a hydroxy protective group, and  
 FG 3  means a phenylsulfonyl group,  
 is reacted with a compound of general formula 4  
                     
 in which  
 FG 4  means an iodine atom or another leaving group, and  
 PG 4  meats a hydroxy protective group,  
 to form a compound of general formula 34-I  
                     
 in which  
 PG 3  and PG 4  have the above-indicated meanings,  
 the compound of general formula 34-I is reacted with a compound of general formula 2  
                     
 in which  
 PG 21  and PG 22 , independently of one another, in each case mean a hydroxy protective group, and  
 R 6  means a straight-chain or branched-chain alkyl group with up to 6 carbon atoms, a cycloalkylalkyl group with up to 10 carbon atoms, a phenyl group, 1- or 2-naphthyl group, heteroaryl group, benzyl group or methylheteroaryl group,  
 to form a compound of general formula 234  
                     
 in which  
 PG 21 , PG 22 , PG 4  and R 6  have the already indicated meanings, and this compound of general formula 234 is reacted over the stages  
                     
 to form epothilone D or a derivative of epothilone D  
                     
 and the latter then is optionally converted by epoxidation into epothilone B (R═CH 3 ) or a derivative of epothilone B.  
                     
 
     
     
         2 . Process for the production of compounds of general formula 2 according to  claim 1   
       
         
           
           
               
               
           
         
       
       in which 
 PG 21  and PG 22 , independently of one another, in each case mean a hydroxy protective group, and  
 R 6  means a straight-chain or branched-chain alkyl group with up to 6 carbon atoms, a cycloalkylalkyl group with up to 10 carbon atoms, a phenyl group, 1- or 2-naphthyl group, heteroaryl group, benzyl group or  
 methylheteroaryl group  
 wherein a compound of general formula 2-I  
                     
 in which  
 PG 21  means a hydroxy protective group,  
 is reacted under chiral catalysis with a silylketenacetal of general formula  
                     
 (R 2 =methyl, ethyl, etc.)  
 with mediation by 7-tosylvaline/diborane to form a compound of general formula 2-II  
                     
 in which  
 PG 21  and R 2  have the above-indicated meanings, then the 3-hydroxy group is protected while a compound of general formula 2-III  
                     
 in which  
 PG 21  and PG 22 , independently of one another, in each case mean a hydroxy protective group, and R 2  has the above-indicated meaning,  
 is obtained, then a methyl group is added to the carbonal group of compound 2-III while a compound of general formula 2-IV  
                     
 in which  
 PG 21  and PG 22 , independently of one another, in each case mean a hydroxy protective group,  
 is obtained, and then is converted with an alkyl, cycloalkylalkyl, aryl, heteroaryl, methyl, aryl or methylheteroaryl halide of general formula 2-X  
 R 6 Hal   (2-X)  
 in which  
 R 6  has the already indicated meaning, and  
 Hal stands for a halogen atom fluorine, chlorine or bromine,  
 into a compound of-general formula 2  
                     
 in which  
 PG 21 , PG 22  and R 6  have the above-indicated meanings, or the compound 2-III is reduced to alcohol, the latter is selectively oxidized to aldehyde, a radical of formula —CH 2 —R 6  is added to the latter with an organometallic compound, and the alcohol that is produced is oxidized to form the ketone of general formula 2.  
 
     
     
         3 . Process for the production of compounds of general formula 3 according to  claim 1   
       
         
           
           
               
               
           
         
       
       in which 
 PG 3  means a hydroxy protective group, and  
 FG 3  means a phenylsulfonyl group,  
 wherein the free hydroxyl group of the compound of general formula 3-I  
                     
 in which  
 PG 3  means a hydroxy protective group,  
 is converted into a better leaving group FG 31  (compound 3-II)  
                     
 and then with disclacement of FG 31 , the group —CH 2 —SO 2 -phenyl (FG 3 =—SO 2 -phenyl) is added while a compound of general formula 3  
                     
 is obtained.  
 
     
     
         4 . Compounds of general formula 234  
       
         
           
           
               
               
           
         
       
       in which 
 PG 21 , PG 22 , and PG 4 , independently of one another, in each case mean a hydroxy protective group, and  
 R 6  means a straight-chain or branched-chain alkyl group with up to 6 carbon atoms, a cycloalkylalkyl group with up to 10 carbon atoms, a phenyl group, 1- or 2-naphthyl group, heteroaryl group, benzyl group or methylheteroaryl group.