Process for making lysine-glutamic acid dipeptide derivatives

Abstract

The invention relates to compounds of the formula and to a process for making same and to the use of the products in the solid phase peptide synthesis. The compounds of formula I are versatile peptide intermediates for the solid phase peptide synthesis (SPPS) of peptide drugs which comprise a Glu-fatty alkyl side chain building block attached to a Lys-part of the peptide chain.

1 . A method for solid phase synthesis of a peptide drug, comprising using a compound of formula I 
       
         
           
           
               
               
           
         
         as a building block in the solid phase synthesis, 
         wherein, 
         R 1  and R 2  are the same or different and denote hydrogen or an ester protecting group, 
         R 3  is hydrogen or an amino protecting group and 
         R 4  is C 12-20 -alkyl, 
         and-enantiomers, diastereomers and salts thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the peptide drug is a GLP-1 analog diabetes type 2 peptide drug. 
     
     
         3 . The method of  claim 2 , wherein the peptide drug is liraglutide. 
     
     
         4 . The method of  claim 3 , wherein the compound of formula I is located at position 26 of the liraglutide. 
     
     
         7 . The method of  claim 1  wherein, the ester protecting group is selected from C 1-4 -alkyl, optionally substituted with phenyl, C 2-4 -alkenyl, piperidinyl or dimethylaminoboranyl. 
     
     
         8 . The method of  claim 1 , wherein R 1  is hydrogen or C 1-4 -alkyl and R 2  is hydrogen or C 2-4 -alkenyl. 
     
     
         9 . The method of  claim 1 , wherein R 1  is t-butyl and R 2  is hydrogen or allyl. 
     
     
         10 . The method of  claim 1 , wherein R 3  is 9H-fluoren-9-ylmethoxycarbonyl. 
     
     
         11 . The method of  claim 1 , wherein R 4  is C 14-16 -alkyl. 
     
     
         12 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  and R 2  are the same or different and denote hydrogen or an ester protecting group, 
         R 3  is hydrogen or an amino protecting group and 
         R 4  is C 12-20 -alkyl, 
         and-enantiomers, diastereomers and salts thereof. 
       
     
     
         13 . A process for the preparation of compounds of formula I, 
       
         
           
           
               
               
           
         
         and enantiomers and salts thereof, wherein: 
         R 1  is hydrogen or an ester protecting group; 
         R 2  is hydrogen; 
         R 3  is hydrogen or an amino protecting group and 
         R 4  is C 12-20 -alkyl; 
         the process comprising: 
         a) coupling the glutamic acid derivative of formula II 
       
       
         
           
           
               
               
           
         
         or a salt thereof with a lysine derivative of formula III 
       
       
         
           
           
               
               
           
         
         wherein R 2′  is an ester protecting group, or a salt thereof to form a compound of the formula Ic; 
       
       
         
           
           
               
               
           
         
         and 
         b) removing the ester protecting group R 2′  to provide the compound of formula I.