Novel method for producing antibody-drug conjugate

Abstract

A method for producing a compound represented by formula (C) wherein R 1 represents an amino group protected with a protecting group, the method comprising a step of subjecting a compound represented by formula (B) wherein R 1 represents the same meaning as above, to intramolecular cyclization to convert the compound into the compound represented by formula (C).

1 . A method for producing a compound represented by formula (E): 
       
         
           
           
               
               
           
         
         wherein R 1  represents an amino group protected with a protecting group, the method comprising a step of coupling a compound represented by formula (D): 
       
       
         
           
           
               
               
           
         
         wherein X represents a leaving group, and R 1  represents the same meaning as above, with 3-butenoic acid to convert the compound represented by formula (D) into the compound represented by formula (E). 
       
     
     
         2 . The method according to  claim 1 , wherein X is a bromo group, an iodo group, a trifluoromethanesulfonyloxy group, or an arylsulfonyloxy group. 
     
     
         3 . The method according to  claim 1 , wherein X is a bromo group. 
     
     
         4 . The method according to  claim 1 , wherein X is an iodo group. 
     
     
         5 . The method according to  claim 1 , wherein R 1  is an amino group protected with an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a trichloroacetyl group, a pivaloyl group, a formyl group, or a benzoyl group. 
     
     
         6 . The method according to  claim 1 , wherein R 1  is an amino group protected with an acetyl group or a trifluoroacetyl group. 
     
     
         7 . The method according to  claim 1 , wherein R 1  is an amino group protected with an acetyl group. 
     
     
         8 . The method according to  claim 1 , which is performed in the presence of a palladium complex prepared from palladium(II) acetate and tri(o-tolyl)phosphine. 
     
     
         9 . The method according to  claim 1 , comprising the steps of: dissolving the compound represented by formula (E) in a basic aqueous solution to wash the compound represented by formula (E) with a first organic solvent and separating the solvents; and then adding an acid to the basic aqueous solution to extract the compound represented by formula (E) with a second organic solvent and separating the solvents. 
     
     
         10 . The method according to  claim 9 , wherein the first organic solvent is 2-methyltetrahydrofuran. 
     
     
         11 . The method according to  claim 9 , wherein the second organic solvent is 2-methyltetrahydrofuran. 
     
     
         12 . The method according to  claim 9 , wherein the basic aqueous solution is an aqueous sodium hydroxide solution. 
     
     
         13 . The method according to  claim 1 , wherein no chromatography is used.