Methods of preparing cytotoxic benzodiazepine derivatives

Abstract

The invention provides novel methods for preparing indolinobenzodiazepine dimer compounds and their synthetic precursors.

1 . A method of preparing a compound of formula (IIIa):
                       or a salt thereof, comprising the steps:
 (a) reacting a compound of formula (Ia1):
                     
 or a salt thereof, with a compound of formula (a): 
                     
 or a salt thereof, in the presence of the activating agent 2.4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide to form a compound of formula (IIa1): 
                     
 
 (b) reacting the compound of formula (IIa1) with a carboxylic acid deprotecting agent to form the compound of formula (IIIa), wherein the carboxylic acid deprotecting agent is an acid. 
   
     
     
         2 . The method of  claim 1 , wherein the method further comprises reacting the compound of formula (IIIa) with a compound of formula (IV):
                       to form a compound of formula (Va):                         .   
     
     
         3 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the acid is trifluoroacetic acid (TFA). 
     
     
         11 - 13 . (canceled) 
     
     
         14 . A method of preparing a compound of formula (Va):
                       comprising the steps of:
 (a) reacting a compound of formula (Ia1):
                     
 or a salt thereof, with a compound of formula (a): 
                     
 or a salt thereof, in the presence of the activating agent 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide to form a compound of formula (IIa1): 
                     
 
 (b) reacting the compound of formula (IIa) with a carboxylic acid deprotecting agent to form the compound of formula (IIIa):
                     
 or a salt thereof, wherein the carboxylic acid deprotecting agent is an acid; and (c) reacting the compound of formula (IIIa) with a compound of formula (IV): 
                     
 
   in the presence of an activating agent to form the compound of formula (Va).   
     
     
         15 - 21 . (canceled) 
     
     
         22 . The method of  claim 14 , wherein the acid is trifluoroacetic acid (TFA). 
     
     
         23 - 29 . (canceled) 
     
     
         30 . The method of  claim 14 , wherein the activating agent is HATU and HOAt. 
     
     
         31 . The method of  claim 30 , wherein the reaction between the compound of formula (IIIa) and the compound of formula (IV) is carried out in the presence of a base. 
     
     
         32 . The method of  claim 31 , wherein the base is triethylamine or diisopropylethylamine.