Methods of preparing cytotoxic benzodiazepine derivatives

Abstract

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

1 - 123 . (canceled) 
     
     
         124 . A method of preparing a compound of formula (15d): 
       
         
           
           
               
               
           
         
         or a salt thereof, said method comprising reacting a sulfonating reagent or an esterification reagent with a compound of formula (14d), 
       
       
         
           
           
               
               
           
         
         wherein X 3  is —Cl; X 4  is a sulfonate ester or an activated ester; and R 100  is (C 1 -C 3 )alkoxy. 
       
     
     
         125 . The method of  claim 124 , wherein the sulfonating reagent is methansufonyl anhydride, methanesufonyl chloride, p-toluenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, or trifluoromethanesulfonyl anhydride. 
     
     
         126 . The method of  claim 125 , wherein the sulfonate ester represented by X 4  is mesylate, tosylate, brosylate, or triflate. 
     
     
         127 . The method of  claim 126 , wherein the sulfonate ester represented by X 4  is mesylate. 
     
     
         128 . The method of  claim 124 , wherein the sulfonate ester is reacted with a compound of formula (14d) in the presence of a non-nucleophilic base. 
     
     
         129 . The method of  claim 128 , wherein the non-nucleophilic base is triethylamine, imidazole, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine. 
     
     
         130 - 132 . (canceled) 
     
     
         133 . A method of preparing a compound of formula (16d): 
       
         
           
           
               
               
           
         
         or a salt thereof, said method comprising reacting a compound of formula (15d) 
       
       
         
           
           
               
               
           
         
         with a monomer compound of formula (a 1 ), 
       
       
         
           
           
               
               
           
         
         wherein X 3  is —Cl; X 4  is a sulfonate ester or an activated ester; and R 100  is (C 1 -C 3 )alkoxy. 
       
     
     
         134 . The method of  claim 133 , wherein the compound of formula (15d) is reacted with a monomer compound of formula (a 1 ) in the presence of a base. 
     
     
         135 . The method of  claim 134 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. 
     
     
         136 . (canceled) 
     
     
         137 . The method of  claim 133 , wherein the compound of formula (15d) is reacted with a monomer compound of formula (a 1 ) in the presence of a polar aprotic solvent. 
     
     
         138 . The method of  claim 137 , wherein the polar aprotic solvent is dimethylacetamide. 
     
     
         139 - 160 . (canceled) 
     
     
         161 . A method of preparing a compound of formula (17d): 
       
         
           
           
               
               
           
         
         or a salt thereof, said method comprising reacting a compound of formula (15d) 
       
       
         
           
           
               
               
           
         
         with a monomer compound of formula (d 1 ), 
       
       
         
           
           
               
               
           
         
         wherein X 3  is —Cl; X 4  is a sulfonate ester or an activated ester; P 3  is H or an amine protecting group; and R 100  is (C 1 -C 3 )alkoxy. 
       
     
     
         162 . The method of  claim 161 , wherein the compound of formula (15d) is reacted with a monomer compound of formula (d 1 ) in the presence of a base. 
     
     
         163 . The method of  claim 162 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. 
     
     
         164 . (canceled) 
     
     
         165 . The method of  claim 161 , wherein the compound of formula (15d) is reacted with a monomer compound of formula (d 1 ) in the presence of a polar aprotic solvent. 
     
     
         166 . The method of  claim 165 , wherein the polar aprotic solvent is dimethylacetamide. 
     
     
         167 . The method of  claim 161 , wherein the compound of formula (15d) is reacted with the monomer compound of formula (d 1 ), wherein P 3  is H, to form a compound of formula (17d′): 
       
         
           
           
               
               
           
         
       
     
     
         168 . (canceled) 
     
     
         169 . The method of  claim 161 , wherein P 3  is an amine protecting group and the method further comprises the step of reacting the compound of formula (17d) with an amine deprotecting reagent to form a compound of formula (17d′): 
       
         
           
           
               
               
           
         
       
     
     
         170 . The method of  claim 169 , wherein the amine deprotecting reagent is selected from the group consisting of tetra-n-butylammonium fluoride, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, acetic acid, or trifluroacetic acid. 
     
     
         171 - 204 . (canceled) 
     
     
         205 . The method of  claim 133 ,
 further comprising the step of reacting the compound of formula of (16d) with a reduced monomer of formula (d 1 ):   
       
         
           
           
               
               
           
         
         to form a compound of formula (18d): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein P 3  is H or an amine protecting group. 
       
     
     
         206 - 216 . (canceled) 
     
     
         217 . The method of  claim 133 ,
 further comprising the steps of:   (3) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d′):   
       
         
           
           
               
               
           
         
         or a salt thereof; and 
         (4) reacting the compound of formula (17d′) with a monomer of formula (a 1 ): 
       
       
         
           
           
               
               
           
         
         to form the compound of formula (Id′): 
       
       
         
           
           
               
               
           
         
       
     
     
         218 - 230 . (canceled)