Methods of preparing cytotoxic benzodiazepine derivatives

Abstract

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

1 . A method of preparing a compound of formula (15a): 
       
         
           
           
               
               
           
         
         or a salt thereof, said method comprising reacting a sulfonating reagent or an esterification reagent with a compound of formula (14a), 
       
       
         
           
           
               
               
           
         
         wherein X 3  is —Cl; X 4  is a sulfonate ester or an activated ester (preferably, a sulfonate ester); and R 101  is (C 1 -C 3 )alkyl, pyridyl, or nitropyridyl. 
       
     
     
         2 . The method of  claim 1 , wherein the sulfonating reagent is methansufonyl anhydride, methanesufonyl chloride, p-toluenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, or trifluoromethanesulfonyl anhydride. 
     
     
         3 . The method of  claim 1 , wherein the sulfonate ester represented by X 1  is mesylate, tosylate, brosylate, or triflate. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the sulfonate ester is reacted with a compound of formula (14a) in the presence of a non-nucleophilic base. 
     
     
         6 . The method of  claim 5 , 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. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , further comprising the step of reacting the compound of formula (15a) with a monomer compound of formula (a 1 ), 
       
         
           
           
               
               
           
         
         to form a compound of formula (16a): 
       
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         9 . The method of  claim 8 , wherein the compound of formula (15a) is reacted with a monomer compound of formula (a 1 ) in the presence of a base, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 8 , wherein the compound of formula (15a) is reacted with a monomer compound of formula (a 1 ) in the presence of a polar aprotic solvent. 
     
     
         12 . The method of  claim 11 , wherein the polar aprotic solvent is dimethylacetamide. 
     
     
         13 . The method of  claim 1 , further comprising the step of reacting the compound of formula (15a) with a monomer compound of formula (d 1 ) 
       
         
           
           
               
               
           
         
       
       to a compound of formula (17a): 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         14 . The method of  claim 13 , wherein the compound of formula (15a) is reacted with a monomer compound of formula (d 1 ) in the presence of a base, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 13 , wherein the compound of formula (15a) is reacted with a monomer compound of formula (d 1 ) in the presence of a polar aprotic solvent. 
     
     
         17 . The method of  claim 16 , wherein the polar aprotic solvent is dimethylacetamide. 
     
     
         18 . The method of  claim 13 , wherein the compound of formula (15a) is reacted with the monomer compound of formula (d 1 ), wherein P 3  is H, to form a compound of formula (17a′): 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 13 , wherein P 3  is an amine protecting group. 
     
     
         20 . The method of  claim 19 , further comprising the step of reacting the compound of formula (17a) with an amine deprotecting reagent to form a compound of formula (17a′): 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 20 , 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. 
     
     
         22 . A method of preparing a compound of formula (18a), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, said method comprising the steps of: 
         (1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14a): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, to form a compound of formula (15a): 
       
       
         
           
           
               
               
           
         
         or a salt thereof; 
         (2) reacting the compound of formula (15a) with a monomer compound of formula (a 1 ), 
       
       
         
           
           
               
               
           
         
         to form a compound of formula (16a): 
       
       
         
           
           
               
               
           
         
         or a salt thereof; and 
         (3) reacting the compound of formula of (16a) with a reduced monomer of formula (d 1 ): 
       
       
         
           
           
               
               
           
         
         to form a compound of formula (18a), or a pharmaceutically acceptable salt thereof, wherein X 3  is —Cl; X 4  is a sulfonate ester or an activated ester (preferably, a sulfonate ester); P 1  is an alcohol protecting group; P 3  is H or an amine protecting group; and R 101  is (C 1 -C 3 )alkyl, pyridyl, or nitropyridyl. 
       
     
     
         23 . The method of  claim 22 , wherein the compound of formula (18a) is further reacted with an amine deprotecting reagent to form a compound of formula (Ia′): 
       
         
           
           
               
               
           
         
       
     
     
         24 . A method of preparing a compound of formula (Ia′), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, said method comprising the steps of: 
         (1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14a): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, to form a compound of formula (15a): 
       
       
         
           
           
               
               
           
         
         or a salt thereof; 
         (2) reacting the compound of formula (15a) with a monomer compound of formula (a 1 ), 
       
       
         
           
           
               
               
           
         
         to form a compound of formula (16a): 
       
       
         
           
           
               
               
           
         
         or a salt thereof; 
         (3) reacting the compound of formula (16a) with an imine reducing agent to form a compound of formula (17a′): 
       
       
         
           
           
               
               
           
         
         or a salt thereof; and 
         (4) reacting the compound of formula (17a′) with a monomer of formula (a 1 ): 
       
       
         
           
           
               
               
           
         
         to form the compound of formula (Ia′); wherein X 3  is —Cl; X 4  is a sulfonate ester or an activated ester (preferably, a sulfonate ester); P 1  is an alcohol protecting group; P 2  is an amine protecting group; and R 101  is (C 1 -C 3 )alkyl, pyridyl, or nitropyridyl.