Process for the preparation of drug linker compounds

Abstract

This disclosure generally relates to novel processes for the preparation of drug linker compounds and compositions comprising such drug linker compounds. The presently disclosed methods for synthesizing Fmoc-Val-Cit-PABOH and related compounds have also been found to minimize formation of diastereomeric impurities.

1 - 34 . (canceled) 
     
     
         35 . A compound of Formula (1D) or a salt thereof, 
       
         
           
           
               
               
           
         
         prepared by a process comprising: 
         reacting a compound of Formula (1B) or a salt thereof, 
       
       
         
           
           
               
               
           
         
         with p-aminobenzyl alcohol (PABOH) in the presence of a peptide coupling reagent, to form a compound of Formula (1A): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein 
         the peptide coupling reagent comprises 
       
       
         
           
           
               
               
           
         
          or an HOAt derivative; 
         wherein Z 1  is a protecting group; 
         and wherein D is a moiety of Formula (D): 
       
       
         
           
           
               
               
           
         
         wherein the wavy line indicates covalent bonding of D to the remainder of the compound;
 R 11  is selected from the group consisting of H and C 1 -C 8  alkyl; 
 R 12  is selected from the group consisting of H, C 1 -C 8  alkyl, C 3 -C 8  carbocyclyl, aryl, C 1 -C 8  alkyl-aryl, C 1 -C 8  alkyl-(C 3 -C 8  carbocyclyl), C 3 -C 8  heterocyclyl, and C 1 -C 8  alkyl-(C 3 -C 8  heterocyclyl); 
 R 13  is selected from the group consisting of H, C 1 -C 8  alkyl, C 3 -C 8  carbocyclyl, aryl, C 1 -C 8  alkyl-aryl, C 1 -C 8  alkyl-(C 3 -C 8  carbocyclyl), C 3 -C 8  heterocyclyl, and C 1 -C 8  alkyl-(C 3 -C 8  heterocyclyl); 
 R 14  is selected from the group consisting of H and methyl; 
 or R 13  and R 14  jointly form a carbocyclic ring and have the formula —(CR a R b ) n- , wherein R a  and R b  are independently selected from the group consisting of H, C 1 -C 8  alkyl and C 3 -C 8  carbocyclyl, and n is selected from the group consisting of 2, 3, 4, 5 and 6; 
 R 15  is selected from the group consisting of H and C 1 -C 8  alkyl; 
 R 16  is selected from the group consisting of H, C 1 -C 8  alkyl, C 3 -C 8  carbocyclyl, aryl, C 1 -C 8  alkyl-aryl, C 1 -C 8  alkyl-(C 3 -C 8  carbocyclyl), C 3 -C 8  heterocyclyl, and C 1 -C 8  alkyl-(C 3 -C 8  heterocyclyl); 
 each R 17  is independently selected from the group consisting of H, OH, C 1 -C 8  alkyl, C 3 -C 8  carbocyclyl, and —O—(C 1 -C 8  alkyl); 
 R 18  is selected from the group consisting of H and C 1 -C 8  alkyl; 
 R 19  is selected from the group consisting of —C(R 17 ) 2 —C(R 17 ) 2 -aryl, —C(R 17 ) 2 —C(R 17 ) 2 —(C 3 -C 8  heterocyclyl), —C(R 17 ) 2 —C(O)—ZR 20 , and —C(R 17 ) 2 —C(R 17 ) 2 —(C 3 -C 8  carbocyclyl); 
 R 20  is selected from the group consisting of H, C 1 -C 8  alkyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 5 -C 10  heteroaryl and C 3 -C 8  heterocyclyl; and
 Z is —O—, or —NH—, or 
 Z— is —O— and R 20  is C 1 -C 4  alkyl or Z is —NH— and R 20  is optionally substituted phenyl or optionally substituted C 5 -C 6  heteroaryl. 
 
 
       
     
     
         36 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein Z 1  is an alkoxy-carbonyl or aryloxy-carbonyl group. 
     
     
         37 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein Z 1  is fluorenylmethyloxycarbonyl (Fmoc). 
     
     
         38 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein the peptide coupling reagent comprises a compound selected from the group consisting of HOAt, 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein the peptide coupling reagent comprises a compound selected from the group consisting of HOAt, HATU, COMU, and PyAOP. 
     
     
         40 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein the peptide coupling reagent comprises HOAt. 
     
     
         41 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein the peptide coupling reagent comprises HATU. 
     
     
         42 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein the peptide coupling reagent comprises PyAOP. 
     
     
         43 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein the peptide coupling reagent comprises COMU. 
     
     
         44 . The compound of Formula (1D) of  claim 40 , wherein the peptide coupling reagent further comprises 
       
         
           
           
               
               
           
         
       
     
     
         45 . The compound of Formula (1D) of  claim 40 , wherein the peptide coupling reagent further comprises 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein the reaction of the compound of Formula (1B) or a salt thereof with the PABOH is performed in the presence of a base. 
     
     
         47 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein the process comprises obtaining the compound of formula (1B) or the salt thereof by reacting a compound of Formula (1C) or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein X 1  is a carboxyl-activating group, with 
       
       
         
           
           
               
               
           
         
          or a salt thereof. 
       
     
     
         48 . The compound of Formula (1D) of  claim 47 , or a salt thereof, wherein X 1  is 
       
         
           
           
               
               
           
         
       
     
     
         49 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein the process further comprises converting the compound of Formula (1A) or a salt thereof to a compound of Formula (1E) or a salt thereof: 
       
         
           
           
               
               
           
         
         and converting the compound of Formula (1E) or a salt thereof to the compound of Formula (1D) or the salt thereof. 
       
     
     
         50 . The compound of Formula (1D) of  claim 49 , wherein the process further comprises reacting the compound of Formula (1E) or a salt thereof with a compound of Formula (1F): 
       
         
           
           
               
               
           
         
         to form a compound of Formula (1G) or a salt thereof: 
       
       
         
           
           
               
               
           
         
         and converting the compound of Formula (1G) or a salt thereof to the compound of Formula (1D) or the salt thereof. 
       
     
     
         51 . The compound of Formula (1D) of  claim 50 , wherein the process further comprises reacting the compound of Formula (1G) or a salt thereof with a compound of Formula (1H): 
       
         
           
           
               
               
           
         
         to form a compound of Formula (1I) or a salt thereof: 
       
       
         
           
           
               
               
           
         
         and converting the compound of Formula (1I) or a salt thereof to the compound of Formula (1D) or the salt thereof. 
       
     
     
         52 . The compound of Formula (1D) of  claim 51 , wherein the process further comprises reacting the compound of Formula (1I) or a salt thereof with a compound of Formula (1J) or a salt thereof: 
       
         
           
           
               
               
           
         
         to form the compound of Formula (1D) or the salt thereof. 
       
     
     
         53 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein D is a moiety of any one of Formulae D E-1 , D E-2 , D F-1  and D F/E-3 : 
       
         
           
           
               
               
           
         
         wherein the wavy line indicates covalent bonding of D to the remainder of the compound;
 R 11  is selected from the group consisting of H and C 1 -C 8  alkyl; 
 R 13  is isopropyl or —CH 2 —CH(CH 3 ) 2 ; 
 R 17  is selected from the group consisting of H, OH, C 1 -C 8  alkyl, C 3 -C 8  carbocyclyl, and —O—(C 1 -C 8  alkyl); 
 R 19B  is —CH(CH 3 )—CH(OH)Ph, —CH(CO 2 H)CH 2 Ph, —CH(CH 2 Ph)-2-thiazole, —CH(CH 2 Ph)-2-pyridyl, —CH(CO 2 Me)—CH 2 Ph, —CH(CO 2 Me)—CH 2 CH 2 SCH 3 , CH(CH 2 CH 2 SCH 3 )C(═O)NH-3-quinolyl, or —CH(CH 2 Ph)C(═O)NH-p-Cl-Ph; 
 R 20  is selected from the group consisting of H, C 1 -C 8  alkyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 5 -C 10  heteroaryl and C 3 -C 8  heterocyclyl; and 
 Ar is optionally substituted C 6 -C 10  aryl or optionally substituted C 3 -C 8  heterocyclyl. 
 
       
     
     
         54 . The compound of Formula (1D) of  claim 35 , or a salt thereof, wherein D is a moiety of Formula (D1): 
       
         
           
           
               
               
           
         
         wherein the wavy line indicates covalent bonding of D to the remainder of the compound.