Methods and processes for the preparation of kdm1a inhibitors

Abstract

Provided in this disclosure are methods for the synthesis of substituted 2-arylcyclopropylamines and 2-heteroarylcyclopropylamines and related compounds. Also provided are methods for reduction of thioesters to aldehydes, and methods for reductive amination of cyclopropylamines.

1 .- 61 . (canceled) 
     
     
         62 . A process for preparing dodecyl (4S)-4-[4-(1H-1,2,3-triazol-1-yl)benzoylamino]-5-(4-methylpiperazin-1-yl)-5-oxopentanethioate (5), comprising converting a compound of formula 4: 
       
         
           
           
               
               
           
         
       
       to a compound of formula 5 
       
         
           
           
               
               
           
         
       
     
     
         63 . The process of  claim 62 , wherein the step of converting comprises reacting the compound of formula 4 with an excess of dodecanethiol in the presence of 4-dimethylaminopyridine and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. 
     
     
         64 . A process for preparing dodecyl (4S)-4-[4-(1H-1,2,3-triazol-1-yl)benzoylamino]-5-(4-methylpiperazin-1-yl)-5-oxopentanethioate (5), comprising converting a compound of formula 5a: 
       
         
           
           
               
               
           
         
       
       to a compound of formula 5 
       
         
           
           
               
               
           
         
       
     
     
         65 . The process of  claim 64 , wherein the step of converting comprises reacting the compound of formula 5a with an excess of aqueous sodium carbonate in methyl tert-butyl ether. 
     
     
         66 . The process of  claim 64 , wherein the compound of formula 5a: 
       
         
           
           
               
               
           
         
       
       is prepared from a compound of formula 4: 
       
         
           
           
               
               
           
         
       
     
     
         67 . The process of  claim 66 , wherein the preparation comprises reacting a compound of formula 4 with an excess of dodecanethiol in the presence of a coupling agent and a base, followed by the addition of hydrochloric acid. 
     
     
         68 . The process of  claim 67 , wherein the coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the base is 4-dimethylaminopyridine. 
     
     
         69 . A process for preparing a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein:
 n is 1 or 2; 
 m is 0-12; 
 R 1  and R 2  together with the nitrogen to which they attach, form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which may be optionally substituted with between 0 and 3 R 6  groups; 
 R 3  is phenyl substituted with halogen, cyano, or heteroaryl; and 
 wherein each R 6  is chosen from hydrogen, hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, cyano, amino, alkylamino, dialkylamino, CONHR 7 , and CONR 7 R 8 ; comprising reacting a compound of Formula V: 
 
       
       
         
           
           
               
               
           
         
         with a compound of Formula VI: 
       
       
         
           
           
               
               
           
         
         in the presence of an appropriate coupling agent. 
       
     
     
         70 . The process of  claim 69 , wherein the coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, or a salt thereof. 
     
     
         71 . The process of  claim 70 , further comprising the addition of a catalytic amount of 4-dimethylaminopyridine. 
     
     
         72 . The process of  claim 69 , wherein m is 11. 
     
     
         73 . The process of  claim 72 , wherein n is 1. 
     
     
         74 . The process of  claim 73 , wherein R 1  and R 2  are taken together to form a nitrogen-containing heterocycloalkyl, which may be optionally substituted with between 0 and 3 R 6  groups. 
     
     
         75 . The process of  claim 74 , wherein the nitrogen-containing heterocycloalkyl is 
       
         
           
           
               
               
           
         
       
     
     
         76 . The process of  claim 75 , wherein R 3  is phenyl substituted with 
       
         
           
           
               
               
           
         
       
     
     
         77 . The process of  claim 69 , wherein the compound of Formula I is subsequently reacted with an acid HX to form the corresponding salt of Formula I, designated I*HX: 
       
         
           
           
               
               
           
         
       
     
     
         78 . The process of  claim 77 , wherein the acid HX is a mineral acid. 
     
     
         79 . The process of  claim 78 , wherein the mineral acid is HCl. 
     
     
         80 . A compound of formula 5: 
       
         
           
           
               
               
           
         
       
       or a salt thereof.