Preparation of c-pyrazine-methylamines

Abstract

A process for preparing a compound of formula (I) or a salt thereof: (I) wherein R1 is H or optionally substituted aryl or heteroaryl; comprising reacting 2,3-dichloropyrazine with a suitable diaryl imine followed by hydrolysis.

1 - 23 . (canceled) 
     
     
         24 . A process for preparing a compound of formula (1) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein R1 is H, —CN, a carboxylate, or optionally substituted aryl or heteroaryl; 
         comprising reacting 2,3-dichloropyrazine with a suitable diaryl imine followed by hydrolysis. 
       
     
     
         25 . The process of  claim 24 , wherein R1 is a carboxylate. 
     
     
         26 . The process of  claim 24 , wherein R1 is —C(O)OCH 3  or —C(O)OCH 2 CH 3 . 
     
     
         27 . The process of  claim 24 , wherein R1 is H. 
     
     
         28 . The process of  claim 25 , wherein the diaryl imine is: 
       
         
           
           
               
               
           
         
       
       wherein R2 is C 1-10 alkyl. 
     
     
         29 . The process of  claim 28  wherein:
 (a) the diaryl imine is prepared by the reaction: 
 
       
         
           
           
               
               
           
         
         (b) the diaryl imine product of (a) and the 2,3-dichloropyrazine are reacted together in the presence of base; and 
         (c) the product of (b) is hydrolyzed to obtain the compound of formula I wherein R1 is H. 
       
     
     
         30 . The process of  claim 29  wherein R2 is methyl. 
     
     
         31 . The process of  claim 29 , wherein in which at least about 0.5 mol of formula I is obtained in an overall yield for the process of at least about 50%. 
     
     
         32 . The process of  claim 29 , wherein (a) is carried out in the presence of triethylamine or ethyldiisopropylamine. 
     
     
         33 . The process of  claim 29 , wherein the base in (b) comprises potassium carbonate or cesium carbonate. 
     
     
         34 . The process of  claim 29 , wherein (b) is carried out at a temperature of about 40-60° C. 
     
     
         35 . The process of  claim 29 , wherein (c) is carried out in the presence of potassium hydroxide, sodium hydroxide, or lithium hydroxide. 
     
     
         36 . The process of  claim 29 , wherein (c) is carried out in the presence of hydrochloric acid, trifluoroacetic acid, acetic acid, or sulfuric acid. 
     
     
         37 . The process of  claim 24 , wherein:
 R1 is aryl or heteroaryl, either of which is optionally substituted by aryl, heteroaryl, C 1 -C 10 alkyl, C 0 -C 10 alkoxy, halo, or —CN;   (a) the diaryl imine is prepared either by Reaction 1:   
       
         
           
           
               
               
           
         
         or by Reaction 2: 
       
       
         
           
           
               
               
           
         
         (b) the diaryl imine product of (a) and the 2,3-dichloropyrazine are reacted together in the presence of base; and 
         (c) the product of (b) is hydrolyzed to obtain the compound of formula I. 
       
     
     
         38 . The process of  claim 37 , wherein Reaction 2 is used to prepare the diaryl imine. 
     
     
         39 . The process of  claim 24 , wherein R1 is a heteroaryl group selected from 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5-pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, or benzothienyl; and the heteroaryl group is optionally substituted with one or more independent substituents selected from C 1 -C 10 alkyl, halo, cyano, hydroxy, or phenyl. 
     
     
         40 . The process of  claim 24 , wherein R1 is 2-phenylquinoline. 
     
     
         41 . The process of  claim 24 , in which at least about 0.5 mol of formula I is obtained in an overall yield for the process of at least about 50%. 
     
     
         42 . The process of  claim 37 , wherein Reaction 1 is used to prepare the diaryl imine in the presence of an organic base and a Lewis acid. 
     
     
         43 . The process of  claim 42 , wherein the Lewis acid comprises titanium tetrachloride. 
     
     
         44 . The process of  claim 24 , wherein the reaction of the diaryl imine with 2,3-dichloropyrazine is carried out in the presence of a tert-butoxide or a metal hexamethyldisilazide. 
     
     
         45 . The process of  claim 24 , further comprising reacting the compound of formula I according to the reactions: 
       
         
           
           
               
               
           
         
         wherein R 3  is C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, aryl, or heteroaryl, any of which is optionally substituted by one or more independent substituents selected from halo, oxo, cyano, hydroxy, and C 1 -C 10 alkyl; and R 4  is hydroxy, alkoxy, chloro, or imidazole. 
       
     
     
         46 . The process of  claim 24 , comprising the reactions: