Pyrazine derivatives, Methods of use, and methods for preparing same

Abstract

The present invention relates to methods for producing N,N′-alkylated diaminopyrazines.

1 . A method for producing a N,N′-alkylated diaminopyrazine, the method comprising:
 combining a diaminopyrazine compound and a carbonyl compound in the presence of a reducing agent.   
   
   
       2 . The method of  claim 1 , wherein the combining comprises combining the diaminopyrazine compound, the carbonyl compound, and a solvent in the presence of the reducing agent. 
   
   
       3 . The method of  claim 2 , wherein the combining occurs at a temperature between about −20° and about 50° C. 
   
   
       4 . The method of  claim 1 , wherein the combining occurs at a temperature between about −20° and about 50° C. 
   
   
       5 . The method of  claim 1 , wherein the combining occurs at a temperature between about −5° and about 30° C. 
   
   
       6 . The method of  claim 1 , wherein the carbonyl compound is of the following Formula III below, and wherein: 
     
       
         
         
             
             
         
       
       each of R 1  and R 2  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 20  aralkyl, C 1 -C 20  hydroxyalkyl, C 2 -C 20  polyhydroxyalkyl, —(CH 2 ) n CO 2 R 3 , —(CH 2 CH 2 O) m R 4 , or mono- or poly-saccharide containing 1 to 50 units; 
       each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50; and 
       each of R 3  and R 4  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 20  aralkyl, C 1 -C 10  acyl, C 1 -C 20  hydroxyalkyl, C 2 -C 20  polyhydroxyalkyl, or mono- or poly-saccharide containing 1 to 50 units. 
     
   
   
       7 . The method of  claim 6 , wherein each of m and n is independently is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30. 
   
   
       8 . The method of  claim 6 , wherein each of R 3  and R 4  is independently hydrogen, C 1 -C 10  alkyl, C 1 -C 20  hydroxyalkyl, or C 2 -C 20  polyhydroxyalkyl. 
   
   
       9 . The method of  claim 1 , wherein the diaminopyrazine compound is of the following Formula II or III below, wherein: 
     
       
         
         
             
             
         
       
       each of X and Y is independently hydrogen, C 1 -C 10  alkyl, —OR 5 , —SR 6 , —NR 7 R 8 , —N( 9 )COR 10 , halo, trihaloakyl, —CN, —NO 2 , —CO-Z-R 11 , —SOR 12 , —SO 2 R 13 , —SO 2 OR 14 , or —PO 3 R 15 R 16 ; 
       Z is a single bond, —O—, —NR 17 —, —NH(CH 2 ) p NH—, —NH(CH 2 ) p O—, —NH(CH 2 ) p CO—, —NH(CH 2 ) p NHCO—, —NH(CH 2 ) p CONH—, —NH(CH 2 ) p NHCONH—, —NH(CH 2 ) p NHCSNH—, or —NH(CH 2 ) p NHCO 2 —; 
       p is 0, 1, 2, 3, 4, 5 or 6; 
       each of R 5  to R 17  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 20  aralkyl, C 1 -C 10  acyl, C 1 -C 20  hydroxyalkyl, C 2 -C 20  polyhydroxyalkyl, —(CH 2 CH 2 O) q R 18 , or mono- or poly-saccharide containing 1 to 50 units; 
       q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50; and 
       R 18  is hydrogen, C 1 -C 10  alkyl, C 5 -C 20  aralkyl, C 1 -C 10  acyl, C 1 -C 20  hydroxyalkyl, C 2 -C 20  polyhydroxyalkyl, or mono- or poly-saccharide containing 1 to 50 units. 
     
   
   
       10 . The method of  claim 9 , wherein each of X and Y is —CO-Z-R 11 . 
   
   
       11 . The method of  claim 10 , wherein R 11  is hydrogen, C 1 -C 10  alkyl, C 1 -C 20  hydroxyalkyl, or C 2 -C 20  polyhydroxyalkyl. 
   
   
       12 . The method of  claim 10 , wherein Z is —NR 17 —. 
   
   
       13 . The method of  claim 12 , wherein R 17  is hydrogen or C 1 -C 10  alkyl. 
   
   
       14 . The method of  claim 10 , wherein Z is —NH(CH 2 ) p NH—. 
   
   
       15 . The method of  claim 14 , wherein p is 0, 1, 2, 3 or 4. 
   
   
       16 . The method of  claim 10 , wherein Z is —NH(CH 2 ) p CO—. 
   
   
       17 . The method of  claim 16 , wherein p is 0, 1, 2, 3 or 4. 
   
   
       18 . The method of  claim 9 , wherein each of X and Y is —CN. 
   
   
       19 . The method of  claim 1 , wherein the reducing agent comprises ammonium formate, diimide, Zn/HCl, sodium triacetoxyborohydride, sodium borohydride, pyridine/borane, lithium aluminium hydride, lithium borohydride, sodium cyanoborohydride, sodium amalgam, H 2 /Pd/C, H 2 /Pt/C, H 2 /Rh/C, and H 2 /Raney® Nickel, or any combination thereof. 
   
   
       20 . The method of  claim 1 , wherein the reducing agent comprises sodium triacetoxyborohydride. 
   
   
       21 . The method of  claim 1 , wherein the reducing agent comprises sodium cyanoborohydride. 
   
   
       22 . The method of  claim 2 , wherein the solvent comprises water, C 1 -C 8  alcohol, C 1 -C 8  ether, C 1 -C 8  ester, dimethyl formamide, dimethyl acetamide, acetic acid, trifluoroacetic acid, dimethyl sulfoxide, or any combination thereof. 
   
   
       23 . The method of  claim 2 , wherein the solvent is essentially methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane, glyme, dimethyl formamide, dimethyl sulfoxide, or any combination thereof.