Novel chiral synthesis of n-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines

Abstract

Disclosed is a novel chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines of Formula (I), avoiding the use of protection/deprotection steps.

1 - 14 . (canceled) 
     
     
         15 . A process of preparing chiral N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine of general Formula I: 
       
         
           
           
               
               
           
         
         or a solvate thereof, wherein
 R 1  is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl; 
 R 2  is alkyl, alkoxyalkyl or haloalkyl; 
 Ar is a phenyl group; 
 X 1  is N and X 2  is S or O; or X 1  is S and X 2  is N; and 
    represents a single or a double bound depending on X 1  and X 2 ; 
 
         said process comprising the following steps: 
         a) reacting a compound of Formula A: 
       
       
         
           
           
               
               
           
         
         wherein R 1  is as defined above;
 with a compound of Formula B: 
 
       
       
         
           
           
               
               
           
         
         wherein Ar is as defined above; and Y is hydroxyl or halo;
 to obtain a compound of Formula C: 
 
       
       
         
           
           
               
               
           
         
         b) converting the compound of Formula C with a tri(C1-C2 alkyl)oxonium salt, a (C1-C2)alkylsulfate, a (C1-C2)chloroformate or PCl 5 /POCl 3 /(C1-C2)hydroxyalkyl, so as to obtain a compound of Formula D: 
       
       
         
           
           
               
               
           
         
         wherein Ar and R 1  are as defined above, and R 3  is C1-C2 alkyl; 
         in the presence of a base; and 
         c) reacting the compound of Formula D with a compound of Formula E 
       
       
         
           
           
               
               
           
         
         or a salt or solvate thereof, wherein X 1 , X 2  and R 2  are as defined above; 
         so as to obtain a compound of Formula I or a solvate thereof. 
       
     
     
         16 . The process according to  claim 15  proceeding with the retention of stereochemistry with respect to the starting material. 
     
     
         17 . The process according to  claim 15 , wherein the reaction of each step is carried out under controlled mild experimental conditions. 
     
     
         18 . The process according to  claim 15 , wherein the reaction is carried out at a temperature equal to or below boiling point of the organic solvent. 
     
     
         19 . The process according to  claim 15 , wherein the process does not use any protecting group. 
     
     
         20 . The process according to  claim 15 , wherein the base in step b) is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. 
     
     
         21 . The process according to  claim 15 , wherein the compound of Formula I is the (R)-enantiomer. 
     
     
         22 . The process according to  claim 15 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         23 . The process according to  claim 15 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         24 . A compound of Formula C: 
       
         
           
           
               
               
           
         
         or a solvate thereof, wherein 
         R 1  is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl; and 
         Ar is a phenyl group. 
       
     
     
         25 . The compound of  claim 24  having Formula C-b2: 
       
         
           
           
               
               
           
         
       
     
     
         26 . A compound of Formula D: 
       
         
           
           
               
               
           
         
         or a solvate thereof, wherein 
         R 1  is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl; 
         R 3  is C1-C2 alkyl; and 
         Ar is a phenyl group. 
       
     
     
         27 . The compound of  claim 26  having Formula D-1: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound according to  claim 24 , wherein the stereoisomer obtained is the (R)-enantiomer. 
     
     
         29 . The compound according to  claim 26 , wherein the stereoisomer obtained is the (R)-enantiomer. 
     
     
         30 . The process of  claim 15 , wherein Ar is substituted by one or more substituent(s) selected from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl. 
     
     
         31 . The compound of  claim 24 , wherein Ar is substituted by one or more substituent(s) selected from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl. 
     
     
         32 . The compound of  claim 26 , wherein Ar is substituted by one or more substituent(s) selected from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl.