Process for the preparation of asenapine and intermediate products used in said process

Abstract

The invention relates to a novel process for the preparation of asenapine, i.e. trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, as well as to novel intermediate products for use in said process.

1 . The trans-pyrrolidine derivative of Formula IIIA, 
       
         
           
           
               
               
           
         
         wherein R 1  is F, Br or I; 
         R 2  and R 3  are different and are each selected from H and Cl; 
         wherein R 5  represents an amino protecting group of formula —CHXY, 
         wherein X is (C 1-6 )alkyl, vinyl (optionally substituted with halogen) or phenyl (optionally substituted with (C 1-3 )alkyl, (C 1-3 )alkoxy, NO 2 , CN, halogen); and Y is H or phenyl; or 
         X is COOR 6  and Y is H, (C 1-6 )alkyl, phenyl or benzyl; 
         R 6  is (C 1-4 )alkyl; or a salt thereof. 
       
     
     
         2 . The trans-pyrrolidine derivative of claim  8 , wherein R 1  is Br; R 2  is H; and R 3  is Cl. 
     
     
         3 . The oxepine derivative of Formula IV 
       
         
           
           
               
               
           
         
         wherein R 5  represents an amino protecting group of formula —CHXY, 
         wherein X is (C 1-6 )alkyl, vinyl (optionally substituted with halogen) or phenyl (optionally substituted with (C 1-3 )alkyl, (C 1-3 )alkoxy, NO 2 , CN, halogen); 
       
       and Y is H or phenyl; or
 X is COOR 6  and Y is H, (C 1-6 )alkyl, phenyl or benzyl; 
 R 6  is (C 1-4 )alkyl; or a salt thereof. 
 
     
     
         4 . The oxepine derivative of Formula VI, wherein R 6  is a methyl or ethyl group.