PROCESS FOR THE PREPARATION OF ASENAPINE AND INTERMEDIATE PRODUCTS USED IN SAID PROCESS
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.