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

1. A process for preparing asenapine of Formula I,

or a pharmaceutically acceptable salt thereof, wherein an E-stilbene derivative of Formula II,

wherein

R 1 is F, Br or I;

R 2 and R 3 are different and are each selected from H and Cl; and

R 4 is H or a hydroxyl protecting group;

is reacted with an azomethine ylide generated from a precursor tertiary amine of Formula A

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 or halogen); and Y is H or phenyl; or X is: COOR 6 wherein R 6 is (C 1-4 )alkyl; and Y is H, (C 1-6 )alkyl, phenyl or benzyl; to provide a trans-pyrrolidine derivative of Formula III,

from which the hydroxyl protecting group R 4 , when present, is removed, and which is subsequently treated under conditions which effect an intramolecular ring closure reaction to yield the oxepino compound of Formula IV,

whereupon the amino protecting group R 5 is replaced by a methyl group, and the resulting asenapine of Formula I is optionally converted into a pharmaceutically acceptable salt thereof.

2. The process of claim 1 , wherein, after the compound of Formula IV has been formed, said R 5 amino protecting group is replaced by a methyl group either by reaction with 1-chloro-ethylchloroformate to give the compound of formula V, which is converted into the compound of Formula I by methylation, or by reaction with ethyl- or methyl-chloroformate to give the compound of formula VI,

wherein R 7 is ethyl or methyl; which is converted into the compound of Formula I by reaction with a hydride reducing agent.

3. The process of claim 1 , wherein R 1 is Br or I.

4. The process of claim 3 , wherein R 1 is Br, R 2 is H, and R 3 is Cl.

5. The process of claim 1 , wherein the azomethine ylide is generated in situ from the precursor tertiary amine of formula

wherein:

R 5 represent —CHXY, wherein X is vinyl (optionally substituted with halogen) or phenyl (optionally substituted with (C 1-3 )alkyl, (C 1-3 )alkoxy, NO 2 , CN or halogen); and Y is H.

6. The process of claim 1 , wherein the azomethine ylide is generated with the aid of trifluoroacetic acid in an aprotic solvent.

7. A process for preparing the compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein (E)-2-(2-bromostyryl)-4-chlorophenyl acetate,

is reacted in an inert solvent with an azomethine ylide generated in situ from a precursor tertiary amine of Formula

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 or halogen); and

Y is H or phenyl;

or:

R 5 represents an amino protecting group of Formula —CHXY, wherein: X is COOR 6 and R 6 is (C 1-4 )alkyl; and Y is H, (C 1-6 )alkyl, phenyl or benzyl;

with the aid of trifluoroacetic acid to provide the trans-N—R 5 -2-bromophenyl-3-(2-acetoxy-5-chlorophenyl)-pyrrolidine derivative of Formula

which pyrrolidine derivative is treated to remove the acetyl group, and which is subsequently treated under Ullmann conditions with the aid of a copper(I) salt to effect the intramolecular ring closure to give the trans-5-chloro-2—R 5 I-2,3,3a,12b-tetra-hydro-1H-dibenz-[2,3:6,7]-oxepino-[4,5-c]pyrrole derivative

and subsequently the R 5 -group is removed either by:

(i) using 1-chloroethylchloroformate to give trans-5-chloro-2-alkyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, which subsequently is converted into the compound of Formula I by N-methylation;

or

(ii) by reaction with methyl- or ethylchloroformate to give trans-5-chloro-2-methoxy(or ethoxy)carbonyl-2,3,3a,12b-tetra-hydro-1H-dibenz-[2,3:6,7]-oxepino-[4,5-c]pyrrole, which is subsequently converted into the compound of Formula I by reduction using a hydride reducing agent; and

optionally the compound of Formula I is converted to a pharmaceutically acceptable salt thereof.