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, characterised in that an E-stilbene derivative of Formula II,

is reacted with an azomethine ylide to provide a trans-pyrrolidine derivative of Formula III,

from which the protecting group, when present, is removed, and which is subsequently treated under conditions which effect an intramolecular ring-closure reaction to yield the compound of Formula I, and optionally converting the compound of Formula I to a pharmaceutically acceptable salt thereof, 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.

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

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

4. The process of claim 1 , wherein the azomethine ylide is generated in situ from trimethylamine-N-oxide or from N-methoxymethyl-N-trimethylsilyl-methyl-N-methylamine.

5. The process of claim 1 , wherein the azomethine ylide is generated in situ from trimethylamine-N-oxide in combination with lithium di-isopropylamide or lithium tetramethylpiperidide.

6. The process of claim 1 , wherein the azomethine ylide is generated from N-methoxymethyl-N-trimethylsilylmethyl-N-methylamine with the aid of trifluoroacetic acid.

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 N-methoxymethyl-N-trimethylsilylmethyl-N-methylamine with the aid of trifluoroacetic acid to provide trans-N-methyl-2-bromophenyl-3-(2-acetoxy-5-chlorophenyl)-pyrrolidine,

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 compound of Formula I, and optionally converting the compound of Formula Ito a pharmaceutically acceptable salt thereof.