FORM 2
THE PATENT ACT, 19?0
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A NOVEL PROCESS FOR PREPARING ASENAPINE MALEATE"
Enallec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL PROCESS FOR PREPARING ASENAPINE MALEATE
FIELD OF THE INVENTION:
The present invention relates to a novel process for the preparation of asenapine maleate. The process comprises the step of cyclizing a compound of structural formula IX or X to get an asenapine compound of structural formula III.

Scheme III R= H or Hydroxyl protecting group

BACKGROUND OF THE INVENTION:
Asenapine maleate is a psychotropic agent that is available for sublingual administration. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical designation is (3aRS, 12bRS)-5-Chloro-2-methyl 2, 3, 3a, 12b-tetrahydro-1Hdibenzo [2, 3: 6, 7] oxepino [4, 5-c] pyrrole (2Z)-2-butenedioate (1:1) and is known from U.S. Patent No. 4,145,434 and is represented by compound of structural formula 1.

U.S. Patent No. 4,145,434 described a general process for the preparation of asenapine compound of structural formula III wherein a compound of structural formula II is being reduced by lithium aluminium hydride in a mixture of dry ether and tetrahydrofuran solvents to get an asenapine compound of structural formula III.

U.S. Patent Publication No. 2006/0229352 described the process of preparing asenapine compound of structural formula III by cyclization of compounds of structural formula IV and VI as described in scheme no. 1.

U.S. Patent No. 7,750,167 describe a process for the preparation of asenapine compound of structural formula III by cyclizalion of compounds of structural formula VII and VIII as described in scheme no. II.

There is a need for the commercially viable synthetic process for the preparation of asenapine maieate compound of structural formula I. Accordingly the present invention provides a commercially viable novel synthetic process for the preparation of asenapine maleate compound of structural formula I.

SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process for the prepartion of asenapine comprises the step of cyclizing a compound selected from the group of structural formula IX or X to get an asenapine compound of structural formula III.

Scheme III R= H or Hydroxyl protecting group
A second aspect of the present invention is to provide a compound of structural formula IX.

Formula IX R= H or Hydroxyl protecting group

A third aspect of the present invention is to provide a compound of structural formula X.

R= H or Hydroxy) protecting group
A fourth aspect of the present invention is to provide compounds of structural formula IX or X for the preparation of asenapine maleate compound of structural formula I.
DETAIL DESCRIPTION OF THE INVENTION:
The specific example of compounds of structural formula IX and X may include following compounds:

The cyclization of compounds of structural formula IX or X may be carried out by Ullmann-type reaction.
The cyclization of compounds of structural formula IX or X may be carried out by treating compound of structural formula IX or X with copper (0) powder or the salts of copper to get asenapine compound of structural formula III.

The reaction of compounds of structural formula IX or X with copper (0) powder or the salts of copper may be carried out in the presence of organic solvent to get asenapine compound of structural formula III.
The reaction of compounds of structural formula IX or X with copper (0) powder or the salts of copper may be carried out in the presence of base to get asenapine compound of structural formula III.
The reaction of compounds of structural formula IX or X with copper (0) powder or the salts of copper may be carried out at a temperature in the rage of 40°C to 160°C for a period of 4 hours to 24 hours to get asenapine compound of structural formula III.
The reaction of compounds of structural formula IX or X with copper (0) powder or the salts of copper may be carried out in the presence of additive.
The examples of additive may include but not limited to N, N-dimethylgiycine, N-methylgiycine 2, 2, 4, 4-tetramethyl-3, 5-heptanedione (TMHD) or 8-hydroxyquinoline.
The examples of base may be selected from the group comprising of cesium carbonate, potassium carbonate, pyridine, sodium hydroxide, potassium hydroxide or cesium fluoride.
The examples of copper sources may be selected from the group comprising of Cu-powder, copper iodide, copper bromide, copper chloride, copper (II) carbonate, copper (II) acetate, copper (II) trifluoromethanesulfonate, copper oxide or coppet- sulfate.
The examples of organic solvent may be selected from the group comprising of dimethylformamide, dimethylacetamide, N-inethylpyrrolidone pyridine, dioxane, toluene, xylene, diglyme, 2-methyltetrahydrofuran or mixture(S) thereof.
The asenapine compound of structural formula III may be isolated by quenching the reaction mixture with water and then resulting reaction mixture is extracted with an organic solvent.

The examples of organic solvent used for the extraction of asenapine compound of structural formula III may include dichloromefhane, dichloroethane, ethyl acetate, n-propyl acetate, tertiary butyl acetate or isopropyl acetate.
The organic layer containing asenapine compound of structural formula III may be washed with a saturated solution of sodium chloride in water and thereafter with water.
The organic layer containing asenapine compound of structural formula III may be concentrated under reduced pressure at 25-50X to get asenapine compound of structural formula III.
The asenapine compound of structural formula III may be converted into asenapine maleate compound of structural formula I by methods known in the art such as those described in U.S Patent nos. 4,145,434; 7,750,167 and U.S Patent publication no. 2006/0229352, which are incorporated herein by reference only.
EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of Asenapine compound of structural formula III.
A solution of 2-((3S, 4S)-4-(2, 5-dichlorophenyl)-l-methylpyrrolidin-3-yl) phenol compound of structural formula XI (50gm) in toluene (400ml) was added cesium carbonate (55gm), copper (I) chloride (5gm) and N,N-dimethylglycine (11gm) in N,N-dimethylacetarnide (110ml) and the reaction mixture was heated to 110°C for 14 hours. The resulting reaction mixture was cooled to 20°C and quenched with water (500ml) followed by extract with ethyl acetate (400mI), washed first with saturated sodium chloride solution (40ml), then with water (50ml) and dry over anhydrous sodium sulfate (20gm). The resulting organic layer was then concentrated under reduced pressure at 40-45°C to get title compound. Yield: 44.3gm Purity: 99.8% (By HPLC)

Example 2: Preparation of Ascnapine compound of structural formula III.
A solution of 4-chloro-2-((3S,4S)-4-(2-chlorophenyl)-l-methylpyrroIidin-3-yl)phenol compound of structural formula XIII (50gm) in dioxane (400ml) was added potassium carbonate (50gm), copper (I) chloride (5gm) and N,N-dimethylglycine (10gm) in N,N-dimethylacetamide (100ml) and the reaction mixture was heated to 110°C for 16 hours. The resulting reaction mixture was cooled to 20°C and quenched with water (4500ml) followed by extract with ethyl acetate (350ml), washed first with saturated sodium chloride solution (40ml), then with water (50ml) and dry over anhydrous sodium sulfate (20gm). The resulting organic layer was then concentrated under reduced pressure at 40-45°C to get title compound. Yield: 44.0gm Purity: 99.8% (By HPLC)

WE CLAIM:
!. A process for the prepartion of asenapine comprises cyclizing a compound selected from the group of structural formula IX or X to get an asenapine compound of structural formula III.

R= H or Hydroxyl protecting group 2. A compound of structural formula IX.

R= H| or Hydroxyl protecting group
3. A compound of structural formula X.


R= H or Hydroxyl prolectinggroup
4. The compounds according to claim nos. 2 and 3 include following compounds:

5. Use of compounds of structural formula IX or X for the preparation of asenapine maleate compound of structural formula 1.
6. Use of compounds of structural formula XT, XII, XIII and XIV for the preparation of asenapine maleate compound of structural formula I.
7. The process according to claim no. 1 wherein, cyclization of compounds of structural formula IX or X is carried out by treating compound of structural formula IX or X with copper (0) powder or the salts of copper such as copper iodide, copper bromide, copper chloride, copper (II) carbonate, copper (II) acetate, copper (II) trifluoromethanesulfonate, copper oxide or copper sulfate to get asenapine compound of structural formula III.
8. The process according to claim no. 7 wherein, reaction of compounds of structural formula IX or X with copper (0) powder or the salts of copper is carried out in the presence of organic

solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, pyridine, dioxane, toluene, xylene, diglyme, 2-methyltetrahydrofuran or mixture(S) thereof to get asenapine compound of structural formula III.
9. The process according to claim no, 7 wherein, reaction of compounds of structural formula
IX or X with copper (0) powder or the salts of copper is carried out in the presence of base
such as cesium carbonate, potassium carbonate, pyridine, sodium hydroxide, potassium
hydroxide or cesium fluoride to get asenapine compound of structural formula III and
additives such as N. N-dimethylglycine. N-methylglycine, 2, 2, 4, 4-tetramethyl-3, 5-
heptanedione (TMHD) or 8-hydroxyquinoline.
10. The process according to claim no. 7 wherein, reaction of compounds of structural
formula IX or X with copper (0) powder or the salts of copper is carried out at a temperature
in the rage of 40°C to 160°C for a period of 4 hours to 24 hours to get asenapine compound
of structural formula III.