FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention, -
PROCESS FOR PREPARATION OF ASENAPINE MALEATE
2. Applicants)
(a) NAME : LUPIN LIMITED
(b) NATIONALITY: An Indian Company
(c) ADDRESS : 159, CST Road, Kalina, Santacruz (East),
Mumbai - 400 098, State of Maharashtra
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed :

Field of the Invention:
The present invention relates to process for the preparation of asenapine and its pharmaceutically acceptable maleate salt.
Background of the Invention:
Asenapine maleate is chemically known as (3aR,12bR)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1) having structure as represented by formula I.

Asenapine has CNS-depressant and antiserotonin activity. It has been established that the maleate salt of asenapine is a broad spectrum, high potency serotonin, noradrenaline and dopamine antagonist.
Preparation of asenapine is disclosed in patent US 4,145,434. Additional synthetic methods for the preparation of asenapine and radio labeled derivatives thereof have also been described in a journal publication Vader et al., Journal of Labelled Compounds and Radiopharmaceuticals, 34, 845-869, 1994.
Summary of the invention:
The present invention provides the improved process for the preparation of asenapine maleate which comprises of intramolecular cyclization of compound (II) to give compound (III), reduction of compound (III) to give mixture of cis isomer (IV) and trans isomer (V), enrichment of trans isomer (V) in the mixture by isomerization of cis isomer (IV) with suitable reagent, separation of cis isomer (IV) and trans isomer (V), reduction of trans isomer (V) to asenapine free base (VI) and treatment of asenapine free base (VI) with maleic acid.

Detailed description of the invention:
The present invention is related to the process for the preparation of asenapine maleate (I) that comprises of following steps:
a) cyclization of 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione (II) to give 11-chloro-2-methyl-2,3-dihydro-lH-dibenzo[2!3:6,7]oxepino[4,5-C] pyrrol-1 -one (III) in the presence of acid and solvent,
b) reduction of compound (III) to give mixture of cis-(3a, 12b)-ll-chloro-2-methyl+2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-C]pyrrol-l-one (IV) and trans-(3a, 12b)-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-C]pyrrol-l-one(V),
c) enrichment of trans isomer (V) in the mixture by isomerization of the cis isomer (IV) with a suitable reagent,
d) separation of cis isomer (IV) and trans isomer (V),
e) reduction of trans isomer (V) to asenapine free base (VI),
f) treatment of asenapine free base (VI) with maleic acid.
The starting compound (II) may be prepared by reaction of ethyl N-[(5-chloro-2-phenoxyphenyl)acetyl]-N-methylglycinate with a metal hydride or a metal alkoxide as described in US 4,145,434. The synthetic scheme for preparation of asenapine maleate (I) is shown below.


The process of step a involves cyclization of 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione (II) to give 11-chloro-2-methyl-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepino[4,5-C] pyrrol-1-one (III) in the presence of acid and solvent.
The acid used in step a is selected from group of hydrochloric acid, sulphuric acid, phosphoric acid, orthophosphoric acid, methane sulphonic acid, para-toluene sulfonic acid, propionic acid, acetic acid, the most preferred acid is orthophosphoric acid.
The process of step a of the present invention can be carried out in organic solvent(s) selected from aromatic hydrocarbons, chlorinated hydrocarbons, ethers or mixtures thereof. Examples of aromatic hydrocarbons include benzene, nitrobenzene, toluene, xylene, monochlorobenzene or 1,2-dichlorobenzene. Examples of chlorinated hydrocarbons include dichloromethane, chloroform, 1,1,2,2-tetrachloroethane or 1,2-dichloroethane. Examples of ethers include diethyl ether, ethyl methyl ether, di-isopropyl ether or 1,4 dioxane. The most preferred solvent for step a is toluene.

The reaction of step a is carried at a temperature ranging from 60 to 150°C, more preferably, at 80 to 120°C, most preferably 100 to 110°C.
The process of step b involves reduction of compound of formula (III) to give a mixture of cis isomer (IV) and trans isomer (V) in the presence of reducing agent and a solvent.
The reduction of step b can also be carried out by catalytic hydrogenation using metal catalyst selected from palladium on carbon, platinum on carbon, PtO2/H2.
Alternatively step b can be carried out by treatment with magnesium in an alcohol in the presence of iodine or a Birch reduction (alkali metal in liquid ammonia, preferably sodium in liquid ammonia).
The solvent used in step b is selected from group of aromatic hydrocarbons, chlorinated hydrocarbons, alcohols or mixtures thereof. Examples of aromatic hydrocarbons include benzene, nitrobenzene, toluene, xylene, monochlorobenzene or 1,2-dichlorobenzene. Examples of chlorinated hydrocarbons include dichloromethane, chloroform, 1,1,2,2-tetrachloroethane or 1,2-dichloroethanemethanol. Examples of alcohols include ethanol, propanol, isopropanol, butanol, n-butanol.
Most preferably step b is carried out in magnesium in an alcohol in the presence of iodine as catalyst in a mixture of toluene and methanol.
The reaction of step b is carried at a temperature ranging from 10 to 80°C, preferably 25 to 50°C.
Step c involves the isomerization of the cis isomer (IV) to trans isomer (V) using a suitable reagent to give mixture enriched with trans isomer (V). Suitable reagents for step c include, but are not limited to, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), potassium hexamethyldisilazane, sodium hexamethyldisilazane or mixtures thereof. The preferred reagent is DBU.

The reaction of step c may be carried out in a solvent such as alcohol like methanol, ethanol, propanol, ketone solvent like acetone, methyl ethyl ketone, aromatic hydrocarbon like toluene, benzene, xylene, ester solvent like ethyl acetate, n-propyl acetate, n-butyl acetate, ether like diethyl ether, tetrahydrofuran, nitrile like acetonitrile, propionitrile, water or any mixtures thereof. The most preferred solvent is toluene.
The reaction of step c is carried at a temperature ranging from 10 to 80°C, preferably 25 to 50°C.
Step d involves the separation of mixture of cis isomer (IV) and trans isomer (V). The separation of cis and trans isomers can be done by means of physico-chemical methods of separation such as fractional crystallization, column chromatography, preparative scale thin layer chromatography or counter current distribution. The preferred method for separation of cis and trans isomer of the present invention is by column chromatography over silica gel with pore size 50-60 °A and 100-200 mesh. The separation of compounds of cis isomer (IV) and trans isomer (V) can be done by column chromatography. The solvents used for separating (IV) and (V) can be selected from alcohol like methanol, ethanol, propanol, ketone solvent like acetone, methyl ethyl ketone, hydrocarbons like toluene, benzene, xylene, cyclohexane, ester solvent like ethyl acetate, n-propyl acetate, n-butyl acetate, ether like diethyl ether, tetrahydrofuran, nitrile like acetonitrile, propionitrile, any mixtures thereof. The most preferred solvent used for column chromatography is mixture of ethyl acetate and cyclohexane.
The cis-isomer can be recycled back to the mixture of cis isomer (IV) and trans isomer (V) by isomerization with DBU.
Step e involves the reduction of trans isomer (V) to asenapine free base (VI) in the presence of suitable reducing agent and a solvent. The suitable reducing agent used in step e may selected from a group of zinc/acetic acid, zinc/hydrochloric acid, iron/acetic

acid, lithium aluminium hydride, diborane, sodium borohydride, vitride, raney nickel, palladium on carbon, rhodium etc. The most preferred reducing agent is lithium aluminium hydride.
The solvents used for step e can be selected from alcohol like methanol, ethanol, propanol, ketone solvent like acetone, methyl ethyl ketone, hydrocarbons like toluene, benzene, xylene, cyclohexane, dichloromethane, ester solvent like ethyl acetate, n-propyl acetate, n-butyl acetate, ether like diethyl ether, tetrahydrofuran, nitrile like acetonitrile, propionitrile, any mixtures thereof. The most preferred solvent used for step e is tetrahydrofuran.
The reaction of step e is carried at a temperature ranging from -10 to 20°C, preferably -5 to 0°C.
Step f involves the conversion of asenapine free base (VI) to asenapine maleate (I) using maleic acid and alcoholic solvent. The alcoholic solvent used in step f can be selected from a group of methanol, ethanol, isopropanol, propanol, butanol, isobutanol etc. The most preferred solvent is ethanol.
The reaction of step f is carried at a temperature ranging from 20 to 50°C, preferably 50-70°C.
The purification of asenapine maleate can be carried out by crystallization in an alcoholic solvent selected from a group of methanol, ethanol, isopropanol, propanol, butanol, isobutanol etc, preferably ethanol.
The preferred embodiments of the present invention have been described in the foregoing examples.

Examples:
Example 1: 1 l-chIoro-2-methyl-23-dihydro-lH-dibenzo [2,3:6,7]oxepino [4,5-C] pyrrol-1-one (III)
Orthophosphoric acid (1250 ml) was added to toluene (500 ml). To the mixture 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrroIidine-2,4-dione (II) (250 gm) was added and the reaction was heated at 110 °C for 1 hour. The reaction mixture was further stirred for 24 hours at 110 °C. The reaction mixture was then cooled to 80 °C followed by addition of water (2500 ml). The reaction mixture was stirred and cooled to 10 °C for 2 hours. The solid obtained was filtered and washed with water followed by slurry washing with 4% aqueous sodium bicarbonate solution (1250 ml). The solid was filtered and dried. The solid was recrystallized from methanol, filtered, washed with methanol and dried under reduced pressure. Yield= 209.5 gm.
Example 2: Mixture of cis isomer (IV) and trans isomer (V)
Iodine (9.5 gm) was added to toluene (380 ml) and the mixture was stirred at 30 °C followed by addition of magnesium turnings (9.5) gm. ll-chloro-2-rnethyl-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepino[4,5-C] pyrrol-1-one (III) (190 gm) was dissolved in mixture of toluene (950 ml) and methanol (950 ml). This mixture was slowly added to the above reaction mass. Magnesium turnings (9.5 gm x 5) were added in lots to the reaction mixture with an interval of thirty minutes. The reaction mass was stirred for 5 hours at 35 °C. The reaction mass was diluted with toluene (2470 ml) and cooled. The reaction mass was quenched using 2N aqueous hydrochloric acid (1875 ml) and was stirred. The reaction mixture was settled and separated. The organic layer was washed with water and then 5% aqueous sodium bicarbonate solution (950 ml) followed by washing with 5% aqueous sodium dithionite solution (950 ml). To the organic layer DBU (38 ml) was added followed by addition of water (950 ml). The pH was adjusted to 3.5 to 4.5 by acetic acid. The organic layer was washed with water and distilled. Isopropanol (380 ml) was further added and heated. The reaction mass was stirred,

cooled to 0 °C and stirred. The solid was filtered, washed with chilled isopropanol and dried under reduced pressure. Yield= 135.2 gm.
Example 3: Separation of compounds of formula (IV) and (V)
Charge mixture of compounds of formula (IV) and (V) obtained in example 2 (130 gm) to toluene (650 ml). The reaction mixture was stirred for 2 hours. The solid (65 gm) was dissolved in toluene (2600 ml). DBU (13 ml) was added to the mass and stirred for 2 hours at 30 °C. Water (325 ml) was charged. Ph was adjusted to 4.10 using acetic acid (15 ml). The organic layers were combined and distilled. Silica (260 gm) was added along with cyclohexane (390 ml). The column was prepared with silica and cyclohexane. The compound was loaded on the column and eluted with cyclohexane. Elution was continued with 10% ethyl acetate followed by 20% ethyl acetate in cyclohexane till trans isomer (V) was eluted. All the fractions of ASP-II were combined and distilled. The solid was washed with cyclohexane (65 ml) and suck dried. Yield = 40 gm
Example 4: Recyciization of cis isomer (IV)
Toluene (2000 ml) was added to cis isomer (IV) (50 gm). DBU (10 ml) was added and mixture was stirred for 2 hours at 30 °C. Water (250 ml) was added to the mixture. The pH was adjusted to 4.21 using acetic acid. The reaction mass was stirred and the organic layer was separated. The organic layer was distilled upto 1 volume. Isopropanol (50 ml) was again added and the mixture was heated to 60-75 °C. The reaction mass was stirred, cooled to 0 °C. The solid was filtered and washed with chilled isopropanol (25 ml). The solid was dried under reduced pressure. Yield = 46.2 gm.
Example 5: Preparation of Asenapine maleate
Aluminium chloride (11.69 gm) was added to tetrahydrofuran (192.5 ml) at -10 °C. Lithium aluminium hydride solution in tetrahydrofuran (73.88 ml) was charged and

stirred. A precooled solution of ASP-II 935 gm in 350 ml tetrahydrofuran) was charged to the mixture and stirred for thirty minutes at -5 °C. Water (7ml) was charged to the reaction mixture followed by addition of 15% aqueous sodium hydroxide solution. The reaction mixture was stirred, filtered and washed with dichloromethane (175 ml). Water (525 ml) was added to the filtrate, stirred and settled. The organic layer was concentrated to 1 volume. To the residue, ethanol (140 ml) was added and distilled to about 1 volume. Ethanol (87.5 ml) was added and stirred. Maleic acid (15.75 gm) was added and the reaction mass was heated to 65 °C to get a clear solution for twenty minutes. The reaction mass was filtered and washed with hot ethanol (17.5 ml). The filtrate was cooled and diisopropyl ether (315 ml) was slowly added. The solid was filtered and washed with cooled 1:3 ethanohdiisopropyl ether. The solid was recrystallized from methanol (76 ml), filtered and dried under reduced pressure. Yield=33gm.
Example 6: Purification of Asenapine maleate
Asenapine maleate (30 gm) was added to ethanol (60 ml) and heated to 70 °C for thirty minutes. The contents were filtered through micron filter and washed with hot ethanol. The filtrate was transferred to a clean flask and cooled. The mixture was stirred, filtered and solid was washed with cold ethanol (15 ml). The solid was dried under reduced pressure. Yield = 26.5 gm.

WE CLAIM:
1) Process for the preparation of asenapine maleate which comprises steps of:
a) cyclization of 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione (II) to give 11 -chloro-2-methyl-2,3 -dihydro-1H-dibenzo[2,3:6,7]oxepino[4,5-C] pyrrol-1 -one (III) in the presence of acid and solvent,
b) reduction of compound (III) to give mixture of cis-(3a, 12b)-ll-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-C]pyrrol-l-one (IV) and trans-(3a, I2b)-ll-chloro-2-methyl-2;3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-C]pyrrol-l-one(V),
c) enrichment of trans isomer (V) in the mixture by isomerization of the cis isomer (IV) with a suitable reagent,
d) separation of cis isomer (IV) and trans isomer (V) by column chromatography.
e) reduction of trans isomer (V) to asenapine free base (VI),
f) treatment of asenapine free base (VI) with maleic acid.

2) The process of claim 1(a) wherein acid is selected from group of hydrochloric acid, sulphuric acid, phosphoric acid, orthophosphoric acid, methane sulphonic acid, para-toluene sulfonic acid, propionic acid, acetic acid, orthophosphoric acid.
3) The process of claim 1(a) wherein organic solvent(s) is selected from aromatic hydrocarbons such as benzene, nitrobenzene, toluene, xylene, monochlorobenzene or 1,2-dichIorobenzene, chlorinated hydrocarbons such as dichloromethane, chloroform, 1,1,2,2-tetrachloroethane or 1,2-dichloroethane, ethers such as diethyl ether, ethyl methyl ether, di-isopropyl ether or 1,4 dioxane or mixtures thereof.

4) The process of claim 1(b), wherein reducing agent used is selected from a group of palladium on carbon, platinum on carbon, PtO2/H2, magnesium optionally in the presence of iodine or sodium in liquid ammonia.
5) The process of claim 1(b) wherein organic solvent(s) is selected from aromatic hydrocarbons such as benzene, nitrobenzene, toluene, xylene, monochlorobenzene or l,2-dichlorobenzene3 chlorinated hydrocarbons such as dichloromethane, chloroform, 1,1,2,2-tetrachloroethane or 1,2-dichloroethane, ethers such as diethyl ether, ethyl methyl ether, di-isopropyl ether or 1,4 dioxane alcohols include ethanol, propanol, isopropanol, butanol, n-butanol or mixtures thereof.
6) The process of claim 1(c) wherein reagent used for isomerization is selected
from l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-
ene (DBN), potassium hexamethyldisilazane, sodium hexamethyldisilazane or
mixtures thereof.
7) The process of claim 1(d) wherein separation is carried out by using silica gel.
8) The process of claim 1(d) wherein organic solvent(s) is selected from alcohol like methanol, ethanol, propanol, ketone solvent like acetone, methyl ethyl ketone, hydrocarbons like toluene, benzene, xylene, cyclohexane, ester solvent like ethyl acetate, n-propyl acetate, n-butyl acetate, ether like diethyl ether, tetrahydromran, nitrile like acetonitrile, propionitrile, any mixtures thereof.
9) The process of claim 1 (e) wherein reducing agent is selected from a group of zinc/acetic acid, zinc/hydrochloric acid, iron/acetic acid, lithium aluminium hydride, diborane, sodium borohydride, vitride, raney nickel, palladium on carbon, rhodium.
10) The process of claim 1 (e) wherein solvent is selected from from alcohol like methanol, ethanol, propanol, ketone solvent like acetone, methyl ethyl ketone, hydrocarbons like toluene, benzene, xylene, cyclohexane, dichloromethane, ester

solvent like ethyl acetate, n-propyl acetate, n-butyl acetate, ether like diethyl ether, tetrahydrofuran, nitrile like acetonitrile, propionitrile, any mixtures thereof.
11) The process of step 1(f) wherein solvent is selected from a group of methanol, ethanol, isopropanol, propanol, butanol, isobutanol.