Field of invention:

The present invention relates to an improved process for the preparation of (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-lHdibenzo[2,3:6,7]oxepino [4,5-c]pyrrole (commonly known as asenapine) compound of formula-1 and its pharmaceutically acceptable salt. Asenapine maleate is represented by structural formula-la.

Asenapine is an antipsychotic drug used for the treatment of schizophrenia and acute mania associated with bipolar disorder. It has an antagonistic activity for dopamine (D2 receptor) as well as serotonin receptor.

Background of the Invention:

Asenapine and its pharmaceutically acceptable salts, specifically asenapine maleate and process for its preparation was disclosed in US 4145434. The disclosed process comprises of reducing ll-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one with magnesium in methanol/toluene to provide a mixture of desired trans-ll-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino [4,5-c]pyrrol-l-one and unwanted cis-ll-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one in 1:4 ratio. The ratio of wanted trans isomer was improved by repeated isomerization of unwanted cis isomer, followed by chromatographic separation with the yield of 38%. The obtained product was reacted with lithium aluminium hydride and aluminium chloride to provide asenapine, which on further reaction with maleic acid provides asenapine maleate. The said process involves chromatographic separation and repeated racemisation and hence not suitable for commercial scale up. The yield and purity of the intermediates and final compounds were also not satisfactory.

EP 1710241 Bl also disclosed a process for the preparation of asenapine, which comprises of hydrolyzing a mixture of lactams i.e. trans-ll-chloro-2,3,3a, 12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one and cis-11-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one or pure cis isomer with strong alkali in alcohol which resulted in formation of a mixture of trans-8-chloro-10,11 -dihydro-11 -[(methylamino)methyl]-dibenz[b,fJoxepin-10-carboxylic acid and cis-8-chloro-10,11-dihydro-ll-[(methylamino)methyl]-dibenz [b,f]oxepin-10-carboxylic acid in a ratio of 10:1. The trans isomer was subsequently isolated using methanol-water, which on further cyclization followed by reduction with lithium aluminium hydride provided trans isomer of asenapine with an yield of 62%. It also disclosed the preparation of asenapine from a mixture of cis and trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c] pyrrole-1-one or from cis isomer alone using the same above said process. Eventhough yields are high the said process involves more steps to get the desired compound and hence increases the production time and overall cost.

Hence there is a need in the art to prepare asenapine maleate which can reliably carried out in an industrial scale with high yield and purity in a convenient and cost efficient manner and avoids problems mentioned in the prior art.

Advantages of the Present Invention:

• Provides an improved process for the preparation of asenapine with high yield and purity. Use of 2-chlorophenyl aceticacid in place of 2-bromophenyl acetic acid reduces the total cost of production.

• Provides an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one with a high yield and purity by avoiding the additional steps for purification.

• Avoid the usage of lithium aluminium hydride, which is pyrophoric in nature and not recommended in large scale process.

• Uses simple, milder reagents which are easier to handle and use in large scale.

• Provides stable asenapine maleate form-H.

• Eco-friendly and cost effective process.

Brief description of the invention:
The first aspect of the present invention is to provide an improved process for the preparation of asenapine, compound of formula-1, which comprises of reducing trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one, compound of formula-10 with a suitable reducing agent in a suitable solvent to provide compound of formula-1.

The second aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one, compound of formula-10, which comprises of reducing 5-chloro-2,3-dihydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one, compound of formula-9 with a suitable reducing agent in a suitable solvent followed by recrystallization from a suitable solvent to provide compound of formula-10.

The third aspect of the present invention is to provide an improved process for the preparation of asenapine maleate salt, compound of formula-la, which comprises of following steps;

a) Esterification of 2-chlorophenyl acetic acid, compound of formula-2 to provide alkyl 2-chlorophenyl acetate, compound of formula-3,

b) condensation of compound of formula-3 with 4-chloro phenol, compound of formula-4 to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid ester, which is hydrolyzed in-situ and further reacted with a suitable amine in a suitable solvent to provide the corresponding amine salt of 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of general formula-5,

c) converting compound of general formula-5 into free acid, and condensing it with 2-(methylamino)acetic acid ester, compound of formula-6 in presence of suitable reagent to provide alkyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methylacetamido) acetate, compound of formula-7,

d) reacting the alkyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methylacetamido)acetate, compound of formula-7 with a suitable base in a suitable solvent to provide 3-(2-(4-chlorophenoxy)phenyl)-1 -methylpyrrolidine-2,4-dione, compound of formula-8,

e) cyclisation of compound of formula-8 using polyphosphoric acid, followed by purification with a suitable solvent to provide 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one, compound of formula-9,

f) reducing compound of formula-9 with a suitable reducing agent in a suitable solvent, followed by recrysallization with a suitable solvent to provide trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one, compound of formula-10,

g) reducing compound of formula-10 with a suitable reducing agent in a suitable solvent to provide asenapine, compound of formula-1,

h) reacting asenapine compound of formula-1 with maleic acid in a suitable solvent, followed by purification with a suitable solvent provides asenapine maleate, compound of formula-la.

The fourth aspect of the present invention is to provide stable asenapine maleate crystalline form-H.

The fifth aspect of the present invention is to provide novel amines salts of 2-(2-(4-chlorophenoxy)phenyl)acetic acid and process for its preparation.
Detailed description of the Invention:

The suitable solvents, wherever necessary, used in the present invention are selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, pet.ether; "hydrocarbon solvents" like toluene, xylene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutaol; "chloro solvents" like dichloromethane, chloroform and ethylene chloride; polar solvents like water; and also mixtures there of.
The first aspect of the present invention provides an improved process for the preparation of asenapine compound of formula-1,


which comprises of reducing trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one, compound of formula-10

with a suitable reducing agent in a suitable solvent to provide compound of formula-1 , characterized in that the reducing agent is selected from BF3-etherate/sodium borohydride, vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN.

The second aspect of the present invention provides an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one, compound of formula-10, which comprises of reducing 5-chloro-2,3-dihydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one, compound of formula-9


with a suitable reducing agent in the presence of an activator in a suitable solvent to provide compound of formula-10, characterized in that the reduction is carried-out in the presence of proton donor like formic acid or acetic acid.

Wherein in suitable reducing agent is selected from magnesium, zinc or iron and the activator is iodine or dibromoethane. The usage of proton donor such as formic acid or acetic acid in the above reduction provides the desired trans-isomer in high ratio compared to the prior art process and hence the present process is more advantageous over the prior art.

The third aspect of the present invention provides an improved process for the preparation of asenapine maleate compound of formula-la, which comprises of the following steps;

a) Esterification of 2-chlorophenyl acetic acid, compound of formula-2
with an alcohol in presence of an acid to provide alkyl 2-chlorophenylacetate, compound of formula-3,

wherein R is C1-C4 alkyl,

b) condensation of alkyl 2-chlorophenylacetate, compound of formula-3 with 4-chloro

phenol, compound of formula-4

in presence of suitable base, Cu (I) catalyst and a ligand in a suitable solvent to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid ester, which is hydrolyzed in-situ in presence of a base like KOH or NaOH in a suitable solvent to provide 2-(2-(4-

chlorophenoxy)phenyl) acetic acid, which is further reacted with a suitable amine in a suitable solvent to provide corresponding amine salt of 2-(2-(4-chlorophenoxy)phenyl)acetic acid, compound of formula-5,

c) converting 2-(2-(4-chlorophenoxy)phenyl)acetic acid amine salt compound of
formula-5 into free acid by treating with a suitable acid in a suitable solvent and
in-situ treating of the obtained free acid with 2-(methylamino)acetic acid ester,
compound of formula-6

in presence of a suitable reagent in a suitable solvent to provide alkyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methylacetamido) acetate, compound of formula-7,

wherein R is defined above

d) reacting the alkyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methylacetamido)acetate, compound of formula-7 with a suitable base in a suitable solvent to provide 3-(2-
(4-chlorophenoxy)phenyl)-1 -methylpyrrolidine-2,4-dione, compound of formula-8,


e) cyclisation of 3-(2-(4-chlorophenoxy)phenyl)-l-methylpyrrolidine-2,4-dione, compound of formula-8 with a suitable reagent in a suitable solvent, followed by purification from a suitable solvent provides 5-chloro-2,3-dihydro-2-methyl-lH-
dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one, compound of formula-9,

f) reducing 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c] pyrrol-1 one, compound of formula-9 with a suitable reducing agent in a suitable solvent,
followed by recrystallization with a suitable solvent to provide the desired trans-5-
chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c] pyrrol-1 -
one, compound of formula-10,

g) reducing trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino
[4,5-c]pyrrol-l-one, compound of formula-10 with a suitable reducing agent in a
suitable solvent to provide asenapine, compound of formula-1,
h) treating of asenapine, compound of formula-1 with maleic acid in a suitable solvent, followed recrystallization from a suitable solvent to provide asenapine maleate, compound of formula-la.
Wherein in step a) alcohol refers to methanol, ethanol, propanol, isopropanol, butanol, isobutanol, secondary butanol, tertiary butanol, preferably methanol; acid is

selected from sulfuric acid, para toluene sulfonic acid, methane sulfonic acid and trifluoro aetic acid, preferably sulfuric acid;
In step b) the suitable base selected from K2CO3, CS2CO3, preferably CS2CO3; Cu'(I) catalyst selected from Cu20, CuX, CuXPPh3, CuX(PPh3)3, Copper bi pyridyl complexes, (wherein X refers to halogens i.e. CI, Br and I, preferably CI) preferably CuCl and a ligand selected from Me4Phen, l,l,l-tris(hydroxymethyl)ethane, diphenyl glycine, dimethyl glycine, Chxn-Py-Al, 1,10-phenonthroline, preferably dimethylglycine; and amine is selected from mono, di and trialkyl amine, preferably tributylamine;

In step c) the suitable reagents selected from dehydrating agents, like carbodiimides optionally in combination with N-hydroxy benzotriazole or N-hydroxy succinamide, N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HOAt), N-hydroxy succinamide (HOSu), 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate- tri ethyl amine, di phenylphosphoroazidate (DPP A), 3-(diethoxyphosphoryloxy)-l,2,3-benzotriazine-4(3H)-one (DEPBT), 1-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), P205, (2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), N,N'-dicyclohexyl carbodiimide (DCC)-dimethyl amino pyridine (DMAP), preferably DCC in combination with DMAP; the suitable acid used for deprotection of amine salt is selected from organic acid selected from acetic acid, oxalic acid and formic acid and inorganic acid selected from hydrochloric acid, sulphuric acid and the like, preferably hydrochloric acid.

In step d) the suitable base selected from sodium tertiary butoxide, potassium tertiary butoxide, sodium methoxide, preferably potassium tertiary butoxide;

In step e) the suitable reagent selected from polyphosphoric acid or P205 and phosphoric acid. The usage of a solvent in the cyclisation reaction improves the yield and purity when compared to the prior art,

In step f) the suitable reducing agent is magnesium in presence of an activator, i.e. I2 or dibromoethane and in the presence of proton donor like formic acid or acetic acid;

In step g) the suitable reducing agent is selected from BF3-etherate and sodium borohydride, vitride, sodium borohydride and aluminium chloride or borane and aluminium chloride, 9-BBN.

In step h) the suitable solvent selected from alcoholic solvents like methanol, ethanol, propyl alcohol and isopropyl alcohol, preferably isopropyl alcohol.

In a preferred embodiment of the present invention, improved process for the preparation of asenapine maleate compound of formula-la comprises of the following steps;

a) Esterification of 2-chlorophenyl acetic acid, compound of formula-2 with methanol in presence of sulfuric acid to provide methyl 2-chlorophenylacetate, compound of formula-3a,

b) condensation of alkyl 2-chlorophenylacetate, compound of formula-3 with 4-chloro phenol, compound of formula-4 in the presence of CS2CO3, CuCl and dimethyl
glycine in dioxane provides 2-(2-(4-chlorophenoxy)phenyl)acetic acid ester which is
insitu hydrolyzed in the presence of KOH in methanol to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid, which on in-situ reaction with tributyl amine in
pet.ether to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine salt,
compound of formula-5a,


c) treating the 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine salt, compound of formula-5a with hydrochloric acid in ethyl acetate and water to provide its free acid, which on in-situ reaction with methyl 2-(rnethylamino)acetate, compound of formula-6 in presence of DCC in combination with DMAP in methylene chloride provides methyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methylacetamido) acetate, compound of formula-7,

d) reacting the methyl 2-(2-(2-(4-chlorophenoxy) phenyl)-N-methylacetamido) acetate, compound of formula-7 with potassium tertiary butoxide in toluene provides 3-(2-(4-chlorophenoxy)phenyl)-1 -methylpyrrolidine-2,4-dione, compound of formula-8,
e) dehydrating 3 -(2-(4-chlorophenoxy)phenyl)-1 -methylpyrrolidine-2,4-dione, compound of formula-8 with polyphosphoric acid or P205 and phosphoric acid in xylene, followed by purification of the obtained compound in methanol to provide pure 5-chloro-2,3-dihydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one, compound of formula-9,

f) reducing 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c] pyrrol-1-one, compound of formula-9 with Mg in presence of h in methanol and formic acid in toluene and methanol mixture, followed by recrystallization of the obtained compound from methanol provides the desired compound trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one, compound of formula-10,

g) reducing trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one, compound of formula-10 with BF3-etherate and sodium boro hydride in THF to provide asenapine, compound of formula-1.

h) treating of asenapine, compound of formula-1 with maleic acid in isopropyl alcohol, followed by recrystallization of the obtained compound from aq.ethanol to provide asenapine maleate, compound of formula-la.

Asenapine maleate compound of formula-la prepared as per the present invention is stable and the crystalline characteristics of the same well matches with the known crystalline form H of asenapine maleate.

According to WO 2006/106135 Al the crystalline form H of asenapine maleate is not stable during micronisation and converted into crystalline form-L or mixture of form-L and form-H. However asenapine maleate prepared as per the present invention is stable even after micronisation and does not converted in to crystalline form-L during micronisation or its storage after micronisation.

The following table shows the stability of asenapine maleate of the present invention before micronisation, after micronisation and during storage of the same.

The present invention further provides a process for the preparation of form-H of asenapine maleate, which comprises of the following steps,

a) Stirring asenapine maleate in ethanol for 15 minutes at 60-65°C,
b) subjecting the reaction mixture to carbon treatment,
c) stirring for 10 minutes at 60-65°C,
d) cooled to 18-22°C over a period of 2 hours,
e) filtered, washed with ethanol and dried to get the stable asenapine maleate form-H.
The fifth aspect of the present invention provides novel amine salts of 2-(2-(4-chlorophenoxy)phenyl)acetic acid represented by the following structural formula,

Where in amine is selected from mono, di and trialkyl amine, preferably methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, isobutyl amine, sec-butyl amine, tertiarybutyl amine, dimethyl amine, diethyl amine, di(n-propyl)amine, di(isopropyl)amine, di(n-butyl)amine, di(isobutyl)amine, di(sec-butyl)amine,

di(tertiarybutyl)amine, trimethyl amine, triethyl amine, tri(n-propyl)amine, tri(isopropyl)amine, tri(n-butyl)amine, tri(isobutyl)amine, tri(sec-butyl)amine, tri(tertiarybutyl)amine, most preferably tri(n-butyl) amine.

Further the present invention provides a process for the preparation of novel amine salts of 2-(2-(4-chlorophenoxy)phenyl)acetic acid salt compound of general formula-5, which comprises of reacting the 2-(2-(4-chlorophenoxy)phenyl)acetic acid with a suitable amine as discussed above in a suitable solvent and isolating the corresponding salt compound of formula-5 in a convenient manner.

The following are the impurities which are formed during the preparation of asenapine and its salts. These impurities are identified, synthesized and characterized.

(3aRS, 12bRS)-2-methyl-2,3,3a, 12b-tetrahydro- lHdibenzo[2,3:6,7] oxepino[4,5-
C]pyrrole herein designated as "deschloroimpurity"; (3aRS,12bRS)-5-chloro-
2,3,3a,12b-tetrahydro-lHdibenzo[2,3:6,7] oxepino[4,5-c]pyrrole, herein designated as
"desmethylimpurity"; (3aR5,12bR5)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-
lHdibenzo [2,3:6,7]oxepino[4,5-c]pyrrole-N-oxide, herein designated as "N-oxide impurity"; 2-chloro-phenyl acetic acid, herein designated as "Impurity-A".

In the asenapine maleate prepared as per the present invention is having purity greater than 99% by HPLC and the impurities which are mentioned above are well controlled with in the limits as per the ICH guidelines
The present invention is schematically represented as follows:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples: Example-1: Preparation of methyl 2-chlorophenyl acetate (formula-3)

A mixture of 2-chlorophenyl acetic acid (100 g), sulfuric acid (2 g) and methanol (1 lit) was stirred for 1 hour at reflux temperature. Distilled off the solvent completely and then added water followed by ethyl acetate. The reaction mixture was neutralized with 10% sodium bicarbonate. Both the organic and aqueous layers were separated; the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined and distilled off the solvent completely to get the title compound. Yield: 100 g

Example-2: Preparation of tributylamine of 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine(formula-5a):

To a mixture of methyl-2-chlorophenyl acetate (100 g), 4-chloro phenol (69.6 g) in dioxane, cesium carbonate (352.9 g) and cuprous chloride (21.5 g) were added, followed by N,N-dimethyl glycine (11.2 g) and stirred upto the completion of reaction at 110-115°C. After completion of the reaction, the reaction mass was cooled to RT and filtered, the solvent was distilled off completely under reduced pressure. Ethyl acetate (250 ml) was added to obtained residue and stirred for 15 minutes at RT and acidified with 1M HC1. The layers were separated and extracted the aqueous layer with ethyl acetate. Washed with sat.sodium chloride and dried with sodium sulfate then distilled off the solvent under reduced pressure. Methanol (500 ml), potasium hydroxide (32.4 g) was added to the obtained residue at 25-35°C, heated to 60-65°C and stirred for 5 hrs. The reaction mass was cooled to 45 °C and solvent was distilled under reduced pressure. Water was added to the residue and acidified with hydrochloric acid. Ethyl acetate was added to the reaction mass and stirred for 15 minutes at RT. Both the layers were separated and the organic layer was dried with sodium sulphite and then distilled off the solvent under reduced pressure. Pet. Ether (300 ml) was added to the reaction mass and stirred for 20 minutes and then cooled to 5-10°C. Tributyl amine (300 ml) was added to

the reaction mass and stirred for lhr. The solid obtained was filtered, washed with pet.ether and then dried to get the title compound. Yield: 65 g

Example-3: Preparation of methyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methyl acetamido)acetate (formula-7):

To the compound of formula-5 obtained in example-2 (62 g), water (300 ml) and methylene chloride (250 ml) were added and PH was adjusted to 1.5 with aqueous hydrochloric acid. Both the aqueous and organic layer were separated. Distilled off the solvent from the organic layer under reduced pressure. Methylene chloride (300 ml), dicyclohexylcarbodiimide (48.7 gm) in methylene chloride (300 ml), 4-dimethyl amino pyridine (0.5 gms) and followed by methyl 2-(methylamino)acetate solution (prepared from methyl 2-(methylamino)acetate.HCl (32.9 g) in methylene chloride (62 ml) by adding triethyl amine (28.6 gms)) was added to the above obtained residue at 0-5°C. The reaction mass was stirred for 45 minutes at 10-15°C. After completion of the reaction, the reaction mass was filtered and washed with methylene chloride. To the filtrate water was added and stirred for 15 minutes at RT. Both the layers were separated; the organic layer was washed with sodium chloride solution and dried with sodium sulfate followed by distilled off the solvent to get the title compound. Yield: 80 grams

ExampIe-4: Preparation of 3-(2-(4-chlorophenoxy)phenyl)-l-methylpyrrolidine-2,4-dione (formula-8):

Potassium tertiary butoxide (21.7 gm) in toluene (40 ml) was added to the compound of formula-7 of example-3 (80 g) in toluene (650 ml) and stirred for 3 hrs at RT. Quenched the reaction mixture with water and washed thrice with ethyl acetate. Acidified the aqueous layer with concentrated hydrochloric acid and stirred for 3 hours at RT. The solid obtained was filtered, washed with water and then dried to get the title compound. Yield: 8.5 grams

Example-5: Preparation of 5-chloro-23-dihydro-2-methyl-lH-dibenz[23:6,7] oxepino [4,5-c] pyrrol-1 -one (formula-9):

Phosphorous pentoxide (90 g) was added to ortho phosphoric acid (90 g) slowly at 140°C and then stirred for 90 minutes at 115-120°C. Added compound of formula-8 of example-4 (30 g) and xylene (300 ml) to the above reaction mass over a period of 15 minutes and then stirred for 4 days at the 115-130°C. Decanted the solvent, quenched the reaction with water and methylene chloride was added to the reaction mass. Both the aqueous and organic layers were separated; the organic layer was distilledoff completely. Acetonitrile was added to the reaction mass and stirred for 2 hours at 0-5°C. The reaction mass was filtered; the obtained filtrate was distilled off to get the title compound as a solid. Yield: 9.8 grams

Example-6: Purification process for 5-chloro-2,3-dihydro-2-methyl-lH-dibenz [2,3:6,7]oxepino[4,5-c]pyrrol-l-one (formula-9):

Compound of formula-9 obtained in example-5 (9.8 g) was in methanol (520 ml) was stirred for 15 minutes at reflux temperature. Distilled off the solvent half of the amount and then stirred for 14 hours at -10 to -12°C. Filtered the solid, washed with chilled methanol and dried to get highly pure title compound.

ExampIe-7: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyI-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one (formula-10):

Iodine (2.13 g) followed by formic acid (25 g) was added to a mixture of magnesium (0.4 g) and toluene (25 ml) at room temperature. Compound of formula-9 obtained from example-6 (5 g) and a mixture of toluene and methanol (1:1 ratio) was added to the above reaction mass slowly over a period of 45 minutes and stirred for 5 hours.at 40°C. The reaction was quenched with water and acidified with conc.HCl at 5-10°C (i.e. PH~1). The reaction mass was extracted with toluene and the organic and aqueous layers were separated. All the organic layers were combined and concentrated to yield the crude trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3:6,7]oxepino[4,5-c]pyrrol-l-one (10). Recrystallization from methanol provides the pure title compound (10). Yield: 0.1 grams

Example-8: Preparation of asenapine (formula-1): Method-I:
Sodium borohydride (0.63 gm) was added to the compound obtained from Example-7 (0.5 gm) in THF (20 ml) at RT and stirred for 15 minutes at the same temperature. To the above reaction mass I2 solution (4.2 gm of I2 in 15 ml THF) was added slowly at reflux temperature for 6 hours. After the reaction completed, cooled to 10-15°C and acidified with 10% HC1 solution (1.5 ml HC1 in 13.5 ml water), followed by treatment with dilute.sodium hydroxide. The reaction mass was extracted with toluene twice, combined both the organic layers and washed with water followed by sat.brine solution and dried and distilled to yield the title compound. Yield: 0.5 gm. Method-I I:

Sodium borohydride (3.2 gm) was added to the compound obtained from Example-7 (5 gm) in THF (100 ml) at RT. BF3 etherate (23.6 gm) was added to the above reaction mass over a period of 1 hour at reflux temperature and stirred for 12 hours at the same temperature. The reaction was quenched with 2.5% sodium hydroxide solution and both the organic and aqueous layers were separated. The aqueous layer was extracted twice with toluene. All the organic layers were combined, washed with water followed by sat. sodium chloride solution, dried and distilled to yield the title compound. Yield: 3.4 gm

Example-9: Preparation of asenapine maleate (formula-la)
Maleic acid (41.1 grams) in isopropyl alcohol (300 ml) was added to asenapine (92 grams) in isopropyl alcohol (500 ml) at 60-65°C over a period of 30 minutes and stirred for 15 minutes at the same temperature and then stirred for 1 hour at RT. Isopropyl alcohol (184 ml) was added to the above reaction mass and stirred for 12 hours at -10 to -5°C. Filtered, washed with isopropyl alcohol and dried to yield the title compound. Yield: 108 grams

Example-10: Purification of asenapine maleate (formula-la):
Stirred the crude asenapine maleate (45 grams) in aq.ethanol (225 ml) for 15 minutes at 65-70°C and followed by 3 hours at RT. The reaction mass was filtered, washed thrice with water and dried to yield pure asenapine maleate, compound of formula-la. Yield: 25.7 gms

Example-11: Preparation of asenapine maleate form-H:

Stirred asenapine maleate (90 grams) in ethanol (225 ml) for 15 minutes at 60-65°C. The reaction mass was treated with C and stirred for 10 minutes at 60-65°C. Filtered the reaction mass, filtered mi's were stirred for 10 minutes at 60-65°C and slowly cooled to 18-22°C over a period of 2 hours. The reaction mass was stirred for 4 hours at -15 to -10°C. Filtered, washed with ethanol and dried to yield asenapine maleate form-H. Yield: 78 gm

Exmaple-12: Preparation of trans-5-chloro-2,33a,12b-tetrahydro-lH-dibenz; [2,3:6,7] oxepino[4,5-c]pyrrole oxalate:

A mixture asenapine maleate (la), water (50 ml) and methylene chloride (50 ml) was stirred for 15 minutes at RT at PH~9 to 9.5 (adjusted with 10% sodium hydroxide). Both the organic and aqueous layers were separated; the aqueous layer was again extracted with methylene chloride. Both the organic layers were combined, dried with sodium sulfate and distilled off the solvent under reduced pressure. Methylene chloride (50 ml) was added to the above reaction mass followed by ethyl chloro format (1.47 gm) and stirred for 45 minutes at RT. After the reaction completed, distilled off the solvent completely. Toluene 0 followed by poly ethylene glycol () and sodium hydroxide () were added to the above reaction mass at RT and stirred for 14 hours at 125-130°C. After the reaction completed, the reaction mass was cooled to RT and the reaction mass was quenched with water. Ethyl acetate was added to the reaction mass and both the organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate. Combined both the organic layers, washed with water followed by satbrine solution and then dried and distilled to remove the solvent completely under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel. Elution with cyclohexane/ethylacetate (1:1) followed by methanol/ethylacetate gave the title compound.

The obtained pure residue in ethanol (25 ml) was added oxalic acid (1.2 gm) and heated to 60-65 °C to obtain a clear solution and then cooled to RT. The reaction mass was stirred for 2 hours at 5-10°C. The reaction mass was filtered, washed with ethanol and dried to yield oxalate salt of title compound.

Yield: 0.7 gms; FT-IR (KBr) 769.39, 1445.73, 1480.17 cm"1;1H NMR (CDC13) 3.470-3.506 (d, 2H), 3.682 (d, 2H), 3.696-3.746 (q, 2H), 7.01-7.32 (m, 7H) 5; MS (LCMS) 272 (M++l).

Example-13: Preparation of (3aRS,12bRS)-2-methyl-2,3,3a,12b-tetrahydro-lH dibenz [2,3:6,7]oxepino[4,5-c] pyrrole oxalate:

Stage-1: Preparation of trans-2,33a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino [4,5-c] pyrrol-1 -one

Treatment of Pd-C (7.5 gm) with a solution of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one (2) (5 gm) in methanol (500 ml) under nitrogen at a pressure of 2.0 kg H2. The reaction mass was stirred for 3 hours at RT. Filtered the reaction mass, washed with methanol and distilled under reduced pressure to yield title compound. Yield: 4 gm

Stage-b: Preparation of (3aRS,12bRS)-2-methyl-2,3,3a,12b-tetrahydro-lHdibenz [2,3:6,7]oxepino[4,5-c] pyrrole oxalate:

10% lithium aluminium hydride solution (prepared by dissolving 1.57 gm lithium aluminium hydride in 40 ml of THF at 5-10°C) was added to aluminium chloride solution (prepared by dissolving aluminium chloride (3.11 gm) in portion wise to THF (40 ml) at below 5°C and stirred for 15 minutes) over a period of 30 minutes at -5 to +5°C and stirred for 15 minutes at the same temperature. Added a solution of trans-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one (4 gm) in THF (40 ml) to the above reaction mass for about 45 minutes at -5 to +5°C and stirred further 45 minutes at the same temperature. After completion of the reaction, the reaction was quenched with 2.4% of sodium hydroxide solution at 0-5°C. Toluene and water were added to the reaction mass at RT. Filtered the reaction mass and separated both the organic and aqueous layers; the aqueous layer was extracted with toluene. Combined both the organic layers, washed with water, dried and distilled to remove the solvent completely to obtain a residue of title compound. To the obtained residue (3 gm) in ethanol (20 ml), a solution of oxalic acid (0.96 gm) in ethanol (10 ml) was added for about 30 minutes at RT. Filtered, washed with ethanol and dried to yield oxalate salt of title compound.

Yield: 2 gm;
FT-IR (KBr) 770.16, 1457.33, 1486.96, 2346.86 cm-1; 'H NMR (CDC13) 2.93-2.86 (s,
3H), 3.84-3.94 (d, 4H), 3.63-3.66 (q, 2H), 7.18-7.33 (m, 8H) 8; MS (LCMS) 251 (M+
+1).

Example-14: Preparation of (3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahy dro -1 Hdibenz[2,3:6,7]oxepino[4,5-c]pyrrole-N-oxide:

Methylene chloride (25 ml) was added to a mixture of asenapine maleate (la) (5 gm) and water (50 ml) and stirred for 15 minutes at PH 9-9.5 (adjusted by 10% sodium hydroxide solution). Both the organic and aqueous layers were separated; the aqueous layer was extracted with methylene chloride. Both the organic layers were combined, dried and distilled under reduced pressure to obtain a residue (3.8 gms). To the obtained residue in methylene chloride (75 ml) was added 30% hydrogen peroxide (30 ml) at RT. After the reaction was completed, the reaction mass cooled to 5-10°C and the reaction was quenched with 10% sodium sulphite solution. Both the organic and aqueous layers were separated; the aqueous layer was extracted with methylene chloride. Combined all the organic layers, dried and distilled under reduced pressure to obtain a solid. Yield: 2.6 grams;

FT-IR (KBr) 768, 1444.36, 1480.79, 2776.16 cm1; NMR (CDC13) 3.083 (s, 3H), 3.938 (s, 4H), 3.696-3.746 (q, 2H), 7.01-7.32 (m, 7H), 6.30 (s, 2H)8; MS(LCMS) 302 (M+ +1).

We Claims:

1. A process for the preparation of asenapine, compound of general formula-1,

which comprises of reducing trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one, compound of formula-10

with a suitable reducing agent in a suitable solvent to provide compound of formula-1 , characterized in that the reducing agent is selected from BF3-etherate/sodium borohydride, vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN.

2. A process for the preparation of asenapine compound of formula-1 comprises of reducing trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H- dibenz[2,3:6,7] oxepino [4,5-c] pyrrol-1-one, compound of formula-10 with BF3-etherate/sodium borohydride in THF.

3. A process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl- lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one, compound of formula-10, which comprises of reducing 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino [4,5-c]pyrrol-l-one, compound of formula-9

with a suitable reducing agent in presence of an activator in a suitable solvent to provide compound of formula-10, characterized in that the reduction carried-out in the presence of proton donor like formic acid or acetic acid.

4. An improved process for the preparation of asenapine maleate compound of formula-la, which comprises following steps;
a) Esterification of 2-chlorophenyl acetic acid, compound of formula-2

with alcohol in presence of an acid to provide alkyl 2-chlorophenylacetate, compound of formula-3, where R refers to C1-C4 carbon alkyl

b) condensation of alkyl 2-chlorophenylacetate, compound of formula-3 with 4-chloro phenol, compound of formula-4

in the presence of a base, Cu catalyst and a ligand in suitable solvent provides 2-(2-(4-chlorophenoxy)phenyl)acetic acid ester which is insitu hydrolyzed in the presence of a base in a suitable solvent to provide 2-(2-(4-chlorophenoxy) phenyl)acetic acid, followed by reaction with tributyl amine in a suitable solvent to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine salt, compound of formula-5,

c) converting of 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine salt, compound of formula-5 into free base by treating with a suitable acid in a suitable solvent and in-situ treating it with 2-(methylamino)acetic acid ester, compound of formula-6

in presence of a suitable reagent in a suitable solvent produces alkyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methylacetamido)acetate, compound of formula-7,

d) alkyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methylacetamido)acetate, compound of formula-7 in presence of a suitable reagent in a suitable solvent produces 3- (2-(4-chlorophenoxy)phenyl)-1 -methylpyrrolidine-2,4-dione, compound of

formula-8,

e) dehydrating 3-(2-(4-chlorophenoxy)phenyl)-1 -methylpyrrolidine-2,4-dione, compound of formula-8 with a suitable dehydrating agent in a suitable solvent, followed by purification from a suitable solvent to provide pure 5-chloro-2,3- dihydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one, compound of

formula-9,

f) reducing 5-chloro-2,3-dihydro-2-methyl-1 H-[2,3:6,7]oxepino[4,5-c] pyrrol-1-one, compound of formula-9 with a suitable reducing agent in a suitable solvent, followed by recrystallization with suitable solvent to produce the desired compound trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3:6,7]oxepino[4,5-c]pyrrol-l-one, compound of

formula-10

g) reducing trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one, compound of formula-10 with a suitable reducing agent in a suitable solvent to produce asenapine, compound of formula-1.

h) treating of asenapine, compound of formula-1 with maleic acid in a suitable solvent, followed by recrystallization with a suitable solvent to provide asenapine maleate, compound of formula-la.

6. An improved process for the preparation of asenapine maleate compound of formula-la, which comprises following steps; a) Esterification of 2-chlorophenyl acetic acid, compound of formula-2

b) with methanol in presence of sulfuric acid to provide methyl 2-
chlorophenylacetate, compound of formula-3a,

c) condensation of alkyl 2-chlorophenylacetate, compound of formula-3 with 4-chloro phenol, compound of formula-4 in the presence of CS2CO3, CuCl and dimethyl glycine in dioxane provides 2-(2-(4-chlorophenoxy)phenyl)acetic acid ester which is insitu hydrolyzed in the presence of KOH in methanol to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid, which on in-situ reaction with
tributyl amine in pet.ether to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine salt, compound of formula-5a,

d) treating the 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine salt, compound of formula-5a with hydrochloric acid in ethyl acetate and water to provide its free acid, which on in-situ reaction with methyl 2-(methylamino)acetate, compound of formula-6 in presence of DCC in combination with DMAP in methylene chloride provides methyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methylacetamido) acetate, compound of formula-7,

e) reacting the methyl 2-(2-(2-(4-chlorophenoxy) phenyl)-N-methylacetamido) acetate, compound of formula-7 with potassium tertiary butoxide in toluene provides 3-(2-(4-chlorophenoxy)phenyl)-1 -methylpyrrolidine-2,4-dione, compound of formula-8,

f) cyclization of 3-(2-(4-chlorophenoxy)phenyl)-l-methylpyrrolidine-2,4-dione, compound of formula-8 with polyphosphoric acid or P2O5 and phosphoric acid in xylene, followed by purification of the obtained compound in methanol to provide pure 5-chloro-2,3-dihydro-2-memyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one, compound of formula-9,

g) reducing 5-chloro-2,3-dihydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c] pyrrol-1-one, compound of formula-9 with Mg in presence of I2 in methanol and formic acid in toluene and methanol mixture, followed by recrystallization of the obtained compound from methanol provides the desired compound trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one, compound of formula-10,

h) reducing trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one, compound of formula-10 with BF3-etherate and sodium boro hydride in THF to provide asenapine, compound of formula-1.

i) treating of asenapine, compound of formula-1 with maleic acid in isopropyl alcohol, followed by recrystallization of the obtained compound from aq.ethanol to provide asenapine maleate, compound of formula-la.

7. Stable crystalline form H of asenapine maleate, characterized in that the crystalline form-H does not convert into crystalline form-L or mixture for form-L and form-H of asenapine maleate after subjecting into micronisation or milling.

8. An improved process for the preparation of stable asenapine maleate form-H, which comprises of

a) Stirring asenapine maleate in a ethanol for 15 minutes at 60-65°C,
b) subjecting the reaction mixture to carbon treatment,
c) stirring for 10 minutes at 60-65 °C,
d) cooled to 18-22°C over a period of 2 hours,
e) filtered, washed with ethanol and dried to get the stable crystalline form H of asenapine maleate.

9. Novel amine salts of 2-(2-(4-chlorophenoxy)phenyl)acetic acid represented by the following structural formula

10. Amine salt of 2-(2-(4-chlorophenoxy)phenyl)acetic acid according to claim-9 is selected from methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, isobutyl amine, sec-butyl amine, tertiarybutyl amine, dimethyl amine, diethyl amine, di(n-propyl)amine, di(isopropyl)amine, di(n-butyl)amine, di(isobutyl)amine, di(sec-butyl)amine, di(tertiarybutyl)amine, trimethyl amine, triethyl amine, tri(n-propyl)amine, tri(isopropyl)amine, tri(n-butyl)amine, tri(isobutyl)amine, tri(sec-butyl)amine and tri(tertiarybutyl)amine.