Field of invention:

The present invention relates to a novel process for the preparation of antipsychotic drug i.e, (3aRS-S',12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l/fdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1) represented by the compound of formula-1.

Background of the Invention:

(Saienb-S-chloro-methyl nb-tetrahydro-l/fdibenzoP iej] oxepino[4,5-c]pyrrole (2Z)-2-butenedioate is commonly known as asenapine maleate.

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.

Asenapine and its pharmaceutically acceptable salts, specifically asenapine maleate and process for its preparation were disclosed in US 4145434. The disclosed process comprises of reducing 5-chloro-2,3-dihydro-2-methyl-lH-dibenzo[2,3:6,7] oxepino[4,5-c]pyrrol-l-one with magnesium in methanol/toluene to provide a mixture of desired trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7]oxepino [4,5-c]pyrrol-l-one and unwanted cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-l-one in 1:4 ratio. The ratio of required 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 racemizations and hence not suitable for commercial scale up. The yield and purity of the intermediates and final compounds were also not satisfactory.

EP 1710241 discloses a process which involves the reduction of double bond in
ll-chloro-2,3-dihydro-2-methyl-lH-dibenzo[2,3,6,7]oxepino[4,5-c]pyrrol-l-one by
treating with magnesium in methanol/toluene solvent to provide a mixture of required 'trans' isomer and the unwanted 'cis' isomer of ll-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3,6,7]oxepino[4,5-c]pyrrol-l-one in a ratio of 1:4 respectively. The trans-isomer is separated from the racemic mixture using chromatography over silica gel. The 'cis' isomer obtained after separation is converted into trans-isomer by isomerization using l,5-diazabicyclo[4.3.0]non-5-ene (DBN). But the isomerization is only partial providing a mixture of 'trans' isomer and 'cis' isomer in the ratio of 1:2. The 'trans' isomer from this racemic mixture is once again separated using chromatography over silica gel. Repeating the cycle for multiple times provided overall yield of 38% of the trans-isomer.

The said process involves chromatographic separation in each cycle. The use of chromatographic separation makes the process cumbersome, time consuming, and uneconomical. It also leads to the generation of lot of spent solvents and solid waste which are difficult to dispose which may lead to the pollution of the environment. Hence it becomes imperative to avoid chromatographic separation for the process to be more effective. The process also involves repeated racemization.

Hence there is a need in the art to develop an alternate process for the preparation of Asenapine maleate, which can reliably be carried out in an industrial scale, in a convenient and cost efficient manner and also the process should be more eco-friendly.

The present invention overcomes the problems of the above mentioned prior art.

Advantages of the Present Invention:

• Avoids chromatographic separation hence conducive to be carried out in large scale process.

• Eco-friendly and cost effective process.

Brief description of the invention:

The present invention relates to a novel process for the preparation of QaRS, 12b7?5)-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-l#dibenzo[2,3:6,7]oxepino [4,5-cjpyrrole (2Z)-2-butenedioate compound of formula-1.

The first aspect of the present invention is to provide a novel process for the preparation of alkyl 2-chloro-11 -oxo-10,11 -dihydrodibenzo[b,f]oxepine-10-carboxylate compound of general formula-6 from 2-(2-chlorophenyl)acetic acid compound of formula-2.

The second aspect of the present invention is to provide a novel process for the preparation of alkyl 2-chloro-11 -oxo-10,11 -dihydrodibenzo[b,f]oxepine-10-carboxylate compound of formula-6 from 8-chlorodibenzo[b,f]oxepin-10(llH)-one compound of formula-4.

The third aspect of the present invention is to provide a novel process for the preparation of alkyl 2-chloro-ll-((methylamino)methyl)-10,ll-dihydrodibenzo[b,f] oxepine-10-carboxylate compound of general formula-9 from alkyl 2-chloro-11-oxo-10,1 l-dihydrodibenzo[b,f]oxepine-l 0-carboxylate compound of general formula-6.

The fourth aspect of the present invention is to provide a one-pot process for the preparation of alkyl ll-(aminomethyl)-2-chloro-10,ll-dihydrodibenzo[b,f] oxepine-10-carboxylate compound of general formula-8 from alkyl 2-chloro-ll-oxo-10,ll-dihydrodibenzo[b,fJoxepine-l 0-carboxylate compound of general formula-6.

The fifth aspect of the present invention is to provide a novel process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10 from alkyl 2-chloro-ll-((methylamino)methyl)-10,ll-dihydrodibenzo [b,fJoxepine-l 0-carboxylate compound of general formula-9.

The sixth aspect of the present invention is to provide a novel process for the preparation of (3a/SS',12bi?5)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l//dibenzo[2,3: 6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1, comprising of:

a) Condensation of 2-(2-chlorophenyl)acetic acid compound of formula-2 with 4-chloro phenol in presence of CuCl catalyst and a suitable base in a suitable solvent to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of formula-3,

b) cyclization of compound of formula-3 in presence of a suitable reagent in a suitable solvent to provide 8-chlorodibenzo[b,fJoxepin-10(l lH)-one compound of formula-4,

c) reacting the compound of formula-4 with compound of formula-5 in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-ll-oxo-10,ll-dihydrodibenzo [b,f] oxepine-10-carboxylate compound of general formula-6,

d) reacting the compound of general formula-6 with nitromethane in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-ll-(nitromethylene)-10,1 l-dihydrodibenzo[b,fjoxepine-10-carboxylate compound of general formula-7,

e) reducing the compound of general formula-7 in-situ with a suitable reducing agent in a suitable solvent to provide alkyl ll-(aminomethyl)-2-chloro-10,ll-dihydrodibenzo [b,fjoxepine-10-carboxylate compound of general formula-8,

f) reacting the compound of general formula-8 with formaldehyde in a suitable solvent in presence of a suitable metal catalyst under hydrogen gas to provide alkyl 2-chloro-11 -((methylamino)methyl)-10,11 -dihydrodibenzo[b,f]oxepine-10-carboxylate compound of general formula-9,

g) cyclization of compound of general formula-9 in presence of a suitable reagent in a suitable solvent to provide trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo [2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-10,

h) reducing the compound of formula-10 with a suitable reducing agent and followed by treating it with maleic acid in a suitable solvent to provide (3&RS,2bRS)-5-chioro-2- methyl-2,3,3a,12b-tetrahydro-l//dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1,

i) optionally, purifying the compound of formula-1 from a suitable solvent to provide pure compound of formula-1.

The seventh aspect of the present invention is to provide an improved process for the preparation of (3a/?5,12b/?5)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l//dibenzo [2,3:6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1, comprising of:

a) Condensation of 2-(5-chloro-2-phenoxyphenyl)acetic acid compound of formula-11 with alkyl 2-(methylamino)acetate compound of general formula-12 or its salts in presence of a suitable condensing agent in a suitable solvent to provide alkyl 2-(2-(5-chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of general formula-13,

b) reacting the compound of general formula-13 in-situ with a suitable base in a suitable solvent provides 3-(5-chloro-2-phenoxyphenyl)-1 -methylpyrrolidine-2,4-dione compound of formula-14,

c) cyclisation of compound of formula-14 in presence of a suitable reagent in a suitable solvent to provide ll-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-15,

d) reducing the compound of formula-15 with magnesium in presence of catalytic amount of iodine in methanol, followed by treating with diazabicyclo[5.4.0]undec-7-ene (DBU) and acetic acid in a suitable solvent to provide (3aRS,12bRS)-trans-ll-chloro-2,3,3 a, 12b-tetrahydro-2-methyl-1 H-dibenzo[2,3,6,7]oxepino[4,5-c]pyrrol-1 -one compound of formula-16,

e) reducing the compound of formula-16 with a suitable reducing agent in a suitable solvent, followed by treating it with maleic acid in a suitable solvent to provide (3ai?1S',12bi?1S)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l//dibenzo[2,3:6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1,

f) optionally, purifying the compound obtained in step-(e) with a suitable solvent to provide pure compound of formula-1.

The eighth aspect of the present invention is to provide novel intermediate compounds which are useful in the preparation of (3a,12bJ?S)-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro- li/dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1.

Detailed description of the invention

The suitable solvents, wherever necessary, used in the present invention is selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; "hydrocarbon solvents" like toluene, xylene, hexane, heptane, cyclohexane and pet. ether; "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 isobutanol; "chloro solvents" like dichloromethane, dichloroethane, carbon tetrachloride and chloroform; polar solvents like water; and also mixtures thereof.

The term "base" herein the present invention is selected from inorganic bases like alkali metal, and alkaline earth metal alkoxides, hydroxides, carbonates and bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and organic bases like ammonia, triethylamine, tributyl amine, dimethyl aniline, N-methyl piperidine and N-methyl pyrrolidine, N-methyl morpholine, diisopropyl methylamine, diisopropyl amine, diisopropyl ethylamine, cyclohexyldimethyl amine, piperidine, dimethyl amino pyridine (DMAP), pyridine, lithium hexamethyldisilazide(LiHMDS), sodium hexamethyldisilazide (NaHMDS) and tetraalkyl ammonium hydroxide such as tetrabutyl ammonium hydroxide.

The suitable reducing agent can be selected from but not limited to transition metals in presence of hydrogen gas like Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and hydroxides and combination thereof, Raney nickel, palladium catalyst such as Pd/C, Pd/SrC03, Pd/Al203, Pd/MgO, Pd/CaC03, Pd/ BaS04j PdO, PdCl2, Rh/C, Ru/C, Re/C, Pt02, Rh/C, Ru02; Metal catalyst in presence of acids like Fe/AcOH, Zn/NaOH, Fe/HCl, Sn/HCl and the like; BrVetherate/sodium borohydride; lithium aluminium hydride (LAH); vitride; sodium borohydride/ aluminium chloride; borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN.

The suitable condensing agents selected from carbodiimides such as N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC), N^-dicyclohexyl carbodiimide (DCC); 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), di phenylphosphoroazidate (DPPA), P205, 3-(diethoxyphosphoryloxy)-l,2,3-benzotriazine-4(3H)-one (DEPBT), N,N'-carbonyl diimidazole. The carbodiimides can be used optionally in combination with 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HOAt), l-hydroxy-lH-1,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu) and organic base; alkyl or aryl halo formates.

Throughout this disclosure, compounds represented by R-substituted general formulas, wherein, 'R' is selected from CM2 straight chain or branched chain alkyl, aryl, cyclo alkyl and aryl-Ci_6 alkyl;

As used herein, the term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms. A "C1.12 alkyl" refers to alkyl group having 1 to 12 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl and the like.

As used herein, the term "cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring i.e C3.7 cycloalkyl refers to a cycloalkyl group having 3,4,5,6 and 7 carbon atoms as ring members.
As used herein, the term "aryl-Ci-6 alkyl" refers to an aryl group attached to the substrate through an alkyl group containing one to six carbon atoms. The term "aryl" refers to monovalent or divalent aromatic groups respectively including 5 and 6 membered monocyclic aromatic groups that contain zero to four heteroatom independently selected from nitrogen, oxygen and sulfur. The aryl groups also include bicyclic groups, tricyclic groups etc including fused 5 and 6 membered rings described above.

As used herein, the term "salt" refers to inorganic acids such as hydrochloric acid, hydro bromic acid, sulfuric acid, nitric acid and the like.

The first aspect of the present invention is to provide a novel process for the preparation of alkyl 2-chloro-ll-oxo-10,ll-dihydrodibenzo[b,fj oxepine-10-carboxylate compound of general formula-6, which comprises of,

a) Condensation of 2-(2-chlorophenyl)acetic acid compound of formula-2 with 4-chloro phenol in presence of CuCl catalyst and a suitable base in a suitable solvent to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of formula-3,

b) cyclization of compound of formula-3 in presence of a suitable reagent in a suitable solvent to provide 8-chlorodibenzo[b,f]oxepin-10(l lH)-one compound of formula-4,

c) reacting the compound of formula-4 with compound of formula-5 in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-ll-oxo-10,ll-dihydro dibenzo[b,f]oxepine-l 0-carboxylate compound of general formula-6.

Wherein, in step-a) & c) the suitable solvent used is selected from hydrocarbon solvents like toluene, xylene, hexane, heptane, cyclohexane and pet.ether;

in step-b) the suitable reagent used is selected from polyphosphoric acid or P2O5 or
phosphoric acid in xylene; the solvent used is chloro solvents like dichloromethane, dichloroethane, carbon tetrachloride and chloroform;

in step-a) & c) the suitable base used is selected from alkali metal, and alkaline earth metal alkoxides, hydroxides, carbonates and bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate;

The second aspect of the present invention is to provide a novel process for the preparation of alkyl 2-chloro-ll-oxo-10,ll-dihydrodibenzo[b,fJ oxepine-10-carboxylate compound of formula-6, which comprising of, reacting the 8-chloro dibenzo[b,fJoxepin-10(llH)-one compound of formula-4 with compound of formula-5 in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-l 1-oxo-10,11-dihydrodibenzo[b,fjoxepine-10-carboxylate compound of general formula-6.

The third aspect of the present invention is to provide a novel process for the preparation of alkyl 2-chloro-l l-((methylamino)methyl)-10,ll-dihydrodibenzo[b,fj oxepine-10-carboxylate compound of general formula-9, which comprises of,

a) Reacting alkyl 2-chloro-11 -oxo-10,11 -dihydrodibenzo[b,fJoxepine-10-carboxylate compound of general formula-6 with nitromethane in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-l l-(nitromethylene)-10,ll-dihydro dibenzo[b,f]oxepine-l 0-carboxylate compound of general formula-7,

b) reducing the compound of general formula-7 in-situ with a suitable reducing agent in a suitable solvent to provide alkyl ll-(aminomethyl)-2-chloro-10,ll-dihydro dibenzo[b,fjoxepine-10-carboxylate compound of general formula-8,

c) reacting the compound of general formula-8 with formaldehyde in a suitable solvent in presence of a suitable metal catalyst under hydrogen gas to provide alkyl 2-chloro-11 -((methylamino)methyl)-10,11 -dihydrodibenzo[b,fjoxepine-10-carboxylate compound of general formula-9. Wherein, in step-a) the suitable base used is as defined above;

in step a) to c) the suitable solvent used is selected from alcoholic solvents; in step-b) the suitable reducing agent used is selected from but not limited to transition metals in presence of hydrogen gas like Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, Raney nickel, palladium catalyst such as Pd/C, Pd/SrC03> Pd/Al203s Pd/MgO, Pd/CaC03, Pd/ BaS04> PdO, Pd Black, PdCl2, Rh/C, Ru/C, Re/C, Pt02, Rh/C, Ru02; Metal catalyst in presence of acids like Fe/AcOH, Zn/NaOH, Fe/HCl, Sn/HCl and the like; in step-c) the metal catalyst used is Raney-Ni or Pd/C;

The fourth aspect of the present invention is to provide a one-pot process for the preparation of alkyl ll-(aminomethyl)-2-chloro-10,ll-dihydrodibenzo[b,fj oxepine-10-carboxylate compound of general formula-8, comprises of,

a) Reacting alkyl 2-chloro-11 -oxo-10,11 -dihydrodibenzo[b,fJoxepine-10-carboxylate compound of general formula-6 with nitromethane in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-ll-(nitromethylene)-10,ll-dihydrodibenzo[b,fjoxepine-l 0-carboxylate compound of general formula-7,

b) reducing the compound of general formula-7 in-situ with a suitable reducing agent in a suitable solvent to provide alkyl ll-(aminomethyl)-2-chloro-10,ll-dihydrodibenzo [b,f]oxepine-l0-carboxylate compound of general formula-8.

Wherein, in step-a) the suitable base used is defined as above; in step a) & b) the suitable solvent used is selected from alcoholic solvents; in step-b) the suitable reducing agent used is as defined above;

The fifth aspect of the present invention is to provide a novel process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7] oxepino [4,5-c]pyrroI-l-one compound of formula-10, which comprises of, cyclization of alkyl 2-chloro-11 -((methylamino)methyl)-10,11 -dihydrodibenzo[b,fjoxepine-10- carboxylate compound of general formula-9 in presence of a suitable reagent in a suitable solvent to provide trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10.

Wherein, the suitable solvent used is selected from alcoholic solvents; and the suitable reagent used is sodium methoxide.

The sixth aspect of the present invention is to provide a novel process for the preparation of (3aitS',12bi?5)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-li/dibenzo[2,3: 6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1, which comprises of,

a) Condensation of 2-(2-chlorophenyl)acetic acid compound of formula-2 with 4-chloro phenol in presence of CuCl catalyst and a suitable base in a suitable solvent to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of formula-3,

b) cyclization of compound of formula-3 in presence of a suitable reagent in a suitable solvent to provide 8-chlorodibenzo[b,fJoxepin-10(llH)-one compound of formula-4,

c) reacting the compound of formula-4 with compound of formula-5 in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-ll-oxo-10,ll-dihydro dibenzo[b,f] oxepine-10-carboxylate compound of general formula-6,

d) reacting the compound of general formula-6 with nitromethane in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-ll-(nitromethylene)-10,1 l-dihydrodibenzo[b,fjoxepine-10-carboxylate compound of general formula-7,

e) reducing the compound of general formula-7 in-situ with a suitable reducing agent in a suitable solvent to provide alkyl 11-(amino methyl)-2-chloro-10,ll-dihydrodibenzo [b,f]oxepine-10-carboxylate compound of general formula-8,

f) reacting the compound of general formula-8 with formaldehyde in a suitable solvent in presence of a suitable metal catalyst under hydrogen gas to provide alkyl 2-chloro-11 -((methylamino)methyl)-10,11 -dihydrodibenzo[b,fjoxepine-10-carboxylate compound of general formula-9,

g) cyclization of compound of general formula-9 in presence of a suitable reagent in a suitable solvent to provide trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo [2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-10,

h) reducing the compound of formula-10 with a suitable reducing agent and treating it with maleic acid in a suitable solvent, followed by recrystallization from a suitable

solvent to provide (3ai?5,12bi?1S)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-li/ dibenzo[2,3:6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1.

Wherein, in step-a) & c) the solvent used is selected from hydrocarbon solvents; in step-b) the suitable reagent used is selected from polyphosphoric acid or P2O5 or phosphoric acid in xylene; the solvent is chloro solvents like dichloromethane, dichloroethane, carbon tetrachloride and chloroform;

in step-a), c) & d) the suitable base used is as defined above;

in step d) to g) the solvent used is selected from alcoholic solvents;

in step-e) the suitable reducing agent used is as defined above;

in step-f) the metal catalyst used is Raney-Ni or Pd/C;

in step-g) the suitable reagent used is sodium methoxide; and

in step-h) the suitable reducing agent used is selected from BF3-etherate/sodium borohydride, lithium aluminium hydride (LAH), vitride, sodium borohydride/ aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN; and the solvent is selected from ether solvents, hydrocarbon solvents and alcoholic solvents;
The above aspects of the present invention are represented in scheme-1.


The seventh aspect of the present invention is to provide an improved process for the preparation of (3a/?5',12b-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l/fdibenzo [2,3: 6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1, comprising of:
a) Condensation of 2-(5-chloro-2-phenoxyphenyl)acetic acid compound of formula-11 with alkyl 2-(methylamino)acetate compound of general formula-12 or its salts in presence of a suitable condensing agent in a suitable solvent to provide alkyl 2-(2-(5-chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of general formula-13,

b) reacting the compound of general formula-13 in-situ in presence of a suitable base in a suitable solvent to provide 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione compound of formula-14,

c) cyclisation of compound of formula-14 in presence of a suitable reagent in a suitable solvent to provide ll-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-15,

d) reducing the compound of formula-15 with magnesium in presence of catalytic amount of iodine in methanol, followed by treating with diazabicyclo[5.4.0]undec-7-ene (DBU) and acetic acid in a suitable solvent to provide (3aRS,12bRS)-trans-ll-chloro-2,3,3 a, 12b-tetrahydro-2-methyl-1 H-dibenzo[2,3,6,7]oxepino[4,5-c]pyrrol-1 -one compound of formula-16,

e) reducing the compound of formula-16 with a suitable reducing agent in a suitable solvent, followed by treating it with maleic acid in a suitable solvent to provide (3ai?5',12bi?5)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l/Wibenzo[2,3:6,7]oxepino [4,5-c]pyrrole (2Z)-butenedioate compound of formula-1,

f) optionally, purifying the compound obtained in step-(e) with a suitable solvent to provide pure compound of formula-1.

Wherein, in step-a) the suitable condensing agent used is dicyclohexyl carbodiimide (DCC) in the presence of a base; and the salt is selected from hydrochloric acid, hydro bromic acid, sulfuric acid, nitric acid and the like;

in step-b) the suitable base used is defined as above;

in step-a, b & d) the suitable solvent used is hydrocarbon solvents;

in step-c) the suitable reagent used is selected from polyphosphoric acid or P2O5 or
phosphoric acid in xylene; the solvent used is selected from chloro solvents and
alcoholic solvents;

in step e) the suitable reducing agent is same as defined in step-(h) of sixth aspect;
in step e) & f) the suitable solvent used is selected from hydrocarbon solvents, ether solvents and alcoholic solvents.

In a preferred embodiment of the present invention to provide an improved process for the preparation of (3ai?5,,12bi?5)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l//dibenzo [2,3: 6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1, comprising of:
a) Condensation of 2-(5-chloro-2-phenoxyphenyl)acetic acid compound of formula-11
with methyl 2-(methylamino)acetate hydrochloride compound of formula-12a

in presence of dicyclohexyl carbodiimide (DCC) and triethylamine in toluene to provide methyl 2-(2-(5-chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of formula-13 a,
b) reacting the compound of formula- 13a

in-situ in presence of potassium tert-butoxide in toluene to provide 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione compound of formula-14,

c) cyclisation of compound of formula-14 with polyphosphoric acid or P2O5 and phosphoric acid to provide ll-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-15,

d) reducing the compound of formula-15 with magnesium in presence of catalytic amount of iodine in methanol, followed by reacting the obtained racemic mixture in presence of Diazabicyclo[5.4.0]undec-7-ene (DBU) and acetic acid in toluene to provide (3 aRS, 12bRS)-trans-11 -chloro-2,3,3 a, 12b-tetrahydro-2-methyl-1 H-dibenzo [2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-16,

e) reducing the compound of formula-16 with lithium aluminium hydride and aluminium chloride in tetrahydrofuran, followed by treating it with maleic acid in isopropyl alcohol to provide (3ai?5',12bitS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l//dibenzo[2,3:6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-
1,
f) optionally, purifying the compound obtained in step-e) from ethanol to provide pure
(3a7?5',12bi?5)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l//dibenzo [2,3:6,7]oxepino
[4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1.

The above aspect of the present invention is represented in scheme-2.

The eighth aspect of the present invention is to provide novel intermediate compounds having the following structural formulas:

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 2-(2-(4-chlorophenoxy)phenyl)acetic acid (formula-3):

Potassium carbonate (109 gm) was charged into a clean and dry RBF at below 20°C under N2 atmosphere. To this toluene (400 ml) and 4-chloro phenol (56.5 gm) were added at the same temperature. To the resulting mixture 0.5 gm of CuCl was added at 20°C and the temperature of the reaction mixture was slowly raised to 100°C. To this 2-chloro phenyl acetic acid (50 gm) was added at 100°C and the obtained mixture was stirred for 1 hr at the same temperature. The reaction mixture was refluxed for 8 hrs at 110°C. K2CO3 (80 gm) was added to the resulting mixture and stirred for 12 hrs at the same temperature. Then the reaction mixture was cooled to room temperature and water was added. The resulting mixture was acidified with HC1 and again water was added. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both the organic layers were combined and washed with 10% NaCl solution. The resulting organic layer was dried over Na2S04 and the solvent was completely distilled off under reduced pressure at below 60°C. n-heptane (50 ml) was added to the obtained residue and stirred for 30-45 min at 25-35°C. The obtained solid was filtered, washed with n-heptane and then dried to get the title compound. Yield: 65 g.

Example-2: Preparation of 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione (formula-14)

A solution of methyl 2-(methylamino)acetate.HCl compound of formula-12a (79.5 g), triethylamine (58 g) and toluene (300 ml) to a reaction mixture of 2-(5-chloro-2-phenoxyphenyl)acetic acid compound of formula-11 (100 g) and toluene (300 ml) at 25-30°C over a period of 60 minutes. A solution of dicyclohexylcarbodiimide (78.4 g) and toluene (200 ml) was added to the reaction mixture and stirred for 2 hours at 25-30°C. After completion of the reaction, the reaction mixture was filtered and washed with toluene. The obtained filtrate was added to a pre-cooled mixture of toluene (200 ml) and potassium tertiary butoxide (64 g) at 20-25°C over a period of 2 hours and then stirred for 2 hours at 20-25°C. After completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes. Both the organic and aqueous layers were separated and washed the aqueous layer with toluene. The pH of the aqueous layer was adjusted to 1.5 using 50% hydrochloric acid and stirred for 2 hours. Filtered the obtained solid, washed with water and then dried to get the title compound. Yield: 75 g Example-3: Preparation of H-chIoro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino [4,5-c] pyrrol-1 -one (formula-15)

A mixture of ortho phosphoric acid (300 g) and phosphorous pentoxide (300 g) was heated to 110-115°C and then stirred for 2 hours. To the above reaction mixture 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione compound of formula-14 (100 g) was added at 110-115°C and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to 25-35°C and the reaction mixture was poured into chilled water. Dichloromethane was added to the reaction mixture and stirred for 25 minutes. Both the dichloromethane and aqueous layers were separated. The aqueous layer was extracted with dichloromethane and both the dichloromethane layers were combined and washed with 10% sodium bicarbonate solution (until pH of the reaction mixture reaches to 7.5) followed by sodium chloride solution. Distilled off the solvent completely from the dichloromethane layer and co-distilled with methanol. Methanol (200 ml) was added to the obtained residue and cooled to -15 to -10°C and stirred for 2 hours. Filtered the precipitated solid, washed with methanol and then dried to get title compound. Yield: 60 g; M.R: 164.5-170 °C.

Example-4: Preparation of (3aRS,12bRS)-trans-ll-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo [2,3,6,7]oxepino[4,5-c]pyrrol-l-one (formula-16)

11 -chloro-2,3 -dihydro-2-methyl-1 H-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-1 -one (40 grams) was added to a mixture of magnesium(16 grams) and iodine (0.8 grams) and 1000 ml of methanol at 25-30°C under nitrogen atmosphere and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction mixture was heated to reflux temperature and stirred for 2 hrs at the same temperature. After completion of the reaction, 30% of the solvent was distilled off under reduced pressure. The reaction mixture was cooled to 10-15°C and water was added to it. The pH of the reaction mixture was adjusted to 6.5 using 20% dil. HC1 solution at 10-15°C. Ethyl acetate was added to the reaction mixture at 10-15°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined and washed with 10% sodium
chloride solution. Distilled off the organic layer under reduced pressure. Isopropanol (80 ml) was added to the obtained residue and cooled to 0-5°C. The reaction mixture was stirred for 2 hrs at 0-5°C. The precipitated product was filtered, washed with isopropyl alcohol and then dried to get the racemic compound.

Toluene (360 ml) was added to the above obtained compound at 25-30°C. The reaction mixture was cooled to 15-20°C and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (6.35 gm) was added to it at the same temperature. The temperature of the reaction mixture was raised to 25-30°C and stirred for 6 hrs at the same temperature. Water was added to the reaction mixture and the pH of the reaction mixture was adjusted to 4.0 with acetic acid. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both the organic layers were combined and washed with water. The solvent was completely distilled off from the organic layer under reduced pressure. Methanol (200 ml) was added to the obtained residue and the reaction mixture was heated to reflux and stirred for 30 min at the same temperature. The resulting mixture was cooled to 25-30°C and stirred for 30 min at the same temperature. The reaction mixture was further cooled to 0-5°C and stirred for 30 min at 0-5°C. The obtained solid was filtered, washed with methanol and then dried at 45-50°C to get the title compound. Yield: 18 grams.

Example-5: Preparation of (3aR5',12bJR5)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-Lffdibenzo [2,3:6,7] oxepino[4,5-c] pyrrole (2Z)-2-butenedioate (Formula-1)

Tetrahydrofuran (1460 ml) was charged into a clean and dry RBF at 25-30°C and cooled to -20 to -15°C under nitrogen atmosphere. Aluminium chloride (69.0 gm) was added to tetrahydrofuran at -20 to -15°C under nitrogen atmosphere and stirred for 30 min at the same temperature. 4% lithium aluminium hydride solution (340 ml) was slowly added to the reaction mixture at -20 to -10°C under nitrogen atmosphere over a period of 90 min and stirred the reaction mixture for 30 mins at the same temperature. A solution of compound of formula-16 (100 gm of compound of formula-16 in 1000 ml of tetrahydrofuran) was added to the reaction mixture at -15 to -10°C over a period of 3 hrs and stirred for 60 min at the same temperature. After completion of the reaction, the reaction mixture was quenched with a mixture of tetrahydrofuran and water at -15 to -10°C under nitrogen blanket. 2.4% NaOH solution was slowly added to the reactionmixture under nitrogen atmosphere at -15 to -10°C and stirred for 60 min at the same temperature. The temperature of the reaction mixture was raised to 20-25°C and stirred for 30 min at the same temperature. The reaction mixture was filtered through hyflow bed and washed with toluene. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both the organic layers were combined and washed with water. The solvent was completely distilled off from the organic layer under reduced pressure. The temperature of the obtained residue was reduced to 40-45 °C and isopropanol (300 ml) was added to it at the same temperature. Maleic acid (42 gm) was added to the resulting mixture and the temperature of the reaction mixture was raised to 60-65°C. Then the reaction mixture was gradually cooled to 40-45°C and seeded with compound of formula-1. The temperature of the reaction mixture was then reduced to 25-30°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture further to -5 to 0°C and stirred for 2 hrs at the same temperature. The precipitated product was filtered, washed with chilled isopropyl alcohol and then dried to get title compound. Yield: 110 grams. The PXRD of the obtained compound matches with the prior art crystalline form-H of asenapine maleate. Example-6: Purification of compound of Formula-1

A mixture of absolute ethanol (500 ml) and compound of formula-1 (100 gm) was heated to 60-65°C. Stirred the reaction mixture for 30 min at 60-65°C. Carbon (9.0 gm) was added to the reaction mixture at 60-65°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethanol. The filtrate was cooled to 20-25°C and stirred for 3 hrs at the same temperature. The reaction mixture was further cooled to -15 to -10°C. The obtained solid was filtered, washed with ethanol and then dried to get pure compound of formula-1. Yield: 90.5 grams. The PXRD of the obtained compound matches with the prior art crystalline form-H of asenapine maleate. Example-7: Preparation of 8-chlorodibenzo[b,f]oxepin-10(llH)-one (Formula-4)

A mixture of 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of formula-3 (100 g) and polyphosphoric acid (300 g) was heated to 90-95°C and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 50-60°C. The reaction mixture was poured into water and stirred for 2 hours at 25-30°C. Dichloromethane was added to the reaction mixture and stirred for 30 minutes at 25-30°C. Both the organic and aqueous layers were separated, the organic layer was washed with 10% sodium bicarbonate solution followed by 10% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with methanol. Methanol (200 ml) was added to the reaction mixture, cooled to -15 to -10°C and then stirred for 2 hours. Filtered the precipitated solid and then dried to get title compound. Yield: 43 g Example-8: Preparation of Ethyl 2-chloro-ll-oxo-10,ll-dihydrodibenzo [b,f] oxepine-10-carboxylate (Formula-6b)

A solution of ethyl chloroformate (44.35 g) and toluene (100 ml) was added to a mixture of 8-chlorodibenzo[b,fjoxepin-10(11 H)-one compound of formula-4 (100 g) and toluene (500 ml) at 25-30°C and stirred for 2 hours at 25-30°C. After completion of the reaction, water was added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated, the organic layer was washed with 10% sodium chloride solution and then distilled off the solvent from the organic layer under reduced pressure to provide compound of formula-6b. Yield: 77.67 g ExampIe-9: Preparation of Methyl 2-chIoro-ll-oxo-10,H-dihydrodibenzo[b,fJ oxepine-10-carboxylate (Formula-6a)

The Methyl 2-chloro-11 -oxo-10,11 -dihydrodibenzo[b,f]oxepine-10-carboxylate compound of formula-6a was obtained by repeating the process disclosed in example-8 by taking methyl chloroformate (38.62 g) in place of ethyl chloroformate from 8-chlorodibenzo[b,fjoxepin-10(l lH)-one compound of formula-4 (100 g). Yield: 74.22 g Example-10: Preparation of Ethyl 11-(amino methyl)-2-chloro-10,ll-dihydro dibenzo[b,f]oxepine-10-carboxylate (Formula-8b)
A mixture of Ethyl 2-chloro-11-oxo-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylate compound of formula-6b (25 g), sodium hydroxide (3.2 g), nitro methane (4.9 g) and methanol (100 ml) was stirred for 3 hours at 25-30°C. After completion of the reaction, the reaction mixture was poured into autoclave vessel and Raney nickel (7.5 g) was added to it. Hydrogen gas with a pressure of 3 Kg/cm2 was applied to the reaction mixture and stirred for 6 hours at 25-30°C. After completion of the reaction, the reaction mixture was filtered through hyflow bed and the solvent from the obtained filtrate was distilled under reduced pressure to get title compound. Yield: 20 g

Example-11: Preparation of Methyl ll-(aminomethyl)-2-chloro-10,ll-dihydro dibenzo[b,fJ oxepine-10-carboxylate (Formula-8a)

The Methyl 2-chloro-11 -(nitromethylene)-10,11 -dihydrodibenzo[b,fjoxepine-10-carboxylate compound of formula-8a was obtained by repeating the process described in example-10 by taking methyl 2-chloro-11 -oxo-10,11 -dihydrodibenzo[b,f]oxepine-10-carboxylate compound of formula-6a (25 g) as a starting material. Yield: 19 g Example-12: Preparation of Ethyl 2-chloro-ll-(nitromethylene)-10,ll-dihydro dibenzo[b,fJ oxepine-10-carboxylate (Formula-7b)

A mixture of Ethyl 2-chloro-11-oxo-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylate compound of formula-6b (25 g), sodium hydroxide (3.2 g), nitro methane (4.9 g) and methanol (100 ml) was stirred for 3 hours at 25-30°C. After completion of the reaction, the solvent from the reaction mixture was distilled off to get title compound. Yield: 19.87 g

Example-13: Preparation of Methyl 2-chloro-ll-(nitromethylene)-10,H-dihydrodibenzo[b,f] oxepine-10-carboxylate (Formula-7a)

The Methyl 2-chloro-11 -(nitromethylene)-10,11 -dihydrodibenzo[b,fjoxepine-10-carboxylate compound of formula-7a was obtained by repeating the process described in example-12 by taking methyl 2-chloro-11-oxo-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylate compound of formula-6a (25 g) as a starting material. Yield: 19.98 g. Example-14: Preparation of Ethyl ll-(amino methyl)-2-chloro-10,ll-dihydrodibenzo[b,f]oxepine-10-carboxylate (Formula-8b)

A mixture of Ethyl 2-chloro-11-(nitromethylene)-10,ll-dihydrodibenzo[b,fJ oxepine-10-carboxylate compound of formula-7b (25 g) and methanol (250 ml) was charged into autoclave vessel and Raney nickel (7.5 g) was added to it. Hydrogen gas with a pressure of 3 Kg/cm was applied to the reaction mixture and stirred for 6 hours at 25-30°C. After completion of the reaction, the reaction mixture was filtered through hyflow bed and the solvent from the obtained filtrate was distilled under reduced pressure to get title compound. Yield: 16.13 g Example-15: Preparation of Methyl ll-(amino methyl)-2-chloro-10,ll- dihydrodibenzo[b,f]oxepine-10-carboxylate(Formula-8a)

The title compound was obtained by repeating the process described in example-14 by taking methyl 2-chloro-ll-(nitromethylene)-10,ll-dihydrodibenzo [b,f] oxepine-10-carboxylate compound of formula-7a (25 g) as a starting material. Yield: 16.08 g Example-16: Preparation of Ethyl 2-chloro-ll-((methylamino)methyl)-10,ll-dihydrodibenzo[b,f] oxepine-10-carboxylate (Formula-9b)

To a mixture of Ethyl 11-(amino methyl)-2-chloro-10,ll-dihydrodibenzo [b,fjoxepine-10-carboxylate compound of formula-8b (20 g), Raney nickel (6 g) and methanol (100 ml), hydrogen gas with a pressure of kg/cm2 was applied and stirred for 6 hours at 25-30°C. After completion of the reaction, the reaction mixture was filtered through hyflow bed and the solvent from the obtained filtrate was distilled under reduced pressure to get title compound. Yield: 15.2 g.

Example-17: Preparation of Methyl 2-chloro-ll-((methylamino)methyl)-10,ll-dihydrodibenzo [b,f]oxepine-10-carboxylate(Formula-9a)

The Methyl 2-chloro-11 -((methylamino)methyl)-10,11 –dihydrodibenzo [b,fjoxepine-10-carboxylate compound of formula-9a was obtained by repeating the process described in example-16 by taking the methyl 11-(amino methyl)-2-chloro-10,l 1-dihydrodibenzo[b,fjoxepine-10-carboxylate compound of formula-8a (20 g) in place of compound of formula-8b. Yield: 15 g

Example-18: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7] oxepino[4,5-c]pyrrol-l-one (Formula-10)

A mixture of Ethyl 2-chloro-ll-((methylamino)methyl)-l 0,11-dihydrodibenzo [b,fjoxepine-10-carboxylate compound of formula-9b (15 g), sodium methoxide (2.34 g) and methanol (150 ml) was stirred for 2 hours at 25-30°C. After completion of the reaction, water followed by dichloromethane were added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated, the organic layer was washed with water and then distilled under reduced pressure to get title compound. Yield: 12 g.

Example-19: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7] oxepino[4,5-c]pyrrol-l-one (Formula-10)

The compound of formula-10 was obtained by repeating the process described in example-18 by taking methyl 2-chloro-ll-((methylamino)methyl)-10,ll-dihydrodibenzo[b,f]oxepine-10-carboxylate compound of formula-9a (15 g) as a starting material. Yield: 12.46 g

Example-20: Preparation of (3aJ?5,12bi?S)-5-Chloro-2-methyl-2,3,3a,12b-tetra hydro-Lffdibenzo [2,3:6,7] oxepino[4,5-c] pyrrole maleate compound of formula-1
The compound of formula-1 can be obtained by repeating the process described in above example-5 by taking the trans-5-cMoro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10 (100 g) as a staring material. Yield: 95 g.
Example-21: Preparation of methyl 2-chloro-ll-cyanodibenzo[b,f]oxepine-10-carboxylate (Formula-17a)

A mixture of methyl 2-chloro-ll-oxo-10,ll-dihydrodibenzo[b,fJoxepine-10-carboxylate compound of formula-6a (25 g), acetone cyanohydrin (7.6 g), triethylamine (8.09 g) and methanol (250 ml) was stirred for 3 hours at 0-5°C. After completion of the reaction, the reaction mixture was quenched with aq.hydrochloric acid. The reaction mixture was extracted with dichloromethane. Both the organic and aqueous layers were separated and the solvent from organic layer was distilled off to get title compound. Yield: 17.1 g.

Example-22: Preparation of Methyl ll-(amino methyl)-2-chloro-10,ll-dihydro dibenzo[b,f]oxepine-10-carboxylate(Formula-8a)

A mixture of methyl 2-chloro-ll-cyanodibenzo[b,fJoxepine-10-carboxylate compound of formula-17a (5 g), methanol (50 ml) was charged into autoclave vessel and 5% Pd/C (7.5 g) was added to it. Hydrogen gas with a pressure of 4 kg/cm2 was applied to the reaction mixture and stirred for 4 hours at 25-30°C. After completion of the reaction, the reaction mixture was filtered through hyflow bed. Acidifying the filtrate with aq. HC1 provides title compound as a hydrochloride salt. Yield: 2.1 g

We Claim:

1. A process for the preparation of of formula-1, comprising of: a) Condensation of 2-(5-chloro-2-phenoxyphenyl)acetic acid compound of formula-11

with alkyl 2-(methylamino)acetate compound of general formula-12 or its salts wherein, 'R' is Ci.g straight chain or branched chain alkyl; and the salt is selected from hydrochloric acid, hydro bromic acid, sulfuric acid and nitric acid; in presence of a suitable condensing agent in a suitable solvent to provide alkyl 2-(2-(5-chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of general formula-13, b) reacting the compound of general formula-13

Formula-13 wherein, 'R' is Ci_8 straight chain or branched chain alkyl; in-situ in presence of a suitable base in a suitable solvent to provide 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione compound of formula-14,


c) cyclisation of compound of formula-14 in presence of a suitable reagent in a suitable solvent to provide ll-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5- c]pyrrol-l-one compound of formula-15,

d) reducing the compound of formula-15 with magnesium in presence of catalytic amount of iodine in methanol, followed by treating with diazabicyclo[5.4.0]undec-7-ene (DBU) and acetic acid in a suitable solvent to provide (3aRS,12bRS)-trans-ll-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-16,

e) reducing the compound of formula-16 with a suitable reducing agent in a suitable solvent, followed by treating it with maleic acid in a suitable solvent to provide (3ai?5,12bi?5)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-li/dibenzo[2,3:6,7]oxepino [4,5-c]pyrrole (2Z)-butenedioate compound of formula-1,

f) optionally, purifying the compound obtained in step-(e) with a suitable solvent to provide pure compound of formula-1.

2. The process according to claim-1, wherein in step-a) the suitable condensing agent is selected from carbodiimides, 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate, di phenyl phosphoroazidate, P205, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one and N,N'-carbonyldiimidazole. The carbodiimides can be used optionally in combination with 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HO At), 1-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu) and organic base;

in step-b) the suitable base used is selected from alkali metal, and alkaline earth metal
alkoxides, hydroxides, carbonates and bicarbonates; in step-a, b & d) the suitable solvent used is hydrocarbon solvents; in step-c) the suitable reagent used is selected from polyphosphoric acid or P2O5 or phosphoric acid in xylene; the solvent used is selected from chloro solvents and
alcoholic solvents; in step e) the suitable reducing agent is selected from BF3-etherate/sodium
borohydride, lithium aluminium hydride (LAH), vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN; in step e) & f) the suitable solvent used is selected from hydrocarbon solvents, ether solvents and alcoholic solvents.

3. A process for the preparation of (3a/?1S',12bJ?6)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-li/dibenzo[2,3: 6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1, comprising of:

a) Condensation of 2-(5-chloro-2-phenoxyphenyl)acetic acid compound of formula-11 with methyl 2-(methylamino)acetate hydrochloride compound of formula-12a in presence of dicyclohexyl carbodiimide (DCC) and triethylamine in toluene to provide methyl 2-(2-(5-chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of formula- 13 a,

b) reacting the compound of formula- 13a in-situ in presence of potassium tert-butoxide in toluene to provide 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione compound of formula-14,

c) cyclisation of compound of formula-14 with polyphosphoric acid or P2O5 and phosphoric acid to provide ll-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-15,

d) reducing the compound of formula-15 with magnesium in presence of catalytic amount of iodine in methanol, followed by reacting the obtained racemic mixture in presence of Diazabicyclo[5.4.0]undec-7-ene (DBU) and acetic acid in toluene to provide (3aRS, 12bRS)-trans-11 -chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenzo [2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-16,

e) reducing the compound of formula-16 with lithium aluminium hydride and aluminium chloride in tetrahydrofuran, followed by treating it with maleic acid in isopropyl alcohol to provide (3a/?5',12biiS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-l//dibenzo[2,3:6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1,

f) purifying the compound obtained in step-e) from ethanol to provide pure
(Saibi-S-chloro-methyl.S b-tetrahydro-liydibenzo [2,3:6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1.

4. A process for the preparation of alkyl 2-(2-(5-chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of general formula-13, comprising of condensing the 2-(5-chloro-2-phenoxyphenyl)acetic acid compound of formula-11 with alkyl 2-(methylamino)acetate compound of general formula-12 or its salts in presence of a suitable condensing agent in a suitable solvent to provide alkyl 2-(2-(5-chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of general formula-13.

5. A process for the preparation of methyl 2-(2-(5-chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of formula-13a comprising of condensation of 2-(5-chloro-2-phenoxyphenyl)acetic acid compound of formula-11 with methyl 2-(methylamino)acetate hydrochloride compound of formula-12a in presence of dicyclohexyl carbodiimide (DCC) and triethylamine in toluene to provide methyl 2-(2-(5-chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of formula-13a.

6. One-pot process for the preparation of 3-(5-chloro-2-phenoxyphenyl)-l-
methylpyrrolidine-2,4-dione compound of formula-14, comprising of:

a) Condensing the 2-(5-chloro-2-phenoxyphenyl)acetic acid compound of formula-11 with alkyl 2-(methylamino)acetate compound of general formula-12 or its salts in presence of a suitable condensing agent in a suitable solvent to provide alkyl 2-(2-(5- chloro-2-phenoxyphenyl)-N-methylacetamido)acetate compound of general formula-
13,

b) reacting the compound of general formula-13 in-situ with a suitable base in a suitable solvent to provide 3-(5-chloro-2-phenoxyphenyl)-l-methylpyrrolidine-2,4-dione compound of formula-14.

7. The 1 l-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-15 as a solid.

8. The process for the preparation of ll-chloro-2,3-dihydro-2-methyl-lH-dibenz [2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-15 comprising of:

a) Adding alcoholic solvent to the compound of formula-15 at room temperature,
b) cooling the reaction mixture to -15 to -10°C,
c) stirring the reaction mixture,
d) filtering the precipitated solid and then drying to get compound of formula-15.

9. A novel process for the preparation of (3a/?5,12bi?5)-5-chloro-2-methyl-2,3,3a,12b- tetrahydro-l//dibenzo[2,3: 6,7]oxepino [4,5-c]pyrroIe (2Z)-2-butenedioate compound of formula-1, which comprises of,

a) Condensation of 2-(2-chlorophenyl)acetic acid compound of formula-2 with 4-chloro phenol in presence of CuCl catalyst and a suitable base in a suitable solvent to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of formula-3,

b) cyclization of compound of formula-3 in presence of a suitable reagent in a suitable solvent to provide 8-chlorodibenzo[b,fJoxepin-10(llH)-one compound of formula-4,

c) reacting the compound of formula-4 with compound of formula-5 in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-ll-oxo-10,ll-dihydro dibenzo[b,fJ oxepine-10-carboxylate compound of general formula-6,

d) reacting the compound of general formula-6 with nitromethane in presence of a suitable base in a suitable solvent to provide alkyl 2-chloro-ll-(nitromethylene)- 10,1 l-dihydrodibenzo[b,fjoxepine-10-carboxylate compound of general formula-7,

e) reducing the compound of general formula-7 in-situ with a suitable reducing agent in a suitable solvent to provide alkyl 11-(amino methyl)-2-chloro-10,l 1-dihydrodibenzo [b,fjoxepine-10-carboxylate compound of general formula-8,

f) reacting the compound of general formula-8 with formaldehyde in a suitable solvent in presence of a suitable metal catalyst under hydrogen gas to provide alkyl 2-chloro-11 -((methylamino)methyl)-10,11 -dihydrodibenzo[b,fjoxepine-10-carboxylate compound of general formula-9,

g) cyclization of compound of general formula-9 in presence of a suitable reagent in a suitable solvent to provide trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10,

h) reducing the compound of formula-10 with a suitable reducing agent and treating it with maleic acid in a suitable solvent, followed by recrystallization from a suitable solvent to provide (3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH dibenzo[2,3:6,7]oxepino [4,5-c]pyrrole (2Z)-2-butenedioate compound of formula-1.

10. Novel intermediate compounds having the following structural formulas:

wherein, R is Q.8 straight chain or branched chain alkyl, aryl, cyclo alkyl and aryl-Ci-6 alkyl.