WO2011138795A2

WO2011138795A2 - Process for preparing (s)-10-acetoxy-10,11-dihydro-5h-dibenz[b,f] azepine-5-carboxamide

Info

Publication number: WO2011138795A2
Application number: PCT/IN2011/000303
Authority: WO
Inventors: Manne Satyanarayana Reddy; Sajja Eswaraiah; Bairy Kondal Reddy; Mummadi Venkatesh
Original assignee: Msn Laboratories Limited
Priority date: 2010-05-03
Filing date: 2011-05-02
Publication date: 2011-11-10
Also published as: WO2011138795A3

Abstract

Processes for preparing (S)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide and its intermediates are provided.

Description

An Improved Process for the preparation of (S O-acetoxy-10.11- dihvdro-5H-dibenz[b,flazepine-5-carboxamide

Related Application:

This application claims the benefit of priority of our Indian patent application number 1229/CHE/2010 filed on 3^rd May 2010, which is incorporated herein by reference.

Field of the Invention:

The present invention relates to an improved process for the preparation of (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1 represented by the following structure.

Formula- 1

(S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide is an antiepileptic drug. It is a prodrug which is converted to (S)-10-hydroxy-10,l 1-dihydro- 5H- dibenz[b,fJazepine-5-carboxamide, an active metabolite of oxcarbazepine. (S)-lO-acetoxy- 10,1 l-dihydro-5H-dibenz[b,fjazepine-5-carboxamide has the same mechanism of action as the structurally related carbamazepine. It blocks voltage-gated sodium channels, making brain cells less excitable.

Apart from adjunctive therapy for partial-onset seizures, potential indications include the treatment of other forms of epilepsy, monotherapy of epilepsy, bipolar disorder and trigeminal neuralgia. The EMEA has recommended granting marketing authorization in 2009. The U.S. Food and Drug Administration (FDA) announced on 2 June 2009 that the drug has been accepted for filing. It is developed by Bial and will be marketed as Zebinix or Exalief by Eisai Co in Europe and as Stedesa by Sepracor in America.

Background of the invention: Oxcarbazepine (OXC), the 10-keto analog of carbamazepine (herein after "CBZ") have been established as first line drugs used in the treatment of epilepsy. Oxcarbazepine is designed to avoid the oxidative metabolic transformation as in CBZ and is claimed to be better tolerated drug (Grant, S.M. etal., Drugs, 1992, 43, 873-888). However oxcarbazepine undergoes rapid and complete metabolism to the racemic 10-hydroxy derivative of oxcarbazepine. More over these are useful intermediates in the synthesis of (S)-lO-acetoxy- 10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide, recently disclosed single enantiomer anti epileptic drug.

(S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide and its related compounds as well as processes for their preparation have been disclosed in US 5753646. The disclosed process involves the reaction of (S)- 10-hydroxy- 10,11-dihydro- 5H-dibenz[b,fJazepine-5-carboxamide with acetyl chloride in dichloromethane using pyridine as base, followed by crystallization from dichloromethane-ethyl acetate providing (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fjazepine-5-carboxamide. The disadvantage in the process is the use of pyridine which is a toxic reagent, hence not recommendable for commercial scale-up.

US 7241886 B2 disclosed process for the preparation of 10-hydroxy- 10,11- dihydro-5H-dibenz[b,fJazepine-5-carboxamide and 10-oxo-10,l 1 -dihydro-5H-dibenz [b,f]azepine-5-carboxamide from carbamazepine via epoxy compound. In this process peroxy acetic acid is used for epoxidation of carbamazepine. The usage of peroxy acids at industrial level is not suggestible.

EP 1828139 Bl disclosed a process for the preparation of 10-hydroxy- 10,11- dihydro-5H-dibenz[b,fJazepine-5-carboxamide from 5-cyano-10,l 1-dihydro-lO-hydroxy-

5H-dibenz[b,fjazepine, which involves the usage of potassium carbonate, hydrogen peroxide in ethanol-water. Cyano compounds are highly toxic and fatal on exposure even in minute quantities. Hence the process is dangerous to carry out on a large scale. Moreover it uses the peroxides in the reaction, as the peroxides are explosive; in nature it is difficult to handle the reaction at a large scale.

US 2008/0139807 Al disclosed a process for the preparation of 10-hydroxy- 10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide from carbamazepine by epoxidation using peroxy acetic acid and followed by the reduction using palladium/C. Peroxy acids are explosive in nature, it is difficult to handle industrially.

US 2009/0203902 Al disclosed a process for the enantio selective synthesis of (S)- 10-hydroxy- 10, 11 -dihydro-5H-dibenz[b,fJazepine-5-carboxamide from 10-oxo- 10,11- dihydro-5H-dibenz[b,fJazepine-5-carboxamide using [RuCl₂(p-cymene)]2 + (S,S)- TsDAEN. These types of reagents are commercially not available and difficult to handle. Hence this process is not viable at industrial level.

WO 2007/117166 Al disclosed a process for the preparation of (S)-lO-acetoxy- 10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide by asymmetric hydrogenation from its corresponding enol acetate using Rh(COD)(RcSp-DuanPhos)BF₄. It is difficult to synthesize this type of complex reagents in laboratory and also commercially not viable.

CA 920587 Al disclosed a process for the preparation of 10-hydroxy- 10,11- dihydro-5H-dibenz[b,fJazepine-5-carboxamide from 10-methoxy-5H-dibenz b,fjazepine, which involves the usage of phosgene in the synthetic process. As the phosgene is harmful, it is not recommended for industrial level batches.

US 7119197 B2 disclosed a process for the preparation of (S)- 10-acetoxy- 10,11- dihydro-5H-dibenz[b,fJazepine-5-carboxamide, which involves the reduction of 10-oxo- 10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide with a reducing agent, followed by resolution using diacetyl L-tartaric acid anhydride in dichloro methane using pyridine and dimethylamino pyridine. As the resolving agent is commercially not available, and the usage of pyridine is not suggestible. Hence the process is not suitable for large-scale production. Hence there is a need for developing a process which can overcome the above problems. W

The present invention provides an improved process which overcomes the problems of prior art and provides the product with high purity and yield.

Summary of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of (S)-10-hydroxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide compound of formula-3, which comprises of the following steps; a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable chiral reducing agent in a suitable solvent to provide the (S)-10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3,

b) optionally purifying/isolating the compound obtained in step-a from a suitable solvent to provide pure compound of formula-3.

The second aspect of the present invention is to provide an improved process for the preparation of (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1 , which comprises of the following steps;

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fjazepine-5-carboxamide compound of formula-2 with a suitable chiral reducing agent in a suitable solvent to provide (S)- 10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3, which on optional purification/isolation in a suitable solvent provides pure compound of formula-3,

b) acetylating the compound of formula-3 using a suitable acetylating agent in the presence of a suitable base in a suitable solvent to provide (S)-10-acetoxy-10,l l- dihydro-5H-dibenz[b,f azepine-5-carboxamide compound of formula- 1,

c) optionally purifying/isolating the compound obtained in step-b from a suitable solvent to provide pure compound of formula- 1. The third aspect of the present invention is to provide a process for the preparation of (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1, which comprises of the following steps;

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 10-hy droxy-

10,1 l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4, b) acetylating the compound of formula-4 using a suitable acetylating agent in the presence of a suitable base in a suitable solvent to provide 10-acetoxy- 10,11-dihydro- 5H-dibenz[b,fJazepine-5-carboxamide compound of formula-5,

c) resolving the compound of formula-5 with a suitable resolving agent in a suitable solvent, followed by treatment with a base to provide compound of formula- 1, d) optionally purifying/isolating the compound obtained in step-c from a suitable solvent to provide pure compound of formula- 1. The fourth aspect of the present invention is to provide an improved process for the preparation of (S)- 10-acetoxy- 10,11 -dihydro-5H-dibenz[b,f]azepine-5-carboxamide compound of formula- 1, which comprises of the following steps;

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 10-hydroxy- 10, 11 -dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4, b) resolving the compound of formula-4 with a suitable resolving agent in a suitable solvent, followed by treating it with a base to provide the (S)-10-hydroxy-10,l 1- dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3,

c) acetylating the compound of formula-3 with a suitable acetylating agent in the presence of a suitable base in a suitable solvent to provide compound of formula- 1,

d) optionally purifying/isolating the compound obtained in step-c from a suitable solvent to provide pure compound of formula- 1.

The fifth aspect of the present invention is to provide an improved process for the preparation of (S)- 10-acetoxy- 10, 1 l-dihydro-5H-dibenz[b,fjazepine-5-carboxamide compound of formula- 1, which comprises of the following steps; a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fjazepine-5-carboxamide compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 10-hydroxy- 10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4, b) condensing the compound of formula-4 with a suitable cyclic amino acid optionally N- substituted such as D-proline derivative compound of general formula-6 in the presence of a suitable condensing agent in a suitable solvent to provide dibenz[b,fjazepine ester derivative compound of general formula-7,

c) hydrolyzing the compound of general formula-7 with a suitable acid or base in a suitable solvent to provide the compound of formula-3,

d) acetylating the compound of formula-3 with a suitable acetylating agent in the presence of a suitable base in a suitable solvent to provide compound of formula- 1,

e) optionally purifying/isolating the compound obtained in step-d from a suitable solvent to provide pure compound of formula- 1.

The sixth aspect of the present invention is to provide dibenz[b,fjazepine ester derivative compounds of general formula-7, useful novel intermediates in the synthesis of (S)- 10-acetoxy- 10, 11 -dihydro-5H-dibenz[b,fJazepine-5-carboxamide.

The seventh aspect of the present invention is to provide a crystalline form of (R)- ((S)-5 -carbamoyl- 10,11 -dihydro-5H-dibenzo[b,f]azepin- 10-yl) 1 -benzylpyrrolidine-2- carboxylate compound of formula-7a (herein designated as crystalline form-M).

The eighth aspect of the present invention is to provide an improved process for the preparation of (S)- 10-acetoxy- 10, 1 l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1, which comprises of the following steps;

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 10-hydroxy-

10,1 l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4, b) condensing the compound of formula-4 with a suitable amino acid optionally N- substituted, compound of general formula-8, in the presence of a suitable condensing agent in a suitable solvent to provide dibenz[b,fjazepine ester derivative compound of general formula-9,

c) hydrolyzing the compound of general formula-9 with a suitable acid or base in a suitable solvent to provide the compound of formula-3,

The ninth aspect of the present invention is to provide a process for the purification of (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1.

Advantages of the Present Invention:

• Provides an improved process for the preparation of (S)-10-acetoxy-10,l 1 dihydro- 5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1 with high yields and high purity.

• Uses simple chiral reducing agent in place of Rh(COD)(RcSp-DuanPhos)BF₄,

[RuCl₂(p-cymene)]₂ + (S,S)-TsDAEN etc., which are commercially not available and difficult to prepare.

• Avoids the use of chemicals which are explosive in nature and preventing the possibility of accidents.

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

• Eco-friendly process. Brief Description of the Drawings:

Figure 1: Illustrates the PXRD pattern of crystalline form-M of (R)-((S)-5-carbamoyl- 10, 11 -dihydro-5H-dibenzo[b,fJazepin- 10-yl) 1 -benzylpyrrolidine-2-carboxylate compound of formula-7a. Figure 2: Illustrates the IR spectrum of crystalline form-M of (R)-((S)-5-carbamoyl-10,l 1- dihydro-5H-dibenzo [b,fjazepin- 10-yl) 1 -benzylpyrrolidine-2-carboxylate compound of formula-7a.

Figure 3: Illustrates the DSC thermogram of crystalline form-M of (R)-((S)-5-carbamoyl- 10,11 -dihydro-5H-dibenzo[b,fJazepin- 10-yl) 1 -benzylpyrrolidine-2-carboxylate compound of formula-7a.

Figure 4: Illustrates the PXRD pattern of crystalline form of (S)-10-acetoxy-10,l l- dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-1 obtained in example-4 and example-7. Detailed Description of the Invention:

The present invention relates to an improved process for the preparation of (S)-IO- acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-1 and its novel intermediates. 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; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, 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, chloroform and dichloroethane, carbon tetrachloride and chloroform; polar solvents like water; and also mixtures thereof.

The term "acid" herein the present invention is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or organic acids such as acetic acid, trifluoroacetic acid, methane sulfonic acid, para toluene sulfonic acid, oxalic acid and tartaric acid.

The term "base" herein the present invention is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, piperidine, dimethyl amino pyridine and pyridine.

The term "N-protecting group" herein the present invention refers to a protecting group which is selected from group consisting of but not limited to, benzyloxy carbonyl (Cbz), p-methoxy benzylcarbonyl (Moz or MeOZ), tert-butyloxy carbonyl (BOC), 9- fiuorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 3,5- dimethyl benzyl, 2,4-dinitro benzyl, 2,4-dibromo benzyl, 3,5-dichloro benzyl and tosyl group.

As used herein, the term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms. A "CM₂ 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-l-yl, pent-2- yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-l- 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. Examples of monocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of bicyclic cycloalkyl groups include without limitation, bicyclo[1.1.0]butyl, bicyclo[l.l.l]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.0]hexyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.0]heptyl and the like.

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. Examples of monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, pyranyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyradazinyl, pyrimidinyl, and the like. The aryl groups also include bicyclic groups, tricyclic groups etc including fused 5 and 6 membered rings described above. Examples of multicyclic aryl groups include, without limitation, naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl. indolyl, benzofuranyl, purinyl, indolizinyl and the like. The aryl groups may be attached to the substrate at any ring atom, unless such attachment would violate valence requirements. Aryl groups may include one or more non hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include, without limitation alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, halo, hydroxy, mercapto, nitro, amino, alkyl amino and the like.

As used herein, the term "Ci- alkyl carbonyl" refers to an alkyl group containing one to six carbons attached to the substrate through a carbonyl group. The term "aryl carbonyl" refers to an aryl group attached to the substrate through a carbonyl group. The term "aryl-Cj_-6 alkyl carbonyl" refers to an aryl-Ci_-6 alkyl group attached to the substrate through a carbonyl group.

As used herein, the term "CM2 alkoxy carbonyl" refers to a

alkoxy group attached to the substrate through a carbonyl group. The term "aryloxy carbonyl" refers to an aryloxy group attached to the substrate through a carbonyl group. The term "aryl-Ci-6 alkoxy carbonyl" refers to aryl-Ci-6 alkoxy group attached to the substrate through a carbonyl group.

The suitable chiral reducing agent is selected from β-chlorodiisopinocampheyl borane (DIP Chloride); or a reducing agent like, borane THF or borane DMS in combination with a chiral catalyst like (R)-tetrahydro-l-methyl-3,3-diphenyl-lH,3H- pyrrolo(l,2-c)(l,3,2)oxazaborole (herein after referred as "R-Methyl CBS") or R-Butyl CBS or R-Phenyl CBS and the like.

The suitable reducing agent can be selected from heterogeneous catalysts containing from about 0.1 % to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, raney nickel, palladium catalyst such as Pd/C, Pd/SrCOs, Pd/Al₂0₃, Pd/MgO, Pd/CaC0_3> Pd/ BaS0₄, PdO, Pd Black, PdCl_2, Rh/C, Ru/C, Re/C, Pt0₂, Rh/C, Ru0_2i sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride and etc;

The suitable condensing agent is selected from carbodiimides such as Ν,Ν¹- diisopropylcarbodiimide (DIC), l-ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide (EDC), NjN'-dicyclohexyl carbodiimide (DCC); alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy-3,4- dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), di phenylphosphoroazidate (DPP A), P2O5, 3-(diethoxyphosphoryloxy)-l,2,3-benzotriazine- 4(3H)-one (DEPBT), Ν,Ν'-carbonyl diimidazole. The carbodiimides can be used optionally in combination with 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HO At), 1 -hydroxy- lH-1, 2,3 -triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoro borate (TBTU), dimethylamino pyridine (DMAP). The alkyl or aryl chloroformates can be used optionally in combination with a base.

The suitable resolving agents which are used herein the present invention are selected from mandelic acid, tartaric acid, malic acid, maleic acid, naproxen, camphor sulfonic acid, bromocamphor-10-sulfonic acid, dibenzoyl-tartaric acid, dibenzoyl- tartaricacid monohydrate, dipara-tolyl-tartaric acid, pyroglutamic acid, lactic acid and lysin.

The first aspect of the present invention is to provide an improved process for the preparation of (S)-10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3, which comprises of the following steps;

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable chiral reducing agent in a suitable solvent to provide (S)- lO-hydroxy-10,1 l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3,

b) optionally purifying/isolating the compound obtained in step-a from a suitable solvent to provide pure compound of formula-3. In a preferred embodiment the reduction of the 10-oxo-10,l l-dihydro-5H- dibenz[b,fJazepine-5-carboxamide compound of formula-2 is carried out with borane- dimethylsulfide in the presence of R-methyl CBS in tetrahydrofuran to provide (S)-IO- hydroxy-10,l l-dihydro-5H-dibenz[b,fJ azepine-5-carboxamide compound of formula-3.

The second aspect of the present invention is to provide an improved process for the preparation of (S)- 10-acetoxy- 10, 11 -dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1, which comprises of the following steps;

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable chiral reducing agent in a suitable solvent to provide (S)- lO-hydroxy-10,1 l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3, which on optional purification/isolation in a suitable solvent provides pure compound of formula-3,

b) acetylating the compound of formula-3 using a suitable acetylating agent in the presence of a suitable base in a suitable solvent to provide (S)- 10-acetoxy- 10,11- dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1,

c) optionally purifying/isolating the compound obtained in step-b from a suitable solvent to provide pure compound of formula- 1.

wherein, in step b) the acetylation can be carried out optionally in the presence of a suitable catalyst such as dimethyl amino pyridine (DMAP),

In step a) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof,

In step b) the suitable acetylating agent is selected from acetic anhydride, acetyl chloride and the like; the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof,

In step c) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof. In a preferred embodiment, an improved process for the preparation of (S)-IO- acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1, which comprises of the following steps;

a) Reducing the lO-oxo-10,1 l-dihydro-5H-dibenz[b,fjazepine-5-carboxamide compound of formula-2 with borane-dimethylsulfide in the presence of R-methyl CBS in tetrahydrofuran to provide (S)-10-hydroxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5- carboxamide compound of formula-3,

b) acetylating the compound of formula-3 with acetic anhydride in the presence of diisopropyl ethyl amine and dimethyl amino pyridine in dichloromethane to provide compound of formula- 1.

The third aspect of the present invention is to provide an improved process for the preparation of (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide compound of formula- 1, which comprises of the following steps;

a) Reducing the lO-oxo-10,1 l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 10-hydroxy- 10,11- dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4, b) acetylating the compound of formula-4 with a suitable acetylating agent in the presence of suitable base in a suitable solvent provides lO-acetoxy-10,11 -dihydro-5H- dibenz[b,fJazepine-5-carboxamide compound of formula-5,

c) resolving the compound of formula-5 with a suitable resolving agent in a suitable solvent, followed by treating it with a base to provide (S)-10-acetoxy-10,l 1-dihydro- 5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1,

wherein, in step b) the acetylation can be carried out optionally in the presence of a suitable catalyst such as dimethyl amino pyridine (DMAP).

The fourth aspect of the present invention is to provide an improved process for the preparation of (S)-10-acetoxy-10,l l-dihydro-5H-dibenz-[b,fJ-azepine-5-carboxamide compound of formula- 1, which comprises of the following steps; a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 10-hydroxy- 10,1 l-dihydro-5H-dibenz[b,fjazepine-5-carboxamide compound of formula-4, b) resolving the compound of formula-4 with a suitable resolving agent in a suitable solvent, followed by treating it with a base to provide (S)-10-hydroxy-10,l l-dihydro- 5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3,

c) acetylating the compound of formula-3 with a suitable acetylating agent in the presence of a base in a suitable solvent to provide (S)-10-acetoxy-10,l 1 -dihydro-5H- dibenz[b,fJazepine-5-carboxamide compound of formula-1,

d) optionally purifying/isolating the compound obtained in step-c from a suitable solvent provides pure compound of formula-1.

wherein, in step c) the acetylation can be carried out optionally in the presence of a suitable catalyst such as dimethyl amino pyridine (DMAP).

The acetylation in the above aspects is carried out using a suitable acetylating agent selected from acetic anhydride, acetyl chloride and the like; the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof.

The above aspects of the invention are represented schematically as follows:

Schem -I:

Formula-3 Formula-1 The fifth aspect of the present invention is to provide an improved process for the preparation of (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1, which comprises of the following steps;

10,1 l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4, b) condensing the compound of formula-4 with a suitable cyclic amino acid optionally N- substituted such as D-proline derivative compound of general formula-6, in the presence of a suitable condensing agent in a suitable solvent provides dibenz[b,fjazepine ester derivative compound of general formula-7,

c) hydrolyzing the compound of general formula-7 with a suitable acid or a base in a suitable solvent to provide the compound of formula-3,

d) acetylating the compound of formula-3 with a suitable acetylating agent in the presence of a suitable base in a suitable solvent provides compound of formula- 1,

wherein, in step d) the acetylation can be carried out optionally in the presence of a suitable catalyst such as dimethyl amino pyridine (DMAP), and in step b) compound of general formula-7 can also be prepared from compound of general formula-6, by converting it into its corresponding acid chloride (by conventional methods known in the art) and then condensing it with compound of formula-4.

In step b) the suitable solvent is selected from chloro solvents such as dichloromethane, dichloro ethane, chloroform, carbon tetrachloride and etc,

In step c) the suitable solvent is selected from alcoholic solvents such as methyl alcohol, ethyl alcohol, isopropyl alcohol and etc,

In step d) the suitable acetylating agent is selected from acetic anhydride, acetyl chloride etc; the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof.

In step e) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof.

The above aspects of the invention are represented schematically as follows: Scheme-Π:

Formula-2 Formula-4 Formula-7

Formula-1 Formula-3 wherein, G is a hydrogen, N-protecting group, C_x._n alkyl, C₃.₇ cycloalkyl, aryl-C_].₆ alkyl, C_j.₆ alkyl carbonyl, aryl carbonyl, aryl-C,_₆ alkyl carbonyl, C _n alkoxy carbonyl, aryloxy carbonyl or an ary!-C^ alkoxy carbonyl group.

In a preferred embodiment, an improved process for the preparation of (S)-IO- acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide compound of formula-1 which comprises of the following steps;

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with sodiumborohydride in aqueous methanol to provide 10-hydroxy- 10, 11 -dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4, b) condensing the compound of formula-4 with N-benzyl-D-proline compound formula-6a,

Formula-6a

in the presence of dicyclohexyl carbodiimide and dimethylamino pyridine in dichloro methane provides (R)-((S)-5-carbamoyl-10,l l-dihydro-5H-dibenzo[b,f]azepin-10-yl)l- benzylpyrrolidine-2-carboxylate compound of formula-7a,

Formula-7a

c) hydrolyzing the compound of formula- 7a with sodium hydroxide in methanol to provide the compound of formula-3,

d) acetylating the compound of formula-3 with acetic anhydride in the presence of diisopropyl ethyl amine and dimethyl amino pyridine in dichloromethane provides compound of formula- 1.

The sixth aspect of the present invention is to provide dibenz[b,fjazepine ester derivative compounds of general formula-7, useful novel intermediates in the synthesis of (S)- 10-acetoxy- 10, 11 -dihydro-5H-dibenz[b,fJazepine-5-carboxamide. The seventh aspect of the present invention is to provide a crystalline form of (R)-

((S)-5 -carbamoyl- 10, 11 -dihydro-5H-dibenzo[b,f]azepin- 10-yl) 1 -benzylpyrrolidine-2- carboxylate compound of formula-7a (herein designated as form-M). The crystalline form-

M of (R)-((S)-5-carbamoyl-10,l l-dihydro-5H-dibenzo[b,fJazepin-l 0-yl) 1 -benzyl pyrrolidine-2-carboxylate compound of formula- 7a, which is characterized by its powder XRD having peaks at about 3.8, 7.7, 10.2, 15.5, 17.0, 18.2 and 19.1± 0.2 degrees two-theta and substantially as shown in figure- 1; its IR spectrum having peaks at about 1651, 1741 and 3474 cm^"1 and substantially as shown in figure-2; by its DSC thermogram showing endotherm at about 187.71 °C as shown in figure-3.

The eighth aspect of the present invention is to provide an improved process for the preparation of (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1, which comprises of the following steps;

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 10-hydroxy- 10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4, b) condensing the compound of formula-4 with a suitable amino acid optionally N- substituted compound of general formula-8

G

O I

Hc cH)_n

I R

Formula-8

wherein n is 1-3; R refers to CM2 alkyl group which may or may not be substituted with -COOH, -CONH₂, -SH, -OH, -NH-C(=NH)-NH₂, imidazole, indole, -NH₂ or C_3-7 cycloalkyl, aryl-Ci.₆ alkyl group; and G is the same as defined above, to provide compound of general formula-9,

Formula-9

Wherein, n is 1-3; R and G are as defined above; c) hydrolyzing the compound of general formula-9 with a suitable acid or base in a suitable solvent to provide the compound of formula-3,

e) optionally purifying/isolating the compound obtained in step-d from a suitable solvent to provide compound of formula- 1.

wherein, in step d) the acetylation can be carried out optionally in the presence of a suitable catalyst such as dimethyl amino pyridine (DMAP), and in step b) compound of general formula-9 can also be prepared from compound of general formula-8, by converting it into its corresponding acid chloride (by conventional methods known in the art) and then condensing it with compound of formula-4.

The ninth aspect of the of the present invention is to provide a purification process for the preparation of highly pure (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f] azepine-5- carboxamide compound of formula- 1, which comprises of the following steps;

a) Dissolving the (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJ azepine-5-carboxamide compound of formula- 1 in a suitable solvent,

b) heating the reaction mixture to reflux temperature,

c) treating it with charcoal,

d) filtering the reaction mixture and washing with the suitable solvent,

e) cooling the obtained filtrate to 0-5°C,

f) filtering the precipitated solid and washing with a suitable solvent,

g) drying the solid to get pure (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJ azepine-5- carboxamide compound of formula- 1.

wherein, the suitable solvent is selected from alcohol solvents, ester solvents and ketone solvents.

The present invention also provides the another process for purification of (S)-IO- acetoxy-10,l l-dihydro-5H-dibenz[b,fJ azepine-5-carboxamide compound of formula- 1, which comprises of the following steps; a) Dissolving the (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f] azepine-5-carboxamide compound of formula- 1 in a suitable solvent,

b) treating it with charcoal,

c) filtering the reaction mixture and washing with the suitable solvent,

d) adding a suitable anti solvent to the obtained filtrate,

e) cooling the reaction mixture to 0-5°C,

f) filtering the precipitated solid and washing with a suitable solvent,

Wherein, the suitable solvent is chloro solvent and the suitable antisolvent is selected from alcohol solvents, ester solvents and ketone solvents.

(S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide obtained as per the prior art processes, for example US 5753646 obtained after crystallization from a mixture of dichloromethane and ethyl acetate is having purity only about 97%. The following are the details of impurities obtained in terms of their RRT in HPLC along with its area %, in (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide prepared according to the process disclosed in example-4 of US 5753646.

In the present invention, (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJ azepine-5- carboxamide obtained after purification is having purity greater than 99.9 % by HPLC. Moreover, the impurities obtained above in the prior-art process (US 5753646) were controlled to meet the ICH guidelines. Hence the process of the present invention is highly advantageous over the prior art process.

(S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f] azepine-5-carboxamide obtained from the present invention is having the chiral purity greater than 99% and the analytical experimental conditions are mentioned as follows: (S)-10-acetoxy-10,ll-dihydro-5H-dibenz[b,f|azepine-5-carboxamide was analyzed by chiral HPLC using the following conditions:

Apparatus: A liquid chromatograph equipped with variable wavelength UV-detector; Column: Chiral pack AD-H, 250 X 4.6 mm, 5 μηι;

Flow rate: 1.0 ml/min;

Wavelength: 230 nm;

Temperature: 40°C;

Injection volume: 20

Run time: 50 min;

Diluent: n-hexane: Ethanol (50:50 v/v);

Elution: Isocratic;

Mobile phase-A: n-hexane: ethanol (88:12 v/v);

(S)-10-acetoxy-10,H-dihydro-5H-dibenz[b,f]azepine-5-carboxamide & related substances were analyzed by HPLC using the following conditions:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator;

Column : Inertsil ODS-4, 250 x 4.6 mm, 5 μπι or equivalent;

Flow rate : 1.0 mL/minute;

Wavelength : 220 nm;

Column temperature : 25 °C;

Injection volume: 10 yL

Run time : 47 minutes;

Diluent: acetonitrile:water (50:50 v/v);

Elution : Gradient;

Solution A: Buffer;

Solution B: acetonitrile: water in the ratio of (95:5 v/v);

Buffer used is 2.8 g of sodium perchlorate into 1000 ml of water, and adjusted p^H to 2.8 with perchloric acid. Filtered the solution through 0.45 μπι Nylon membrane filter paper and sonicate to degas it. 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 10-hydroxy-10,H-dihydro-5H-dibenz[b,fJazepine-5- carboxamide compound of formuIa-4

Sodium borohydride (11.3 g) was added to the solution of 10-oxo-10,l 1-dihydro- 5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 (50 g) in water (100 ml), followed by methanol (200 ml) at 25-35°C. The reaction mixture was heated to 55-60°C and then stirred for 7 hours at 55-60°C. After completion of the reaction, distilled off methanol completely under reduced pressure and then cooled to 25-30°C. Water was added to the reaction mixture and then stirred for 60 minutes at 25-30°C. Filtered the solid, washed with water and then dried to get the title compound. Yield: 45 grams Example 2: Preparation of (R)-((S)-5-carbamoyl-10,ll-dihydro-5H-dibenzo[b,fJ azepin- 10-y 1) 1 -benz lpy rrolidine-2-carboxy late (Formula-7a)

10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4 (11.79 g) was added to a solution of N-benzyl-D-proline compound of formula- 6a (10 g) in dichloro methane (100 ml), followed by dimethylamino pyridine (1.49 g) and then cooled to 0-5°C. Dicyclohexylcarbodiimide (15.1 g) was added to the reaction mixture and stirred for 10 minutes, Further the reaction mixture temperature was raised to 25-35°C and stirred the reaction mixture for 5 hours at 25-35°C. After completion of the reaction, the reaction mixture was cooled to 0-5°C. Filtered the reaction mixture to remove the undissolved product and washed with dichloro methane. The obtained filtrate was washed with 10% sodium bicarbonate solution, followed by water. Distilled off dichloromethane from organic layer under reduced pressure and then cyclohexane was added to the obtained residue. The reaction mixture was stirred for 1 hour at 25-35°C. Filtered the solid and washed with cyclohexane. The wet compound was slurred in water for 1 hour at 25-35°C. Filtered the solid, washed with water and then dried to get the title compound. The obtained compound was further recrystallized twice from isopropyl alcohol to get the pure title compound. Yield: 6 grams; Purity by HPLC: 98%.

Example 3: Preparation of (S)-10-hydroxy-10,H-dihydro-5H-dibenz[b,f]azepine- 5-carboxamide (Formula-3)

10% sodium hydroxide (0.9 g) was added to a solution of (R)-((S)-5-carbamoyl- 10, 11 -dihydro-5H-dibenzo[b,fjazepin- 10-yl) 1 -benzylpyrrolidine-2-carboxylate compound of formula-7a (4 g) in methanol (40 ml) at 25-35°C, heated to 45-50°C and then stirred the reaction mixture for 45 minutes at 45-50°C. After completion of the reaction, distilled off methanol from the reaction mixture under reduced pressure and water was added to it. Filtered the obtained solid, washed with water and then dried to get title compound.

Yield: 2 grams; Chiral purity by HPLC: 98%; Purity by HPLC: 99%.

Example 4: Preparation of (S)-10-acetoxy-10,H-dihydro-5H-dibenz[b,fJazepine-5- carboxamide (Formula-1)

A mixture of dichloro methane (15 ml), diisopropyl ethyl amine (1.59 ml), dimethyl amino pyridine (0.03 g) and (S)-10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJ azepine-5- carboxamide compound of formula-3 (1.5 g) was cooled to 0-5°C and then slowly added acetic anhydride (0.66 ml) over a period of 15 minutes at 25-35°C, further the reaction mixture was stirred for 60 minutes at 25-35°C. After completion of the reaction, the reaction mixture was washed with water, followed by 10% sodium bicarbonate solution and then distilled off the solvent from the reaction mixture under reduced pressure. Dichloro methane (5 ml) was added to the obtained residue and stirred for 15 minutes to get clear solution. The resultant reaction mixture was added to n-heptane (20 ml) over a period of 15 minutes at 25-35°C and cooled to 0-5°C. The reaction mixture was stirred for 60 minutes at 0-5 °C. Filtered the obtained solid, and washed with n-heptane and then dried to get the title compound.

Yield: 1.5 grams; Purity by HPLC :> 99%; Chiral purity by HPLC: 99%. Example 5: Preparation of 10-acetoxy- 10,11 -dihydro-5H-dibenz [b,f]azepine-5- carboxamide compound of formula-5 To the 10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4 (10 g) in dichloromethane (100 ml) added diisopropylethylamine (11 ml) and dimethyl aminopyridine (0.5 g) at 20 to 25°C. Stirred the reaction mixture for 10 minutes. Added acetyl chloride (3.0 g) to the reaction mixture dropwise at the same temperature. Stirred the reaction mixture for 1 hour at the same temperature. Quenched the reaction mixture with hydrochloric acid and extracted with dichloromethane. Distilled off the solvent completely to get the title compound. Yield: 8.0 grams

Example 6: Preparation of (S)-lO-hydroxy-lO, ll-dihydro-5H-dibenz[b,fjazepine-5- carboxamide compound of formula-3.

Tetrahydrofuran (40 ml) was taken in a round bottom flask and cooled to 0°C. To this added borane dimethyl sulfide (3.05 g) and (R)-2-methyl-cbs-oxazaborolidine (1.1 g) under nitrogen atmosphere. To this reaction mixture slowly added 10-oxo-10,l l-dihydro- 5H-dibenz[b,fjazepine-5-carboxamide compound of formula-2 (10 g) dissolved in tetrahydrofuran (10 ml). Stirred the reaction mixture for 3 hrs at 0-5°C and quenched with methanol and followed by IN hydrochloric acid solution. Separated the organic layer and washed with 5% hydrogen peroxide solution and followed by 5% sodium sulfate solution and with 10% sodium chloride solution. Distilled off the solvent completely from organic layer under reduced pressure to get the title compound. Yield: 6.5 grams.

Example 7: Preparation of (S)-lO-acetoxy-lO, ll-dihydro-5H-dibenz[b,f]azepine-5- carboxamide compound of formula-1

To the (S)-10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3 (10 g) in dichloromethane (100 ml) added diisopropylethylamine (11 ml) and dimethyl aminopyridine(0.5 gms) at 20 to 25°C. Stirred the reaction mixture for 10 minutes. Added acetyl chloride (3.0 g) to the reaction mixture dropwise at same temperature. Stirred the reaction mixture for 1 hour at same temperature. Quenched the reaction mixture with hydrochloric acid and extracted with dichloromethane. Distilled off the solvent completely to get the title compound. Yield: 7.0 grams

Example 8: Purification of (S)-10-acetoxy-10,H-dihydro-5H-dibenz[b,fJazepine-5- carboxamide (Formula-1) A mixture of Isopropyl alcohol (7.5 ml) and (S)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,fj azepine-5-carboxamide compound of formula-1 (1.5 g) was heated to reflux temperature and then stirred for 10 minutes at the same temperature. Carbon (0.15 g) was added to the reaction mixture and then stirred for 30 minutes. Filtered the reaction mixture, washed with isopropyl alcohol. The obtained filtrate was cooled to 0-5°C and stirred for 2 hours. Filtered the solid, washed with chilled isopropyl alcohol and then dried to get pure title compound. Yield: 1.3 grams

Example 9: Purification of (S)-10-acetoxy-10,ll-dihydro-5H-dibenz[b,f]azepine-5- carboxamide (Formula-1)

Dichloro methane (4.5 ml) was added to (S)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,fJazepine-5-carboxamide compound of formula-1 (1.5 g) at 25-35°C and then stirred for 10 minutes. Carbon (0.15 g) was added to the reaction mixture and then stirred for 30 minutes. Filtered the reaction mixture, washed with dichloro methane. To the obtained filtrate isopropyl alcohol (22.5 ml) was added at 25-35°C. The reaction mixture was cooled to 0-5°C and then stirred for 2 hours. Filtered the solid, washed with chilled isopropyl alcohol and then dried to get pure title compound. Yield: 1.2 grams.

Example 10: Process for the preparation of N-benzyl-D-proIine (Formula-6a)

Benzyl chloride (119.9 g) was added to a mixture of isopropyl alcohol (1000 ml),

D-proline (100 g) and potassium hydroxide (144.6 g) over a period of 15 minutes and stirred the reaction mixture for 10 hours at 25-35°C. The p^H of the reaction mixture was adjusted to 7.3 with isopropanolic hydrochloric acid. Dichloromethane was added to the reaction mixture and stirred it for 2 hours at 25-35°C. The obtained inorganic salts were removed by filtration and distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with acetone. Acetone (300 ml) was added to the obtained residue and then heated to 50-60°C. The reaction mixture was stirred for 5 minutes and cooled it to 0-5°C. The reaction mixture was stirred for 60 minutes at 0-5°C. Filtered the solid, washed with acetone and then dried to get the title compound. Yield: 105 grams.

Example 11: Preparation of 10-hydroxy-lO, ll-dihydro-5H-dibenz[b,f]azepine-5- carboxamide compound of formula-4. Added sodium borohydride (1.0 g) to the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5- carboxamide compound of formula-2 (10 g) in ethanol (40 ml) and water (20 ml) in portion wise. The reaction mixture was stirred for 2 hours at 45°C. Quenched the reaction mixture with aqueous hydrochloric acid. Extracted the reaction mixture with dichloromethane. Distilled off the solvent completely from organic layer. The obtained compound was recrystallized from water to get the title compound. Yield: 8.5 grams.

Example 12: Preparation of (S)-((S)-5-carbamoyl-10,ll-dihydro-5H-dibenzo [b,fj azepin-10-yI) 2-amino-2-phenylacetate compound of formula-9a.

10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4 (1 g) was added to a solution of (S)-2-amino-2-phenyl acetic acid compound of formula-8a (0.62 g) in dichloro methane (10 ml), followed by dimethylamino pyridine (0.12 g) and then cooled to 0-5°C. Dicyclohexylcarbodiimide (1.269 g) was added to the reaction mixture and stirred for 10 minutes, Further the reaction mixture temperature was raised to 25-35°C and stirred for 5 hours at 25-35°C. After completion of the reaction, the reaction mixture was cooled to 0-5°C. Filtered the reaction mixture to remove the undissolved product and washed with dichloro methane. The obtained filtrate was washed with 10% sodium bicarbonate solution, followed by water. Distilled off dichloromethane completely under reduced pressure and then added cyclohexane, further the reaction mixture was stirred for 1 hour at 25-35°C. Filtered the solid and washed with cyclohexane. To the obtained solid further added water and stirred for 1 hour at 25-35°C. Filtered the solid, washed with water and then dried to get the title compound. The obtained compound was further recrystallized twice from isopropyl alcohol to get the pure title compound. Yield: 6 grams; Purity by HPLC: 98%.

Example 13: Preparation of (S)-((S)-5-carbamoyl-10,ll-dihydro-5H-dibenzo[b,fJ azepin-10-yl) l-benzylpyrrolidine-2-carboxylate compound of formula-7b.

10-hydroxy-10,l l-dihydro-5H-dibenz[b,fjazepine-5-carboxamide compound of formula-4 (16.85 g) was added to a solution of N-benzyl-L-proline (17 g) in dichloro methane (170 ml), followed by dimethylamino pyridine (1 g) at 0-5°C. Dicyclohexylcarbodiimide (51.3 g) was added to the reaction mixture and stirred for 60 minutes. The unwanted solid was removed by filtration, and washed with dichloromethane and the filtrate was extracted with aqueous hydrochloric acid. The p^H of the aqueous layer was adjusted to 7.0 with 10% sodium bicarbonate solution. The aqueous layer was extracted twice with dichloromethane and distilled off the solvent completely under reduced pressure to get the residue. The obtained residue was recrystallized thrice with ethylacetate and then dried to get pure title compound. Yield: 5.5 grams.

Claims

We Claim:

1. A compound of general formula-7,

Formula-7

wherein G is a hydrogen, N-protecting group, C_M2 alkyl, C_3-7 cycloalkyl, aryl-Ci-_ό alkyl, Ci_-6 alkyl carbonyl, aryl carbonyl, aryl-C_!. alkyl carbonyl, Ci_-12 alkoxy carbonyl, aryloxy carbonyl or an aryl-Ci_-6 alkoxy carbonyl group.

2. A compound of general formula-9 or its stereoisomer thereof,

Formula-9

wherein n is 1-3; R refers to Ci-12 alkyl group which may or may not be substituted with -COOH, -CONH₂, -OH, -SH, -NH-C(=NH)-NH₂, imidazole, indole, -N¾ or C_3-7 cycloalkyl, aryl-Ci-₆ alkyl group; and G is a hydrogen, N-protecting group, .n alkyl, C₃.₇ cycloalkyl, aryl-d-₆ alkyl, C_1-6 alkyl carbonyl, aryl carbonyl, aryl-C_1-6 alkyl carbonyl, Ci_-12 alkoxy carbonyl, aryloxy carbonyl or an aryl-Ci- alkoxy carbonyl group.

3. A crystalline form-M of (R)-((S)-5 -carbamoyl- 10, 11 -dihydro-5H-dibenzo [b,fj azepin- 10-yl)l-benzylpyrrolidine-2-carboxylate compound of formula-7a characterized by a) its powder X-ray difiractogram having peaks at about 3.8, 7.7, 10.2, 15.5, 17.0, 18.2 and 19.1± 0.2 degrees two-theta as illustrated in figure-1, b) its Infrared spectrum having peaks at about 1651, 1741 and 3474 cm^"1 as illustrated in figure-2,

c) its DSC thermogram showing endotherm at 187.71°C as illustrated in figure-3.

An improved process for the preparation of (S)- 10-hydroxy- 10,11 -dihydro-5H- dibenz[b,fJazepine-5-carboxamide compound of formula-3, comprises of reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable chiral reducing agent in a suitable solvent to provide compound of formula-3, characterized in that the suitable chiral reducing agent is selected from β- chloro diisopinocampheyl borane (DIP Chloride); or a reducing agent like borane-THF or borane-DMS in combination with a chiral catalyst like R-Methyl CBS or R-Butyl CBS or R-Phenyl CBS.

An improved process for the preparation of (S)-10-hydroxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide compound of formula-3, comprises of reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with Borane-DMS in the presence of R-methyl CBS in tetrahydrofuran to provide the compound of formula-3. An improved process for the preparation of (S)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide compound of formula-1, comprises of:

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 10-hydroxy- 10, 11 -dihydro-5H-dibenz[b,f]azepine-5-carboxamide compound of formula-4,

b) condensing the compound of formula-4 with a suitable amino acid, optionally N- substituted such as D-proline derivative compound of general formula-6 in the presence of a suitable condensing agent in a suitable solvent to provide dibenz[b,fjazepine ester derivative compound of general formula-7,

c) hydrolyzing the compound of general formula-7 with a suitable acid or base in a suitable solvent to provide the compound of formula-3, d) acetylating the compound of formula-3 with a suitable acetylating agent in the presence of a suitable base in a suitable solvent to provide compound of formula- 1, e) optionally purifying/isolating the compound obtained in step-d from a suitable solvent provides pure compound of formula- 1.

7. A process according to claim 6, wherein,

In step a) the suitable reducing agent is selected from heterogeneous catalysts containing from about 0.1% to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, raney nickel, palladium catalyst such as Pd/C, Pd/SrC0₃, Pd/Al₂0_3> Pd/MgO, Pd/CaC0_3, Pd/ BaS0_4, PdO, Pd Black, PdCl₂, Rh/C, Ru/C, Re/C, Pt0₂, Rh/C, Ru0_2, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride; the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof.

In step b) the suitable condensing agent is selected from carbodiimides such as NjN'-diisopropylcarbodiimide, l-ethyl-3-(3-dimethyl aminopropyl) carbodiimide, Ν,Ν'-dicyclohexyl carbodiimide; alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy- 3,4-dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate, di phenylphosphoroazidate, P₂0₅, 3-(diethoxyphosphoryloxy)- 1 ,2,3-benzotriazine- 4(3H)-one and Ν,Ν'-carbonyl diimidazole. The carbodiimides can be used optionally in combination with 1-hydroxybenzotriazole, 1 -hydroxy-7- azatriazole, 1- hydroxy-lH-l,2,3-triazole-4- carboxylate, N-hydroxy succinamide, (2-(lH- benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoro borate and dimethylamino pyridine; the suitable solvent is selected from chloro solvent such as dichloro methane, dichloroethane, chloroform and carbon tetrachloride.

In step c) the suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid; or organic acids such as acetic acid, trifluoroacetic acid, methane sulfonic acid, para toluene sulfonic acid, oxalic acid and tartaric acid; the suitable base is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; and the suitable solvent is selected from alcoholic solvents such as methyl alcohol, ethyl alcohol and isopropyl alcohol.

In step d) the suitable acetylating agent is selected from acetic anhydride, acetyl chloride; the suitable base is selected from organic bases such as triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, piperidine and pyridine; the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof,

In step e) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents and ketone solvents.

An improved process for the preparation of (S)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide compound of formula- 1, comprises of:

a) Reducing the 10-oxo-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 with sodiumborohydride in aqueous methanol to provide 10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4,

b) condensing the compound of formula-4 with N-benzyl-D-proline compound of formula-6a,

Formula-6a

in the presence of dicyclohexylcarbodiimide and dimethylamino pyridine in dichloro methane to provide (R)-((S)-5-carbamoyl-10,l l-dihydro-5H-dibenzo [b,fjazepin- 10-yl) 1 -benzylpyrrolidine-2-carboxylate compound of formula-7a,

Formula-7a

c) hydrolyzing the compound of formula-7a with sodium hydroxide in methanol to provide the compound of formula-3,

9. An improved process for the preparation of dibenz[b,fjazepine ester derivative compound of general formula-7 comprises of, condensing the 10-hydroxy- 10,11- dihydro-5H-dibenz[b,fJazepin-5-carboxamide compound of formula-4 with a suitable amino acid, optionally N-substituted such as D-proline derivative compound of general formula-6 in the presence of a suitable condensing agent in a suitable solvent provides compound of general formula-7.

10. A process according to claim 9, the preparation of (R)-((S)-5 -carbamoyl- 10,11- dihydro-5H-dibenz[b,fJazepin-10-yl)l -benzyl pyrrolidine-2-carboxylate compound of formula-7a comprises of, condensing the 10-hydroxy- 10,l l-dihydro-5H- dibenz[b,f]azepin-5-carboxamide compound of formula-4 with N-benzyl-D-proline compound of formula-6a in the presence of dicyclohexylcarbodiimide and dimethylamino pyridine in dichloro methane provides the compound of formula-7a.

11. An improved process for the preparation of (S)-l 0-hydroxy- 10,l l-dihydro-5H-dibenz [b,fJazepine-5-carboxamide compound of formula-3 comprises of, hydrolyzing dibenz[b,fjazepine ester derivative compound of general formula-7 with a suitable acid or base in a suitable solvent to provide the compound of formula-3.

12. According to claim 11, an improved process for the preparation of (S)-lO-hydroxy- 10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3 comprises of, hydrolyzing the ((R)-((S)-5 -carbamoyl- 10,1 l-dihydro-5H-dibenz [b,fjazepin-10-yl) 1 -benzyl pyrrolidine-2-carboxylate compound of formula-7a with a suitable acid or base in a suitable solvent to provide the compound of formula-3.

13. According to claims 11 & 12, the suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; or organic acids such as acetic acid, trifluoro acetic acid, methane sulfonic acid, para toluene sulfonic acid, oxalic acid and tartaric acid; and the suitable base is selected from inorganic bases such as alkali metal hydroxides, alkoxides, carbonates and bicarbonate; or organic bases such as triethyl amine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethyl amine, piperidine, dimethylamino pyridine and pyridine. 14. Usage of diisopropyl ethyl amine as a base in acetylating the (S)-l 0-hydroxy- 10,11- dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-3, to provide (S)- 10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula- 1. 15. (R)-((S)-5-carbamoyl-10,l l-dihydro-5H-dibenzo[b,fJazepin-l 0-yl) 1 -benzyl pyrrolidine -2-carboxylate compound having the structural formula,

Formula-7a 16. (S)-((S)-5 -carbamoyl- 10,l l-dihydro-5H-dibenzo[b,f]azepin-l 0-yl) 1 -benzylpyrrolidine -2-carboxylate compound having the structural formula,

17. (S)-((S)-5 -carbamoyl- 10,1 l-dihydro-5H-dibenzo[b,f]azepin-10-yl) 2-amino-2-phenyl acetate and its isomers.

18. (R)-((S)-5 -carbamoyl- 10,1 l-dihydro-5H-dibenzo[b,fJazepin-10-yl) 2-amino-2-phenyl acetate and its isomers.

19. An improved process for the preparation of dibenz[b,fjazepine ester derivative compound of general formula-9 comprises of, condensing the 10-hydroxy-10,l 1- dihydro-5H-dibenz[b,fJazepin-5-carboxamide compound of formula-4 with 2-amino-2- phenylacetic acid, in the presence of suitable condensing agent in a suitable solvent to provide the compound of general formula-9.

20. An improved process for the preparation of dibenz[b,f]azepine ester derivative compound of general formula-9 comprises of, condensing the 10-hydroxy-10,l 1- dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4 with 2-amino- 2-phenylacetyl chloride.

21. An improved process for the preparation of (R)-((S)-5-carbamoyl-10,l 1 -dihydro-5H- dibenzo[b,f]azepin-10-yl)l -benzyl pyrrolidine-2-carboxylate compound of formula-7a comprises of, condensing the lO-hydroxy-10,1 l-dihydro-5H-dibenz[b,f]azepine-5- carboxamide compound of formula-4 with (R)-l-benzylpyrrolidine-2-carbonyl chloride.

Dated this day of April 2011.

atyanarayana

MSN Laboratories Limited.