FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Tolvaptan. The present invention further relates to a process for the preparation of Tolvaptan by using Keto protected intermediate.

BACKGROUND OF THE INVENTION:

Tolvaptan, chemically known as (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-lH-l-benzazepin-1-yl) carbonyl]-o tolu-w-toluidide (OPC-41061), is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). The trade name of tolvaptan is Samsca and is structurally represented as shown below.

U.S patent 5258510 discloses the benzazepines compounds, derivatives and process for the preparation thereof. The process for the preparation of Tolvaptan according to the prior art process has certain especially when a Cs-substituent is required or an electron with -drawing groups are present in the aromatic ring. The preparation of tolvaptan invloves 11 steps, few of them are done under very critical conditions that limit the generality of this approach.

U.S application No US20090306369 discloses a process for the preparation of Tolvaptan and its derivatives thereof by using a benzazepine compound of formula 2 and compound of formula X;

The present invention relates to an improved process for the preparation of Tolvaptan via Keto intermediate or keto protected intermediate. Current process is safe, cost effective and eco-friendly.

SUMMARY OF THE INVENTION:

The main object of the present invention relates to an improved process for thepreparation of pure Tolvaptan.

Another object of the present invention relates to a process for the preparation of Tolvaptan by using keto protected intermediates.

Yet another object of the present invention relates to process for the preparation of Tolvaptan wherein the compound of formula A is reacted with 2-methyl-4-nitro benzoyl chloride in the absence of a base.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Tolvaptan. In one embodiment of the present invention relates to process for the preparation of Tolvaptan as depicted in the scheme I below:

In another embodiment, the present invention is to provide an improved process for the preparation of Tolvaptan comprising the steps of:

i) treating compound of formula A with 2-methyl-4-nitro benzoyl chloride in the absence of a base and in presence of an organic solvent to give compound of formula B

ii) Optionally purifying compound of formula B

iii) reducing compound of formula B in the presence of an organic solvent to give compound of formula C

iv) optionally purifying compound of formula C

v) treating the compound of formula C with toluoyl chloride in the presence of an organic solvent to give compound of formula D

vi) optionally purifying compound of formula D

vii) reducing compound of formula D in the presence of an organic solvent and isolating compound of formula I

viii) reducing compound of formula D and isolating compound of formula I

According to the present invention, compound of formula A is treated with the substituted benzoyl intermediate in presence of an organic solvent and in the absence of a base. Further conversion of nitro to amino is done by reducing the compound of formula B to compound of formula C using Raney nickel, palladium carbon, tin chloride, tin chloride dihydrate, Iron in acidic media, Samarium(II) iodide ("Kagan reagent"), SYNHYDRID Solution (70% solution of bis-(2-methoxyethoxy) sodium aluminum hydride), enzymatic reduction using e.g. Bakers Yeast whole cell & immobilized . The final reduction of keto to hydroxy is done using alkali borohydride such as sodium borohydride, enzymatic reduction using bakers Yeast whole cell & immobilized. The crude tolvaptan obtained by the above process is optionally purified from methanol, ethanol, methylisobutylketone, ethyl acetate and the like.

Yet another object of the present invention relates to a process for the preparation of Tolvaptan as depicted in the scheme II below

Yet another embodiment of the present invention provides a process for the preparation of Tolvaptan using keto protected intermediate.

Yet another embodiment of the present invention provides an improved process for the preparation of Tolvaptan comprising the steps of:

a) protecting the compound of formula 2 in an organic solvent

b) treating compound of formula 3 with 2-methyl-4-nitro benzoyl chloride in the presence of an organic solvent to give compound of formula 4

c) optionally purifying compound of formula 4

d) reducing compound of formula 4 in the presence of an organic solvent to give compound of formula 5

e) optionally purifying compound of formula 5

f) treating compound of formula 5 with toluoyl chloride in an organic solvent to give compound of formula 6

g) deprotecting the compound of formula 6 to give compound of formula D

h) reducing compound of formula D in the presence of an organic solvent to give compound of formula 1

i) Optionally purifying the compound of formula 1

According to the present invention, keto protected compound of formula 3 is treated with the substituted benzoyl intermediate in presence of an organic solvent optionally in the presence of a base. Further conversion of nitro to amino is done by reducing the compound of formula 4 to compound of formula 5 using Raney nickel, palladium carbon, tin chloride, Iron in acidic media, Samarium(II) iodide ("Kagan reagent") enzymatic reduction using e.g. Bakers Yeast whole cell & immobilized . The final reduction of keto to hydroxy is done using alkali borohydride such as sodium borohydride, SYNHYDRID Solution (70% solution of bis-(2-methoxyethoxy) sodium aluminum hydride), enzymatic reduction using Bakers Yeast whole cell & immobilized affords Tolvaptan. The crude tolvaptan obtained form the above process is optionally purified from methanol, ethanol, methylisobutylketone, ethyl acetate and the like.

According to the present invention, purification or crystallization or recrystallization may be initiated by methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof.

According to the present invention, the keto group protection is done by using Schiff base, ethylene glycol and 1, 3-propane diol etc and the deprotection is done by aqueous acid such as hydrochloric acid, or organic acid such as oxalic acid, acetic acid. According to the present invention, isolated solid product can optionally be dried using any technique, such as fluid bed drying, aerial drying, oven drying or other techniques known in the art at temperatures of about 25 to 100°C, or 50 to 60°C, with or without application of vacuum and/or under inert conditions.

Yet another embodiment, the present invention provides an enzymatic process for the preparation of compound of formula C or compound of formula 5 comprising the steps of:

a) heating a solution of baker yeast in water;

b) adding compound of formula B taken in an organic solvent to a solution of step (a) in presence of a base;

c) removing the solvent; and

d) isolating compound of formula C or compound of formula 5.

According to the present invention, compound of formula B taken in an organic solvent, adding baker yeast, is treated with the substituted benzoyl intermediate in presence of an organic solvent optionally in the presence of a base. Further conversion of nitro to amino is done by reducing the compound of formula 4 to compound of formula 5 using Raney nickel, palladium carbon, tin chloride, Iron in acidic media, Samarium(II) iodide ("Kagan reagent") enzymatic reduction using e.g. Bakers Yeast whole cell & immobilized.

According to the present invention, organic solvents include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, tertiary-butyl alcohol, and the like; ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA) and the like; and mixtures thereof or their combinations with water in various proportions without limitation

The keto protected process of the present invention avoids the formation of dimmer impurity of formula M

According to the present invention, the optional purifications done at the intermediate stages will provide pure tolvaptan.

Certain specific aspects and embodiments of the present invention will be explained in detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

Examples

Example-1a: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one

2-Methyl-4-nitro benzoic acid (5 g) was stirred with Toluene (100 ml), and was added thionyl chloride (3 ml) with stirring at room temperature in about one hour. The reaction mixture was heated to reflux for two hours. To the clear solution obtained, added 7-chloro-1, 2, 3, 4-tetrahydrobenzo[b]azepin-5-one (6 g) dissolved in toluene (100 ml) in about one hour at reflux temperature. The reaction mixture was maintained under stirring at reflux temperature till the completion of the reaction. The resulted reaction mixture was slowly added to a vessel containing 100 ml of 10 % sodium chloride under stirring. The organic layer was separated and washed twice with 5% sodium hydroxide solution and dried over sodium sulphate, Sodium sulfate was removed by filtration ,the filtrate was concentrated under reduced pressure to give 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one (7.5 g) HPLC purity - 98.9 %.

Example -1b: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l, 2,3,4-tetrahy dro-benzo [b] azepin-5-one

2-Methyl-4-nitro benzoic acid (5 g) was stirred with dichloromethane (100 ml) and was added thionyl chloride (3 ml) with stirring at room temperature in about one hour. The reaction mixture was heated to reflux. To the reaction clear solution obtained was added 7-chloro-l, 2, 3, 4-tetrahydrobenzo[b]azepin-5-one (6 g) which was pre-dissolved in dichloromethane (50 ml) in about one hour at reflux temperature. Reaction mixture stirred at room for about sixteen hours till the completion of the reaction. The resulted reaction mixture was slowly added to a vessel containing 100 ml of 10 % sodium chloride under stirring. The organic layer was separated and washed twice with 5% sodium hydroxide solution and dried over sodium sulphate, Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one (yield-7.6 g) HPLC purity-98.67%.

Example -1c: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahy dro-benzo [b] azepin-5-one

2-Methyl-4-nitro benzoic acid (5 g) is stirred with dichloromethane (100 ml) there was added thionly chloride (3 ml) with stirring at room temperature about one hour. During which reaction mixture was heated to reflux for two hours. Dichloromethane was removed by distillation under vacuum; the reaction mixture obtained was added to solution of 7-chloro-l, 2, 3, 4-tetrahydrobenzo[b]azepin-5-one (6 g) which was dissolved in dichloromethane 50 ml about one hour at room temperature. Reaction mixture stirred at room for sixteen hours to complete reaction. The resulted reaction mixture slowly added to a vessel containing 100 ml of 10 % sodium chloride under stirring. The organic layer is separated and washed twice with 5% sodium hydroxide solution and dried over sodium sulphate, Sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to give 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one (7.5 g) purity 99.3 % Example -Id:

Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one 2-methyl-4-nitro benzoic acid (5 g) was stirred with toluene (100 ml) and was added thionyl chloride (3 ml) with stirring at room temperature in about one hour. The reaction mixture was heated to reflux. Toluene was removed by distillation under vacuum and added to solution of 7-chloro-l, 2, 3, 4-tetrahydrobenzo[b]azepin-5-one (6 g) dissolved in dichloromethane (50ml) in about one hour at room temperature. Reaction mixture was stirred at room temperature for about sixteen hours to confirm the completion reaction by TLC. The resulted reaction mixture was slowly added to a vessel containing 100 ml of 10 % sodium chloride under stirring. The organic layer is separated and washed twice with 5% sodium hydroxide solution and dried over sodium sulphate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give 7-chloro-1 -(2-methyl-4-nitro-benzoyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one (6.6 g) Example-le: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one 2-Methyl-4-Nitrobenzoic Acid (10 g) was stirred with toluene (100 ml) and there was added dimethylformamide (1ml) and thionyl chloride (9.8 g) with stirring at room temperature. During which reaction mixture was heated to reflux for 2-3 hours, after confirming the disappearance of starting material solvent was removed by atmospheric distillation upto 5V. The resulted reaction mixture slowly added with stirring to a solution of 7-Chloro-l, 2, 3, 4-Tetrahydrobenzo[b]azepin-5-One (10 g) in toluene (100 ml) and potassium carbonate (22 g) at 0°C-10°C. Reaction mixture stirred at room temperature for 10-30 hrs, after confirming the disappearance of starting material washed with DM Water (100 ml). The organic layer was separated and concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (Yield-48 %) (HPLC - 98.50 %)

Example-lf: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one 2-Methyl-4-Nitrobenzoic Acid (10 g) was stirred with toluene (50 ml) and there was added thionyl chloride (9.8 g) with stirring at room temperature. During which reaction mixture was heated to reflux for 2-4 hrs, after confirming the disappearance of starting material solvent was removed by atmospheric distillation upto lv-2v. The resulted reaction mixture slowly added with stirring to a solution of 7-Chloro-l, 2, 3, 4- Tetrahydrobenzo[b]azepin-5-One (12 g) in methylenedichloride (200 ml) and dimethylformamide (20 ml) at 0°C-5°C .Reaction mixture stirred at room temperature for 20-50 hrs, after confirming the disappearance of starting material washed with DM Water (3X100 ml).The organic layer was separated and concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One

(Yield-1.29w/w) (HPLC - 87.10 %)

Example-1g: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one2-Methyl-4-Nitrobenzoic Acid (5 g) was stirred with toluene (25 ml) and there was added thionyl chloride (3 ml) with stirring at room temperature. During which reaction mixture was heated to reflux for 2-3 hours, after confirming the disappearance of starting material solvent was removed by atmospheric distillation upto 5V. The resulted reaction mixture slowly added with stirring to a solution of 7-Chloro-l, 2, 3, 4-Tetrahydrobenzo[b]azepin-5-One (6 g) in dichloromethane(50 ml) and N-Methyl morpholine at 0°C-5°C. Reaction mixture was stirred at room temperature for 5-10 hrs, after confirming the disappearance of starting material washed with DM Water (25 ml), IN Hcl (25 ml) and DM Water (25 ml).The organic layer was separated and concentrated under reduced pressure. The resultant crude was recrystallized in methanol and triethylamine to give 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3,4-Tetrahydro benzo[b]azepin-5-One

(Yield-1.15 w/w) (HPLC - 99.29 %)

Example-lb: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo [b] azepin-5-one

2-Methyl-4-Nitrobenzoic Acid (5 g) was stirred with toluene (25 ml) and there was added thionyl chloride (4.50 g) with stirring at room temperature. During which reaction mixture was heated to reflux for 2-3 hours, after confirming the disappearance of starting material solvent was removed by atmospheric distillation upto lv-2v. The resulted reaction mixture slowly added with stirring to a solution of 7-Chloro-l, 2, 3, 4-Tetrahydrobenzo[b]azepin-5-One (6 g) in dichloromethane (60 ml) at 0°C-5°C. Reaction mixture stirred at room temperature for 10-15 hrs, after confirming the disappearance of starting material washed with DM Water (60 ml). The organic layer was separated and concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5- One

(Yield-1.30w/w) (HPLC - 98.83%)

Example-11: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one

2-Methyl-4-Nitrobenzoic Acid (25 g) was stirred with toluene (125 ml) and there was added dimethylformamide (0.25ml) and thionyl chloride (24 g) with stirring at room temperature. During which reaction mixture was heated to reflux for 2-3 hours, after confirming the disappearance of starting material solvent was removed by atmospheric distillation upto lv-2v. The resulted reaction mixture slowly added with stirring to a solution of 7-Chloro-l,2,3,4-Tetrahydrobenzo[b]azepin-5-One (32 g) in dichloromethane(200 ml) and triethylamine (41 g) at 0°C-10°C. Reaction mixture stirred at 0°C-10°C for 5-10 hrs, after confirming the disappearance of starting material washed with DM Water (2X250 ml). The organic layer was separated and concentrated under reduced pressure.

The resultant crude was recrystallized in methanol to give 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One

(Yield-1.52w/w) (HPLC - 85.58 %)

Example-1J: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one (Without base)

2-Methyl-4-Nitrobenzoic Acid (4.6 g) was stirred with toluene (25 ml) and there was added thionyl chloride (3.6 g) with stirring at room temperature. During which reaction mixture was heated to reflux for 2-3 hours, after confirming the disappearance of starting material and there was added solution of 7-Chloro-l, 2, 3, 4-Tetrahydrobenzo[b]azepin-5-One (5 g) in toluene (100 ml) at 100°C. Reaction mixture was heated to reflux for 2-3hrs, after confirming the disappearance of starting material washed with DM Water (25 ml), 5% sodium bicarbonate (2X25 ml) and DM Water (25 ml). The organic layer was separated and concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4- Tetrahydro benzo[b]azepin-5-One

(Yield-1.29w/w) (HPLC - 98.2%)

Example-1K: Preparation of 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one

2-Methyl-4-Nitrobenzoic Acid (100 g) was stirred with toluene (1300 ml) and there was added dimethylformamide (5 ml) and thionylchloride (82 g) with stirring at room temperature. During which reaction mixture was heated to reflux for 2-3 hours, after confirming the disappearance of starting material and there was added solution of 7-Chloro-1, 2, 3, 4-Tetrahydrobenzo[b]azepin-5-One (108 g) in methylenedichloride (300 ml) at 50-70°C. Reaction mixture was heated to 100-120°C by removing methylenedichloride and stirred at 100-120°C for 4-8 hrs, after confirming the disappearance of starting material concentrated under reduced pressure. The crude obtained was diluted with methylenedichloride (1000 ml) and washed with DM Water (500 ml) and 5% sodium bicarbonate (500 ml) and DM Water (500 ml). The organic layer was separated and concentrated under reduced pressure. The resultant crude was recrystallized in methanol and triethylamine to give 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3,4-Tetrahydro benzo[b]azepin-5-One (Yield-1.7w/w) (HPLC - 98.95%)

Purification 1

To a stirred suspension of 7-Chloro-l-(2-methyl-4-nitro-benzoyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one(10 g) in methanol (100 ml) there was added triethylamine (10 ml) and stirred at it for 10 minutes, the stirred suspension obtained was heated to reflux and continued the reflux for 1 to 3 hours , slowly cooled to room temperature and stirred at same temperature for 2 to 5 hours and filtered the reaction mass and washed with methanol and dried to give 8.5 g pure compound HPLC : 99.5 %

Purification 2

To a stirred solution of 7-Chloro-l-(2-methyl-4-nitro-benzoyl)-l, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one (10 g) in toluene (20 ml) there was added triethylamine (10 ml) There was added methanol for one hour. The stirred suspension obtained was stirred for overnight at room temperature. The resulted solids were filtered and washed with methanol and dried to give 8.1 g pure compound. HPLC purity: 99%

Purification 3

7-Chloro-l-(2-methyl-4-nitro-benzoyl)-l, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one (10 g) was further recrystallised in dimethylformamide and water (1:1) and dried to give 7.1 g pure compound. HPLC purity: 99%

Purification 4

7-Chloro-l-(2-methyl-4-nitro-benzoyl)-l, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one (10 g) is dissolved in toluene 60 ml with stirring at 80-90° C over a period of 60 minutes.

During which the clear solution was stirred at reflux temperature for one to two hours.
The resulted solution was cooled to room temperature and stirred for overnight. Thus obtained solids were separated by filtration and dried to give 6.6 g pure compound HPLC 99.22 %

Purification 5

7-chloro-l-(2-methyl-4-nitro-benzoyI)-l, 2, 3,4-tetrahydro-benzo[b]azepin-5-one (10 g) is dissolved in ethyl acetate 60 ml with stirring at 80-90° C over a period of 60 minutes.

During which the clear solution was stirred at reflux temperature for one to two hours.

The resulted solution was cooled to room temperature and stirred for overnight. Thus obtained solids were separated by filtration to give 6.6 g pure compound 7.2 g HPLC 99.27 %

Purification 6

To a stirred suspension of 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (25 g) in methanol (250 ml) and there was added triethylamine (25 ml) and stirred at room temperature for 10-30 minutes. The stirred suspension obtained was heated to reflux for 1- 2 hrs. The resulted mass cooled to room temperature and stirred for 1-2 hrs and filtered the reaction mass and washed with methanol to obtain good purity.

(Yield-89 %) (HPLC- 99.45 %)

Purification 7

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (5g) was dissolved in toluene (30 ml) with stirring at 80-90° C for 30-60 minutes. The resulted solution was cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with toluene to obtain good purity. (Yield-62 %) (HPLC- 99.22 %)

Purification 8

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2,3,4-Tetrahydro benzo[b]azepin-5-One (lOg) was dissolved in a mixture of methylenedichloride (100 ml) and methanol (100 ml) with stirring at room temperature for 30-60 minutes and there was added triethylamine(10 ml).The solvent was removed by atmospheric distillation upto 5v-8v. The resulted mass cooled to room temperature and stirred for 2-4 hrs. Thus obtained solid was filtered and washed with methanol to obtain good purity. (Yield-65 %) (HPLC- 99.40 %)

Purification 9

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (l0g) was dissolved in acetone (180 ml) with stirring at reflux temperature for 30-60 minutes and the solvent was removed by atmospheric distillation upto 4v- 5v. The resulted mass cooled to room temperature and stirred for 2-4 hrs. Thus obtained solid was filtered and washed with DM Water to obtain good purity. (Yield-57 %) (HPLC 99.-52 %) Purification 10 To stirred solution of 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (5g) in acetone (50 ml) there was added DM Water (25 ml) with stirring at room temperature. The stirred suspension obtained was heated to reflux for 1-2 hrs. The resulted mass cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with DM Water to obtain good purity. (Yield-78 %) (HPLC 98.77 %)

Purification 11

To stirred solution of 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (5g) in dimethylformamide(30 ml) there was added DM Water (30 ml) with stirring at room temperature. The stirred suspension obtained was heated to reflux for 1-2 hrs. The resulted mass cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with DM Water to obtain good purity. (Yield-71 %) (HPLC 97.90 %) Purification 12 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (5 g) was dissolved in ethyl acetate(30 ml) with stirring at reflux temperature for 30-60 minutes. The resulted solution was cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with ethyl acetate. (Yield-55 %) (HPLC 99.27 %)

Example-2a: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one 7-Chloro-l-(2-methyl-4-nitro-benzoyl)-l, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one (30 g) was added ethanol (300 ml) and cone. HC1 (210 ml) under stirring and then added Tin chloride dihydrate (SnCl22H20) (65 g) at room temperature. The reaction mass was maintained at room temperature for overnight. After confirming the disappearance of starting material, solvents were removed by vacuum distillation. The crude obtained was diluted with dichloromethane and added water. The pH of the biphasic solution obtained was adjusted to 12-14 using 40 % NaOH solution. Separated the layers and washed with water (2 x 300 ml) and sodium bicarbonate (2 x 300 ml) dried over sodium sulfate. After filtering off sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was recrystalised in isopropyl ether to give l-(4-Amino-2-methyl-benzoyl)-7-chloro-l, 2, 3, 4-tetrahydro-benzo[6]azepin-5-one (23.2 g), HPLC purity: 98.8%

Example-2a: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[£]azepin-5-one

7-Chloro-l-(2-methyl-4-nitro-benzoyl)-l, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one (10 g) was added ethanol (100 ml) and cone. HC1 (75 ml) under stirring and then added Tin chloride (19 g) at room temperature. The reaction mass was maintained at room temperature for overnight. After confirming the disappearance of starting material, solvents were removed by vacuum distillation. The crude obtained was diluted with dichloromethane and added water. The pH of the biphasic solution obtained was adjusted to 12-14 using 40 % NaOH solution. Separated the layers and washed with water (2 x 100 ml) and sodium bicarbonate (2 x 100 ml) dried over sodium sulfate. After filtering off sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was recrystalised in isopropyl ether to give l-(4-Amino-2-methyl-benzoyl)-7-chloro-l, 2, 3, 4-tetrahydro-benzo[6]azepin-5-one (8.1 g), HPLC purity: 98.7%

Example-2: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[£]azepin-5-one

7-Chloro-l-(2-methyl-4-nitro-benzoyl)-l, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one (5 g) was added Methanol (100 ml) and cone. HC1 (30 ml) under stirring and then added iron (2.4 g) at room temperature. The reaction mass was maintained at reflux for 2-4 hr. After confirming the disappearance of starting material, reaction mass filtered, solvents were removed by vacuum distillation. The crude obtained was diluted with dichloromethane and added water. The pH of the biphasic solution obtained was adjusted to 12-14 using NaOH solution. Separated the layers and washed with water (2 x 300 ml) and sodium bicarbonate (2 x 300 ml) dried over sodium sulfate. After filtering off sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was recrystalised in isopropyl ether to give l-(4-Amino-2-methyl-benzoyl)-7-chloro-1, 2, 3, 4-tetrahydro-benzo[6]azepin-5-one (3.8 g), HPLC purity: 98 %

Example-2b: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one

7-Chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro-benzo[b]azepin-5-one ( 30 g ) was stirred with methanol (300 ml) and was added Raney Nickel (3 g) with stirring at room temperature in a 1 liter autoclave . Applied hydrogen gas up to 2 kg pressure and heated the reaction mass to 45-50° C for two to three hours. After confirming the disappearance of starting material, catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The crude obtained was diluted with dichloromethane and added water. Dichloromethane layer was washed with water (2X300 ml) and sodium bicarbonate (2X300 ml) and dried over sodium sulfate. After filtering off sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was recrystalised in isopropyl ether to give l-(4-Amino-2-methyl-benzoyl)-7-chloro-l, 2, 3, 4-tetrahydro-benzo[6]azepin-5-one, (Yield-76%)(HPLC-91.8%)

Example-2c: Preparation of l-(4-Amino-2-methyl-benzoyI)-7-chloro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one

7-Chloro-l-(2-methyl-4-nitro-benzoyl)-l,2,3,4-tetrahydro- enzo[b]azepin-5-one ( 10 g ) was stirred with methanol (100 ml) and was added Pd/C (10% ; 1 g) with stirring at room temperature in a 1 liter autoclave . During which hydrogen gas applied up to 2 kg pressure and heated the reaction mass to 25-40° C for two to three hours, .after confirming the disappearance of starting materiaf, cataiyst was removed by filtration. The filtrate was concentrated under reduced pressure. The crude obtained was diluted with Dichloromethane and added water. DCM layer was washed with water (2 x 300 ml) and sodium bicarbonate (2 x 300 ml) and dried over sodium sulfate, after filtering off sodium sulfate; the filtrate was concentrated under reduced pressure to give the crude product, the resultant crude was recrystalised in isopropyl ether to give l-(4-Amino-2-methyl-benzoyl)-7-chloro-l, 2, 3, 4-tetratiydro-benzo[&]azepin-5-one to give 6.7 g (HPLC-97.8 %)

Example-2d: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro enzo[b]azepin-5-One ( 10 g) was stirred in methanol (100 ml) and cone. Hcl (70 ml) and there was added SnC12.2H20 (25 g) with stirring at room temperature. During which reaction mixture was stirred at room temperature for 10-30 hrs, after confirming the disappearance of starting material, there was added dichloromethane (300 ml).The biphase obtained was adjusted the PH of reaction mass 12-14 with 40 % NaOH solution. The organic layer was separated and washed with DM water (2X100 ml) and concentrated under reduced pressure. The resultant crude was recrystallized in isopropyl ether to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 25 3, 4-Tetrahydro benzo[6]azepin-5-One. (Yield-85 %) (HPLC-98.93%)

Example-2e: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro enzo[b]azepin-5-One ( 50 g) was stirred in methanol (500 ml) and cone. Hcl (350 ml) and there was added SnC12.2H20 (125 g) with stirring at room temperature. During which reaction mixture was heated to reflux for 1-2 hrs, after confirming the disappearance of starting material, there was added dichloromethane (1000 ml). The biphase obtained was adjusted the PH of reaction mass 12-14 with 40 % NaOH solution. The organic layer was separated and washed with DM water (3X250 ml) and concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-1,2, 3,4-Tetrahydro benzo[6]azepin-5-One. (Yield-80 %) (HPLC-99.72%)

Example-2f: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahy dro-benzo [b] azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro enzo[b]azepin-5-One ( 30 g ) was stirred in a mixture of methanol (450 ml), acetone (300 ml) and cone. Hcl (210 ml) and there was added SnC12.2H20 (75 g) with stirring at room temperature . During which reaction mixture was stirred at room temperature for 5-10 hrs, after confirming the disappearance of starting material, solvents was concentrated under reduced pressure. The crude obtained was diluted with Dichloromethane (900 ml), DM water (150 ml) and methanol (150 ml). The biphase obtained was adjusted the PH of reaction mass 12-14 with 40 % NaOH solution. The organic layer was separated and washed with DM water (2X300 ml) and concentrated under reduced pressure. The resultant crude was recrystallized in isopropyl ether to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3, 4-Tetrahydro benzo[%zepin-5-One. (Yield-71 %) (HPLC-97.90%)

Example-2g: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chIoro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro benzo[b]azepin-5-One ( 30 g ) was stirred in ethanol (300 ml) and cone. Hcl (180 ml) and there was added SnC12.2H20 (75 g) with stirring at room temperature. During which reaction mixture was heated to reflux for 2-4 hrs, after confirming the disappearance of starting material, there was added dichloromethane (900 ml) and DM Water (150 ml). The biphase obtained was adjusted the PH of reaction mass 12-14 with 40 % NaOH solution. The organic layer was separated and washed with DM water (2X300 ml) and concentrated under reduced pressure. The resultant crude was recrystallized in isopropyl ether to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3, 4-Tetrahydro benzo[6]azepin-5-One. (Yield-48 %) (HPLC-97.36%)

Example-2h: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro enzo[b]azepin-5-One (l00g) was stirred in Water(100 ml) and Acetone (1900 ml) mixture and there was added Raney Ni (10 g) with stirring at room temperature in a autoclave. During which hydrogen gas applied up to 5 kg pressure and stir at room temperature at about 10-20 hrs, after confirming the disappearance of starting material, catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3, 4-Tetrahydro benzo [b] azepin-5-One. (Yield-84 %) (HPLC-99.57 %)

Example-2i: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[Z>]azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-1,2,3,4-Tetrahydro enzo[b]azepin-5-One (100 g) was stirred in Water(400 ml) and Acetone (1600 ml) mixture and there was added Raney Ni (10 g) with stirring at room temperature in a autoclave. During which hydrogen gas applied up to 10 kg pressure and stir at 50°C about 5-10 hrs, after confirming the disappearance of starting material, catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3, 4-Tetrahydro-benzo[6]azepin-5-One. (Yield-80 %) (HPLC-96.15 %)

Example-2j: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro enzo[b]azepin-5-One (100 g) was stirred in acetone (3000 ml) and there was added Raney Ni (10 g) with stirring at room temperature in a autoclave. During which hydrogen gas applied up to 10 kg pressure and stir at 50°C about 10-40 hrs, after confirming the disappearance of starting material, catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give 1 -(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3, 4-Tetrahydro-benzo[Z>]azepin-5-One. (Yield-80 %) (HPLC-98.97 %)

Example-2k: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[A]azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro enzo[b]azepin-5-One (30 g) was stirred in methanol (900 ml) and there was added Raney Ni (3 g) with stirring at room temperature in a autoclave. During which hydrogen gas applied up to 5 kg pressure and stir at room temperature about 5-10 hrs, after confirming the disappearance of starting material, catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The resultant crude was recrystallized in isopropyl ether to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3, 4-Tetrahydro benzo[6]azepin-5-One. (Yield-80 %) (HPLC-89.18 %)

Example-21: Preparation of l-(4-Amino-2-methyI-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro enzo[b]azepin-5-One (20 g) was stirred in ethyl acetate (300 ml) and there was added Pd/C (lg) with stirring at room temperature in a autoclave. During which hydrogen gas applied up to 3 kg pressure and stir at 45 °C about 5-10 hrs, after confirming the disappearance of starting material, catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The resultant crude was recrystallized in isopropyl ether to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3,4-Tetrahydro-benzo[6]azepin-5-One. (Yield-80 %) (HPLC-90.23 %)

Example-2m: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chIoro-l,2,3,4-tetrahydro-benzo [b] azepin-5-one

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (5 g) was stirred in dimethylformamide (75 ml) and there was added Pd/C (0.25g) with stirring at room temperature. During which hydrogen gas purged and stir at room temperature about 5-10 hrs, after confirming the disappearance of starting material, catalyst was removed by filtration. The filtrate was concentrated under reduced pressure upto 2V and recrystallized followed by DM Water (50 ml) addition to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3, 4-Tetrahydro-benzo[6]azepin-5-One. (Yield-70 %) (HPLC-64.51 %)

Example-2n: Preparation of l-(4-Amino-2-methyl-benzoyI)-7-chloro-l,2,3,4-tetrahydro-benzo[Z>] azepin-5-one 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro benzo[b]azepin-5-One (10 g) was stirred in a mixture of methanol(200 ml), DM Water(30 ml) and Con. Hcl(10 ml) and there was added Pd/C (lg) with stirring at room temperature. During which hydrogen gas purged and stir at room temperature about 5-10 hrs, after confirming the disappearance of starting material, catalyst was removed by filtration. The crude obtained was diluted in Dichloromethane (100 ml) and washed with water (3X50 ml), the organic layer was concentrated under atmospherically to give the crude product. The resultant crude was recrystallized in methanol to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3, 4-Tetrahydro benzo[6]azepin-5-One. (Yield-62 %) (HPLC-97.82 %) Example-2o: Preparation of l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4-tetrahydro-benzo[6]azepin-5-one 7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l,2,3,4-Tetrahydro benzo[b]azepin-5-One (20 g) was stirred in a mixture of methanol (200 ml) and acetone (200 ml) and there was added Raney Ni (2g) with stirring at room temperature. During which hydrogen gas applied upto 5 kg pressure and stir at 28°C-50°C about 10-40 hrs, after confirming the disappearance of starting material, catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l, 2, 3, 4-Tetrahydro benzo[6]azepin-5-One. (Yield-70 %) (HPLC-98.84 %

Purification-1

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (lOg) was dissolved in acetone (300 ml) with stirring at reflux temperature for 30-60 minutes and the solvent was removed by atmospheric distillation upto 4v- 5v. The resulted mass cooled to room temperature and stirred for 2-4 hrs. Thus obtained solid was filtered and washed with DM Water to obtain good purity.

Purification-2

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3,4-Tetrahydro benzo[b]azepin-5-One (l0g) was dissolved in a mixture of methylenedichloride (100 ml) and methanol (100 ml) with stirring at room temperature for 30-60 minutes. The solvent was removed by atmospheric distillation upto 4v-5v. The resulted mass cooled to room temperature and stirred for 2-4 hrs. Thus obtained solid was filtered and washed with methanol to obtain good purity.

Purification-3

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (l0g) in toluene (50 ml) was stirred at 50-60° C for 30-60 minutes. The resulted mass was cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with toluene to obtain good purity.

Purification-4

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (l0g) in ethyl acetate (50 ml) was heated to reflux temperature for 30-60 minutes. The resulted solution was cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with ethyl acetate to obtain good purity.

Purification-5

7-Chloro-l-(2-Methyl-4-Nitrobenzoyl)-l, 2, 3, 4-Tetrahydro benzo[b]azepin-5-One (l0g) in methanol (40 ml) was heated to reflux temperature for 30-60 minutes. The resulted solution was cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with methanol to obtain good purity.

Example 3a: Preparation of IV-[4-(7-chloro-5-oxo-2,3,4,5-tetrahydro- benzo[£]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide 1 -(4-Amino-2-methyl-benzoyl)-7-chloro-1,2,3,4-tetrahydro-benzo[Z>]azepin-5-one (50 g) was dissolved in dichloromethane (500 ml) and Triethylamine ( 63 ml) and there is added toluoyl chloride with stirring under ice cooling over a period of 30 minutes. During which reaction mass stirred at same cooling temperature for two to three hours. After confirming the disappearance of starting material, dichloromethane layer was washed with water (2 x 300 ml) and sodium bicarbonate (2X300 ml) and dried over sodium sulfate, after filtering off sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was recrystalised in isopropyl ether to give IV-[4-(7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-benzo[6]azepin-l-carbonyl)-3- methyl-pheyl]-2-methyl-benzamide (60 g; HPLC-98.51)

Example 3b: Preparation of JV-[4-(7-chloro-5-oxo-2,3,4,5-tetrahydro- benzo[6]azepin-l-carbonyl)-3-methyI-pheyI]-2-methyI-benzamide

l-(4-Amino-2-Methylbenzoyl)-7-Chloro-l,2,3,4-Tetrahydrobenzo[6]azepin-5-One(10 g) was dissolved in dichloromethane (50 ml) and Triethylamine (4.6 ml) and there is added toluoyl chloride (5.6 g) with stirring under ice cooling over a period of 1-2 hrs. During which reaction mass stirred at same cooling temperature for 2-4hrs. After confirming the disappearance of starting material, washed with DM Water (30 ml) and sodium bicarbonate (30 ml) and DM Water (30 ml). The organic layer was separated and concentrated under reduced pressure. The resultant crude was recrystallized in methanol to give JV-[4-(7-Chloro-5-Oxo-2, 3, 4, 5-Tetrahydrobenzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide. (Yield-1%) (HPLC-99.78%)

Purification -1

IV-[4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[Z>]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (10 g) is dissolved in dichloromethane 30 ml with stirring at 40-50° C over a period of 60 minutes. During which the clear solution was stirred at reflux temperature for one to two hours. The resulted solution was cooled to room temperature and added 100 ml of Isopropyl ether and stirred for overnight. Thus obtained solids were separated by filtration & dried to give (9 g; HPLC 99.22 %)

Purification -2

IV-[4-(7-Chloro-5-Oxo-2, 3,4, 5-Tetrahydro benzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (13 g) in methanol (65 ml) was heated to reflux temperature and the solvent was removed by atmospheric distillation and there was added methanol (65 ml). The resulted mass was cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with methanol to obtain good purity. (Yield-76%) (HPLC-99.43%)

Purification -3

Af-[4-(7-Chloro-5-Oxo-2,3,4,5-Tetrahydro benzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (10 g) is dissolved in a mixture of methanol (100 ml) and acetic acid (10ml) with stirring at reflux temperature for 30-60 minutes. The resulted solution was cooled to room temperature and stirred for 2-4 hrs. Thus obtained solid was filtered and washed with methanol to obtain good purity.

Purification -4

Aq4-(7-Chloro-5-Oxo-2, 3,4, 5-Tetrahydrobenzo[&]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (10 g) in isopropyl ether (100 ml) was heated to reflux temperature for 30-60 minutes. The resulted mass was cooled to room temperature and stirred for 2-4 hrs. Thus obtained solid was filtered and washed with isopropyl ether to obtain good purity.

Example 4a: Preparation of JV-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[6]azepin-l-carbonyI)-3-methyl-pheyl]-2-methyl-benzamide iV-[4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[6]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide was dissolved in methanol (100 ml) and there was added sodium borohydride (1.5 g) with stirring under ice cooling over a period of one hour. During which reaction mixture was stirred at same cooling temperature for two to three hours. After confirming the disappearance of starting material, solvents were removed by vacuum distillation. The crude obtained was diluted with Dichloromethane and added water. Dichloromethane layer was washed with water (2X300 ml) and 5 % sodium bicarbonate (2X300 ml) and dried over sodium sulfate, after filtering off sodium sulfate; the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was recrystalised in methanol and water (1:1) to give Af-[4-(7-chloro-5-hydroxy-2, 3, 4, 5-tetrahydro-benzo[£]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (8.6 g) (HPLC-99.44 %)

Example 4b: Preparation of JV-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[Z>]azepin-l-carbonyI)-3-methyl-pheyl]-2-methyl-benzamide iV-[4-(7-Chloro-5-Oxo-2,3,4,5-Tetrahydrobenzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (100 g) was dissolved in methanol (1000 ml) and there was added sodium borohydride (5.1g) dissolved in 5 % aqueous NaOH solution (100 ml) with stirring under ice cooling over a period of 1-2 hrs. During which reaction mixture was stirred at same cooling temperature for 1-4 hrs. After confirming the disappearance of starting material, there was added DM Water (500 ml) and stirred for 2-4 hrs. The resultant was filtered and washed with DM Water to give JV-[4-(7-Chloro-5-Hydroxy-2, 3, 4, 5-Tetrahydrobenzo[6]azepin-1 -carbonyl)-3-Methylpheyl]-2-Methylbenzamide. (Yield-86 %) (HPLC-99.44 %)

Example 4c: Preparation of JV-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[6]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide

N-[4-(7-Chloro-5-Oxo-2, 3, 4, 5-Tetrahydrobenzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (10 g) was dissolved in a mixture of methanol (40 ml) and methylenedichloride (30 ml). There was added sodium borohydride (0.33g) dissolved in 2% aqueous NaOH solution (10ml) with stirring under ice cooling over a period of 1-2 hrs. During which reaction mixture was stirred at same cooling temperature for 1-4 hrs. After confirming the disappearance of starting material, there was added DM Water (40 ml) and methylenedichloride (30 ml). The organic layer was separated and washed with DM water (40 ml) and concentrated under reduced pressure. The resultant crude was recrystallized in ethyl acetate to give N-[4-(7-Chloro-5-Hydroxy-2, 3, 4, 5-Tetrahydrobenzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide. (Yield-86 %) (HPLC-99.99 %) Purification -1 V-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[6]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (10 g) is dissolved in methanol 100 ml with stirring at room temperature over a period of 60 minutes. During which the clear solution was stirred at reflux temperature there was added 200 ml of water for one to two hours. The resulted solids was cooled to room temperature and stirred for overnight. Thus obtained solids were separated by filtration and dried to 8.1 g Purification-2

Ar-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[6]azepin-l-carbonyl)^3-methyl-pheyl]-2-methyl-benzamide (5 g) is dissolved in Methylisobutylketone 150 ml with stirring at 120-130° C over a period of 60 minutes. During which the clear solution was stirred at reflux temperature for one to two hours. The resulted solution was cooled to room temperature and stirred for overnight. Thus obtained solids were separated by filtration & dried to give 7.6 g

Purification-3

A^-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[6]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (5 g) is dissolved in ethanol 150 ml with stirring at 80-90° C over a period of 60 minutes. During which the clear solution was stirred at reflux temperature for one to two hours. The resulted solution was cooled to room temperature and stirred for overnight. Thus obtained solids were separated by filtration & dried to give 6.9 g Purification-4 ^-^-(y-chloro-S-hydroxy^^^^-tetrahydro-benzo^jazepin-l-carbonyO-S-methyl- pheyl]-2-methyl-benzamide (5g) was dissolved in ethyl acetate (250ml) and stirred at 80-90° C over a period of 60 minutes. The clear solution thus obtained was stirred at reflux temperature for one to two hours. The resulted solution was distilled off atmospherically up to first crystal appeared. The resulted suspension was cooled to room temperature and stirred for overnight and the obtained solids were separated by filtration and dried to give 7.8 g of compound.

Purification-5

IV-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (80 g) was dissolved in a mixture of ethyl acetate (800 ml) and methanol (320 ml) at reflux temperature over a period of 30-60 minutes. The solvent was removed by atmospheric distillation upto 5v-10. The resulted suspension was cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with ethyl acetate to obtain good purity. (Yield-83%) (HPLC-99.55%)

Purification-6

IV-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[*]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (50) g was dissolved in methanol (750 ml) at reflux temperature for 30-60 minutes. The methanol was removed by atmospheric distillation upto 5v-10v. The resulted suspension was cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with methanol to obtain good purity. (Yield-75%) (HPLC-99.66%)

Purification-7

IV-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (5 g) was dissolved in ethanol (75ml) with stirring at reflux temperature over a period of 30-60 minutes. The ethanol was removed by atmospheric distillation upto 4v-5v. The resulted suspension was cooled to room temperature and stirred for overnight. Thus obtained solid was filtered and washed with ethanol to obtain good purity.

(Yield-75%) (HPLC-99.21%)

Purification-8

A/-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[6]azepin-l-carbonyl)-3- Methylpheyl]-2-Methylbenzamide (5 g) was dissolved in ethyl acetate (250ml) at reflux temperature over a period of 30-60 minutes. The ethyl acetate was removed by atmospheric distillation upto 4v-5v. The resulted suspension was cooled to room temperature and stirred for 2-4 hrs. Thus obtained solid was filtered and washed with ethyl acetate to obtain good purity.

(Yield-91%) (HPLC-99.49 %)

Purification-9

iv-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[6]azepin-l- arbonyl)-3-Methylpheyl]-2-Methylbenzamide (50 g) was dissolved in methanol (1000 ml) at reflux temperature. The solvent was removed by atmospheric distillation upto 6v-12v. and there was added DM water (500ml) over a period of 1-2 hrs.The resulted suspension was cooled to room temperature and stirred for 2-4 hrs.Thus obtained solid was filtered and washed with DM Water to obtain good purity. (Yield-90 %) (HPLC -99.81 %)

Purification-10

A^-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (20 g) was dissolved in butanol (200 ml) at reflux temperature and there was added DM water (200ml) over a period of 1-2 hrs.The resulted suspension was cooled to room temperature and there was added DM water (400ml) over a period of 1-2 hrs.The resulted suspension was stirred for2-6-4 hrs.Thus obtained solid was filtered and washed with DM Water to obtain good purity. (Yield-81 %) (HPLC -99.70 %)

Purification-11

A^-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (5g) was dissolved in Isopropyl alcohol (150 ml) at reflux temperature for 30-60 minutes and there was added DM Water (100ml) over a period of 1-2 hrs. The resulted suspension was cooled to room temperature and stirred for2-4 hrs.Thus obtained solid was filtered and washed with DM Water to obtain good purity.

(Yield-80 %)(HPLC 99.50 %) Purification-12

Ar-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[Z»]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (20 g) was dissolved in ethanol (300 ml) at reflux temperature and there was added DM water (200ml) over a period of 1-2 hrs. The resulted suspension was cooled to room temperature and stirred for2-4 hrs. Thus obtained solid was filtered and washed with DM Water to obtain good purity. (Yield-56 %) (HPLC -99.23 %)

Purification-13

A/-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[i]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (5 g) was dissolved in acetone (100 ml) at reflux temperature and there was added DM water (150ml) over a period of 1-2 hrs. The resulted suspension was cooled to room temperature and stirred for 1-2 hrs. Thus obtained solid was filtered and washed with DM Water to obtain good purity. (Yield-40 %) (HPLC -99.41 %)

Purification-14

JV-[4-(7-Chloro-5-Hydroxy-2, 3, 4, 5-Tetrahydro benzo[6]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (5 g) in toluene (100 ml) heated to reflux temperature over a period of 1-2 hrs.The resulted suspension was cooled to room temperature and stirred for30-60 minutes. Thus obtained solid was filtered and washed with toluene to obtain good purity. (Yield-95 %) (HPLC -99.65 %) Purification-15 iv-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydrobenzo[Z>]azepin-l-carbonyl)-3-Methylpheyl]-2-Methylbenzamide (10 g) is dissolved in a mixture of Methylisobutylketone (100ml) and methylenedichloride (100 ml) with stirring at room temperature over a period of 30-60 minutes. The solvent was removed by atmospheric distillation upto 5v-10. The resulted suspension was cooled to room temperature and stirred for 2-4 hrs. Thus obtained solid was filtered and washed with Methylisobutylketone to obtain good purity.

Example-5a: Preparation of protected 7-Chloro-l,2,3,4 tetra hydro [b] azepin-5- ones

To a stirred suspension of 7-Chloro-1,2,3,4 tetra hydro [b] azepin-5-ones 1.95 g (10 mmol), cyclohexyl amine 1 g (10 mmol) in toluene, there was added 0.05 ml of acetic acid. During which the mixture is heated to reflux for two hours, meanwhile remove the water formed by azeotrophic distillation .After confirming absence of staring material reaction mass cooled and concentrated under vacuum to obtain the product 2.43 g. yield 88 %.

Example-5b: Preparation of protected 7-ChIoro-l, 2, 3, 4 tetra hydro [b] azepin-5- ones

To a stirred suspension of 7-chloro-l, 2, 3, 4-tetrahydro[b] azepin-5-one 1.95 g (10 mmol), Ethylene glycol 1.23 g (20 mmol) in toluene 40 ml, there was added 0.05 g of P-TSA-H2O. During which the mixture is heated to reflux for six hours, meanwhile remove the water formed by azeotrophic distillation .After confirming absence of staring material reaction mass cooled and was concentrated under vacuum to obtain the product 1.77 g.

Example-5c: Preparation of protected 7-Chloro-l, 2, 3, 4 tetra hydro [b] azepin-5- Ones

To a stirred suspension of 7-chloro-l, 2, 3, 4 tetrahydro [b] azepin-5-ones 1.95 g (10 m mol), 1, 3 propane diol 1.52 g (20 mmol) in toluene 40 ml, there was added 0.1 g of p- TSA-H2O. During which the mixture is heated to reflux for six hours, meanwhile remove the water formed by azeotrophic distillation .After confirming absence of staring material reaction mass cooled and was concentrated under vacuum to obtain the product 2.07 g.

Example -6: Preparation of keto protected 7-chloro-l-(2-methyl-4-nitro-benzoyl)-l, 2,3,4-tetrahydro-benzo[b]azepin-5-one 2-methyl-4-nitro benzoic acid (5 g) was stirred with Toluene (100 ml) and added Thionyl chloride (3 ml) with stirring at room temperature in about one hour. The reaction mixture was heated to reflux. Toluene was removed by atmospheric distillation. To the reaction mixture thus obtained was added with stirring a solution of Keto protected 7-chloro-l, 2, 3, 4-tetrahydrobenzo[b]azepin-5-one (6 g) taken in dichloromethane (50ml) and Triethylamine (3.5 ml) in about one hour at reflux temperature. Reaction mixture was stirred at room for about four hours to complete the reaction. The resulted reaction mixture was slowly added to a vessel containing 100 ml of 10 % sodium chloride under stirring. The organic layer is separated and washed twice with 5% sodium bi carbonate solution and dried over sodium sulphate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give Keto protected 7-chloro-l-(2- methyl-4-nitro-benzoyl)-l, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one (7.2g)

Example -7: Preparation of Keto Protected l-(4-Amino-2-methyl-benzoyl)-7-chloro- 1,2,3,4-tetrahydro-benzo[6]azepin-5-one Keto Protected 7-Chloro-l-(2-methyl-4-nitro-benzoyl)-l, 2, 3, 4-tetrahydro- benzo[b]azepin-5-one (30 g) was stirred with methanol (300 ml) and cone. HC1 (210 ml) and there was added SnCl2.2H20 (75 g) with stirring at room temperature. During which reaction mass stirred at room temperature for overnight .after confirming the disappearance of starting material solvents were removed by vacuum distillation. The crude obtained was diluted with Dichloromethane and added water. The biphase obtained was adjusted the PH of reaction mass 12-14 using 40 % NaOH solution, layer was washed with water (2X300 ml) and sodium bicarbonate ( 2 x 300 ml) and dried over sodium sulfate , after filtering off sodium sulfate , the filtrate was concentrated under reduced pressure to give the crude product . The resultant crude was recrystalised in isopropyl ether to give Keto Protected l-(4-Amino-2-methyl-benzoyl)-7-chloro-l,2,3,4- tetrahydro-benzo[6]azepin-5-one 20 g

Purification:

l-(4-Amino-2-methyl-benzoyl)-7-chloro-l, 2, 3, 4-tetrahydro-benzo[6]azepin-5-one (10 g) is dissolved in dichloromethane 30 ml with stirring at 40-50° C over a period of 60 minutes. During which the clear solution was stirred at reflux temperature for one to two hours. The resulted solution was cooled to room temperature and added 100 ml of Isopropyl ether and stirred for overnight. Thus obtained solids were separated by filtration & dried to get 8.1g pure compound. HPLC 99.22 %

Example-8: Preparation of Keto protected A^-[4-(7-chloro-5-oxo-2,3, 4, 5-tetrahydro- benzo[Z>]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamid]azepin-1 -carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (10 g) was dissolved in dichloromethane 30 ml with stirring at 40-50° C over a period of 60 minutes. During which the clear solution was stirred at reflux temperature for one to two hours. The resulted solution was cooled to room temperature and added 100 ml of Isopropyl ether and stirred for overnight. Thus obtained solids were separated by filtration & dried to give (9 g ; HPLC 99.22 %) Example 9: JV-[4-(7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-benzo[6]azepin-l-carbonyl)-3-methyl-pheyI]-2-methyl-benzamide (Deprotection of keto group) Protected JV-[4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[6]azepin-1 -carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (5 g) was dissolved in methanol 30 ml added cone hydrochloric acid ( 5 ml) stir, progress of reaction monitered by TLC. After confirming the disappearance of starting material, removed solvent and add DCM, dichloromethane layer was washed with water (2 x 30ml) and sodium bicarbonate (2 x 30 ml) and dried over sodium sulfate, after filtering off sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was recrystalised in methanol to give 7V-[4-(7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-benzo[£]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (3 g; HPLC-98)

Example-10: Preparation of iv-[4-(7-chIoro-5-hydroxy-2,3,4,5-tetrahydro-benzo[A]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyI-benzamide

IV-[4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[6]azepin-1 -carbonyl)-3-methyl-pheyl]-2-methyl-benzamide was dissolved in methanol (100 ml) and there was added sodium borohydride (1.5 g) with stirring under ice cooling over a period of one hour. During which reaction mixture was stirred at same cooling temperature for two to three hours. After confirming the disappearance of starting material, solvents were removed by vacuum distillation. The crude obtained was diluted with dichloromethane and added water. Dichloromethane layer was washed with water (2X300 ml) and 5 % sodium bicarbonate (2X300 ml) and dried over sodium sulfate, after filtering off sodium sulfate; the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was recrystalised in methanol and water (1:1) to give jV-[4-(7-chloro-5-hydroxy-2, 3, 4, 5-tetrahydro-benzo[6]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (8.6 g)

Example-11: Preparation of JV-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[6]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide iV-[4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[6]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (lOg) was reacted with SYNHYDRID Solution 70% solution of bis-(2-methoxyethoxy) sodium aluminum hydride In toluene organic layer, after completion of reaction, organic layer was washed with water (2 x 300 ml) and 5 % sodium bicarbonate (2 x 100 ml) was concentrated under reduced pressure to give the crude product. The resultant crude was recrystallized in methanol and water (1:1) to give N-[4-(7-chloro-5-hydroxy-2, 3, 4, 5-tetrahydro-benzo[6]azepin-l-carbonyl)-3-methyl-pheyl]-2-methyl-benzamide (8.6 g)

We claim:

1. An improved process for the preparation of tolvaptan comprising the steps of:

i) treating compound of formula A with 2-methyl-4-nitro benzoyl chloride in absence of a base and in presence of an organic solvent to give compound of formula B,

ii) optionally purifying compound of formula B,

iii) reducing the compound of formula B to give compound of formula C ,

iv) optionally purifying compound of formula C,

v) treating the compound of formula C with toluoyl chloride in presence of an organic solvent to give compound of formula D,

vi) optionally purifying compound of formula D,

vii) reducing compound of formula D in the presence of an organic solvent and isolating compound of formula I,

2. An improved process for the preparation of tolvaptan comprising the steps of:

a) protecting the compound of formula A in an organic solvent

b) treating compound of formula 3 with 2-methyl-4-nitro benzoyl chloride in the presence of an organic solvent to give compound of formula 4,

c) optionally purifying compound of formula 4

d) reducing compound of formula 4 to give compound of formula 5,

e) optionally purifying compound of formula 5,

f) treating compound of formula 5 with toluoyl chloride in an organic solvent to give compound of formula 6,

g) deprotecting the compound of formula 6 to give compound of formula D; and

h) reducing compound of formula D in the presence of an organic solvent to give compound of formula 1,

3. A process for the preparation of pure Tolvaptan comprising the steps of:

a) dissolving Tolvaptan in an organic solvent or a mixture thereof,

b) removing the solvent and

c) isolating pure Tolvaptan.

4. Process according to Claim 1, 2 or 3 , wherein organic solvent is selected from alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, tertiary-butyl alcohol; ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone;

esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary- butyl acetate; nitrile solvents such as acetonitrile; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform; aprotic polar solvents such as N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO),or mixtures thereof or their combinations with water.

5. Process according to Claim 1 or 2, wherein nitro reduction is carried by using Tin chloride, Raney Ni, Pd/C, Samarium(II) iodide ("Kagan reagent"), SYNHYDRID Solution (70% solution of bis-(2-methoxyethoxy) sodium aluminum hydride) and keto reduction is carried by using sodium borohydride.

6. Process according to Claim 2, wherein protecting group is selected from Schiff s base, acetals or Ketals such as ethylene glycol, 1, 3 propanediol, Acylals and Dithianes.

7. A compound of formula

or salts thereof.

8. Process according to Claim 3, wherein step b removing the solvent by using conventional techniques such as filtration, evaporation, atmospheric distillation.

9. Tolvaptan having HPLC purity more than 99.5%.

10. Tolvaptan free of dimmer impurity of formula M.