FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF DIAMINO BENZAZEPINE DERIVATIVE
2. APPLICANT:
(a) NAME: Centaur Pharmaceuticals Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956.
(c) ADDRESS: Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai, Maharashtra India Pin Code: 400055.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
Present invention relates to a process for preparation of diamino benzazepine derivative compound represented by structural formula (I) by reduction of dinitro benzazepine derivative compound represented by structural formula (II) using metal/acid as a reagent.

Wherein R is a group selected from H, -COH, -COCH3, -COCF3, -COCBr3, -COCl3, -BOC and -COOX, wherein X is C1-C6 alkyl or any other amino protecting group.
BACKGROUND OF THE INVENTION:
Diamino benzazepine derivative compound represented by structural formula (I) is used as intermediate in preparation of Vareriicline compound represented by structural formula (III). Varenicline is chemically defined as 7,8,9;10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h] [3]benzazepine and is known from the US patent number 6,410,550 and is represented by structural formula (III).

Varenicline is approved in the US as the tartrate salt and is indicated as an aid to smoking cessation treatment and is marketed by brand name Chantix.
U.S. Patent No. 6,410,550 discloses process for preparation of 2,3,4,5-tetrahydro-7,8-diamino-3-(trifluoroacetyl)-l, 5-methano-lH-3-benzazepine compound represented by structural formula (IV) wherein 2,3,4,5-tetrahydro-7,8-dinitro-3-(trifluoroacetyl) -1,5-methano-lH-3-benzazepine compound represented by structural formula (V) is reacted with hydrogen gas in presence of palladium hydroxide 20% w/w on carbon to provide 2,3,4,5-

tetrahydro-7,8-diamino-3-(trifluoroacetyl)-1,5-methano-lH-3-benzazepine compound
represented by structural formula (IV). 2,3,4,5-tetrahydro-7,8-diamino-3-(trifluoroacetyI)-l,5-methano-1H-3-benzazepine compound represented by structural formula (IV) is further converted to varenicline compound represented by structural formula (III) by treatment with glyoxal sodium bisulfite addition compound hydrate to provide compound represented by structural formula (VI) followed by treatment with sodium carbonate.

U.S. Patent Publication No. 2008275051 discloses process for preparation of 2,3,4,5-
tetrahydro-7,8-diamino-3-(trifluoroacetyl)-l,5-methano-lH-3-benzazepine compound
represented by structural formula (IV) wherein 2,3,4,5-tetrahydro-7,8-dinitro-3-(trifluoroacetyl) -1,5-methano-1 H-3-benzazepine compound represented by structural formula (V) is reacted with hydrogen gas in presence of palladium 5% w/w on carbon to provide 2,3;4,5-tetrahydro-7,8-diamino-3-(trifluoroacetyl)-1,5-methano-lH-3-benzazepine compound represented by structural formula (IV).

PCT Publication No. 2018/163190 discloses process for preparation of 2,3,4,5-tetrahydro-7,8-diamino-3-(trifluoroacetyl)-1,5-methano-lH-3-benzazepine compound represented by structural formula (IV) wherein 2,3,4,5-tetrahydro-7,8-dinitro-3-(trifluoroacetyl) -1,5-methano- 1H-3-benzazepine compound represented by structural formula (V) is reacted with hydrogen gas in presence of Raney nickel to provide 2,3,4,5-tetrahydro-7,8-diamino-3-

(trifluoroacetyl)-1,5-methano-1H-3-benzazepine compound represented by structural formula (IV).

The prior art process is disadvantageous as it involves use of hydrogen gas which is potentially explosive and palladium hydroxide which is not commercially viable. Further, prior art process require specific equipment i.e. Autoclave/ Hydrogenator for above mentioned conversion.
In view of the above the inventors of present invention have designed an efficient, economical and safe process for the preparation of diamino benzazepine derivative compound represented by structural formula (I).
OBJECT OF THE INVENTION:
An object of the present invention is to provide an efficient, economical and safe process for preparation of diamino benzazepine derivative compound represented by structural formula (I) by reduction of dinitro benzazepine derivative compound represented by structural formula (II) using metal/acid as a reagent.

Wherein R is a group selected from H, -COH, -COCH3, -COCF3, -COCBr3, -COCl3, -BOC and -COOX, wherein X is C1-C6 alkyl or any other amino protecting group.
Another object of present invention is to provide an efficient, economical and safe process for preparation of Varenicline compound represented by structural formula (III).


SUMMARY OF THE INVENTION:
First aspect of this invention is to provide an efficient, economical and safe process for preparation of diamino benzazepine derivative compound represented by structural formula (I) by reduction of dinitro benzazepine derivative compound represented by structural formula (II) using metal/acid as a reagent.

Wherein R is a group selected from H, -COH, -COCH3, -COCF3, -COCBr3, -COCl3, -BOC and -COOX, wherein X is C1-C6 alkyl or any other amino protecting group.
Second aspect of this invention is to provide a process for preparation of diamino benzazepine derivative compound represented by structural formula (I) by reduction of dinitro benzazepine derivative compound represented by structural formula (II) using metal selected from the group comprising of zinc, tin and iron in the presence of acid selected from the group comprising of hydrochloric acid, sulphuric acid, acetic acid and formic acid in an organic solvent.

Wherein R is a group selected from H, -COH, -COCH3, -COCF3, -COCBr3, -COCl3, -BOC and -COOX, wherein X is C1-C6 alkyl or any other amino protecting group.

Third aspect of this invention is to provide a process for preparation of varenicline compound
represented by structural formula (III) comprising steps of:
i. reduction of dinitro benzazepine derivative compound represented by structural formula (II) using metal selected from the group comprising of zinc, tin and iron in the presence of acid selected from the group comprising of hydrochloric acid, sulphuric acid, acetic acid and formic acid in an organic solvent to obtain diamino benzazepine derivative compound represented by structural formula (I);

ii. treating diamino benzazepine derivative compound represented by structural formula (I) with glyoxal sodium bisulfite or 40% aqueous glyoxal to obtain compound represented by structural formula (VII);

iii. treating compound represented by structural formula (VII) with base to obtain varenicline compound represented by structural formula (III).

Wherein R is a group selected from H, -COH, -COCH3, -COCF3, -COCBr3, -COCl3, -BOC and -COOX, wherein X is C1-C6 alkyl or any other amino protecting group.

DETAIL DESCRIPTION OF THE INVENTION:
According to an aspect present invention provides an efficient, economical and safe process for preparation of diamino benzazepine derivative compound represented by structural formula (I) by reduction of dinitro benzazepine derivative compound represented by structural formula (II) using metal/acid as a reagent in an organic solvent.

Wherein R is a group selected from H, -COH, -COCH3, -COCF3, -COCBr3, -COCl3, -BOC and and -COOX, wherein X is C1-C6 alkyl or any other amino protecting group.
Dinitro benzazepine derivative compound represented by structural formula (II) can be prepared by method known in the art such as those described in U.S. Patent No. 6,410,550.
Metal can be selected from the group comprising of zinc, tin and iron. Metal for reduction can be used 1 to 3 times weight by weight of dinitro benzazepine derivative compound represented by structural formula (II).
Acid can be selected from the group comprising of concentrated hydrochloric acid, sulphuric acid, acetic acid and formic acid. Acid can be used 1.5 to 4.5 volumes by weight of dinitro benzazepine derivative compound represented by structural formula (II).
Organic solvent can be alcoholic solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

Reduction of dinitro benzazepine derivative compound represented by structural formula (II) can be carried out at a temperature in the range of 5°C to 40°C for a period of 1 hour to 5 hour.
Diamino benzazepine derivative compound represented by structural formula (I) can be isolated by steps of filtration, centrifugation, drying or combination thereof.
According to another aspect present invention provides a process for preparation of varenicline compound represented by structural formula (III) comprising steps of:
i. reduction of dinitro benzazepine derivative compound represented by structural formula (II) using metal/acid as a reagent in an organic solvent to obtain diamino benzazepine derivative compound represented by structural formula (I);

ii. treating diamino benzazepine derivative compound represented by structural formula (I) with glyoxal sodium bisulfite or 40% aqueous glyoxal to obtain compound represented by structural formula (VII);

iii. treating compound represented by structural formula (VII) with base to obtain varenicline compound represented by structural formula (III).


Wherein R is a group selected from H, -COH, -COCH3, -COCF3, -COCBr3, -COCl3, -BOC and -COOX, wherein X is C1-C6 alkyl or any other amino protecting group.
Dinitro benzazepine derivative compound represented by structural formula (II) can be prepared by method known in the art such as those described in U.S. Patent No. 6,410,550.
Metal can be selected from the group comprising of zinc, tin and iron. Metal for reduction can be used 1 to 3 times weight by weight of dinitro benzazepine derivative compound represented by structural formula (II).
Acid can be selected from the group comprising of concentrated hydrochloric acid, sulphuric acid, acetic acid and formic acid. Acid can be used 1.5 to 4.5 volumes by weight of dinitro benzazepine derivative compound represented by structural formula (II).
Organic solvent can be alcoholic solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.
Reduction of dinitro benzazepine derivative compound represented by structural formula (II) can be carried out at a temperature in the range of 5°C to 40°C for a period of 1 hour to 5 hour.
Diamino benzazepine derivative compound represented by structural formula (I) can be isolated by steps of filtration, centrifugation, drying or combination thereof.
Diamino benzazepine derivative compound represented by structural formula (I) can be treated with glyoxal sodium bisulfite or 40% aqueous glyoxal in organic solvent to obtain compound represented by structural formula (VII).
Organic solvent can be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, THF DMF or mixture thereof with water.

Diamino benzazepine derivative compound represented by structural formula (I) can be treated with glyoxal sodium bisulfite or 40% aqueous glyoxal at a temperature in the range of 20°C to 80°C for a period of 2 hours to 5 hours.
Compound represented by structural formula (VII) can be isolated by steps of filtration, centrifugation, drying or combination thereof.
Compound represented by structural formula (VII) can be treated with base in organic solvent to obtain varenicline compound represented by structural formula (III).
Base can be selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
Organic solvent can be alcoholic solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.
Compound represented by structural formula (VII) can be treated with base at a temperature in the range of 20°C to 80°C for a period of 2 hours to 5 hours.
Varenicline compound represented by structural formula (III) can be isolated by steps of filtration, centrifugation, drying or combination thereof.
EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example-l: Synthesis of 2,3,4,5-tetrahydro-7,8-diamino-3-(trifluoroacetyl)-1,5-methano-1H-3-benzazepine compound represented by structural formula (IV):
To a solution of 2,3,4,5-tetrahydro-7,8-dinitro-3-(trifluoroacetyl) -1,5-methano-1H-3-benzazepine compound represented by structural formula (V) (50 g) in methanol (250 ml) was added zinc dust (100 g). The reaction mixture was added hydrochloric acid (150 ml) at a

temperature in the range of 15°C to 20°C. The resultant reaction mixture was stirred at a temperature in the range of 15°C to 20°C for 2 hours. The reaction mixture was filtered and filtrate was concentrated. Concentrated mass was added MDC (250 ml) followed by aqueous ammonia (500 ml). The product was extracted in MDC layer. MDC layer was concentrated and degassed under vacuum to obtain 2,3,4,5-tetrahydro-7,8-diamino-3-(trifluoroacetyl)-1,5-methano-1H-3-benzeepine compound represented by structural formula (IV). Weight: 39.3 g. Purity: 99.5%
Example-2: Synthesis of varenicline compound represented by structural formula (III):
To a solution of 2,3,4,5-tetrahydro-7,8-diamino-3-(trifluoroacetyl)-1,5-methano-1H-3-benzazepine compound represented by structural formula (IV) (39 g) in methanol (200 ml)
*
was added glyoxal sodium bisulfite (45.32 g) at a temperature in the range of 25-35°C. The reaction mixture was heated to a temperature in the range of 60°C to 70°C and was stirred for a period of 2 hours. The reaction mixture was concentrated and added with water (750 ml). The product was extracted in MDC (500 ml). MDC layer was concentrated and the product - 7,8,9,10-tetrahydro-8-(trifluoroacetyl)-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine compound represented by structural formula (VI) was isolated in isopropyl alcohol (250 ml). 7,8,9,10-tetrahydro-8-(trifluoroacetyl)-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine compound represented by structural formula (IV) was added methanol (60 ml) and water (60 ml). The resultant solution was added sodium carbonate (31 g). The reaction mixture was heated to a temperature in the range of 65°C to 75°C and was stirred for a period of 2 hours. The reaction mixture was concentrated and added with water (250 ml). The product was extracted in MDC (200 ml). MDC layer was concentrated and the product varenicline compound represented by structural formula (I) was isolated in methanol (120 ml) and dried in oven at a temperature in the range of 40°C to 50°C.
Yield: 28 g Purity: 99.9%

We claim:
1. A process for preparation of diamino benzazepine derivative compound represented by structural formula (I) by reduction of dinitro benzazepine derivative compound represented by structural formula (II) using metal/acid as a reagent.

Wherein R is a group selected from H, -COH, -COCH3, -COCF3, -COCBr3, -COCl3, -BOC and -COOX, wherein X is C1-C6 alkyl or any other amino protecting group.
2. The process as claimed in claim 1 wherein metal is selected from the group consisting of zinc, tin and iron.
3. The process as claimed in claim 1 wherein metal is used 1 to 3 times weight by weight of dinitro benzazepine derivative compound represented by structural formula
(ii).
4. The process as claimed in claim 1 wherein acid is selected from the group comprising of concentrated hydrochloric acid, sulphuric acid, acetic acid and formic acid.
5. The process as claimed in claim 1 wherein acid is used 1.5 to 4.5 volumes by weight of dinitro benzazepine derivative compound represented by structural formula (II).
6. The process as claimed in claim 1 wherein reduction of dinitro benzazepine derivative compound represented by structural formula (II) is carried out in alcoholic solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol at a temperature in the range of 5°C to 40°C.
7. A process for preparation of varenicline compound represented by structural formula (III) comprising steps of:

i. reduction of dinitro benzazepine derivative compound represented by
structural formula (II) using metal/acid as a reagent in an organic solvent to obtain diamino benzazepine derivative compound represented by structural formula (I);

ii. treating diamino benzazepine derivative compound represented by structural
formula (I) with glyoxal sodium bisulfite or 40% aqueous glyoxal to obtain compound represented by structural formula (VII);


Wherein R is a group selected from H, -COH, -COCH3, -COCF3s -COCBr3, -COCl3, -BOC and -COOX, wherein X is C1-C6 alkyl or any other amino protecting group.
8. The process as claimed in claim 7, step ii) wherein Diamino benzazepine derivative compound represented by structural formula (I) is treated with glyoxal sodium bisulfite or 40% aqueous glyoxal in organic solvent selected from the group

consisting of methanol, ethanol, propanol, isopropanol, butanol, THF, DMF or mixture thereof with water at a temperature in the range of 20°C to 80°C.
9. The process as claimed in claim 7, step iii) wherein base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
10. The process as claimed in claim 7, step iii) wherein compound represented by structural formula (VII) is treated with base in organic solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol at a temperature in the range of 20°C to 80°C.