FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF VARENICLINE
TARTRATE"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivli (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for the preparation of 7, 8, 9, 10-tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h][3]benzazepine, (2R,3R)-2, 3-dihydroxybutanedioate represented by formula (I), commonly known as Varenicline Tartrate.

The process provides Varenicline Tartrate in higher yield and purity compared to the previously known processes.
BACKGROUND OF THE INVENTION
Varenicline Tartrate is nicotinic receptor partial agonist and is used for treatment of nicotine addiction. Varenicline Tartrate has been approved by FDA and is sold under the brand name Chantix® as an aid to smoking cessation treatment.
U.S. Patent No. US 6,410,550, hereinafter referred to as '550 patent, discloses a variety of benzazepine derivatives and their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. US 6,890,927, hereinafter referred to as '927 patent, discloses tartrate salt of varenicline.
The synthesis of Varenicline as disclosed in the '550 patent describes a method of preparation of Varenicline Tartrate, a compound of formula (I) and its intermediates. The patent exemplifies the process for preparation of an intermediates such as l-(4,5-Diamino-
a
compound of formula (B) from l-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7), 3,5-trien-10-yl)-2,2,2-triflouro-ethanone, a compound of formula (A). The '550 patent also

discloses process to prepare l-(558,14-Triazatetracyclo[10.3.1.02,I1.04,9]hexadeca-2(ll),3,5,9-pentaene)-2,2,2-trifluoro-ethanone, a compound of formula (D) from l-(4,5-Diamino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2?2-trifluoroethanone, the compound of formula (B).

(A) (B) (D)
The said reaction to obtain the compound of formula (D) from the compound of formula (B) involves the reaction between the compound of formula (B) and glyoxal sodium bisulfite in presence of tetrahydrofuran and water. The use of sodium bisulfite causes the deprotection which subsequently results in less yield of compound of formula (D). Use of sodium bisulfite as well as use of flammable solvent like tetrahydrofuran makes the process more hazardous and commercially unviable for industrial purpose.
U.S. Publication No. US 20080275051 discloses preparation of varenicline by cyclizing the compound of formula (B) with aqueous glyoxal in protic alcoholic solvent.
International Publication No. WO/2010/023561 discloses preparation of Varenicline by reacting the compound of formula (B) with haloacetaldehyde, optionally in presence of oxygen source to obtain the compound of formula (D) which subsequently undergoes deprotection to get varenicline.
International Publication No. WO/2011/080758 discloses preparation of Varenicline intermediate of formula (D) by cyclising the compound of formula (B) with aqueous glyoxal in the presence of an ion exchange resin.
The processes for the preparation of Varenicline Tartrate and its intermediates, as defined in the aforementioned prior arts suffer from several disadvantages such as the use of highly flammable solvents; low yield and low purity. Therefore, there is a need for a simple, efficient and commercially viable process for preparation of Varenicline Tartrate and/or intermediates thereof with higher purity levels which avoids the above mentioned drawbacks.

The present invention provides such an improved process for the preparation of Varenicline Tartrate and/or intermediates thereof, avoiding the above mentioned drawbacks.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of Varenicline Tartrate, a compound of formula (I), comprising,

(a) converting a compound of formula (A) to a compound of formula (B);
(b) reacting the compound of formula (B) with aqueous glyoxal solution in presence of a suitable solvent and an organic base to obtain a compound of formula (D);

(D)
(c) converting the compound of formula (D) obtained in step (b) to Varenicline, a compound of formula (II) in presence of an inorganic base and suitable solvent; and


(d) converting Varenicline, the compound of formula (II) to Varenicline Tartrate, the compound of formula (I).
Another object of the present invention is to provide an improved process for preparation of the Varenicline Tartrate intermediate, a compound of formula (D), comprising reacting the compound of formula (B) with aqueous glyoxal solution in presence of a suitable solvent and an organic base.

BRIEF DESCRIPTION OF THE DRAWINGS
The present invention provides the novel polymorphic form of varenicline base. Fig. 1 is a XRPD pattern of Varenicline base as obtained after example 5; Fig. 2 is a XRPD pattern of Varenicline base as obtained after example 6 and Fig. 3 is a XRPD pattern of Varenicline base as obtained after example 7.
DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification, the term "suitable solvent" refers to, but is not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; halogenated solvents such as methylene chloride (dichloromethane), chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, chlorinated fluorocarbons, tetrachloroethylene (perchloroethylene), 1,1,1 -trichloroethane (methyl chloroform, chlorothene) and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert. butyl acetate and the like; hydrocarbons such

as toluene, xylene and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 4-hydroxy-4-methyl pentanone and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water or mixtures thereof.
As used throughout the specification, the term "organic base" refers tertiary amines such as triethylamine, N,N-diisopropylethylamine, tertiary butylamine and the like. The term "inorganic base" includes, but is not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, caesium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.
(a) converting a compound of formula (A) to a compound of formula (B);
In one embodiment, the present invention provides a process for preparation of Varenicline Tartrate, a compound of formula (I), comprising


(b) reacting the compound of formula (B) with aqueous glyoxal solution in presence of a suitable solvent and an organic base to obtain a compound of formula (D);

(c) converting the compound of formula (D) obtained in step (b) to Varenicline, a compound of formula (II) in presence of an inorganic base and suitable solvent; and


(II)
(a) converting Varenicline, the compound of formula (II) to Varenicline Tartrate, the compound of formula (I).
In one embodiment, step (a) comprises converting a compound of formula (A) to a compound of formula (B) under hydrogen pressure, in presence of a suitable catalyst and a suitable solvent.
The suitable solvent used in step (a) is as defined supra. Preferably, the solvent used for the process in step (a) is an alcoholic solvent. More preferably, the solvent used in step (a) is methanol.
In one embodiment, a compound of formula (A) may be converted to a compound of formula (B) by catalytic hydrogenation. The suitable catalyst used may be selected from the group consisting of palladium, platinum, nickel, rhodium, ruthenium or derivatives thereof.
The catalytic hydrogenation reaction can be carried under hydrogen pressure at about 7 Kg/Cm2, preferably at a pressure of about 6 Kg/Cm2, more preferably at a pressure of about 5 kg/Cm2. The catalyst used is preferably deposited on an inert support selected from the group consisting of carbon, barium hydroxide, alumina, calcium carbonate. In one

embodiment, a suitable catalyst used for the said reaction is the palladium catalyst deposited on an inert support of carbon, herein referred to as Pd-C catalyst.
In one embodiment, the suitable catalyst used is about 3% to about 7% Pd-C solution, preferably is about 4% to about 6% Pd-C solution, more preferably the suitable catalyst used is 5% Pd-C solution.
In one embodiment, the suitable catalyst solution is prepared by mixing of about 1.5 gm to about 3.5 gm of Pd-C (of about 7% to about 13%) in methanol solvent, more preferably the suitable catalyst solution is prepared by mixing of about 2.5 gm of 10% Pd-C in methanol solvent.
In one embodiment, the reaction in step (a) is carried out in autoclave vessel under hydrogen pressure at about 2 Kg/Cm2 to about 8 Kg/Cm2, preferably at a pressure of about 3 Kg/Cm2 to about 7 Kg/Cm2, more preferably at a pressure of about 4 Kg/Cm2 to about 6 Kg/Cm2. Further, the hydrogen pressure is maintained at about 7 Kg/Cm2, preferably at a pressure of about 6 Kg/Cm2, more preferably at a pressure of about 5 Kg/Cm2 till the completion of reaction.
In one embodiment, the conversion of a compound of formula (A) to a compound of formula (B) in step (a) may be performed under hydrogen pressure and in presence of methanol as a solvent and Pd-C solution as a catalyst.
After the completion of the reaction in step (a), suitable work up may be performed, as known to a skilled artisan. In one embodiment, after completion of reaction in step (a), the reaction mixture may be cooled at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C, more preferably at a temperature of about 25°C to about 30°C. Further, the hydrogen pressure is released through water and the reaction mass is filtered through hyflo bed after unloading from autoclave. The hyflo bed is then washed with a suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvent used is an alcoholic solvent. More preferably, the solvent used is methanol. The wet cake obtained may be treated under vacuum, to distill-off the methanol,

at a temperature of about 50°C, preferably at a temperature of about 45°C, more preferably at a temperature of about below 45°C to obtain a compound of formula (B).
In one embodiment, step (a) comprises converting a compound of formula (A) in presence of methanol as a solvent and 10% Pd-C solution as a catalyst under hydrogen pressure at a pressure of about 5 Kg/Cm2 to about 7 Kg/Cm2, preferably at about 5 Kg/Cm2 to a compound of formula (B).
In one embodiment, the step (b) comprises reacting a compound of formula (B) obtained in step (a) with aqueous glyoxal solution in presence of suitable solvent and an organic base.
The suitable solvent used in step (b) is as defined supra. Preferably, the solvent used for the process in step (b) is a halogenated solvent. More preferably, the solvent used in step (b) is dichloromethane. Further, an organic base used in step (b) is as defined supra. Preferably, an organic base used is a tertiary amine. More preferably, an organic base used is a N,N-diisopropylethylamine.
In one embodiment, the step (b) comprises, adding and subsequently stirring a compound of formula (B) in a suitable solvent such as dichloromethane at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C , more preferably at a temperature of about 25°C to about 30°C. Further, an organic base preferably N,N-diisopropylethylamine may be added at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C , more preferably at a temperature of about 25°C to about 30°C. The reaction mixture obtained may be stirred for about 5 minutes to about 35 minutes, preferably for about 10 minutes to about 30 minutes, more preferably for about 15 minutes to about 20 minutes. Further, an aqueous glyoxal solution may be added to the reaction mixture in about 5 minutes to about 40 minutes, preferably in about 10 minutes to about 35 minutes, more preferably in about 15 minutes to about 30 minutes.
In another embodiment, the aqueous glyoxal solution used is comprised of about 30% to about 50% by weight glyoxal, preferably the aqueous glyoxal used for the reaction in step

(b) is 40% glyoxal solution. The reaction mixture obtained may be stirred for about 25 minutes to about 80 minutes, preferably for about 35 minutes to about 70 minutes, more preferably for about 45 minutes to about 60 minutes.
After the completion of the reaction in step (b), suitable work up may be performed, as known to a skilled artisan. In one embodiment, after completion of reaction in step (b), the product obtained after the reaction in step (b) may be purified by techniques known in the art such as crystallization, fractional crystallization, liquid-liquid extraction and the like. The said purification may be carried out using a suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvent used is an alcoholic solvent. More preferably, the solvent used is isopropyl alcohol.
The process of step (b) as defined in prior art patent '550 involves the use of glyoxal sodium bisulfite to obtain a compound of formula (D) while, the present invention as defined in step (b) gives improved quality and higher yield of a compound of formula (D) as compared to '550 patent, by using aqueous glyoxal solution and an organic base which avoids the deprotection in same stage and subsequently results in higher yield.
In one embodiment, step (b) comprises reacting a compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base to obtain a compound of formula (D).
In one embodiment, the present invention provides a process of preparation of Varenicline Tartrate intermediate of formula (D) comprising, reacting a compound of formula (B) with aqueous glyoxal solution in presence of suitable solvent and an organic base.
In one embodiment, the present invention provides a process of preparation of Varenicline Tartrate intermediate of formula (D) comprising, reacting a compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base.
In one embodiment, the present invention provides a process of preparation of Varenicline Tartrate intermediate of formula (D) comprising, reacting a compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-

diisopropylethylamine as an organic base at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C , more preferably at a temperature of about 25°C to about 30°C to obtain a compound of formula (D).
In one embodiment, the present invention provides a process of preparation of Varenicline Tartrate intermediate of formula (D) comprising, reacting a compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base at a temperature of about 25°C to about 30°C to obtain a compound of formula (D).
In one embodiment, the present invention provides a process of preparation of Varenicline Tartrate of formula (I) comprising, reacting a compound of formula (B) with aqueous glyoxal solution in presence of suitable solvent and an organic base to obtain a compound of formula (D).
In one embodiment, the present invention provides a process of preparation of Varenicline Tartrate of formula (I) comprising, reacting a compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base to obtain a compound of formula (D).
In one embodiment, the present invention provides a process of preparation of Varenicline Tartrate of formula (I) comprising, reacting a compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C , more preferably at a temperature of about 25°C to about 30°C to obtain a compound of formula (D).
In one embodiment, the present invention provides a process of preparation of Varenicline Tartrate of formula (I) comprising, reacting a compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base at a temperature of about 25°C to about 30°C to obtain a compound of formula (D).

In one embodiment, step (c) comprises converting a compound of formula (D) to Varenicline, a compound of formula (II).

In one embodiment, the step (c) is subjected to removal of protecting group by methods known in the art such as acidic or alkaline hydrolysis. In another embodiment, step (c) comprises converting a compound of formula (D) in presence of an inorganic base and a suitable solvent.
The suitable solvent used in step (c) is as defined supra. Preferably the solvent used for the reaction in step (c) is an alcoholic solvent. More preferably, the solvent used in step (c) is methanol. Further, an inorganic base used in step (c) is as defined supra. Preferably, an inorganic base used is an alkali metal hydroxide solution. More preferably, an inorganic base used in sodium hydroxide solution.
In one embodiment, the step (c) comprises converting a compound of formula (D) in presence of suitable inorganic base such as sodium hydroxide solution and suitable solvent such as methanol to varenicline, a compound of formula (II). The reaction mixture obtained may be further heated at a temperature of about 20°C to about 60°C, preferably at a temperature of about 30°C to about 50°C, more preferably at a temperature of about 40°C to about 45°C and maintained for about 2 hrs, preferably for about 1 hr.
After the completion of the reaction in step (c), suitable work up may be performed, as known to a skilled artisan to isolate Varenicline of formula (II). In one embodiment, after completion of reaction in step (c), the reaction mixture may be quenched with water, followed by extraction with a suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvent used for extraction is halogenated solvent. More preferably, the solvent used is dichloromethane. The organic layer, preferably dichloromethane layer, may be washed with water and the product may be isolated by techniques known in the art,

preferably by distillation of the solvent under vacuum at a temperature of about 30°C to about 70°C, preferably at a temperature of about 40°C to about 60°C, more preferably at a temperature of about 50°C to about 55°C.
In one embodiment, step (d) comprises converting Varenicline, a compound of formula (D) as obtained after step (c) to Varenicline Tartrate, a compound of formula (I). In one embodiment, step (d) comprises reacting a compound of formula (D) with tartaric acid in presence of a suitable solvent. The suitable solvent used in step (d) is as defined supra. Preferably the solvent used for the reaction in step (d) is an alcoholic solvent. More preferably, the solvent used in step (d) is methanol.
In one embodiment, step (d) comprises process for the preparation of Varenicline Tartrate, a compound of formula (I), comprising, reacting a compound of formula (D) with Tartaric Acid in methanol as solvent to obtain a clear solution. To the obtained solution, activated charcoal may be added and the reaction mixture may be stirred for about 50 minutes, preferably for about 40 minutes and more preferably, for about 30 minutes. Further, the reaction mixture may be filtered through hyflo bed. Tartaric acid may be added to the filtered reaction mixture and stirred for about 4 hrs, preferably for about 3 hrs and more preferably for about 2 hrs.
After the completion of the reaction in step (d), suitable work up may be performed, as known to a skilled artisan to isolate Varenicline Tartrate of formula (I). In one embodiment, after completion of reaction in step (d), the reaction mixture may be filtered and washed with suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvent used is an alcoholic solvent. More preferably, the solvent used is methanol. The wet cake obtained may be further treated under vacuum, to distill off the methanol, at a temperature of about 20°C to about 70°C, preferably at a temperature of about 40°C to about 60°C, more preferably at a temperature of about 45°C to about 55°C to obtain Varenicline Tartrate of formula (I).
In one embodiment, step (d) comprises converting Varenicline, a compound of formula (D) to Varenicline Tartrate, a compound of formula (I) in presence of Tartaric Acid and in methanol.

In one embodiment, the present invention provides a process for preparation of Varenicline Tartrate, a compound of formula (I), comprising

(a) converting a compound of formula (A) to a compound of formula (B)

(b) reacting the compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base;

(D)
(c) converting the compound of formula (D) obtained in step (b) to Varenicline, a compound of formula (II) in presence of sodium hydroxide solution as a base and methanol as a solvent;

(II) (d) converting Varenicline, the compound of formula (II) to Varenicline Tartrate, the
compound of formula (I).

In one embodiment, the present invention provides a process for preparation of Varenicline Tartrate, a compound of formula (I), comprising

(a) converting a compound of formula (A) to a compound of formula (B) under hydrogen pressure and in presence of Pd-C catalyst

(b) reacting the compound of formula (B) with 40% aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base;

(c) converting the compound of formula (D) obtained in step (b) to Varenicline, a compound of formula (II) in presence of sodium hydroxide solution as a base and methanol as a solvent at a temperature of about 40°C to about 45°C;

(d) converting Varenicline, the compound of formula (II) in presence of tartaric acid to Varenicline Tartrate, the compound of formula (I).

In one embodiment, the present invention provides a process for preparation of Varenicline Tartrate, a compound of formula (I), comprising reacting the compound of formula (B) with aqueous glyoxal solution in presence of suitable solvent and an organic base to obtain a compound Varenicline Tartrate intermediate of formula (D).
In one embodiment, the present invention provides a process for preparation of Varenicline Tartrate, a compound of formula (I), comprising reacting the compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base to obtain a compound Varenicline Tartrate intermediate of formula (D).
In one embodiment, the present invention provides a process for preparation of Varenicline Tartrate intermediate, a compound of formula (D), comprising reacting the compound of formula (B) with aqueous glyoxal solution in presence of suitable solvent and an organic base to obtain a compound Varenicline Tartrate intermediate of formula (D).
In one embodiment, the present invention provides a process for preparation of Varenicline Tartrate intermediate, a compound of formula (D), comprising reacting the compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane as a solvent and N,N-diisopropylethylamine as an organic base to obtain a compound Varenicline Tartrate intermediate of formula (D).
In one embodiment, the present invention also provides the novel polymorphic form of Varenicline base with XRPD as shown in FIG. 01, FIG. 02 and FIG. 03.
the present invention is explained in detail by referring to examples, which are not to be construed as limitative.
Example-1: Preparation of l-(4,5-Diamino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoroethanone
50.0 g (0.145 moles) of l-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7), 3,5-trien-10-yl)-2,2,2-triflouro-ethanone compound was added to 450 ml (8 V) of methanol into 2 L autoclave, followed by addition of 5 % Pd-C solution at a temperature of about 25°C to

30°C. The vessel was tightly closed and autoclaved to give 5.0 Kg/Cm2 Hydrogen pressure. After completion of autoclaving, the reaction mixture was stirred under hydrogen pressure at 5.0 Kg/Cm2 and exotherm up to 43°C was observed with decreased pressure up to 2.5 Kg/Cm2. The hydrogen pressure was maintained up to 5.0 Kg/Cm2 and the progress of reaction was monitored by TLC. After completion on TLC, reaction mixture was cooled at 25°C to 30°C. and hydrogen pressure was released through water. The obtained reaction mixture was further filtered through hyflo bed and hyflo bed was washed with 200 mL Methanol. The methanol was later distilled off under vacuum below 45°C. to obtain brownish red solid. (Yield: 41.31 g).
Example-2: Purification of l-(4,5-Diamino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoroethanone
250 mL isopropyl alcohol was added to above obtained brownish red solid. The reaction mass was heated to 60°C to 65°C and maintained it for 30 min. The reaction mass was allowed to cool at 25°C to 30°C and then at 0°C to 5°C. The temperature of reaction mass was maintained at 0°C to 5°C for 2 h. On completion of reaction, the solid was filtered and washed with chilled 25 mL isopropyl alcohol. The wet cake was dried under vacuum below 45°C. (Yield: 39.8 g, % Yield: 96% and HPLC Purity: 99%)
Example-3: Preparation of l-(5,8,14-Triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(ll),3,5,9-pentaene)-2,2,2-trifluoro-ethanone
24.0 (0.084 moles) g solid residue obtained in Example-2 was added to 120.0 mL of dichloromethane and stirred at 25°C to 30°C till the clear solution appears. N,N-Diisopropylethylamine (16.32 g 0.126 moles) was added to the above mixture and further stirred for 15 min to 20 min at 25°C to 30°C. Later, 10.8 mL 40% glyoxal solution was added slowly in 15 min to 30 min. and stirred the reaction mass for 45 min to 60 min. Progress of reaction was checked on TLC. After completion of reaction, water (120 mL) was charged, layers were separated and solvent was distilled out under vacuum. (Yield: 24 g, % Yield: 92% and HPLC Purity: 99%)
Example-4: Purification of 1-(5,8,14-Triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(ll),3,5,9-pentaene)-2,2,2-trifluoro-ethanone

The solid product as obtained in Example-3 was purified by using isopropyl alcohol to get
pure
trifluoro-ethanone. (Yield: 22 g, % Yield: 85% and HPLC Purity: 99.8%)
Example-5: Preparation of Varenicline Base
200 mL methanol, the solid residue obtained in Example-4 (20 g, 0.065 moles) and Sodium hydroxide solution (5.2 g, 0.13) in 10 mL water were all added together. The reaction mass was heated up to 40°C to 45°C and maintained the temperature for 1 h. The progress of reaction was monitored on TLC. After completion of reaction, the solvent was distilled off. 200 mL dichloromethane and 100 mL water were added to the residue obtained, the reaction mass was stirred and layers were separated. The product was extracted in dichloromethane layer and the layer was washed with water which is further distilled off under vacuum at 50°C to 55°C. (Yield: 12 g, % Yield: 87% and HPLC Purity: 99.9%). The XRPD of obtained varenicline base depicted the characteristic peaks at 11.27,17.22,19.29, 20.65, 21.88, 27.37, 29.36 and 33.71. The XRPD also depicted the further peaks at 11.27, 12.16, 12.34, 13.36, 14.19, 15.90, 17.22, 19.29, 19.80, 19.99, 20.37, 20.65, 21.88, 22.46, 22.81, 24.28, 24.47, 25.34, 25.96, 26.79, 27.06, 27.37, 28.18, 29.36, 29.61, 30.21, 30.89, 31.36, 31.69, 32.08, 33.71, 34.48, 34.86, 35.97, 37.14, 37.77, 38.43, 38.61, 39.25, 39.46, 41.45, 43.70, 44.00, 44.62, 44.85, 46.30, 46.92 and 48.81. (FIG. 01)
Example-6: Preparation of Varenicline Base
200 mL methanol, the solid residue obtained in Example-4 (20 g, 0.065 moles) and Sodium hydroxide solution (5.2 g, 0.13) in 10 mL water were all added together. The reaction mass was heated up to 40°C to 45°C and maintained the temperature for 1 h. The progress of reaction was monitored on TLC. After completion of reaction, the solvent was distilled off. 200 mL dichloromethane and 100 mL water were added to the residue obtained, the reaction mass was stirred and layers were separated. The product was extracted in dichloromethane layer and the layer was washed with water which is further distilled off under vacuum at 50°C to 55°C. To the obtained residue, acetonitrile (48 mL) was added and reaction mass was heated up to 60°C to 65°C. The reaction mixture was further cooled to 0°C to 5°C and maintained the temperature for 1 h to 1.5 hrs. The obtained product was

filtered, washed with acetonitrile (10 mL) and dried under vacuum at temperature of about 50°C to 55°C (Yield: 8 g, % Yield: 58.18% and HPLC Purity: 99.9%). The XRPD of obtained varenicline base depicted the characteristic peaks at 11.25, 13.35, 17.21, 19.28,
20.63, 21.87, 27.36, 29.35 and 33.72. The XRPD also depicted the further peaks at 11.25,
12.14, 12.33, 13.35, 14.17, 15.90, 17.21, 19.28, 19.79, 19.97, 20.36, 20.63, 21.87, 22.45,
22.79, 24.23, 25.34, 25.93, 26.78, 27.04, 27.36, 28.17, 29.35, 29.62, 30.21, 30.87, 31.35,
31.70, 32.10, 33.72, 34.47, 34.86, 35.95, 37.12, 37.76, 38.50, 39.26, 39.44, 41.49, 43.70,
44.01, 44.62, 44.89, 46.28, 46.90, 48.79 and 49.09 (FIG. 02)
Example-7: Preparation of Varenicline Base
200 mL methanol, the solid residue obtained in Example-4 (20 g, 0.065 moles) and Sodium hydroxide solution (5.2 g, 0.13) in 10 mL water were all added together. The reaction mass was heated up to 40°C to 45°C and maintained the temperature for 1 h. The progress of reaction was monitored on TLC. After completion of reaction, the solvent was distilled off. 200 mL dichloromethane and 100 mL water were added to the residue obtained, the reaction mass was stirred and layers were separated. The product was extracted in dichloromethane layer and the layer was washed with water which is further distilled off under vacuum at 50°C to 55°C. To the obtained residue, acetone (30 mL) was added and reaction mass was heated up to 50°C to 55°C for about 30 min. to about 45 min. The reaction mixture was further cooled to 0°C to 5°C and maintained the temperature for 1 h to 1.5 hrs. The obtained product was filtered, washed with acetone (10 mL) and dried under vacuum at temperature of about 50°C to 55°C (Yield: 10 g, % Yield: 72.72% and HPLC Purity: 99.9%). The XRPD of obtained varenicline base depicted the characteristic peaks at 11.26, 17.21, 19.29, 21.88, 26.78,29.34 and 33.71. The XRPD also depicted the further peaks at 11.26, 12.16,12.35,13.35,14.18, 15.90, 17.21,17.76,19.29, 19.79, 19.98,20.36,
20.64, 21.88, 22.46, 22.79, 24.25, 24.47, 25.34, 25.92, 26.78, 27.05, 27.36, 28.18, 29.34,
29.62, 30.21, 30.86, 31.36, 31.71, 32.10, 33.71, 34.49, 34.85, 35.93, 37.13, 37.76, 38.43,
39.27,39.47,41.37,41.57,42.60,43.72,44.03,44.67,44.83,45.76,46.30 and 46.87. (FIG.
03)
Example-8: Preparation of Varenicline Tartrate

Varenicline free base (10.85 g, 0.051 moles) obtained in Exmaple-5, Example-6 or Example-7 was added to methanol (81 mL) and stirred to get clear solution. Further, activated charcoal (1 g) was added and stirred for 30 min. The reaction mass was filtered through hyflo. To this, L(+) tartaric acid (8.48 g, 0.051 moles) was added slowly and the reaction mass was stirred for 2 h. The product obtained was filtered, washed with methanol and dried under vacuum at 45°C to 55°C. (Yield: 17.8 g, % Yield: 96% and HPLC Purity: 99.9%).

We claim:
(a) converting a compound of formula (A) to a compound of formula (B);
1. A process for preparation of Varenicline Tartrate, a compound of formula (I), comprising:


(b) reacting the compound of formula (B) with aqueous glyoxal solution in presence of a suitable solvent and an organic base to obtain a compound of formula (D);

(c) converting the compound of formula (D) obtained in step (b) to Varenicline, a compound of formula (II) in presence of an inorganic base and suitable solvent; and

(a) converting Varenicline, the compound of formula (II) to Varenicline Tartrate, the compound of formula (I),

2. A process according to claim 1, wherein the suitable solvent used in step (b) is a halogenated solvent selected from the group consisting of dichloromethane, chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, chlorinated fluorocarbons, tetrachloroethylene and 1,1,1-trichloroethane.
3. A process according to claim 1, wherein the organic base used in step (b) is selected from the group consisting of triethylamine, N,N-diisopropylethylamine and tertiary
butylamine.
4. A process for preparation of Varenicline Tartrate intermediate, a compound of formula
(D), comprising reacting the compound of formula (B) with aqueous glyoxal solution
in presence of a suitable solvent and an organic base.

5. A process according to claim 4, wherein suitable solvent used is a halogenated solvent selected from the group consisting of dichloromethane, chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, chlorinated fluorocarbons, tetrachloroethylene and 1,1,1-trichloroethane.
6. A process according to claim 4, wherein organic base used is selected from the group consisting of triethylamine, N,N-diisopropylethylamine and tertiary butylamine.
7. A process according to claim 5, wherein halogenated solvent used is dichloromethane.
8. A process according to claim 6, wherein organic base used is N,N-diisopropylethylamine.

9. A process for preparation of Varenicline Tartrate intermediate, a compound of formula (D), comprising, reacting the compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane and N,N-diisopropylethylamine.

10. A process for preparation of Varenicline Tartrate, a compound of formula (I), comprising, reacting the compound of formula (B) with aqueous glyoxal solution in presence of dichloromethane and N,N-diisopropylethylamine to obtain varenicline intermediate of formula (D).