FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
1. Title of the invention
"Process for preparation of Varenicline and salts thereof
2. Applicant(s)
Name Nationality Address
USV LIMITED Indian company incorporated B.S.D marg station Road Govandi, Mumbai - 400088
under Companies Act, 1956 Maharashtra India

3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical Held:
The present invention relates to an improved process for preparation of Varenicline (1) and pharmaceutical ly acceptable salts thereof. The present invention further relates to Varenicline salts, polymorph thereof and process for preparation thereof.

Background of the Invention:
Varenicline, chemically known as 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino [2,3-h][3]benzazepine or 5,8,14-triazatetracyclo[10.3.1.021,.04'9]- hexadeca-2(ll),3, 5,7,9-pentaene' is a nicotine receptor partial agonist. Varenicline L-tartrate, useful for the treatment of smoking addiction, is commercially marketed in the United States, under the trade name CHANTIX and in Europe, under the trade name CHAMPIX. Varenicline is a partial agonist selective for α4p2 nicotinic acetylcholine receptor subtypes. Varenicline binds with high affinity and selectivity at a4p2 neuronal nicotinic acetylcholine receptors. The efficacy of CHANTIX in smoking cessation is believed to be the result of varenicline's activity at a4p2 sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to these receptors. Thus Varenicline exhibits dual action as a partial agonist at the a4p2 nicotinic acetylcholine receptor, stimulating the receptor to decrease craving and withdrawal symptoms, and as an antagonist to the receptor to decrease the reinforcement associated with smoking.
US6410550 describes process for preparation of Varenicline hydrochloride which involves reaction of 1 -bromo-2-fluorobenzene (2) with cyclopentadiene (3) in presence of magnesium in THF to get l,4-dihydro-l,4-methano naphthalene (4). The resulting compound (4) is dihydroxylated using N-methyl morpholine-N-oxide and osmium tetroxide in acetone-water to get l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol (5). The compound (5) is converted into 2,3-dihydro-lH-indene-l,3-dicarbaldehyde (6) by oxidative cleavage using sodium periodate in 1,2-

dichloroethane-water in presence of triethyl benzyl ammonium chloride. The obtained compound (6) is, without isolation, converted into 10-benzyl-10-aza-tricyclo[6.3.1.027]dodeca-2(7),3,5-triene (7) by reductive animation using benzyl amine and sodium triacetoxy borohydride in 1,2-dichloroethane. The crude N-benzyl compound (7) is taken in minimum quantity of diethyl ether and filtered through a silica pad by elution with 15% ethyl acetate-hexanes + 1% of 37% aqueous ammonium hydroxide solution to remove baseline red colour. N-benzyl compound (7) is then treated with 3N HCI in ethyl acetate to get hydrochloride salt of N-benzyl compound (7) which is further debenzylated using 20% palladium hydroxide on carbon to form 10-aza-tricyclo[6.3.1.027]dodeca-2(7),3,5-triene (8). The compound (8) is protected with trifluoroacetyl group using trifluoroacetic anhydride in presence of pyridine to form l-(10-azatricyclo[6.3.1.027]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (9). The compound (9) is purified by filtration through a silica pad and eluted with ethyl acetate/dichloromethane. Compound (9) is nitrated with nitric acid in presence of trifluoromethane sulphonic acid to get l-(4,5-dinitro-10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoroethanone (10). The dinitro compound is hydrogenated to l-(4,5-diamino-10-azatricyclo [6.3.1.027] dodeca-2(7),3,5-trien-10-yl) -2,2,2-trifluoro ethanone(ll) in presence of 20% palladium hydroxide on carbon. The diamino compound (11) is treated with glyoxal sodium bisulfite addition compound hydrate in THF-water to get crude compound, l-(5,8,14-triazatetracyclo [10.3.1.02l1.04'9] hexadeca-2(ll),3,5,7,9-pentaene)-2;2,2-trifluoro-ethanone (12) which is purified by column chromatography. The compound (12) is deprotected using aqueous sodium carbonate to get Varenicline of formula (1) which is treated with 3M HCl/ethyl acetate to get Varenicline hydrochloride. Varenicline hydrochloride thus obtained is recrystallized from MeOH/Et20 to get the product.


The above process is represented by reaction scheme shown below.
WO2009065872 discloses process for preparation of Varenicline L-tartrate salt comprising crystallizing intermediate N-protected 4,5-dinitro-lO-aza-tricyclo [6.3.1.02.7]dodeca-2(7),3,5-triene or a salt or solvate thereof in an organic solvent and converting the nitro intermediate compound or a salt or solvate thereof into Varenicline L-tartrate salt.
WO2009143347 discloses process for purification of Varenicline base comprising converting Varenicline base starting material to Varenicline tosylate and further converting Varenicline tosylate to Varenicline base. WO'347 further discloses crystalline forms of Varenicline tosylate, Form I, II. III and IV and process for preparation thereof.
US6890927 discloses Varenicline tartrate and various polymorphs thereof, including anhydrous polymorphs (Forms A and B) and a hydrate polymorph (Form C).
US2009215787 relates to novel polymorphic forms of varenicline tartrate, an amorphous form and three crystalline forms, namely Form D, Form E and Form F.

WO2009111623 discloses amorphous Varenicline tartrate, amorphous solid dispersions of Varenicline tartrate and processes for the preparation thereof.
WO2009101185 describes crystalline polymorphic form of Varenicline base (Form II) and process for preparation thereof.
WO2008060487 discloses polymorphic forms of intermediates used in the process for preparation of Varenicline tartrate. This patent also discloses polymorphic forms of Varenicline base, namely Form A, Form C, Form D and Form E.
WO2009109651 discloses various dicarboxylic salts of Varenicline and polymorphic forms thereof, such as Varenicline hemi-adipate (Form I), fumarate (Form I), glutarate (Form I), glycolate (Form I), hydrochloride (Forms I, II and III), a-ketoglutarate (Form I), L-malate (Form I), malare (Form II, III and IV), makate (Form I), malonate (Form I), DL-mandelate (Form I), di-mesylate (Form I), oxalate (Form I), phosphate (Form I, II, and III), S-2-pyrrolidinon-5-carboxylate (Form I), galactarate (Form I), DL-lactate (Form I), hemi-l,2-ethane disulfonate (Form I), hemi-L-lactate (Form I), succinate (Form I) and gluconate (amorphous),
US6787549 discloses citrate salt of Varenicline, various forms of citrate salt of Varenicline and pharmaceutical composition thereof.
US6794388 discloses succinate salts of Varenicline and pharmaceutical compositions thereof.
Object of the invention:
An object of the present invention is to provide an improved process for the preparation of Varenicline or pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide novel polymorphs of Varenicline mesylate, Varenciline fumarate, Varenciline oxalate and Varenciline phosphate and process for preparation thereof.
Yet another object of the present invention is to provide a novel polymorph of

intermediate compounds, used in the synthesis of Varenicline.
Summary of the invention:
According to the present invention, there is provided a process for preparation of Varenicline or pharmaceutically acceptable salt thereof said process comprising:
a) reducing l-(4,5-dinitro-10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifiuoro-ethanone (10), optionally in presence of catalyst to obtain l-(4,5-diamino-10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene-10 -yl)-2,2,2-trifluoro-ethanone (11);
b) treating l-(4,5-diamino-10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene-10-yI)-2,2,2-trifluoro-ethanone (11), in situ with glyoxal sodium bisulphite to obtain 1-(5,8,14- mazatetracyclo[10.3.1.02.11,04'9]hexadeca-2( 1 l),3,5,7,9-pentaene>2,2,2-trifluoro-ethanonef 12);
c) converting l-(5,8,14-triazatetracyclo [10.3.1.0211,04'9] hexadeca-2(11),3,5, 7,9-pentaene)-2,2,2-trifluoro-ethanone(12) to Varenicline or pharmaceutically acceptable salt thereof.
Preferably, 1 -(4,5-dinitro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-l 0-yl)-2,2,2-trifluoro-ethanone (10) is prepared by a process comprising the steps of:
a) dihydroxylating l,4-dihydro-l,4-methano naphthalene(4) using osmium tetroxide to obtain l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol (5), which is isolated;
b) converting said l,2,3,4-tetrahydro-l,4-methano-naphthalene-2.3-diol (5) to 10-benzyl-10-aza-tricyclo[6.3.1.02-7]dodeCa-2(7),3,5-triene(7);
c) optionally purifying 10-benzyI-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (7) by acid-base purification;
d) debenzylating said 10-ben2yl-10-azatricyclo[6.3.1.02-7]dodeca-2(7),3,5-triene (7) to obtain 10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-rriene (8);
e) treating said 10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (8) with trifluoroacetic anhydride to get l-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-yI)-2,2,2-trifluoro-ethanOne(9);

f) nitrating said l-(10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone(9) to obtain l-(4,5-dinitro-10-azatricyclo [6.3.1.02.7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone (10).
Preferably, mother liquor containing osmium tetroxide, obtained after the isolation of said lJ2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol (5), is used for dihydroxylation of 1,4-dihydro -1,4-methano naphthalene(4) in the presence of N-methyl morpholine-N-oxide to obtain the corresponding dialdehyde compound which is further converted to 10-benzyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene(7).
Preferably, pharmaceutically acceptable salt of Varenicline is selected from the group consisting of hydrochloride, tartrate, mesylate, oxalate, fumarate or phosphate.
According to one aspect of the present invention, there is provided a process for preparation of Varenicline hydrochloride comprising treating Varenicline with ammonium chloride or thionyl chloride.
According to another aspect of the present invention, there is provided a compound selected from the group consisting of l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol (5) characterized by X-ray diffraction pattern as shown in Fig. 11; 10-azatricyclo[6.3.1.02-7]dodeca-2(7),3,5-triene (8) characterized by X-ray diffraction pattern as shown in Fig. 12; Varenicline fumarate characterized by X-ray diffraction pattern as shown in Fig. 6; Varenicline mesylate characterized by X-ray diffraction pattern as shown in Fig. 5; Varenicline oxalate characterized by X-ray diffraction pattern as shown in Fig. 7; Varenicline phosphate characterized by X-ray diffraction pattern as shown in Fig. 8; Varenicline phosphate characterized by X-ray diffraction pattern as shown in Fig. 9; and Varenicline phosphate characterized by X-ray diffraction pattern as shown in Fig. 10.

Brief Description of the Drawings:
Fig. 1: X-ray powder diffractogram of Varenicline base.
Fig. 2: X-ray powder diffractogram of Varenicline tartrate Form B .
Fig. 3: X-ray powder diffractogram of Varenicline tartrate Form G.
Fig. 4: X-ray powder diffractogram of Varenicline hydrochloride.
Fig. 5: X-ray powder diffractogram of Varenicline mesylate.
Fig. 6: X-ray powder diffractogram of Varenicline fumarate Form II.
Fig. 7: X-ray powder diffractogram of Varenicline oxalate.
Fig. 8: X-ray powder diffractogram of Varenicline phosphate Form IV.
Fig. 9: X-ray powder diffractogram of Varenicline phosphate Form V.
Fig. 10: X-ray powder diffractogram of Varenicline phosphate Form VI.
Fig. 11: X-ray powder diffractogram of Compound (5) of present invention.
Fig. 12: X-ray powder diffractogram of Compound (8) of present invention.
Fig. 13: X-ray powder diffractogram of Compound (10) of present invention.
Fig. 14: X-ray powder diffractogram of Compound (12) of present invention.
Detailed description of the invention:
The present invention provides an improved process for preparation of Varenicline or its pharmaceutically acceptable salt thereof. Preferably, the pharmaceutic ally acceptable salt is selected from tartrate, hydrochloride, mesylate, maleate, fumarate. oxalate and phosphate. The present invention further provides polymorph of intermediates used in the preparation of Varenicline.
According to one embodiment of the present invention, there is provided a process for preparation of Varenicline or pharmaceutically acceptable salts thereof comprising the steps of:
a) reducing l-(4,5-dinitro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone (10), optionally in presence of catalyst to obtain 1 -(4,5-diamino-10-azatricyclo[6.3.1.027]dodeca-2(7),3,5-triene-10 -yl)-2J2,2-trifluoro-ethanone (11);
b) treating 1 -(4,5-diamino-10-azatricyclo[6.3.1.027]dodeca-2(7),3,5-triene-

10-yl)-2,2,2-trifluoro-ethanone (11), in situ with glyoxal sodium bisulphite to obtain 1-(5,8,14- triazatetracyclof[l0.3.1.0211,049]hexadeca-2(11 ),3,5,7,9-pentaene)-2,2,2-trifluoro-ethanone(12): c) converting l-(5,8,14-triazatetracyclo[10.3.1.0211,04-9]hexadeca-2(l 1),3,5, 7,9-pentaene)-2,2,2-trifiuoro-ethanone(12) to Varenicline or pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, process for preparation of Varenicline or pharmaceutically acceptable salt thereof comprises the steps of reducing l-(4,5-dinitro-10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene -10-yl)-2,2,2-trifluoro-ethanone (10) using hydrogen in presence of catalyst, preferably 10% Pd/C (50% wet) at 50 psi (4-5 kg/cm2) in a suitable solvent. After complete hydrogenation, the catalyst is filtered and washed with solvent, preferably a mixture of solvents. The obtained filtrate is directly subjected to cyclization to produce 1 -(5,8,14-triazatetracyclo [10.3.1.02-n.04-9] hexadeca-2(l l),3,5,7,9-pentaene)-2,2;2-trifluoroethanone (12) by treatment with glyoxal sodium bisulfite, without isolating the intermediate diamino compound (11). The step of isolation of compound 11 is avoided which makes the process cost effective.
In an alternate embodiment of the present invention, the dinitro compound (10) is hydrogenated in presence of 10% Pd/C (50% wet) at 50 psi (4-5 Kg/cm2) of hydrogen pressure in suitable solvent, preferably methanol. After complete hydrogenation, the catalyst is filtered and washed with solvent mixture, preferably methanol-1,4-dioxane. The diamino compound (11) may be isolated by concentrating the solvent mixture. As dry catalyst with methanol is risky due to fire hazards, moist catalyst is taken for ease of charging at a large scale. The pyrazine ring formation is performed by cyclizing diamino compound (11) with glyoxal sodium bisulfite in suitable solvent, preferably THF-water at 55°C to get 1-(5,8,14-triazatetracyclo [10.3.1.02,11.04,9] hexadeca-2(ll),3,5,7,9-pentaene) -2,2,2-trifluoro ethanone(12). The obtained compound (12) is purified by neutral alumina treatment in ethyl acetate.

The reduction of dinitro compound can be accomplished using catalytic hydrogenation, zinc/acid, tin/acid, iron/acid or metal hydrides such as LiAlFU, preferably catalytic hydrogenation. Catalyst is selected from palladium, platinum. ruthenium or rhodium, in metallic or oxidized form, on carbon or alumina support or raney nickel, preferably palladium/carbon. Solvent is selected from alcohol, ketone, ester, ether, water or mixture thereof, preferably alcohol or alcohol-ether mixture. Alcohol is selected from methanol, ethanol, n-propanol or isopropanol. Ketone is selected from acetone or methyl ethyl ketone. Ether is selected from tetrahydrofuran (THF), diethyl ether or 1,4-dioxane. Ester is selected from ethyl acetate, methyl acetate or isopropyl acetate.
l-(5,8,14-triazatetracyclo [10.3.1.021l.04'9] hexadeca-2(ll),3,5,7,9-pentaene)-2;2,2-trifluoroethanone(12) obtained by the present invention is characterized by X-ray diffraction pattern as shown in Fig. 14.
Another embodiment of the present invention provides process for conversion of 1-(5,8,14-triazatetracyclo [10.3.1.02.1l.O4.9] hexadeca-2(l l),3,5,7,9-pentaene)-2,2,2-trifluoro ethanone(12) to Varenicline comprising deprotecting 1-(5,8,14-triazatetracyclo [10.3.1.02.11,04.9] hexadeca-2(l l),3,5,7,9-pentaene)-2,2,2-trifluoro ethanone(12) in presence of a base and solvent to get 7,8,9,10-Tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine(l). After completion of the reaction, the reaction mass is quenched in water and extracted with an organic solvent. Varenicline extracted in organic solvent is subjected to acid-base treatment. The prior art process discloses purification of compound (12) by column chromatography on silica gel. This purification requires large quantities of solvents and tedious operations and hence is not feasible on a large scale. Preferably, the dichloromethane extract of Varenicline (1) is treated with aqueous hydrochloric acid solution followed by separation of the dichloromethane layer. The aqueous layer is then basified with aqueous sodium carbonate solution followed by extraction with dichloromethane to get pure Varenicline (1). The compound (1) .i.e.. Varenicline obtained according to the present invention is characterized by X-ray diffraction pattern as shown in Fig.l.

Base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. Solvent is selected from methanol, ethanol, n-propanol, isopropanol, ethyl acetate, dichloromethane, ethylene dichloride, chloroform, water or mixture thereof.
Another embodiment of the present invention, there is provided a process for preparation of l-(4,5-dinitro-10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene -10-yl)-2,2,2-trifluoro-ethanone (10) comprising the steps of,
a) reacting 1-bromo-2-fluorobenzene (2) with cyclopentadiene (3) in presence
of Grignard reagent to get l,4-dihydro-l,4-methano naphthalene (4), which
is optionally purified;

b) dihydroxylating compound (4) using osmium tetroxide and N-methyl morpholine-N-oxide to get l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol (5), which is isolated;

c) oxidising compound (5) with sodium metaperiodate in presence of benzyl triethyl ammonium chloride to get compound (6);

d) subjecting compound (6) to reductive amination in presence of benzyl amine to get 10-benzyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (7) which is optionally purified;

e) debenzylating compound (7) to get 10-azatricyclo[6.3.1.027]dodeca-2(7),3,5-triene (8);


f) treating compound (8) using trifluoroacetic anhydride/triethyl amine to get 1-(10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene-10-yl)-2,2>2-trifluoro-ethanone (9);

g) nitrating compound (9) to get 1 -(4,5-dinitro-l 0-azatricyc]o[6,3.1.02.7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifIuoro-ethanone (10), which is optionally purified.

In a preferred embodiment of the present invention, process for the preparation of 1-(4,5-dinitro-lO-azatricyclo [6.3.1.0"] dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone (10), intermediate of Varenicline, comprises Step I:
Reacting l-bromo-2-fluorobenzene (2) with cyclopentadiene (3) in presence of magnesium and ethyl magnesium bromide in suitable solvent, preferably ether such as tetrahydrofuran or 1,4-dioxane, at reflux temperature to obtain l,4-dihydro-1.4-methano naphthalene (4) which, if required, is purified by vacuum distillation to get pure compound (4). Cyclopentadiene is very unstable at room temperature, hence it is freshly prepared by cracking distillation of dicyclopentadiene at temperature 200-250°C, preferably at 210-240°C and stored below - 40 °C to prevent the dimerisation of the compound.
Step II:
l,4-dihydro-l,4-methano naphthalene (4) is dihydroxylated using N-methyl morpholine-N-oxide and catalytic amount of osmium tetroxide in suitable solvent at 50-55°C to get l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol(5). The mother

liquor containing osmium tetroxide obtained after isolation of compound 5 is used for dihydroxylation of compound 4. Osmium tetroxide is very expensive. Use of oxidizing agent such as N-methylmorphoIine N-oxide enables regeneration of the osmium tetroxide. The process of the present invention involves the use of regenerated osmium tetroxide.
Prior art discloses that the oxidation reaction is carried out at room temperature and the mixture is stirred vigorously, which takes 60 hours to complete the reaction. In the process of the present invention, oxidation reaction is carried at temperature of 50-55°C, which takes 8 hours for completion of the reaction.
l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol(5) obtained by the process is characterized by X-ray diffraction pattern as represented in Fig. 11. It is further characterized by X-ray diffraction pattern having peaks at 2-theta values of about 12.63, 16.83, 17.55,19.02, 19.51, 22.32, 28.64 and 29.41.
Step III:
l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-dioI (5) is subjected to oxidative cleavage with sodium metaperiodate in a solvent, preferably a solvent mixture, more preferably dichloromethane-water mixture in presence of benzyl triethyl ammonium chloride as phase transfer catalyst to get dialdehyde .i.e., 2,3-dihydro-lH-indene-l,3-dicarbaldehyde(6). The sodium metaperiodate is added to the reaction mass maintaining the temperature below 5°C under nitrogen purging. The dialdehyde compound (6) is unstable thus immediately converted to imine using benzyl amine. The imine mixture is added to freshly prepared sodium triacetoxy borohydride suspension in dichloromethane at 0-5°C to get 10-benzyl-10-aza-tricyclo[6.3.1.02,7] dodeca-2(7),3,5-triene (7). The sodium triacetoxy borohydride is prepared by adding glacial acetic acid (about 3.25 eqv) to the sodium borohydride suspension in dichloromethane at 0-5°C.
Prior art discloses purification of crude N-benzyl compound (7) by dissolving in minimum quantity of diethyl ether followed by filtration through a silica pad by

elution with 15% ethyl acetate-hexanes + 1% of 37% aqueous ammonium hydroxide solution to remove baseline colour. This purification requires large quantities of solvents and tedious operations on a large scale.
According to the present invention, crude N-benzyl amine (7) is purified by dissolving compound (7) in aqueous hydrochloric acid solution and washing the aqueous layer with suitable organic solvent. The aqueous layer is then basified with aqueous sodium carbonate solution and free N-benzyl amine is extracted using suitable organic solvent. The organic layer is concentrated to get pure N-benzyl compound (7). This method of purification of crude compounds using acid and base treatment is referred herein as acid-base purification.
Suitable organic solvent is selected from polar aprotic solvent. Polar aprotic solvent is selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethyl formamide, acetonitrile, dimethyl sulfoxide.
Step IV:
N-benzyl amine compound (7) is debenzylated in the presence of a suitable catalyst such as Pd/C catalyst to get compound (8) which is purified by trituration in acetone or ether or mixture thereof to get pure compound (8) or by acid-base purification as described above.
10-azatricyclo[6.3.1.027]dodeca-2(7),3,5-triene(8), obtained by the process of the present invention is characterized by X-ray diffraction pattern as represented in Fig. 12. It is further characterized by X-ray diffraction pattern having peaks at 2-theta values of about 6.42, 12.86, 17.75, 19.21, 19.35, 21.06, 21.62, 23.15, 23.21, 25.90 and 28.15.
Step V:
The obtained compound (8) is protected with trifiuoroacetic anhydride in presence of base such as triethyl amine or diisopropyl ethylamine in suitable solvent preferably dichloromethane to get N-trifluoroacetyl protected compound (9). The reaction is performed at 0-5°C.

Step VI:
N-trifluoroacety] protected compound (9) is nitrated with fuming nitric acid in presence of trifluoromethane sulphonic acid in suitable solvent preferably dichloromethane at 0-5°C to get dinitro compound (10). The crude dinitro compound (10) is purified by trituration in suitable solvent mixture, preferably ethyl acetate-hexane to get pure compound (10).
Prior art discloses nitration of compound (9) to get dinitro compound(lO). The reaction time takes nearly 26.5 hrs for completion of the reaction. The present invention takes 10 to 18 hrs, preferably 10 hrs for the nitration reaction.
1 -(4,5-dinitro-10-azatricyclo[6.3.1.02 7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone(lO) obtained by the process of the present invention is characterized by X-ray diffraction pattern as represented in Fig. 13. ft is further characterized by X-ray powder diffraction pattern having peaks at 2-theta values of about 9.33, 12.51, 14.12, 14.74, 15.17, 15.85, 16.92, 18.19, 18.61, 19.84, 20.28, 21.36, 21.93, 22.37, 22.98, 23.35, 23.52, 24.86, 25.14, 26.16, 27.05, 28.39, 29.22, 30.05, 30.67, 31.19, 32.14, 33.42, 34.33, 36.35, 36.77, 37.68, 38.54, 39.34, 40.58, 41.14, 43.12, 44.72, 46.59 and 49.06.
The present invention further provides various salts of Varenicline, polymorphic forms thereof and process for preparation thereof.
According to another embodiment, the present invention provides process for preparation of hydrochloride salt of Varenicline comprising treating Varenicline or salt thereof with a suitable salt forming agent to get the hydrochloride salt of Varenicline and optionally purifying the hydrochloride salt of Varenicline.
Suitable salt forming agent is selected from thionyl chloride, ammonium chloride or HC1, preferably ammonium chloride. HC1 may be used as a gas or as a solution. Solvent used is selected from alcohol, water or mixture thereof. Alcohol is selected from CM alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol or n-butanol, preferably ethanol.

Preparation of hydrochloride salt of Varenicline is disclosed in Example 26[C] of US 6410550 wherein Varenicline (1) in methanol is treated with 3M HC1 in ethyl acetate, concentrated and azeotroped with methanol to get solid which is recrystallized from methanol/diethyl ether. It is observed that the hydrochloride salt obtained by the process is colored which is not suitable for pharmaceutical formulation. The present invention provides a process for preparation of Varenicline hydrochloride comprising the steps of treating Varenicline (1) with ammonium chloride in ethanol; and purifying the obtained residue by crystallization, using a suitable solvent preferably ethanol to get analytically pure material. The hydrochloride salt is obtained in high purity (HPLC purity above 99.9%).
Varenicline hydrochloride obtained according to the present invention is characterized by X-ray diffraction pattern as shown in Fig. 4. It is further characterized by X-ray diffraction pattern having peaks at 2-theta values of about 8.26, 10.19, 10.85, 12.36, 13.23, 16.22, 19.48, 20.63, 21.75, 22.70, 23.40, 24.83, 26.07, 27.50, 29.05, 29.95, 30.98, 32.69, 37.64, 39.63 and 41.74.
The process for preparation of Varenicline and salts thereof, according to the present invention is represented in the below scheme:


According to another embodiment, the present invention provides process for preparation of tartrate salt of Varenicline comprising treating Varenicline with tartaric acid in suitable solvent; and optionally isolating the tartrate salt of Varenicline.
In preferred embodiment, L-tartrate salt of Varenicline is prepared by a process comprising the steps of adding L-tartaric acid solution in alcohol preferably methanol to a solution of Varenicline in ethyl acetate or vice-versa to get Varenicline tartrate. The crude compound is purified to get Varenicline tartrate (Form B) which is characterized by X-ray powder diffraction pattern (XRPD) as represented in Fig.2. XRPD of Varenicline tartrate obtained according to the present invention matches with the XRPD of Varenicline tartrate (Form B) provided in US6890927.
According to another embodiment of the present invention, tartrate salt of Varenicline is purified by dissolving the tartrate salt of Varenicline in alcohol preferably methanol containing water and isolating pure tartrate salt of Varenicline in high purity (HPLC purity above 99.9%).
According to another embodiment of the present invention, Varenicline tartrate is purified by basifying Varenicline tartrate; and further isolating Varenicline tartrate by addition of tartaric acid to Varenicline base.
Suitable base selected for basification is selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate cesium carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, sodium t-butoxide, calcium oxide, sodium acetate, sodium methoxide, triethyl amine, N,N-diisopropylethylamine, N,N-diethylethanamine, 4-ethylmorpholine, pyridine, and the like.
Another embodiment of the present invention provides Varenicline Tartrate Form G characterized by X-ray powder diffraction pattern as represented in Fig. 3. It is

further characterized by X-ray powder diffraction pattern having peaks at 2-theta values of about 5.90, 11.87, 13.15, 16.52, 16.68, 17.57, 20.34, 21.39, 23.12, 23.79, 29.29 and 29.82.
Another embodiment of the present invention provides process for preparation of Varenicline tartrate Form G comprising dissolving Varenicline tartrate in water: optionally filtering the solution to remove any insoluble/suspended particles and isolating Varenicline Tartrate Form G.
Varenicline tartrate used for synthesis of Form G can be selected from Varnecline tartrate Form A, B, C, D, E or F.
Another embodiment of the present invention provides process for preparation of mesylate salt of Varenicline comprising treating Varenicline in a suitable solvent with methane sulphonic acid and isolating mesylate salt of Varenicline.
Solvent used is selected from alcohol, water or mixture thereof. Alcohol is selected from C1-4 alcohols such as methanol, ethanol, n-propanol or isopropyl alcohol.
Mesylate salt of Varenicline obtained according to the present invention is characterized by X-ray powder diffraction pattern as shown in Fig. 5. It is further characterized by X-ray powder diffraction pattern having peaks at 2-theta values of about 6.21, 8.35, 10.59, 11.06, 14.04, 15.12, 15.94, 16.63, 17.21, 17.81, 18.41, 18.71, 19.44, 20.21, 20.48, 22.61, 23.48, 24.42, 24.95, 25.26, 25.77, 26.36, 26.94, 27.55 and 27.95.
According to another embodiment, the present invention provides process for preparation of maleate salt of Varenicline comprising treating Varenicline in a suitable solvent with maleic acid and isolating maleate salt of Varenicline.
Solvent used is selected from alcohol, water or mixture thereof. Alcohol is selected from C1-4 alcohols such as methanol, ethanol, n-propanol or isopropyl alcohol.
Maleate salt of Varenicline obtained according to the present invention is

characterized by X-ray powder diffraction pattern having peaks at 2-theta values of about 11.31, 13.49, 14.10, 15.17, 16.71, 18.04, 18.25, 21.04, 22.07, 22.45, 23.23, 25.61, 25.95, 27.95, 28.24, 28.50, 29.01, 29.15, 30.12, 31.22, 32.15, 33.49, 36.72, 37.87, 38.14, 39.84, 40.94, 44.82, 46.47 and 47.60.
Another embodiment of the present invention provides process for preparation of Varenicline fumarate Form I comprising treating Varenicline in a suitable solvent with fumaric acid and isolating fumarate salt of Varenicline.
Solvent used is selected from alcohol, water or mixture thereof. Alcohols is selected from C1-4 alcohol such as methanol, ethanol, n-propanol or isopropyl alcohol.
Fumarate salt of Varenicline Form 1 obtained according to the present invention is characterized by X-ray powder diffraction pattern having peaks at 2-theta values of about 7.17, 10.65, 11.33, 11.92, 13.25, 13.83, 14.43, 16.23, 16.62, 16.75, 17.99, 18.12, 19,34, 20.51, 21.53, 21.75, 22.73, 23.77, 24.20, 24.50, 24.96, 25.82, 26.19, 26.46, 27.00, 27.88, 28.52, 28.70, 29.20, 29.36, 29.86, 31.82, 34.54, 35.18, 36.06, 39.19, 42.12 and 43.22.
Another embodiment of the present invention provides Varenicline Fumarate Form II characterized by X-ray powder diffraction pattern as represented in Fig. 6. It is further characterized by X-ray powder diffraction pattern having peaks at 2-theta values of about 5.35, 6.32, 7.70, 8.84, 10.68, 11.61, 13.21, 14.43, 16.07, 17.30, 17.73,18.14, 19.22 and 20.37.
Another embodiment of the present invention provides process for preparation of Varenicline fumarate Form II which comprises the steps of,
a) obtaining a solution of Varenicline fumarate in a suitable solvent:
b) optionally adding an antisolvent to the obtained solution; and
c) isolating Varenicline fumarate Form II.
In a preferred embodiment, Varenicline is suspended in a suitable solvent and the suspension is refluxed followed by addition of water to get a clear solution. The hot

solution is optionally filtered to remove any insoluble/suspended particles. The filtrate is cooled to 25-30° C to get Form II of Varenicline Fumarate. In another preferred embodiment, Varenicline is suspended in a suitable solvent and the suspension is refluxed followed by addition of water to get a clear solution. The hot solution is optionally filtered to remove any insoluble/suspended particles. The filtrate is cooled to 25-30° C followed by addition of an antisolvent to get Form II of Varenicline fumarate.
Solvent used is selected from alcohol, nitrile, ketone, ether, water or mixture thereof. Alcohol is selected from C1-4 alcohol such as methanol, ethanol, n-propanol or isopropanol. Nitrile is selected from C1-4 nitriles such as acetonitrile or propionitrile. Ketone is selected from acetone, methyl ethyl ketone or diethyl ketone. Ether is selected from tetrahydrofuran (THF), diethyl ether, 1,4-dioxane or diisopropyl ether. Antisolvent is selected from chlorinated hydrocarbon, aliphatic or aromatic hydrocarbon, water or mixture thereof. Chlorinated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform or mixture thereof. Aliphatic hydrocarbon is selected from pentane. hexane or heptane. Aromatic hydrocarbon is selected from toluene or xylene.
Varenicline fumarate used for synthesis of Varenicline fumarate Form II are selected from Varenciline fumarate Form I or any other polymorphic form of Varenicline fumarate.
According to another embodiment, the present invention provides process for preparation of oxalate salt of Varenicline comprising treating Varenicline in a suitable solvent with oxalic acid and isolating oxalate salt of Varenicline.
Oxalate salt of Varenicline obtained according to the present invention is characterized by X-ray powder diffraction pattern as shown in Fig. 7. It is further characterized by X-ray powder diffraction pattern having peaks at about 7.12, 8.74, 10.12, 12.38, 14.31, 15.21, 16.23, 17.03, 20.35, 20.97, 21.58, 22.38, 28.59 and 28.96.

Solvent is selected from alcohol, water or mixture thereof. Alcohol is selected from C1-4 alcohol such as methanol, ethanol, n-propanol or isopropyl alcohol.
Another embodiment of the present invention provides novel polymorphs of Varenicline Phosphate namely Form IV, Form V and Form VI.
Varenicline Phosphate Form IV is characterized by X-ray powder diffraction pattern as shown in Fig. 8. It is further characterized by X-ray powder diffraction pattern having peaks at 2-theta values of about 6.86, 11.60, 13.73, 14.06, 14.41, 15.02, 15.41, 15.64, 16.41, 16.98, 17.53, 18.14, 19.26, 19.71, 20.02, 20.28, 20.76, 22.46, 25.49, 26.42, 29.05 and 30.06.
Another embodiment of the present invention provides process for preparation of Varenicline phosphate Form IV comprising treating Varenicline in a suitable solvent with phosphoric acid and isolating Varenicline Form IV.
Solvent is selected from C1-4 alcohol such as methanol, ethanol, n-propanol or isopropyl alcohol.
Varenicline phosphate Form V is characterized by X-ray powder diffraction pattern as shown in Fig. 9. It is further characterized by X-ray powder diffraction pattern having peaks at 2-theta values of about 6.82, 11.57, 11.73, 13.67, 14.40, 14.99, 15.35, 19.67, 19.93, 20.26, 20.61, 22.44, 23.34, 26.37, 26.84, 27.58, 29.04, 29.33, and 29.77.
Another embodiment of the present invention provides process for preparation of Varenicline phosphate Form V comprising a) dissolving/suspending Varenicline Phosphate in suitable solvent and refluxing the solution; b) optionally, adding water to the obtained solution to get a clear solution c) optionally, adding antisolvent to the obtained solution to get Varenicline phosphate Form V.
Solvent is selected from alcohol, water or mixture thereof. Antisolvent is selected from tetrahydrofuran (THF), acetonitrile, acetone, 1,4-dioxane, isopropanol or diisopropyl ether.

Varenicline phosphate Form VI is characterized by X-ray powder diffraction pattern as in Fig. 10. It is further characterized by X-ray powder diffraction pattern having peaks at 2-theta values of about 6.82, 10.75, 11.31, 11.59, 11.74, 12.81, 13.71, 14.38, 15.00, 15.36, 16.16, 17.59, 17.82, 19.95, 20.28, 20.73, 21.39, 21.67, 22.44, 22.76, 23.30, 23.66, 24.00, 24.34, 24.90, 29.05, 29.31, 29.82 and 30.27.
Another embodiment of the present invention provides process for preparation of Varenicline phosphate Form VI comprising obtaining a solution/suspension of Varenicline phosphate in a first solvent; optionally adding water to the obtained solution; optionally, adding a second solvent to the obtained solution; isolating Varenicline phosphate Form VI.
First solvent and second second is selected from C1-4 alcohol such as methanol, ethanol, n-propanol or isopropyl alcohol.
Varenicline phosphate used for the synthesis of Varenicline phosphate Form IV, V and VI are selected from Varenicline phosphate Form I, II or III .
Varenicline or salts thereof or polymorphic forms thereof obtained by the process of the present invention may be micronized by conventional micronization techniques for improving the flow characteristics of the material and uniformity of dosage forms and thus suitable for bulk preparation and formulation. Varenicline or salts thereof obtained according to the present invention exhibits particle size distribution such that about 90% particles have particle size less than or equal to 500 microns preferably less than or equal to 300 microns, more preferably less than or equal to 150 microns. Varenicline or salts thereof obtained according to the present invention can be micronized using conventional micronization techniques to get reduced particle size such that 90% particles have particle size less than or equal to about 100 microns, preferably less than or equal to about 50 microns, more preferably less than or equal to about 10 microns.
According to another embodiment of the present invention, there is provided a pharmaceutical composition of Varenicline or pharmaceutically acceptable salt thereof, in particular Varenicline tartrate or Varenicline hydrochloride. Varenicline

or pharmaceutically acceptable salt thereof is blended with pharmaceutically acceptable excipient to obtain a blend. The obtained blend is then lubricated and the lubricated blend is then formulated into a finished dosage form. Varenicline or pharmaceutically acceptable salt thereof can also be formulated by wet granulation or slugging-deslugging method. This finished dosage form may be in the form of tablet, capsule, granules, powder or syrup, preferably tablet.
Varenicline or salts thereof in accordance with the present invention are characterized by Xpert'PRO PANalytical diffractometer equipped with accelerator detector using Copper Koc (X =1.5406 A) radiation with scanning range between 4-50 2-theta at scanning speed of 2°/min.
The present invention is further illustrated by reference to the following examples which does not limit the scope of the invention in any way.
Example 1
Preparation of l,4-dihydro-l,4-methano naphthalene (4)
A mixture of magnesium turnings (58.4 g, 2.43 moles) in dry tetrahydrofuran (400 ml) under nitrogen atmosphere was heated to reflux. 1-bromo-2-fluoro benzene (3.2 g) was added to the refluxed mixture followed by addition of ethyl magnesium bromide (2.4 ml, 2.0 M in THF). A mixture of 2-fluoro-l-bromo benzene (400 g, 2.3 moles) and cyclopentadiene (151 g, 2.3 moles) [prepared by the method described in Org Syn. Col. Vol. V, 414-418] was separately chilled below -40°C in dry ice-acetone bath and the mixture was slowly added (The mixture is transferred to the addition funnel in small lots to keep it chilled as cyclopentadiene is highly unstable at high temperatures) to the above reaction mixture. After the initiation of reaction. (exotherm and excessive reflux) water bath was removed and further addition was slowly continued maintaining the reflux. After complete addition, water bath was again applied and the reaction was maintained at reflux temperature for further 1-2 hrs. The reaction mixture was chilled to 5-10°C and quenched with water (800 ml) and IN HC1 (320 ml) followed by addition of cone HC1 (80 ml) to dissolve the

solids. The reaction mass was saturated with the addition of saturated sodium chloride solution (480 ml) and extracted with ethyl acetate (1200 ml+ 400 ml +400 ml). The combined organic layer was washed with saturated sodium bicarbonate solution (480 ml), dried on sodium sulphate and concentrated to get an oil. This crude product was distilled under vacuum to get pure oil (212 g, 65%).
Example 2
Preparation of l,23,4-Tetrahydro-l,4-methano-naphthalene-2,3-diol (5)
Method I
l,4-dihydro-l,4-methano naphthalene (314 g, 2.21 moles) in acetone (3.14 L) and water (314 ml) was treated with N-methyl morpholine N-oxide (267 g, 2.28 moles) and osmium tetroxide (1 g) at temperature of 50-55°C for 8 hours. The reaction mass was concentrated to approximately half of its volume and cooled to 5°C to get the product which was filtered, washed with acetone and dried (335 g, 86%).
Method II
N-methyl morpholine N-oxide (80 g, 0.682 moles) was added to the solution of 1,4-dihydro-1,4-methano naphthalene (94 g, 0.66 moles) in acetone (700 ml) and water (70 ml). Mother liquor of example 2 (Method I) (240 ml containing Os04 equivalent to 0.6 g) was added to the obtained solution and mixture was heated to temperature of 50-55°C for 8 hrs. After the completion of reaction, the reaction mass was concentrated to approximately half of its volume and cooled to 5aC to get product which was filtered, washed with acetone and dried (97 g, 83%).
Example 3
Preparation of 10-BenzyI-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7), 3,5-triene (7)
l,2,3,4-Tetrahydro-l,4-methano-naphthalene-2,3-diol (350 g, 1.99 moles) was taken in water (7L) and dichloromethane (3.5 L) at 0-5 °C. Triethyl benzyl ammonium chloride (0.44 g) was added to the obtained solution. The nitrogen gas was purged in the reaction mass. 448 g of sodium meta periodate ( 2.093 moles) was added lot wise to the reaction mixture and the reaction mixture was stirred for 1 hr. The

separated aqueous layer was extracted with dichloromethane (1750 ml). The combined organic layer was washed with water (4X1750 ml) till starch iodide paper showed negative test of aqueous wash and dried on sodium sulphate. Benzyl amine (124 g, 2.093 moles) was added to the organic layer containing dialdehyde, stirred for 5 mins and immediately added to the sodium triacetoxy borohydride mixture [sodium borohydride (284 g, 7.68 moles) in dichloromethane under nitrogen cooled to 0-5°C and glacial acetic acid (1494 g, 24.9 moles) was slowly added to this mixture at 0-5 °C]. After complete addition of mixture the temperature was raised to 25-30°C within 1 hr. After completion of reaction, the reaction mass was quenched with 10% sodium carbonate solution (10.16 L. pH 8-9). The separated aqueous layer was extracted with dichloromethane (1.75 L). The organic layers were combined, washed with water (2X3.5 L) and concentrated to give dark brown colored oil. The oil obtained was taken in water (3.5 L) and concentrated HC1 (315 ml) was added (pH-2) to it. The clear solution was washed with ethyl acetate (2X1.75 L) to remove impurities. The aqueous layer was basified by adding 10% sodium carbonate solution (3.5 L, pH 8-9) and extracted with dichloromethane (2X 1.75 L). The organic layers were combined, washed with water (2X1.75 L), dried on sodium sulphate and concentrated to get oil. (421 g, 85%).
Example 4
Preparation of 10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (8)
10-Benzyl-l0-aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene (176 g) was taken in ethanolic HC1 (264 ml) and methanol (528 ml) in an autoclave pressurised with 5 Kg/cm2 H2 pressure and 10% Pd/C (50% moist, 71.4 g) was added to the reaction mass. The reaction mixture was heated at temperature of 50-55°C with stirring for 8 hrs. After completion of reaction, the reaction mixture was filtered on celite pad to remove catalyst. The pad was washed with methanol-1,4-dioxane mixture and the clear filtrate was concentrated under vacuum to get oily solid (132 g, 95%).

Example 5
Preparation of 1-(10-Azatricyclo [6.3.1.02.7]dodeca-2(7), 3,5-triene-10-yl)2,2,2-
trifluoro-ethanone (9)
10-Aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene hydrochloride salt (150 g5 0.763 moles) was taken in dichloromethane (2.25 L) and chilled to 5-10° C. 252g of triethylamine (2.5 moles) was added to the mixture and the mixture was stirred for 15 minutes. Trifluoroacetic anhydride (210 g, 1.0 moles) was slowly added at 5-10° C to the reaction mass and stirred at 5-10° C for 3 hrs. The reaction mass was quenched by addition of 1 N HC1 (1.5 L). The separated aqueous layer was extracted with dichloromethane (3X 600 ml). The dichloromethane layers were combined and washed with 1 N HC1 (300 ml), water (2X600 ml) and saturated sodium bicarbonate solution (600 ml). The organic layer was dried over sodium sulphate and concentrated to get oily compound. This oily compound was taken in ethyl acetate (1.5 L), treated with neutral alumina (150 g), filtered and concentrated to get oil (187 g, 96%).
Example 6
Preparation of l-(4,5-Dinitro-10-Aza-tricyclo[6.3.1.027]dodeca- 2(7),3,5- trien-
10-yi)-2,2,2-trifIuoro-ethanone(10)
Trifluoromethane sulphonic acid (472 g, 3.14 moles) was taken in dichloromethane (1.74 L) and chilled to 0°C. Fuming nitric acid (99 g, 1.57 moles) was slowly added to the solution in 15-20 minutes. The solution of l-(10-Aza-tricyclo [6.3.1.02-7] dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone (174 g. 0.682 moles) in dichloromethane (1.05 L) was slowly added to the reaction mixture and stirred at 0°C for 2 hrs and at room temp for 8 hrs. After completion of reaction, the reaction mixture was poured on a ice-water mixture (1:1, 2.4 Kg) and stirred for 1 hr. The separated aqueous layer was extracted with dichloromethane (2X1.05 L). The organic layer were combined, washed with saturated sodium bicarbonate solution (700 ml) and water (700 ml), dried over sodium sulphate and concentrated to oily solid. This oily solid was triturated with ethyl acetate-hexane. (178 g, 75%).

Example 7
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-trifluoro-ethanone (11):
l-(4,5-Dinitro-10-Aza-tricyclo [6.3.1.02.7] dodeca-2(7),3,5-trien-10-yl)- 2,2,2-trifluoro-ethanone (122 g, 0.428 moles) was taken in methanol (1220 ml) and 10% Pd/C (24.4 g, 50% wet) was added to the autoclave with 5 Kg/cm2 H2 pressure. After 2 hrs the catalyst was removed by filtration over celite pad. The pad was washed with methanol and 1,4-dioxane mixture. The solution was concentrated under vacuum to get a light brown oily solid (99 g, 98%).
Example 8
Preparation of l-(5,8,14-Triazatetracyclo[10.3.1.02.I,04'9]hexadeca-2(ll),3,5,7,9-
pentaene)-2,2,2-trifluoro-ethanone (12)
Method I
l-(4,5-Diamino-10-Aza-tricyclo [6.3.1.02'7] dodeca-2(7),355-trien-10-yl)-2,2,2-trifluoro-ethanone (99 g, 0.347 moles) was taken in THF (396 ml) and water (396 ml). Glyoxal sodium bisulphite hydrate (184 g, 0.693 moles) was added to the solution and stirred at 55°C for 2 hrs. After completion of reaction, 495ml of ethyl acetate was added to the reaction mixture and stirred for 15 minutes. The reaction mixture was filtered to remove undissolved solids and washed the solids with ethyl acetate (100 ml). To the clear filtrate, water (1485 ml) was added. The layers were separated after 15 minutes. The aqueous layer was extracted with ethyl acetate (2X 495 ml). The organic layers were combined and washed with water (495 ml), 0.5% EDTA solution (495 ml) and again with water (2X495 ml). The washed organic layer was dried over sodium sulphate, treated with neutral alumina (100 g) and concentrated to get a solid. (85 g, 80%).
Method II
l-(4,5-Dinitro-10-Aza-tricyclo[6.3.1.02'7]dodec-2(7),3,5-trien-10-yl)-2J2,2-trifiuoro-ethanone (113 g, 0.396 moles) in methanol (1130 ml) was taken in autoclave with 5 Kg/cm2 H2 pressure and 10% Pd/C (22.6 g, 50% wet) was added to it. The catalyst

was removed by filtration over celite pad after two hours. The pad was washed with methanol and 1,4-dioxane mixture. Glyoxal sodium bisulphite addition compound hydrate (174, 0.654 moles) and water (396 ml) was added to the obtained filtrate. The reaction mass was stirred at 55° C for 2 hrs. After the completion of reaction. ethyl acetate (450 ml) was added to the reaction mixture and stirred for 15 minutes. After complete conversion of starting material, the reaction mass was filtered to remove undissolved solids and the solids were washed with ethyl acetate (110 ml). To the clear filtrate, water (1415 ml) was added and stirred for 15 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate (2X 450 ml). The organic layers were combined, washed with water (450 ml), 0.5% EDTA solution (450 ml) and again with water (2X450 ml). The organic layer was dried over sodium sulphate, treated with neutral alumina (100 g) and concentrated to get a solid. (86 g, 85%).
Example 9
Preparation of 7,8,9,10-te(rahydro-6,10-methano-6H-pyrazino [2,3-hJ [3]
benzazepine [Varenicline] (I)
l-(5,8,14-triazatetracyclo [10.3.1.02n,049] hexadeca-2(ll),3,5,7,9-pentaene)-2,2,2-trifiuoro-ethanone (79 g, 0.257) was taken in methanol (651 ml). To this mixture sodium carbonate (65.1 g) in water (651 ml) was added. The reaction mixture was refluxed for 2 hrs. After the completion of reaction, reaction mass was quenched in water (4.9 L) and extracted with dichloromethane (3X 1.6 L) . The organic layer was washed with water (1.6 L) and aqueous HC1 (Cone HC1, 48 ml + water 2.15 L) was added to it followed by stirring for 30 mins. The separated organic layer was washed with water (715 ml). The organic layer was discarded. The aqueous layers were combined and washed with dichloromethane (715 ml). The aqueous layer was basified by adding aqueous sodium carbonate solution (59.6 g in 1200 ml water). The aqueous layer was extracted with dichloromethane (3X 1.6 L ). The dichloromethane layers were combined, washed with water (1.6 L) then with 0.5% EDTA solution (790 ml) and again with water (1.6 L). The organic layer was dried

over sodium sulphate and concentrated to get oil, which solidified on standing. (40g,74%).
Example 10:
Preparation of Varenicline L-Tartrate
A solution of L-Tartaric acid (26.7 g, 0.178 moles) in methanol (257 ml) was filtered and charged in a flask. A solution of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3] benzazepine (34 g, 0.161 mol) was prepared in methanol (257 ml) and charcoalized. The mixture was filtered and the clear filtrate was slowly added to the above L-tartaric acid solution at 20-25°C. The product was stirred at 20-25°C overnight, filtered, washed with methanol and dried under vacuum at 35 to 45° C to give solid. (53.5 g, 92%).
Example 11:
Purification of Varenicline L-Tartrate
The crude L-Tartrate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h] [3] benzazepine (50 g) was taken in methanol (900 ml) and heated to reflux temperature. At reflux, water (300 ml) was added to obtain a clear mixture. The mixture was charcoalized and filtered. To the clear filtrate, methanol (1L) was added for precipitating the material and the precipitated solids were stirred at ambient temperature for 6 to 8 hrs. The solid was filtered, washed with methanol (50 ml) and dried under vacuum at 35 to 45°C to get the solid (40 g, 80%).
Example 12:
Preparation of Varenicline L-Tartrate Form B
A solution of L-Tartaric acid (3.95 g, 26.3 mmoles) in methanol (35 ml) was filtered and charged in a flask. A solution of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3] benzazepine (5 g, 23.7 mmoi) was prepared in ethyl acetate (125 ml) and charcoalized. The mixture was filtered and the clear filtrate was slowly added to the above prepared L-tartaric acid solution at 20-25°C and the mixture was stirred overnight at the same temperature. The product was filtered, washed with

methanol and dried under vacuum at 35 to 45°C to get solid (7.7 g). The obtained solid was dissolved in methanol (140 ml) and water (46 ml) at reflux temperature and charcoalized. The mixture was filtered and to the clear filtrate, methanol (154 ml) was added to precipitate the material and the mixture was stirred at ambient temperature for 6 to 8 hrs. The solid obtained was filtered, washed with methanol (10 ml) and dried under vacuum at 35 to 45°C to get the title compound (6 g, 70%).
Example 13
Preparation of Varenicline tartrate Form G
lg Varenicline Tartrate was dissolved in 20 ml water at 30°C. The solution was filtered to remove any insoluble particles. The solution was evaporated under vacuum at 70°C. The solid obtained was maintained under vacuum for 2 hrs to get Varenicline Tartrate Form G.
Example 14:
Preparation of Varenicline hydrochloride
A solution of 7,8,9,10-tetrahydro-6;10-methano-6H-pyrazino[2,3-h][3] benzazepine (7 g, 33.2 mmol) in ethanol (250 ml) was subjected to charcoal treatment and filtrate was treated with ammonium chloride (5,32 g, 99.5 mmol). The mixture was filtered and heated to reflux for 12 hrs. The reaction mixture was concentrated to approximately 30% of original volume, chilled to 5°C, stirred for 2 hrs at this temperature, filtered and residue was washed with ethanol. The wet material (6.1 g, 74%) was dried under vacuum at 40-45°C and recrystallized in ethanol to get the analytically pure compound (5.2 g, 85%).
Example 15:
Preparation of Varenicline hydrochloride
A solution of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3] benzazepine (2 g, 9.5 mmol) in ethanol (70 ml) was subjected to charcoal treatment. The mixture was filtered and filtrate was treated with ammonium chloride (1,53 g, 28.5 mmol). The mixture was heated to reflux for 12 hrs and concentrated to dryness to get solid

which was recrystallized with methanoI/Et20 to get Varenicline hydrochloride. (1.64 g, 70%).
Example 16:
Preparation of Varenicline Methane sulphonate (Varenicline Mesylate)
To a suspension of Varenicline (4 g, 19 mmol) in methanol (40 ml), Methane sulphonic acid (1.82 g, 19 mmol) was added and the mixture was stirred for 2 hrs. The separated solid was filtered and dried to get the title compound (4.35 g, 75%).
Example 17:
Preparation of Varenicline maleate
To a suspension of Varenicline (4 g, 19 mmol) in methanol (40 ml), maleic acid (2.2 g, 19 mmol) was added and the mixture was stirred for 2 hrs. The separated solid was filtered and dried to get the title compound (5.3 g, 85%).
Example 18:
Preparation of Varenicline fumarate Form I
To a suspension of Varenicline (4 g, 19 mmol) in methanol (40 ml), fumaric acid (2.2 g, 19 mmol) was added and the mixture was stirred for 2 hrs. The separated solid was filtered and dried to get titled compound (5.5 g, 89%).
Preparation of Varenicline Fumarate Form II Example 19
0.3g of Varenicline fumarate was suspended in acetone (10 ml). The solution was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxing solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. The solution was cooled to 25-30°C and maintained at the same temperature for I hr. The solid was filtered and dried at 60°C to get Varenicline fumarate Form II.
Example 20
0.3g of Varenicline fumarate was suspended in THF (10 ml). The solution was

heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxing solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. The solution was cooled to 25-30°C and maintained at the same temperature for 1 hr. The solid was filtered and dried at 60°C to get Varenicline fumarate Form II.
Example 21
0.3g of Varenicline fumarate was suspended in acetonitrile (10 ml). The solution was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxing solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. The solution was cooled to 25-30°C and maintained at the same temperature for 1 hr. The solid was filtered and dried at 60°C to get Varenicline fumarate Form II.
Example 22
0.3g of Varenicline fumarate was suspended in isopropanol (10 ml). The solution was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxing solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. The solution was cooled to 25-30°C and maintained at the same temperature for 1 hr. The solid was filtered and dried at 60°C to get Varenicline fumarate Form II.
Example 23
0.3g of Varenicline fumarate was suspended in 10 ml isopropanol. The solution was heated to reflux and maintained for 10 minutes. At reflux, 2 ml water was added to get the clear solution. The hot solution was filtered to remove any insoluble particle. The solution was cooled to 25-30°C and to this solution 20 ml hexane was added. The solution was maintained at the same temperature for 1 hr. The solid was filtered and dried at 60°C to get Varenicline fumarate Form II.

Example 24
0.3g of Varenicline fumarate was suspended in 10 ml acetone. The solution was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxed solution to get a clear solution. The hot solution was filtered to remove any insoluble particle and cooled to 25-30°C. Dichloromethane (20ml) was added to the cooled solution and maintained at the same temperature for 1 hr. The obtained solid was filtered and dried at 60°C to get Varenicline fumarate Form II.
Example 25
Preparation of Varenicline oxalate
To a suspension of Varenicline (4 g, 19 mmol) in methanol (40 ml), oxalic acid (1.7 g, 19 mmol) was added and the mixture was stirred for 2 hrs. The separated solid was filtered and dried to get Varenicline oxalate. (4.5 g, 79%).
Example 26
Preparation of Varenicline phosphate Form IV
To a suspension of Varenicline (4 g, 19 mmol) in methanol (40 ml), phosphoric acid (1.86 g, 19 mmol) was added and the mixture was stirred for 2 hrs. The separated solid was filtered and dried to get titled compound. (5.5 g, 94%).
Preparation of Varenicline phosphate Form V Example 27
0.3g of Varenicline phosphate was suspended in methanol (10 ml). The solution was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxed solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. 20 ml of THF was added to hot filtrate and maintained at the same temperature for 1 hr. The solid obtained was filtered and dried at 60°C to get Varenicline phosphate Form V.
Example 28
0.3g of Varenicline phosphate was suspended in methanol (10 ml). The solution was

heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxed solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. 30 ml acetonitrile was added to hot filtrate and maintained at the same temperature for 1 hr. The solid obtained was filtered and dried at 60°C to get Varenicline phosphate Form V.
Example 29
0.3g of Varenicline phosphate was suspended in methanol (10 ml). The solution was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxed solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. 20 ml acetone was added to hot filtrate and maintained at the same temperature for 1 hr. The solid obtained was filtered and dried at 60°C to get Varenicline phosphate Form V.
Example 30
0.3g of Varenicline phosphate was suspended in methanol (10 ml). The solution was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxed solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. 30 ml 1,4-dioxane was added to hot filtrate and maintained at the same temperature for 1 hr. The solid obtained was filtered and dried at 60°C to get Varenicline phosphate Form V.
Example 31
0.3g of Varenicline phosphate was suspended in methanol (10 ml). The solution was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxed solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. 10 ml isopropanol was added to hot filtrate and maintained at the same temperature for 1 hr. The solid obtained was filtered and dried at 60°C to get Varenicline phosphate Form V.

Example 32
0.3g of Varenicline phosphate was suspended in methanol (10 ml). The mixture was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxed solution to get a dear solution. The hot soJution was filtered to remove any insoluble particle. 20 ml DIPE was added to hot filtrate and maintained at the same temperature for 1 fir. The solid obtained was filtered and dried at 60°C to get Varenicline phosphate Form V.
Example 33
Preparation of Varenicline phosphate Form VI
0.3g of Varenicline phosphate was suspended in methanol (10 ml). The solution was heated to reflux and maintained for 10 minutes. 2 ml water was added to the refluxed solution to get a clear solution. The hot solution was filtered to remove any insoluble particle. 55 ml ethanol was added to hot filtrate and maintained at the same temperature for 1 hr. The solid obtained was filtered and dried at 60°C to get Varenicline phosphate Form VI.

We claim,
1, A process for preparation of Varenicline or pharmaceutically acceptable salt
thereof, said process comprising:
a) reducing l-(4,5-dinitro-10-azatricycIo[6.3.1.02,7]dodeca-2(7),3;5-triene-10-yl)-2,2,2-trifluoro-ethanone (10), optionally in presence of catalyst to obtain 1 -(4,5-diamino-l 0-azatricyclo[6.3.1.02'7]dodeca-2(7).3,5-triene-10 -yl)-2,2.2-trifluoro-ethanone (11);
b) treating l-(4,5-diamino-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone (11), in situ with glyoxal sodium bisulphite to obtain 1-(5,8,14- triazatetracyclo[10.3.1.021I,04'9]hexadeca-2(ll),3,5,7,9-pentaene)-2,2.2-trifluoro-ethanone(12);
c) converting l-(5J8,14-triazatetracyclo[10.3.1.02.1l,04.9]hexadeca-2(l 1),3,5, 7,9-pentaene)-2,2,2-trifluoro-ethanone(12) to Varenicline or pharmaceutically acceptable salt thereof.
2. The process as claimed in claim 1. wherein the process for preparation of
said l-(4,5-dinitro-10-azatricyclo[6.3.1.02.7]dodeca-2(7)!3,5-triene-10-yl)-
2,2,2-trifluoro-ethanone (10) comprises the steps of,
a) dihydroxylating l,4-dihydro-l,4-methano naphthalene(4) using osmium tetroxide to obtain l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol (5), which is isolated;
b) converting said l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol (5) to 10-benzyl-10-aza-tricyclo [6.3.1.02-7]dodeca-2(7),3,5 -triene(7);
c) optionally purifying 10-ben2yl-10-azatricyclo[6.3.1.02'7]dodeca-2(7),3. 5-triene (7) by acid-base purification;
d) debenzylating said 10-benzyl- 10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene (7) to obtain 10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene (8);
e) treating said 10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene (8) with trifhioroacetic anhydride to get l-(10-azatricyclo[6.3.1.027]dodeca-2(7),3,5-triene- 10-yl)-2,2,2-trifluoro-ethanone (9);
f) nitrating said l-(10-azatricyclo[6.3.1.02'7]dodeca-2(7),3?5-triene-10-yl)-

2,2,2-trifluoro-ethanone(9) to obtain l-(4,5-dinitro-10-azatricyclo [6.3.1.02.7]dodeca-2(7))3,5-triene-10-yl)-2,2,2-trifluoro-ethanone(10).
3. The process as claimed in claim 1, wherein said reduction of l-(4,5-dinitro-10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone (10) is performed by catalytic hydrogenation.
4. The process as claimed in claim 2, wherein the mother liquor containing osmium tetroxide, obtained after the isolation of said l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol (5), is used for dihydroxylation of 1,4-dihydro -1,4-methano naphthalene(4) in the presence of N-methyl morpholine-N-oxide to obtain the corresponding dialdehyde compound which is further converted to 10-benzyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene(7).
5. The process as claimed in claim 1 or claim 2, wherein said pharmaceutically acceptable salt is selected .from the group consisting of hydrochloride, tartrate, mesylate, maleate, oxalate, fumarate or phosphate.
6. The process as claimed in claim 5, wherein said pharmaceutically acceptable salt is prepared by treating Varenicline with a salt forming agent selected from HC1, thionyl chloride, ammonium chloride, tartaric acid, methane sulphonic acid, maleic acid, oxalic acid, fumaric acid or phosphoric acid.
7. The process as claimed in claim 5, wherein said hydrochloride salt of Varenicline is prepared by treating Varenicline with a salt forming agent selected from ammonium chloride, thionyl chloride or HC1.
8. A process for preparation of Varenicline hydrochloride comprising treating Varenicline with ammonium chloride or thionyl chloride.
9. The process as claimed in claim 2, wherein said l,2,3,4-tetrahydro-l,4-methano-naphthalene-2,3-diol (5) exhibits X-ray diffraction pattern as shown in Fig, 11; said 10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene (8) exhibits

X-ray diffraction pattern as shown in Fig. 12; said l-(4,5-dinitro-10-azatricyclo [6.3.1.02.7]dodeca-2(7),3.5-triene-10-yl)-2,2,2-trifluoro-ethanone (10) exhibits X-ray diffraction pattern as shown in Fig. 13; and said 1-(5,8,14- triazatetracyclo [10.3.1.02.11,04.9] hexadeca-2(ll),3,5,7,9-pentaene)-2.2,2-trifluoro-ethanone (12) exhibits X-ray diffraction pattern as shown in Fig. 14.
10. A compound selected from the group consisting of l,2,3,4-tetrahydro-l}4-methano-naphthaIene-2,3-diol (5) characterized by X-ray diffraction pattern as shown in Fig. 11; 10-azatricyclo[6.3.1.02,7]dodeca-2(7),3.5-triene (8) characterized by X-ray diffraction pattern as shown in Fig. 12; Varenicline fumarate characterized by X-ray diffraction pattern as shown in Fig. 6; Varenicline mesylate characterized by X-ray diffraction pattern as shown in Fig. 5; Varenicline oxalate characterized by X-ray diffraction pattern as shown in Fig. 7; Varenicline phosphate characterized by X-ray diffraction pattern as shown in Fig. 8; Varenicline phosphate characterized by X-ray diffraction pattern as shown in Fig. 9; and Varenicline phosphate characterized by X-ray diffraction pattern as shown in Fig. 10.