FIELD OF THE INVENTION

The present invention relates to novel pharmaceutically acceptable salts selected from benzoate and 4-aminosalicylate salts of Varenicline Formulae I and II.

The present invention also relates to an improved process for the preparation of Varenicline of Formula III.
Formula HI

BACKGROUND OF THE INVENTION

Varenicline is chemically known as 7,8,9,10-Tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine.

Varenicline is a partial agonist of the subtype of the nicotinic acetylcholine receptor.

Varenicline binds with high affinity and selectivity at neuronal nicotinic acetylcholine receptors. The efficacy of Varenicline in smoking cessation is believed to be the result of

Varecline's activity at a sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to receptors. Varenicline blocks the ability of nicotine to activate receptors and thus to stimulate the central nervous mesolimic dopamine system.

Varenicline is marketed under the name Chantix® in the US. It has been approved for the treatment of Smoking cessation.

US 6,410,550 disclosed Varenicline and its pharmaceutically acceptable salts. However, US '550 exemplified only Varenicline hydrochloride (IIIa). US '550 discloses a process for the preparation of Varenicline hydrochloride by de benzylating 10-benzyl-10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene (VI) using Pd(0H)2 in methanol produce 10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene hydrochloride (VII), which is further reacted with trifluoroacetic anhydride [(CF3CO)2O] in the presence of pyridine in dichloromethane to produce l-(10-azatricyclo[6.3.1.0 ' ]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoroethanone (VIII). Compound (VIII) is further reacted with trifluoromethanesulfonic acid and nitric acid in a chlorinated hydrocarbon solvent to produce 1-(4,5-dinitro-10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoroethanone (IX).

Reduction of l-(4,5-dinitro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoroethanone (IX) in the presence of Pd(OH)2 in methanol to produce l-(4,5-diamino-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene-10-yl)-2,2,2trifluoroethanone (X), which is then reacted with glyoxal sodium bisulfite or glyoxal in tetrahydrofuran (THF) solvent to produce 1-(5,8,14-triazatetracyclo-[10.3.1.02'704'9]hexadeca-2(ll),3,5,7,9-pentaene)-2,2,2-trifluoroethanone (XI), De-protection of compound (XI) in the presence of aqueous sodium carbonate in aqueous methanol to produce Varenicline free base (III), which is further treated with hydrogen chloride in ethyl acetate produce Varenicline hydrochloride (IIIa). The process is as shown in Scheme -I below:

Crystalline forms of Varenicline citrate and succinate salts are disclosed in the US 6,787,549 and US 6,794,388, respectively.

Varenicline L-tartrate and its crystalline Forms A, B, and C are disclosed in the US 6,890,927 and US 7,265,119 respectively.

Varenicline L-tartrate and its crystalline Forms E, F, G & amorphous form are disclosed in the US 2009/0318460 Al.

Varenicline tosylate crystalline Forms I, II, III & IV are disclosed in the US 2010/0004451 Al.

Crystalline forms of Varenicline maleate, fumarate, pyroglutamate, hemi-adipate, galactarate, L-maleate and other dicarboxylic acid salts are disclosed in WO 2009/109651 Al.

Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, chemical reactivity etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailability.

In addition, polymorphism, which is defined as ability of a substance to crystallize in more than one crystal lattice arrangement, can also influence many aspects of solid state properties of a drug. Different crystal modifications of a substance may differ considerably from one another in many respects such as their solubility, dissolution rate and finally bioavailability.

Hence, there is a need for new salt forms, in addition salt form might be in crystalline form, of such material that have superior chemical and /or physical properties that are useful in drug delivery applications.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide novel benzoate and 4-aminosalicylate salts of 7,8,9,10-tetrahydro-6,10-methano-5H-pyrazino[2,3-h][3]benzazepine of Formulae I and II.

SUMMARY OF THE INVENTION

The present invention provides a novel benzoate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline benzoate) of Formula I.

Another embodiment of the present invention provides the benzoate salt of 7,8,9,10-tetrahydro-6,10-methano-677-pyrazino[2,3-h][3]benzazepine (Varenicline benzoate) of Formula I, characterized by X-ray diffraction spectrum which shows peaks at the diffraction angles of about 8.72, 9.13, 13.20, 13.94, 16.58, 17.35, 18.33, 19.09, 21.47, 22.66, 25.35, 26.58 and 28.18° ±0.2° 20.

Another embodiment of the present invention provides the benzoate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline benzoate) of Formula I characterized by a Infrared (IR) spectrum having its main peaks at about 673.0, 688.2, 705.1, 716.7, 781.1, 800.2, 832.6, 850.1, 882.5, 898.9, 916.5, 940.9, 1026.1, 1035.4, 1054.5, 1064.43, 1086.11, 1134.3, 1157.5, 1190.7, 1208.31, 1246.3, 1272.2, 1300.7, 1310.8, 1370.6, 1386.5, 1442.7, 1460.3, 1478.1, 1552.1, 1597.4, 1628.2, 2612.9, 2617.9, 2821.8, 2867.1, 2930.4, 2958.4, 3024.35, 3055.1 and 3410.5 cm"1.

Another embodiment of the present invention provides the benzoate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline benzoate) of Formula I characterized by a differential scanning calorimetric (DSC) having an onset of melting transition at about 163°C.

Another embodiment of the present invention provides a novel 4-aminosalicylate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline 4-aminosalicylate) of Formula II.

Another embodiment of the present invention provides the 4-aminosalicylate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline 4-aminosalicylate) of Formula II, characterized by X-ray diffraction spectrum which shows peaks at the diffraction angles of about 8.95, 15.86, 16.64, 17.93, 18.79, 19.48, 19.83, 20.17, 20.47, 22.21, 28.39 and 28.84° ±0.2° 20.

Another embodiment of the present invention provides the 4-aminosalicylate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline 4-aminosalicylate) of Formula II, characterized by a Infrared (IR) spectrum having its main peaks at about 655.9, 703.9, 724.8, 752.8, 778.6, 786.1, 803.1, 825.9, 840.3, 895.1, 878.8, 913.2, 940.3, 986.4, 1012.1, 1025.1, 1037.7, 1047.8, 1088.1, 1133.6, 1156.2, 1188.2, 1198.0, 1229.2, 1248.0, 1305.2, 1356.0, 1377.9, 1388.2, 1407.1, 1457.7, 1474.5, 1508.2, 1561.8, 1597.7, 1642.7, 1775.5, 1936.7, 2306.9, 2401.2, 2551.7, 2603.9, 2664.3, 2711.6, 2769.6, 2839.2, 2952.3, 3024.8, 3220.4, 3411.5, 3329.3, 3743.3, 3884.7 and 3851.9 cm"1.

Another embodiment of the present invention provides the 4-aminosalicylate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline 4-aminosalicylate) of Formula II, characterized by a Differential Scanning Calorimetric (DSC) shown in Figure 6.

Another embodiment of the present invention provides a process for the preparation of the benzoate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline benzoate) of formula I, which comprises, i) reacting 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine
(Varenicline) of formula III;

Formula III with benzoic acid of formula (IV);

(ii) isolating crystalline benzoate salt of Varenicline of formula I.
Another embodiment of the present invention provides a process for the preparation of the 4-aminosalicylate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline 4-aminosalicylate) of Formula II, which comprises:

(i) reacting 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h] [3]benzazepine
(Varenicline) of formula III;

Formula III with 4-aminosalicylic acid of formula (V);
Formula V

(ii) isolating crystalline 4-aminosalicylate salt of Varenicline of formula II.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the novel benzoate and 4-aminosalicylate salts of Varenicline, with pharmaceutically acceptable carriers.

In another embodiment, the present invention provides a process for the preparation of Varenicline (III):

Formula III which comprises,

i) debenzylation of 10-benzyl-10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene (VI);
in the presence of hydrogenation catalyst in a solvent to produce compound of formula VII;

ii) reacting 10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene hydrochloride (VII) with trifluoroacetyl protecting agent in the presence of a base to produce compound of Formula (VIII);

(iii) nitrating the compound of formula VIII to produce compound of Formula IX;

(iv) reducing the compound of formula IX to produce compound of Formula X;

(v) cyclization of compound of formula V to produce compound of Formula VI;

(vi) deprotecting of compound of formula VI to produce Varenicline free base of
Formula III. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the X-ray powder diffraction pattern of crystalline form of Varenicline
benzoate salt.

Figure 2 illustrates the Infrared (IR) spectra of crystalline form of Varenicline benzoate salt.

Figure 3 illustrates the differential scanning calorimetric (DSC) of crystalline form of Varenicline benzoate salt.

Figure 4 illustrates the X-ray powder diffraction pattern of crystalline form of Varenicline 4-aminosalicylate salt.

Figure 5 illustrates the Infrared (IR) spectra of crystalline form of Varenicline 4-aminosalicylate salt.

Figure 6 illustrates the differential scanning calorimetric (DSC) of crystalline form of Varenicline 4-aminosalicylate salt.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel benzoate salt of 7,8,9,10- tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline benzoate) of Formula I.

The Varenicline benzoate salt (I) is in solid form, preferably in crystalline form, which is characterized by a powder X-ray diffraction pattern (XRD) pattern having characteristic peaks at about 8.72, 9.13, 13.20, 13.94, 16.58, 17.35, 18.33, 19.09, 21.47, 22.66, 25.35, 26.58 and 28.18° ± 0.2° 20.

The crystalline form of Varenicline benzoate (I) may be further characterized by a powder XRD pattern substantially as illustrated in Figure 1.

The crystalline form of Varenicline benzoate (I) may be characterized by a Infrared (IR) spectrum having characteristic peaks at about 673.0, 688.2, 705.1, 716.7, 781.1, 800.2, 832.6, 850.1, 882.5, 898.9, 916.5, 940.9, 1026.1, 1035.4, 1054.5, 1064.43, 1086.11, 1134.3, 1157.5, 1190.7, 1208.31, 1246.3, 1272.2, 1300.7, 1310.8, 1370.6, 1386.5, 1442.7, 1460.3, 1478.1, 1552.1, 1597.4, 1628.2, 2612.9, 2617.9, 2821.8, 2867.1, 2930.4, 2958.4, 3024.35, 3055.1 and 3410.5 cm"1. The crystalline form of Varenicline benzoate (I) may be further characterized by a Infrared (IR) spectrum substantially as illustrated in Figure 2.

The crystalline form of Varenicline benzoate may be characterized by a differential scanning calorimetric (DSC) having an onset of melting transition at about 163°C.

The crystalline form of Varenicline benzoate (I) may be further characterized by differential scanning calorimetric (DSC) substantially as illustrated in Figure 3.

Another embodiment of the present invention further relates to the process for the preparation of the crystalline form of Varenicline benzoate (I).

The process comprises: reacting 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline) of formula III with benzoic acid of formula (IV) in a solvent selected from alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tet-butanol, ketone such as acetone, ethyl methyl ketone; ether such as diethyl ether, diisopropyl ether, di-tertiary butyl ether etc; esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate etc. or mixtures thereof to produce a reaction mixture, optionally heating the reaction mixture and then cooling the reaction mixture to produce crystalline Varenicline benzoate salt (I). Preferably, the reaction step is carried out over a period of between 1 and 12 hours, more preferably between 1 and 2 hours, and comprising stirring or mixing the resulting mixture.

Crystalline form of Varenicline benzoate salt (I) obtained is isolated from the reaction mixture by techniques which may be employed to isolate from the solution include those wherein the precipitate may be separated by techniques well known in the art. Preferably, the precipitate is separated by filtration. Optionally, vacuum filtration may be utilized.

The recovered crystalline form of Varenicline benzoate salt (I) can be dried and the drying is carried out under a pressure of less than one atmosphere, or less than 100 mm/Hg, most preferably less than 25 mm/Hg at about 20 to 60 °C for about 4 to 24 hours.

The aqueous solubility of the Varenicline benzoate salt (I) of about 50 mg/ml and pH of about 6.40 (5% aqueous solution) in aqueous solution. In addition, crystalline Varenicline benzoate (I) has a hygroscopicity of approximately 1.3% at 80% relative humidity.

The 1:1 salt correlation of Varenicline benzoate (I) was confirmed by 1H NMR spectrum.
In another embodiment, the present invention provides a novel 4-aminosalicylate salt of 7,8,9,10-tetrahydro-6,10-methano-677-pyrazino[2,3-h][3]benzazepine (Varenicline 4-aminosalicylate) of Formula II.

The Varenicline 4-aminosalicylate salt (II) is in solid form, preferably in crystalline form, which is characterized by a powder X-ray diffraction pattern (XRD) pattern having characteristic peaks at about 8.95, 15.86, 16.64, 17.93, 18.79, 19.48, 19.83, 20.17, 20.47, 22.21, 28.39 and 28.84° ±0.2° 20.

The crystalline form of Varenicline 4-aminosalicylate (II) may be further characterized by a powder XRD pattern substantially as illustrated in Figure 4.

The crystalline form of Varenicline 4-aminosalicylate (II) may be characterized by a Infrared (IR) spectrum having characteristic peaks at about 655.9, 703.9, 724.8, 752.8, 778.6, 786.1, 803.1, 825.9, 840.3, 895.1, 878.8, 913.2, 940.3, 986.4, 1012.1, 1025.1, 1037.7, 1047.8, 1088.1, 1133.6, 1156.2, 1188.2, 1198.0, 1229.2, 1248.0, 1305.2, 1356.0, 1377.9, 1388.2, 1407.1, 1457.7, 1474.5, 1508.2, 1561.8, 1597.7, 1642.7, 1775.5, 1936.7, 2306.9, 2401.2, 2551.7, 2603.9, 2664.3, 2711.6, 2769.6, 2839.2, 2952.3, 3024.8, 3220.4, 3411.5, 3329.3, 3743.3, 3884.7 and 3851.9 cm-1.

The crystalline form of Varenicline 4-aminosalicylate (II) may be further characterized by a Infrared (IR) spectrum substantially as illustrated in Figure 5.

The crystalline form of Varenicline 4-aminosalicylate (II) may be characterized by a differential scanning calorimetric (DSC) having an onset of melting transition at about 197°C.

The crystalline form of Varenicline 4-aminosalicylate (II) may be further characterized by differential scanning calorimetric (DSC) substantially as illustrated in Figure 6.

Another embodiment of the present invention further relates to the process for the preparation of the crystalline form of Varenicline 4-aminosalicylate (II).

The process comprises: reacting 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline) of formula III with 4-aminosalicylic acid of formula (V) in a solvent selected from alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tet-butanol, ketone such as acetone, ethyl methyl ketone; ether such as diethyl ether, diisopropyl ether, di-tertiary butyl ether etc; esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate etc. or mixtures thereof to produce a reaction mixture, optionally heating the reaction mixture and then cooling the reaction mixture to produce crystalline Varenicline 4-aminosalicylate salt (II).

Preferably, the reaction step is carried out over a period of between 1 and 12 hours, more preferably between 1 and 2 hours, and comprising stirring or mixing the resulting mixture. A preferred embodiment of the process is wherein reaction is carried out between ambient temperature and the refluxing temperature of the solvent; the process is carried out in between 30 and 60°C.

Crystalline form of Varenicline 4-aminosalicylate salt (II) obtained is isolated from the reaction mixture by techniques which may be employed to isolate from the solution include those wherein the precipitate may be separated by techniques well known in the art. Preferably, the precipitate is separated by filtration. Optionally, vacuum filtration may be utilized.

The recovered crystalline form of Varenicline 4-aminosalicylate salt (II) can be dried and the drying is carried out under a pressure of less than one atmosphere, or less than 100 mm/Hg, most preferably less than 25 mm/Hg at about 20 to 60 °C for about 4 to 24 hours.

The aqueous solubility of the Varenicline 4-aminosalicylate salt (II) of about 20 mg/ml and pH of about 60.7 (2% aqueous solution) in aqueous solution. In addition, crystalline Varenicline benzoate has a hygroscopicity of approximately 0.17% at 80% relative humidity.

The 1:1 salt correlation of Varenicline 4-aminosalicylate (II) was confirmed by 'H NMR spectrum.

In another embodiment of the present invention, Varenicline benzoate (I) and Varenicline 4-aminosalicylate (II) salts are converted to Varenicline base by treating Varenicline benzoate (I) or Varenicline 4-aminosalicylate (II) with water and a base selected from sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, lithium hydroxide, calcium hydroxide etc. Preferably, first a solution of Varenicline benzoate (I) or Varenicline 4-aminosalicylate (II) in water is prepared, followed by addition of the base to obtain a slurry. Varenicline can then be extracted into a water immiscible solvent selected from C6-C8 aromatic hydrocarbons; C4-C6 esters and C1-C2 halogenated hydrocarbons. Preferably, Varenicline base is then extracted from the reaction mixture using ethyl acetate and n-heptane is added in order to precipitate Varenicline base as a solid material.

The present invention also provides a process for preparing Varenicline L-tartrate, treating Varenicline free base with L-tartaric acid in a solvent selected from alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol and tet-butanol.

The present invention also relates to a pharmaceutical composition comprising an effective amount of benzoate and 4-aminosalicylate salts of the Varenicline, in association with one or more non¬toxic pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients and the quantity of the compound or composition of the present invention administered will vary depending on the patient and the mode of administration and can be any effective amount.

In particular, a composition of the present invention is presented as a unit dose and taken preferably from 1 to 2 times daily.

In general, pharmaceutical compositions of the present invention are prepared using conventional materials and techniques, such as mixing, blending and the like.

According to the present invention, pharmaceutical composition containing benzoate and 4-aminosalicylate salts of the Varenicline can also include, but are not limited to, suitable adjuvants, carriers, excipients, or stabilizers, etc. and can be in solid or liquid form such as, tablets or suspensions.

The present invention further provides benzoate and 4-aminosalicylate salts of the Varenicline, for use in the manufacture of a medicament for the treatment in smoking cessation therapy, and certain complications thereof.

Varenicline used in the present invention can be prepared by de benzylating 10-benzyl-10-aza-tricyclo[6.3.1.02J]dodeca-2(7),3,5-triene(VI) using hydrogenating catalyst in a solvent to produce 10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene hydrochloride (VII). The hydrogenating catalyst is selected from nickel catalysts such as reduced nickel, nickel oxide, Raney nickel and the like; platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire and the like; palladium catalysts such as palladium sponge, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate and the like. The solvent used is selected from methanol, ethanol, isopropyl alcohol and n-propanol; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; ketone solvents such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ether solvents such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran and 1 ,4- dioxane; hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane and n-hexane; nitrile solvents such as acetonitrile and propionitrile; dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); N,N-dimethylacetamide; water; ,and mixtures thereof. In embodiments, the reaction may be carried out in an autoclave vessel. The compound of Formula VI, Raney nickel and an organic solvent may be mixed together and stirred under hydrogen pressure until the reaction is complete. The reaction time typically varies from about 5 hours to 20 hours. Optionally, the reaction may be conducted at higher temperatures to enhance progress of the reaction as may be determined by person skilled in the art. After the completion of the reaction, the product may be isolated by conventional techniques known in the art.

Compound (VII) is reacted with trifluoroacetyl protecting agent such as trifluoroacetic acid [(CF3CO)20], trifluoroacetyl choride in the presence of base selected from organic amine such as primary amines such as methylamine, ethylamine, propylamine, isopropylamine etc. and secondary amines such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, pyridine etc. and tertiary amines such as trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine etc. in a solvent selected from chlorinated hydrocarbon such as methylene produce l-(10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoroethanone (VIII).

Compound (VIII) is reacted with nitrating mixture selected from sulfuric acid and nitric acid in chlorinated hydrocarbon solvent produce l-(4,5-dinitro-10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoroethanone (IX).

l-(4,5-Dinitro-10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoroethanone (IX) is reduced in the presence of hydrogenating catalyst in a solvent produce l-(4,5-diamino-10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoroethanone (X). The hydrogenation catalyst is selected from nickel catalysts such as reduced nickel, nickel oxide, Raney nickel and the like; platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire and the like; palladium catalysts such as palladium sponge, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate and the like. The solvent used is selected from methanol, ethanol, isopropyl alcohol and n-propanol; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; ketone solvents such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate;

ether solvents such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran and 1,4- dioxane; hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane and n-hexane; nitrile solvents such as acetonithle and propionithle; dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); NN-dimethylacetamide; water; and mixtures thereof. In embodiments, the reaction may be carried out in an autoclave vessel. The compound of Formula VI, Raney nickel and an organic solvent may be mixed together and stirred under hydrogen pressure until the reaction is complete. The reaction time typically varies from about 5 hours to 20 hours. Optionally, the reaction may be conducted at higher temperatures to enhance progress of the reaction as may be determined by person skilled in the art. After the completion of the reaction, the product may be isolated by conventional techniques known in the art.

Cyclization of compound (X) is carried out using reagents such as 2,3-dihydroxy-l,4-dioxane, glyoxal or glyoxal sodium bisulfite hydrate +produce 1-(5,8,14-triazatetracyclo-[10.3.1.02.704..9]hexadeca-2(ll),3,5,7,9-pentaene)-2,2,2-trifluoroethanone (XI). The cyclisation reaction is carried out in a solvent selected from water or other polar solvents such as tetrahydrofuran, dimethylformamide or dimethylsulfoxide at a temperature of about 10°C to about 100°C.

De-protection of compound (XI) is carried out in the presence of lower alkanol and an aqueous alkali metal, alkaline earth metal, or ammonium hydroxide or carbonate, such as aqueous sodium carbonate, at a temperature from about 50°C to about 100°C, such as at about 70°C, for about two to about six hours. The Varenicline free base thus obtained may be isolated by recrystallization or by precipitation by addition of anti solvent.

The details of the process of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1:

Preparation of crystalline Varenicline benzoate.

Varenicline base (0.5 gm, 0.0023 mole) was dissolved in isopropanol (5 ml) and a solution of benzoic acid (0.318 gm, 0.0026 mole) in isopropanol (1.5 ml) was added slowly at 30-40°C. It was then cooled to 20-30°C and stirred for 3 hr during which Varenicline benzoate salt separates out. It was filtered and dried at 25-30°C under reduced pressure for 8 hr.

Yield: 0.75 gm
HPLC Purity: 99.45%
1H NMR Correlation: 1:1 salt
1H NMR (DMSO-D6): 2.08-2.11 (m, 1H), 2.34-2.38 (m. 1H), 2.97-3.02 (m, 2H), 3.19-3.23 (m, 2H), 3.38 (brs, 2H), 7.35-7.40 (m, 2H), 7.45-7.50 (m, 1H, ArH), 7.80-7.91 (m, 2H, ArH), 7.91 (s, 2H, ArH), 8.85 (s, 2H, ArH).

Example 2:
Preparation of crystalline Varenicline 4-aminosalicylate.
Varenicline base (0.50 gm, 0.0023 mole) was dissolved in methanol (2 ml) and a solution of 4-aminosalicyclic acid (0.35 gm, 0.0023 mole) in methanol (6 ml) was added slowly at 20-30°C. It was then cooled to 10-15°C and stirred for 2 hr during which Varenicline 4-aminosalicylate salt separates out. It was filtered and dried at 25-35°C under reduced pressure for 8 hr.

Yield: 0.80 gm
HPLC Purity: 99.20%
1H NMR Correlation: 1:1 salt
1H NMR (DMSO-D6): 2.13-2.16 (m, 1H), 2.32-2.36 (m. 1H), 3.10-3.17 (m, 2H), 3.31-3.35 (m, 2H), 3.50 (brs, 2H), 5.82 (s, 1H, ArH), 5.87 (dd, 1H, ArH), 7.20 (d, 1H, ArH), 7.97 (s, 2H, ArH), 8.87 (s, 2H, ArH).

Example 3:
Preparation of Varenicline: Stepl:
Preparation of 10-azatricyclo[6,3,l,02'7]dodeca-2(7),3,5-triene hydrochloride

[Benzazepine hydrochloride]
10-Benzyl-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (VI) (-70 g) was dissolved in methanol 9420 ml) and cooled to 0-5°C and methanolic hydrochloric acid (28.5 g, 35% w/w) was added.

The temperature was raised to 20-30°C. Raney Nickel (Active, 15 g) was added at 20-30°C to the above solution under nitrogen atmosphere. The above slurry was transferred into an autoclave (hydrogenator), replaced the air with nitrogen, evacuated and hydrogen pressure (10±0.2 kg /cm2) was applied at 20-30°C. The stirring was continued at 20-30°C while maintaining a hydrogen pressure of 10±0.2 kg /cm2 for -24 h. The catalyst was filtered and washed with methanol (70 ml). The filtrate was concentrated at 45-55°C under reduced pressure (100-20 mm Hg) to obtain a semi solid. Methanol (70 ml) was added to the above concentrated mass, cooled to 0-5°C and stirred for ~ 2 h. The product was filtered and washed with precooled methanol (35 ml) and dried at 40-45°C for ~8 h. Yield: Benzazepine hydrochloride: 35 g Step 2:

Preparation of l-(10-azatricyclo[6.3.1.0]dodeca-2,4,6-trien-10-yl)-2,2,2-trifluoroethanone [N-Tfa Benzazepine] l,5-Methano-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride (Benzazepine 30+10 at 0-5°C and the temperature was raised to 20-30°C. The methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride (1.25 Lt). The combined hydrochloride, 100gm) was suspended in methylene chloride (1.0 Lt) and cooled to 0-5°C. N,N- diisopropylethyl amine (199.48 gm) was added to it followed by trifluoroacetic anhydride (161.12 gm) slowly in-30 min by keeping the temperature of the reaction mass below 5°C. Stirring was continued at 0-5°C till the starting material, benzazepine, left unreacted is < 1.0 % by qualitative HPLC analysis.

Thereafter, -IN aqueous hydrochloric acid (1.25 Lt) was added to the reaction mass slowly in methylene chloride extract was washed with -1N aqueous hydrochloric acid (1.25 Lt) followed by ith -7% w/w aqueous sodium bicarbonate (1.0 Lt) and finally with -20% w/w aqueous sodium hloride (1.0 Lt). The solvent was evaporated at 35-45°C under reduced pressure to get the product as an oily residue.

Yield: N-Tfa Benzazepine: -120 G Step 3:
Preparation of l-(4,5-dinitro-10-azatricyclo[6.3.1.0]dodeca-2,4,6-trien-10-Yl)-2,2,2-trifluoroethanone [Dinitro benzazepine]

Sulfuric acid (250.0 g) was added to methylene chloride (500 ml) Under nitrogen atmosphere at 20-30°C and it was cooled to 0-5°C. Nitric acid (Fuming, 78.30 g) was slowly added in -30 min by keeping the temperature of the reaction mass below 5°C. Stirring was continued at 0-5°C for -30 min. N-TFA benzazepine (-120 g, as obtained from example-4) was dissolved in methylene chloride (500 ml) and was slowly added to the above reaction mass at 0-5°C. Stirring was continued for -2 h and the progress of the reaction was monitored by HPLC. The reaction was quenched by pouring into pre-cooled DM water (1.20 Lt, 0-5°C). The organic layer was separated and aqueous layer was extracted with methylene chloride (600 ml). The combined methylene chloride extract was washed with DM water (2 x 600 ml), -7% w/w aqueous sodium bicarbonate (500 ml) and with DM water (500 ml). The methylene chloride extract was concentrated at 35-50°C under reduced pressure (100-20 mm Hg) and ethyl acetate (150 ml) was added to it. It was cooled to 0-5°C and stirred for -2 h. The product was filtered, washed with precooled ethyl acetate (50 ml) and dried at 40-45°C. Yield: Dinitro benzazepine: 94.0 G
Step 4:

Preparation of l-(4,5-diamino-10-azatricyclo[6.3.1.0]dodeca-2,4,6-trien-10-Yl)-2,2,2-trifluoroethanone [Diamino benzazepine]

Dinitro benzazepine (100 g,) was dissolved in methanol (1.0 Lt) at 20-30°C. Raney Nickel (Active, 20 g) was added at 20-30°C under nitrogen atmosphere to the above solution. The above slurry was transferred into an autoclave (hydrogenator), replaced the air with nitrogen, evacuated and hydrogen pressure (10+0.2 kg / cm2) was applied at 20-30°C. The stirring was continued at 20-30°C while maintaining a hydrogen pressure of 10+0.2 kg / cm2 for -5 h. The catalyst was filtered and washed with methanol (100 ml). The filtrate was concentrated partially at 45-55°C under reduced pressure (100-20 mm Hg) and seeded with diamino benzazepine (0.10 g). The above contents were cooled to 0-5°C and stirred for 4 h. The product was filtered and washed it with precooled methanol (25 ml). The product was dried at 40-45°C under reduced pressure for -12 h. Yield: Diamino benzazepine: 70.0 G

Step 5:
Preparation of l-(5,8,14-triazatetracyclo[10.3.1.0211.,04.9]hexadeca-2(ll),3,5,7,9-pentaene)-2,2,2-trifluoroethanone [N-Tfa Varenicline]

Diamino benzazepine (100 g,) was suspended in tetrahydrofuran (400 ml) and dilute glyoxal solution (-40% w/w, 56.0 g) in DM water (280 ml) was added slowly to the above mass at 20-30°C. The contents were heated to 55-60°C and stirred for ~5 h. Thereafter, the reaction mass was concentrated at 45-55°C under reduced pressure. The above concentrated mass was dissolved in ethyl acetate (500 ml) and washed with DM water (250 ml). Subsequently, it was washed with -0.5 N aqueous hydrochloric acid (2 x 100 ml). Finally, the ethyl acetate extract was washed with -20% w/w aqueous sodium chloride solution (100 ml). Carbon (granular- G-5, 5 g) was added to the above ethyl acetate extract and stirring was continued for -30 min at 20-30°C. Carbon was removed through filtration and ethyl acetate layer was concentrated at 40-50°C under reduced pressure. n-Heptane (400 ml) was added to the above residue and was stirred at 20-30°C for -1 h. The above slurry was cooled to 0-5°C, filtered, washed with precooled n-heptane (25 ml) and dried at 35-45°C under reduced pressure for 12 h. Yield: N-Tfa Varenicline: 100.0 G

Step 6:

Preparation of 5,8,14-triazatetracyclo[10.3.1.02,1104.9]hexadeca-2(ll),3,5,7,9-pentaene

[Varenicline Base]
N-TFA Varenicline (100 g) was suspended in methanol (600 ml) at 20-30°C. A solution of sodium carbonate (69.0 g) in DM water (690 ml) was prepared and was slowly added to the above suspension at 20-30°C. The contents were heated to 65-70°C and stirred for ~2 h. Thereafter, the reaction mass was concentrated at 45-55°C under reduced pressure. The above concentrated mass was dissolved in methylene chloride (1.0 Lt) and washed with DM water (100 ml). Carbon (granular- G-5, 5 g) was added to the above methylene chloride extract and stirring was continued for -30 min at 20-30°C. Carbon was filtered through filtration and solvent was evaporated under reduced pressure to obtain Varenicline base as a semi solid mass. Yield: Varenicline (Base): -68 G.

WE CLAIM:

1. A benzoate salt of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline benzoate) of Formula I.

2. A Crystalline Form of Varenicline benzoate characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1; characterized by an Infrared (IR) spectrum substantially as shown in Figure 2; characterized by a differential scanning calorimetric (DSC) substantially as shown in Figure 3.

3. A 4-aminosalicylate salt of 7,8,9,10-tetrahydro-6,l0-methano-6H-pyrazino[2,3-h][3]benzazepine (Varenicline 4-aminosalicylate) of Formula II.

4. A Crystalline Form of Varenicline 4-aminosalicylate characterized by an X-ray powder diffraction pattern substantially as shown in Figure 4; characterized by an Infrared (IR) spectrum substantially as shown in Figure 5; characterized by a differential scanning calorimetric (DSC) substantially as shown in Figure 6.

5. A process for the preparation of Varenicline benzoate of Formula I, which comprises:

i) reacting 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine
(Varenicline) of formula III;

with benzoic acid of formula (IV);

ii) isolating crystalline benzoate salt of Varenicline of formula I.

6. A process for the preparation of Varenicline 4-aminosalicylate of Formula II, which comprises:

i) reacting 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazep- ine
(Varenicline) of formula III;

with 4-aminosalicylic acid of formula (V);

ii) Isolating crystalline 4-aminosalicylate salt of Varenicline of formula II.

7. A process for the preparation of Varenicline free base of Formula III:
which comprises,

i) debenzylation of 10-benzyl-10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene (VI);
in the presence of a hydrogenation catalyst in a solvent to produce compound of formula VII;

ii) reacting 10-azatricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene hydrochloride (VII) with trifluoroacetyl protecting agent in the presence of an organic base to produce compound of Formula (VIII);

iii) nitrating the compound of formula VIII with a nitrating mixture to produce
compound of Formula IX;

iv) reducing the compound of formula IX with a hydrogenating catalyst in a solvent to produce compound of Formula X;

v) cyclization of compound of formula X with a cyclizing reagent to produce compound of Formula XI;

vi) deprotecting of compound of formula XI to produce Varenicline free base of Formula III.