WO2009065872A2

WO2009065872A2 - Improved processes for the synthesis of varenicline l-tartrate

Info

Publication number: WO2009065872A2
Application number: PCT/EP2008/065866
Authority: WO
Inventors: Stephen Winter; Luis Botella; Carmen NÁJERA; José SOTO
Original assignee: Medichem, S.A.
Priority date: 2007-11-20
Filing date: 2008-11-19
Publication date: 2009-05-28
Also published as: AR071443A1; WO2009065872A3

Abstract

This invention provides a process of preparing varenicline L-tartrate salt. This invention also provides varenicline L-tartrate produced by the instant method, as well as a pharmaceutical composition comprising same.

Description

Improved processes for the synthesis of varenicline L- tartrate

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to an improved process for preparing varenicline L-tartrate with enhanced color quality and a high purity. Background of the Invention Varenicline L-tartrate (Compound I) is the international commonly accepted name for 7,8,9,10- tetrahydro-6, 10-methano-6i7-pyrazino [2, 3- h] [3 ] benzazepme, (2R, 3R) -2 , 3-dihydroxybutanedioate (1:1) (which is also known as 5,8,14- tπazatetracyclo [10.3.1. O²'¹¹. O⁴'⁹] -hexadeca-

2 (11) , 3, 5, 7, 9-pentaene, (2R, 3R)-2,3- dihydroxybutanedioate (1:1)) and has an empirical formula of C13H13N3 ^• C4H6O6 and a molecular weight of 361.35. Varenicline L-tartrate is a commercially marketed pharmaceutically active substance known to be useful for the treatment of smoking addiction.

(D

Varenicline L-tartrate is a partial agonist selective for (X₄β₂ nicotinic acetylcholine receptor subtypes. In the United States, varenicline L-tartrate is marketed under the name Chantix™ for the treatment of smoking cessation. Varenicline base and its pharmaceutically acceptable acid addition salts are described in U.S. Patent No. 6,410,550. In particular, Example 26 of U.S. Patent No. 6,410,550 describes the preparation of varenicline hydrochloride salt using 1- (4 , 5-dinitro-10- aza-tπcyclo [6.3.1.O²'⁷] dodeca-2, 4, 6-trien-10-yl) -2,2,2- tπfluoroethanone (compound of formula (III)) as starting compound. On the other hand, Example HA) of U.S. Patent No. 6,410,550 illustrates the preparation of compound of formula (III) via nitration of compound of formula (II) using an excess of nitronium triflate (>4 equiv) as a nitrating agent. The process disclosed in U.S. Patent No. 6,410,550 is depicted in Scheme 1.

VareniclineΗCl

Scheme 1

However, Coe et al., J. Med. Chem., 48, 3474 (2005), describes the same process and examples as U.S. Patent No. 6,410,550, and it also reveals that this process affords intermediate ortho-4 , 5-dinitrocompound of formula (III) together with the meta-3, 5-dinitro- isomer (i.e. the meta-dinitrocompound) in a ratio 9:1. The presence of the meta-dinitrocompound may affect not only the purity of the intermediate compound of formula III but it may also have an effect on the purity of the final varenicline tartrate, given that it can be carried along the synthetic pathway and/or it can also give rise to other derivative impurities. Thereby, as well as in U.S. Patent No. 6,410,550, in order to isolate pure compound of formula (III) , the raw product is triturated with ethyl acetate/hexane to afford compound of formula (III) with 77% yield. Additionally, the mother liquor is purified by chromatography on silica gel to improve the yield to a total of 82.8%. However, this process is not desirable for industrial implementation since it requires extensive and complicated purification procedures, i.e. trituration of the solid product along with column chromatography purification of the mother liquor, which is not very efficient or suitable for industrial scale-up.

Several improved processes for the synthesis of varenicline or its salts have been reported in the literature (e.g. WO2006/090236) . However, none of these processes tackle the optimization of the purification step of compound of formula (III).

There is therefore the need for providing an improved process for the preparation of varenicline L- tartrate which involves simple experimental procedures well suited to industrial production, which avoids the use of column chromatography purifications, and which affords high pure varenicline L-tartrate which hence can be used directly as a starting product for the preparation of the marketed pharmaceutical speciality.

Additionally, it has been observed that varenicline L-tartrate is usually obtained as a yellow solid under - A -

standard synthetic conditions. In this regard, colour must be attributed to the presence of some specific impurities that may or may not be detectable by conventional methods such as HPLC. The presence of impurities may adversely affect the safety and shelf life of formulations. In this connection, International application No. WO2006/090236 describes the isolation of vareniclme L- tartrate as a white solid. However, in order to remove coloured impurities, the varenicline L-tartrate obtained in WO2006/090236 is treated with a particular activated carbon having a specific grade (i.e. Darco KB-B™) . In fact, Example 5 of WO2006/090236 describes a large reprocessing step which comprises: dissolving varenicline L-tartrate in water, adding toluene, basifying with NaOH aqueous solution, collecting the toluene phase containing varenicline free base, distilling, adding methanol, azeotropically distilling the mixture, and adding more methanol to obtain a methanolic solution containing varenicline free base, adding Darco KB-B™ (10% w/w) , stirring for one hour, filtering through a pad of celite, and treating with L-tartaric acid to give varenicline L- tartrate salt as a white solid. Further, WO2006/090236 provides the absorbance at 430 nm of a varenicline L- tartrate salt solution, either in dichloromethane or in toluene, with or without using Darco KB-B™ activated carbon. However, this measure cannot be used to corroborate the whiteness of the solid varenicline L- tartrate. In addition, Example 3 of International application No. WO2002/092089, also disclose the preparation of varenicline L-tartrate polymorphic form C (i.e. a hydrate polymorph) as a white precipitate. Therefore, there is also a need for a simple and efficient method for preparing varenicline L-tartrate with enhanced whiteness and having a high purity.

Summary of the Invention

The invention provides an improved process for preparing varenicline L-tartrate.

The invention provides an improved process for preparing varenicline L-tartrate salt (I), which involves simple experimental procedures well suited to industrial production, which avoids the use of column chromatography purifications, and which affords varenicline L-tartrate with enhanced colour quality and a high purity, and which hence can be used directly as a starting product for the preparation of the marketed pharmaceutical speciality.

In particular, the invention relates to a process for preparing varenicline L-tartrate salt (I) with enhanced colour quality and a high purity, by means of crystallizing intermediate compound of formula (III) or a salt or solvate thereof in an organic solvent.

The procedures disclosed in the prior art (i.e.,

U.S. Patent No. 6,410,550, International Patent No.WO/2006/090236, and International Patent

No.WO2002/092089) lead to varenicline L-tartrate with low purity levels. Further, the varenicline L-tartrate obtained by these procedures shows a poor colour quality

(i.e., "poor whiteness"), which is corroborated by colorimetric measurements that are distant from the values of absolute white. It has been surprisingly observed that the drawbacks of prior art can be overcome by crystallizing compound of formula (III) or a salt or solvate thereof in an organic solvent. Namely, the GC purity of intermediate compound of formula (III) or a salt or solvate thereof is improved from 89.9% to 98.5%, and the corresponding varenrcline L-tartrate HPLC purity rs improved from 95.5% to 99.9%.

In a first aspect, the invention includes an improved process for preparing varenicline L-tartrate salt (I) with enhanced color quality (i.e., "whiteness") and a high level of purity, said process comprising the steps of: (i) crystallizing intermediate compound of formula (III) or a salt or solvate thereof,

(III) wherein R is a nitrogen protecting group, in an organic solvent, and (ii) converting said compound of formula (III) into varenicline L-tartrate salt.

In an embodiment of the invention, the compound of formula (III) or a salt or solvate thereof, as obtained after the crystallization step (i) has a purity greater than approximately 98.5% as measured by GC.

The nitrogen protecting group R is preferably trifluoroacetyl or tert-butoxycarbonyl . In an embodiment of the invention, the nitrogen protecting group R is trifluoroacetyl .

The organic solvent is preferably an aromatic hydrocarbon solvent, more preferably is at least one of toluene, xylene, and mixtures thereof. In an embodiment of the invention, the organic solvent is toluene.

In another aspect, the invention includes a method for assessing the purity of varenicline L-tartrate by means of a quantitative colorimetric measurement of solid varenicline L-tartrate. The method includes using a colorimeter or spectrophotometer apparatus to measure the L*, a* and b* coordinates of the solid sample of varenicline L-tartrate. Thus, the color of the solid sample is located in the CIE 1976 L*, a*, b* Color Space (CIELAB; CIE stands for Commission Internationale de l'Eclairage or International Commission on Illumination) . The three parameters in the model represent the lightness of the color {i.e., L*, an L* = 0 indicates black and L* = 100 indicates white), its position between magenta and green {i.e., a*, negative values indicate green while positive values indicate magenta) and its position between yellow and blue {i.e., b*, negative values indicate blue and positive values indicate yellow) .

Thus, the colour quality {i.e., "whiteness") of varenicline L-tartrate is corroborated by the colorimetric measurements that yield values in the CIELAB colour space that are very close to the values of absolute white, namely L* = 100, a* = 0; b* = 0. See, e.g., US Pharmacopoeia 29^th ed., General Chapter 1061, p. 2896.

In another aspect, the invention includes varenicline

L-tartrate with enhanced colour quality {i.e., "whiteness") and high level of purity that is prepared by the above-described process. In particular, the varenicline L-tartrate prepared by the above-described process has a purity greater than approximately 99% as measured by HPLC, preferably has a purity greater than approximately 99.9% as measured by HPLC.

The varenicline L-tartrate prepared by the above- described process also exhibits enhanced whiteness in the CIE (1976) L*, a*, b* Colour Space (CIELAB) . In particular, the obtained varenicline L-tartrate has the following CIE (1976) L*, a*, b* Colour Space (CIELAB) measurements when using a colorimeter or spectrophotometer, illummant D65 (daylight) and a 2° angle of observation: L* = 92 to 100, and a* = -3.00 to

+3.00, and b* = -20.00 to +20.00; preferably L* = 93 to

100, and a* = -3.00 to +3.00, and b* = -12.00 to +12.00.

Another aspect of the invention includes a formulation including varenicline L-tartrate obtained according to the process of the invention.

Detailed Description of the Invention

Specific examples General Experimental Conditions GC Method

The GC analysis was performed on a Hewlett Packard 4890A connected to a HP3395 integrator. The following parameters were used: Gas carrier: N₂; Column head pressure: 13 psi; Injector Temp.: 270 ⁰C; Detector Temp. (FID) : 300 ⁰C; Column: HP-5 (cross-linked 5% phenyl methyl siloxanes) , 15 m length, 0.53 mm internal diameter, 1.5 mm film thickness. The following temperature programme was used: Initial Temp.: 80 ⁰C; Initial time: 3 min; Rate: 15 °C/min; Final Tern.: 270 ⁰C; Final time: 30 mm; Injection volume: 0.7 mL (manual) . Sample preparation: the sample is dissolved m ethyl acetate to a concentration of 4 mg/mL.

Approximate GC Retention Times:

HPLC Method

The chromatographic separation was carried out in a ZORBAX Eclipse XDB-C18 5 mm 4.6x150 mm column at room temperature (20-25° C) . Mobile phase A was prepared by dissolving 1.3 g of ammonium formate in 1000 mL of water and adjusting the pH of the solution to 8.0 ± 0.1 with ammonia 25%. The solution was then filtered through a 0.22 μm nylon membrane under vacuum. Mobile phase B was acetonitrile and filtered through a 0.22 μm nylon membrane under vacuum. The flow rate was 1 mL per minute and the chromatograph was recorded at 230 nm. Test samples (10 μL) were prepared by dissolving the appropriate amount of sample in a 1:1 mixture of mobile phases A and B in order to obtain 1 mg of sample per mL . The following gradient was used:

Approximate HPLC Retention Times:

Colorimetric Measurement:

Colorimetric measurements of the solid samples were obtained using a Minolta Chroma meter CR-300, using illuminant D65 and a measurement geometry of 2°.

Comparative Example 1: Preparation of 7,8,9,10- tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h] [3] benzazepine L-tartrate (i.e. varenicline L-tartrate)

A) Preparation of compound of formula (III)

This example is based on U.S. Patent No. 6,410,550.

A 250 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with 10-aza-tricyclo [ 6.3.1. O²'⁷] dodeca-2, 4, 6- triene para-toluene sulfonic acid salt (12.4g, 37.5 mmol) and 44 mL of CH₂Cl₂. Triethylamine (8.3 g, 82.5 mmol) was added to the slurry and the resulting solution was cooled to 0-5 ⁰C. The addition funnel was charged with a solution of (CF₃CO)₂O (8.1q, 41.25 mmol) in 19 mL of CH₂Cl₂. This solution was slowly added to the reaction mixture, maintaining the temperature < 15 ⁰C. The resulting mixture was stirred for 1 hour, and the complete conversion was monitored by GC. The crude reaction mixture was washed with water (2 * 40 mL) and brine (40 mL) . The organic phase was used in the next step without further purification.

On the other hand, a 500 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with CF₃SO₃H (25.9 g, 172.5 mmol), CH₂Cl₂ (110 mL) and cooled to 0-5 ⁰C. At this temperature, fuming nitric acid (5.4 g, 86.25 mmol) was added slowly. To the resulting slurry at 0-5 ⁰C, the solution obtained in the previous step was slowly added, maintaining the temperature < 15 ⁰C. After the addition, the reaction mixture was stirred overnight. The complete dinitration was confirmed by GC. The crude reaction mixture was poured into water (60 mL) an ice (80 g) and stirred. The phases were separated and the aqueous phase was extracted with CH₂Cl₂ (3 x 50 mL) . The mixture of the organic phases was washed with aqueous saturated NaHCO₃, dried over Na₂SO₄ and volatiles evaporated under vacuum to obtain 11.9 g of a solid that was suspended and stirred for 2 hours in AcOEt (12 mL) and hexanes (24 mL) . The solid was filtered and washed with hexanes to obtain the compound of formula (III), 9.1g with a purity of 88.9% by GC (9.8% of meta-dimtrocompound impurity) .

B) Preparation of compound of formula (IV)

This example is based on International Patent No. WO/2006/090236.

A 200 mL autoclave was charged with (III) (9.1 g, 26.3 mmol), damp 5% Pd/C 50% and 180 mL of a 2- propanol/water (80/20 wt/wt) . The reaction was stirred under 50 psi of hydrogen for 18 hours. The complete hydrogenation was confirmed by GC analysis. The reaction was filtered through Celite and washed with 2-propanol (40 mL) . To this solution, K₂HPO₄ (458 mg, 2.63 mmol) was added. The mixture was cooled at 0-5 ⁰C and a solution of 4.07 g of 40% aqueous glyoxal diluted with water (14.5 mL) was added slowly. The resulting solution was stirred 2 hours at this temperature and overnight at room temperature. The complete conversion was confirmed by GC analysis. The reaction was concentrated under vacuum to a volume of 68 mL and water (128 mL) was added drop- wise. The resulting suspension was stirred for 2 hours at room temperature, 1 hour in a ice/water bath, filtered, washed with water (20 mL) and dried m a oven at 50 ⁰C to obtain the compound of formula (IV), 6.78 g.

C) Preparation of vareniclme L-tartrate (compound of formula (I) )

This example is based on International Patent No. WO/2006/090236.

A 250 mL round bottom flask with thermometer, condenser, and magnetic stirring was charged with compound of formula (IV) (6.78 g, 22 mmol) and toluene

(47 mL) . To this solution was added a solution of NaOH (2.7 g, 68.2 mmol) in water (34 mL) . The mixture was heated to 40 ⁰C and stirred for 4 hours. The complete hydrolysis was confirmed by GC analysis. Toluene (68 mL) was added and the reaction was cooled. The phases were separated and the aqueous phase was extracted with toluene (30 mL) . The organic phases were evaporated under vacuum. The residue was dissolved in MeOH (90 mL) and evaporated again. The final residue was dissolved in 156 mL of MeOH. 1.3 g of activated carbon "Darco G-60 100 mesh" were added and the mixture was stirred for 30 min and filtered through Celite to obtain an intense yellow solution. The process with activated carbon was repeated without any improvement in the colour. This solution was added drop-wise over a solution of L- tartaric acid (3.63 g, 24.2 mmol) in MeOH (47 mL) . The slurry was stirred for 72 hours at room temperature, filtered, washed with MeOH and dried in an oven at 50 ⁰C for 8 hours, to obtain 5.05 g of varenicline L-tartrate as a yellow solid with a 95.5% purity by HPLC (4.4% of unknown impurity A). Colour L: 92.75, a*: -7.19, b*:43.08.

Comparative Example 2: Preparation of 7,8,9,10- tetrahydro-6, 10-methano-6H-pyrazmo [2, 3-h] [3 ] benzazepine L-tartrate (i.e. varenicline L-tartrate) A) Preparation of compound of formula (IV)

This example is based on International Patent No. WO/2006/090236.

A 200 mL autoclave was charged with (III) prepared according to Comparative Example 1.A) (4.1 g) , 123 mg of damp 5% Pd/C 50% and 81 mL of a 2-propanol/water (80/20 wt/wt) . The reaction was stirred under 50 psi of hydrogen for 24 hours. The complete hydrogenation was confirmed by GC analysis. The reaction was filtered through Celite and washed with 2-propanol (16 mL) . To this solution, K₂HPO₄ (207 mg, 1.19 mmol) was added. The mixture was cooled at 0-5 ⁰C and a solution of 1.84 g of 40% aqueous glyoxal diluted with water (6.6 mL) was added slowly. The resulting solution was stirred 2 hours at this temperature and overnight at room temperature. The complete conversion was confirmed by GC analysis. The reaction was concentrated under vacuum to a volume of 30 mL and water (56 mL) was added drop-wise. The resulting suspension was stirred for 2 hours at room temperature, 1 hour in a ice/water bath, filtered, washed with water and dried in a oven at 50 ⁰C to obtain 3.15 g of compound of formula (IV) .

B) Preparation of vareniclme L-tartrate (compound of formula (I) )

This example is based on International application No. WO/2006/090236. A 100 mL round bottom flask with thermometer, condenser, and magnetic stirring was charged with

7, 8, 9, 10-tetrahydro-8- (tπfluoroacetyl) -6, 10-methano-6H- pyrazino [2 , 3-h] [3] benzazepine, i.e. compound of formula

(IV) (3.14 g, 10.2 mmol) and toluene (22 mL) . To this solution was added a solution of NaOH (1.3 g, 31.6 mmol) in water (16 mL) . The mixture was heated to 40 ⁰C and stirred for 2.5 hours. The complete hydrolysis was confirmed by GC analysis. Toluene (30 mL) was added and the reaction was cooled. The phases were separated and the aqueous phase was extracted with toluene (15 mL) . The organic phases were evaporated under vacuum. The residue was dissolved in MeOH (45 mL) and evaporated again. The final residue was dissolved m 70 mL of MeOH. 314 mg of activated carbon "Darco G-60 100 mesh" were added and the mixture was stirred for 30 mm and filtered through Celite to obtain a yellow solution. This solution was added drop-wise over a solution of L- tartaπc acid (1.68 g, 11.22 mmol) m MeOH (22 mL) . The slurry was stirred for 1 hour at room temperature, filtered, washed with MeOH (2 x 5 mL) and dried under vacuum, to obtain vareniclme L-tartrate (2.48 g) as a yellow solid with a 95.6% purity by HPLC (4.4% of unknown impurity A). Colour L: 99.50, a*: -4.98, b*:43.02

Comparative Example 3: Preparation of 7,8,9,10- tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h] [3 ] benzazepine L-tartrate (i.e. vareniclme L-tartrate)

This example is based on International application No. WO/2002/092089.

2 g of vareniclme L-tartrate as obtained from Comparative Example 1 were dissolved in 3 mL of water.

To this solution, 100 mL of CH₃CN were added, and the resulting slurry was stirred for 10 mm and filtered.

After drying the product was analysed to be a 98.2% purity by HPLC (1.7% of unknown impurity A) . Colour L: 91.44, a*: -3.24, b* : 33.47

Example 1: Preparation of 7, 8, 9, lO-tetrahydro-6, 10- methano-6H-pyrazmo [2, 3-h] [3] benzazepine L-tartrate

(i.e. vareniclme L-tartrate)

A) Preparation of compound of formula (III) This example is based on U.S. Patent No. 6,410,550, except for the purification step, which is the object of the present invention (i.e. crystallization in toluene) .

A 500 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with 10-aza-tricyclo [ 6.3.1. O²'⁷] dodeca-2, 4, 6- tπene para-toluene sulfonic acid salt (32.5g, 98.2 mmol) and 115 mL of CH₂Cl₂. Triethylamine (21.8 g, 216 mmol) was added to the slurry and the resulting solution was cooled to 0-5 ⁰C. The addition funnel was charged with a solution of (CF₃CO)₂O (22.7 g, 108 mmol) in 50 mL of CH₂Cl₂. This solution was slowly added to the reaction mixture, maintaining the temperature < 15 ⁰C. The resulting mixture was stirred for 1 hour, and the complete conversion was monitored by GC. The crude reaction mixture was washed with water (2 x 100 mL) and brine (100 mL) . The organic phase was used in the next step without further purification.

A l L round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with CF₃SO₃H (67.8 g, 452 mmol), CH₂Cl₂ (280 mL) and cooled to 0-5 ⁰C. At this temperature, fuming nitric acid (14.2 g, 226 mmol) was slowly added. To the resulting slurry at 0-5 ⁰C, the solution obtained in the previous step was slowly added, maintaining the temperature < 15 ⁰C. After the addition, the reaction mixture was stirred overnight. The complete dinitration was confirmed by GC. The crude reaction mixture was poured into water (150 mL) an ice (200 g) and stirred. The phases were separated and the aqueous phase was extracted with CH₂Cl₂ (100 mL) . The mixture of the organic phases was washed with aqueous saturated NaHCO₃ (2x100 mL) , water (100 mL) , dried over Na₂SO₄ and volatiles evaporated under vacuum to obtain 30.5 g of a solid with a 83.6% purity by GC (12.5% of meta- dinitrocompound impurity) . 20 g of this solid were crystallized in toluene (100 mL) to obtain the compound of formula (III), 15 g of a pale brown solid with a 98.5 % purity by GC (meta-dinitrocompound impurity not detected) .

B) Preparation of compound of formula (IV) This example is based on International Patent No. WO/2006/090236.

A 200 mL autoclave was charged with (III) (9.1 g, 26.3 mmol, crystals from toluene), damp 5% Pd/C 50% and 180 mL of a 2-propanol/water (80/20 wt/wt) . The reaction was stirred under 50 psi of hydrogen for 18 hours. The complete hydrogenation was confirmed by GC analysis. The reaction was filtered over Celite and washed with 2- propanol (40 mL) . To this solution, K₂HPO₄ (458 mg, 2.63 mmol) was added. The mixture was cooled at 0-5 ⁰C and a solution of 4.07 g of 40% aqueous glyoxal diluted with water (14.5 mL) was added slowly. The resulting solution was stirred 2 hours at this temperature and overnight at room temperature. The complete conversion was confirmed by GC analysis. The reaction was concentrated under vacuum to a volume of 68 mL and water (128 mL) was added drop-wise. The resulting suspension was stirred for 2 hours at room temperature, 1 hour in a ice/water bath, filtered, washed with water (20 mL) and dried m a oven at 50 ⁰C to obtain the product, 7.16 g of compound of formula (IV) with a 99.9% purity by HPLC. C) Preparation of varenicline L-tartrate (compound of formula ( I) )

Thrs example rs based on International Patent No. WO/2006/090236. A 250 mL round bottom flask with thermometer, condenser, and magnetic stirring was charged with a solution of NaOH (2.89 g, 72.23 mmol) in water (36 mL) , compound of formula (IV) (7.15 g, 23.3 mmol) and toluene (50 mL) . The mixture was heated to 40 ⁰C and stirred for 4 hours. The complete hydrolysis was confirmed by GC analysis. Toluene (71 mL) was added and the reaction was cooled. The phases were separated and the aqueous phase was extracted with toluene (36 mL) . The organic phases were evaporated under vacuum. The residue was dissolved in MeOH (110 mL) and evaporated again. The final residue was dissolved in 164 mL of MeOH. 750 mg of activated carbon "Darco G-60 100 mesh" were added and the mixture was stirred for 30 min and filtered through Celite to obtain a yellow solution. This solution was added drop- wise over a solution of L-tartaric acid (3.84 g, 25.6 mmol) in MeOH (50 mL) . The slurry was stirred for 14 hours at room temperature, filtered, washed with MeOH and dried under vacuum, to obtain varenicline L-tartrate

(7.04 g) as an off-white solid with a >99.9% purity by HPLC (unknown impurity A not detected) . Colour L: 94.39, a*: 2.27, b*:9.02.

Claims

What is claimed is :

1. A process for preparing vareniclme L-tartrate salt (I),

(D said process comprising: crystallizing intermediate compound of formula (II) or a salt or solvate thereof,

(III) wherein R is a nitrogen protecting group, in an organic solvent, and (ii) converting said compound of formula (III) or a salt or solvate thereof into vareniclme L-tartrate salt.

2. The process of claim 1, wherein compound of formula (III) or a salt or solvate thereof, as obtained after crystallization, has a purity greater than approximately 98.5% as measured by GC.

3. The process of any of the claims 1 or 2, wherein the nitrogen protecting group R is trifluoroacetyl or tert-butoxycarbonyl .

4. The process of claim 3, wherein the nitrogen protecting group R is trifluoroacetyl .

5. The process of any of the claims 1 to 4, wherein the organic solvent is an aromatic hydrocarbon solvent .

6. The process of claim 5, wherein the organic solvent is toluene, xylene, or a mixture thereof.

7. The process of claim 6, wherein the organic solvent is toluene.

8. Varenicline L-tartrate prepared by the process of any of the claims 1 to 7.

9. The varenicline L-tartrate of claim 8, wherein said varenicline L-tartrate has a purity greater than approximately 99% as measured by HPLC

10. The varenicline L-tartrate of claim 9, wherein said varenicline L-tartrate has a purity greater than approximately 99.9% as measured by HPLC.

11. The varenicline L-tartrate of any of the claims 8 to 10, wherein said varenicline L-tartrate has a CIE (1976) L*, a*, b* Color Space (CIELAB) measurements when using a colorimeter or spectrophotometer, illummant D65 (daylight) and a 2° angle of observation of approximately L* = 92 to 100, and a* = -3.00 to +3.00, and b* = -20.00 to +20.00.

12. The varenicline L-tartrate of any of the claims 8 to 10, wherein said varenicline L-tartrate has a CIE (1976) L*, a*, b* Color Space (CIELAB) measurements when using a colorimeter or spectrophotometer, illummant D65 (daylight) and a 2° angle of observation of approximately L* = 93 to 100, and a* = -3.00 to +3.00, and b* = -12.00 to +12.00.

13. A formulation comprising a pharmaceutrcally acceptable carrier and vareniclme L-tartrate according to any of the claims 8 to 12.