DESC:FIELD OF THE INVENTION
The field of the invention relates to an improved process for the preparation of vildagliptin.

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Vildagliptin (previously identified as LAF237) is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-IV, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas.
Vildagliptin is chemically, (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile, having molecular weight 303.39 g/mol and empirical Formula is C17H25N3O2. Vildagliptin can be structurally represented as Formula (I).

(I)
U.S. Patent No. 6,166,063 (the US ‘063 Patent) discloses the vildagliptin and process for preparation thereof. The US ‘063 Patent discloses a process comprising reaction of 1-chloroacetyl-2-cyanopyrrolidine with 1-amino-3-adamentanol in the presence of base and an inert solvent.
J. Med. Chem. Vol. 46, p. 2774-2789, (2003) also discloses a similar process for the preparation of vildagliptin. The reference article discloses a compound of Formula II as compound (12k),

(II)
in Scheme-2 and discloses a process for its preparation. The compound 12k was characterized as a white hygroscopic solid with a melting range 138-140°C.
International (PCT) publication No. WO 2004/092127 A1 discloses a process for the preparation of vildagliptin and intermediates thereof. The WO ‘127 discloses a one pot process for preparation of N-(N’-substituted glycyl)-2-cyanopyrrolidine compounds.
International (PCT) publication No. WO 2008/084383 A2 discloses a process for the preparation of vildagliptin comprising reacting 2-cyanopyrrolidine derivative with 1-amino-3-adamentanol wherein -OH group is protected group.
International (PCT) publication No. WO 2010/022690 A2 discloses a process for the preparation of vildagliptin comprising the isolation of a 1-haloacetyl-2(S)-pyrrolidin-carboxyamide with a trialkyl amine salt and its subsequent conversion into its corresponding cyano derivative, which react with 1-amino-3-adamantanol to produce vildagliptin.
International (PCT) publication No. WO 2011/012322 A2 discloses a process for preparation of vildagliptin using phase transfer catalyst.
International (PCT) publication No. WO 2012/004210 A1 discloses a process for preparation of vildagliptin and its novel intermediates.
International (PCT) publication No. WO 2013/083326 A1 (the WO ‘326 A1) discloses a process for the preparation of vildagliptin using a salt of L-prolinamide. The WO ‘326 A1 discloses the converting L-prolinamide to its haloacetic acid salt of Formula VI which is further converted to a compound of Formula II and finally to vildagliptin.

(VI)
In view of the above, it is therefore, desirable to provide an efficient process for the preparation and purification of vildagliptin. Synthetic process as available in the existing art is suffering from the disadvantage of having bis impurity and use of high cost bearing reagents. The present invention discloses a process with high yield and significantly low impurity, which makes this process suitable for large scale production having economic significance. The present invention thereby provides useful alternative for the preparation of vildagliptin with substantial purity. Further, the present invention thereby extends to the process for the purification of vildagliptin.

SUMMARY OF THE INVENTION
In general aspect, there is provided a process for the preparation of pure vildagliptin of Formula (I),

(I)
the process comprising:
(a) reacting L-prolinamide of Formula (V),

(V)
with haloacetyl chloride in one or more organic solvents in the presence of a base to obtain the compound of Formula (IV),

(IV)
wherein, X represents chloro or bromo group and haloacetyl chloride may be chloro or bromoacetyl chloride;
(b) condensing the compound of Formula (IV) with 1-amino-adamantane-3-ol of Formula (III) in the presence of a base to obtain the compound of Formula (II),

(III) (II)
(c) dehydrating the compound of Formula (II) with dehydrating agent to obtain vildagliptin of Formula I; and
(d) optionally, purifying the vildagliptin to obtain pure vildagliptin of Formula (I).
In another general aspect, there is provided a process for the purification of vildagliptin Formula (I),

(I)
the process comprising:
(a) providing a solution of vildagliptin in water,
(b) extracting the solution with one or more of first organic solvents,
(c) removing the first organic solvent to obtain a residue,
(d) adding one or more of second organic solvents to the residue; and
(e) obtaining the pure vildagliptin by addition of one or more of an anti-solvent.
In another general aspect, there is provided a process for the purification of vildagliptin of Formula (I), the process comprising:
(a) providing a solution of vildagliptin containing impurities VD-1 ((S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide), VD-2((S)-1-(2-chloroacetyl) pyrrolidine-2-carbonitrile), dimer-1 impurity, dimer-2 impurity and adamantanol impurity more than 0.1% by area percentage of HPLC in one or more of first organic solvents,
(b) removing the first organic solvents to obtain a residue,
(c) dissolving the residue in one or more of second organic solvents; and
(d) obtaining the pure vildagliptin by addition of one or more of an anti-solvent.
In another general aspect, there is provided vildagliptin of Formula (I) substantially free from dimer impurity, prepared by the process of present invention.
In another general aspect, there is provided a vildagliptin of Formula (I) substantially free from adamantanol impurity, prepared by the process of present invention.
In another general aspect, there is provided a substantially pure vildagliptin of Formula (I) having a total purity of at least about 99%, particularly of at least about 99.5%, more particularly of at least about 99.8% and most particularly of at least about 99.9%, by area percentage of HPLC.
In another general aspect, there is provided pure vildagliptin having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 100 µm, the 50th volume percentile particle size (D50) is less than about 200 µm, or the 90th volume percentile particle size (D90) is less than about 400 µm, or any combination thereof.
In further aspect, the pure vildagliptin may be micronized to achieve the better particle size distribution in order to make suitable Formulation.
In another general aspect, there is provided a pharmaceutical composition comprising pure vildagliptin together with one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION
The above and other objects of the present invention are achieved by the process of the present invention, which leads to an improved process for the preparation of vildagliptin substantially free from one or more of its impurities.
Optionally, the solution, prior to any solids formation, can be filtered to remove any un-dissolved solids, or solid impurities to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
Terms such as “about”, “generally”, “substantially,” and the like are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
As used herein, the terms “pure vildagliptin” refers to vildagliptin having total purity of at least about 99%, particularly of at least about 99.5%, more particularly of at least about 99.8% and most particularly of at least about 99.9%, by area percentage of HPLC.
As used herein the term “substantially free” means one or more impurities selected from VD-1 ((S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide), VD-2 ((S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile), dimer impurities 1&2 and adamantanol impurity present to the level of about 0.15% or less, in particular of about 0.1 % or less by area percentage of HPLC.
As used herein, the term “purifying” refers to crystallization or recrystallization process which comprises: heating a mixture of a starting vildagliptin and a solvent at a suitable temperature wherein a clear solution is obtained, and addition of suitable anti-solvent.
In another general aspect, there is provided a process for the preparation of pure vildagliptin of Formula (I)

(I)
the process comprising:
(a) reacting L-prolinamide of Formula (V),

(V)
with haloacetyl chloride in one or more of organic solvents in the presence of a base to obtain a compound of Formula (IV),

(IV)
wherein, X represents chloro or bromo group and haloacetyl chloride may be chloro or bromoacetyl chloride;
(b) condensing the compound of Formula (IV) with 1-amino-adamantane-3-ol of Formula (III) in the presence of a condensing agent to obtain the compound of Formula (II),

(III) (II)
(c) dehydrating the compound of Formula (II) with a dehydrating agent to obtain vildagliptin of Formula I; and
(d) optionally, purifying the vildagliptin to obtain pure vildagliptin of Formula (I).
In general aspect, the compound L-prolinamide is reacted with chloroacetyl chloride in one or more organic solvent comprises of methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dimethyl formamide, dichloromethane, dimethyl acetamide, dimethyl sulfoxide, N-methyl pyrrolidone, tetrahydrofuran, and 2-methyl tetrahydrofuran. In particular dichloromethane, dimethylformamide, and tetrahydrofuran is used to obtain the compound of Formula (IV).
In general aspect, the base comprises of inorganic bases selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, and cesium carbonate; an organic bases selected from one or more of triethylamine, diisopropyl ethyl amine, diethylamine, pyridine, piperidine, and DBU. In particular, triethylamine is used.
In general aspect, the condensing agent comprises of carbonyldiimidazole, dicyclohexylcarbodiimide, and 2,4,6-tri-n-propyl-2,4,6-trioxo-1,3,5,2,4,6-trioxa-triphosphorinane. In particular, dicyclohexylcarbodiimide is used.
The further embodiment of the process comprises condensation compound of Formula (IV) with 1-amino-adamantan-3-ol compound of Formula (III) in the presence of a base. The base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydroxide, potassium tert-butoxide, and cesium carbonate. In particular, potassium carbonate is used to obtain a compound of Formula (II).
The embodiments of process further includes dehydration of the compound of Formula (II) in one or more organic solvents comprise of methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dimethyl formamide, dichloromethane, dimethyl acetamide, dimethyl sulfoxide, N-methyl pyrrolidone, tetrahydrofuran, and 2-methyl tetrahydrofuran. In particular dichloromethane, dimethyl formamide, and tetrahydrofuran is used to obtain the compound of Formula (I).
The dehydrating agent comprises one or more of vilsmeier’s reagent, phosphoryl chloride, trifluoroacetic anhydride, phosphorus pentoxide, and diethylchlorophosphate. In particular phosphoryl chloride may be used.
The further embodiment of the process includes purification of the starting vildagliptin to pure vildagliptin of Formula (I) by suitable purification method.
In another general aspect, there is provided a process for the purification of vildagliptin Formula (I)

(I)
the process comprising:
(a) providing a solution of vildagliptin in water,
(b) extracting the solution with one or more of a first organic solvent,
(c) removing the first organic solvents to obtain the residue,
(d) adding one or more of a second organic solvents to the residue; and
(e) obtaining the pure vildagliptin by addition of one or more of an anti-solvent.
In general, the process comprises extracting the solution of vildagliptin in water by one or more of first organic solvents comprises of methylene dichloride, ethylene dichloride, methyl ethyl ketone, isobutyl ketone, toluene, xylene, ethyl acetate, isopropyl acetate, and butyl acetate. In particular, methylene dichloride is used
In general, the process comprises purification of vildagliptin of Formula (I) in one or more of second organic solvent, which is obtained by removal of the first organic solvent by distillation. The second organic solvent comprises one or more of methanol, n-butanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and N-methyl- pyrrolidone. In particular, methanol may be used.
The purified vildagliptin (I) may be obtained by addition of an anti-solvent to the solution. The anti-solvent comprises one or more of ethers selected from methyl-tert-butyl ether, di-tert-butyl ether, diethyl ether, diisopropylether, dimethoxyethane, 1,4-dioxane, and ethyl-tert-butyl ether; hydrocarbons selected from hexane, heptane, and cyclohexane and the like. In particular, methyl tert-butyl ether may be used.
In another general aspect, there is provided a process for the purification of vildagliptin of Formula (I), the process comprising:
(a) providing a solution of vildagliptin containing impurities VD-1((S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide), VD-2((S)-1-(2-chloroacetyl) pyrrolidine-2-carbonitrile), dimer-1 impurity, dimer-2 impurity and adamantanol impurity more than 0.1% by area percentage of HPLC in one or more of a first organic solvents,
(b) removing the first organic solvents to obtain a residue,
(c) dissolving residue in one or more of second organic solvents; and
(d) obtaining pure vildagliptin by addition of one or more of an anti-solvent.
Impurity “VD-1” is (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide.

Impurity “VD-2” is (S)-1-(2-chloroacetyl) pyrrolidine-2-carbonitrile

Impurity “dimer-1” is having the following structure

Impurity “dimer-2” is having the following structure

Impurity “adamantanol” is having the following structure

In another general aspect, there is provided a pure vildagliptin of Formula (I) has a purity of at least about 99%, or of at least about 99.5%, or of at least about 99.8%, or of at least about 99.9%, by area percentage of HPLC.
In another general aspect, there is provided vildagliptin of Formula (I) substantially free from dimer impurity, prepared by the process of present invention.
In another general aspect, there is provided vildagliptin of Formula (I) substantially free from adamantanol impurity, prepared by the process of present invention.
In another general aspect, there is provided substantially pure vildagliptin having particle size distributions wherein the 10th volume percentile particle size (D10) of about 100 µm or less, the 50th volume percentile particle size (D50) of about 200 µm or less, or the 90th volume percentile particle size (D90) of about 400 µm or less, or any combination thereof. In further aspect, the vildagliptin may be micronized to achieve the better particle size distribution in order to make suitable Formulation.
The active ingredient may be micronized prior to compression and shearing. Micronisation may be by any suitable method. Micronization is the process of reducing the average diameter of a solid material's particles, for example by milling or grinding. In one aspect a micronized active is an active ingredient that has been subjected to a mechanical process which applies sufficient force to the active ingredient that the process is capable of breaking coarse particles down to fine particles.
In one aspect micronization of the active ingredient may be achieved using one or a combination of the following methods: ball milling, jet milling, jet blending, high-pressure homogenation, or any other milling method.
Ball milling is a milling method used in many of the prior art co-milling processes. Centrifugal and planetary ball milling may also be used.
Jet mills are capable of reducing solids to particle sizes in the low-micron to submicron range. The grinding energy is created by gas streams from horizontal grinding air nozzles. Particles in the fluidised bed created by the gas streams are accelerated towards the centre of the mill, colliding within. The gas streams and the particles carried in them create a violent turbulence and, as the particles collide with one another, they are pulverized.
Alternatively micronized active ingredient may be produced by using a high energy media mill or an agitator bead mill, for example, the Netzsch high energy media mill, or the DYNO-mill (Willy A. Bachofen AG, Switzerland).
In another general aspect, there is provided substantially pure vildagliptin of Formula (I) substantially free from one or more of its impurities as determined using high performance liquid chromatography (HPLC).
In another general aspect, there is provided a pharmaceutical composition comprising pure vildagliptin together with one or more pharmaceutically acceptable excipients.
In another general aspect, there is provided process for the preparation of pure vildagliptin of Formula (I) according the reaction scheme-1 substantially as depicted herein after.

Scheme-1

The invention also encompasses pharmaceutical compositions comprising pure vildagliptin of the invention. As used herein, the term "pharmaceutical compositions" includes pharmaceutical Formulations like tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
In another general aspect, there is provided a pharmaceutical composition comprising vildagliptin substantially free from impurities together with one or more pharmaceutically acceptable carriers, excipients or diluents.
The examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.

Examples
Example-1: Preparation of 1-(2-chloroacetyl) pyrrolidine-2-carboxamide (IV)
In a 250 mL four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, methylene dichloride (30 mL) was cooled to 0 to 5ºC. Chloroacetyl chloride (10.87 g) was added and subsequently L-prolinamide solution (L-prolinamide 10 g and triethylamine 11.52 g in MDC 120 mL) was added and reaction mixture was stirred for 1 hr. The reaction mixture was distilled under vacuum to obtain residue. 50 mL of ethyl acetate was added and again stirred for 30 min at 40-45°C. The reaction mixture was cooled to 20-25°C. The product thus obtained was filtered, washed with ethyl acetate and dried under vacuum at 60°C for 4 hrs.

Example-2: Preparation of (2S)-1-[2-[(3-hydroxy-1-adamentyl) amino]-acetyl] pyrrolidine-2-carboamide (II)
In a 100 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 1-(2-chloroacetyl) pyrrolidine-2-carboxamide (52.15 g) and MDC (300 mL) were cooled to 10-15°C. Dicyclo-hexylcarbodiimide (56.74 g) was charged and the reaction was warmed up to 25°C. MDC was completely removed by distillation from the reaction mixture till residue remained. THF (500 mL) and 3-amino-1-adamentanol (91.98 g) were added to the residue and the reaction mixture was then stirred for 3 hours at 45°C. The reaction mass was then filtered and washed with THF and dried under vacuum at 60ºC for 5 hours to obtain the titled compound.

Example-3: Preparation of (2S)-1-[2-[(3-hydroxy-1-adamentyl) amino]-acetyl] pyrrolidine-2-carboamide (II)
In a 100 mL round bottomed flask equipped with nitrogen atmosphere, mechanical stirrer, thermometer and an addition funnel, 3-amino-1-adamentanol (2.89 g, 17.31 mmol) and DMF (12 L) were cooled to 0 to 5°C. Potassium carbonate (2.39 g, 17.31 mmol) and 1-(2-chloroacetyl) pyrrolidine-2-carboxamide (3 g, 15.737 mmol) were added to the reaction mass and stirred at 0-5°C for 3 hr.
The reaction mass was heated to 50-55°C for 3 hr and cooled to 25-35°C. The reaction mass was then filtered and washed with methanol and dried at 60-65°C to obtain the residue. The obtained residue was cooled to 35-35°C and then dichloromethane (45 mL) was added. The reaction mass was cooled to 0-5°C and stirred for 1 Hr. The reaction mass was then filtered and washed with dichloromethane and dried at 50°C to obtain the title compound.

Example-4: Preparation of (2S)-1-[2-[(3-hydroxy-1-adamentyl) amino]-acetyl] pyrrolidine-2-carboamide (II)
In a 100 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 1-(2-chloroacetyl) pyrrolidine-2-carboxamide (53.2 g) and DMF (200 mL) were cooled to 0-5°C. Potassium carbonate (44.0 g) and 3-amino-1-adamentanol (50 g) were added to the reaction mixture and stirred for 3 hours at 0-5°C and for 3 hours at 50-55°C. The reaction mass was then cooled to 20-25°C and MDC (400 mL) was charged and stirred. The reaction mass is then filtered and washed with MDC and distilled to remove methylene dichloride. Methyl tert-butyl ether (500 mL) was added to the residue and heated at 40º to 45ºC for 15 min and cooled to 0º to 5ºC. The reaction mixture was filtered and washed with methyl tert-butyl ether and dried at 60°C for 5 hours to obtain the titled compound.

Example-5: Preparation of Vildagliptin (I)
In a 3.0 L four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, (2S)-1-[2-[(3-hydroxy-1-adamentyl)amino]acetyl]pyrrolidine-2-carboamide (6.4 g) and MDC (128 mL) were cooled to 10°C and phosphorous oxychloride (6.48 mL) was added. The reaction was refluxed for 4 hours and cooled to 25°C. Water (20 mL) was charged and pH was adjusted to 9. The layers were separated and the organic layer was washed with water (40 mL). The organic layer was distilled under vacuum to get the residue which was recrystallized in methyl ethyl ketone (50 mL) filtered, washed with methyl ethyl ketone and dried.

Example-6: Purification of Vildagliptin (I)
In a 2.0 L four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, [[(3-hydroxy-1-adamentanyl)amino]acetyl]-2-cyano-(S)-pyrrolidine (115 g) and water (345 mL) were heated to 40 to 45ºC to get the clear solution. Solution was cooled to 25-35°C and MDC (1.15 L) was charged and stirred for 15 to 20 min. MDC layer was separated and aqueous layer was extracted with MDC (757 ml). The combined methylene dichloride layer was filtered through 0.45 micron filter and distilled till residue was obtained. Methanol (115 mL) was added to the residue and heated to 50-55ºC to obtain clear solution. Methyl-tert-butyl ether (575 mL) was added drop wise and stirred for 1 hour at 0-5ºC. The product thus obtained was filtered and dried under vacuum at 60ºC for 5 hours.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
,CLAIMS:We Claim:
1. A process for the preparation of pure vildagliptin of Formula (I)

(I)
the process comprising:
a) reacting L-prolinamide of Formula (V),

(V)
with haloacetyl chloride in one or more of organic solvents and in the presence of base to obtain a compound of Formula (IV),

(IV)
wherein, X represents chloro or bromo group and haloacetyl chloride may be chloro or bromoacetyl chloride;
b) condensing the compound of Formula (IV) with 1-amino-adamantane-3-ol of Formula (III) in the presence of a base to obtain the compound of Formula (II);

(III) (II)
c) dehydrating the compound of Formula (II) with dehydrating agent to obtain vildagliptin of Formula I; and
d) optionally, purifying the vildagliptin to obtain pure vildagliptin of Formula (I).

2. The process according to claim 1, wherein the organic solvent comprises one or more of methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dimethylformamide, dichloromethane, dimethyl acetamide, dimethyl sulfoxide, N-methyl- pyrrolidone, tetrahydrofuran, and 2-methyl tetrahydrofuran.

3. The process according to claim 1, wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, cesium carbonate, triethylamine, diisopropylethyl amine, diethylamine, pyridine, piperidine, and DBU.

4. The process according to claim 1, wherein the dehydrating agent comprises one or more of vilsmeier’s reagent, phosphoryl chloride, trifluoroacetic anhydride, phosphorus pentoxide and diethylchloro phosphate.

5. The process according to claim 1, wherein the pure vildagliptin has a purity of at least about 99% by area percentage of HPLC.

6. The process for the purification of vildagliptin of Formula (I), according to claim 1,

(I)
comprising:
(a) providing a solution of vildagliptin in water,
(b) extracting the solution with one or more of a first organic solvent,
(c) removing the first organic solvents to obtain a residue,
(d) adding one or more of a second organic solvents to the residue; and
(e) obtaining the pure vildagliptin by addition of one or more of an anti-solvent.

7. The process according to claim 6, wherein the first organic solvent comprises one or more of methylene dichloride, ethylene dichloride, methyl ethyl ketone, isobutyl ketone, toluene, xylene, ethyl acetate, isopropyl acetate, and butyl acetate.

8. The process according to claim 6, wherein the second organic solvent comprises one or more of methanol, butanol, ethanol, isopropanol, acetone, acetonitrile, dimethylformamide, dimethylacetamide, dimethyl- sulfoxide, and N-methylpyrrolidone, or mixture thereof.
9. The process according to claim 6, wherein the anti-solvent comprises one or more of ethers selected from methyl tertbutyl ether, ditertbutyl ether, diethyl ether, diisopropylether, dimethoxyethane, 1,4-dioxane, and ethyltertbutyl ether; hydrocarbons selected from hexane, heptane, and cyclohexane.

10. The process for the purification of vildagliptin of Formula (I) according to claim 1, the process comprising:
(a) providing a solution of vildagliptin containing impurities VD-1 ((S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide), VD-2 ((S)-1-(2-chloroacetyl) pyrrolidine-2-carbonitrile), dimer-1 impurity, dimer-2 impurity and adamantanol impurity more than 0.1% by area percentage of HPLC in one or more of first organic solvents,
(b) removing the organic solvents to obtain a residue,
(c) dissolving the residue in one or more of second solvents; and
(d) obtaining the pure vildagliptin by addition of one or more of an anti-solvent.

11. The process according to claim 10, wherein the first organic solvent comprises one or more of methylene dichloride, ethylene dichloride, methyl ethyl ketone, isobutyl ketone, toluene, xylene, ethyl acetate, isopropyl acetate, and butyl acetate.

12. The process according to claim 10, wherein the second organic solvent comprises one or more of methanol, butanol, ethanol, isopropanol, acetone, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone, or mixture thereof.

13. The process according to claim 10, wherein the anti-solvent comprises one or more of ethers selected from methyl tertbutyl ether, ditertbutyl ether, diethyl ether, diisopropylether, dimethoxyethane, 1,4-dioxane, and ethyltertbutyl ether; hydrocarbons selected from hexane, heptane, and cyclohexane.

14. A pharmaceutical composition comprising pure vildagliptin of Formula (I) according to claim 1 and a pharmaceutically acceptable carrier or excipient.

Dated this the 12th day of September 2014.

(H. SUBRAMANIAM)
Of SUBRAMANIAM & ASSOCIATES
Attorneys for the Applicants