FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
" AN ADVANCED AND COST-EFFECTIVE PROCESS FOR PREPARING HIGHLY PURE VILDAGLIPTIN "
2. APPLICANT:
(a) NAME: HARMAN FINOCHEM LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: 107, Vinay Bhavya Complex, 159-A , C.S.T. Road, Kalina,
Mumbai - 400098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION:
The present invention relates to an improved process for preparing highly pure (S)-1-[N-(3-hydroxy-l-adamantyl) glycyl] pyrrolidine-2-carbonitrile, known as Vildagliptin (Formula-I).
BACKGROUND OF INVENTION:
Vildagliptin (Formula-1) is a dipeptidyl peptidase IV (DPP-IV) inhibitor and is first disclosed in U.S. Patent No. 6,166,063 ("the '063 patent").It is known that DPP-IV is responsible for inactivating glucagon-like peptide-1 (GLP-1). GLP-1 is a major stimulator of pancreatic insulin secretion and positively influences glucose transformation. DPP-IV is effective for the treatment of non-insulin-dependent diabetes mellitus (NIDDM).

US 7,375,238 discloses a process for preparation of pyrrolidine, 1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-(S) comprising (a) reacting chloroacetyl chloride with L-prolinamide in the presence of dimethyl formamide (b) reacting the resultant compound without isolation with a dehydration agent, (chloromethylene)dimethyl ammonium chloride to obtain crude (S)-l-chloroaceryl-pyrrolidine-2-carbonitriIe(c) reacting crude (S)-l-chloroacetyl-pyrrolidine-2-carbonitrilewith3-hydroxyaminoadamantane in presence of base (d) recovering Vildagliptin in free form or in acid addition salt form.
WO 20100022690 describes a method of preparation of highly pure Vildagliptin comprising three steps and proceeds according to scheme 1 as shown below.


Scheme-I
(a) R3N (R=alkyl), solvent (linear or cyclic ether), (b) TFAA, solvent (linear or cyclic ether), (c) K2CO3, KI, mixture of solvents (mixture of an ester, polar aprotic solvent and ketone, e.g. isopropyl acetate, DMF, 2-butanone)
According to WO'690 scheme stage (a) describes preparation and isolation of the intermediate l-haIoacetyl-2-(S) pyrrolidinecarboxamide in solid state which further reacts with trialkyl amine hydrohalide to give l-haloacetyI-(S)-2-cyanopyrrolidine in stage-(b). Stage -3 includes reaction of l-haloacetyI-(S)-2-cyanopyrrolidine with 3-amino-l-adamantanol in the presence of mixture of ketone, ester & polar aprotic solvent to yield Vildagliptin.
WO 2011101861 discloses a process for preparing Vildagliptin by reacting 1-aminoadamantane-3-ol with 2-halo acid derivative or its salt in presence of base in a suitable solvent to provide the corresponding 2-(3-hydroxyadamantan-l-yl amino)acid derivative or its salt, hydrolyzing 2-(3-hydroxyadamantan-l-yl amino)acid derivative or its salt with a suitable base in presence or absence of a solvent to provide the corresponding acid which further reacts with pyrrolidine-2-carbonitrile in presence of a suitable condensing agent to provide Vildagliptin.(Scheme-II)


Wherein X is a halogen, R is C1 -12 alkyl group which may be a straight or branched chain, aryl C1-6 alkyl,aryl group which is substituted or unsubstituted aromatic group, or R is M wherein M is an alkali metal.

Scheme-Ill
In another process variant, WO'861 discloses preparation of Vildagliptin, which comprises: reacting the L-prolinamide with 2-chloro acetyl chloride in presence of suitable base in a suitable solvent to provide (S)-l-(2-chloroacetyI)pyrrolidine-2-carboxamide which istreated with trifluoroacetic anhydride in a suitable solvent to

provide the (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile.(S)-l-(2-
chIoroacetyl)pyrrolidine-2-carbonitrile thus obtained is reacted with 1 -aminoadamantane-3-ol in presence of a suitable base in suitable solvent to provide the Vildagliptin.
WO 2008084383 describes a process for preparing Vildagliptin with high chemical and enantiomeric purity and composition comprising Vildagliptin. WO 2011012322 describes synthesis of Vildagliptin in the presence of Phase transfer catalysts.
One disadvantage of prior art processes involves in use of toxic materialssuch astrifluoroaceticanhydride which isenvironmentally harmful. Another drawback is multiple process steps that results in lower purity and yield.
Therefore, there is need in the in the art to develop an efficient insitu process for preparation of (2S)-l-(chloro acetyl) pyrrolidine-2-carbonitrile of formula-Ill, a key intermediate of Vildagliptin, which can be further converted into Vildagliptin in a cost effective manner that results in good yields and high purity.
Therefore the object of present invention is to provide robust, economical, industrially applicable and safe process for preparing Vildagliptin with high purity and high yield.
SUMMARY OF THE INVENTION:
In accordance with the above objective, the present invention provides an improved and cost-effective process for preparing of Vildagliptin of formula-I which includes the following steps:
(a) esterifying formula-IV insitu in presence of thionyl chloride and alcohol to form formula-V at an elevated temperature ;
(b) converting formula-V insitu into formula-VI by treating the reaction mass of step (a) with aqueous ammonia followed by treating with alcohol;
(c) treating formula-VI insitu with chloroacetyl chloride in presence of polar aprotic solvent to obtain formula-VII;
(d) reacting formula-VII insitu with phosphorous oxy chloride in presence of polar aprotic solvent to obtain formula-Ill;
(e) isolatingcarbonitrile compound of formula-Ill followed by crystallization in an

alcohol solvent or mixture of two or more alcohol solvents;
(f) reacting carbonitrile compound of formula-Ill with formula-II at an elevated temperature in presence of an inorganic/organic base, in presence/absence of suitable catalyst and ketone solvent or mixture of ketone solvent with non-polar solvents to obtain Vildagliptin of formula-I; and optionally
(g) purifying the Vildagliptin of formula-I
According to the above process, step (a) and (f) are carried out at an elevated temperature of 40-75°C and steps (b), (c) and (d) are carried out at a temperature of-5 to 30 °C. In another aspect, the invention provides a process for producing (2S)-1-(chloro acetyl) pyrrolidine-2-carbonitrile of formula-Ill which process comprises:
(a) esterifying formula-IV insitu in presence of thionyl chloride and alcohol to yield formula-V at temperature 40-70 °C;
(b) convertingformula-V into formula-Vl by insitu reaction in presence of aqueous ammonia and alcohol;
(c) reacting formula-VI insitumth chloroacetyl chloride in presence of polar aprotic solvent to obtain formula-VII; and
(d) reacting formula-VII insitu with phosphorous oxy chloride in presence of polar aprotic solvent to form (2S)-l-(chloroacetyl)pyrrolidine-2-carbonitrile of formula-IH and
(e) crystallizing formula III in alcohol solvent or mixture of two or more alcohol solvents.
According to the above process steps (b), (c) and (d) are carried out at a temperature of-5 to 30 °C to obtain (2S)-l-(chloro acetyl) pyrrolidine-2-carbonitrile.
In another aspect, the invention discloses preparation of dimer impurity of formula-VIII obtained during the preparation of Vildagliptin which comprises:
(a) reacting(2S)-l-(chloroacetyl)pyrrolidine-2-carbonitri!eof formula III with excess adamantanolin presence of solvent, inorganic base and suitable catalyst; and
(b) isolating formula-VIII
An improved process for preparation of Vildagliptin according to the present invention is described by following reaction scheme-IV


DETAILED DESCRIPTION OF THE INVENTION:
The present invention discloses an improved process for preparation of (s)-l-[N-(3-hydroxy-1-adamantyl) glycyl] pyrrolidine-2-carbonitrile of formula-].

In a preferred embodiment, the invention describes process for manufacturing Vildagliptin which comprises;
(a) esterifying formula-IV insitu in presence of thionyl chloride and alcohol to form formula-V at an elevated temperature;
(b) converting formula-V insitu into formula-VI by treating the reaction mass of step (a) with aqueous ammonia followed by treating with alcohol;
(c) treating formula-VI insitu with chloroacetyl chloride in presence of polar aprotic

solvent to obtain formula-VII;
(d) reacting formula-VII insitu with phosphorous oxy chloride in presence of polar aprotic solvent to obtain formula-Ill;
(e) isolating carbonitrile compound of formula-Ill followed by crystallization in an alcohol solvent or mixture of two or more alcohol solvents;
(f) reacting carbonitrile compound of formula-Ill with 3-aminotricyclo [ 3.3.1.13,7] decan-1-ol of formula-II at an elevated temperature in presence of an inorganic/organic base, in presence/absence of suitable catalyst and ketone solvent or mixture of ketone solvent with non-polarsolvents to obtain Vildagliptin of formula-I; and optionally
(g) purifying the Vildagliptin of formula-I
According to the above process, step (a) and (f) are carried out at an elevated temperature
of 40-75°C and steps (b), (c) and (d) are carried out at a temperature of-5 to 30°C.
In the said process "alcohol" refers to methanol, ethanol, n-propanol, isopropanol, n-
butanol. The term "polar aprotic solvent" refers to dimethylformamide,
dimethylacetamide,dimethylsulfoxide, tetrahydrofuran,ethyl acetate, acetonitrile. The
term "ketone solvent" indicates acetone, methyl ethyl ketone, diethyl ketone, methyl iso
butyl ketone, isopropyl ketone. The term "non-polar solvents" refers to toluene, hexane,
1,4-dioxane, chloroform, diethyl ether, dichloromethane.
For the purpose of reaction, the inorganic base is selected from alkali and alkaline earth
metal carbonates like sodium carbonate, potassium carbonate, sodium bi carbonate,
potassium bi carbonate and the organic base is selected from triethyl amine, diisopropyl
ethyl amine, N-methyl morpholine, N-methyl pyrrolidine.
The suitable catalyst is selected from potassium iodide, sodium iodide, potassium
bromide, sodium bromide.
In another preferred embodiment, the invention describes a process for producing (2S)-1-(chloro acetyl) pyrrolidine-2-carbonitrile of formula-Ill which involves:
(a) esterifying formula-IV insitu in presence of thionyl chloride and alcohol to form formula-V at a temperature of from 40-70°C;
(b) converting formula-V insitu into formula-Vl by treating the reaction mass of step (a) with aqueous ammonia followed by treating with alcohol;
(c) treating formula-Vl insitu with chloroacetyl chloride in presence of polar aprotic

solvent to obtain formula-VII;
(d) reacting formula-VII insitu with phosphorous oxy chloride in presence of polar aprotic solvent to obtain formula-Ill; and
(e) isolating carbonitrile compound of formula-Ill followed by crystallization in alcohol solvent or mixture of two or more alcohol solvents;
In the said process alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-
butanol. The "polar aprotic solvent" is selected from dimethylformamide,
dimethylacetamide,dimethylsulfoxide, tetrahydrofuran,ethyI acetate, acetonitrile. The
reaction in steps (b) to (e) is carried out at a temperature range of-5 to 30 °C.
The HPLC purity of the carbonirile compound thus obtained is 96-100%.
In a further embodiment, the invention'discloses the process for preparing Vildagliptin of
formula-l which involves:
(a) reacting (2S)-l-(chloroacetyl)pyrrolidine-2-carbonitrile of formula-Ill with 3-aminotricyclo [ 3.3.l.l3,7] decan-1-ol in ketone or mixture of ketone solvent with non-polar solvents in presence of an inorganic/organic base and suitable catalyst at ambient temperature; and
(b) isolating and purifyingVildagliptin.
In the said process ketone is selected from acetone, methyl ethyl ketone,diethyl ketone,
methyl iso butyl ketone, isopropyl ketone and non-polar solvent is selected from toluene,
hexane, 1,4-dioxane, chloroform, diethyl ether, dichloromethane.
The inorganic base is selected from alkali and alkaline earth metal carbonates like sodium
carbonate, potassium carbonate, sodium bi carbonate, potassium bi carbonate and the
organic base is selected from triethyl amine, diisopropyl ethyl amine, N-methyl
morpholine, N-methyl pyrrolidine.
The suitable catalyst is selected from potassium iodide, sodium iodide, potassium
bromide, sodium bromide.
In another preferred embodiment, the invention discloses the preparation of dimer
impurity of formula-VIII also obtained during the preparation of Vildagliptin which
comprises:
(a) reacting excess 3-amino-l-adamantanol with (2S)-l-(chloroacetyl)pyrrolidine-2-carbonitrile in presence of solvent, inorganic base and suitable catalyst and


The dimer impurity thus obtained having HPLC purity of 91.5-95%. The solvent is selected from ethers such as tetrahydrofiiran, ketones like acetone, methyl ethyl ketone,diethyl ketone, methyl iso butyl ketone, isopropyl ketone. The inorganic base is selected from alkali and alkaline earth metal carbonates like sodium carbonate, potassium carbonate, sodium bi carbonate, potassium bi carbonate. The suitable catalyst is selected from potassium iodide, sodium iodide, potassium bromide, sodium bromide.
In yet another preferred embodiment the purification process of Vildagliptin is described which includes;
(a) dissolution of crude Vildagliptin into solvent and heating at 40- 60°C; followed by
(b) treatment with charcoal and
(c) isolation of pure Vildagliptin.
The ketonereferred in the purification includes acetone, methyl ethyl ketone, diethyl
ketone, methyl iso butyl ketone and isopropyl ketone.
The HPLC purity of Vildagliptin thus obtained is more than 99.9- 100% with less than
0.1% dimer impurity.
The chiral HPLC purity of Vildagliptin is more than 99.94%.
The following examples, which include preferred embodiments, will serve to illustrate the
practice of this invention, it being understood that the particulars shown are by way of
example and for purpose of illustrative discussion of preferred embodiments of the
invention.

Examples:
Example I:Preparation of 2(S)-l-(chIoro acetyl) pyrrolidine-2-carbonitrile (formula-Ill)
To the 550 cc methanol charged 0.87 mole of formula-IV and stirred for 10-30 min at room temperature below 10°C preferably at 0±5°C. Added 1.45 mole thionylchloride at 40-70°C. After completion of reaction methanol was distilled out toobtain formula-V. Added 500cc 1-butanol and 60 cc aq. ammonia at 5-30°C and stirred for 30-60 mins. Filtered solid ammonium chloride and charged excess 600cc 1-butanol and 590cc aqueous ammonia at 5-30°C. After stirring for 10-14 hrs at ambient temperature separated butanol layer and solvent was distilled out to obtain formula-VI. To the degassed mass charged 375cc N, N-dimethylformamide and 0.82 mole chloro acetyl chloride and stirred at -5 to 25°C to produce formula-VII. Charged 0.47 mole phosphorous oxy chloride in the temperature range of-5 to 20 °C and stirred for l-2hrs.Then charged saturated sodium bi carbonate solution and extracted in lOOOcc ethyl acetate. Collected ethyl acetate layer and washed with 500cc saturated sodium chloride solution and distilled out ethyl acetate and crystallized with 2-isopropanol to afford nitrile compound of formula 111 with an yield of 40%. HPLC PURITY: 96-99%
Example II: Preparation of crude Vildagliptin (formula-l)
To the 750 cc acetone charged 0.72 mole of formula-II with 1.45 mole of potassium carbonate and 0.003 mole potassium iodide. The reaction mass stirred for 15min at ambient temperature.Then charged 0.58 mole formula-IIIin 200cc acetone and stirred for 4-5 hrs at 40-65°C. After completion of reaction, filtered the solid potassium chloride and potassium carbonate.Concentrated the filtrate up to minimum volume and stirred for 60 min at 15-40°C to get 82% yield of crude Vildagliptin. HPLC PURITY: 97-99%, Dimer IMP: 2.0-3.0%
Example-III: Preparation of crude Vildagliptin (formula-I)
To the mixture of 71.2 cc acetone and 3.75 cc toluene chargedO.072 mole of formula-II with 0.145 mole potassium carbonate and 0.0003 mole potassium iodide. The reaction mass stirred for 10-30min at ambient temperature. Then charged 0.058 mole formula-Ill in 20 cc acetone mixture at 40-75°C and stirred atthe same temperature for 4-5 hrs. After

completion of reaction, filtered the solid potassium chloride and potassium carbonate. Concentrated the filtrate up to minimum volume and stirred for 60-90min at 15-40°C to get 80% yield of crude Vildagliptin. HPLC PURITY: 97-99%, Dimer IMP: 1.5-2.0%
Example IV: Preparation of pure Vildagliptin
To the 1200 cc acetone dissolved 0.33 mole crude Vildagliptin and heated at 40-65°C. After charcoal treatment filtered the reaction mass and distilled the solvent up to 350 cc. Charged 200 cc ethyl acetate and heated at 30-60°C for 1-2 hrs. Again charged 1000 cc acetone and distilled up to 520 cc to obtained 75-90% yield of pure Vildagliptin. PURITY BY HPLC: 99.9-100%, Dimer: less than 0.1% CHIRAL PURITY BY HPLC: 99.5-100%
Example: V Preparation of dimer impurity
To the 30cc tetrahydrofuran charged 0.011 mole formula-ll, 0.03 mole formula-Ill, 0.0006 mole potassium iodide and 0.036 mole potassium carbonate at reflux temperature for 5-7hrs. Filtered inorganic salt and degas tetrahydrofuran from filtrate at 30-60°C.10cc acetone and 29.8cc isopropyl ether added to obtain 65% yield of dimer impurity. HPLC purity: more than 91.5-95%.

We claim,
1. An improved process for preparing highly pure Vildagliptin of formula-I

comprising:
(a) esterifying formula-IV insitu in presence of thionyl chloride and alcohol to form formula-V at a temperature of from 40 to 70°C;
(b) converting formula-V insitu into formula-VI by treating the reaction mass of step (a) with aqueous ammonia followed by treating with alcohol;
(c) treating formula-VI insitu with chloroacetyl chloride in presence of polar aprotic solvent to obtain formula-VII;
(d) reacting formula-VII insituwiih phosphorous oxy chloride in presence of polar aprotic solvent to obtain formula-Ill;
(e) isolating carbonitrile compound of formula-Ill followed by crystallization in alcohol solvent or mixture of two or more alcohol solvents;
(f) reacting carbonitrile compound of formula-Ill with 3-aminotricyclo [ 3.3.1.13,7] decan-1-ol of formula-II in presence of a base, optionally in presence of suitable catalyst and ketone solvent or mixture of ketone with non polar solvents at 40-75°C to obtain Vildagliptin of formula-I; and optionally
(g) purifying the Vildagliptin of formula-I
2.The insitu process for preparing an intermediate (2S)-l-(chloroacetyI) pyrrolidine-2-carbonitrile of formula-Ill according to claim 1


Whichcomprises:
(a) esterifying formula-IV insitu in presence of thionyl chloride and alcohol to form formula-V at a temperature of 40-70°C;
(b) converting formula-V insitu into formula-VI by treating the reaction mass of step (a) with aqueous ammonia followed by treating with alcohol
(c) treating formula-VI insitu with chloroacetyl chloride in presence of polar aprotic solvent to obtain formula-VII
(d) reacting formula-VII insitu with phosphorous oxy chloride in presence of polar aprotic solvent to obtain formula-Ill; and
(e) isolating carbonitrile compound of formula-Ill followed by crystallization in alcohol solvent or mixture of two or more alcohol solvents.
3. The process according to claims 1 and 2, wherein the alcohol used in step-(a),(b)
and (f) is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and n-butanol.
4. The process according to claims 1 and 2, wherein the polar aprotic solvent is
selected from the group consisting of dimethylforrnamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, ethyl acetate, acetonitrile.
5. The process according to claim 1, wherein the base is an inorganic base selected
from the group consisting of alkali and alkaline earth metal carbonates like sodium carbonate, potassium carbonate, sodium bi carbonate, potassium bi carbonate or anorganic base selected from the group consisting of trisubstituted amines like triethyl amine, diisopropyl ethyl amine, N-methyl morpholine, N-methyl pyrrolidine.

6. The process according to claim 1, wherein, the suitable catalyst is selected from the
group consisting of potassium iodide, sodium iodide, potassium bromide and sodium bromide.
7. The process according to claim 1 and 2, wherein the reaction in step (b) to (e) is carried out at a temperature of preferably -5 to 30°C.
8. The process according to claim 1, wherein the purification of Vildagliptin comprising;

(a) dissolving crude Vildagliptin in a ketone solvent and heating at 40-65°C; and
(b) treating with charcoal prior to isolate pure Vildagliptin.
9. The process according to claims 1 and 8, wherein, the ketone solvent is selected
from the group consisting of acetone, methyl ethyl ketone, diethyl ketone, methyl iso butyl ketone, isopropyl ketone and the non-polar solvent is selected from the group consisting of toluene, hexane, 1,4-dioxane, chloroform, diethyl ether, dichloromethane.
10. A novel process for preparing dimer impurity of formula-VIII which comprises;

(a) reacting excess 3-amino-l-adamantanol with (2S)-l-(chloroacetyl)pyrrolidine-2-carbonitrile in presence of solvent, inorganic base and suitable catalyst and
(b) isolating formula-VIII

11. The process according to claim 10, wherein the solvent is tetrahydrofuran, the inorganic base is potassium carbonate and suitable catalyst is potassium iodide.
12. The process according to any of the preceding claims, wherein the purity of (2S)-l-(chloroacetyl) pyrrolidine-2-carbonitrile and Vildagliptin is 96-99% and 99.5-100% respectively.
13. The process accordingtoany of the preceding claims, wherein the % yield of Vildagliptin is 75-90%.
14. The process according to any of the preceding claims, wherein, the undesired dimer impurity is not more than 0.1%.