FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PROCESS FOR THE PURIFICATION OF VILDAGLIPTIN
2. APPLICANT:
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House,166 C.S.T. Road, Santacruz East,
Mumbai - 400 098, Maharashtra, India

TITLE: Process for the purification of vildagliptin.
FIELD OF INVENTION:
The present invention relates to a process for purification of vildagliptin.
The present invention further discloses a process for the preparation of vildagliptin devoid of process related impurities and having HPLC purity of more than 99%.
BACKGROUND OF THE INVENTION:
The compound (2S)-l-[[(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)amino]acetyl]-2-pyrrolidine carbonitrile is known by non-proprietary name vildagliptin, having the chemical structure of Formula I.

Vildagliptin is an oral anti-hyperglycemic agent of the dipeptidylpeptidase IV (DPP-IV) inhibitor, useful in the treatment of type 2 diabetes and marketed by trade names Galvus and Zomelis.
Vildagliptin, the compound of formula I, and its process for preparation is first disclosed in U. S. Patent 6,166,063 [US'063'Patent] wherein l-aminoadamantane-3-ol is reacted with l-chloroacetyl-2-cyanopyrrolidine in presence of potassium carbonate in methylene chloride or tetrahydrofuran (THF) for about 6 days to yield crude vildagliptin. The crude compound further purified on silica gel flash chromatography to get pure vildagliptin compound of Formula I.
The process disclosed in the US' 063' requires longer reaction duration and the yield of vildagliptin was observed to be low. The process also involves chromatographic technique for purification, which leads to the increase in cost of production and renders the process unviable for commercial scale.

PCT application WO2004092127 discloses a process for purification of vildagliptin, wherein the process involves treatment of crude vildagliptin with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in isopropanol solvent at hot condition. The compound is isolated by adding methyl tert-butyl ether solvent and cooling to -10°C. The isolated vildagliptin is dried and further purified using 2-butanone and methyl tert-butyl ether solvents. The solution obtained requires seeding with crystals of vildagliptin to isolate pure vildagliptin.
The drawback of the process is in use of mixture of the solvent, seeding solution to isolate vildagliptin and use of costly reagent l,8-diazabicyclo[5.4.0]undec-7-ene.
The formation of a major impurity (2S,2'S)-l,1'-(((3-hydroxytricyclo[3.3.1.13,7 ]dec-l-yl)imino]bis(l-oxo-2, l-ethanediyl)]bis(2-pyrrolidinecarbonitrile) of Formula II in the process of preparation of vildagliptin described in PCT application WO2008084383. The application discloses purification of vildagliptin from a solvent mixture of isopropanol and methyl tributyl ether. However, it resulted in very low yield and impurity observed to be present along with drug substance. Purification method disclosed in this patent application found to be unsuccessful for removing impurity by simple solvent purification process.

Another PCT application WO2010022690 discloses process for the preparation of vildagliptin and purification of the crude vildagliptin using mixture of solvents.
An Indian Patent application 61/MUM/2012 discloses an acid-base treatment process to isolate pure vildagliptin, wherein the steps involve dissolution of crude vildagliptin in water immiscible solvent and treating with dilute acid and impurities are removed by extracting with suitable organic solvents. Further the acid salt of vildagliptin neutralized with a suitable base and the vildagliptin free base extracted with a suitable organic

solvent which then concentrated and treated with solvent to isolate pure vildagliptin. However, the process disclosed in this patent application requires tedious workup, which makes the process unviable for commercial scale.
There is always a need to develop an alternate purification process with less cumbersome and cost effective reagent for purification of vildagliptin.
The inventors of the present invention ameliorate the problems of the prior art processes by employing economical and commercially available reagent which forms an adduct with the compound and leaving the process impurities unreacted, thereby eliminating the use of column chromatography for the purification and isolation of pure vildagliptin compound of Formula I.
OBJECTIVES OF THE INVENTION:
The objective of the present invention is to prepare pure vildagliptin, the compound of Formula I with an industrially viable and cost effective process.
Another objective of the present invention is to prepare pure vildagliptin comprising in situ formation of vildagliptin-saccharin adduct.
Another objective of the present invention is to prepare pure vildagliptin, devoid of dimer impurity, the compound of Formula II and other process related impurities.
Yet another objective of the present invention is to prepare pure vildagliptin having purity of more than 99%.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for preparing pure vildagliptin, the compound of Formula I using readily available, industrially viable and cost effective reagents.
According to one aspect of the present invention provides a process for preparing pure vildagliptin, the compound of Formula I using in situ formation of vildagliptin-saccharin adduct, the compound of Formula III.


According to another aspect of the present invention provides a process to prepare pure vildagliptin, devoid of dimer impurity the compound of Formula II and other process related impurities.
According to primary object of the present invention, there is provided a novel, simple, cost effective and industrially safe process for the preparation of pure vildagliptin, the compound of Formula I,

which comprises the steps of:
a) suspending crude vildagliptin in water;
b) reacting with saccharin to form vildagliptin-saccharin adduct and get clear solution;
c) extract the clear aqueous solution with first solvent;
d) adjust the aqueous layer pH to alkaline;
e) extract the aqueous layer with second solvent;
f) distilling out solvent completely and isolate the pure vildagliptin compound of Formula I with suitable solvent;
g) optionally, recrystallising the compound of Formula I from suitable solvent.
In another aspect, the present invention provides a novel vildagliptin-saccharin adduct the compound of Formula III.

DETAILED DESCRITION OF THE INVENTION:
The present invention relates to a process for preparing pure vildagliptin, the compound of Formula I;

In an aspect, the present invention provides a process for the preparation of pure vildagliptin the compound of Formula I, which comprises the steps of;
a) suspending crude vildagliptin in water;
b) reacting with saccharin to form vildagliptin-saccharin adduct and get clear solution;
c) extract the clear aqueous solution with first solvent;
d) adjust the aqueous layer pH to alkaline;
e) extract the aqueous layer with second solvent;
f) distilling out solvent completely and isolate pure vildagliptin compound of Formula I using suitable solvent;
g) optionally, recrystallising the compound of Formula I from isopropyl alcohol.
In an embodiment of the present invention, the compound crude vildagliptin used in this invention can be prepared as per the prior art or according the process, wherein the compound l-aminoadamantane-3-ol was reacted with (S)-l-2(chloroacetyl)pyrrolidine-2-carbonitrile in presence of base potassium carbonate in acetonitrile solvent at about 55°C to 80°C. After the completion of reaction, the reaction mass cooled and solid filtered. The filtrate is concentrated under vacuum maintaining temperature below 40°C to obtain crude vildagliptin containing the dimer impurity, the compound of Formula II and other process impurities.
In an embodiment of the present invention, the compound crude vildagliptin obtained as above suspended in water and stirred.

In an embodiment of the present invention, as per the process in step (b) saccharin is added to the suspension obtained in step (a) to form vildagliptin-saccharin adduct, the compound of Formula III. The vildagliptin-saccharin adduct results a clear solution.
In an embodiment of the present invention, as per the process in step (c), the clear aqueous solution is extracted with first solvent selected from the group consisting of ethyl acetate, toluene, methyl ethyl ketone, methyl isobutyl ketone and dichloromethane. The preferred solvent for the extraction of the aqueous layer is dichloromethane.
In an embodiment of the present invention, the solvent extraction in step (c) removes the dimer impurity the compound of Formula 11 and other process related impurities leaving vildagliptin-saccharin adduct in the aqueous medium.
In an embodiment of the present invention, the aqueous layer obtained after extraction as in step (c) above is treated with suitable base as in step (d) to adjust the pH of the solution to alkaline. The suitable base used for the pH adjustment is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia. The preferred base used for the pH adjustment is sodium hydroxide.
In an embodiment of the present invention, the aqueous layer after the pH adjustment as in step (d) is extracted with second solvent as in step (e) to get the product vildagliptin in the solvent layer. The second solvent used for the extraction is selected from the group consisting of ethyl acetate, toluene, methyl ethyl ketone, methyl isobutyl ketone and dichloromethane, wherein the preferred solvent for the extraction is dichloromethane.
In an embodiment of the present invention, the extracted solvent layer is distilled off as in step (f) under vacuum to get the residual mass of pure vildagliptin compound of Formula I. The compound is isolated using solvent selected from the group consisting of ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl alcohol and isopropyl alcohol or mixture thereof.

The isolated pure vildagliptin compound of Formula I have purity of more than 99.0% and the dimer impurity well below the limit of 0.5% as measured on High Performance Liquid Chromatography (HPLC).
The isolated pure vildagliptin compound of Formula I have purity of more than 99.50% and the dimer impurity well below the limit of 0.15% as measured on High Performance Liquid Chromatography (HPLC).
In an embodiment of the present invention, the compound pure vildagliptin optionally recrystallised from isopropyl alcohol to get pure crystalline vildagliptin the compound of Formula I.
In an additional embodiment, the present invention provides a novel vildagliptin-saccharin adduct of Formula III.

The advantage of the present invention is use of economical and easily available saccharin reagent for the adduct formation with vildagliptin.
Further taking the advantages of insoluble nature of saccharin in water, it can be easily precipitated from aqueous layer by treating the aqueous layer with acidic reagents and filtering the precipitated solid. The recovered saccharin is dried and reused for the adduct formation with vildagliptin.
The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.

EXAMPLES:
Example 1: Preparation of crude vildagliptin:
In a round bottom flask, l-aminoadamantane-3-ol (29.07 gm), potassium carbonate (24.02gm) and acetonitrile (175 ml) were heated to 55°C - 60°C under stirring. A solution of (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile (20 gm) in acetonitrile (75 ml) was added and reaction temperature increased to 75°C to 80°C, stirred for about 3 hours. The completion of the reaction was monitored on HPLC. After reaction completion, the reaction mass was cooled to 45°C to 55°C, solid mass filtered and washed with acetonitrile (40 ml). The solvent was distilled out under vacuum by maintaining temperature below 40°C to obtain residual mass of crude vildagliptin. Saccharin (26 gm) and water (100ml) was added to the above residual mass and stirred the suspension to get clear solution. The aqueous solution extracted with dichloromethane (80 ml, 4 x20ml), and pH of the aqueous layer adjusted to 12 to 13 using 15% sodium hydroxide solution (50 ml). The above aqueous layer extracted with dichloromethane (80 ml, 4x20) and collected in round bottom flask. The dichloromethane solvent was distilled out under vacuum to obtain residual mass of pure vildagliptin. Ethyl acetate (140 ml) added to the residual mass and heated to 75°C to 80°C for 1 hour. Cooled the reaction mass to 30°C to 35°C and stirred for about 1 hour. Solid mass filtered, washed with ethyl acetate (20 ml) and dried at 50°C - 55°C to get pure vildagliptin (Yield - 18.06 gm, HPLC purity - 99.5%).
Example 2: Preparation of crude vildagliptin:
In a round bottom flask, l-aminoadamantane-3-ol (10.06 gm), potassium carbonate (9.9 gm), (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile (10 gm) in dimethylformamide (40 ml) were heated to 40°C - 45°C under stirring. Reaction mixture stirred for about 8 hours at 40°C - 45°C. The completion of the reaction was monitored on HPLC. After reaction completion, potassium carbonate was filtered off and filtrate concentrated under vacuum at 40°C - 45°C. Reaction mass cooled to 25°C - 30°C and 50 ml of purified water added. Saccharin (16 gm) added to the reaction mixture and stirred the suspension to get clear solution.. The aqueous layer was extracted with dichloromethane (4 x 20 ml) to remove impurities. pH of the aqueous layer adjusted to 12-13 using 15% sodium hydroxide solution (20 ml). Extract the product with dichloromethane (4 x 20

ml) from aqueous layer. The solvent was distilled out under vacuum to get thick residual mass. 2-Butanone (70 ml) added to the residual mass and heated to 75°C - 80°C and maintained for an hour. Cool the reaction mass to 20°C - 25°C, stir for an hour and filter, dry the product at 50°C - 55°C. Yield - 10.1 gm.
Example 3: Preparation of crude vildagliptin:
In a round bottom flask, l-aminoadamantane-3-ol (9.7 gm), potassium carbonate (7.76 gm) in tetrahydrofuran (SO ml) were heated to 40°C - 45°C under stirring. A solution of (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile (10 gm) in tetrahydrofuran (20 ml) was added slowly to the above reaction mass. Reaction maintained for 2 hours at 40°C -45°C under stirring. After completion of the reaction, potassium carbonate was filtered off, washed with dimethylformamide (10 ml) and filtrate concentrated under vacuum at 40°C - 45°C. Cool the reaction mass to 25°C - 35°C and purified water (50 ml) added. Saccharin (16 gm) was added to the reaction mass and stirred the suspension to get clear solution.. Extract the aqueous layer with dichloromethane (3 x 30 ml) to remove impurities. Aqueous layer pH adjusted to 12 - 13 using 15% sodium hydroxide solution (20 ml). Extract product from aqueous layer with dichloromethane (4 x 20 ml). Concentrate dichloromethane layer under vacuum, to get thick mass. Ethyl acetate (70 ml) added to the above mass, heated to 75 - 80°C and maintained for an hour. Cool and stir the ethyl acetate layer at 25°C - 30°C for an hour and filter the precipitated solid product. Wash the solid with ethyl acetate (20 ml) and dry the product at 50°C - 55°C to get pure vildagliptin. Yield - 9.7 gm.
Example 4: Purification of Vildagliptin:
In a round bottom flask, crude vildagliptin (15gm) and isopropyl alcohol (120 ml) heated to reflux and maintained for about 1 hour and hot mass filtered. Reaction mass gradually cooled to 0 °C to 5°C and stirred for about an hour. The solid crystalline product filtered. & washed with cold isopropyl alcohol. Solid product dried at 50°C -55°C to get pure crystalline vildagliptin (Yield - 12.06 gm, HPLC purity - .9.9.84%).
Example 5: Preparation of vildagliptin-saccharin adduct:
In a round bottom flask, vildagliptin (5 gm) and saccharin (3.02 gm) were stirred in methanol (10 ml) at 25°C to 30°C to get clear solution. Added isopropyl alcohol (20 ml) to the above solution and concentrated at about 40°C under vacuum. Degassed the solid

mass and dried under vacuum at 40°C to isolate the product vildagliptin-saccharin
adduct (Yield - 7.95 gm).
IR(cm-1): 3428.7,2924.7, 1660.0, 1579.5, 1457.0, 1340.0, 1259.6, 1146.0, 947.4.
!H NMR (400MHz, CDC13): 0.93-0.95 δ (d, 3H); 1.16-1.23 5 (m, 2H); 1.40 (m, 4H);
1.63-1.72 5 (m, 4H); 1.84-1.90 δ (m, 5H); 2.01 δ (bs, 3H); 3.33 δ (s, 2H); 3.68-3.80 δ
(m, 1H); 3.97-4.01 δ (d, 1H); 4.46-4.48 δ (m, 1H); 7.33-7.35 δ (s, 2H); 7.48-7.55 δ (d,
2H).
13C NMR (400 MHz, CDC13): 8 19.7, 19.9, 24.2, 24.9, 28.8, 31.8, 32.0, 36.5, 37.7, 40.7,
40.8, 41.7, 54.6, 58.9, 63.5, 113.3, 114.7, 118.3, 126.8, 127.2, 128.3, 138.68, 160.5,
165.6.
Example 6: Preparation of vildagliptin-saccharin adduct:
In a round bottom flask, vildagliptin (5 gm) and saccharin (3.02 gm) were stirred in dichloromethane (15 ml) at 25°C to 30°C to get clear solution. Concentrated the above solution below 40°C under vacuum. Degassed the solid mass and dried under vacuum at 40°C to isolate the product vildagliptin-saccharin adduct (Yield - 7.96 gm).

Claims:
1. A process for purification of vildagliptin, comprising the formation of vildagliptin-saccharin adduct.
2. A process for purification of vildagliptin, which comprises the steps of:

(a) suspending crude vildagliptin in water;
(b) reacting with saccharin to form vildagliptin adduct and get clear solution;
(c) extract the clear aqueous solution with first solvent;
(d) adjust the aqueous layer pH to alkaline;
(e) extract the aqueous layer with second solvent;
(f) distilling out solvent completely and isolate pure vildagliptin compound of Formula I using suitable solvent; and
(g) optionally, recrystallising the compound of Formula I from isopropyl alcohol.

3. The process according to claim 2, wherein in step (c), the clear aqueous solution is extracted with first solvent selected from the group consisting of ethyl acetate, toluene, methyl ethyl ketone, methyl isobutyl ketone and dichloromethane.
4. The process according to claim 3, wherein the first solvent used for the extraction of the aqueous layer in step (c) is dichloromethane.
5. The process according to claim 2, wherein the pH adjustment in step (d), is carried out using suitable base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia.
6. The process according to claim 2, wherein the second solvent used for extraction in step (e), is selected from the group consisting of ethyl acetate, toluene, methyl ethyl ketone, methyl isobutyl ketone and dichloromethane.
7. The process according to claim 6, wherein the second solvent used for the
extraction in step (e) is dichloromethane.
8. The process according to claim 2, wherein the suitable solvent used in step (f)
for isolation of pure vildagliptin compound of Formula I is selected from the
group consisting of ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate,

acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl alcohol and isopropyl alcohol or mixture thereof. 9. The compound, vildagliptin-saccharin adduct of Formula III.