WO2013179300A2

WO2013179300A2 - A process for the preparation of vildagliptin and its intermediate thereof

Info

Publication number: WO2013179300A2
Application number: PCT/IN2013/000296
Authority: WO
Inventors: Vijayavitthal MATHAD VIJAYAVITTHAL THIPPANNACHAR; Nilesh PATIL NILESH SUDHIR; Pavankumar SOLANKI PAVANKUMAR VRAJLAL; Sharad IPPAR SHARAD SUBHASH; Mahendra BODAKE MAHENDRA BHAGIRATH; Rajesh TALLA RAJESH; Anil MALI ANIL CHATURLAL
Original assignee: Megafine Pharma (P) Ltd.
Priority date: 2012-05-04
Filing date: 2013-05-03
Publication date: 2013-12-05
Also published as: IN2012MU01383A; WO2013179300A3

Abstract

A process for preparation of vildagliptin is discussed wherein 3-amino-1- adamantanol is reacted with 1-chloroacetyl(S)-2-cyanopyrrolidine in solvent and base to obtain vildagliptin. This invention also relates to a process for preparation of 1-chloroacetyl(S)-2-cyanopyrrolidine, a vildagliptin intermediate is provided. Further, the present invention also provides a co- precipitate of amorphous form of vildagliptin along with pharmaceutically acceptable excipients.

Description

TITLE OF THE INVENTION:

A PROCESS FOR THE PREPARATION OF VILDAGLIPTIN AND ITS INTERMEDIATE THEREOF

This application claims priority from Indian patent application no.

1383/MUM/2012 filed on 4^th May, 2012.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of (2S)-1-{[(3- hydroxytricyclo [3.3.1.1 (3,7)dec-1-yl)amino]-2-pyrrolidine carbonitrile, vildagliptin of formula (I) and its intermediates.

The present invention also relates to a process for purification of vildagliptin; wherein the said process substantially eliminates the impurities.

The present invention also relates to novel co-precipitate of amorphous form of vildagliptin of formula (I) with a pharmaceutically acceptable carrier and the process for the preparation thereof.

BACKGROUND OF THE INVENTION

Vildagliptin, chemically known as (2S)-1-{[(3-hydroxytricyclo [3.3.1.1(3,7)dec- 1-yl)amino]-2-pyrrolidine carbonitrile is a dipeptidyl peptidase-IV (DPP-IV) inhibitor, used effectively for treatment of non-insulin-dependent diabetes mellitus. Vildagliptin has CAS number of 274901-16-5 and the following structure:

Vildagliptin is disclosed in US 6166063 (henceforth USO63), the disclosure of which is incorporated herein as reference. The Ό63 patent discloses the synthesis of vildagliptin using the synthetic process as represented in scheme-l.

Formula (III)

1. Chloroacetylchloride/ ₂C0₃/ THF 1. H₂S0₄ / HN0₃

2. TFAA 2. OH

Scheme-I

USO63 discloses the process for preparation of vildagliptin of formula (I) wherein, 1-aminoadamantane-3-ol of formula (IV) is reacted with 1- chloroacetyl-(S)-2-cyanopyrrolidine of formula (V) in tetrahydrofuran or dichloromethane in the presence of potassium carbonate to yield vildagliptin of formula (I). The compound of formula (I) is further purified by column chromatography.

Further, we have analyzed the reported synthetic route in US'063 for synthesis of vildagliptin and its intermediates; following limitations have been observed and identified in the reported synthetic route:

1. the synthetic route involves use of column chromatography for purification, which is not feasible and economical at commercial scale;

2. process disclosed in US Ό63 is lengthy and time consuming, wherein the reaction between 1-aminoadamantane-3-ol and l-chloroacetyl-(S)- 2-cyanopyrrolidine using dichloromethane as a solvent consumes six days, hence makes the process commercially not viable.

3. US'063 involve the use of 2 equivalents of 1-aminoadamantane-3-ol for the preparation of vildagliptin which decreases atomic efficiency of the process. However, laboratory data indicates when two equivalents of 1-aminoadamantane-3-ol was used; the formation of (2S,2S 1 ,1'[[3-hydroxytricyclo[3.3.1.1.³'⁷]dec-1-yl)imino]bis(1-oxo-2,1 ,- ethanediyl]bis(2-pyrrolidinecarbonitrile) impurity (Dimer impurity) of formula (VI) is significantly reduced but at the same time it is also observed that removal of un-reacted 1-aminoadamantane-3-ol from vildagliptin is very difficult.

4. 1-chloroacetyl-(S)-2-cyanopyrrolidine intermediate of formula (V) prepared as per US Ό63 process results in low yield, and hence, is not economically feasible at commercial scale.

US Ό63 also disclose the process for the preparation of 1-chloroacetyl-(S)-2- cyanopyrrolidine of formula (V). We have analyzed the reported process, which exhibits various draw-backs: 1. process is not consistent in terms of yield;

2. Further, the yield of vildagliptin as per US'063 patent was observed to be low i.e. about 40% and hence process is not commercially viable.

It is known that the synthetic compounds can contain impurities resulting from their synthesis or degradation. These impurities can be un-reacted starting materials, by-products of the reaction, products of side reaction, or degradation products. Impurities in active pharmaceutical ingredient (API) are undesirable and might be harmful.

Hence, the regulatory authorities worldwide require the drug manufacturer to isolate, identify and characterize the impurities in their product. Furthermore, the manufacturers are required to control the levels of these impurities in the final drug compound obtained by manufacturing process and ensure that the impurity is present in the lowest possible levels, even if structural determination is not possible.

Few of the patents that disclose the purification of vildagliptin are discussed herewith:

US 7375238 disclose the novel process for the preparation of pure vildagliptin using mixtures of solvents. This patent also exemplifies the purification of vildagliptin using methyl ethyl ketone as solvent.

PCT application WO2010/022690 discloses the preparation of vildagliptin and purification of the same using various solvents such as acetone, methyl ethyl ketone, cyclohexanone, or mixture of these; toluene, 2-methyl tetrahydrofuran or mixture of these; dimethylcarbonate, ethyl acetate and isopropyl acetate or mixture of these; methanol ethanol, isopropyl alcohol, butanol, and amyl alcohols or mixtures thereof.

PCT application WO2011/101861 A1 reports the novel routes for preparation of vildagliptin, and also discloses the purification of vildagliptin using mixture of ethyl acetate and methanol.

It is desirable to develop a purification process to control the below mentioned process related impurities within the desired limits as per ICH guidelines:

a. 1-aminoadamantane-3-ol of formula (IV),

b. (2S,2S')-1 ,1'[[3-hydroxytricyclo[3.3.1.1.³-⁷]dec-1-yl)imino]bis(1-oxo- 2, 1 ,-ethanediyl]bis(2-pyrrolidinecarbonitrile) impurity (Dimer impurity) of formula (VI),

c. Adamantine- , 3-diol impurity (Di-hydroxyl impurity) of formula

(VII)

deshydroxy impurity of formula (VIII), and

Formula (VIII) Formula (IX) International publication number WO 2006/078593 discloses the crystalline form as well as amorphous form of vildagliptin. The patent application discloses amorphous form of vildagliptin and discloses that the amorphous form of vildagliptin was obtained by lypholization from water solution. The patent application does not discuss the amorphous co-precipitates of vildagliptin. Further, the use of lypholization technique for the preparation of the amorphous vildagliptin is not commercially viable.

Although pure amorphous form of vildagliptin was obtained in this publication, it does not provide means to stabilize the pure amorphous vildagliptin. Pure amorphous vildagliptin is particularly not stable due to its inherent characteristic nature to exist in a mixture of amorphous and crystalline forms. Therefore pure amorphous vildagliptin itself is not suitable for direct use in preparation of pharmaceutical dosage form due to its polymorph instability and fluffy nature with low density. This can be overcome by co-precipitating the amorphous vildagliptin or its acid addition salts with a pharmaceutically acceptable carrier. Hence, there is a need for process that overcomes the limitations stated above.

The present invention provides an improved process for the preparation and purification of vildagliptin; wherein the said process substantially eliminates the impurities formed during the preparation and thereby overcomes the above said limitations.

The present invention also provides amorphous co-precipitate of vildagliptin or its acid addition salt with a pharmaceutically acceptable excipient and the process for the preparation thereof. OBJECT OF THE INVENTION

The primary object of the present invention is to provide an improved process for the preparation of highly pure vildagliptin.

Another object of the present invention is to provide an improved process for the preparation of 1-chloroacetyl-(S)-2-cyanopyrrolidine.

Yet another object of the present invention is to provide a process for purification of vildagliptin, wherein the said process substantially eliminates the impurities of formula (IV), formula (VI) and formula (VII), formula (VIII) and formula (IX) formed during the process.

Yet another object of the present invention is to provide a process for preparation of vildagliptin of formula (I) wherein the overall yield is improved thereby making the process efficient, high throughput and cost-effective.

Yet another object of the present invention is to provide co-precipitate of amorphous vildagliptin or its acid addition salt with a pharmaceutically acceptable excipient and the process for preparation thereof.

BRIEF DESCRITPION OF DRAWINGS

Figure 1 of the present invention illustrates X-ray powder diffraction (XRD) pattern of co-precipitates of amorphous form of vildagliptin of the formula (I) with povidone as a pharmaceutically acceptable excipient, prepared as per example 16.

Figure 2 of the present invention illustrates an infrared absorption spectrum of co-precipitates of amorphous form of vildagliptin of the formula (I) with povidone as a pharmaceutically acceptable excipient, prepared as per example 16.

Figure 3 of the present invention illustrates X-ray powder diffraction (XRD) pattern of co-precipitates of amorphous form of vildagliptin hydrochloride with povidone as a pharmaceutically acceptable excipient, prepared as per example 18. . ^*

Figure 4 of the present invention illustrates an infrared absorption spectrum of co-precipitates of amorphous form of vildagliptin hydrochloride with povidone as a pharmaceutically acceptable excipient, prepared as per example 18.

DETAIL DESCRIPTION OF THE INVENTION

Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.

Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.

The term "highly pure vildagliptin or a pharmaceutically acceptable acid addition salt thereof as used herein refers to the vildagliptin or a pharmaceutically acceptable acid addition salt thereof having total purity of greater than about 99%, specifically greater than 99.5%, more specifically greater than about 99.8% and most specifically about 99.99% (measured by HPLC)

A term means the herein "reflux temperature" at which the solvent or the solvent system refluxes or boils at atmospheric pressure.

The term "coprecipitates" or "co-precipitates" as used herein refers to compositions comprising amorphous vildagliptin together with at least one pharmaceutically acceptable excipient, being prepared by removing the solvent from the solution containing both of them. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use

The term "excipient" means a component of a pharmaceutical product that is not the active ingredient, such as filler, diluents, carrier, and so on. The excipient those are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.

In one of the embodiments, the present invention provides a process for preparation of vildagliptin of formula (I);

wherein, the said process comprises:

a. reacting, 3-amino-1-adamantanol of formula (IV) with 1- chloroacetyl(S)-2-cyanopyrrolidine of formula (V) in a solvent and a base to obtain crude vilda li tin and

Formula (IV)

Formula (V) Formula (I)

b. isolating pure vildagliptin of formula (I). According to another embodiment of the present invention, crude vildagliptin of step (a) of the process can be optionally isolated and purified.

In a preferred embodiment of the present invention, the solvent used in step (a) is selected from the group comprising of aromatic hydrocarbons such as but not limited to toluene and xylene; aliphatic hydrocarbons such as but not limited to heptanes and hexane; ethers such as but not limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether; cyclic ethers such as but not limited to tetrahydrofuran, and 1 ,4-dioxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran and the like; nitriles such as but not limited to acetonitrile, and propionitrile; dialkylformamides, dialkylacetamides; dialkylsulfoxides; halogenated hydrocarbons such as dichloromethane, and dichloroethane; ketones such as acetone or mixtures thereof.

The base used in step (a) is either organic or inorganic base. The inorganic base used in step (a) is selected from the group comprising of alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, and lithium hydroxide.

The organic base used in step (a) is selected from the group comprising of alkyl amines such as but not limited to di-isopropyl ethyl amine, di-isopropyl amine, and triethyl amine; pyridine; or lutidines. In a preferred embodiment of the present invention, step (a) of the reaction is carried out at 10°C to 60°C; preferably at 25°C to 60°C,the reaction mass is cooled and filtered the solid, and the filtrate is concentrated to obtain crude vildagliptin. The obtained crude vildagliptin may be isolated in solid form by treating the crude with methyl ethyl ketone, heating till reflux temperature of the solvent followed by cooling at 0 to 5°C.

Alternatively, the obtained reaction mass of step (a) is concentrated to obtain crude vildagliptin.

In another embodiment of the present invention, the process for isolation of of pure Vildagliptin; wherein the said process comprises the steps of:

i. treating the crude vildagliptin with acid and water;

ii. washing the contents of step (i) with organic solvent;

iii. basifying the aqueous layer of step (ii) ;

iv. extracting vildagliptin from step (iii) using organic solvent;

v. separating the organic layer, repeating steps (i) to (iv) and concentrating the organic layer to obtain pure vildagliptin; or concentrating the organic layer , repeating steps (i) to (iv), and concentrating the organic layer to obtain pure vildagliptin, vi. treating the vildagliptin obtained from step (v) with organic solvent, heating to provide clear solution, partially distilling the solvent, cooling, filtering and drying to obtain pure vildagliptin.

The pH of the solution of step (i) is in the range of 1 to 7, preferably in the range of about 4 to 7 using organic or inorganic acid. The organic acid used in step (i) and (v) may be either same or different and the acid is selected from the group comprising of acetic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, malic acid, glutamic acid, lactic acid, citric acid, salicylic acid, methane sulfonic acid, benzene sulfonic acid, p- toluene sulfonic acid, malonic acid, mandelic acid, succinic acid or mixtures thereof; preferably the said organic acid used is acetic acid or tartaric acid.

The inorganic acid used in step (i) is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, preferably the acid used is hydrochloric acid.

The organic solvent used in step (ii) and (iv) may be either same of different and the organic solvent is selected from the group comprising of aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptanes and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; carboxylic acid esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ethers such as di-ethyl ether, di-isopropyl ether, di-methyl ether, methyl tertiary butyl ether, substituted cyclic ether such as 2-methyl tetrahydrofuran and the like; or mixtures thereof. Preferably the solvent used is dichloromethane.

The pH of the solution of step (iii) is in the range of 7 to 14, preferably in the range of about 8 to 10 using base; wherein the said base may be organic or inorganic base. Preferably, the base used is aqueous ammonia.

The obtained crude vildagliptin contains less than about 0.2% (2S,2S ')- 1 , 1 '[[3-hydroxytricyclo[3.3.1. .3,7]dec-1 -yl)imino]bis(1 -oxo-2, 1 ,- ethanediyl]bis(2-pyrrolidinecarbonitrile) impurity (Dimer impurity) of formula (VI); 1-aminoadamantane-3-ol impurity of formula (IV) and adamantane-1 ,3- diol impurity (Di-hydroxyl impurity) of formula (VII), deshydroxy impurity of formul

Formula (VI)

Formula (VIII) Formula (IX)

Organic solvent used in step (vi) is selected from the group comprising of aliphatic hydrocarbons such as hexane, heptanes and the like; aromatic hydrocarbons such as toluene, xylene and the like; ketones such as acetone, methyl ethyl ketone methyl isobutyl ketone and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; ethers such as di-methyl ether, di-ethyl ether, di-isopropyl ether, methyl tertiary butyl ether and the like; cyclic ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1 ,4-dioxane and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like or mixtures thereof. Preferably the solvent used is methyl ethyl ketone, methanol or mixture thereof.

The solution obtained in step (vi) may be in suspension or slurry form or in solution form after addition of the said organic solvent. The solution obtained in step (vi) may be partially distilled out under reduced pressure or at atmospheric pressure.

The solution obtained in step (vi) can be stirred at appropriate temperature over suitable period to recover highly pure vildagliptin by filtration.

In yet another aspect of the step (vi), the obtained highly pure vildagliptin may be further subjected to drying. The drying may be done at atmospheric pressure or reduced pressures, such as below 200 mm/Hg, or below 50 mm/Hg, and at temperature in the range of about 35°C to 80°C.

According to another embodiment of the present invention, the process for purification of vildagliptin of formula (I) having less than about 0.2% of dimer compound of formula (VI), the said process comprises the steps of:

1. suspending the crude vildagliptin of formula (I) in suitable solvent;

2. stirring the suspension obtained from step (1) and filtering to obtain vildagliptin as solid; and

3. drying the obtained solid of step (2) to yield pure vildagliptin having less than about 0.2% dimer compound of formula (VI).

The suspension obtained in step (1) is prepared using solvent.crude vildagliptin in the ratio of about 1 : 1 to about 1 :15

In a preferred embodiment, the suspension obtained in step (2), is heated at a temperature of about 25°C to the reflux temperature of the solvent over a period of 30 min to 2 hour. The suspension or clear solution obtained in step (2) containing vildagliptin and solvent may be optionally cooled to obtain slurry before filtration at temperature between 0°C-75°C, particularly between 0°C to 40°C.

The slurry obtained may be optionally maintained for a period 30 min to 12 hours, preferably for 2 to 4 hours, at temperature about 0°C to 40°C prior to filtration.

The solid obtained after filtration in step (2) may be optionally washed with organic solvent before subjecting the same to drying.

Organic solvent used in step (1) for suspension may be either same or different and is selected from the group comprising of aliphatic hydrocarbons such as hexane, heptanes and the like; aromatic hydrocarbons such as toluene, xylene and the like; ketones such as acetone, methyl ethyl ketone methyl isobutyl ketone and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; ethers such as di-methyl ether, di-ethyl ether, di- isopropyl ether, methyl tertiary butyl ether and the like; cyclic ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1 ,4-dioxane and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like or mixtures thereof.

In another embodiment, the solid is filtered and may be subjected to drying to get pure vildagliptin of formula (I). Drying may be carried out using conventional methods such as Air tray drier (ATD), Vacuum Tray Drier (VTD), Fluidized bed drier (FBD), Spin Flash Drier (SFD), Flash Drier (FD), and the like. Further, the overall yield of vildagliptin of formula (I) obtained using the process of the present invention is at least about 65% with purity of at least about 99% (by HPLC).

More particularly, the total purity of vildagliptin of formula (I) obtained is at least about 99.80% (by HPLC).

According to another embodiment of the present invention, the present invention provides pure vildagliptin of formula (I) containing less than about 0.2% of impurities namely:

1. (2S,2S')-1 , 1'[[3-hydroxytricyclo[3.3.1.1.3,7]dec-1 -yl)imino]bis(1 -oxo- 2,1 ,-ethanediyl]bis(2-pyrrolidinecarbonitrile) impurity (Dimer impurity) of formula (VI);

2. 1-aminoadamantane-3-ol impurity of formula (IV);

3. Adamantane-1 ,3-diol impurity (Di-hydroxyl impurity) of formula (VII);

4. deshydroxy impurity of formula (VIII); and

Formula (VIII) Formula (IX)

According to another embodiment of the present invention, the present invention provides a one-pot process for the preparation of 1-chloroacetyl- (S)-2-cyanopyrrolidine, a vildagliptin intermediate; wherein the said process comprises the steps of:

I. reacting, L-prolinamide of formula (II) with chloroacetyl chloride in a solvent optionally in presence of a first base ;

II. reacting the reaction mass of step (I) with a dehydrating agent optionally in presence of a second base; and

III. isolating pure 1-chloroacetyl-(S)-2-cyanopyrrolidine.

In a preferred embodiment of the present invention, step (I) of the reaction is carried out at 10° C to 60° C; preferably at 25°C to 60°C, over a period of 2- 12 hours, preferably for about 3-4 hrs.

In a preferred embodiment of the present invention, the solvent used in step (I) is selected from the group comprising of aromatic hydrocarbons such as but mot limited to toluene and xylene; aliphatic hydrocarbons such as but not limited to heptanes, and hexane; ethers such as but not limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether; cyclic ethers such as but not limited to tetrahydrofuran; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran and the like; halogenated hydrocarbons such as dichloromethane, and dichloroethane; or mixtures thereof; preferably tetrahydrofuran and/or dichloromethane

The first base and second base used in step (I) and (II) respectively is either organic or inorganic base; wherein the first base and second base used in step (I) and (II) can be either same or different.

The inorganic base used in step (I) and (II) is selected from the group comprising of alkali metal carbonates such as but not limited to potassium

18 carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, and lithium hydroxide.

The organic base used in step (I) and (II) is selected from the group comprising of alkyl amines such as but not limited to di-isopropyl ethyl amine, di-isopropyl amine, and triethyl amine; heterocyclic amines such as but not limited to imidazole pyridine; and lutidines.

Dehydrating agent used in step (II) includes but does not limit to trifluoroacetic anhydride, phosphorous oxychloride, thionyl chloride, or phosphorous pentoxide.

In a preferred embodiment of the present invention, step (II) of the reaction is carried out at 10° C to 60° C; preferably at 25°C to 60°C over a period of 2- 20 hours, preferably for about 14-15 hrs. Optionally, acetic acid may be added to obtain the homogenous the reaction mass.

Isolation of 1-chloroacetyl-(S)-2-cyanopyrrolidine can be carried out by the process known in skilled art which involves steps such as quenching of reaction mass, washings of aqueous acid, followed by washings of aqueous basic solutions, followed by water washings, distillation, filtration etc.

A process for isolation of 1-chloroacetyl-(S)-2-cyanopyrrolidine; wherein the said process comprises the steps of:

A. quenching the reaction mass of step (III) containing 1-chloroacetyl-(S)-2- cyanopyrrolidine with water and ammonium carbonate; B. separating the organic layer, washing with aqueous acid solution, aqueous basic solution and with water

C. distillating organic layer of step (B) to obtain 1-chloroacetyl-(S)-2- cyanopyrrolidine; and

D. purifying the product of step (C) by crystallization using organic solvent to provide1-chloroacetyl-(S)-2-cyanopyrrolidine.

In a preferred embodiment of the present invention, the solvent used in step (D) may be an organic solvent or inorganic solvent or mixture thereof.

The solvent comprises of aromatic hydrocarbons such as but not limited to toluene and xylene; aliphatic hydrocarbons such as but not limited to heptanes and hexane; ethers such as but not limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether; cyclic ethers such as but not limited to tetrahydrofuran, and 1 ,4-dioxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran and the like; nitriles such as but not limited to acetonitrile, and; halogenated hydrocarbons such as dichloromethane, and dichloroethane; ketones such as acetone or; esters; alcohols such as but not limited to methanol, ethanol, isopropanol, butanol and the like or mixtures thereof.

According to another embodiment of the invention, there is provided a co- precipitate of amorphous form of vildagliptin of the formula (I) or its acid addition salt with a pharmaceutically acceptable excipient; characterized by their X-ray diffraction (XRD) pattern and infrared absorption (IR) spectrum.

The XPRD pattern of co-precipitate of amorphous form of vildagliptin of the formula (I) with a pharmaceutically acceptable excipient having characteristic peaks at 5.96, 6.79, 9.09, 9.26, 10.52, 16.64, 17.60, 18.14, 18.53, 22.49, 24.29, 24.91 , and 27.5 ± 0.2 degrees 2Θ. The X-ray diffractogram was measured on Bruker Axe, DS advance Power X-ray Diffractometer with Cu K alpha-1 Radiation source having the wavelength 1.541A° as depicted in figure 1

The IR spectrum of co-precipitate of amorphous form of vildagliptin of the formula (I) with a pharmaceutically acceptable excipient having characteristic major peaks at 1100 cm^"1, 1300 cm^"1, 1400 cm^"1, 1700 cm^"1, 2200 cm^'1, 2900 cm^"1, 3400 cm^"1, etc as depicted in figure 2. The IR spectrum of amorphous from of vildagliptin hydrochloride with pharmaceutically acceptable excipient having major peaks at 1019.98 cm^"1, 1288.99 cm^"1, 1422.70 cm^"1, 1459.56 cm^" ¹, 1664.16 cm^"1, 2242.90 cm^"1, 2858.17 cm^"1, 2925.24 cm^"1, 3419.94 cm^"1. The IR spectra of co-precipitates of the invention has been recorded on a Fourier Transform Infrared Spectroscopy, Perkin Elmer model 100 instrument using potassium bromide pellet method.

The weight ratio of amorphous form of vildagliptin of the formula (I) to the pharmaceutically acceptable excipient is in the range from 10% to 100%; preferably, the weight ratio is in the range from 25% to 50%.

The pharmaceutically acceptable excipients which is used in the co- precipitate of invention includes but does not limit to, pharmaceutical hydrophilic carriers such as polyvinylpyrrolidone (homopolymers, also called "povidone", or copolymers of N-vinylpyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose and others), cyclodextrins, gelatins, hypromellose phthalate, sugars, polyhydric alcohols, etc. The use of mixture of more than one of the pharmaceutical carriers to provide desired release profiles or for the enhancement of stability is within the scope of the invention. Also, all viscosity grades, molecular weight, commercially available products, their copolymers, mixtures are all within the scope of this invention without limitation. Preferably, the said excipient used in the co-precipitation of vildagliptin is povidone.

The co-precipitate according to the invention comprises either amorphous form of vildagliptin of formula (I) or its acid addition salts like hydrochloride, fumarate, tartarate, succinate, methane sulfonate, toluene sulfonate, benzene sulfonate, maleate, malate, lactate, citrate, malonate, mandelate, and the like.

According to another embodiment of the invention, there is provided a process for the preparation of co-precipitate of amorphous form of vildagliptin or its acid addition salts with pharmaceutically acceptable excipients, wherein the said process comprising the steps of:

a) preparing solution of vildagliptin or its acid addition salt and pharmaceutically acceptable excipients in solvent; and

b) removing the solvent from solution obtained in step (a)to provide amorphous co-precipitate of vildagliptin or its acid addition salts with the pharmaceutically acceptable excipient.

Optionally, the solution prepared in step (a) is filtered to remove insoluble matter; wherein the removal of the said insoluble matter can be done by subjecting the solution of step (a) to filtration, centrifugation, decantation, and other techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or particulate filtration medium such as celite or calcined diatomaceous earth (Hyflo). Depending upon the equipment used and the solution properties, such as concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid crystallization.

In a preferred embodiment, the solution of vildagliptin or its acid addition salt and pharmaceutically acceptable excipients prepared in step (a) can be done by any of the following methods:

1. dissolving vildagliptin or its acid addition salt in at least one solvent followed by addition and dissolution of a pharmaceutically acceptable excipient in the said solution; or

2. dissolving pharmaceutically acceptable excipient in at least one solvent followed by addition and dissolution of vildagliptin or its acid addition salt in the said solution; or

3. alternatively, by the following steps:

i. dissolving vildagliptin or its acid addition salt in a first solvent to form a solution (A);

ii. dissolving a pharmaceutically acceptable excipient in second solvent to form a solution (B);

iii. combining solution (A) and the solution (B) to obtain solution as desired for step a).

The solvents used for preparing the solution (A) and the solution (B) need not be the same as long as the solvents have mutual solubility and form a single phase.

In any event, vildagliptin or its acid addition salt should be completely soluble in the solvents used and should provide a clear solution. The presence of un- dissolved crystals could lead to the formation of a material that is not completely amorphous.

The solution of step (a) may be obtained directly from a reaction in which vildagliptin or its acid addition salts is formed.

Vildagliptin or its acid addition salts used to prepare the solution of step (a) is in any form of vildagliptin or its acid addition salts such as crystalline form, solvates and hydrates thereof.

The solvent used for the preparation of solution of .step (a) includes; but does not limit to alcohols such as methanol, ethanol, isopropanol, and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, diisopropyl ether and the like; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n-hexane and the like; nitriles such as acetonitriles, propionitrile and the like; or mixtures thereof.

The dissolution temperature to prepare the solution of step (a) is in the range from about 20°C to 120°C or reflux temperature of the solvent/mixture of solvents used for dissolution. The temperature used for dissolution can be of any temperature as long as the solution obtained is a clear solution.

The quantity of solvent used for dissolution depends on the kind of solvent and the dissolution temperature adopted to prepare the solution of step (a). The concentration of vildagliptin or its acid addition salt in the solution may range from about 0.1 g/ml to about 10 g/ml in the solvent, and the volume of the solvent may be kept to a minimum so as to facilitate the effective solvent removal.

The removal of solvent in step (b) can be accomplished by filtration, distillation, evaporation, atmospheric distillation, concentration, distillation under vacuum such as rotary evaporator, lyophilization, freeze drying, spray drying, agitated thin film drying (ATFD), or the like.

The removal of the solvent from the solution of vildagliptin or its acid addition salts and a pharmaceutical excipient may be affected at increased temperature, preferably at reflux temperature, and/or reduced pressure.

The drying of the residue in step (c) is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm/Hg, or below about 50 mm/Hg, at temperatures such as about 35°C to about 70°C. The drying may be carried for any time such as about 1 to 15 hours depending on the product specifications. Temperatures and pressures will be chosen based on volatility of the solvent used in the preparation of solution.

The co-precipitate of the invention makes the amorphous form of vildagliptin or its acid addition salt stable and thus they can be handled easily. A process for the preparation of co-precipitate of amorphous form of vildagliptin or its acid addition salts with pharmaceutically acceptable excipients is simple and easy to carry out. Further, according to another embodiment of the present invention, amorphous vildagliptin (without excipients) may be obtained using the above described process.

The present invention is described with reference to the following examples illustrating the process for preparation and purification of vildagliptin; process for preparation and purification of 1-chloroacetyl-(S)-2-cyanopyrrolidine, and improved and novel process for the preparation of the coprecipitates of amorphous vildagliptin or its acid addition salts. However, these examples are provided for illustrative purposes only and or not to be construed as limitations on scope of the process of this invention.

Example-1 : Preparation of 1-aminoadamantane-3-ol

To a rapidly stirred, ice water chilled mixture of concentrated sulfuric acid (300 ml) and concentrated nitric acid (100 ml) was added 1-adamantyl amine hydrochloride (100g) in small portions over a period of 2 hours. During the addition of 1- adamantyl amine hydrochloride, slight exotherm was observed. The resulted yellow solution was stirred at 0°C to 5°C for 1 hour. The temperature of the reaction mass was raised to 25°C to 30°C and further heated to 55°C to 60°C for 10 to 12 hour. Upon completion of the reaction, reaction mass was cooled to 25°C to 30°C. The reaction mass was then quenched drop wise to ice-water mixture (1.6 L) with maintaining the temperature OX to 5°C. To this solution, 50% aqueous KOH or NaOH solution was added to adjust pH about 13 to 14 (temperature controlled up to 50°C). The aqueous reaction mass was extracted thrice by mixture of n- butanol and toluene at 25°C to 30°C (800 ml butanol and 200 ml toluene). Organic layer was concentrated under vacuum to get residue, n- heptane (400 ml) and methanol (40 ml) was added to residue at temperature 60°C to 65°C, the resulting slurry was stirred at 60°C to 65°C for 30 minutes and cooled to 10°C to 15°C for 30 minutes to obtain solid, which was further filtered, washed with n-heptane (100 ml) and dried in air oven at 60°C to 65°C for 10 to 12 hours. [Yield: 70 to 75 g; Moisture content: 4.5 to 5.5%]

Example-2: Preparation of 1-chloroacetyl (S)-2-carboxamidepyrrolidine

To a mechanically stirred solution of L-prolinamide (20 g), potassium carbonate (48.4 g) and chloroform (370 ml), the solution of chloroacetyl chloride (15.3 ml) in chloroform (30 ml) was added slowly over a period of 1 hour at temperature 25 to 30°C (exotherm observed till 40°C). Reaction mass was stirred for additional 2 hours at 25°C to 30°C. Upon completion of reaction, the reaction mass was filtered and the obtained solid was washed with chloroform (200 ml <2). Filtrate was dried over anhydrous sodium sulfate and filtrate was concentrated under reduced pressure to get residue. Ethyl acetate (100 ml) was added to the residue at temperature 25°C to 30°C and the slurry was stirred for 30 minutes. Obtained solid was filtered and washed with ethyl acetate (20 ml) and dried under vacuum at 35°C to 40°C for 5 to 6 hours. [Yield: 24 to 26 g]

Example-3: Preparation of 1-chloroacetyl (S)-2-cyanopyrrolidine

To a stirred solution of 1-chloroacetyl (S)-2-carboxamidepyrrolidine (5 g) and tetrahydrofuran (50 ml), trifluoro acetic anhydride (7.3 ml) was charged at 0 to 5° C. Reaction mass was stirred at 25°C to 30°C until reaction completion. Upon completion of the reaction, ammonium bicarbonate (15.8 gm) was added lot-wise at temperature 5°C to 10°C, the resulting reaction mixture was stirred for 1 hour at 25 to 30°C. Reaction mass was then concentrated under vacuum to obtain oily residue, followed by addition of water (20 ml), washing with n-heptane (10 ml x 2). Aqueous layer was separated and extracted with toluene (60 ml X 3). Toluene layer was concentrated under reduced pressure to get 1-chloroacetyl (S)-2-cyanopyrrolidine as a product.

[Yield: 2.3 to 2.5 g]

Example-4: Preparation of 1-chloroacetyl (S)-2-cyanopyrrolidine

To a mechanically stirred solution of L-prolinamide (5g) and dichloromethane (50 ml), solution of chloroacetyl chloride (3.76 ml) in dichloromethane (10 ml) was added drop-wise over a period of 20-25 min at temperature 25 to 30°C(exotherm observed till 40°C). Reaction mass was then stirred for additional 3 h at 25 to 30°C followed by addition of 2, 6 lutidine (10.2 ml) to the reaction mass and stirred for 15 minutes. Trifluoroacetic anhydride was added slowly to the reaction mass and stirred for 3-4 hr. Upon completion of reaction, the reaction mass was cooled to 0-5°C. Ammonium bicarbonate was added slowly to reaction mass and stirred for 30 minutes. DM water was charged and organic layer was separated. Organic layer was washed with 6% aqueous HCI (3X 20 ml). The organic layer was washed with D.M. water (2X20 ml) and dried over sodium sulfate, concentrated the organic layer under reduced pressure to give yellow syrup which solidifies upon cooling [Yield: 5.3 gm; Purity: 97.15%]

Example-5: Preparation of 1-chloroacetyl (S)-2-cyanopyrrolidine

To a mechanically stirred solution of L-prolinamide (10g), dichloromethane (90 ml) and 2,6 lutidine (40 ml), solution of chloroacetyl chloride (7.5 ml) in dichloromethane (20 ml) was slowly added over a period of 30-45 min at temperature 25 to 30°C (exotherm observed till 40°C). Reaction mass was then stirred for additional 3 h at 25 to 30°C. Upon completion of reaction, trifluoroacetic anhydride was slowly added, the reaction mass was stirred for 3-4 h. Upon completion of reaction, the reaction mass was cooled to 0-5°C. Ammonium bicarbonate added slowly and stirred for 30 minutes. DM water was charged and organic layer was separated. Organic layer was washed with 6% aqueous HCI (5 X 50 ml), followed by washing with D.M. water (2X50 ml), separation of organic layer and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to obtain 1- chloroacetyl (S)-2-cyanopyrrolidine. [Yield: 9.8 gm; Purity: 94.48%]

Example-6: Preparation of 1-chloroacetyl (S)-2-cyanopyrrolidine

To a mechanically stirred solution of L-prolinamide (5g) and dichloromethane (50 ml), a solution of chloroacetyl chloride (3.76 ml) in dichloromethane (10 ml) was added drop-wise over a period of 20-25 minute at temperature 25 to 30°C (exotherm observed till 40°C). Reaction mass then stirred for additional 3 h at 25 to 30°C. Pyridine (10.6 ml) was added to reaction mass and stirred for 15 minutes. Trifluoroacetic anhydride was slowly added to reaction mass and the reaction mass was stirred for 3-4 h. Upon completion of reaction, reaction mass was cooled to 0-5°C. Ammonium bicarbonate was charged slowly and stirred for 30 minutes. DM water was charged, organic layer was separated followed by washing with 6% aqueous HCI (3X 20 ml). Finally the organic layer was washed with D.M. water (2X20 ml), dried over sodium sulfate and concentrated under reduced pressure to obtain 1-chloroacetyl (S)-2-cyanopyrrolidine. [Yield: 5.1gm; Purity: 93.14%]

Example-7: Preparation of 1-chloroacetyl (S)-2-cyanopyrrolidine

To a mechanically stirred solution of L-prolinamide (5g), and dichloromethane (50 ml), solution of chloroacetyl chloride (3.76 ml) in dichloromethane (10 ml) was added drop wise over a period of 20-25 minutes at temperature 25 to 30°C, exotherm observed till 40°C. Reaction mass then stirred for additional 3 h at 25 to 30°C. Pyridine (14.1 ml) was charged and reaction mass was stirred for 15 minutes. Solution of POCI₃ (6.12 ml) in dichloromethane was slowly added to the reaction mass (10 ml) and stirred for 2-3 h. Upon completion of reaction, reaction mass was cooled to 0-5X. DM water was charged slowly, exotherm was observed up to 40°C. Organic layer was washed again with aqueous NaHCO₃ solution (2X30 ml), separated, dried over sodium sulfate and concentrated under vacuum to obtain 1-chloroacetyl (S)-2-cyanopyrrolidine. [Yield: 5.1 gm; Purity: 91.53%]

Exampie-8: Preparation of 1-chloroacetyl (S)-2-cyanopyrroiidine

To a mechanically stirred solution of L-prolinamide (5g), and dichloromethane (40 ml), solution of chloroacetyl chloride (3.76 ml) in dichloromethane (10 ml) was added drop-wise over a period of 20-25 minute at temperature 25 to 30°C, exotherm observed till 40°C. Reaction mass was then stirred for additional 3 h at 25 to 30°C. 2, 6 lutidine (14.1 ml) was added to reaction mass and stirred for 15 minutes. Solution of POCI₃ (6.12 ml) in dichloromethane (10 ml) was added slowly to reaction mass at 5 to 10°C. The reaction mass was stirred for 2-3 h at room temperature. Upon completion of reaction, the reaction mass was cooled to 0-5°C. DM water was slowly added to reaction mass, exotherm observed upto 40°C. Organic layer was washed with NaHCO₃ solution (2X50 ml), followed by washing with aqueous 6% HCI (3 X 30 ml) and DM water (2X30 ml). Organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give 1-chloroacetyl (S)-2-cyanopyrrolidine. [Yield: 5.2 gm; Purity: 97.31%]

Example-9: Preparation of (2S)-1-{[(3-hydroxytricyclo[3.3.1.1(3,7)dec-1- yl)amino]-2-pyrrolidine carbonitrile (Crude vildagliptin) To a heterogeneous solution of 3-amino- 1-adamantanol (3.0 g) and tetrahydrofuran (30 ml), potassium carbonate (6.94 g) and Kl (0.15 g) were charged. Resulting reaction mass was then stirred for 10 minutes at 25°C to 30°C. To this reaction mass, solution of 1-chloroacetyl (S)-2-cyanopyrrolidine (2.9 g) in tetrahydrofuran (10ml) was added over a period of 30 minutes. Reaction mass was then heated to 50°C to 55°C for 3 to 4 hours. Upon completion of reaction, the reaction mass was filtered and washed the solid with tetrahydrofuran (10 ml). Filtrate was concentrated under reduced pressure to obtain crude vildagliptin. Methyl ethyl ketone (15 ml) was charged to crude vildagliptin and the reaction mass was heated to reflux for 30 minutes followed by gradual cooling to 25°C to 30°C. Reaction mass was finally chilled to 0°C to 5°C for 30 minutes. Solid was filtered and washed with methyl ethyl ketone (05 ml) [Yield: 3.21 ; Purity: 98.09% (HPLC); Compound (IV) impurity: 5 88% (GC), Dimer Impurity. 1.50%]

Example- 0: Purification of vildagliptin

Crude vildagliptin (0.5 g) was added to acetonitrile (3.0 ml), and the resulting suspension was heated at 50°C to 55°C for 15 to 20 minutes, cooled at 10°C to 15°C, stirred for 30 minutes at 10°C to 15°C, filtered the solid and washed the solid with acetonitrile (1 ml). [Yield: 0.32 g; Purity (HPLC):99.82%, Dimer Impurity: 0.18%]

Example- 11 : Purification of vildagliptin

Crude vildagliptin (3 g) was added to acetonitrile (18 ml), and the resulting suspension was heated at 50°C to 55°C for 30 minutes, cooled at 25°C to 30°C, filtered small portion [Purity: 99.81% (HPLC purity); Dimer Impurity: 0.11%]. Remaining reaction mixture further cooled at 5°C to 10°C, stirred for 30 minutes and filtered the solid. [Purity: 99.77% (HPLC); Dimer Impurity: 0.12%]

Example- 12: Purification of vildagliptin

Crude vildagliptin (5g) was added to acetonitrile (50ml), and the resulting suspension was heated at 75°C to 82°C (reflux) for 2 hours. Clear solution was then allowed to cool at 25°C to 30°C, stirred for 1 hour at 25°C to 30°C, the solid was filtered and washed the solid with acetonitrile (5ml). [Purity: 99.88% (HPLC); Dimer Impurity: 0.03%]

Example-13: Preparation of (2S)-1-{[(3-hydroxytricyclo[3.3.1.1(3,7)dec-1- yl)amino]-2-pyrrolidine carbonitrile (highly pure vildagliptin)

To a heterogeneous solution 3-amino- -adamantanol (120 g) and tetrahydrofuran (1200 ml), potassium carbonate (99 g) and potassium iodide (5.9 g) were added. The resulting reaction mass was then stirred for 10 minutes at 25°C to 30°C. To this reaction mass, solution of 1-chloroacetyl (S)-2-cyanopyrrolidine (124 g) in tetrahydrofuran (200 ml) was added over a period of 40-45 minutes at 35°C to 40°Cand the reaction mass was stirred at 40°C to 45°C for 1.5 to 2 hours. Reaction mass was filtered and washed the solid with tetrahydrofuran (100 ml). Filtrate was concentrated under reduced pressure to obtain crude vildagliptin. DM water (600 ml) was charged to crude vildagliptin and pH of aqueous solution was adjusted to 5-6 using acetic acid. Aqueous acidic solution was then washed with dichloromethane (4 X 500 ml). Aqueous layer was separated and basified using aqueous ammonia till pH 9-10. Product was extracted from aqueous layer using dichloromethane (4 X 500 ml) and distilled off the organic layer under reduced pressure to obtain crude vildagliptin . Methyl ethyl ketone (200 ml) was added to crude vildagliptin at temperature 25°C to 30°C and distilled under reduced pressure at 40°C to 45°C to obtain crude vildagliptin. Methyl ethyl ketone (200 ml) was charged at 25°C to 30°C, and the mixture was gradually cooled at 0°C to 5°C for 30 minutes. Crude vildagliptin was filtered and washed with methyl ethyl ketone (50 ml). [Wet weight of solid =151g; Purity (HPLC): 99.83%; Dimer impurity: Not detected (ND); Compound (IV) impurity: 0.56% (GC Purity)]

Water (600 ml) was added to crude vildagliptin and pH of solution was adjusted to 5-6 using tartaric acid. Acidic aqueous solution was then washed with dichloromethane (4 X 500 ml). Aqueous layer separated and basified using aqueous ammonia till pH 9-10. Product was extracted from aqueous solution using dichloromethane (4 X 500 ml). Organic solvent was then distilled off under reduced pressure to get crude vildagliptin. Methyl ethyl ketone (2 X 200 ml) was added to crude vildagliptin and distilled under reduced pressure to obtain crude vildagliptin. Methyl ethyl ketone (200 ml) was added at 25°C to 30°C, and the mixture was gradually cooled at 0°C to 5°C for 30 minutes. Solid was filtered and washed with methyl ethyl ketone (50 ml). [Yield = 140 g; Purity: 99.97% (HPLC); Dimer Impurity: ND; Compound (IV) impurity: 0.03% (GC)

Compound (VII) impurity less than 0.05% (GC Purity)

Example-14: Preparation of (2S)-1-{[(3-hydroxytricyclo[3.3.1.1(3,7)dec-1- yl)amino]-2-pyrrolidine carbonitrile

To a heterogeneous solution of 3-amino- 1-adamantanol (70 g) and tetrahydrofuran (560 ml), potassium carbonate (57.8 g) and potassium iodide (3.47 g) were charged. The resulting reaction mass was stirred for 10 minutes at 25°C to 30°C. To this reaction mass, solution of 1 -chloroacetyl (S)-2-cyanopyrrolidine (72.2 g) in tetrahydrofuran (140 ml) was added over a period of 40-45 minutes at 35°C to 40°C and the reaction mass was stirred at 40°C to 45°C for 1.5 to 2 hours. Reaction mass was filtered and washed the solid with tetrahydrofuran (70 ml). Filtrate was concentrated under reduced pressure to obtain crude vildagliptin. DM water (280 ml) was charged to the obtained crude vildagliptin and pH of aqueous solution was adjusted to 5-6 using acetic acid. Aqueous solution was then washed with dichloromethane (4 X 280 ml). Aqueous layer was separated and basified using aqueous ammonia till pH 9-10. Product was extracted from aqueous layer using dichloromethane (3 X 280 ml) and distilled off the organic layer under reduced pressure to obtain crude vildagliptin. [Syrup wt. =115 g; Purity: 99 64% (HPLC); Dimer Impurity: ND]

Water (280 ml) was added to obtained crude vildagliptin and pH of solution was adjusted to 5-6 using tartaric acid. Aqueous acidic solution was then washed with dichloromethane (4 X 280 ml). Aqueous layer was separated and basified using aqueous ammonia till pH 9-10. Product was extracted using dichloromethane (3 X 280. ml) and organic layer was distilled off atmospherically to obtain vildagliptin. Methyl ethyl ketone (385 ml) was charged to vildagliptin and the reaction mass was heated at 78±2°C to get clear solution. Obtained clear solution was gradually cooled at 25°C to 30°C and further cooled at 0°C to 5°C for 30 minutes. Solid was filtered and washed with methyl ethyl ketone (25 ml) [Yield = 70 g; HPLC Purity: 99.99%; Dimer Impurity: ND; compound (IV): Less than 0.05% (GC Purity); Compound (VII): Less than 0.05% (GC Purity)

Example-15: Preparation of (2S)-1-{[(3hydroxytricyclo[3.3.1.1(3,7)dec-1- yl)amino]-2-pyrrolidine carbonitrile

To a heterogeneous solution of 3-amino- 1-adamantanol (70 g) and tetrahydrofuran (560 ml), potassium carbonate (57.8 g) and potassium iodide (3.47 g) were charged. The resulting reaction mass was stirred for 10 minutes at 25°C to 30°C. To this reaction mass, solution of 1 -chloroacetyl (S)-2-cyanopyrrolidine (72.2 g) in tetrahydrofuran (140 ml) was added over a period of 40-45 minutes at 35°C to 40°C and reaction mass was stirred at 40°C to 45°C for 1.5 to 2 hours. Reaction mass was filtered and washed the solid with tetrahydrofuran (70 ml). Filtrate was concentrated under reduced pressure to obtain crude vildagliptin. DM water (280 ml) was charged to crude vildagliptin and pH of aqueous solution was adjusted to 5-6 using acetic acid. Aqueous solution was washed with dichloromethane (4 X 280 ml). Aqueous layer was separated and basified using aqueous ammonia till pH 9-10. Product was extracted from aqueous layer using dichloromethane (3 X 280 ml) and organic layer was distilled off under reduced pressure to obtain crude vildagliptin. [Syrup wt. =100 g]

Water (280 ml) was added to crude vildagliptin and pH of solution was adjusted to 5-6 using tartaric acid. Aqueous acidic solution Was then washed with dichloromethane (4 X 280 ml). Aqueous layer was separated and basified using aqueous ammonia till pH 9-10. Product was extracted using dichloromethane (3 X 280 ml) and distilled off the organic layer atmospherically to obtain vildagliptin. Methanol (140 ml) was added to vildagliptin and stirred to get clear solution, obtained clear solution was distilled off completely under reduced pressure at 35°C to 45°C. Methyl ethyl ketone (175 ml) was charged to the vildagliptin and stirred at 25°C to 30°C. Resulted slurry was cooled at 0°C to 5°C for 30 minutes. Filtered the solid and washed with methyl ethyl ketone (35 ml). The solid was dried at 45°C to 50°C under vacuum. [Yield:70g; Dimer Impurity: ND; Compound (IV): Less than 0.05% (GC Purity); Compound (VII): Less than 0.05% (G C purity)] Example 16: Co-precipitate of vildagliptin with providone in a ratio of 1:1 using dichloromethane as a solvent

Crystalline vildagliptin (5 g) and providone (5 g) (PVP K30) were dissolved in dichloromethane (200 ml) at temperature of 35°C to 40°C. The solution was filtered in hot condition and the dichloromethane was removed under reduced pressure using buchi rotavapor apparatus to obtain co-precipitate of amorphous vildagliptin with povidone (9.5 g)

Example 17: Co-precipitate of vildagliptin with providone in a ratio of 1 :1 using dichloromethane as a solvent

To a heterogeneous solution 1-aminoadamantane-3-ol (12 g) and tetrahydrofuran (100 ml), potassium carbonate (9.9 g) & potassium iodide (0.59 g) were added. The reaction mass was stirred for 10 minutes at 25°C to 30°C. To this reaction mass, solution of 1-chloroacetyl 2-cyanopyrrolidine (12.4 g) in tetrahydrofuran (20 ml) was added over a period of 40-45 minutes at 35°C to 40°C. The reaction mass was stirred for 1.5 to 2 hours at 40°C to 45°C. Upon completion of reaction, the solid was filtered and washed with tetrahydrofuran (10 ml). The washings were combined with the filtrate and concentrated under reduced pressure to obtain syrup. The syrup was dissolved in dichloromethane (120 ml) to obtain clear solution. To this clear solution, solution of providone (12 g) (PVP K30) in dichloromethane (120 ml) was added. The clear solution then concentrated under reduced pressure at 35°C to 40°C using Buchi Rotavapor to get co-precipitate of amorphous vildagliptin (23.4 g)

Example 18: Co-precipitate of vildagliptin hydrochloride with povidone in a ratio of 1 :1 using dichloromethane as a solvent

Vildagliptin hydrochloride (2.5 g) and povidone (2.5 g) were dissolved in dichloromethane (50 ml). The obtained solution was stirred for 5 minutes at 25°C to 30°C and methanol (2.5 ml) was added to get a clear solution. The obtained solution was filtered through hyflo. The filtrate was concentrated under reduced pressure to obtain co-precipitate of amorphous vildagliptin hydrochloride (4.5 g)

Example 19: Co-precipitate of vildagliptin hydrochloride with providone in a ratio of 1 :1 using dichloromethane as a solvent

To the mixture of vildagliptin hydrochloride (2.5 g) and povidone (2.5 g), dichloromethane (50 ml) was added and stirred for 5 minutes at 25°C to 30°C. To this solution, methanol (2.5 ml) was added to get a clear solution. The solution was then filtered through a celite bed. The obtained filtrate was distilled on a Buchi Rotavapor at a temperature of 35°C to 40°C under vacuum to yield the co-precipitate of amorphous vildagliptin hydrochloride (4.5 g).

Example-20: Preparation of 1-Chloroacetyl (S)-2-cyanopyrrolidine

To a mechanically stirred solution of L-Prolinamide (100 g) and dichloromethane (1750 ml), solution of chloroacetyl chloride (83.6 ml) in dichloromethane (250 ml) was added drop-wise over a period of 20-25 minutes at temperature 38 to 42°C. Reaction mass was stirred for additional 4-5 h at 38 to 42°C. Upon completion of reaction, the reaction mass was cooled to 0-5°C. Imidazole (120 gm) was added to reaction mass and stirred for 15 minutes. Then solution of POCI₃ (160 ml) was charged slowly to the reaction mass and stirred for 10-12 h at 10 to 15°C. Upon completion of reaction, the reaction mass was cooled to 0-5°C. DM water (1000 ml) was charged slowly; organic layer was separated and washed with aqueous 6% HCI (2 X 300 ml). Organic layer was washed with aqueous NaHCO₃ solution (2X500 ml). Again organic layer was washed with (100 ml) DM water and concentrated under vacuum to get residue. Methyl ethyl ketone (100 ml) was charged to the residue and the reaction mass was heated to 38- 42°C. n- heptane (1000 ml) was charged and stirred for 30-45 minutes and the reaction mass was cooled to 0-5°C and obtained solid was . filtered. The obtained solid was dried at 40°C under vacuum. [Yield: 92.0 gm, Purity: 96.68%, R isomer: 0.17%]

Example 21 : Preparation of Vildagliptin

To a mechanically stirred solution of 3-amino- 1-adamantanol (50 gm), K2CO3 (41.1 gm) and potassium iodide (2.4 gm) in acetone (400 ml), solution of 1-chloroacetyl (S)-2-cyanopyrrolidine in acetone (100 ml), was added drop wise. The reaction mass was stirred for 6-10 h at 25°C to 30°C. Upon completion of reaction, acetone was distilled out under reduced pressure. DM water (500 ml) was charged to crude vildagliptin and pH of aqueous solution was adjusted to 5-6 using acetic acid. Aqueous acidic solution was washed with dichloromethane (3 X 250 ml). Aqueous layer was separated and basified using aqueous ammonia till pH 9-10. Product was extracted from aqueous layer using dichloromethane (3 X 250 ml). DM water (250 ml) was charged to the organic layer and pH was adjusted to 5-6 using tartaric acid. Aqueous layer was washed with MDC (3X250 ml), and aqueous layer was separated, basified with aq.NH₃ to pH 9-10. Product was extracted with MDC (3X250 ml) and organic layer was distilled off atmospherically to obtain vildaglitpin. Methyl ethyl ketone (250 ml) was charged and heated the reaction mass at 78±2°C to^' get clear solution. Obtained clear solution was distilled approx. 5 to 10 % under reduced pressure then gradually cooled at 25°C to 30°C and further cooled to 0°C to 5°C for 30 minutes. Solid was filtered and washed with methyl ethyl ketone (5 ml). [Yield: 60.0 gm; Purity: 99.96%] Example-22: Preparation of 1-chloroacetyl (S)-2-cyanopyrrolidine

To a mechanically stirred solution of L-prolinamide (100 g), 2, 6-lutidine (188 g) and dichloromethane (1750 ml), a solution of chloroacetyl chloride (71.0 ml) in dichloromethane (250 ml) was added drop-wise over a period of 20-25 minute at temperature 38 to 42°C. Reaction mass was stirred for additional 1-2 h at 38 to 42°C. Upon completion of reaction, the reaction mass was cooled to 20-30°C. Solution of TFAA (256 ml) was slowly charged and the reaction mass was stirred for 2-3 h at 25 to 30°C. Upon completion of reaction, reaction mass was cooled to 5-10°C. Ammonium bicarbonate (416 g) was slowly charged to the mass, followed by addition of DM water (500 ml) at temperature below 20°C. The reaction mass was stirred at 25-30°C. Organic layer and aqueous layers were separated and organic layer was washed with aqueous 6% HCI (4 X 400 ml), followed by aqueous NaHCO₃ solution (300 ml) and finally washed with (100 ml) DM water and concentrated under vacuum to get residue. IPA (200 ml) was charged to the residue and reaction mass was heated to 45-50°C, followed by addition of n- heptane (200 ml) and stirred for 30-45 minutes. Reaction mass was cooled to 10-15°C and solid was filtered and washed with n-heptane (50 ml). The obtained solid was dried at 35°C under vacuum. [Yield: 94.0 gm, Purity: 99.40%, R isomer: 0.05%]

Example 23: Preparation of Vildagliptin

To a mechanically stirred solution of 3-amino- 1-adamantanol (50 gm), K₂CO₃ (41.3 gm) and Kl (2.5 gm) in acetone (375 ml), solution of 1- chloroacetyl (S)-2-cyanopyrrolidine (51.6 g) in acetone (125 ml) was added drop wise. The reaction mass was stirred for 6-8 h at 25°C to 30°C. Upon completion of reaction, acetone was distilled out under reduced pressure to obtain crude vildagliptin. DM water (500 ml) was added to the crude vildagliptin and pH of aqueous solution was adjusted to 5-6 using acetic acid. Aqueous acidic solution was washed with dichloromethane (3 X 250 ml). Aqueous layer was separated and basified using aqueous ammonia till pH 9- 10. Product was extracted from aqueous layer using dichloromethane (400 ml and 2 X 100 ml). DM water (200 ml) was charged into organic layer and pH was adjusted to 5-6 using tartaric acid solution. Reaction mass was stirred and organic layer was separated. Aqueous layer was washed with MDC (3X250 ml), separated and aqueous layer was basified with aq.NH₃ to pH 9- 0.Product was extracted with MDC (400 ml and 2 X 100 ml), organic layer was distilled off atmospherically to obtain vildagliptin. Methyl ethyl ketone (300 ml) was charged to vildagliptin and heated the reaction mass at 78±2°C to get clear solution. Obtained clear solution was distilled approx. 5 to 10 % under reduced pressure then gradually cooled at 25°C to 30°C and further cooled at 0°C to 5°C for 30 minutes. Solid was filtered and washed with methyl ethyl ketone (12.5 ml). [Yield: 56.5 gm, Purity: 99.98%]

Claims

We claim:

1. A process for preparati (I);

wherein the said process comprises:

a. reacting, 3-amino-1-adamantano! of formula (IV) with 1- chloroacetyl(S)-2-cyanopyrrolidine of formula (V) in a solvent and a bas

b. isolating pure Vildagliptin of formula (I).

2. The process of claim 1 , wherein crude Vildagliptin of step (a) can be

optionally isolated and purified

3. The process of claim 1 , wherein the solvent used in step (a) is selected from the group comprising of aromatic hydrocarbons, aliphatic hydrocarbons, ethers, cyclic ethers other than tetrahydrofuran, substituted cyclic ethers, nitriles, dialkylformamides, dialkylacetamides, dialkylsulfoxides, halogenated hydrocarbons other than dichloromethane, ketones or mixtures thereof.

4. The process of claim 1 , wherein the base used in step (a) is an organic base selected from the group comprising of alkyl amines, pyridine, or lutidines; or inorganic base selected from the group comprising of alkali metal carbonates; alkali metal bicarbonates; and alkali metal hydroxides or mixtures thereof.

5. The process of claim 2, wherein the process for purification of vildagliptin of formula (I), having less than about 0.2% of dimer compound of formula (VI) comprises the steps of:

i. suspending the crude vildagliptin of formula (I) in suitable solvent;

ii. stirring the suspension obtained from step (i) and filtering to obtain vildagliptin as solid; and

iii. drying the obtained solid of step (ii) to yield pure vildagliptin having less than about 0.2% dimer compound of formula (VI).

6. The process of claim 5, wherein the solvent used in step (i) for suspension is selected from the group consisting of aliphatic hydrocarbons; aromatic hydrocarbons; ketones; esters; nitriles; ethers; cyclic ethers; alcohols or mixtures thereof.

7. A process for isolation of pure Vildagliptin as per any of the preceding claims; wherein the said process comprises the steps of:

i. treating the crude Vildagliptin with acid and water;

ii. washing the contents of step (i) with organic solvent;

iii. basifying the aqueous layer of step (ii) ;

iv. extracting vildagliptin from step (iii) using organic solvent;

v. separating the organic layer, repeating steps (i) to (iv) and concentrating the organic layer to obtain pure vildagliptin; or concentrating the organic layer , repeating steps (i) to (iv), and · concentrating the organic layer to obtain pure vildagliptin, vi. treating the vildagliptin obtained from step (v) with organic solvent, heating to provide clear solution, partially distilling the solvent, cooling, filtering and drying to obtain pure vildagliptin.

8. The process of claim 7, wherein the organic solvent used in step (ii) and step (iv) is selected from the group comprising of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, carboxylic acid esters, ethers, substituted cyclic ethers, or mixtures thereof.

9. The process of claim 7, wherein the organic solvent used in step (vi) is selected from the group comprising of aromatic hydrocarbons, aliphatic hydrocarbons, carboxylic acid esters, ethers, substituted cyclic ethers, ketones, alcohols or mixtures thereof.

10. The process of claim 7, wherein the obtained pure vildagliptin having less than about 0.2% of 1-aminoadamantane-3-ol impurity of formula (IV), adamantane-1 ,3-diol impurity (Di-hydroxyl impurity) of formula (VII), dimer impurity of formula (VI), deshydroxy impurity of formula (VIII), and amide impurity of formula (IX).

11. The process of claims 7, wherein the acid is an organic acid is selected from the group comprising of acetic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, malic acid, glutamic acid, lactic acid, citric acid, salicylic acid, methane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, malonic acid, mandelic acid, succinic acid or mixtures thereof and inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

12. A one-pot process for the preparation of 1-chloroacetyl-(S)-2- cyanopyrrolidine, a vildagliptin intermediate; wherein the said process comprises the steps of:

i. reacting, L-prolinamide of formula (II) with chloroacetyl chloride in a solvent optionally in presence of a first base;

iii. isolating pure 1-chloroacetyl-(S)-2-cyanopyrrolidine.

13. The process of claim 12, wherein the solvent used in step (i) is selected from the group comprising of aromatic hydrocarbons, aliphatic hydrocarbons, ethers, cyclic ethers, substituted cyclic ethers, halogenated hydrocarbons, or mixtures thereof.

14. The process of claim 12, wherein the first base and second base may be same or different.

15. The process of claim 14, wherein the first and second base is an organic base selected from the group comprising of alkyl amines, heterocyclic amines, pyridine, or lutidines; or inorganic base selected from the group comprising of alkali metal carbonates; alkali metal bicarbonates and alkali metal hydroxides.

16. The process of claim 12, wherein the dehydrating agent used in step ( ii) is selected from trifluoroacetic anhydride, phosphorous oxychloride, thionyl chloride, or phosphorous pentoxide

17. The process of claim 12, wherein process for isolation of 1-chloroacetyl- (S)-2-cyanopyrrolidine comprises the steps of:

i. quenching the reaction mass of step (ii) of claim 12 with water and ammonium carbonate;

ii. separating the organic layer, washing with aqueous acid solution, with aqueous basic solution, and with water;

iii. distilling organic layer of step (ii) to obtain 1-chloroacetyl-(S)-2- cyanopyrrolidine;; and

iv. purifying the product of step (iii) by crystallization using organic solvent to provide 1-chloroacetyl-(S)-2-cyanopyrrolidine

18. The process of claim 17, wherein the solvent used in step (iv) is selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, ethers, cyclic ethers, substituted cyclic ethers, nitriles, halogenated hydrocarbons, ketones, esters, alcohols or mixtures thereof.

19. A co-precipitate of amorphous form of vildagliptin of the formula (I) or its acid addition salt with a pharmaceutically acceptable excipient; characterized by their X-ray diffraction (XRD) pattern as depicted in figure 1 and 3.

20. A process for the preparation of co-precipitate of amorphous form of vildagliptin or its acid addition salts with pharmaceutically acceptable excipients, wherein the said process comprising the steps of:

i. preparing solution of vildagliptin or its acid addition salt and pharmaceutically acceptable excipients in solvent; and ii. removing the solvent from solution obtained in step (i) to provide amorphous co-precipitate of vildagliptin or its acid addition salts with the pharmaceutically acceptable excipients.

21. The process of claim 20, wherein the solution of vildagliptin or its acid addition salt and pharmaceutically acceptable excipients prepared in step (i) of claim 20 can be prepared by either:

i. dissolving vildagliptin or its acid addition salt in at least one solvent followed by addition and dissolution of a pharmaceutically acceptable excipients in the said solution; or

ii. dissolving pharmaceutically acceptable excipients in at least one solvent followed by addition and dissolution of vildagliptin or its acid addition salt in the said solution; or

iii. Alternatively, by the following steps: a. dissolving vildagliptin or its acid addition salt in a first solvent to form a solution (A);

b. dissolving a pharmaceutically acceptable excipient in second solvent to form a solution (B);

c. combining solution (A) and the solution (B) to obtain solution as desired for step (i) of claim 20.

22. The process of claims 20 and 21 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of polyvinylpyrrolidone (povidone), gums, cellulose derivatives including but not limited to hydroxypropyl methylcellulose and hydroxypropyl cellulose, cyclodextrins, gelatins, hypromellose phthalate, sugars or polyhydric alcohols.

23. The process of claims 20 and 21 , wherein the solvent used is selected from alcohols, halogenated hydrocarbons, ketones, esters, ethers, hydrocarbons, nitriles or mixtures thereof.

24. The process of any of the preceding claims, Vildagliptin of formula (I) has less than about 0.2% of (2S,2S')-1 ,1'[[3-hydroxytricyclo[3.3.1.1.3,7]dec-1- yl)imino]bis( -oxo-2, 1 ,-ethanediyl]bis(2-pyrrolidinecarbonitrile) impurity (dimer impurity) of formula (VI); has less than about 0.2% of 1- aminoadamantane-3-ol impurity of formula (V); and has less than about 0.2% of adamantane-1 ,3-diol impurity (di-hydroxyl impurity) of formula (VII); deshydroxy impurity of formula (VIII) and amide impurity of formula (IX).

Formula (VIII) Formula (IX)