WO2015145467A1 - An improved process for preparing vildagliptin - Google Patents

Abstract

The present invention relates to efficient, environment friendly and economical processes for the preparation of vildagliptin without isolating the intermediate compounds. Also provided is a process for the recovery of expensive 1-aminoadamantane-3-ol and use thereof in the preparation of vildagliptin.

Description

"AN IMPROVED PROCESS FOR PREPARING VILDAGLIPTIN" PRIORITY

This application claims the benefit under Indian Provisional Application No. 1679/CHE/2014 filed on Mar 28, 2014 entitled "An improved process for preparing Vildagliptin", and 4243/CHE/2014 filed on Sep 01, 2014 entitled "An improved process for preparing Vildagliptin", the content of each of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention generally relates to improved processes for the preparation of Vildagliptin. The present invention also relates to a method for recovery of expensive key raw materials involved in the synthesis of vildagliptin.

BACKGROUND OF THE INVENTION

Vildagliptin is chemically known as (S)-l-[2-(3-Hydroxyadamantan-l-ylamino) acetyl] pyrrolidine-2-carbonitrile and exist as (2S) and (2R) enantiomers. The stereoisomer with the desired biological activity is the (2S) enantiomer, represented by the following structure:

U.S. Patent No. 6,166,063 ("the Ό63 patent") discloses new class of Dipeptidyl peptidase 4 (DPP-4) inhibitors such as vildagliptin. The '063 patent further discloses a process for the preparation of vildagliptin by acylation of L-prolinamide with chloroacetyl chloride in the presence of a base in dichloromethane or tetrahydrofuran as solvent, filtration and subsequent dehydration with trifluoroacetic anhydride (TFAA) to provide (S) -1- (2- chloroacetyl) pyrrolidin-2-carbonitrile. The carbonitrile intermediate is isolated by distilling out the solvent, co-distillation with ethyl acetate, partitioning between water and ethyl acetate, extraction of the resulting aqueous layer with ethyl acetate followed by aqueous washings of the organic layer and concentrating to obtain carbonitrile intermediate as yellow solid. This is later reacted with about 2 moles of l-aminoadamantane-3-ol in the presence of about 4 moles of potassium carbonate in dichloromethane (DCM) or tetrahydrofuran (THF) for 6 days. Finally, the obtained crude vildagliptin is subjected to chromatography employing SIMS/Biotage Flash chromatography system providing vildagliptin with melting point of 138°C-140°C. The disclosed process is schematically represented as follows:

Amide Carbonitrile

A similar process is described in J. Med. Chem. 2003, 46, 2774-2789, where acylation of L-prolinamide with chloroacetyl chloride is carried out in the presence of potassium carbonate in tetrahydrofuran as solvent and subsequent dehydration with TFAA to provide (S) -1- (2-chloroacetyl) pyrrolidin-2 -carbonitrile. The carbonitrile intermediate was isolated by adding ethyl acetate, distillation of the solvent, partitioning between water and aqueous sodium bicarbonate, extraction of the resulting aqueous layer with ethyl acetate followed by aqueous washings of the organic layer and concentrating to obtain carbonitrile intermediate as yellow- white solid which was reacted with about 2-3 moles of 1- aminoadamantane-3-ol in the presence of about 3 moles of potassium carbonate in DCM or THF for 1-3 days followed by purification from a mixture of ethyl acetate and isopropanol provided Vildagliptin as a white solid.

U.S. Patent No. 6,011,155 discloses a process for the preparation of (S) -1- (2- bromooacetyl) pyrrolidin-2-carbonitrile by acylation of L-prolinamide with bromoacetyl bromide in the presence of triethyl amine and catalytic amount of DMAP in DCM as solvent wherein the resulting (S)-l -(2 -bromoacetyl) pyrrolidin-2-carboxamide is isolated and subsequently dehydrated with TFAA to obtain the carbonitrile intermediate as dark yellow solid.

U.S. Patent application No. 2008/0167479 discloses preparation of Vildagliptin with high chemical and enantiomeric purities wherein (S) -1- (2-chloroacetyl) pyrrolidin-2- carbonitrile is prepared in one step process by acylation of prolinamide with chloroacetyl chloride in a mixture of isopropyl acetate and DMF followed by dehydration with cyanuric chloride to obtain the carbonitrile intermediate as an oil which was crystallized from isopropanol. The resulting carbonitrile intermediate is reacted with l-aminoadamantane-3- ol in the presence of alkali metal carbonates such as potassium carbonate and an optional additive such as I in a solvent comprising at least an ester or ether or nitrile solvent and purification of vildagliptin from methyl ethyl ketone or from a mixture of isopropanol and methyl t-butyl ether.

PCT Publication No. 2010/022690 discloses a process for the preparation of vildagliptin wherein (S)-l -(2-chloroacetyl) pyrrolidin-2-carboxamide intermediate is isolated as a trialkylamine hydrohalide salt in two fractions and. dehydrated with TFAA to obtain (S)-l- (2-chloroacetyl) pyrrolidin-2-carbonitrile as light yellow powder after crystallization from heptane. The resulting carbonitrile intermediate is then reacted with 3-amino-l- adamantanol in the presence of alkali metal carbonate base and an alkali metal iodide as a catalyst in a mixture of organic ketones, ester and polar aprotic solvents. The crude product was subjected to multiple crystallizations in order to achieve high chemical purity of vildagliptin. This publication also disclosed final crystallization of vildagliptin from 2- butanone, toluene, 2-methyl tetrahydrofuran, isopropyl acetate, dimethyl carbonate, isopropanol. This process adds an extra step of isolation of the said carboxamide intermediate, uses mixture of solvents in the preparation of vildagliptin and to multiple crystallizations which makes the process uneconomical on large scale.

PCT Publication No. 2011/101861 discloses a process for the preparation of vildagliptin wherein (S)-l-(2-chloroacetyl) pyrrolidin-2-carboxamide and (S)-l-(2-chloroacetyl) pyrrolidin-2-carbonitrile intermediates are isolated as solids after purification and drying. Further, (S)-l-(2-chloroacetyl) pyrrolidin-2-carbonitrile is then converted to vildagliptin by reacting it with l-aminoadamantane-3-ol in the presence of potassium carbonate and KI in a suitable ether solvent like THF and purifying the obtained vildagliptin from a mixture of ethyl acetate and methanol. This publication also provided an alternate process for the preparation of vildagliptin by reacting 2-(3-hydroxyadamantan-l-yl amino) acid or derivative thereof with pyrrolidine-2-carbonitrile and various solvents from which vildagliptin may be crystallized such as ethyl acetate, 2-butanone, or mixture of ethyl acetate-methanol, ethyl acetate-isopropanol, methanol-DCM, ethyl acetate-cyclohexane and 2-butanone-methyl t-butyl ether.

U.S. Patent No. 7,375,238 discloses a one-pot process for the preparation of vildagliptin without isolation of the carboxamide and carbonitrile intermediates and further involves preparation of Vildagliptin by using potassium carbonate and potassium iodide (KI) as catalysts in 2-butanone solvent. Purification of the crude vildagliptin was carried out from a mixture of isopropanol and methyl t-butyl ether in the presence of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) base and final recrystallization from 2-butanone afforded pure vildagliptin. This process suffers from certain draw backs such as use of mixture of solvents for the acylation and condensation reactions; use of base and expensive additive such as KI in the condensation reaction.

PCT Publication No. 2011/012322 discloses a process wherein the (S) -1- (2-chloroacetyl) pyrrolidin-2-carbonitrile intermediate is isolated, purified and reacted with 1- aminoadamantane-3-ol in the presence of a phase transfer catalyst, optionally an inorganic base and a solvent selected from nitrile, ketone, ether, ester and mixtures thereof in a two phase reaction system wherein the first phase consist of a liquid phase and the second phase consists of an inorganic base. The final purification of vildagliptin was carried out in 2- butanone solvent.

PCT Publication No. 2013/179300 discloses preparation of vildagliptin from organic solvents such as aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, nitrile, dialkyl formamides, dialkylacetamides, dialkyl sulfoxides in the presence of organic or inorganic base. The resulting crude vildagliptin was purified by acid-base treatment and crystallization from a solvent selected from aliphatic hydrocarbons, aromatic hydrocarbons, ketones, esters, nitrile, ether, cyclic ether and alcohol or mixtures thereof.

PCT Publication No. 2012/022994 involves conversion of racemic vildagliptin to (S)- enantiomer via formation of vildagliptin adducts and final purification from ethyl acetate or mixture of ethyl acetate with 1% water.

U.S. Application No. 2006/0210627 discloses crystalline Form A of vildagliptin and its preparation from 2-butanone, isopropanol, acetone or a mixture of isopropanol-ethyl acetate in the presence of DBU base. This publication also discloses amorphous vildagliptin and its preparation by lyophilization from a water solution.

PCT Publication No. 2014/102815 disclosed a process for the preparation of vildagliptin by isolating the carboxamide and carbonitrile intermediates after crystallization and drying. The resulting carbonitrile intermediate is reacted with l-aminoadamantane-3-ol in the presence of organic base or inorganic base in nitrile, ester or alcohol solvent.

IN 3965 MUM/2013 publication discloses a process for the preparation of vildagliptin by preparing and crystallizing (S) -1- (2-chloroacetyl) pyrrolidin-2-carbonitrile intermediate and reacting it with l-aminoadamantane-3-ol in the presence of a potassium carbonate, optionally in presence of suitable catalyst such as KI in ketone solvent or in mixture of ketone with non polar solvents.

C.N. publication No. 102617434 discloses a one pot process for the preparation of Vildagliptin by reacting salt of pyrrolidine carbonitrile such as TFA salt with haloacetyl halide in the presence of a base followed by insiru reaction with l-aminoadamantane-3-ol in the presence of tertrabutyl ammonium iodide in halogenated hydrocarbon or ether as solvent to get vildagliptin which is further crystallized from ethyl acetate-petroleum ether.

C.N. publication No. 103804267 discloses a process for the preparation of vildagliptin by reacting (S)-l -(2 -haloacetyl) pyrrolidin-2-carbonitrile with l-aminoadamantane-3-ol in a mixed system of an organic solvent and water in the presence of a base and phase transfer catalyst followed by crystallization of the obtained crude vildagliptin.

C.N. publication No. 103787944 disclosed dehydration of-1- (2-chloroacetyl) -2- (S) - pyrrolidine carboxamide in the presence of a dehydrating agent and an acid-binding agent in an organic solvent followed by crystallization from mixture of isopropyl ether and ethyl acetate to provide l-(2-chloroacetyl)-2-(S)-pyrrolidine carbonitrile as white or pale yellow solid powder.

Furthermore, several techniques are known in the art for the purification of vildagliptin such as chromatography (US 6,166,063); or acid-base purification (IN 61 /MUM/2012 publication) or via formation of inorganic salt complexes (WO 2011/042765); or by solvent crystallizations such as mixture of ethyl acetate and isopropanol (J. Med. Chem. 2003, 46, 2774-2789); isopropanol and MTBE in the presence of DBU base and final recrystallization from 2-butanone (US 7,375,238); methyl ethyl ketone or from a mixture of isopropanol and MTBE (US 2008/0167479); acetone, 2-butanone, cyclohexanone, ethyl acetate, isopropyl acetate or dimethyl carbonate (IN 61 /MUM/2012 publication); 2- butanone (WO 2011/012322); aliphatic hydrocarbons, aromatic hydrocarbons, ketones, esters, nitrile, ether, cyclic ether and alcohol or mixtures thereof (WO 2013/179300); or from ethyl acetate or mixture of ethyl acetate with 1% water (WO 2012/022994).

Most of the processes known in the art for synthesizing vildagliptin are associated with one or more of the following disadvantages:

a) use of toxic TFAA for dehydration which is costly and environmentally harmful, b) lengthy and time consuming condensation process,

c) conventional solvents used in the condensation stage are costly, volatile, flammable, toxic, causing adverse health effects, in, addition to this potentially unsafe peroxide forming solvents such as THF were used, which process is more costlier than the process not having such elements,

d) purification of vildagliptin by chromatographic purification or by formation of inorganic salt complexes or by multiple crystallizations which are tedious, labor intensive, uses high amounts of solvents, require precise monitoring and time consuming and hence not viable for commercial scale operations.

Therefore, the present invention fulfills the need in the art and provides simple, industrially feasible and scalable processes for the preparation and purification of vildagliptin that circumvent disadvantages associated with the prior art process, proved to be advantageous from environmental and industrial point of view and also fulfill purity criteria. These processes allow the final product to be produced in a higher yield and purity by minimizing number of processing steps and reducing the number of solvent usage which is very practical for scale-up production, especially in terms of operating efficiency.

The new processes has a further advantage in recovering the expensive 1- aminoadamantane-3-ol from the reaction mixture and recycling in a simple manner that avoids use of inorganic salt complexes, which is economical and applicable on an industrial scale.

SUMMARY OF THE INVENTION

The main object of the present invention is to provide convenient, commercially viable, economical and environment friendly process for the preparation of Vildagliptin of Formula (I), wherein the process employs a one-pot process with minimum purification steps and minimum wastage of material. In accordance with one embodiment, the present invention provides an improved process for the preparation of vildagliptin of formula (I);

comprising:

a) reacting L-prolinamide of formula (II) with haloacetyl halide in presence of a base in a suitable organic solvent;

b) treating the reaction mixture of s compound of Formula (Ila)

na

with a suitable dehydrating agent to obtain (S)-l -(2 -haloacetyl) pyrrolidin-2- carbonitrile of formula (III);

III

wherein X represents a halogen selected from chloro, fluoro, bromo or iodo;

c) reacting the (S)-l -(2 -haloacetyl) pyrrolidin-2-carbonitrile of formula (III) with 1- aminoadamantane-3-ol of formula (IV) in water optionally in presence of a base; and

IV

d) isolating the vildagliptin of formula (I). In accordance with a second embodiment, the present invention provides an improved process for the preparation of vildagliptin of formula (I); comprising:

a) reacting (S)-l-(2-haloacetyl) pyrrolidin-2-carbonitrile of formula (III) with 1- arninoadamantane-3-ol of formula (IV) in water optionally in presence of a base; wherein X represents a halogen selected from chloro, fiuoro, bromo or iodo; and b) isolating the vildagliptin of formula (I).

In accordance with a third embodiment, the present invention provides an improved process for the preparation of vildagliptin of formula (I); comprising:

a) reacting L-prolinamide of formula (II) with haloacetyl halide in presence of a base in a suitable organic solvent to obtain a reaction mixture containing compound of Formula (Ila);

b) adding suitable dehydrating agent to the reaction mixture of step a) to obtain (S)-l- (2 -haloacetyl) pyrrolidin-2-carbonitrile of formula (III); wherein X represents a halogen selected from chloro, fiuoro, bromo or iodo;

c) adding water to the resulting reaction mass of step b);

d) separating the organic layer from the aqueous layer;

e) adding water to the organic layer of step d) followed by a base to adjust pH of the reaction mass to about 6 to about 8;

f) separating the organic layer from the aqueous layer and removing the solvent from the organic layer to obtain compound of formula (III) as a residue;

g) adding water to the residue obtained in step f);

h) treating the reaction mass of step g) with l-aminoadamantane-3-ol of formula (IV) at a temperature of about ambient to about reflux to obtain vildagliptin of formula

(i);

i) optionally purifying the vildagliptin of formula (I); and

j) isolating pure vildagliptin of formula (I).

In accordance with a fourth embodiment, the present invention provides an improved process for the preparation of vildagliptin of formula (I); comprising:

a) reacting (S)-l -(2 -haloacetyl) pyrrolidin-2-carbonitrile of formula (III) with 1- aminoadamantane-3-ol of formula (IV) in water optionally in presence of a base at a temperature of about ambient to about reflux; wherein X represents a halogen selected from chloro, fiuoro, bromo or iodo;

b) adding water immiscible organic solvent to the reaction mixture of step a);

c) separating the organic layer;

d) concentrating the solvent from the organic layer of step c) to obtain a residue;

e) adding a suitable organic solvent to the residue of step d); and

f) isolating the vildagliptin of formula (I). In accordance with a fifth embodiment, the present invention provides an improved process for the preparation of vildagliptin of formula (I); comprising:

a) reacting L-prolinamide of formula (II) with chloroacetyl chloride in presence of a base in a suitable organic solvent to obtain a reaction mixture containing chloro compound of Formula (Ila);

b) adding suitable dehydrating agent to the reaction mixture of step a) to obtain (S)-l- (2-chloroacetyl) pyrrolidin-2-carbonitrile of formula (III);

c) adding water to the resulting reaction mass of step b);

d) separating the organic layer from the aqueous layer;

e) adding water to the organic layer of step d) followed by a base to adjust pH of the reaction mass to about 6 to about 8;

f) separating the organic layer from the aqueous layer and removing the solvent from the organic layer -to obtain compound of formula (III) as a residue;

g) adding water to the residue obtained in step f);

h) treating the reaction mass of step g) with l-aminoadamantane-3-ol of formula (IV) at a temperature of about ambient to about reflux;

i) adding water immiscible organic solvent to the reaction mixture of step h);

j) separating the organic layer from the aqueous layer;

k) concentrating the solvent from the organic layer of step j) to obtain a residue;

1) adding a suitable organic solvent to the residue of step k); and

m) isolating the vildagliptin of formula (I).

In accordance with a sixth embodiment, the present invention provides an improved process for the preparation of vildagliptin of formula (I); comprising:

a) reacting L-prolinamide with chloroacetyl chloride in presence of a base in a suitable organic solvent;

b) treating the reaction mixture of step (a) with a dehydrating agent to obtain (S)-l-(2- chloroacetyl) pyrrolidin-2-carbonitrile;

c) reacting the (S)-l-(2-chloroacetyl) pyrrolidin-2-carbonitrile with 1- aminoadamantane-3-ol in water optionally in the presence of a base;

d) adding water immiscible organic solvent to the reaction mixture of step c);

e) separating the organic layer and aqueous layers;

f) treating the aqueous layer of step e) with a suitable base to precipitate out the

unreacted l-arninoadamantane-3-ol of formula (IV);

g) extracting the precipitated l-aminoadamantane-3-ol of formula (IV) with a suitable water immiscible organic solvent;

h) separating the water immiscible organic solvent layer;

i) concentrating the solvent from the organic layer of step h) to obtain a residue;

j) adding a suitable organic solvent to the residue of step i);

k) isolating the l-aminoadamantane-3-ol of formula (IV);

1) concentrating the solvent from the organic layer of step e) to obtain a residue; m) adding a suitable organic solvent to the residue of step 1); and

n) isolating vildagliptin of formula (I).

In accordance with a seventh embodiment, the present invention provides a process for recovery of l-aminoadamantane-3-ol of formula (IV), comprising:

i) providing a reaction mixture comprising vildagliptin (I) and unreacted 1- aminoadamantane-3-ol of formula (IV) in water and a water immiscible organic solvent;

ii) separating aqueous layer containing unreacted l-arninoadarnantane-3-ol of formula (IV);

iii) treating the aqueous layer with a suitable base to precipitate out the 1- aminoadamantane-3-ol of formula (IV); and

iv) isolating the l-aminoadamantane-3-ol of formula (IV). In accordance with an eighth embodiment, the present invention provides a process for recovery of l-aminoadamantane-3-ol of formula (IV); comprising:

i) providing a reaction mixture comprising vildagliptin (I) and unreacted 1- aminoadamantane-3-ol of formula (IV) in water and a water immiscible organic solvent;

ii) separating aqueous layer containing unreacted l-aminoadamantane-3-ol of formula

(IV);

iii) treating the aqueous layer with a suitable base to precipitate out the 1- aminoadamantane-3-ol of formula (IV);

iv) extracting the precipitated l-aminoadamantane-3-ol of formula (IV) with a suitable water immiscible organic solvent;

v) separating the water immiscible organic solvent layer;

vi) concentrating the solvent from the organic layer of step v) to obtain a residue;

vii) adding a suitable organic solvent to the residue of step vi); and

viii) isolating l-aminoadamantane-3-ol of formula (IV);

wherein the reaction mixture of step i) is obtained by the process comprising: reacting (S)- l-(2-haloacetyl) pyrrolidin-2-carbonitrile of formula (III) with l-aminoadamantane-3-ol of formula (IV) in water optionally in the presence of a base at a temperature of about ambient to about reflux; wherein X represents a halogen selected from chloro, fluoro, bromo or iodo; and adding water immiscible organic solvent to the reaction mixture.

In accordance with a ninth embodiment, the present invention provides a process for purification of vildagliptin of formula (I), comprising:

a) treating vildagliptin of formula (I) with an organic solvent; and

b) isolating pure vildagliptin of formula (I); wherein the organic solvent is selected form the group consisting of alcohols, esters, ketones, ethers, halogenated solvents, hydrocarbons, nitriles, carbonates, alkyl nitrates, glycols, water or mixtures thereof. In accordance with a tenth embodiment, the present invention provides a pharmaceutical composition comprising vildagliptin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention addresses the need in the art by providing an improved process for the preparation of vildagliptin of formula (I).

In accordance with one embodiment, the present invention provides an improved process for the preparation of vildagliptin of formula (I);

comprising:

a) reacting L-prolinamide of formula (II) with haloacetyl halide in presence of a base in a suitable organic solvent;

II

b) treating the reaction mixture of step a) containing compound of Formula (Ila)

Ha

with a suitable dehydrating agent to obtain (S)-l -(2 -haloacetyl) pyrrolidin-2- carbonitrile of formula (III);

III

wherein 'X' represents a halogen selected from chloro, fluoro, bromo or iodo;

c) reacting the (S)-l-(2-haloacetyl) pyrrolidin-2-carbonitrile of formula (III) with 1- arninoadamantane-3-ol of formula (IV) in water optionally in presence of a base; and

IV

d) isolating the vildagliptin of formula (I).

In a preferred embodiment, the present invention provides an improved process for the preparation of vildagliptin of formula (I); comprising:

a) reacting L-prolinamide of formula (II) with chloroacetyl chloride in presence of a base in a suitable organic solvent to obtain a reaction mixture containing chloro compound of Formula (Ha);

b) adding suitable dehydrating agent to the reaction mixture of step a) to obtain (S)-l- (2-chloroacetyl) pyrrolidin-2-carbonitrile of formula (III);

c) adding water to the resulting reaction mass of step b);

d) separating the organic layer from the aqueous layer;

e) adding water to the organic layer of step d) followed by a base to adjust pH of the reaction mass to about 6 to about 8;

f) separating the organic layer from the aqueous layer and removing the solvent from the organic layer to obtain compound of formula (III) as a residue;

g) adding water to the residue obtained in step f);

h) treating the reaction mass of step g) with l-aminoadamantane-3-ol of formula (TV) at a temperature of about ambient to about reflux;

i) adding water immiscible organic solvent to the reaction mixture of step h);

j) separating the organic layer from the aqueous layer;

k) concentrating the solvent from the organic layer of step j) to obtain a residue;

1) adding a suitable organic solvent to the residue of step k); and

m) isolating the vildagliptin of formula (I). The starting L-prolinamide compound of Formula (II) is known in the art and can. be prepared by any known methods, for example starting compound of Formula (II) may be synthesized according to WO 2011/101861 and CN 102491928. l-aminoadamantane-3-ol of formula (rV) is known in the art and can be prepared by any known methods, for example starting compound of Formula (FV) may be synthesized according to US 6,166,063.

The step a) of the foregoing process may include reacting L-prolinamide of formula (II) with haloacetyl chloride in the presence of a base in a suitable organic solvent.

According to one embodiment, halide in haloacetyl halide and "X" in compound of formula Ila is selected from the group consisting of chloro, fluoro, bromo or iodo; preferably chloro.

The base used in step (a) is either inorganic or organic base. The inorganic base used herein is selected from the group comprising of alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide and lithium hydroxide and the like; alkali metal hydride such as sodium hydride, potassium hydride and the like. The organic base used herein is selected from the group comprising of alkyl amines such as di-isopropyl ethyl amine, di-isopropyl amine, triethyl amine and the like; heterocyclic amines such as pyridine and the like. Preferably the base is selected from sodium carbonate, potassium carbonate, di-isopropyl amine, triethyl amine; more preferably triethyl amine.

The step a) reaction is optionally carried out in presence of catalyst such as 4- dimethylamino pyridine (DMAP). Examples of suitable organic solvent used herein for step (a) include but are not limited to aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as heptanes, hexane and the like; ethers such as methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methyl tetrahydrofuran and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, cUoroform and the like; ketones such as acetone, methyl ethyl ketone and the like; dialkylformamides, dialkylacetamides; dialkylsulfoxides or mixtures thereof. Preferably the suitable organic solvent is dichloromethane.

The step a) reaction is carried out at a temperature of about -10° C to 30° C; preferably at 0°C to 20°C, over a period of 30 mins to 6 hours. The resulting reaction mixture containing (S) .-l- (2- chloroacetyl) pyrrolidin-2-carboxamide of Formula (Ila) is continued directly to the dehydration step without isolating the said intermediate. In another embodiment, after completion of the step a) reaction, the resultant reaction mass can be continued directly to step (b) reaction in the same solvent without involving any additional process steps such as separation of unwanted inorganic salts as reported in the art, isolation and purification of formed intermediate, (S)-l- (2- chloroacetyl) pyrrolidin-2- ^' carboxamide.

In a preferred embodiment, after completion of the step a) reaction, the dehydrating agent can be added in to step a) reaction solution to obtain the compound of Formula III (carbonitrile compound).

The dehydrating agent used herein for step (b) includes but are not limited to phosphorous oxychloride, thionyl chloride, cyanuric chloride, Vilsmeier reagent or phosphorous pentoxide; preferably phosphorous oxychloride. The step b) reaction may typically be carried out at a suitable temperature of about 10° C to 60° C. The reaction is typically stirred for a period of time from about 1 hr until completion of the reaction, preferably about 4-8 hrs.

After completion of the reaction, the resultant reaction mass may be diluted with water and the aqueous phase may be separated. The resultant organic layer may be further diluted with water and treated with a suitable base to adjust pH of the reaction mass to about 6 to about 8. The suitable base used in step e) for pH adjustment is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; preferably Sodium bicarbonate.

The (S)-l-(2-chloroacetyl) pyrrolidin-2-carbonitrile of formula (III) containing organic layer may be separated and concentrated completely under vacuum to obtain a residue. The residue obtained can be used as such in the subsequent reaction or it can be isolated through a crystallization process in a suitable solvent before the subsequent step.

In a preferred embodiment, the compound of formula III is not isolated and purified; instead it is used as such in the subsequent reaction with a compound IV to obtain Vildagliptin of Formula I.

The reported literature involved isolation of (S)-l-(2-haloacetyl) pyrrolidin-2-carboxamide (Formula Ila) (US 6,01 1,155 and WO 2010/022690) or separation of the inorganic salt byproducts from the reaction mixture, which are produced by the use of potassium carbonate in the acylation reaction (US 6,166,063) or isolation, purification and drying of the (S)-l-(2-chloroacetyl) pyrrolidin-2-carbonitrile (III) (WO 2010/022690). These processes are not suitable on commercial scale as they involve either isolation, purification & drying of compounds of formula (Ila) and formula (III) or filtration of the reaction mass prior to dehydration to remove inorganic salts which adds extra steps to the final process and the use of expensive TFAA in the dehydration step rendering the process costly and not viable on commercial scale.

In contrast, the process described herein does not require isolation, purification and drying of the compounds of formula (Ila) and formula (III), thereby avoiding the workup process in step a) or additional solvents for subsequent dehydration step and purification of the intermediates. It is certain that lesser number of steps correlates with less yield loss due to less processing steps, lesser equipment usage and inevitably produces better yields.

In addition to the above, the reported literatures also disclosed a process for preparation of vildagliptin, which involves use of organic solvents, base and catalysts in the reaction of compound of Formula (III) with compound of Formula (IV). A growing concern in recent years of international environmental conservation has caused great demands in the chemical industry to reduce the utilization of chemicals that are identified as harmful to and their discharge into the environment. In response to this global concern, once established processes are revisited and, alternative raw materials, reagents and solvents that are environmentally benign including, alternate processes having higher conversion rate, yield and selectivity need to be developed. Under these environmental endeavors, the processes herein described are safer for the environment, for producing vildagliptin with the use of water as a solvent and avoids use of base and catalysts in the reaction of compound of Formula (III) and Formula (rV). The present process involves reaction of compound of Formula III with 1- aminoadamantane-3-ol of formula (IV) in water optionally in presence of a base to obtain vildagliptin.

In another embodiment, the present invention provides an improved process for the preparation of vildagliptin of formula (I); comprising:

a) reacting (S)-l-(2-haloacetyl) pyrrolidin-2-carbonitrile of formula (III) with 1- aminoadamantane-3-ol of formula (IV) in water optionally in presence of a base; wherein X represents a halogen selected from chloro, fluoro, bromo or iodo; and b) isolating the vildagliptin of formula (I).

Preferably, l-aminoadamantane-3-ol of formula (IV) is used herein in an amount of about 1.5 to about 5 equivalents with respect to L-prolinamide, more preferably about 2 to 2.5 equivalents.

In another embodiment, the amount of water to be used is about 1 to 20 vol of the L- prolinamide compound; preferably about 2 to 10 vol of the L-prolinamide compound. Suitable base used herein for the reaction of Formula III and Formula rV includes but are not limited to inorganic base such as alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal hydrides such as lithium hydride, sodium hydride and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate and the like; organic bases such as triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and buffers like dipotassium hydrogen phosphate; or mixtures thereof.

The reaction may be optionally carried out in presence of a catalytic amount of an additive such as potassium iodide; however the use of such catalyst in the reaction of Formula III and Formula IV is not critical.

In another embodiment, the compound of Formula (III) obtained as a residue from the dehydration step is used as such without purification, isolation and drying in the reaction with l-aminoadamantane-3-ol of formula (IV) in water optionally in presence of a base to obtain vildagliptin.

In a preferred embodiment, the reaction of compound of Formula III with 1- aminoadamantane-3-ol of formula (IV) is carried out in the absence of a base and a catalyst. In a further preferred embodiment, the reaction of compound of Formula III with 1- aminoadamantane-3-ol of formula (rV) is carried out in the absence of a base, an organic solvent and a catalyst, rather in a single solvent such as water.

The reaction is typically carried out at a temperature of about ambient temperature to reflux temperature, preferably at a temperature of about 30°C to about 60°C over a period of 2- 12 hours.

In a preferred embodiment, the reaction of compound of Formula (III) with compound of formula (IV) is carried out in about 5 to 7 vol of water to the L-prolinamide compound at a temperature of about 40°C to about 50°C.

Isolation of the vildagliptin of Formula (I) can further comprising the steps of: i) adding water and water immiscible organic solvent to the reaction mixture; ii) separating the organic layer; iii) concentrating the solvent from the organic layer to obtain a residue; iv) adding a suitable organic solvent to the obtained residue; and v) isolating the vildagliptin of formula (I). A suitable water immiscible organic solvent for step i) can be selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; halogenated solvents such as chloroform, dichloromethane and the like; aromatic hydrocarbon solvents such as toluene or mixtures thereof; preferably dichloromethane.

Then, the product containing organic layer is separated and aqueous layer is stored for recovery of unwanted l-aminoadamantane-3-ol of formula (IV). The product containing organic layer is concentrated under reduced pressure to obtain a residue. If necessary, the obtained residue may be redistilled by adding a suitable organic solvent to remove the traces of water immiscible organic solvent to obtain a residue.

The suitable organic solvent for isolating vildagliptin includes but is not limited to alcohols, esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons and mixtures thereof. The alcohols include but are not limited to methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and the like; esters include but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; ketones include but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; amides include but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; nitriles include but are not limited to acetonitrile, propionitrile and the like; ethers include but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4-dioxane and the like; halogenated hydrocarbons include but are not limited to dichloromethane, chloroform, dichloroethane and the like; aromatic hydrocarbons include but are not limited to toluene, xylene and the like; cyclic hydrocarbons include but are not limited to n-hexane, n-heptane, cyclohexane and the like; and mixtures thereof; preferably ethyl acetate, acetone, n-hexane and mixtures thereof; more preferably ethyl acetate.

The isolation of vildagliptin of formula (I) according to step v) can be accomplished by dissolving the crude vildagliptin as residue obtained from step iv) in a suitable organic solvent such as ethyl acetate, then heating the solution to reflux temperature, cooling the solution to less than about 30°C to precipitate out the product.

Isolation of vildagliptin of formula (I) may be carried out by employing conventional techniques, for example filtration and the resultant wet product may be further dried to obtain pure vildagliptin. The drying can be carried out for a period of about 5 hrs to about 12 hrs at a temperature ranging from about 25°C to about 75°C, preferably from about 50°C to about 60°C. In another embodiment, the present invention provides a process for purification of vildagliptin of formula (I), comprising: a) treating vildagliptin of formula (I) with an organic solvent; and

b) isolating pure vildagliptin of formula (I);

wherein the organic solvent is selected form the group consisting of alcohols, esters, ketones, ethers, halogenated solvents, hydrocarbons, nitriles, carbonates, alkyl nitrates, glycols, water or mixtures thereof.

Examples of organic solvent for treating vildagliptin include but are not limited to alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, tert-butanol, isoamyl alcohol, 2,2,2-trifluoroethanol, cyclohexanol and the like; esters such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; ketones such as acetone, methyl isopropyl ketone, methyl isobutyl ketone, 2-pentanone, 3- pentanone, cyclopentanone, cyclohexanone and the like; ethers such as diisopropyl ether, di tert-butyl ether, ethyl tert-butyl ether, dimethoxymethane and the like; halogenated solvents such as 1-chlorobutane, trichloroethylene and the like; hydrocarbons such as hexane, heptane, pentane, cyclohexane, methyl cyclohexane, cyclopentane and the like; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile and the like; carbonates such as diethyl carbonate, propylene carbonate, ethylene carbonate, dibenzyl carbonate and the like; alkyl nitrates such as nitromethane, nitroethane and the like; glycols such as ethylene glycol, propylene glycol and the like; water or mixtures thereof; preferably isopropanol, ethyl acetate, isopropyl acetate, acetone, water and mixtures thereof.

The reaction mass obtained by treating vildagliptin (I) with an organic solvent may be in suspension form or slurry form or in solution form after addition of the said organic solvent. The reaction mass may be further heated to a temperature of 30°C to reflux temperature in case the compound is not completely dissolved in the solvent. Thus obtained solution can be stirred at appropriate temperature over suitable period of time to recover highly pure vildagliptin by filtration.

Then the reaction mass obtained is heated at a temperature of about 25 °C to the reflux temperature over a period of 30 min to 2 hour; preferably at about 50°C to about 60°C. The resulting clear solution containing vildagliptin (I) and solvent may be optionally filtered on a hyflo bed in hot condition to remove any extraneous mass. Then, the solution may be optionally concentrated to partially reduce the solvent volume and cooled at a temperature from about 20°C or less such that the vildagliptin can be isolated by conventional techniques, for example by filtration and the resultant product may optionally be further dried by methods known in the art.

It has been observed that in the prior art process, purification of Vildagliptin of formula (I) is carried out by processes involving chromatographic purification; or by formation of inorganic salt complexes; or by crystallization from mixed solvents; or by multiple crystallizations, or restricted to use of only 2-butanone or methyl ethyl ketone (MEK). These processes use high volumes of solvents hence not viable for commercial scale operations.

In contrast, purification process according to the present invention provides high purity vildagliptin of formula (I) in single purification directly from the crude by a simple process and circumvents the disadvantages associated in the prior art process. Further, the present process is carried out in a single solvent and provides choice of using different solvents instead of 2-butanone or ME . According to the present invention, high purity Vildagliptin of formula (I) is obtained having a chemical purity of at least about 98%, as measured by HPLC, preferably at least about 99%, as measured by HPLC, and more preferably at least about 99.8%, as measured by HPLC; substantially free of dimer impurity of formula (V), l-aminoadamantane-3-ol of formula (IV) and R-isomer of formula (VI).

As used herein, the term "substantially free" refers to vildagliptin of Formula (I) having less than 0.1% as measured by HPLC of dimer impurity or R-isomer of formula (VI) and less than 0.1%) as measured by GC of l-aminoadamantane-3-ol of formula (IV); preferably less than 0.05% of dimer impurity or R-isomer of formula (VI) as measured by HPLC and less than 0.05% as measured by GC of l -aminoadamantane-3-ol of formula (IV).

Further it has been observed that during the preparation of vildagliptin of formula (I), the final product is likely contaminated with dimer impurity of formula (V), which is generated due to the further alkylation of vildagliptin (I) with another molecule of compound of formula (III), and also with compounds that were formed or used in previous steps such as compound of formula (IV). Further, the purity of the vildagliptin of formula (I) may also be compromised by the presence of R-isomer of formula (VI) originating from the isomeric

The formation of the dimer impurity can be significantly minimized by use of excess amounts of compound of formula (IV) with respect to L-prolinamide. Many of the reported literatures uses excess amounts of compound of formula (IV), however, the use of excess amounts of compound of formula IV is associated with contamination of the final vildagliptin product, and it is difficult to separate it from vildagliptin.

In order to remove dimer impurity from the vildagliptin, the reported literatures suggested that formation of inorganic salt complexes of vildagliptin can remove compound of formula III, compound of formula IV and dimer impurity since such compounds do not form inorganic salt complexes. However, this process is complex and involves extra steps of preparation of inorganic salt complexes of vildagliptin, and its conversion to vildagliptin free base in order to remove unreacted compound of III, IV and dimer impurity making the process uneconomical on commercial scale.

Hence, it is an object of the present invention to provide a more economical process, which involves use of an excess quantity of compound of formula (IV) (about 2 to 2.5 equivalents to L-prolinamide) in the reaction of compound of Formula III thereby substantially minimizing the formation of dimer impurity. However, accordingly the unreacted compound of formula (IV), if any, in the reaction can be recovered back by a novel process thereby eliminating the contamination of the same with vildagliptin (I).

In another embodiment, the present invention provides a process for recovery of 1- aminoadamantane-3-ol of formula (IV), comprising:

i) providing a reaction mixture comprising vildagliptin (I) and unreacted 1- aminoadamantane-3-ol of formula (IV) in water and a water immiscible organic solvent;

ii) separating the aqueous layer containing unreacted l-aminoadamantane-3-ol of formula (IV);

iii) treating the aqueous layer with a suitable base to precipitate out the 1- aminoadamantane-3-ol of formula (IV); and

iv) isolating the l-aminoadamantane-3-ol of formula (IV). In a preferred embodiment, the present invention provides a process for recovery of 1- aminoadamantane-3-ol of formula (IV), comprising:

i) providing a reaction mixture comprising vildagliptin (I) and unreacted 1- aminoadamantane-3-ol of formula (IV) in water and a water immiscible organic solvent;

ii) separating the aqueous layer containing unreacted l-aminoadamantane-3-ol of formula (IV);

iii) treating the aqueous layer with a suitable base to precipitate out the 1- aminoadamantane-3-ol of formula (IV);

iv) extracting the precipitated l-aminoadamantane-3-ol of formula (IV) with a suitable water immiscible organic solvent;

v) separating the water immiscible organic solvent layer;

vi) concentrating the solvent from the organic layer of step v) to obtain a residue, vii) adding a suitable organic solvent to the residue of step vi); and

viii) isolating the l-aminoadamantane-3-ol of formula (IV).

wherein the reaction mixture of step i) is obtained by the process comprising: reacting (S)- l-(2-haloacetyl) pyrrolidin-2-carbonitrile of formula (III) with l-aminoadamantane-3-ol of formula (IV) in water optionally in the presence of a base at a temperature of about ambient to about reflux; wherein X represents a halogen selected from chloro, fluoro, bromo or iodo; and adding water immiscible organic solvent to the reaction mixture. The reaction mixture of step i) containing vildagliptin (I) and unreacted compound of formula (IV) in water and water immiscible organic solvent is obtained by any known process of vildagliptin, for example reaction mixture of step i) is obtained by the step h) process described for the preparation of vildagliptin as described just as above. The suitable water immiscible organic solvent used in step i) is selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; halogenated solvents such as chloroform, dichloromethane and the like; aromatic hydrocarbon solvents such as toluene or mixtures thereof; preferably ethyl acetate, toluene, dichloromethane and the like; more preferably dichloromethane.

The step ii) of the process includes separation of aqueous layer containing unreacted compound of formula (IV) along with minor levels of vildagliptin and organic layer containing vildagliptin (I). The aqueous layer containing unreacted compound of formula (IV) and minor levels of vildagliptin is treated with a suitable base at a suitable temperature at about 10°C to about 85 °C.

The suitable base include but are not limited to alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate and the like; preferably sodium hydroxide, sodium bicarbonate and the like.

During the treatment of suitable base with the aqueous layer, the unreacted compound of formula (IV), is precipitated out from the solution. The precipitated solid can be separated by filtration to isolate the compound of formula (IV).

Alternatively, the reaction mass containing precipitated compound of formula (IV) may be stirred for an appropriate period of time at about 30°C to about 80°C, cooled to about 10°C to about 45°C and extracted with a water immiscible organic solvent such as dichloromethane, ethyl acetate, toluene and the like; preferably dichloromethane. Then, the organic layer may be separated and concentrated under vacuum to obtain a residue. The concentration step may be repeated to remove traces of water immiscible solvent using a suitable organic solvent to obtain a residue. The residue so obtained is dissolved in a suitable organic solvent at a suitable temperature of about 30°C to about reflux temperature. The resultant solution may be allowed to cool to precipitation and then filtration. ^{' '} The suitable organic solvent is selected from aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as hexane, heptane and the like; 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 ethyl acetate.

Isolation of compound of formula (IV) may be carried out by conventional techniques, for example by filtration and the resultant product may optionally be further dried by known techniques.

The compound of Formula (IV) recovered using the recovery process of the present invention having a chemical purity of at least about 95% as measured by Gas chromatography (GC), preferably at least about 96% as measured by GC, more preferably at least about 97% as measured by GC.

According to the present invention, unreacted compound of formula (IV) can be easily recovered, while vildagliptin (I) is not contaminated with the excess compound of formula (IV) used in the reaction. Thus, the process described in the present invention permits convenient recovery of compound (IV) and using the recovered compound (IV) further in the preparation of vildagliptin (I).

EXAMPLES

The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE 1: Preparation of (2S)- 1 -(Chloroacetyl)-2-pyrrolidinecarbonitrile.

To a solution of L-Prolinamide (100 gms) dissolved in DCM (1000 mL) was added triethyl amine (88.6 gms) and DMAP (1.07 gms) at 25-30°C under N₂ atmosphere and stirred for 15 min at 25-30°C. This solution was added to a solution of chloroacetyl chloride (98.9 gms) in DCM (500 mL) under N₂ atmosphere at -5 to 0°C over 2-3 hr. Raised the reaction mass temperature to 0-5°C and stirred for lhr. After reaction completion, charged phosphorus oxy chloride (201.5 gms) to the reaction mass at 0-5 °C, heated the reaction mass temperature to reflux and stirred for 6hr at same temperature. After reaction completion, allowed to cool to 10-20°C and added DM water (500 mL). Aqueous layer was separated and the organic layer was washed with DM water. To the organic layer DM water (300 mL) was added at 25-30°C and adjusted the reaction mass pH to 6.5-7.5 with -500 mL of sodium bicarbonate solution (-40 g of NaHC0₃ dissolved in 500 mL of DM Water). Separated the aqueous layer and concentrated the organic layer under vacuum at temperature of 30-40°C to get residual mass. Charged isopropanol (100 mL) and distilled out solvent completely under vacuum at <50°C. The resulting residue was allowed to cool to 30-40°C and charged isopropanol (500 mL). Heated the reaction mass temperature to 40- 45°C, stirred for 30 min at 40-45°C, allowed to cool to 0-5°C, stirred for 2 hr, filtered and washed wet cake with chilled isopropanol (100 mL), dried at 40-45°C for 6 hr to provide 115 gms of (2S)-l-(CMoroace1yl)-2-pyrrolidinecarbonitrile.

HPLC Purity: 99.86%.

Example 2: Preparation of Vildagliptin

To (2S)-l-(Chloroacetyl)-2 -Pyrrolidine carbonitrile (100 gms) dissolved in DM Water (500 mL), charged l-aminoadamantane-3-ol (242.2 g) at 25-35°C. Heated the reaction mass temperature to 40-45°C and stirred for 8-10 hr at 40-45°C. After reaction completion, allowed to cool to 25-30°C and charged DM water (700 mL) and DCM (600 mL). Separated the organic layer and extracted the aqueous layer with DCM. The total organic layer was concentrated under vacuum at temperature 30-40°C to get residual mass. Ethyl acetate (100 mL) was added to the residual mass and distilled completely under vacuum at <50°C. Charged ethyl acetate (500 mL) and refluxed for 1 hr. Allowed to cool to 25-30°C and stirred for 2 hr. Filtered the reaction mass and washed with ethyl acetate (100 mL) then dried at 50-55°C for 6 hr to provide 130 gms of crude vildagliptin.

HPLC Purity: 99.56%.

Dimer impurity content: <0.32%;

R-isomer content (by chiral HPLC): <0.2%;

l-aminoadamantane-3-ol content (by GC): 0.56%.

EXAMPLE 3: Preparation of Vildagliptin (using K₂C0₃ and KI)

To l-aminoadamantane-3-ol (19.4 g) taken in DM Water (50 mL), added potassium carbonate (8.0 gms), potassium iodide (0.1 gm) and stirred for 15 mins at 25-35°C. (2S)-1- (Chloroacetyl)-2-Pyrrolidine carbonitrile (10 gms) was added at 25-35°C and stirred for 15 mins at 25-35°C. Raised the reaction mass temperature to 40-45°C and stirred for 4 hr at 40-45°C. After reaction completion, cooled to 25-30°C and charged DCM (50 mL). Separated the organic layer and extracted the aqueous layer with DCM. The total organic layer was washed with DM water and the resulting organic layer was concentrated under vacuum at temperature <40°C to get residual mass. Charged ethyl acetate (70 mL) to above residual mass and refluxed for 1 hr. Cooled to 25-30°C and stirred for 2 hr. Filtered the reaction mass and wash wet cake with ethyl acetate (10 mL). Suck dried for 30 min, dried initially at 25-35°C for 1 hr and then at 50-55°C for 6 hr to provide 12 gms of crude vildagliptin.

HPLC Purity: 99.11%

Dimer impurity content: 0.50%; R-isomer content (by chiral HPLC): not detected

1- aminoadamantane-3-ol content (by GC): 2.09%.

EXAMPLE 4; Preparation of Vildagliptin (using K₂HP0₄ buffer and KI)

·

To l-aminoadamantane-3-ol (19.4 g) taken in DM Water (100 mL), added K₂HP0₄ (10.1 gms), potassium iodide (0.1 gm) and stirred for 15 rnins at 25-35°C. (2S)-l-(Chloroacetyl)-

2- Pyrrolidine carbonitrile (10 gms) was added at 25-35°C and stirred for 15 mins at 25- 35°C. Raised the reaction mass temperature to 40-45°C and stirred for 8-10 hr at 40-45°C. After reaction completion, cooled to 25-30°C and filtered the reaction mass to remove salts. The resulting filtrate was extracted with DCM, and the resulting organic layer was concentrated initially by atmospheric distillation and later under vacuum at temperature 30- 40°C to get residual mass. Charged ethyl acetate (50 mL) to above residual mass and refluxed for 1 hr. Cooled to 25-30°C and stirred for 2 hr. Filtered the reaction mass and washed the wet cake with ethyl acetate (10 mL). Suck dried for 30 min, dried initially at 25-35°C for 1 hr and then at 50-55°C for 6 hr to provide 12 gms of crude vildagliptin.

HPLC Purity: 96.54%

Dimer impurity content: 2.55%;

R-isomer content (by chiral HPLC): not detected

l-aminoadamantane-3-ol content (by GC): 0.86%.

Example 5: Purification of Vildagliptin.

Vildagliptin crude (100 gms) was dissolved in isopropanol (900 mL) by heating to 50-55°C and stirred for 30 min. Filtered the reaction mass over hyflo bed (10 gms) at 50-55°C and washed the hyflo bed with hot isopropanol (100 mL). Distilled out solvent under vacuum at

35-40°C up to 4 volumes remains and allowed to cool to 20-25°C and stirred for 1 hr at same temperature. Further, allowed to cool to 5-10°C, stirred for 2 hrs, filtered and washed with isopropanol (100 mL). The wet product was dried at 50-55°C under vacuum for 8 hr to provide 80 gms of pure vildagliptin.

HPLC Purity: 99.89%;

Dimer impurity content: <0.1 %;

R-isomer content (by chiral HPLC): not detected

l-aminoadarnantane-3-ol content (by GC): 0.06%.

The purified vildagliptin (I) was analyzed by powder X-ray diffraction (PXRD) and is set forth in Figure. 01.

EXAMPLE 6: Preparation of Vildagliptin To a solution of L-Prolinamide (100 gms) dissolved in DCM (1000 mL) was added triethyl amine (88.6 gms) and DMAP (1.07 gms) at 25-30°C under N₂ atmosphere and stirred for 15 min at 25-30°C. This solution was added to a solution of chloroacetyl chloride (118.7 gms) in DCM (500 mL) under N₂ atmosphere at -5 to 0°C over 2-4 hr. Heated the reaction mass temperature to 10-15°C and stirred until reaction completion, charged phosphorus oxychloride (201.5 gms) to the reaction mass at 0-5°C, heated the reaction mass temperature to reflux and stirred for 6hr at same temperature. After reaction completion, allowed to cool to 5-15°C and slowly added DM water (500 mL). Aqueous layer was separated and the organic layer was washed with DM water. To the organic layer, DM water (300 mL) was added at 25-30°C and adjusted the reaction mass pH to 6.5-7.5 with -200 mL of sodium bicarbonate solution (-16 g of NaHC0₃ dissolved in 200 mL of DM Water). Separated the aqueous layer and concentrated the organic layer under vacuum at temperature of 30-40°C to get residual mass. The residual mass was dissolved in DM Water (640 mL), charged l-aminoadamantane-3-ol (310.6 g) at 25-35°C. Heated the reaction mass temperature to 40-45 °C and stirred for 9 hr at the same temperature. After reaction completion, allowed to cool to 25-30°C and charged DM water (900 mL) and DCM (1280 mL). Separated the organic layer and extracted the aqueous layer with DCM. The aqueous layer was separated and kept aside for l-aminoadamantane-3-ol recovery. The total organic layer was treated with P.S. 133 carbon, stirred for 30 rnins at 25-30°C and filtered over hyflo bed. The resulting filtrate was concentrated under, vacuum at temperature 30-40°C to get residual mass. To the residual mass, charged ethyl acetate (128 mL) and distilled completely under vacuum at 30-40°C to get semi solid mass. Charged ethyl acetate (640 mL) to the obtained semi solid and refluxed for 1 hr. The reaction mass was allowed to cool to 25-30°C and stirred for 2 hr. Filtered the reaction mass and washed with ethyl acetate (128 mL) to obtain wet cake. Again charged ethyl acetate (512 mL) to the obtained wet cake and refluxed for 1 hr. The reaction mass was allowed to cool to 25- 30°C and stirred for 2 hr. Filtered the reaction mass and washed with ethyl acetate (128 mL) and then dried at 50-55°C for 6 hr to provide 175 gms of crude vildagliptin.

HPLC Purity: 99.66%.

Dimer impurity content: <0.2%;

R-isomer content (by chiral HPLC) : <0.1 %;

l-aminoadamantane-3-ol content (by GC): <0.7%.

DSC: 150.12°C.

EXAMPLE 7: Purification of Vildagliptin. Vildagliptin crude (100 gms) was dissolved in isopropanol (1100 mL) by heating to 50- 55°C and stirred for 30 min. Filtered the solution over hyflo bed at 50-55°C and wash with hot isopropanol (100 mL). Distilled out solvent under vacuum at <55°C up to 5 volumes remains and allowed to cool to 20-25 °C and stirred for 1 hr at same temperature. Further allowed to cool to 10-15 °C, stirred for 2 hrs, filtered and washed with chilled isopropanol (100 mL). The wet product was dried at 50-55°C under vacuum for 8 hr to provide 80 gms of pure vildagliptin. HPLC Purity: >99.8%;

Dimer impurity content: <0.1%;

R-isomeri content (by chir^'al HPLC) : <0.1%;

l-aminoadamantane-3-ol content (by GC): <0.1%.

DSC: 151.92°C.

Example 8: Recovery of l-aminoadamantane-3-ol of formula (IV).

To aqueous layer (1700 mL) from example 1, 50% C.S.lye (435 mL) was added to adjust the pH to 13.0-14.0 at 25-35°C and stirred for 15 mins at 25-35°C. Raised the reaction mass temperature to 60-70°C and stirred for 3 hrs. Cooled to 25-35°C and added DCM (1700 mL), stirred for 15 min and separated the organic layer. The aqueous layer was extracted with DCM and the total organic layer was distilled out completely under vacuum at <40°C to get semisolid mass. Charged ethyl acetate (150 mL) and distilled out solvent completely under vacuum at <50°C to get semisolid material. Charged ethyl acetate (400 mL), stirred for 30 min at 40-45°C and cooled to 25-35°C. Further allowed to cool to 0- 5°C, stirred for 2hr, filtered the reaction mass at 5-10°C and washed with ethyl acetate (100 mL). The wet product was dried at 50-55°C under vacuum for 8 hr to obtain 140 gms of 1- aminoadamantane-3-ol.

Purity by GC: 99.8 %.

Claims

Claim 1: An improved process for the preparation of vildagliptin of formula (I);

comprising:

a) reacting (S)-l-(2-haloacetyl) pyrrolidin-2-carbonitrile of for (III)

III

with l-aminoadamantane-3-ol of formula (IV)

IV

in water; wherein X represents a halogen selected from chloro, fluoro, bromo or iodo; and

b) isolating the vildagliptin of formula (I).

Claim 2 The process of claim 1, wherein the X represents chloro.

Claim 3 The process of claim 1, wherein the reaction is (Carried out at a temperature of about 40°C to about 50°C.

Claim 4: The process of claim 1, wherein the process further comprising the steps of:

i) adding water and water immiscible organic solvent to the reaction mixture of step a);

ii) separating the organic layer;

iii) concentrating the solvent from the organic layer to obtain a residue; iv) ; adding a suitable organic solvent to the obtained residue; and v) isolating the vildagliptin of formula (I).

Claim 5: The process of claim 4, wherein the water immiscible organic solvent is selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; halogenated solvents such as chloroform, dichloromethane; aromatic hydrocarbon solvents such as toluene or mixtures thereof.

Claim 6: The process of claim 5, wherein the solvent is dichloromethane.

Claim 7: The process of claim 4, wherein the suitable organic solvent is alcohols, esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons and mixtures thereof.

Claim 8: The process of claim 7, wherein the organic solvent is selected from ethyl acetate, acetone, n-hexane and mixtures thereof.

Claim 9: The process of claim 8, wherein the organic solvent is ethyl acetate.

Claim 10: An improved process for the preparation of vildagliptin of formula (I),

comprising:

a) reacting L-prolinamide of formula (II) with haloacetyl halide in presence of a base in a suitable organic solvent;

II

treating the reaction mixture of step a) containing compound of Formula (Ila)

Ila

with a suitable dehydrating agent to obtain (S)-l -(2 -haloacetyl) pyrrolidin-2-carbonitrile of formula (III);

III wherein X represents a halogen selected from chloro, fluoro, bromo or iodo;

C) reacting the (S)-l-(2-haloacetyl) pyrrolidin-2-carbomtrile of formula (III) with l-aminoadamantane-3-ol of formula (IV) in water; and

IV

. d) isolating the vildagliptin of formula (I).

Claim 11 : The process of claim 10, wherein the halogen is chloro. Claim 12: The process of claim 10, wherein the base is selected from the group comprising sodium carbonate, potassium carbonate, di-isopropyl amine and triethyl amine.

The process of claim 12, wherein the base is triethyl amine.

The process of claim 10, wherein the suitable organic solvent is dichloromethane.

The process of claim 10, wherein the step a) is carried out in presence of 4- dimemylamino pyridine (DMAP).

Claim 16: The process of claim 10, wherein the suitable dehydrating agent is selected from phosphorous oxychloride, thionyl chloride, cyanuric chloride, Vilsmeier reagent or phosphorous pentoxide.

Claim 17: The process of claim 10, wherein the step b) further comprises:

a) adding water to the resulting reaction mass of step b);

b) separating the organic layer from the aqueous layer;

c) adding water to the organic layer followed by a base to adjust pH of the reaction mass to about 6 to about 8;

d) separating the organic layer from the aqueous layer and removing the solvent from the organic layer to obtain compound of formula (III) as a residue.

Claim 18: The process of claim 17, wherein the base is Sodium bicarbonate.

Claim 19: The process of claim 10, wherein the compound of formula (III) is not crystallized as solid.

The process of claim 10, wherein the isolation of vildagliptin further comprising the steps of: i) adding water and water immiscible organic solvent to the reaction mixture of step c);

ii) separating the organic layer;

iii) concentrating the solvent from the organic layer to obtain a residue; iv) adding a suitable organic solvent to the obtained residue; and v) isolating the vildagliptin of formula (I).

The process of claim 20, wherein the water immiscible organic solvent is selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; halogenated solvents such as chloroform, dichloromethane; aromatic hydrocarbon solvents such as toluene or mixtures thereof.

The process of claim 20, wherein the suitable organic solvent is selected from ethyl acetate, acetone, n-hexane and mixtures thereof.

The process of claim 20, wherein the water immiscible organic solvent is dichloromethane and the suitable organic solvent is ethyl acetate.

A process for purification of vildagliptin of formula (I), comprising:

a) treating vildagliptin of formula (I) with an organic solvent; and b) isolating pure vildagliptin of formula (I); ■ · ■ wherein the organic solvent is selected form the group consisting of alcohols, esters, ketones, ethers, halogenated solvents, hydrocarbons,^' nitriles, carbonates, alkyl nitrates, glycols, water or mixtures thereof.

The process of claim 24, wherein the organic solvent is selected from isopropanol, ethyl acetate, isopropyl acetate, acetone, water and mixtures thereof.

The process of claim 24, wherein the organic solvent is isopropanol.

The process of claim 24, wherein the step a) further comprises heating the reaction mass to about 50°C to about 60°C.

The process of claim 24, wherein the isolation of vildagliptin is carried out by cooling the solution to less than 20°C and filtration.

Claim 29: A process for recovery of l-aminoadamantane-3-ol of formula (IV), comprising:

i) providing a reaction mixture comprising vildagliptin (I) and unreacted 1- aminoadamantane-3-ol of formula (IV) in water and a water immiscible organic solvent;

ii) separating the aqueous layer containing unreacted l-aminoadamantane-3-ol of formula (IV); iii) treating the aqueous layer with a suitable base to precipitate out the 1- aminoadamantane-3-ol of formula (IV);

iv) isolating the l-aminoadamantane-3-ol of formula (IV), (or)

v) extracting the precipitated l-aminoadamantane-3-ol of formula (IV) with a suitable water immiscible organic solvent;

vi) separating the water immiscible organic solvent layer;

vii) concentrating the solvent from the organic layer of step vi) to obtain a residue, viii) adding a suitable organic solvent to the residue of step vii); and

ix) isolating the l-aminoadamantane-3-ol of formula (IV).

Claim 30: The process of claim 29, wherein the suitable water immiscible organic solvent of step i) and step v) is selected from ethyl acetate, toluene or dichloromethane.

Claim 31 : The process of claim 29, wherein the suitable base is sodium hydroxide.

Claim 32: The process of claim 29, wherein the suitable organic solvent is ethyl acetate.

Claim 33: An improved process for the preparation of vildagliptin of formula (I); comprising:

a) reacting L-prolinamide with chloroacetyl chloride in presence of triethyl amine in dichloromethane;

b) treating the reaction mixture of step (a) with phosphorous oxychloride to obtain (S)- l-(2-chloroacetyl) pyrrolidin-2-carbonitrile;

c) adding water to the resulting reaction mass of step b);

d) separating the organic layer from the aqueous layer;

e) adding water to the organic layer of step d) followed by Sodium bicarbonate to adjust pH of the reaction mass to about 6 to about 8;

f) separating the organic layer from the aqueous layer and removing the solvent from the organic layer to obtain compound of formula (III) as a residue;

g) adding water to the residue obtained in step f);

h) reacting the (S)-l-(2-chloroacetyl) pyrrolidin-2-carbonitrile of step f) with 1- aminoadamantane-3-ol in water;

i) adding dichloromethane to the reaction mixture of step h);

j) separating the organic layer and aqueous layers;

k) treating the aqueous layer of step j) with sodium hydroxide to precipitate out the unreacted l-arninoadamantane-3-ol of formula (IV);

1) extracting the precipitated l-aminoadamantane-3-ol of formula (IV) with

dichloromethane and separating the dichloromethane layer;

m) concentrating the solvent from the organic layer of step 1) to obtain a residue;

n) adding ethyl acetate to the residue of step m);

o) isolating the solid l-aminoadamantane-3-ol of formula (IV);

p) concentrating the solvent from the orgamc layer of step j) to obtain a residue;

q) adding ethyl acetate to the residue of step p); and

r) isolating vildagliptin of formula (I).