WO2015173779A1

WO2015173779A1 - Process for the preparation of teneligliptin and its novel intermediates

Info

Publication number: WO2015173779A1
Application number: PCT/IB2015/053590
Authority: WO
Inventors: Sushil Kumar Dubey; Neeraj Kumar; Suresh NARWAL; Shailendra Kumar Dubey; Pramod Kumar
Original assignee: Micro Labs Ltd
Current assignee: Micro Labs Ltd
Priority date: 2014-05-16
Filing date: 2015-05-15
Publication date: 2015-11-19
Anticipated expiration: 2016-11-16

Abstract

The present invention relates to a novel process for the preparation of Teneligliptin or its pharmaceutically acceptable salts and its hydrates thereof. The invention also relates to novel intermediates used in the synthesis of Teneligliptin and their preparation.

Description

PROCESS FOR THE PREPARATION OF TENELIGLIPTIN AND ITS NOVEL INTERMEDIATES

FIELD OF THE INVENTION

BACK GROUND OF THE INVENTION

Teneligliptin hydrobromide hydrate is indicated for the treatment of Type 2 Diabetes Mellitus and marketed as Tenelia in Japan.

Teneligliptin hydrobromide hydrate chemically known as {(2S,4S)-4-[4-(3-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)- 1 -piperazinyl] -2-pyrrolidinyl } ( 1 ,3 -thiazolidin-3 -yl) methanone hydrobromide and is represented by the general Formula I

H

Formula I

.2.5 HBr .H₂0

Teneligliptin or a pharmaceutically acceptable salt thereof was first disclosed in US7074794 and the process described therein is as depicted in scheme 1:

3-{(2S,4SH-t-butoxycarbonyl-4-[4-(3-raethyl-l -phenyl-5-pyrazolyl)- l-piperazinyl]-2-pyrrolidinylcarbonyl}-l,3-thiazolidine hydrochloric acid-l,4-dioxane

H

Scheme 1

US '794 discloses a process which comprising the steps of: reaction of 1-tert- butoxycarbonylpiperazine with a diketene to obtain l-acetoacetyl-4-tert- butoxycarbonylpiperazine; reaction of the l-acetoacetyl-4-tert-butoxycarbonyl piperazine with phenylhydrazine in the presence of methane sulfonic acid, followed by the addition of pyridine and cyclization with POCI₃ to obtain l-tert-butoxycarbonyl-4-(3-methyl-l-phenyl-5- pyrazolyl)piperazine as an oil; and its deprotection with trifluoroacetic acid to obtain l-(3- methyl-l-phenyl- 5 -pyrazolyl)piperazine .

Due to the unstable nature of diketenes, their use for the preparation of l-(3-methyl-l

-phenyl-lH-pyrazol-5-yl)piperazine on a large scale results in decreased yield and purity of the l-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazine and {(2S,4S)-4-[4-(3-methyl-l-phenyl- lH-pyrazol-5-yl)piperazin-l-yl]pyrrolidin-2-yl}(l,3-thiazolidin-3-yl)methanone, or salts thereof.

Further Teneligliptin Hydrobromide hydrate is claimed in US8003790 and the process disclosed therein is as depicted in scheme 2:

Scheme 2

Apart from the above patents, Teneligliptin Hydrobromide process is also described in PCT publication No WO2015/019239 A and the process described therein is as depicted in sche

Scheme 3

Similarly WO2015/019239 using the 3-((S)-l-tert-butoxycarbonyl-4-oxo-2- pyrrolidinylcarbonyl)-l,3-thiazolidine as one of the key intermediate which involves lengthy reaction procedures, irritant and hazardous reagents for its preparation. The use of this key intermediate leads to high level of impurities which are carried forward in subsequent steps and difficult to remove in purification also.

Apart from that, Teneligliptin Hydrobromide is also known to have polymorphism and exits in three crystalline forms i.e. Form A, Form B and Form C, which are described in US8604198. Teneligliptin in amorphous form is also described in PCT Publication No. WO2014/041560.

3 The processes for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof, described in the above mentioned patents, publications suffer from many disadvantages like it involves tedious and cumbersome work up procedures, uneconomical intermediates and multiple crystallizations or isolation steps, use of excess reagents and solvents, column chromatographic purifications, etc. which effects the overall yield as well as the quality of the final product.

Based on the above facts there is a need to get the improved process for the preparation of Teneligliptin or a pharmaceutically acceptable salts or hydrates thereof of high purity and yield which overcome the drawback of prior publications. The present inventors have found an efficient process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof which offers the advantages over the prior publications such as simple scalable procedures suitable for large scale production, high yields, less effluent and highly pure Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof.

OBJECTS OF THE INVENTION

The main objective of the present invention is to provide a novel process for the preparation of Teneligliptin and its pharmaceutically acceptable salts and hydrates thereof.

Another object of the present invention is to provide novel intermediates for the preparation of Teneligliptin and its pharmaceutically acceptable salts and hydrates thereof.

Yet another object of the present invention is to provide the process for the preparation of novel intermediates used for Teneligliptin synthesis.

SUMMARY OF THE INVENTION

The present invention provides an improved, economical, and industrially advantageous process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof involving using novel intermediates of Formulae IV and III.

IV ΠΙ

wherein, Ri is Hydrogen or amino protecting group

R₂ is alkyl group

A first aspect of the present invention provides a process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof, wherein the process comprises the steps of:

a) reacting compound of Formula Vila

Formula Vila with an l-(3-methyl-l-phenyl- lH-pyrazol-5-yl)piperazine or a salt thereof of

Formula VI

Formula VI

to obtain a compound of Formula IV;

ormu a b) hydrolyzing the compound of Formula IV to obtain a compound of Formula III;

Formula III ^Rl c) reacting the compound of Formula III with a thiazolidine of Formula V or its salt thereof

Formula V to obtain a compound of Formula II; and

Formula II d) deprotecting the compound of Formula II to obtain Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof,

wherein,

Ri is Hydrogen or amino protecting group; R₂ is alkyl group;

R₃ is alcohol protecting group.

A second aspect of the present invention provides a process for the preparation of Teneligliptin intermediate of Formula III or salt thereof, wherein the process comprises the steps of:

a) reacting compound of Formula Vila

Formula Vila with an l-(3-methyl-l-phenyl- lH-pyrazol-5-yl)piperazine or a salt thereof Formula VI

Formula VI

to obtain a compound of Formula IV;

Formula IV 1 b) hydrolyzing the compound of Formula IV to obtain a compound of Formula III;

Formula III c) optionally converting the compound of Formula III to its pharmaceutically acceptable salts,

wherein,

Ri is Hydrogen or amino protecting group; R₂ is alkyl group; R₃ is alcohol protecting group.

The intermediates of Formulae IV and III used for Teneligliptin synthesis are either crystalline or amorphous in nature.

In accordance with yet another aspect of the present invention, the process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof overcomes the disadvantages associated with the process disclosed in the cited prior arts, which concerns with the use of hazardous and irritant agents, such as POCl₃, pyridine, trifluoroacetic acid, sodium triacetoxyborohydride, uneconomical 3-((S)-l-tert- butoxycarbonyl-4-oxo-2-pyrrolidinyl carbonyl)-l,3-thiazolidine and large volume of organic solvents, which renders the process industrially disadvantageous.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 of the present invention illustrates X-ray powder diffraction (XRPD) pattern of Teneligliptin hydrobromide hydrate.

Figure 2 of the present invention illustrates Infrared spectrum (IR) of Teneligliptin hydrobromide hydrate.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

The term "Pharmaceutically acceptable salt" according to the present invention includes salt of Teneligliptin or its intermediates with organic and/or inorganic acids.

As used herein, the term organic acid addition salts include salts formed with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid. Examples of inorganic acid addition salts include salts formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.

The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical. Alkyl substituents, as well as other hydrocarbon substituents, may contain number designators indicating the number of carbon atoms in the substituent (i.e. Ci-C₈ means one to eight carbons), although such designators may be omitted. Unless otherwise specified, the alkyl groups of the present invention contain 1 to 20 carbon atoms. For example, an alkyl group can contain 1-2, 1-3, 1-4, 1-5, 1- 6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 or 5-6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec -butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

As used herein, the term "protecting group" refers to a compound that renders a functional group unreactive, but is also removable so as to restore the functional group to its original state. Such protecting groups are well known to one of ordinary skill in the art and include compounds that are disclosed in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety.

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

The term "about", as used herein, refers to any value which lies within the range defined by a number up to + 10% of the value.

As used herein, the term "hydrates" can occur in different ratios of hydration. Water content of the crystal may vary in different ratios depending on the conditions applied. Hydrate forms of Teneligliptin or its salt may comprise up to 5 molecules of water per molecule of Teneligliptin or its salt, appearing in different hydrated states including, amongst others, hemi-hydrate, monohydrate, di-hydrate, trihydrate crystals, intermediate hydrate crystals, and mixtures thereof. Conveniently, the ratio of compound of Teneligliptin or its salt to the water may range between(5: l) and (1:5). In particular, the ratio may range from about 0.2 to about 3 molecules of water per 1 molecule of compound of Teneligliptin or its salt, more in particular, the ratio may range from about 1 to about 2 molecules of water per 1 molecule of compound of Teneligliptin or its salt.

The term "substantially pure Teneligliptin hydrobromide" as used herein shall be understood to mean Teneligliptin hydrobromide formed with little or no content of the impurities. The amount of any impurity of Teneligliptin hydrobromide resulting from the process of the preparation will be relatively minor, e.g., less than about 0.15

weight percent, or less than about 0.1 weight percent, or less than about 0.05 weight percent, of any impurity of Teneligliptin hydrobromide. 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.

One embodiment of the present invention provides a process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof,

wherein the process comprises the steps of:

a) reacting compound of Formula Vila

Formula Vila with an l-(3-methyl-l-phenyl- lH-pyrazol-5-yl)piperazine or a salt thereof of Formula VI

to obtain a compound of Formula IV;

Formula III c) reacting the compound of Formula III with a thiazolidine of Formula V or its salt thereof

Formula V to obtain a compound of Formula II; and

d) deprotecting the compound of Formula II to obtain Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof,

wherein,

Ri is Hydrogen or amino protecting group; R₂ is alkyl group;

R₃ is alcohol protecting group.

The starting compounds of Formulae Vila or VI may be obtained by known processes or by the process described in this present application.

Ri represents Hydrogen or amino protecting group comprising of 9-fluorenylmethyl carbamate (Fmoc), 2,2,2-trichloroethyl carbamate (Troc), ethyl carbamate, t-butyl carbamate (Boc), 2-(trimethylsilyl)ethyl carbamate (Teoc), allyl carbamate (Alloc), carboxybenzyl (Cbz), p-Methoxybenzyl carbonyl (MeOZ), p-Methoxybenzyl (PMB), p- methoxyphenyl (PMP), acetyl (Ac), benzoyl (Bz), benzyl (Bn), trifluoroacetamide, benzylamine, allylamine, and tritylamine. In a specific embodiment, Ri is t-butyl carbamate (Boc);

R₂ represents alkyl group containing 1 to 20 carbon atoms. For example, an alkyl group can contain 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 or 5-6 carbon atoms. In an embodiment, R₂ include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. In a specific embodiment, R₂ represents methyl, ethyl, t-butyl.

R₃ is alcohol protecting group comprising of /?-toluenesulfonyl (Tosyl), p- bromobenzenesulfonyl (Brosyl), 2- or 4-nitrobenzenesulfonyl (Nosyl), methanesulfonyl (Mesyl), trifluoromethanesulfonyl (Triflyl) or 5-(dimethylamino)naphthalene-l-sulfony (Dansyl). In a specific embodiment R₃ is 4-nitrobenzenesulfonyl (Nosyl).

The reaction of step a) is carried by reacting the compound of Formula Vila with compound of Formula VI in the presence of a solvent and base. In an embodiment, the solvent used in step a) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol; 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxy ethanol, diethylene glycol, 1 -, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. In a specific embodiment, solvent used in step a) is acetonitrile.

In an embodiment, the base used in step a) is selected from organic base or inorganic base. In an embodiment, the organic base is selected from trimethylamine, triethylamine, tributylamine, N,N-dimethylaniline, Ν,Ν-dimethylbenzylamine, N,N- diisopropylethylamine, N-methyl morpholine, piperidine, l,4-diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and inorganic bases selected from ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate.

In a particular embodiment, the base used in step a) is sodium carbonate.

In an embodiment, the above reaction step a) may be carried out at temperatures ranging from about 25°C to about reflux temperature or about 50°C to 75°C or about 60°C to 80°C or about 80°C to 90°C.

After the completion of the reaction, the compound of Formula IV may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula IV may be taken forward for the next steps, without isolating the compound of Formula IV.

In an embodiment, the reaction mixture comprising the compound of Formula IV is cooled, filtered and distilled the filtrate under vacuum. In an embodiment, obtained reaction mass is diluted with an ethyl acetate and water and the organic layer is separated. In a further embodiment, the organic layer is washed with acetic acid solution followed by sodium bicarbonate solution and the organic layer comprising the compound of Formula IV, is optionally distilled or taken forward for the next step.

In an embodiment, compound of Formula IV may be converted into its pharmaceutically acceptable salts. In a specific embodiment, Formula IV is reacted with an acid selected from methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid.

The reaction of step b) involves hydrolyzing the compound of Formula IV to obtain a compound of Formula III in present of solvent and base.

In an embodiment, solvent used in step b) is a solvent mixture comprising a solvent and water. In an embodiment, the solvent used in step b) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. In a specific embodiment, solvent system used in step b) is tetrahydrofuran and water mixture.

In an embodiment, the base used in step b) is an inorganic base selected from ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate or the like. In a particular embodiment, the base used in step b) is lithium hydroxide.

In an embodiment, the above reaction may be carried out at temperatures ranging from about 25°C to about 80°C or 50°C to about 75°C or 60°C to 70°C or about 70°C to 80°C. In a particular embodiment, reaction is carried out at about 25°C to about 30°C. After the completion of the reaction, the compound of Formula III may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula III may be taken forward for the next steps, without isolating the compound of Formula III.

In an embodiment, the reaction mixture comprising the compound of Formula III is distilled under vacuum. In a further embodiment, obtained reaction mass containing the compound of Formula III is diluted with toluene and water and the aqueous layer is separated. In a further embodiment, the aqueous layer pH is adjusted and further diluted with methylene dichloride. In an embodiment, the organic layer comprising the compound of Formula III, is optionally distilled or taken forward for the next step.

In an embodiment, the compound of Formula III obtained in step b) is further purified by dissolving in a solvent under heating and precipitating out the pure compound of Formula III.

In an embodiment, solvent used in purification of compound of Formula III is selected from group comprising of esters such as methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate and ethyl propionate or the like. In a specific embodiment, solvent used in purification of compound of Formula III is ethyl acetate.

In an embodiment, compound of Formula III may be converted into its pharmaceutically acceptable salts. In a further embodiment, compound of Formula III is reacted with an acid selected from methane sulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid.

The reaction of step c) involves reacting the compound of Formula III with a thiazolidine of Formula V or its salt thereof to obtain a compound of Formula II using condensation reagent and solvent.

In an embodiment, the compound of Formula V used in step c) can be used in the form of free base or its pharmaceutically acceptable salt form. In a specific embodiment, compound of Formula V is used in the form thiazolidine hydrochloride.

The compound of Formula V may be obtained by known processes or by the processes described in the present application.

In an embodiment, the solvent used in step c) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. In a specific embodiment, solvent used in step c) is methylene chloride.

In an embodiment, the condensation reagents used in step c) are selected from the group comprising of but not limited to dicyclohexylcarbodiimide (DCC), Ν,Ν'- diisopropylcarbodiimide (DIC), Ι,Γ-Carbonyldiimidazole (CDI), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), N,N,N',N'-Tetramethyl-0-(lH-benzotriazol-l- yl)uronium hexafluorophosphate (HBTU), 0-(Benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), Propylphosphonic Anhydride (T3P), 2- chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), 4-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium chloride (DMTMM), N-hydroxybenzotriazole (HOBt), 4,5- dicyanoimidazole, dicyclopentylcarbodiimide, cyclohexylisopropylcarbodiimide (CIC), bis[[4-(2,2-dimethyl-l,3-dioxolyl)]methyl] carbodiimide, N,N'-bis(2-oxo-3-oxazolidinyl)- phosphinic chloride (BOP-CI), an acid chloride, ethyl chloroformate, and the like or the any two or more reagents combination thereof or any other suitable reagents known in the art. In a specific embodiments, the condensation reagents used in step c) is EDC.HC1 and HOBt. In an embodiment, step (c) may be optionally be carried out in the presence of a suitable catalyst, such as, for example, triethylamine, pyridine, diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,4-diazabicyclo [2.2.2]octane (DABCO), 1- methylmorpholine, 1-methylpiperidine, 1,5-diazabicyclo [4.3.0]non-5-ene, N,N- dimethylpiparazine, Ν,Ν-dimethylaniline, 4-(dimethylamino)-pyridine (DMAP), hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), collidine, 2,3,5, 6-tetramethylpyridine (TEMP), and the like.

In an embodiment, the above reaction step c) may be carried out at temperatures ranging from about 0°C to about 50°C or about 10°C to 40°C or about 20°C to 40°C or about 20°C to 30°C.

In an embodiment, the reaction mixture obtained from step (c) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (c) may be isolated directly from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (d) or it may be isolated as a solid. The isolation of the step (c) product may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, and the like. Stirring or other alternate methods, such as for example, shaking, agitation, and the like, that mix the contents may also be employed for isolation.

In an embodiment, the reaction mixture comprising the compound of Formula II is diluted with water and N-methylmorpholine and separated the organic layer. In an further embodiment, obtained organic layer containing compound of Formula II is washed with hydrochloric acid solution, water and optionally distilled or taken forward for the next step.

The reaction of step d) involves deprotection of compound of Formula II using an acid in presence of alcohol solvent to obtain Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof.

In an embodiment, the acid used in step d) is selected from organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulphamic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid; and inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid. In a preferred embodiment, acid used in step d) is hydrobromic acid.

In an embodiment, the acids used in step d) are commercially available in several strengths and are selected such that required reaction is performed. In a preferred embodiment, the acid used is 47% aqueous Hydrobromide.

The deprotection reaction is typically done with an acid strength in the range of about 0.5 M to about 12 M. In one embodiment the acid strength is about 1 M to about 12 M. In one embodiment the acid strength is at least about 3 M. The acidic deprotection reaction is usually done with from about 1 to about 30 molar equivalents of acid, typically in the range of about 1 to about 20 molar equivalents of acid. In one embodiment the molar equivalents of acid are at least about 2, and in another embodiment at least about 3. The volume of alcohol used in the deprotection reaction is typically from about 1 v/w to about 20 v/w. In an embodiment, the solvent used in step d) is selected from alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol and the like. In a preferred embodiment, solvent used in step d) is isopropyl alcohol.

In an embodiment, the above reaction step d) may be carried out at temperatures ranging from about 20°C to about reflux temperature or about 50°C to 75°C or about 60°C to 80°C or about 80°C to 90°C.

In an embodiment, after the completion of the reaction of step d) the compound of

Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof may be isolated by known methods or by the methods disclosed in the instant application or the reaction mixture containing the compound of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof may be taken up for purification by methods disclosed in the instant application.

In an embodiment, after completion of deprotection, the step further involves simultaneous salt formation with the same acid used in the deprotection step.

In an embodiment, the product of step (d) may be isolated directly from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with techniques such as filtration, washing with a suitable alcohol, drying, or the like.

In a specific embodiment, the product obtained from step d) is Teneligliptin hydrobromide hydrate.

In another embodiment, Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof optionally subjected to a purification process, which process includes the step of recrystallizing or slurrying the compounds of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof from a suitable solvent(s) to afford the desired pure compound of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof. Purity may also include essentially pure, substantially pure and/or pure in terms of impurities other than of the stereogenic or optical isomers. Thus, in a particularly preferred embodiment, the compound of Formula I is both optically or stereogenically pure and pure with regard to other contaminants, reactants, reaction byproducts and the like. And, the purity, in terms of stereogenic or optical purity and freedom from other contaminants may be different. For example only, a product could be essentially pure in terms of contaminants and substantially pure in terms of other optical or stereogenic species. Preferably, however, they are both "pure" as defined herein.

In an embodiment, Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof may be purified by dissolving Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof in a suitable alcohol solvent, or such a solution may be obtained directly from a chemical synthesis mixture in which Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof is formed.

In an embodiment, suitable alcohol solvents that can be used in purification include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, n-propanol, tertiary-butyl alcohol, and the like, including any mixtures thereof. In a specific embodiment, the alcohol used is methanol.

In an embodiment, the solution may be prepared at any temperatures upto the reflux temperature of the solvent. For example, the solution may be prepared at ambient temperatures, such as below 35 °C, or in the range of about 40°C to about 80 °C.

In an embodiment, the solution may optionally be treated with activated carbon and then filtered to remove the carbon. The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite®. Depending upon the equipment used, as well as the concentration and temperature of the solution, the filtration apparatus may need to be heated or cooled to avoid undesired crystallization.

In an embodiment, after the completion of the purification the compound of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof may be isolated by known methods or by the methods disclosed in the instant application or the reaction mixture containing the compound of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof in the instant application.

In a preferred embodiment, the filtrate obtained after carbon treatment may optionally be partially distilled, diluted with water, cooled and filtered to give pure Teneligliptin or pharmaceutically acceptable salt or hydrates thereof. In a preferred embodiment, obtained pure compound is Teneligliptin Hydrobromide hydrate of Formula I.

In one embodiment the present invention provides a process for the preparation of

Teneligliptin or its pharmaceutically acceptable salts and hydrates thereof. The process of the present invention is as depicted in the following scheme:

Wherein,

Ri is Hydrogen or amino protecting group

R₂ is alkyl group.

The second embodiment of the present invention provides a process for the preparation of Teneligliptin intermediate of Formula III or salt thereof, wherein the process comprises the steps of:

a) reacting compound of Formula Vila

with an l-(3-methyl-l-phenyl- lH-pyrazol-5-yl)piperazine or a salt thereof Formula VI

Formula VI to obtain a compound of Formula IV;

Formula IV b) hydrolyzing the compound of Formula IV to obtain a compound of Formula III;

wherein,

Ri is Hydrogen or amino protecting group; R₂ is alkyl group;

R₃ is alcohol protecting group.

Ri_, R₂ and R₃ are same as defined above.

The reaction of step a) is carried by reacting the compound of Formula Vila with compound of Formula VI in the presence of a solvent and base.

In an embodiment, the solvent used in step a) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol; 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxy ethanol, diethylene glycol, 1 -, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. In a specific embodiment, solvent used in step a) is acetonitrile.

In a particular embodiment, the base used in step a) is sodium carbonate.

In an embodiment, solvent used in step b) is a solvent mixture comprising a solvent and water. In an embodiment, the solvent used in step b) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxy ethanol, diethylene glycol, 1 -, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. In a specific embodiment, solvent system used in step b) is tetrahydrofuran and water mixture.

In an embodiment, the above reaction may be carried out at temperatures ranging from about 25°C to about 80°C or 50°C to about 75°C or 60°C to 70°C or about 70°C to 80°C. In a particular embodiment, reaction is carried out at about 25°C to about 30°C.

After the completion of the reaction, the compound of Formula III may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula III may be taken forward for the next steps, without isolating the compound of Formula III.

In an embodiment, the reaction mixture comprising the compound of Formula III is distilled under vacuum. In a further embodiment, obtained reaction mass is diluted with toluene and water and the aqueous layer is separated. In a further embodiment, the aqueous layer pH is adjusted and further diluted with methylene dichloride. In an embodiment, the organic layer comprising the compound of Formula III, is optionally distilled or taken forward for the next step.

In an embodiment, the compound of Formula III obtained in step b) may be further purified by dissolving in a solvent under heating and precipitating out the pure compound of Formula III.

In an embodiment, solvent used in purification of compound of Formula III is selected from group comprising of esters such as methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate and ethyl propionate or the like. In a specific embodiment, solvent used in purification of compound of Formula III is ethyl acetate. In an embodiment, obtained compound of Formula III may be optionally isolated in the form of free base or its pharmaceutically acceptable salts.

In an embodiment, compound of Formula III obtained in step b) is treated with organic or inorganic acids to form its corresponding pharmaceutically acceptable salts.

In third embodiment the present invention provides novel intermediates III and IV.

The novel intermediate compounds of the present invention can be in amorphous or in crystalline form.

It has been observed that both reaction temperature and reaction time of the reaction steps described in this specification may be substantially minimized by the addition of an additive selected from a group of an ionic additive, a phase transfer catalyst and mixture thereof. Thus, addition of an additive makes the condensation reaction effective in terms of both energy and cost.

Ionic additive includes, but not limited to sodium salts such as sodium iodide, sodium sulfate, sodium chloride; potassium salts such as potassium iodide, potassium sulfate, potassium chloride; or mixtures thereof. Specifically, the ionic additive is selected from a group of sodium iodide, sodium sulfate and potassium iodide. More specifically, the ionic additive is selected from a group of sodium iodide and sodium sulfate. Phase transfer catalyst includes, but not limited to tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetraethylammonium tetrafluoroborate, triphenylphosphonium chloride, benzyltrimethylammonium chloride and hexadecyltributylphosphonium bromide. Specifically, the phase transfer catalyst is selected from a group of tetrabutylammonium bromide, tetrabutylammonium iodide and tetrabutylammonium chloride. More specifically, the phase transfer catalyst is tetrabutylammonium bromide.

In an embodiment of the present invention, the above processes for the preparation and purification of Teneligliptin hydrobromide provides substantially pure Teneligliptin hydrobromide having purity greater than or equal to about 99.5% w/w or greater than or equal to about 99.8% w/w as determined using HPLC.

In a further embodiment, the present invention includes substantially pure Teneligliptin hydrobromide, wherein the amount of each individual process-related impurity listed in Table 1 is less than about 0.15% w/w or less than about 0.1% w/w, and/or the sum of all of these impurities is less than about 0.1% w/w. Table 1

X-ray powder diffraction (XRPD) was performed on X-Ray powder diffractometer: Pan Analytical X'pert Pro powder diffractometer, CuKa radiation, λ = 1.5405980 A. PIXcel detector active length (2 theta) = 3.3473, laboratory temperature 22-25°C. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a microscopic glass slide.

The FTIR of the samples were determined by using Instrument: Shimadzu®; Model: IR Affinity-1 ; SCAN: 35 scans; Resolution: 2.0 cm^"1; potassium bromide pellet method, in a wavelength range of from 4000 to 400 cm^"1, and application of baseline correction.

BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION

The invention is described in more detail by the following examples. These examples are designated to illustrate the invention, but do not limit its scope.

Example 1: Preparation of l-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazine (Formula

Yii

DMF (200 mL) and NaH (95 g; 60% dispersion in oil) were charged into a round bottom flask at room temperature and the mixture was cooled to 0 to 5 °C. To the reaction mixture 3-methyl-l-phenyl-lH-pyrazol-5-amine (100 g in DMF) was added slowly and stirred for 1 hour. Bis-(2-chloroethylamine)hydrochloride (113 g in DMF) was then added and stirred for 30 minutes. The reaction mixture was raised to room temperature and stirred for 2-4 hours. Ammonium chloride solution (110 mL) and sodium chloride solution (2000 mL) were added to the reaction mixture and stirred at for 3-4 hours. The obtained compound is filtered. The obtained wet cake first washed with water and then slurred washed with cyclohexane (400 mL). The obtained product was filtered, washed and dried under vacuum at 50-55°C.

Example 2: Preparation of Thiazolidine hydrochloride (Formula V)

Cysteamine hydrochloride (500 g) and isopropyl alcohol (1500 mL) was charged into a round bottom flask at room temperature and stirred. Aqueous Formaldehyde solution was added to the reaction mixture and stirred further for 1 hour. The reaction mixture temperature was raised to 75-80°C and stirred for another 1-2 hours. The reaction mass was cooled slowly to 5-10°C. The obtained compound is filtered, washed with acetone (500 mL) and dried under vacuum at 50-55°C.

Example 3: Preparation of N-Boc-trans-4-hydroxy-L-proline methyl ester (Formula

N-Boc-L-hydroxyproline (100 g) and acetone (1100 mL) was charged into a round bottom flask at room temperature and stirred. To the reaction mixture potassium carbonate (120 g) was added at room temperature followed by addition of Dimethyl sulphate (54.65 g). The reaction mixture temperature was raised to reflux temperature and stirred for 3-4 hours. The reaction mass was distilled under vacuum. The obtained reaction mass (Oily mass) was stirred with ethyl acetate (400 mL). The obtained organic layer was washed with water (300 mL) and separated. The obtained organic layer is concentrated under vacuum at 40-45 °C to obtain compound of above Formula IX.

Example 4: Preparation of (2S,4R)-l-tert-butyl-2-methyl-4-(4-nitrobenzene

N-Boc-trans-4-hydroxy-L-proline methyl ester (100 g), toluene (180 mL) and triethylamine (100 g) were charged into the round bottom flask at room temperature which was then cooled to 10-15°C. Nosyl chloride solution (88 g in toluene) was added to reaction mass. The reaction mixture temperature was raised to room temperature and stirred for 4-5 hours. Water (450 mL) was charged in to the reaction mass and organic layer was separated, washed with NaHC0₃ solution. The obtained organic layer was concentrated under vacuum at 50-55°C and cooled to room temperature. Cyclohexane (550 mL) was added to above reaction mass and stirred for 30 minutes. The obtained reaction mass temperature was raised to 40-45°C and stirred. The reaction mass was further cooled and stirred for 2 hours. The obtained reaction mass was filtered, washed with cyclohexane (100 mL) and dried under vacuum at 50-55°C to obtain the title compound.

(2S,4R)-l-tert-butyl-2-methyl-4-(4-nitrobenzenesulfonyloxy)pyrrolidine-l,2- dicarboxylate (100 g), acetonitrile (800 niL), sodium carbonate (49.1 g) and 1 -(3 -methyl- 1- phenyl-lH-pyrazol-5-yl)piperazine (70 g) were charged into the round bottom flask consecutively at room temperature. The obtained reaction temperature was refluxed and stirred for 35-40 hours. The reaction mass was filtered, washed with acetonitrile (80 mL). The filtrate obtained was concentrated completely under vacuum at 50-55°C. Ethyl acetate (300 mL) and water (200 mL) were added to the above reaction mass and stirred for 15 minutes. The obtained organic layer was separated, washed with acetic acid solution and separated the organic layer. The organic layer was further washed with NaHC0₃ solution, the organic layer was separated and concentrated under vacuum at 45-50°C to obtain the title compound.

Compound of Formula IV obtained from the previous stage, tetrahydrofuran (300 mL), water (100 mL), lithium hydroxide (19.5 g) were charged consecutively into a round bottom flask and stirred for 6-7 hours. The obtained reaction mass concentrated and water (200 mL) was added to it at room temperature. Toluene (200 mL) was then added and the reaction mass was stirred for 30 minutes. The aqueous layer obtained was separated and again extracted with toluene. All organic layers were combined followed by pH adjustment to 4.5 to 5.0 by using acetic acid. The obtained reaction mass was diluted with methylene chloride and the organic layer was separated. The combined organic layer was washed with water (150 mL) and concentrated under vacuum at 40°C. Ethyl acetate (300 mL) was added to above reaction mass at room temperature heated to 45-50°C and stirred for 1 hour. Reaction mass was cooled and stirred. The obtained solid was filtered, washed with ethylacetate (100 mL) and dried under vacuum at 50-55°C to obtain the title compound.

Thiazolidine hydrochloride (41.3 g), methylene chloride (600 mL) and aqueous sodium bicarbonate solution (500 mL) were charged into a round bottom flask at room temperature and stirred for 30 minutes. The reaction mixture was settled and separated the methylene chloride layer. The aqueous layer is extracted with methylene chloride (200 mL) and separated. The methylene chloride layers were combined and compound of Formula III (100 g) was charged into it followed by cooling to 0-5°C. EDC.HC1 (50.37 g) and HOBt (10.06 g) was added to the reaction mass and stirred for 1 hour. The reaction mass temperature was raised to 25-30°C and further stirred for 10-12 hours. The obtained reaction mass was diluted with water (1000 mL) followed by charging of N-methyl morpholine (47 g). The reaction mass was stirred for 30 minutes, settled and separated the organic layer. The obtained organic layer was washed with aqueous HC1 solution, followed by water. The organic layer was concentrated completely under vacuum to obtain title compound.

Example 8: Preparation of Compound of Teneligli tin Hydrobromide (Formula I)

Compound of Formula II (wherein Ri=Boc) obtained above and isopropyl alcohol (1000 mL) was charged into a round bottom flask at room temperature. The reaction mass heated to 80-85°C. Aqueous hydrobromide (47%, 113.6g) was added to the reaction mass in 30 minutes and stirred for 3 hours. The obtained reaction mass was cooled to room temperature and stirred for 1 hour. The reaction mass was further cooled to 10-15°C and stirred for 2 hours. The obtained solid was filtered, washed with pre-chilled isopropyl alcohol (100 mL) and the compound was dried under vacuum at 45-50°C to obtain Teneligliptin Hydrobromide hydrate of Formula I.

Example 9: Purification of Teneligliptin Hydrobromide (Formula I)

Teneligliptin Hydrobromide (100 g) and methanol (300 mL) was charged into a round bottom flask at room temperature. The reaction mass was heated to 40-55°C followed by addition of activated carbon (5 g). The reaction mass temperature was further raised to 60-65°C and stirred for 30 minutes followed by filtration through hyflo bed. Water (10 mL) was added to the obtained filtrate and stirred for 1 hour. The reaction mass was cooled and stirred for another 2 hours followed by cooling to 0-5°C and stirred. The obtained solid was filtered, washed with chilled methanol (50 mL) and dried under vacuum at 45-50°C to obtain Teneligliptin Hydrobromide hydrate of Formula I.

Claims

WE CLAIM:

1. A process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof, wherein the process comprises the steps of:

a) reacting compound of Formula Vila

Formula Vila with an l-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazine or a salt thereof Formula VI

Formula VI

to obtain a compound of Formula IV;

b) hydrolyzing the compound of Formula IV to obtain a compound of Formula III;

Formula V to obtain a compound of Formula II; and

wherein,

Ri is Hydrogen or amino protecting group; R₂ is alkyl group;

R₃ is alcohol protecting group.

2. The process according to claim 1, wherein step a) is carried out in the presence of a base and solvent.

3. The process according to claim 2, wherein the base is selected from organic and inorganic base.

4. The process according to claim 3, wherein the base is selected from organic bases comprising of trimethylamine, triethylamine, tributylamine, Ν,Ν-dimethylaniline, N,N- dimethylbenzylamine, Ν,Ν-diisopropylethylamine, N-methyl morpholine, piperidine, 1 ,4- diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) and inorganic bases selected from group comprising of ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate.

5. The process according to claim 2, wherein the solvent is selected from hexane, heptanes, petroleum ether, benzene, toluene, xylene and mesitylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, methanol, ethanol, propanol, isopropanol, n-butanol; 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2- methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, methyl acetate, ethyl acetate, methyl propionate and ethyl propionate, acetonitrile; N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethyl sulfoxide or mixtures thereof.

6. The process according to claim 1, wherein step b) is carried out in the presence of a base and solvent.

7. The process according to claim 6, wherein the base is selected from group comprising ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate or ammonium bicarbonate.

8. The process according to claim 6, wherein the solvent is selected from hexane, heptanes, petroleum ether, benzene, toluene, xylene, mesitylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2- dimethoxyethane, methanol, ethanol, propanol, isopropanol, n-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2- methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, acetonitrile, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof.

9. The process according to claim 1, wherein step c) is carried out in the presence of a condensation reagent and solvent.

10. The process according to claim 9, wherein the condensation reagent is selected from dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropylcarbodiimide (DIC), 1,1'- Carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), N,N,N',N'-Tetramethyl-0-(lH-benzotriazol-l-yl)uronium hexafluorophosphate (HBTU), O- (Benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), Propylphosphonic Anhydride (T3P), 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), 4- (4,6-Dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), N- hydroxybenzotriazole (HOBt), 4,5-dicyanoimidazole, dicyclopentylcarbodiimide, cyclohexylisopropylcarbodiimide (CIC) , bis [ [4-(2,2-dimethyl- 1 ,3 -dioxolyl)] methyl] carbodiimide, N,N'-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-C1), an acid chloride, ethyl chloroformate, or mixture thereof.

11. The process according to claim 9, wherein the solvent is selected from hexane, heptanes, petroleum ether, benzene, toluene, xylene and mesitylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2- dimethoxyethane, acetonitrile, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethyl sulfoxide or mixtures thereof.

12. The process according to claim 1, wherein step d) is carried out in the presence of acid and alcohol solvent.

13. The process according to claim 12, wherein the acid is selected from methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulphamic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid.

14. The process according to claim 12, wherein alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2- trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol or its combinations.

15. A process for the preparation of Teneligliptin intermediate of Formula III or salt thereof, wherein the process comprises the steps of: a) reacting compound of Formula Vila

Formula VI

to obtain a compound of Formula IV;

Formula III ^l c) optionally converting the compound of Formula III to its pharmaceutically acceptable salts,

wherein,

16. The process according to claim 15, wherein step a) is carried out in the presence of a base and solvent.

17. The process according to claim 16, wherein the base is selected from organic and inorganic base.

18. The process according to claim 17, wherein the base is selected from organic bases comprising of trimethylamine, triethylamine, tributylamine, Ν,Ν-dimethylaniline, N,N- dimethylbenzylamine, Ν,Ν-diisopropylethylamine, N-methyl morpholine, piperidine, 1,4- diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) and inorganic bases selected from group comprising of ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate.

19. The process according to claim 16, wherein the solvent is selected from hexane, heptanes, petroleum ether, benzene, toluene, xylene and mesitylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, diethyl ether, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, methanol, ethanol, propanol, isopropanol, n-butanol; 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, methyl acetate, ethyl acetate, methyl propionate and ethyl propionate, acetonitrile; N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethyl sulfoxide or mixtures thereof.

20. The process according to claim 15, wherein step b) is carried out in the presence of a base and solvent.

21. The process according to claim 20, wherein the base is selected from group comprising ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate or ammonium bicarbonate.

22. The process according to claim 20, wherein the solvent is selected from hexane, heptanes, petroleum ether, benzene, toluene, xylene, mesitylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, methanol, ethanol, propanol, isopropanol, n-butanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, acetonitrile, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof.

23. A process for the preparation of Teneligliptin intermediate of Formula IV or salt thereof, wherein the process comprises the steps of:

a) reacting compound of Formula Vila

Formula VI

Formula VI

to obtain a compound of Formula IV;

b) optionally the compound of formula IV is converted to its salts thereof.

24. The process according to claim 23, wherein step a) is carried out in the presence of a base and solvent.

25. The process according to claim 24, wherein the base is selected from organic and inorganic base.

26. The process according to claim 25, wherein the base is selected from organic bases comprising of trimethylamine, triethylamine, tributylamine, Ν,Ν-dimethylaniline, N,N- dimethylbenzylamine, Ν,Ν-diisopropylethylamine, N-methyl morpholine, piperidine, 1,4- diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) and inorganic bases selected from group comprising of ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate.

27. The process according to claim 24, wherein the solvent is selected from hexane, heptanes, petroleum ether, benzene, toluene, xylene and mesitylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, diethyl ether, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, methanol, ethanol, propanol, isopropanol, n-butanol; 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, methyl acetate, ethyl acetate, methyl propionate and ethyl propionate, acetonitrile; N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethyl sulfoxide or mixtures thereof.

28. A compound of Formula IV

or its pharmaceutically acceptable salts thereof;

wherein,

Ri is Hydrogen or amino protecting group;

R₂ is alkyl group.

29. A compound of Formula III

Formula I I I ^l or its pharmaceutically acceptable salts thereof;

wherein,

Ri is Hydrogen or amino protecting group.

30. The process according to claim 1, provide substantially pure Teneligliptin hydrobromide having purity greater than or equal to about 99.5% w/w.

31. The process of claim 1, wherein the amount of each individual process-related impurity listed in table 1, is less than about 0.15%, w/w.

32. The process of claim 1, wherein the sum of all process-related impurity listed in table 1 is less than about 0.1% w/w.