FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)
Process for preparation of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyI-lH-pyrazol-5-yl)-l-
piperazinyl]-2-pyrrolidinylcarbonyl}-l,3-thiazoUdmeand pharmaceutically
acceptable salts thereof
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivili (West)
Mumbai - 400067, Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention provides a novel and improved process for preparation of 3-{(2S,4S)-4-[4-(3-methy 1-1 -phenyl-1 H-pyrazol-5-y 1)-I -piperazinyl]-2-pyrroIidiny Icarbo nyl}-l,3-thiazolidine and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)-I-piperazinyl]-2-pyrrolidinylcarbo nyl}-l,3-thiazofidine, also known as Teneligliptin, belongs to the class of dipeptidyl peptidase-4 (DPP-IV) inhibitors or "gliptins". DPP-1V inhibitors inhibit inactivation of glucagon-like peptide-1 (GLP-1) in plasma and potentiate their incretin action. Therefore, they are useful as drugs potentially effective for the treatment of diabetes, particularly type-2 diabetes. Teneligliptin is represented by structural formula given below:
U.S. Patent No. 7,060,722 describes various proline derivatives including Teneligliptin and pharmaceutically acceptable acid addition salt thereof. It also discloses process for the preparation of Teneligliptin.
According to the process disclosed in U.S. Patent No. 7,060,722, 1-tert-butoxycarbonylpiperazine (I) is reacted with diketene to give l-acetoacetyl-4-tert-butoxycarbonylpiperazine (II) which further reacted with phenyl hydrazine and cyclized to give l-tert-butoxycarbonyl-4-(3-methyl-l-phenyl-5-pyrazoIyl)piperazine (III). 1-tert-butoxycarbonyl-4-(3-methyI-l-phenyI-5-pyrazoIyI) piperazine (III) is deprotected using trifluoroacetic acid to give l-(3-methyl-l-phenyl-5-pyrazolyl)piperazine (IV). N-Boc-4-hydroxyproline (V) is coupled with thiazolidine and resulting 3-[(2S,4R)-l-tert-

butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-l,3-thiazoIidine (VI) is oxidized using sulfur trioxide pyridine complex to give 3-((S)-l-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-l,3-thiazolidine (VII). This thiazolidine derivative (VII) is condensed with piperazine derivative (IV) to give 3-{(2S,4S)-l-tert-butoxycarbonyI-4-[4-(3-methyl-l-phenyI-5-pyrazolyl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l,3-thiazolidine (VIII) which on deprotection gives Teneligliptin (A).
PCT Application No. 2012/165547 also discloses an alternative method for preparation of Teneligliptin. According to the process, ethylpiperazine-t-carboxylate (I) is reacted with diketene and resulting ethyl 4-(3-oxobutanoyI)piperazine-I-carboxylate (II) is reacted with phenyl hydrazine and cyclized to give ethyl 4-(3-methyl-l-phenyl-lH-pyrazoI-5-yl)piperazine-l-carboxylate (IV) which on deprotection gives l-(3-methyI-l-phenyl-5-pyrazolyl)piperazine (V). N-Boc-4-oxoproline (VI) is coupled with thiazolidine and resulting 3-((S)-l-tert-butoxycarbonyI-4-oxo-2-pyrro!idinylcarbonyI)-l,3-thiazo[idine (VII) is condensed with piperazine derivative (V) to give 3-{(2S,4S)-l-tert-

butoxycarbonyl-4-[4-(3-methyl-l-phenyl-5-pyrazoIyl)-l-piperazinyl]-2-pyrroIidinyl carbonyl}-l,3-thiazolidine (VIII) which on deprotection gives Teneligliptin (A).
Aforementioned reported processes are not viable for industrial scale due to use of hazardous reagents. Also these processes are not viable commercially because they are uneconomical due to use of expensive reagents and low yields.
Hence there is a significant need to provide an industrially and commercially feasible process for preparation of Teneligliptin which avoids use of hazardous and expensive reagents, while affording the desired product, Teneligliptin or a pharmaceutically acceptable salt thereof, in high yield and purity.

The present invention provides such an alternative process. The process of the present invention is simple, economic, reproducible, robust and is well amenable on industrial scale.
SUMMARY OF THE INVENTION
The present invention relates to a novel and improved process for preparation of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)-l-piperazinyl]-2-pyrrolidinyl carbonyl}-1,3-miazolidine, known as Teneligliptin (A), and its pharmaceutically acceptable salts.
The first aspect of the present invention is to provide a novel intermediate of formula (H), which can be used in the synthesis of 3-{(2S, 4S)-4-[4-(3-methyI-l-phenyl-lH-pyrazoI-5-yl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l,3-thiazolidine.
The second aspect of the present invention is to provide a process for the preparation of compound of formula (H), comprising steps of;

(a) esterifying (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid of formula (B) using a catalyst in a suitable solvent to give (2S,4R)-4-hydroxypyrroIidine-2-carboxylic acid ester derivative of formula (C),
(b) protecting compound of formula (C) using suitable protecting group and a base in a suitable solvent to give N-protected-(2S,4R)4-hydroxypyrroIidine-2-carboxylic acid ester derivative of formula (D),
(c) oxidizing compound of formula (D) using an oxidizing agent to give N-protected-(2S,4R)-4-oxopyrroIidine-2-carboxylic acid ester derivative of formula (E),
(d) condensing compound of formula (E) with l-(3-methyl-l -phenyl- lH-pyrazol-5-yl)piperazine of formula (F) by reductive amination to give N-protected-(2S,4S)-4-t4-(3-Methyl-l-phenyl-lH-pyrazoI-5-yl)-l-piperazinyl]-2-(3-thiazoIidinyIcarbo nyl)-l-pyrrolidinecarboxylic acid ester derivative of formula (G),

(e) hydrolysing compound of formula (G) using a base in a suitable solvent to provide N-protected-(2S,4S)-4-[4-(3-Methyl-1 -phenyl-1 H-pyrazol-5-yl)-1 -pipera ziny)]-2-(3-thiazolidinylcarbonyl)-l-pyrroiidinecarboxylic acid derivative of formula (H).
Third aspect of the present invention is to provide a process for the preparation of Teneligliptin by reacting compound of formula (H) with 1,3-thiazolidine to give N-protected teneligliptin of formula (I),
which on deprotection using suitable acid gives Teneligliptin (A) or pharamaceutically acceptable salt thereof.


DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel and improved process for the preparation of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)-lpiperazinyl]-2-pyrrolidinylcarbo nyI}-l,3-thiazolidine, known as Teneligliptin (A) and its pharmaceutically acceptable salts using novel intermediates.
In one of the embodiment of the present invention, there is provided a novel intermediate of formula (H) for the preparation of 3-{(2S, 4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l,3-thiazolidine,.

wherein R2 is an N-protecting group.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect a nitrogen atom against undesirable reactions during synthetic procedures and is selected from the group consisting of tert-butyloxycarbonyl (Boc), ethyloxycarbonyl, p-methoxybenzyl carbonyl (Moz), acetyl (Ac), benzoyl (Bz), benzyl (Bn), tosyl (Ts) or p-methoxyphenyl (PMP) and the like. Preferably, R is tert-butyloxycarbonyl (Boc).

In another embodiment of the invention, there is provided a process for preparation of the intermediate of formula (H) comprising steps of;
(a) esterifying (2S,4R)-4-hydroxypyrrolidine-2-carboxyIic acid of formula (B) using a catalyst in a suitable solvent to give (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid ester derivative of formula (C),
(b) protecting compound of formula (C) using a protecting group and base in a suitable solvent to give N-protected-(2S)4R)-4-hydroxypyrrolidine-2-carboxylic acid ester derivative of formula (D),
(c) oxidizing compound of formula (D) using an oxidizing agent to give N-substituted-(2S,4R)-4-oxopyrrolidine-2-carboxylic acid ester derivative of formula (E),
(d) condensing compound of formula (E) with l-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazine of formula (F) by reductive amination to give N-substituted-

(2S,4S)-4-[4-(3-Methyl-l-phenyl-lH-pyrazol-5-yl)-l-piperazinyl]-2-(3-thiazoIidinylcarbonyI)-l-pyrrolidinecarboxylic acid ester derivative of formula
(e) hydrolysing compound of formula (G) using a base in a suitable solvent to provide N-substituted-(2S,4S)-4-[4-(3-Methyl-l-phenyl-lH-pyrazol-5-yl)-l-piper azinyI]-2-(3-thiazoIidinylcarbonyI)-l-pyrroIidinecarboxylic acid derivative of formula (H).
R is a carboxylic acid protecting group selected from C1-4 alkyl such as methyl, ethyl, isopropyl, n-butyl group and depends upon the alcohol solvent used in step (a). Preferably R1 is methyl group. The suitable solvent used in step (a) can be selected from C1-4 alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol. Preferably methanol is being used.
R2 is as defined above.
The catalyst used in step (a) can be selected from the group consisting of thionyl chloride, hydrochloric acid, sulfuric acid, p-toluene sulfonic acid. Preferably, sulfuric acid is being used.

The base used in step (b) can be an organic base such as triethyl amine, pyridine, diisopropylethyl amine, sodium methoxide, sodium ethoxide or an inorganic base such as sodium bicarbonate, potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide. Preferably triethyl amine is being used.
The suitable solvent(s) that can be used in step (b) include but are not limited to halogenated solvents such as dichloromethane, chloroform, ethylene dichloride and the like; esters such as ethyl acetate, propyl aceteate, isopropyl acetate and the like; alcohol like methanol, ethanol and the like; ethers like tetrahydrofuran, 1,4-dioxane and the like; aprotic polar solvents such as dimethyl formamide, dimethyl sulfoxide; aromatic hydrocarbon solvents such as toluene, xylene and the like; water; or a mixture thereof. Preferably methanol is being used as suitable solvent. The reaction temperature in step (b) can range from about 0°C to about 80°C, preferably from about 40°C to about 60°C.
The oxidizing agent used in step (c) can be selected from the group consisting of pyridinium chlorochromate, pyridinium dichromate, chromium trioxide, sodium hypochlorite, manganese dioxide, n-bromosuccinamide, potassium permanganate, sodium perborate, and the like. Preferably, the oxidizing agent is pyridinium chlorochromat.
The solvent used in step (c) can be selected from group consisting of tetrahydrofuran, 1,4-dioxane, isopropyl ether, diethylether, dichloromethane, chloroform, toluene, methanol, ethanol, isopropyl alcohol, n-butanol, water, or mixture thereof. Preferably, the suitable solvent is selected from dichloromethane and isopropylether.
The reducing agent used for reductive amination in step (d) can be selected from the group consisting of sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, and the like. Preferably, sodium triacetoxy borohydride is used as reducing agent. The suitable solvent used in step (d) can be selected from the group consisting of toluene, dichloromethane, chloroform, N,N-dimethyl formamide, dimethylsulfoxide, tetrahydrofuran, methanol, ethanol, n-butanol, water, or mixture thereof. Preferably, the suitable solvent is toluene.

The reaction temperature required for reductive amination can range from about 0°C to about 60°C, preferably from about 0°C to about 30°C. The time period required for completion of reaction can range from about I h to about 24 h.
The base used for hydrolysis of compound of formula (G) in step (e) is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. Preferably, hydrolyzing agent is lithium hydroxide. The suitable solvent used for hydrolysis can be selected from tetrahydrofuran, acetone, N,N-dimethyl formamide, methanol, n-butanol, ethanol, water or mixture thereof. Preferably, the suitable solvent is mixture of methanol, tetrahydrofuran and water.
The reaction temperature required for hydrolysis of compound (G) can range from about 10°C to about 70°C, preferably from about 20°C to about 30°C.
In another embodiment of the invention, there is provided a process for preparation of Teneligliptin by reacting compound of formula (H) with 1,3-thiazolidine in presence of a coupling agent to give N-protected teneligliptin of formula (I),
which on deprotection using suitable acid gives Teneligliptin or its pharmaceutically acceptable salt.

The coupling agent used for coupling of compound of formula (H) with 1,3-thiazolidine can be selected from the group consisting of N,N'-dicyclohexylcarbodiirnide (DCC), N,N'-diisopropyIcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazoIe (HOAt), 0-benzotriazole-N,N,N'-tetramethyl-uronium-hexafluorophosphate (HBTU), N,N,N',N'-tetramethyl-0-(benzotriazol-l-yl)uronium tetrafluoroborate (TBTU), 2-(lH-7-aza benzotriazol-l-yl)-l,l,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU), ethyl(hydroxyimmo)cyanoacetate, (l-Cyano-2-ethoxy-2-oxoethyliden amino oxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), and the like. Preferable coupling agent is DCC or HOBt.
The solvent for the coupling of composition of formula (H) with 1,3-thiazolidine can be selected from the group consisting of tetrahydrofuran, acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane, 1,4-dioxane, toluene or mixture thereof. Preferably, the solvent is N,N-dimethyIformamide. The reaction temperature required for coupling step can range from about 0°C to about 70°C, preferably from about 0°C to about 30°C. The time period required for completion of reaction can range from about 1 h to about 24 h.
Deprotection of compound of formula (I) can be carried out using an acid such as hydrogen bromide, hydrogen chloride, trifluoroacetic acid and the like in a solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, methanol, ethanol, chloroform and the like. The reaction temperature required for deprotection of compound (I) can range from from -30°C to 60°C. The time period required for completion of reaction can range from about 10 min to about 24 h.
In one of the embodiment, teneligliptin hydrobromide salt can be prepared directly by deprotecting compound of formula (I) using hydrogen bromide. Teneligliptin hydrobromide obtained according to the process of the invention is having a purity of at least 95%, preferably at least 99% when measured by high performance liquid chromatography.

Teneligliptin obtained according to the process of the invention can be converted in to its pharmaceutically acceptable salts. The pharmaceutically acceptable salt includes, for example, inorganic acid addition salts (e.g., salts with hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid and the like), organic acid addition salts (e.g., salts 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, methylsulfuric acid and the like), salts with amino acids (e.g., salts with glutamic acid, aspartic acid and the like), and the like.
In one embodiment, the present invention provides a process for preparation of crystalline Teneligliptin hemipenta hydrobromide salt or a hydrate thereof comprising crystallizing teneligliptin hydrobromide or a hydrate thereof from a solvent selected from the group consisting of methanol, n-butanol, tertiary butanol, N,N-dimethyl acetamide, N,N-dimethyI formamide, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, propyl acetate, isopropyl acetate and methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof.
The present invention is explained in detail by referring to examples, which are not to be construed as limitative. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
Example-1: Preparation of (2R,4S)-methyl-4-hydroxypyrrolidine-2-carboxylate
(2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid (200 g) was dissolved in methanol (1.6 L). N, N-dimethyl formamide (2 mL) was added to the above solution and cooled to 0°C-5°C. Thionyl chloride (156mL) was added thereto dropwise at the same temperature and the reaction mass was stirred for 18 h at room temperature. After completion of reaction the reaction mixture was distilled out under reduced pressure and stripped out with methanol (200 mL). Acetone (500 mL) was added to the solid residue and stirred for 1 h at 15°C-20°C. The solid was filtrated off to obtain the titled compound as white solid (250 g, Yield: 90%).

Example-2: Preparation of (2R,4S)-l-tert-butyl-2-methyl-4-hydroxypyrrolidine-l,2-dicarboxylate
(2R,4S)-Methyl-4-hydroxypyrrolidine-2-carboxylate (247 g) was dissolved in methanol (1.44 L) and cooled to 10°C-20°C. Triethyl amine (578 mL) was added thereto. Diterbutylpyrocarbonate (403.6g) was added to above reaction mixture slowly and stirred for 16 h at room temperature. After completion of reaction the reaction mixture was distilled out under reduced pressure. The obtained residue was dissolved in water (400 mL) and extracted with ethyl acetate (600 mL x 2). The organic layer was washed with water (400 mL), followed by 2.5% aqueous acetic acid (400 mL) and 2.5% aqueous sodium bicarbonate (400 mL). Final 10% brine solution (400 mL) wash was given to the organic layer, it was dried over sodium sulfate and distilled under reduced pressure to obtain the titled compound as colorless oil (290 g, Yield: 87%).
Example-3: Synthesis of (R)-l-tert-butyl 2-methyl-4-oxopyrrolidine-l,2-dicarb oxylate
(2R,4S)-1 -tert-butyI-2-methyI 4-hydroxypyrrolidine-1,2-dicarboxylate (100.0 g) was dissolved in dichloromethane (2.0 L), and cooled to 0°C-5°C. Pyridinium chlorochromate (307.6 g) was added portion wise thereto and the reaction mixture was stirred for 18 h, while warming the reaction mixture to room temperature. Diisopropyl ether (2.0 L) was added to the reaction mixture, followed by addition of activated charcoal (50 g) and hyflow (70.0 g), and the reaction mixture was stirred for 1 h and filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in diisopropyl ether (1.5 L), mixed and stirred with activated charcoal (30.0 g) and hyflow (40.0 g) for 1 h at room temperature. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to obtain the titled compound as light green oil (89.0 g, Yield: 90.0%).
ExampIe-4: Synthesis of (2S,4S)-methyI 4-(4-(3-methyl-l-phenyl-lH-pyrazol-5-yI)-piperazin-l-yl)-pyrro!idine-2-carboxylate
l-(3-methyI-l-phenyl-lH-pyrazol-5-yl)-piperazine (35 g) was dissolved in toluene (300 mL) at room temperature. Thereto glacial acetic acid (8 g) was added slowly. (R)-l-tert-butyl 2-methyl 4-oxopyrrolidine-l, 2-dicarboxylate (32 g) obtained in example 1 was

added to the above mixture and flushed with toluene (20 mL). The resulting mixture was stirred for 1.5 h at room temperature. To the reaction mixture sodium triacetoxy borohydride (30.7 g) was added and flushed with toluene (100 mL). The resulting mixture was further stirred for 6 h at room temperature. Another lot of Sodium triacetoxy borohydride (14 g) was added thereto and stirred for 12 h at room temperature. After completion of reaction water (250 mL) was added two get bilayerd mixtue. Both the layers were separated and toluene layer was collected and washed with 5% aq. acetic acid (200 mL) followed by washing with 5% aqueous sodium hydrogen carbonate solution. Toluene layer was dried over sodium sulfate and distilled under vacuum to obtain crude compound as reddish oil (60 g, Yield: 97%).
ExampIe-5: Synthesis of (2S, 4S)-l-(tert-butoxycarbonyl)-4-(4-(3-methyI-l-phenyl-lH-pyrazol-5-yl)-piperazin-l-yl)-pyrrolidine-2-carboxylicacid
(2S,4S)-methyl-4-(4-(3-methyl-l -phenyl- lH-pyrazol-5-yl)-piperazin-l-yl)-pyrroIidine-2-carboxylate (459 g) was dissolved in methanol (1.62L). Thereto added a solution of lithium hydroxide (90.73 g) in water (381 mL), and the reaction mixture was stirred for 1.5 h at room temperature. After completion of reaction, solvent was evaporated under reduced pressure. The residue was suspended in water (2 L) and ethyl acetate (2 L) wash was given thereto. Both the layers separated and the aqueous layer was acidified with glacial acetic acid to pH 3 to 5. The acidified aqueous layer was extracted with dichloromethane (2 L). The organic layer was washed with aqueous sodium hydrogen carbonate solution (500 mL), dried and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (1 L) with heating and the resulting solution stirred at 65°C for 1 h. The reaction mixture cooled to room temperature, and then to 0°C-5°C. The precipitates were collected by filtration, washed with chilled ethyl acetate (225mL) and dried with warm air to give title compound as off white solid (188.5 g, Yield: 42.33%).
Example-6: Synthesis of 3-{[(2S, 4S)-4-[4-(3-methyM-phenyI-lH-pyrazole-5-yl)-l-piperazinyl]-2-pyrro!idinyl]-carbonyl}thiazoIidine
(2S,4R)-l-(tert-butoxycarbonyl)-4-(4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)-piperazin-l-yl)-pyrrolidine-2-carboxylic acid (80 g) was dissolved in N,N-dimethyl formamide (400

mL) under stirring at room temperature. 1-hydroxybenozotriazole (29.4 g) and dicyclohexyl carbodiimide (43.4 g) were charged thereto and stirred at room temperature for 30 min. Solution of thiazolidine (18.7 g) in N,N-dimethyl formamide (40 mL) was added to the above mixture and stirred for 18 h at room temperature. After completion of reaction water (750 mL) was added to the reaction mixture and resulting mixture was extracted with ethyl acetate (400 mL x 2). Combined organic layer was washed with 5% aqueous glacial acetic acid (200 mL x 2), aqueous saturated sodium bicarbonate solution (200 mL x 2) and water (200 mL x 2), dried and evaporated completely under vacuum to get the title compound as white solid (84 g, Yield: 90.0%).
Example-7: Synthesis of Teneligliptin hemipenta hydrobromide dihydrate
(I)3-{(2S,4S)-I-(l,l-Dimethylethyloxycarbonyl)-4-[4-(3-methyl-l-phenyI-lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yIcarbonyl}thiazolidine (75 g) was dissolved in isopropyl alcohol (600 mL) under stirring and heated at 78°C-80°C. Aqueous hydrobromic acid (48 %, 74.5 g) was added drop wise to above solution at 78°C-80°C and resulting mixture was refluxed for 3-4 h. After completion of the reaction, the reaction mass was cooled and stirred at 60°C-62°C for 2 h, followed by stirring at 40°C-42°C for 2 h and stirring at room temperature for 2 h. The precipitates were collected by filtration, washed with isopropyl alcohol (75 mL x 2) and dried at 40°C-45°C to give title compound (75.4 g).
II) The solid (75 g) obtained in (I) was dissolved in ethanol (450 mL) at 68°C-70°C with stirring and filtered. The filtrate was heated at 68°C-70°C and water (8 mL) was added to it. The resulting mixture was cooled gradually and stirred at 15°C-20°C for 1 h. The crystallized product was filtered and washed with chilled ethanol (50 mL x 2) to obtain the titled compound as white solid (44.9 g, Yield: 47%)

We claim:
1) A process for preparation of Teneligliptin of formula (A) or its pharmaceutically acceptable salts comprising;
(a) coupling compound of formula (H) with 1,3-thiazoIidine in presence of a reducing agent to give compound of formula (I),
(b) deprotecting compound of formula (I) to give Teneligliptin or its pharmaceutically acceptable salt,
wherein R2 is an N-protecting group.
2) A process according to claim 1, compound of formula (H) is coupled with 1,3-thiazolidine in step (a) using a coupling agent selected from the group consisting of DCC, EDC and HOBt.
3) A process according to claim 1, compound of formula (I) is deprotected by treatment with hydrobromic acid in step (b).
4) A process according to claim 1, wherein compound of formula (H) is prepared by;
(a) esterifying compound of formula (B) using to give compound of formula (C),

wherein, R1 is a carboxylic acid protecting group (b) protecting compound of formula (C) to give compound of formula (D),
wherein R2 is an N-protecting group
(c) oxidizing compound of formula (D) using an oxidizing agent to give compound of formula (E)
(d) condensing compound of formula (E) with compound of formula (F) to give compound of formula (G)
(e) hydrolysing compound of formula (G) using a base in a suitable solvent,

5) A process according to claim 4, wherein R2 is an protecting group selected from the group consisting of tert-butyloxycarfaonyl (Boc), ethyloxycarbonyl, p-methoxybenzyl carbonyl (Moz), acetyl (Ac), benzoyl (Bz), benzyl (Bn), tosyl (Ts) and p-methoxyphenyl (PMP).
6) A process according to claim 4, the oxidizing agent in step (c) is selected from the group consisting of Pyridinium chlorochromate, Pyridinium dichromate, chromium trioxide, sodium hypochlorite, manganese dioxide, n-bromo succinamide, potassium permanganate and sodium perborate.
7) A process according to claim 4, wherein reducing agent in step (a) is selected from the group consisting of sodium borohydride, sodium triacetoxy borohydride and sodium cyanoborohydride.
8) A process according to claim 4, wherein compound (F) is hydrolysed using hydrolyzing agents selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide and mixture thereof.
9) A compound having formula (F) or its acid addition salts.
wherein, Rl is a carboxylic acid protecting group & R2 is an N-protecting group

10) A compound having formula (G) or its acid addition salts.
wherein, R1 is a carboxylic acid protecting group