Claims:We Claim:
1. A process for preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof comprising:

converting compound of formula (5a) to compound of formula 13 in
presence of carbodiimide and DMSO.

wherein R is an amino protecting group
2. The process as claimed in claim 1, wherein carbodiimide is selected from group consisting of N,N'-Dicyclohexylcarbodiimide (DCC), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC), N,N’-Diethylcarbodiimide, N,N’-Diisopropylcarbodiimide.
3. The process as claimed in claim 2, wherein carbodiimide is N,N'-Dicyclohexylcarbodiimide (DCC).
4. The process as claimed in claim 1, wherein the amino protecting group R is selected from group consisting of aralkyl such as benzyl, p-nitrobenzyl, benzhydryl, trityl; acyl such as formyl, acetyl, propionyl, methoxyacetyl, methoxypropionyl, benzoyl, thienylacetyl, thiazolylacetyl, tetrazolylacetyl, thiazolylglyoxyloyl, thienylglyoxyloyl; lower alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl; aralkyloxy-carbonyl such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl; lower alkane sulfonyl such as methane sulfonyl, ethane sulfonyl; aryl sulfonyl such as toluene sulfonyl; tri-(lower alkyl) silyl such as trimethylsilyl; and triphosgene.
5. The process as claimed in claim 4, wherein the amino protecting group R is selected from group consisting of acetyl, tert-butoxycarbonyl and 9-fluorenylmethyloxycarbonyl.
6. A process for preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof comprising:

a. converting compound of formula (5a) to compound of formula 13 in presence of carbodiimide and DMSO to compound of formula (13),

wherein R is an amino protecting group
b. reacting the compound of formula (13) with compound of formula Int-B or an N-protected derivative or salt thereof to obtain compound of formula 14; and

c. deprotecting compound of formula 14 to obtain Teneligliptin, a compound of formula I or salt or hydrate thereof.
7. The process as claimed in claim 6, wherein carbodiimide is selected from group consisting of N,N'-Dicyclohexylcarbodiimide (DCC), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC), N,N’-Diethylcarbodiimide, N,N’-Diisopropylcarbodiimide.
8. The process as claimed in claim 7, wherein carbodiimide is N,N'-Dicyclohexylcarbodiimide (DCC).
9. The process as claimed in claim 6, wherein the amino protecting group R is selected from group consisting of aralkyl such as benzyl, p-nitrobenzyl, benzhydryl, trityl; acyl such as formyl, acetyl, propionyl, methoxyacetyl, methoxypropionyl, benzoyl, thienylacetyl, thiazolylacetyl, tetrazolylacetyl, thiazolylglyoxyloyl, thienylglyoxyloyl; lower alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl; aralkyloxy-carbonyl such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl; lower alkane sulfonyl such as methane sulfonyl, ethane sulfonyl; aryl sulfonyl such as toluene sulfonyl; tri-(lower alkyl) silyl such as trimethylsilyl; and triphosgene.
10. The process as claimed in claim 9, wherein the amino protecting group R is selected from group consisting of acetyl, tert-butoxycarbonyl and 9-fluorenylmethyloxycarbonyl.
11. The process as claimed in claim 1 or claim 6, wherein the process of converting compound of formula (5a) to compound of formula (13) is carried out in presence of mild acid.
12. The process as claimed in claim 11, wherein mild acid is selected from group consisting of pyridinium trifluoroacetate, pyridinium tosylate, pyridinium phosphate, pyridinium chloride.
13. The process as claimed in claim 12, wherein mild acid is pyridinium trifluoroacetate.
14. The process as claimed in claim 1 or claim 6, wherein the compound of formula I is Teneligliptin 2.5 hydrochloride or Teneligliptin 2.5 hydrobromide or hydrate thereof.

Dated this 16th day of March, 2016. , Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENTS RULES, 2003
PROVISIONAL/COMPLETE SPECIFICATION
(See section 10; rule13)

PROCESS FOR THE PREPARATION OF TENELIGLIPTIN

Glenmark Pharmaceuticals Limited
An Indian Company
Glenmark House,
HDO – Corporate Bldg,
Wing -A, B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai – 400 099, India

The following specification particularly describes the invention and the manner in which it is to be performed.

The present invention comprises an improvement in the invention claimed in the specification of the Indian complete application number 2544/MUM/2012 dated August 28, 2013.

Priority:
This application claims the benefit of Indian provisional application(s) 2544/MUM/2012, filed on August 31, 2012 and 678/MUM/2013, filed on March 06, 2013, the entire content of which is incorporated by reference herein.

Field of Invention
The present invention relates to an improved process for the preparation of Teneligliptin, 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine and pharmaceutically acceptable salts or hydrates thereof.

Background of the Invention
Teneligliptin which is chemically known as 3-{(2S,4S)-4-[4-(3.methyl-l-phenyl-lH-pyrazol-5-yl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l,3-thiazolidine is
represented structurally by compound of formula (I):

Formula I
United States Patent No. 7,074,794 (US'794) describes the process for preparation of trihydrochloride salt of formula I. tert-butyl (2S)-4-oxo-2-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidine-1-carboxylate, hereinafter referred to as Int-A, is one of the key intermediates in the synthesis of compound I. Int-A is represented by following chemical formula:

The process described in US'794 patent employs sulphur trioxide pyridine complex for the synthesis of Int-A from tert-butyl (2S,4R)-4-hydroxy-2-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidine-1-carboxylate. One of the disadvantages associated with the use of sulphur trioxide pyridine complex is that it is expensive and increases the process cost. Further, Int-A obtained by US'794 patent process is isolated by column chromatography which results in loss of yield.
The present inventors have surprisingly designed an improved process to overcome the problems of prior art which leads to increased yield of product obtained in cost-effective manner.

Object of the Invention
The object of the present invention is to provide an improved process to overcome aforesaid problems and to provide simple, cost effective and industrially feasible process for manufacture of Teneligliptin or salt or hydrates thereof.

Summary of the Invention
In one embodiment the present invention provides an improved process for the preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof comprising:
converting compound of formula (5a) to compound of formula 13 in presence of carbodiimide and dimethyl sulfoxide (DMSO)

wherein R is an amino protecting group
In one embodiment, the present invention provides a process for preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof comprising:

a. converting compound of formula (5a) to compound of formula 13 in presence of carbodiimide and DMSO

wherein R is an amino protecting group
b. reacting the compound of formula (13) with a compound of formula Int-B or an N-protected derivative or salt thereof to obtain compound of formula 14,

c. deprotecting the compound of formula 14 to obtain Teneligliptin, a compound of formula I or salt or hydrate thereof.
In one embodiment the present invention provides an improved process for the preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof comprising:
converting compound of formula (5) to compound of formula Int-A in presence of carbodiimide and DMSO

wherein R is an amino protecting group
In one embodiment, the present invention provides compound of formula Int-A having purity of atleast 99.0% by HPLC and having 100% chiral purity.
In one embodiment, the present invention provides a process for the preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof,

I.
by using compound of formula Int-A having purity of atleast 99.0% by HPLC and having 100% chiral purity.
In one embodiment, the present invention provides use of carbodiimide and DMSO in preparation of compound of formula 13 or compound of formula Int-A or Teneligliptin, a compound of formula I or salt or hydrate thereof.
In one embodiment, the present invention provides use of N,N’- dicyclohexylcarbodiimide (DCC) and DMSO in preparation of compound of formula 13 or compound of formula Int-A or Teneligliptin, a compound of formula I or salt or hydrate thereof.

Detailed Description of the Invention
In one embodiment, the present invention provides an improved process for the preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof comprising:

converting compound of formula (5a) to a compound of formula 13 in presence of carbodiimide and DMSO.

wherein R is an amino protecting group
The amino protecting group represented by R in compound of formula 5a and compound of formula 13 can be selected from the group consisting of aralkyl such as benzyl, p-nitrobenzyl, benzhydryl, trityl; acyl such as formyl, acetyl, propionyl, methoxyacetyl, methoxypropionyl, benzoyl, thienylacetyl, thiazolylacetyl, tetrazolylacetyl, thiazolylglyoxyloyl, thienylglyoxyloyl; lower alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl; aralkyloxy-carbonyl such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl; lower alkane sulfonyl such as methane sulfonyl, ethane sulfonyl; aryl sulfonyl such as toluene sulfonyl; tri-(lower alkyl) silyl such as trimethylsilyl; and triphosgene. The preferred amino protecting group represented by R can be selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl and acetyl. Most preferred amino protecting group is tert-butoxycarbonyl.
A suitable carbodiimide used in the process of present invention can be selected from group consisting of N,N'-Dicyclohexylcarbodiimide (DCC), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC), N,N’-Diethylcarbodiimide, N,N’-Diisopropylcarbodiimide and like. The preferred carbodiimide used in the process of present invention is N,N'-Dicyclohexylcarbodiimide (DCC).
In one embodiment, when R is tert-butoxycarbonyl, the present invention provides a process for preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof comprising:
converting compound of formula (5) to compound of formula Int-A in presence of carbodiimide and DMSO

The suitable carbodiimide used in above process is same as defined above.
In one embodiment, the present invention provides process for converting compound of formula (5a) to compound of formula 13 and process for converting compound of formula (5) to compound of formula Int-A in presence of mild acid.
Suitable mild acid used in the process of present invention is selected from group consisting of pyridinium trifluoroacetate, pyridinium tosylate, pyridinium phosphate, pyridinium chloride. Preferably, the mild acid used in the process of present invention is pyridinium trifluoroacetate and is formed in-situ by addition of pyridine and trifluoroacetic acid to reaction mass.
In one embodiment, the process for converting compound of formula (5a) to compound of formula (13) or the process for converting compound of formula (5) to compound of formula Int-A is carried out in halo hydrocarbon solvent. The halohydrocarbon solvent is selected from group consisting of dichloromethane, 1,2-dichloroethane, chloroform, carbontetrachloride, and chlorobenzene. Preferred halo hydrocarbon solvent is dichloromethane.
In one embodiment, the present invention provides a process for preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof comprising:

a. converting compound of formula (5a) to compound of formula (13) in presence of carbodiimide and DMSO,

wherein R is an amino protecting group
b. reacting the compound of formula (13) with a compound of formula Int-B or an N-protected derivative or salt thereof to obtain compound of formula 14; and

c. deprotecting the compound of formula 14 to obtain Teneligliptin, a compound of formula I or salt or hydrate thereof.
The amino protecting group in above process has same meaning as defined above.
The term “N-protected derivative” is intended to mean an amino protecting group selected from the group consisting of aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl, and tri-(loweralkyl)silyl. The preferred amino protecting group is lower alkoxy carbonyl like tert-butoxycarbonyl.
In one embodiment, the present invention relates to a process for the preparation of a salt of Int-B as described in the specification of Indian complete application 2544/MUM/2012, the entire content of which is incorporated by reference herein.

In one embodiment, suitable carbodiimide used in step (a) of above process is same as defined above.
In one embodiment, step (a) of above process for converting compound of formula 5a to compound of formula 13 is carried out in presence of mild acid in halo hydrocarbon solvent. The terms “mild acid” and “halo hydrocarbon solvent” have the same meaning as defined above.
In one embodiment, step (b) of above process for preparation of compound of formula 14 is same as described in the specification of Indian complete application 2544/MUM/2012, the entire content of which is incorporated by reference herein.
In one embodiment, step (c) of above process for deprotection of compound of formula 14 to obtain Teneligliptin a compound of formula I or salt or hydrate thereof, is same as described in the specification of Indian complete application 2544/MUM/2012, the entire content of which is incorporated by reference herein.
In one embodiment, the present invention provides process for preparation of compound of formula 12,

comprising reacting compound of formula Int-A with compound of formula Int-B

In one embodiment, process for preparation of compound of formula 12 is analogous to process for preparation of compound of formula 14 described in specification of Indian complete application 2544/MUM/2012, the entire content of which is incorporated by reference herein.
In one embodiment, the present invention provides a process for preparation of Teneligliptin, a compound of formula I or salt or hydrate thereof comprising:
a. converting compound of formula (5) to compound of formula Int-A in presence of carbodiimide and DMSO,

b. reacting compound of formula Int-A with compound of formula Int-B or an N-protected derivative or salt thereof to obtain compound of formula (12); and

c. deprotecting compound of formula (12) to obtain Teneligliptin, a compound of formula I or salt or hydrate thereof.
In one embodiment, suitable carbodiimide used in step (a) of above process is same as defined above.
In one embodiment, step (a) of above process is carried out in presence of mild acid in halo hydrocarbon solvent. The terms “mild acid” and “halo hydrocarbon solvent” have the same meaning as defined above.
In one embodiment, step (b) of above process for preparation of compound of formula 12 is analogous to process for preparation of compound of formula 14 described in specification of Indian complete application 2544/MUM/2012, the entire content of which is incorporated by reference herein.
In one embodiment, step (c) of above process for deprotection of compound of formula 12 to obtain Teneligliptin a compound of formula I or salt or hydrate thereof, is analogous to process for deprotection of compound of formula 14 described in specification of Indian complete application 2544/MUM/2012, the entire content of which is incorporated by reference herein.
In one embodiment, Teneligliptin obtained by the process of present invention is Teneligliptin 2.5HBr hydrate.
In one embodiment, Teneligliptin obtained by the process of present invention is Teneligliptin 2.5HCl.

EXAMPLES
The examples described herein below were prepared using the intermediates and synthetic scheme discussed above. The organic and inorganic acids, solvents, aldehydes, anhydrides, oxidizing agents, coupling agents, amino group protecting agents, condensation reagents required in the preparation of the compounds of the present invention are commercially available or can be prepared by following the procedures known in the literature.

The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The examples provided below are merely illustrative of the invention and are not intended to limit the same to disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention.

Example 1: Preparation of Int-A
3-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidine

Int-A
Step-1: Preparation of 1, 3-thaizolidine
To a saturated solution of sodium carbonate (500 g) in water (3.5 L), cysteamine hydrochloride (100 g, 0.88 mol) was added. The reaction mixture was cooled at 15-20 °C. To the reaction mass was added 35-37 % formaldehyde solution (0.70 g, 0.70 times) and stirred at 15-20 °C for 2 h. The reaction mixture was extracted with dichloromethane (4.0 L). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.70 g of the desired product.

Step-2: Preparation of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine
To a solution of Trans-4-hydroxy-L-proline (100 g, 0.76 mol) in mixture of Tetrahydrofuran (THF) (400 mL) and water (400 mL), sodium hydroxide (35 g, 0.87 mol) and di-t-butyl dicarbonate (200 g, 0.91 mol) was added at 0-5 °C. The reaction mixture was stirred at 25-30 °C for 16 h. The reaction was monitor by HPLC. The reaction mixture was diluted with water and extracted with hexane. The organic layer was separated and acidified the aqueous layer with conc. hydrochloric acid and extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous sodium sulphate and concentrated to afford N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline as oily mass.
The oily mass of N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline was dissolved in dichloromethane (MDC) (1000 mL). HOBT (66g, 0.48 mol), N-methylmorpholine (83g, 0.82 mol) and 1,3-thaizolidine (66 g, 0.74 mol) were added to this mixture at 0-5 °C. After stirring for about 1h, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150 g, 0.78 mol) was added to reaction mass at 0-5 °C. The reaction mixture was further stirred for 2 h at 0-5 °C and stirring was continued for further 24 h at 25-30 °C. The reaction was monitored by HPLC. The reaction mass was concentrated and aqueous sodium hydroxide solution was added. The aqueous solution was washed with Diisopropyl ether. The pH of aqueous solution was adjusted to 8.0-9.0 by dilute HCl solution and aqueous solution was extracted with ethyl acetate. The extract was dried and the solvent was evaporated under reduced pressure. The product was isolated from industrial solvent (150 mL) and Diisopropyl ether (1500 mL) mixture to afford 105 g of desired product as off white solid.

Step-3: Preparation of 3-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinyl carbonyl)-1,3-thiazolidine
3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3- thiazolidine (25 g, 0.082 mol) was dissolved in dichloromethane (50 mL) and dimethyl sulphoxide (100 mL). The solution was cooled to 0-5 °C and pyridine (4.25 mL) and N,N’-dicyclohexylcarbodiimide (54.6 g, 0.264 mol) were added followed by dropwise addition of Trifluoroacetic acid (4.5 mL) at 0-5 °C. The reaction mixture was stirred for 2-3 h at 25-30 °C. Reaction was monitored by HPLC. Reaction mass was quenched with dropwise addition of oxalic acid solution (25 g oxalic acid dissolved in 50 mL methanol). The reaction mass was further quenched in water (1000 mL) and ethyl acetate (250 mL) at 10-15 °C. After stirring for about 15-20 min, the reaction mixture was filtered through hyflo bed in buncher funnel. Filtrate was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution followed by brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the crude product was treated with ethyl acetate (125 mL) and filter through hyflo to remove insoluble white solid N,N’-dicyclohexyl urea (DCU). The solvent was evaporated under reduced pressure and the final product was isolated from Isopropanol (12.5 mL), Ethyl Acetate (12.5 mL) and Hexane (250 mL) mixture to afford 18 g of title compound as a white solid.

Example 2: Preparation of Int-A
3-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidine

Int-A
Step-1: Preparation of 1, 3-thaizolidine
To a saturated solution of sodium carbonate (500 gm) in water (3.5 L) was added cysteamine hydrochloride (100gm, 0.88 mol). The reaction mixture was cooled to 15-20 °C. To the reaction mass was added 35-37 % formaldehyde solution (0.70 gm, 0.70 times) and the reaction mass was stirred at 15-20 °C for 2 h. The reaction mass was extracted with dichloromethane (4.0 L). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.70 gm of title compound.
Step-2: Preparation of 3-[(2S, 4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1, 3-thiazolidine
To a solution of Trans-4-hydroxy-L-proline (150 gm, 0.76 mol) in mixture of Acetone (750 mL) and water (750 mL), sodium hydroxide (52.5 gm, 1.31 mol) and di-t-butyl-dicarbonate (300 gm, 1.38 mol) was added at 5-10 °C. The reaction mixture was stirred at 25-30 °C for 12 h. The reaction was monitored by HPLC. The reaction mixture was diluted with water (750 mL) and extracted with dichloromethane (750 mL x 2). The organic layer was separated. Aqueous layer was acidified with conc. hydrochloric acid and extracted with ethyl acetate (750 mL x 2). All organic layer were combined and washed with saturated brine, dried over anhydrous sodium sulphate and concentrated to afford N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline as oily mass.
The oily mass of N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline was dissolved in dichloromethane (2500 mL). To this solution, 1,3-thiazolidine (98 g, 1.099 mol) and N,N’-dicyclohexylcarbodiimide (248 g, 1.20 mol) were added at 0-5 °C. The reaction mixture was stirred for 1 h at 0-5 °C and further for 6-8 h at 25-30 °C. The reaction was monitored by HPLC. The reaction mass was quenched in water (1000 mL) and ethyl acetate at 10-15 °C. After stirring for 15-20 mins, the reaction mixture was filtered through hyflo in buncher funnel. The solvent was evaporated under reduced pressure and aqueous sodium hydroxide solution (173 gm NaOH in 2.5 L water) was added at 10-15 °C and stirred for 30-45 mins. The aqueous solution washed with hexane (750 mL x 2). The pH of aqueous solution was adjusted to 6.0-7.0 by using 50 % dilute HCl solution (870 mL) and aqueous solution was extracted with ethyl acetate (1.5 L, 750 mL). The extract was dried, and the solvent was evaporated under reduced pressure. The product was isolated from IPA (150 mL) and DIPE (1500 mL) mixture to afford 196 g of desired product as off white solid.
Step-3: Preparation of 3-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinyl carbonyl)-1,3-thiazolidine
3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (150 gm, 0.496 mol) was dissolved in dichloromethane (450 mL) and Dimethyl sulphoxide (600 mL). The solution was cooled to 0-5 °C and pyridine (25.5mL) and N,N’-Dicyclohexylcarbodiimide (233 g, 1.13 mol) were added followed by dropwise addition of Trifluoroacetic acid (27 mL). The reaction mixture was stirred for 2-3 h at 25-30 °C. Reaction was monitored by HPLC. Reaction mass was quenched with dropwise addition of oxalic acid solution (150g oxalic acid dissolved in 300 mL methanol). The reaction mass quenched in water (6000 mL) and MDC (1500 mL) at 10-15 °C. After stirring for 15-20 min the reaction mixture was filtered through hyflo in buncher funnel. Reaction mixture was extracted with MDC. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution followed by brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the crude product treated with ethyl acetate (1500 mL) and filtered through hyflo to remove insoluble white solid (DCU). The solvent was evaporated under reduced pressure and product was isolated from IPA (75 mL), Ethyl acetate (75 mL) and Hexane (1500 mL) mixture to afford 108 g desired product as a white solid.
Example 3: Synthesis of 9H-fluoren-9-ylmethyl-(2S)-4-oxo-2-(1,3-thiazolidin-3-ylcarbonyl) pyrrolidine-1-carboxylate

Step-1: Preparation of crude 9H-fluoren-9-ylmethyl-(2S)-4-oxo-2-(1,3-thiazolidin-3-yl carbonyl) pyrrolidine-1-carboxylate
To a stirred solution of 3-[(2S,4R)-1-fluorenylmethoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl] 1,3-thiazolidine (125 g, 0.29 mol) in dichloromethane (250 mL) & DMSO (375 mL) were added pyridine (16.25 mL) & N,N’-Dicyclohexylcarbodiimide (194 g, 0.94 mol) at 0-5 °C. To this solution, trifluoroacetic acid (17.5 mL) was added slowly at 0-5 °C. The reaction mixture was stirred for 30 min at 5-10 °C & further stirred at 25-30 °C for 3 h. The reaction mixture was monitored by TLC/HPLC. The reaction mixture was quenched in dil.HCl solution (63 mL conc.HCl diluted in 3.75 L of water) at 10-15 °C. Ethyl acetate (1.875 L) was added to reaction mixture and was stirred for 30 min. Reaction mixture was filtered through hyflo bed and bed was washed with ethyl acetate (625 mL). Layers were separated; aqueous layer was extracted with ethyl acetate. All organic layers were combined and washed with sodium bicarbonate solution (150 g dissolved in 625 mL of water), brine solution and dried over sodium sulphate. Ethyl acetate was distilled and co-distilled with methanol under reduced pressure at 45 °C. Added Ethyl acetate (125 mL) & methanol (625 mL) at 50°C & stirred for 30 min. Further stirred for 3h at 25-30 °C. The solid was collected by filtration & washed with methanol to get 94.8 g of title compound as white solid.
Step-2: Purification of crude 9H-fluoren-9-ylmethyl-(2S)-4-oxo-2-(1,3-thiazolidin-3-ylcarbonyl) pyrrolidine-1-carboxylate
Crude compound (25.0 g) obtained in Step-1 was dissolved in methanol (250 mL) & ethyl acetate (280 mL) at reflux temperature. The reaction mixture was allowed to cool and stirred at 25 °C for 3h. The precipitate was collected by filtration, washed with methanol (25 mL) and dried under reduced pressure at 55-60 °C to get 12.5 g of pure 9H-fluoren-9-ylmethyl-(2S)-4-oxo-2-(1,3-thiazolidin-3-yl carbonyl) pyrrolidine-1-carboxylate.

Example 4: Synthesis of 9H-fluoren-9-ylmethyl-(2S)-4-oxo-2-(1,3-thiazolidin-3-ylcarbonyl) pyrrolidine-1-carboxylate

To a stirred solution of 3-[(2S,4R)-1-fluorenylmethoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (250 g, 0.59 mol) in dichloromethane (750 mL) and DMSO (1000 mL) was added pyridine (33 mL) and N,N’-Dicyclohexylcarbodiimide (388 g, 1.88 mol) at 0-5 °C. To this reaction mass, trifluoroacetic acid (35 mL) was added slowly at 0-5 °C. The reaction mixture was stirred for 30 min at 0-10 °C and further stirred at 25-30 °C for 3 h. The reaction mixture was monitored by TLC/HPLC. The reaction mixture was quenched in oxalic acid solution (312 gm oxalic acid diluted in 500 mL of methanol) at 10-15 °C. Ethyl acetate (3.75 L) and sodium chloride solution (63 gm sodium chloride in 10 L water) were added and the reaction mixture was stirred for 30 min. Reaction mixture was filtered through hyflo and washed bed with ethyl acetate (1250 mL). Layers were separated and aqueous layer was extracted with ethyl acetate. Organic layer was washed with sodium bicarbonate solution (250 g dissolved in 2.5 L of water), brine solution and dried over sodium sulphate. Organic layer was distilled and co-distilled with methanol under reduced pressure at 45 °C. Ethyl acetate (250 mL) and methanol (1250 mL) were added at 50 °C and stirred for 30 min. The reaction mass was further stirred for 3h at 25-30 °C. The solid was collected by filtration and washed with methanol to get 187 g of title compound as white solid.

Example 5a: Synthesis of l-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazine acetate

Step-1: Preparation of 1-Phenyl-3-methyl-5-aminopyrazole
To a stirred solution of 3-Aminocrotononitrile (60 gm, 0.7142 mol) and 1N HCI (600 mL) was added phenyl hydrazine (72 mL). The reaction mass was stirred for 4 hrs at 110-115 °C. The reaction mixture was cooled to room temperature and quenched in ice water (3.0 L). Further the reaction mixture was neutralized with sodium bicarbonate solution. The precipitated solid was then stirred, filtered and dried to get 110 gm of the title compound.
Step-2: Synthesis of l-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazine acetate
To the stirred solution of sodium hydride (60 % dispersion in mineral oil, 69 gm, 1.734mol) and N,N-Dimethyl formamide (400 mL) was slowly added Step-1 compound solution (50 gm, 0.289 mol in 50 mL of DMF) at 0-5 °C and stirred for 0.5 hrs. Bis(2-chloroethyl)-amine hydrochloride solution (55 gm, 0.308 mol in 50 mL of Dimethylformamide) was added to the reaction mass at 0-5 °C in 30 minutes and stirred overnight at 25-30 °C. The reaction mass was slowly quenched in ice water and then filtered. The aqueous layer was basified with KOH solution and extracted with MDC. The MDC layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude compound (60 gm). Ethyl acetate, activated carbon was added to the above crude and stirred for 15 minutes at 50 °C. The reaction mass was filtered and the bed was washed with ethyl acetate and the filtrate concentrated to get crude compound (60 gm). Toluene and acetic acid was added to the above crude over a period of 15 minutes. The reaction mass was stirred for 2 hrs at 0-5 °C and precipitated solid was filtered and washed with chilled toluene to get 17 gm of acetate salt as white solid.

Example 5b: Synthesis of l-(3-methyl-l-phenyl-lH-pyrazoI-5-yl) piperazine acetate

Step-1: Synthesis of N-Boc bis (2-chloroethyl)-amine
To a stirred mixture of bis (2-chloroethyl) amine hydrochloride (20 g, 0.112 mol) and dichloromethane (100 mL) was added triethyl amine (12.45 g, 0.1232 mol) in one lot followed by boc anhydride over a period of 30 minutes at 25-30 °C. The resulted reaction mass was stirred for a period of about 12 to about 18 hours at 25-30 °C. Water was added to the above reaction mass and dichloromethane layer was separated. Separated dichloromethane layer was dried over anhydrous sodium sulphate and concentrated to get 25 g of title compound as light yellow oil.
Step-2: Synthesis of tert-butyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine-1-carboxylate
To the stirred mixture of 1-Phenyl-3-methyl-5-aminopyrazole (10 g, 0.0578 mol; prepared as per Step-1 of Example 5a) and N,N-Dimethylformamide (70 mL) was slowly added sodium hydride (6.9 g, 0.1734mol, 60 % dispersion in mineral oil) at 0-5 °C and stir for 1.0 hr. To this the above Step-1 oil was added (14 g, 0.0578 mol in 30 mL of DMF) at 0-5 °C in 30 minutes and stir for overnight at 25-30 °C. The reaction mass slowly quenched in ice water and filtered via celite bed. The aqueous phase extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude (25 g). The crude purified by eluting with n-hexane and ethyl acetate (80:20) to get 6 g of product as off white solid.
Step-3: Synthesis of l-(3-methyl-l-phenyl-lH-pyrazoI-5-yl)piperazine acetate Step-2 compound (6 g, 0.0175 mol) was dissolved in dichloromethane (60 mL) and trifluoroacetic acid (30 mL) was added to this at 25-30 °C and stirred for 1.5 hr. The solvent was evaporated under reduced pressure and water (3.0 L) was added to this residue. The mixture was washed with diethyl ether. The aqueous layer was basified with sodium bicarbonate solution and the mixture was extracted with chloroform. The chloroform layer dried over sodium sulphate and evaporated under reduced pressure to give residue (4.0 g). Toluene (12 mL) and acetic acid (1 mL) was added over a period of 15 minutes and stirred for 1.5-2.0 hr at 0-5 °C and precipitated solid filtered a 3.2 g of acetate salt as white solid.

Example 6: Preparation of l-(3-methyl-l-phenyl-lH-pyrazoI-5-yl)piperazine (Int-B)
l-(3-methyl-l-phenyl-lH-pyrazoI-5-yl)piperazine acetate (10.0 g) obtained as per Example 5a or Example 5b was dissolved in 50 mL water. Dichloromethane (100 mL) was added to this solution and the pH of solution was adjusted to about 8.0 by adding aqueous sodium bicarbonate solution. Organic layer was separated and aqueous layer was extracted with 50 mL dichloromethane. All organic layers were combined and washed with 50 mL brine solution. Dichloromethane was distilled at temperature below 40 °C. Hexane (50 mL) was added to the residue and stirred for 2-3 h at 25-30 °C. Solution filtered and washed with 20 mL hexane. Solid obtained was dried at about 50 °C to obtain 6.8 g of title compound.

Example 7: Synthesis of Teneligliptin hydrochloride
3-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (10.0 g, 0.033 mol) as obtained in Example 1 or Example 2, was dissolved in dichloromethane (100.0 mL) alongwith l-(3-methyl-l-phenyl-lH-pyrazoI-5-yl)piperazine (Int-B) (8.63 g, 0.035 mol). To this solution, acetic acid (2.20 g, 0.0366 mol) and sodium triacetoxy borohydride (14.10 g, 0.066 mol) were added at 25-30 °C. The reaction mixture was stirred for 4-5 h at same temperature. The reaction was quenched with water (100 mL) and aqueous layer was extracted with dichloromethane (50 mL). The combined organic layer was washed with water (100 mL), brine (50 mL) and dried. The solvent was evaporated & co-distilled with t-Butanol (30 mL) under reduced pressure at 40 °C. To this was added t-Butanol (130 mL) and the reaction mixture was heated to 75-80 °C and conc. HCl (11.5 mL) was added slowly. Furthermore the reaction mass was stirred to 75-80 °C for 4-5 h. After completion of reaction, obtained solid mass was cooled to room temperature and stirred for 3-4 h at room temperature. The precipitate was collected by filtration, washed with t-Butanol (5 mL) and dried under reduced pressure at 55-60 °C to give 12.1 g of title compound as a solid.

Example 8: Synthesis of Teneligliptin hydrochloride
3-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (10.0 g, 0.033 mol) as obtained in Example 1 or Example 2, was dissolved in dichloromethane (100.0 mL) alongwith l-(3-methyl-l-phenyl-lH-pyrazoI-5-yl)piperazine (Int-B) (8.63 g, 0.035 mol). To this solution, acetic acid (2.20 g, 0.0366 mol) and sodium triacetoxy borohydride (14.10 g, 0.066 mol) were added at 25-30 °C. The reaction mixture was stirred for 4-5 h at same temperature. The reaction was quenched with water (100 mL) and aqueous layer was extracted with dichloromethane (50 mL). The combined organic layer was washed with water (100 mL), brine (50 mL) and dried. The solvent was evaporated & co-distilled with isopropyl alcohol (30 mL) under reduced pressure at 40 °C. To this was added isopropyl alcohol (130 mL) and the reaction mixture was heated to 75-80 °C and conc. HCl (11.5 mL) was added slowly. Furthermore the reaction mass was stirred to 75-80 °C for 4-5 h. After completion of reaction, obtained solid mass was cooled to room temperature. To the reaction mixture was added ethyl acetate (50 mL) and stirred for 3-4 h at room temperature. The precipitate was collected by filtration, washed with isopropyl alcohol/Ethyl acetate mixture (5 mL) and dried under reduced pressure at 55-60 °C to give 13.5 g of title compound as a solid.

Example 9: Teneligliptin hemi-penta hydrobromide hydrate
Teneligliptin hydrochloride (10.0 g; obtained as per Example 7 or Example 8) was stirred in dichloromethane (100.0 mL) and saturated sodium bicarbonate solution (100.0 mL) was added to this solution. The mixture was stirred and pH of aq. layer was checked (pH to be maintained at 7.5-8.0 at room temperature). The layers were separated. Aqueous layer was further extracted with dichloromethane (100.0 mL x 2). All organic layers were combined, dried with anhydrous sodium sulfate and evaporated under reduced pressure followed by co-distillation with methanol (30.0 mL). Methanol (50.0 mL) was added to the obtained residue followed by slow addition of ~48% aqueous hydrobromic acid (6.5 mL) at 55-60 °C. The resulting mixture was stirred for 30 min at 55-60 °C and filtered through hyflo bed. To the clear filtrate was added t-Butanol (250 mL) slowly at 55-60 °C and allowed to cool at room temperature. The solid mass obtained was further stirred for 3-4 h at room temperature. The precipitate was collected by filtration, washed with 20 % methanol in t-Butanol (5.0 mL) solution and dried under reduced pressure at 55-60 °C to give 10.0 g of title compound as a solid.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.