Claims:

1. A process for preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine of Formula I

Formula I

comprising the steps of:
(a) reacting N-protected derivative of 1-piperazin-1-ylbutane-1,3-dione of Formula II with phenyl hydrazine or hydrochloride salt thereof in presence of a solvent to form hydrazone derivative of Formula III, wherein the reaction is carried out at 0-10 0C;

Formula II Formula III

wherein, Pr is N-protecting group selected from aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl and tri-(loweralkyl)silyl

(b) cyclizing hydrazone derivative of Formula III using a suitable cyclizing agent to form pyrazole derivative of Formula IV; and

Formula IV

wherein, Pr is N-protecting group selected from aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl and tri-(loweralkyl)silyl

(c) de-protecting pyrazole derivative of Formula IV using suitable de-protecting agent in the presence of a solvent.

2. The process as claimed in claim 1, wherein step (a) is carried out at 0-5 0C.

3. The process as claimed in claim 1, wherein the solvent used in step (a) is selected from C1-3 alcohol such as methanol, ethanol, isopropyl alcohol, tertiary amine such as pyridine, triethylamine and di-isopropylethyl amine.

4. The process as claimed in claim 1, wherein the cyclizing agent used in step (b) is selected from phosphorous pentoxide, acetic acid, acetic anhydride, sodium hydroxide, sodium ethoxide and phosphorous oxy-chloride.

5. The process as claimed in claim 1, wherein the cyclization in step (b) is carried out using phosphorous pentoxide in acetic acid.

6. The process as claimed in claim 1, wherein the cyclization in step (b) is carried out by heating with acetic acid.

7. The process as claimed in claim 1, wherein the cyclization in step (b) is carried out by heating with acetic anhydride.

8. The process as claimed in claim 1, wherein the cyclization in step (b) is carried out by refluxing with sodium hydroxide in alcoholic solvent.

9. The process as claimed in claim 1, wherein the cyclization in step (b) is carried out by refluxing with sodium ethoxide in alcoholic solvent.

10. The process as claimed in claim 1, wherein the cyclization in step (b) is carried out by using phosphorous oxy-chloride in presence of a base.

11. The process as claimed in claim 10, wherein the base is selected from pyridine, triethylamine and di-isopropylethyl amine.

12. The process as claimed in claim 1, wherein step (b) is carried out at room temperature.

13. The process as claimed in claim 1, wherein de-protecting agent used in step (c) is selected from palladium compound, acid hydrolysis agent and alkali hydrolysis agent.

14. The process as claimed in claim 1, wherein when the N-protecting group Pr is aralkyl or aralkyloxy carbonyl, the de-protecting agent used is palladium compound, selected from palladium on carbon, palladium acetate, palladium hydroxide and palladium chloride.

15. The process as claimed in claim 14, wherein the solvent is water optionally along with acetic acid.

16. The process as claimed in claim 14, wherein the solvent is alcohol selected from methanol, ethanol and isopropyl alcohol optionally along with acetic acid.
17. The process as claimed in claim 1, wherein when the N-protecting group Pr is lower alkoxy carbonyl, the de-protecting agent used is acid hydrolysis agent selected from hydrochloric acid and trifluoroacetic acid.

18. The process as claimed in claim 17, wherein the solvent is hydrocarbon solvent selected from toluene or cyclohexane, halogenated solvent selected from chloroform or methylene dioxide, ester solvent selected from ethyl acetate and butyl acetate.

19. The process as claimed in claim 1, wherein when the N-protecting group Pr is acyl, the de-protecting agent is alkali hydrolysis agent selected from potassium hydroxide, potassium carbonate, sodium hydroxide and sodium carbonate.

20. The process as claimed in claim 19, wherein the solvent is alcoholic solvent selected from methanol, ethanol and isopropyl alcohol.

21. The process as claimed in claim 1, wherein the step (c) is carried out at temperature range of 50-120 0C.

22. The process as claimed in claim 1, wherein the step (c) is carried out at temperature range of 90-110 0C.

23. The process as claimed in claim 1, wherein the N-protected pyrazole derivative of Formula IV is prepared by one pot synthesis.

24. A process for preparation of Teneligliptin of Formula V

Formula V
comprising the steps of:

(a) reacting N-protected derivative of 1-piperazin-1-ylbutane-1,3-dione of Formula II with phenyl hydrazine or hydrochloride salt thereof in presence of a solvent to form hydrazone derivative of Formula III, wherein the reaction is carried out at 0-10 0C;

Formula II Formula III

wherein, Pr is N-protecting group selected from aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl and tri-(loweralkyl)silyl

(b) cyclizing hydrazone derivative of Formula III using a suitable cyclizing agent to form pyrazole derivative of Formula IV;

Formula IV

wherein, Pr is N-protecting group selected from aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl and tri-(loweralkyl)silyl

(c) de-protecting pyrazole derivative of Formula IV using suitable de-protecting agent in the presence of a solvent to form compound of Formula I;

Formula I

(d) reacting compound of Formula I with N-protected derivative of 3-((S)-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidine of Formula VI in presence of a solvent and a reducing agent to form N-protected Teneligliptin of Formula VII; and

Formula VI Formula VII
wherein, Pr1 is an amino protecting group selected from aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl and tri-(loweralkyl)silyl

(e) de-protecting N-protected Teneligliptin of Formula VII using suitable de-protecting agent.

25. The process as claimed in claim 24, wherein the reducing agent is selected from borohydrides such as sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, hydride such as lithium hydride and lithium aluminium hydride, preferably sodium triacetoxy borohydride.

26. The process as claimed in claim 24, wherein the de-protecting agent used is selected form palladium compounds, alkali hydrolysis agent and acidic hydrolysis agent.

27. The process as claimed in claim 24, wherein solvent is selected from halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride, alcohols such as methanol, ethanol, 1-propyl alcohol, 2-propanol, tert-butanol, esters such as ethyl acetate, isopropyl acetate and butyl acetate, amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, nitrile such as acetonitrile, propionitrile, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofiiran, tetrahydropyran, hydrocarbons such as benzene, toluene, cyclohexane, methyl cyclohexane or mixtures thereof.

Dated 12th day of May, 2016
For Aarti Industries Limited
By their Agent

(ANAND GOPALKRISHNA MAHURKAR) (IN/PA 1862)
KRISHNA & SAURASTRI ASSOCIATES
, Description:FORM 2
The Patent Act 1970
(39 of 1970)
&
The Patent Rules, 2005
COMPLETE SPECIFICATION
[See Section 10 and Rule 13]

Improved process for preparation of 1-(3-methyl-1- phenyl-1H-pyrazol-5-yl)piperazine”

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ADDRESS, 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON LINK ROAD, MULUND (W) MUMBAI, 400080, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Field of the invention
The present invention relates to Teneligliptin intermediate and more particularly, to an improved process for preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine.

Background of the invention

1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine of Formula I, is well-known in the art as an important intermediate in the manufacturing of Teneligliptin. The structure of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine of Formula I is illustrated below-

Formula I

Various processes are known in the art for the preparation of Formula I. Reference may be made to U.S. Patent No. 7,074,794 which discloses a process for the preparation of l-(3-methyl-l-phenyl-5-pyrazolyl)piperazine, or salts thereof. The process comprises the reaction of 1-tert-butoxycarbonylpiperazine with diketene to obtain l-acetoacetyl-4-tert- butoxycarbonylpiperazine; l-acetoacetyl-4-tert-butoxycarbonylpiperazine is reacted with phenylhydrazine in the presence of methanesulfonic acid followed by cyclization with phosphous oxy chloride in pyridine to obtain l-tert-butoxycarbonyl-4-(3-methyl-1-phenyl- 5-pyrazolyl)piperazine as an oil and its deprotection with trifluoroacetic acid.

Due to the unstable nature of diketenes, their use for the preparation of Formula I on a large scale results in decreased yield and purity. In addition, the solvent volumes used in the process reported are very high, the reaction time is longer and also the yield obtained is very low (Yield 12%).

PCT application WO 2014/041560 discloses a process for preparation of Teneliglitin. The process comprises reacting 5-methyl-2-phenyl-pyrazol-3-amine with bis (2-chloroethylamine) or N-protected derivative or salt thereof. Alternatively, 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde is reacted with piperazine or N-protecting derivative thereof. However, the process involves many stages which make the reaction lengthy and time consuming.

Another PCT application WO 2015/063709 claims cyclizing 1-(N-protected-piperazin-1-yl)-3-(2-phenylhydrazino)but-1-en-1-ol using Lawesson’s reagent. The reagent is chemically designated as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadophosphetane-2,4-disulfide. However, use of this reagent is not industrially feasible due to its cost and its strong and unpleasant smell.

In addition, PCT application WO 2012/165547 and its Indian equivalent IN 10292/CHENP/2013 claim process for preparation of Formula I by cyclization of N-protected-1-[3-(2-phenylhydrazono)butyryl]piperazine with phosphorus pentasulfide. However, the reagent used for cyclization is toxic and not suitable industrial scale up.

Accordingly, there is a need of simple, efficient and industrially feasible process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine that overcomes the above mentioned drawbacks of the prior art.

Objects of the invention

An object of the present invention is to provide an improved process for preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine that is suitable for industrial production.
Another object of the present invention is to provide the improved process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine having higher yield and better purity.

Yet another object of the present invention is to provide the improved process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine which avoids use of costly and hazardous reagents.

Further object of the present invention is to provide the process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine and its use in the preparation of Teneligliptin.

Summary of the invention
Accordingly, the present invention teaches a process for preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine of Formula I. The process comprises reacting N-protected derivative of 1-piperazin-1-ylbutane-1,3-dione of Formula II with phenyl hydrazine or hydrochloride salt thereof in presence of a solvent to form hydrazone derivative of Formula III, wherein the reaction is carried out at 0-10 0C. More particularly, the temperature is maintained at 0-5 0C until the completion of the reaction. The hydrazone derivative of Formula III is further cyclized using a suitable cyclizing agent to form pyrazole derivative of Formula IV. Protecting groups form pyrazole derivative of Formula IV are cleaved using suitable de-protecting agent in the presence of a solvent to form compound of Formula I.

Formula II Formula III

Formula IV Formula I

wherein, Pr is N-protecting group selected from aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl and tri-(loweralkyl)silyl.

The present invention also provides one pot synthesis of N-protected pyrazole derivative of Formula IV. The N-protected pyrazole derivative of Formula IV by one spot synthesis is prepared by reacting N-protected derivative of 1-piperazin-1-ylbutane-1,3-dione of Formula II with hydrazine or hydrochloride salt thereof to form hydrazone derivative of Formula III followed by in situ cyclization of hydrazone derivative of Formula III using a suitable cyclizing agent.

The present invention also relates to a process for preparation of Teneligliptin of Formula V. The compound of Formula II obtained by the process of the present invention is reacted with N-protected derivative of 3-((S)-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidine of Formula VI to form N-protected Teneligliptin of Formula VII. The reaction is carried out in presence of a suitable solvent and a reducing agent. Further, the protecting groups from the compound of Formula VI are cleaved to form Teneligliptin of Formula V.

Formula VI Formula VII

Formula V
wherein, Pr1 is an amino protecting group selected from aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl and tri-(loweralkyl)silyl.

Detailed description of the invention

The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.

In one aspect, the present invention relates to a process for preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine of Formula I. The process comprises reacting N-protected derivative of 1-piperazin-1-ylbutane-1,3-dione of Formula II with phenyl hydrazine or hydrochloride salt thereof to form hydrazone derivative of Formula III. The temperature of the reaction is maintained in a range of 0 0C to 10 0C. Specifically, compound of Formula II is added to a solvent and the reaction mass is cooled to 0-10 0C. The solvent is selected from C1-3 alcohols such as methanol, ethanol, isopropyl alcohol, tertiary amine solvents such as pyridine, triethylamine and di-isopropylethyl amine. Phenyl hydrazine or hydrochloride salt thereof is added at 0-10 0C to compound of Formula II and the reaction mass is maintained at 0-10 0C to form hydrazone derivative of Formula III. More particularly, the temperature is maintained at 0-5 0C until the completion of the reaction.

Further, the hydrazone derivative of Formula III is cyclized to form pyrazole derivative of Formula IV. However, it is understood here that N-protected pyrazole derivative of Formula IV may be prepared by one pot synthesis by reacting N-protected derivative of 1-piperazin-1-ylbutane-1,3-dione of Formula II with hydrazine or hydrochloride salt thereof to form hydrazone derivative of Formula III followed by in situ cyclization of hydrazone derivative of Formula III using a suitable cyclizing agent.

The hydrazone derivative of Formula III obtained is optionally isolated and cyclized using the suitable cyclizing agent. The cyclizing agent is selected from phosphorous pentoxide, acetic acid, acetic anhydride, sodium hydroxide, sodium ethoxide and phosphorous oxy-chloride.

In one embodiment, the cyclization is carried out using phosphorous pentoxide in acetic acid. In another embodiment, the cyclization of Formula III is carried out by heating with acetic acid. In yet another embodiment, the cyclization of Formula III is carried out by heating with acetic anhydride. In yet another embodiment, the cyclization of Formula III is carried out by refluxing with sodium hydroxide in alcoholic solvent. In yet another embodiment, the cyclization of Formula III is carried out by refluxing with sodium ethoxide in alcoholic solvent. In yet another embodiment, the cyclization of Formula III is carried out by using phosphorous oxy-chloride in presence of a base. The base used in cyclization using phosphorous oxy-chloride is preferably tertiary amine selected from pyridine, triethylamine and di-isopropylethyl amine, which also acts as solvent. The reaction is carried out at room temperature.

Further, the protecting groups from the cyclized pyrazole derivative of Formula IV are cleaved using suitable de-protecting agent in the presence of a solvent to form 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine of Formula I. The de-protection reaction is carried out at 50-120 0C, preferably at 90-110 0C and more particularly at 100 0C. The de-protecting agent is selected form palladium compounds, alkali hydrolysis agent and acidic hydrolysis agent. The solvent is selected from alcoholic solvents, halogenated solvents, hydrocarbon solvents and ester solvents.

The reaction scheme of preparing compound of Formula 1 is represented below:

Group Pr in compound of Formula II, Formula III and Formula IV is N-protecting group selected from the group consisting of aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl and tri-(loweralkyl)silyl, preferably benzyl, bezyloxy carbonyl and tert-butyloxy carbonyl, more particularly bezyl.

In one embodiment, when Pr is aralkyl or aralkyloxy carbonyl, palladium compound is used as the de-protecting agent. Preferably, when Pr is benzyl and benzyloxycarbonyl, the palladium de-protecting agent is selected from palladium on carbon, palladium acetate, palladium hydroxide and palladium chloride. In this one embodiment solvent used is water optionally along with acetic acid. However, it is understood here that an alcoholic solvent may be used in other alternative embodiments such as methanol, ethanol and isopropyl alcohol optionally along with acetic acid.

In another embodiment, when Pr is lower alkoxy carbonyl, acid hydrolysis agent is used as the de-protecting agent. Preferably, when Pr is tert butyloxy carbonyl, the acid hydrolysis agent is selected from hydrochloric acid and trifluoroacetic acid. The solvent used is hydrocarbon solvents such as toluene, cyclohexane, halogenated solvents such as chloroform, methylene dioxide and ester such as ethyl acetate and butyl acetate.

In yet another embodiment, when Pr is acyl, the de-protecting agent used is alkali hydrolysis agent selected from potassium hydroxide, potassium carbonate, sodium hydroxide and sodium carbonate. The solvent is alcoholic solvent selected from methanol, ethanol and isopropyl alcohol.

In another aspect, the present invention provides a process for the preparation of Teneligliptin of Formula V. The compound of Formula II obtained by the process of the present invention is reacted with N-protected derivative of 3-((S)-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidine of Formula VI to form N-protected Teneligliptin of Formula VII. The reaction is carried out in presence of a suitable solvent and a reducing agent. Further, the protecting groups from the compound of Formula VI are cleaved to form Teneligliptin of Formula V.

The reaction scheme of preparing compound of Formula V is represented below:

Group Pr1 in compound of Formula VI and Formula VII is an amino protecting group 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.

The suitable solvent is selected from halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride, alcohols such as methanol, ethanol, 1-propyl alcohol, 2- propanol, tert-butanol, esters such as ethyl acetate, isopropyl acetate and butyl acetate, amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, nitrile such as acetonitrile, propionitrile, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofiiran, tetrahydropyran, hydrocarbons such as benzene, toluene, cyclohexane, methyl cyclohexane, or mixtures thereof. Preferably, the solvent is methylene dichloride.

The reducing agent is selected from borohydrides such as sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, hydride such as lithium hydride and lithium aluminium hydride. Preferably, the reducing agent is sodium triacetoxy borohydride.

The de-protecting agent is selected form palladium compounds, alkali hydrolysis agent and acidic hydrolysis agent.

EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.
Example 1
Preparation of 1-(4-benzylpiperazin-1-yl)butane-1,3-dione

N-benzyl piperazine (100 g) was added to toluene (650 ml) and the reaction mass was stirred at 25-30 0C for 15 minutes. Ethyl acetoacetate (70.17 g) was added to the reaction mass and stirred for 10 minutes. The temperature of the reaction mass was raised to 105-110 0C and maintained till the completion of the reaction. The mass was cooled to 25-30 0C and water (100 ml) was added and stirred for 30 minutes. The layers were separated and the organic layer was washed with 10% acetic acid (100 ml) followed by water (100 ml). The organic layer was distilled off under vacuum to get 1-(4-benzylpiperazin-1-yl)butane-1,3-dione (133 g).
Yield = 90%
HPLC Purity = 98%
LCMS: M+1 = 261

Example 2
Preparation of 1-(4-benzylpiperazin-1-yl)butane-1,3-dione

Ethyl acetoacetate (3 L) was added to N-benzyl piperazine (1 kg) and the reaction mass was heated at 100-120 0C with concomitant removal of ethanol by distillation. Reaction mass was cooled to room temperature on completion of reaction. The reaction mass was washed with water (3 L), followed by 1% acetic acid solution (1L). The mixture was subjected to high vacuum distillation. Ethyl acetoacetate was separated from reaction mass at 30-50 0C under vacuum of 1 to 1.5 mm/Hg to yield 1-(4-benzylpiperazin-1-yl)butane-1,3-dione (1.35 Kg) as yellowish to brown oil.
Yield = 91.21%
HPLC Purity = 99.5%
LCMS: M+1 = 261

Example 3
Preparation of 1-(4-benzylpiperazin-1-yl)-3-(phenylhydrazono)butan-1-one

Ethanol (5 ml) was added to 1-(4-benzylpiperazin-1-yl)butane-1,3-dione (1 gm) obtained in example 1. The reaction mass was cooled to 0-5 0C and phenyl hydrazine hydrochloride (0.56 g) was added and mixture was stirred. The reaction mass was maintained at 0-5 0C till the completion of the reaction. Water (50 ml) and methylene dichloride (20 ml) was added to the reaction mass after completion of the reaction. The mass was stirred at 25-30 0C for 30 minutes. The layers were separated and aqueous layer was back extracted with methylene dichloride (20 ml X 2 times) and combined organic layer dried over sodium sulfate and evaporated under vacuum to get 1-(4-benzylpiperazin-1-yl)-3-(phenylhydrazono)butan-1-one (1.3 g)
Yield = 96.6%
LCMS: M+1 = 351

Example 4
Preparation of 1-benzyl-4-(5-methyl-2-phenyl-pyrazol-3-yl)piperazine

1-(4-benzylpiperazin-1-yl)-3-(phenylhydrazono)butan-1-one (2 gm) obtained in example 2 was added to the mixture of pyridine (10 ml) and phosphorous oxychloride (1.5 g). The mass was stirred at 25-30 0C for 2 hours. Chloroform (20 ml) and water (50 ml) was added after completion of the reaction and the mass was stirred for 30 minutes. The layers were separated and aqueous layer was back extracted with chloroform (20 ml). Combined organic layers were dried over sodium sulfate and distilled to get 1-benzyl-4-(5-methyl-2-phenyl-pyrazol-3-yl)piperazine (1.5 g)
Yield: 79%
LCMS: M+1 = 333

Example 5
One pot preparation of 1-benzyl-4-(3-methyl-1-phenyl-pyrazol-5-yl)piperazine

1-(4-benzylpiperazin-1-yl)butane-1,3-dione (50 gm) obtained in example 1 was added to pyridine (250 ml). The reaction mass was cooled to 0-5 0C and phenyl hydrazine hydrochloride (27.78 g) was added and mixture was stirred. The reaction mass was maintained at 0-5 0C till the completion of the reaction. Phosphorous oxychloride (60 g) was added dropwise to the reaction mass over 30 minutes at 0-5 0C. The mass was warmed to 25-30 0C and stirred for 2-3 hours. After completion of the reaction, water (2000 ml) was added to the reaction mixture and extracted with Chloroform (500 ml X 2 times). The layers were separated and the combined organic layers were distilled off under vacuum to get 1-benzyl-4-(3-methyl-1-phenyl-pyrazol-5-yl)piperazine (58 g). The compound was purified by dissolving in chloroform (100 ml) and adding 2M hydrochloric acid (200 ml). The mass was stirred for 30 minutes and the layers were separated. The aqueous layer was basified with sodium hydroxide and extracted with chloroform (100 ml X 3 times). The combined organic layers were distilled under vacuum to get pure 1-benzyl-4-(3-methyl-1-phenyl-pyrazol-5-yl)piperazine (47 gm) (yield: 50%)
Yield = 73.6%
HPLC purity = 98%
LCMS: M+1 = 333

Example 6
One pot preparation of 1-benzyl-4-(3-methyl-1-phenyl-pyrazol-5-yl)piperazine

1-(4-benzylpiperazin-1-yl)butane-1,3-dione (1.3 kg) obtained in example 2 was added to pyridine (3 L) and stirred at 0-5 0C under nitrogen atmosphere. Phenyl hydrazine hydrochloride (725 gm) was added portion wise to above reaction mixture over 30 minutes. Reaction was maintained at 0-5 0C for next 2-3 hours. After completion of the reaction, phosphorous oxychloride (1.2 L) was charged to reaction mass at 0-5 0C. Reaction was maintained at 25-30 0C for 2 hours followed by addition of methylene dichloride (5 L). Reaction mass was stirred at 25-30 0C till the completion of the reaction. Reaction mass was slowly quenched over ice-water and methylene dichloride layer was separated and distilled to get crude 1-benzyl-4-(3-methyl-1-phenyl-pyrazol-5-yl)piperazine (1.55 Kg) as Orange-brown oil. The compound was purified by dissolving in methylene dichloride (5 L) and water (5 L). Reaction mass was stirred and acidified to pH = 1 using concentrated hydrochloric acid. The aqueous layer was separated and basified with 2M sodium hydroxide and extracted with methylene dichloride (3 L). Distillation of methylene dichloride layer yield 1-benzyl-4-(3-methyl-1-phenyl-pyrazol-5-yl)piperazine (1.2 Kg) as yellowish-brown oil which solidified at room temperature.
Yield = 74.7 %
HPLC purity = 98.2%
LCMS: M+1 = 333

Example 7
Preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine

1-benzyl-4-(3-methyl-1-phenyl-pyrazol-5-yl)piperazine (5 gm) obtained in example 5 was charged in a mixture of acetic acid (30 ml) and ethanol (20 ml). 10% pd/C (0.5 g) was added to the reaction mixture and reaction mass was hydrogenated in autoclave at 100 0C for 8 hours under hydrogen pressure of 10 kg. The mass was cooled to 25-30 0C after completion of the reaction and filtered. The solvent was evaporated under vacuum to give 1-(3-methyl-1-phenyl-1h-pyrazol-5-yl)piperazine (4 gm) as oil. The oil obtained was basified with saturated sodium hydroxide and extracted with methylene dichloride. Methylene dichloride was distilled under vacuum and re-crystallized from ethyl acetate/DIPE to obtain 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (2.6 g) as a off-white solid (yield: 71.3%)
Percent yield = 71.3%
HPLC purity = 98 %
LCMS: M+1 = 243

Example 8
Preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine

1-benzyl-4-(3-methyl-1-phenyl-pyrazol-5-yl)piperazine (1 Kg) obtained in example 6, was charged to acetic acid (3 L) and IPA (1.0 L). 10% Pd/C catalyst (100 g) was added to the reaction mixture. The reaction mass was hydrogenated in an autoclave at 60 -70 0C under a hydrogen pressure of 3-5 Kg. The catalyst was separated after the completion of reaction and the reaction mass was distilled under vacuum. The residue obtained was dissolved in methylene dichloride and basified with 2M NaOH. Methylene dichloride layer was distilled off under vacuum and product obtained was recrystallized in di-isopropyl ether to get pure 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (620 gm) as off-white solid.
Percent yield = 85.05%
HPLC purity = 99.7%
LCMS: M+1 = 243

Example 9
Preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine

To the mixture of acetic acid (200 ml) and water (50 ml), 1-benzyl-4-(3-methyl-1-phenyl-pyrazol-5-yl)piperazine (50 gm) obtained in example 5 was charged. 10% pd/C (5 g) was added to the reaction mixture and reaction mass was hydrogenated in autoclave at 100 0C for 5 hours under hydrogen pressure of 5 kg. The mass was cooled to 25-30 0C after completion of the reaction and filtered. The reaction mass was basified with saturated sodium hydroxide and extracted with methylene dichloride. Methylene dichloride was distilled under vacuum and re-crystallized from ethyl acetate/DIPE to obtain 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (32 g) as a off-white solid (yield: 87.79%)
Percent yield = 87.79%
HPLC purity = 98 %
LCMS: M+1 = 243

Example 10
Preparation of Teneligliptin

To a solution of tert-butyl (2S)-4-oxo-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate (9.01 g), 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine prepared in example 8 (8 g), acetic acid (17 mL) in 1,2-dichloroethane (1500 mL) and sodium triacetoxyborohydride (127 g) were added and the mixture was stirred at room temperature. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-tert-butyl (2S,4S)-4-[4-(5-methyl-2-phenyl-pyrazol-3-yl)piperazin-1-yl]-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate (7.97 gm) (Yield: 50%).

To the solution of 1-tert-butyl (2S,4S)-4-[4-(5-methyl-2-phenyl-pyrazol-3-yl)piperazin-1-yl]-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate (25.45g) in dichloromethane (200 mL), trifluoroacetic acid (50 mL) was added at room temperature. The mixture was stirred and then concentrated under reduced pressure. The residue was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with chloroform/methanol (9:1, v/v) to give free base of Teneligliptin (19.28 g, 93%) as a solid.