Claims:1. An improved process for the preparation of compound of formula (I),

Formula (I)

comprising the steps of:
a) heating N-protected piprazine of formula (IV) with an alkyl acetoacetate in presence of organic solvent to obtain ketoamide of formula (V);

b) reacting compound (V) with phenyl hydrazine in presence of alcoholic solvent to obtain compound of formula (VI);

c) cyclization of compound (VI) in the presence of dehydrating agent, suitable solvent and base to obtain compound of formula (VII);

d) deprotection of compound (VII) in the presence of lower alkyl chloroformate and base to obtained compound of formula (I) ;

2. The process as claimed in claim1, wherein compound (I) is converted to compound of formula (II);

comprising the steps of:
iii. coupling of compound (I) with compound of formula (VIII) to form N-protected compound of formula (IX) by reductive amination;

iv. deprotection of compound (IX) in presence of aqueous inorganic acid to obtain compound of formula (II) and its salt.

3. The process as claimed in step (i) of claim 1, wherein the protecting group (PG) is selected from group comprising amides, carbamates, sulphonamides, alkyl and benzyl derivatives preferably, C1-C3 alkyl, more preferably methyl.
4. The process as claimed in step (i) of claim 1, wherein alkyl acetoacetate is selected from group comprising ethyl acetoacetate, isopropyl acetoacetate, t-butyl acetoacetate preferably, t-butylacetoacetate.
5. The process as claimed in step (i) claim 1, wherein heating is preferably carried out at 130-135oC, more preferably 120-125oC, and most preferably 110-115oC for 14 hours.
6. The process as claimed in step (i) of claim 1, wherein organic solvent is selected from group comprising toluene, benzene, xylene, tetrahydrofuran, chlorobenzene, dichlorobenzene, ethyl acetate, butyl acetate, dimethyl formomide, dimethyl acetamide, n-butanol, t-butanol preferably, toluene.
7. The process as claimed in step (ii) of claim 1, wherein alcoholic solvent is selected from group comprising methanol ethanol, n-propanol, isopropanol, n-butanol preferably, isopropanol.
8. The process as claimed in step (iii) of claim 1,wherein dehydrating agent is selected from group comprising phosphoric acid, trifluroacetic anhydride-pyridine in presence of ammonium sulphide, phosphorous pentasulfide, lawesson’s reagent preferably, phosphorous pentasulfide, suitable solvent is selected from group comprising acetonitrile, toulene, tetrahydrofuran, ethanol, isopropyl alcohol or mixture thereof preferably tetrahydrofuran, and base is selected from group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate preferably, sodium carbonate.
9. The process as claimed in step (iii) of claim 1, wherein reaction is carried out preferably at 80-85oC, more preferably 75-80oC, and most preferably 70-75oC for 5 hours.
10. The process as claimed in step (iv) of claim 1 and claim 3, wherein inorganic base is selected from group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide for deprotection of amide protecting group.
11. The process as claimed in step (iv) of claim 1 and claim 3, wherein organic solvent is selected from group comprising toluene, benzene, tetrahydrofuran, 1, 4-dioxane, dichloromethane, ethylene dichloride, chloroform for deprotection of carbamate protecting group.
12. The process as claimed in step (iv) of claim 1 and claim 3, wherein process for deprotection of alkyl and benzyl derivative is selected from catalytic hydrogenation or debenzylation.
13. The process as claimed in claim 12, wherein catalyst for catalytic debenzylation is selected from group comprising raney nickel, palladium, platinium on carbon preferably raney nickel.
14. The process as claimed in step (iv) of claim 1, wherein alkylchloroformate is selected from group comprising ethyl chloroformate, chloroethylchloroformate, isopropyl chloroformate, n-propyl chloroformate preferably, ethyl chloroformate.
15. The process as claimed in step (iv) of claim 1, wherein base is selected from group comprising triethyl amine, diethyl amine, methyl amine, propylamine, di-isopropyl ethyl amine preferably, triethylamine.
16. The process as claimed in step (i) of claim 2, wherein the reducing agent is selected from group comprising sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride preferably, sodium triacetoxyborohydride.
17. The process as claimed in step (ii) of claim 2,wherein aqueous inorganic acid is selected from group comprising hydrobromic acid, hydrochloric acid, hydroiodic acid preferably, hydrobromic acid. , Description:FIELD OF INVENTION
The present invention generally relates to chemical process. In particular it pertains to a novel and improved process for preparation of Teneligliptin intermediate 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I). A further aspect of the present invention relates to conversion of said intermediate to Teneligliptin and its salt (II).

BACKGROUND OF THE INVENTION
Teneligliptin (II), is novel pyrrolidine based dipeptidylpeptidase 4 (DPP-4) inhibitor. It belongs to the class of anti-diabetic drugs and used for management of type 2 diabetes mellitus. It is chemically {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}(1,3-thiazolidin-3-yl)methanone.

Formula (II)
U.S.Pat.No.7, 074,794 discloses a process for preparation of compound of formula (I), by reacting 1-t-butoxycarbonylpiperazine with di-ketene to obtain 1-acetoacetyl-4-t-butoxycarbonyl piperazine. The compound 1-acetoacetyl-4-t-butoxycarbonyl piperazine which is further reacted with phenyl hydrazine, followed cyclization in presence of phosphorus oxychloride to obtain 1-t-butoxy carbonyl-4-(3-methyl-1-phenyl-5-pyrazoyl)piperazine. 1-t-butoxy carbonyl-4-(3-methyl-1-phenyl-5-pyrazoyl)piperazine is deprotected utilizing trifluroacetic acid to obtain teneligliptin intermediate 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I).

Formula (I)
The above process is not viable for industrial scale up due to unstable nature of di-ketene which makes it difficult to handle and leads to low yield and purity of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I). Moreover, it is not industrially feasible as starting material diketene is not available commercially and reagents like phosphorous oxychloride and trifluoroacetic acid are hazardous in nature.
WO2012/099915 discloses an alternative process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I) by refluxing ethyl acetoacetate with phenyl hydrazine in presence of phosphorous oxychloride to afford pyrrazolene derivative, which on further reaction with piperizine in presence of excess palladium acetate and DMF to obtain 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I). This process is not commercially viable due to utilization of large amount of expensive palladium acetate which is not economically favorable.
WO2015/019239 discloses another process for preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I) by reaction of ethyl acetoaceate with ethylpiperazine 1-carboxylate, followed by addition of phenyl hydrazine and then cyclized in presence of phosphorus pentasulfide to obtain N-carboethoxy protected piperazine derivative. The N-carboethoxy protected piperazine derivative is further deprotected using metal hydrogen complexes to obtain 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine(I). The protecting group utilized in process such as carboethoxy which is highly unstable and interferes in multi step synthetic process which leads to formation of impurities resulting in decreased yield and purity of product. Moreover, starting material used is not commercially available in large scale.
Accordingly therefore, based on the drawbacks mentioned in all the prior arts, there is a need of simple, cost effective and industrially feasible process for preparation of Teneligliptin intermediate 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I), Teneligliptin(II) and its salt.

OBJECTIVE OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of preparation of Teneligliptin intermediate 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I).

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine of formula (I) and {2S,4S)-4-[4-[3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl)pyrrolidine-2-ylcarbonyl}thiazolidine of formula (II) and its salt.

Formula (I)

Formula (II)

which comprises the steps of :
(A) Preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I)
i. by reacting N-protected piprazine of formula (IV) with an alkyl acetoacetate in presence of organic solvent to obtain ketoamide of formula (V);

ii. compound of formula (V) is reacted with phenyl hydrazine in presence of alcoholic solvent to obtain compound of formula (VI);

iii. cyclization the compound (VI) in the presence of dehydrating agent, suitable solvent and base to obtain compound of formula (VII);

iv. the deprotection of formula (VII) in presence of lower alkyl chloroformate in the presence of base to obtained compound of formula (I).

(B) Conversion of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I) to {2S,4S)-4-[4-[3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl)pyrrolidine-2-ylcarbonyl}thiazolidine (II)

i. compound of formula (I) is coupled with compound of formula (VIII) to form compound of N-protected compound of formula (IX) by reductive amination;
ii. deprotection of N-protected compound of formula (IX) in presence of aqueous inorganic acid to obtain compound of formula (II) and its salt.

The above process is illustrated in the figure 1:


Figure 1

DETAIL DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine of formula (I) and {2S,4S)-4-[4-[3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl)pyrrolidine-2-ylcarbonyl}thiazolidine of formula (II) and its salt.

Formula (I)

Formula (II)
which comprises the steps of :

(A) Preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I)
i. by reacting N-protected piprazine of formula (IV) with an alkyl acetoacetate in presence of organic solvent to obtain ketoamide of formula (V).

ii. ketoamide of formula (V) is reacted with phenyl hydrazine in presence of alcoholic solvent to obtain compound of formula (VI).

iii. cyclization the compound (VI) in the presence of dehydrating agent , suitable solvent and base to obtain compound of formula (VII)

iv. the deprotection of formula (VII) in presence of using lower alkyl chloroformate in the presence of base to obtained compound of formula (I).

(B) Conversion of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I) to {2S,4S)-4-[4-[3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl)pyrrolidine-2-ylcarbonyl}thiazolidine (II)

i. compound of formula (I) is coupled with compound of formula (VIII) to form compound of N-protected compound of formula (IX) by reductive amination.
ii. deprotection of N-protected compound of formula (IX) in presence of aqueous inorganic acid to obtain compound of formula (II).
(A) Preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I)
The process of present invention discloses improved process for the preparation of compound of formula (I),
Formula (I)

comprising the steps of:
i. heating N-protected piprazine of formula (IV) with an alkyl acetoacetate in presence of organic solvent to obtain ketoamide of formula (V);

a.
ii. reacting compound (V) with phenyl hydrazine in presence of alcoholic solvent to obtain compound of formula (VI);
a.

iii. cyclization of compound (VI) in the presence of dehydrating agent, suitable solvent and base to obtain compound of formula (VII);

iv. deprotection of compound (VII) in the presence of lower alkyl chloroformate and base to obtained compound of formula (I) ;

N-protected piprazine is heated with alkyl acetoacetate in presence of organic solvent to obtain ketoamide of formula (V).
The protecting group of piperazine ring may be selected from group of formula comprising
Amides: PG=R-CO-
R-is alkyl, aryl or aryl alkyl are or more hydrogen optionally substituted by halogen;
Carbamates: PG=R1-O-CO-
R1- in alkyl, aryl or aryl alkyl or more hydrogen optionally substituted by halogen;
Sulfonamide: PG=R2-SO2-
R2 is alkyl or aryl ;
Alkyl & benzyl derivative: PG=R3-CH2-
R3 is H, alkyl, aryl substituted phenyl preferably, C1-C3 alkyl, more preferably R3 is H.
In an embodiment of present invention, the protecting group (PG) is selected from group comprising amides, carbamates, sulphonamides, alkyl and benzyl derivatives preferably, C1-C3 alkyl, more preferably methyl.
The alkyl acetoacetate used in step (i) may be selected from group comprising ethyl acetoacetate, isopropyl acetoacetate, t-butyl acetoacetate preferably t-butylacetoacetate. The organic solvent used in step (i) may be selected from group comprising toluene, benzene, xylene, tetrahydrofuran, chlorobenzene, dichlorobenzene,ethyl acetate, butyl acetate, dimethyl formomide, dimethyl acetamide, n-butanol, t-butanol preferably, toluene. The reaction of step (i) heating may be preferably carried out at 130-135oC, more preferably 120-125oC, and most preferably 110-115oC for 14 hours.
The reaction of step (i) addition of alkyl acetoacetate may be carried out at temperature 20-60 oC preferably 30-50 oC.
In the present invention, alkyl acetoacetate is selected from group comprising ethyl acetoacetate, isopropyl acetoacetate, t-butyl acetoacetate preferably, t-butylacetoacetate,
In an embodiment of present invention, heating is preferably carried out at 130-135oC, more preferably 120-125oC, and most preferably 110-115oC for 14 hours.
In the present invention, organic solvent is selected from group comprising toluene, benzene, xylene, tetrahydrofuran, chlorobenzene, dichlorobenzene, ethyl acetate, butyl acetate, dimethyl formomide, dimethyl acetamide, n-butanol, t-butanol preferably, toluene.
The process of the present invention wherein in step (ii) ketoamide of formula (V) is reacted with phenyl hydrazine in presence of alcoholic solvent to obtain compound of formula (VI). The alcoholic solvent may be selected from group comprising methanol ethanol, n-propanol, isopropanol, n-butanol preferably, isopropanol.
In the present invention, alcoholic solvent is selected from group comprising methanol ethanol, n-propanol, isopropanol, n-butanol preferably, isopropanol.
The reaction of step (ii) addition of phenyl hydrazine may be carried out at temperature -15 oC- 10 oC preferably, -10 oC -5 oC.
The process of the present invention wherein in step (iii) compound of formula (VI) is cyclised in presence of dehydrating agent , suitable solvent and base to obtain compound of formula (VII).
The dehydrating agent may be selected from group comprising phosphoric acid, trifluroacetic anhydride-pyridine in presence of ammonium sulphide, phosphorous pentasulfide, lawesson’s reagent preferably, phosphorous pentasulfide.
The suitable solvent may be selected from group comprising acetonitrile, toulene, tetrahydrofuran, ethanol, isopropyl alcohol or mixture thereof preferably, tetrahydrofuran.
The base may be selected from group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate preferably, sodium carbonate.
In the present invention, dehydrating agent is selected from group comprising phosphoric acid, trifluroacetic anhydride-pyridine in presence of ammonium sulphide, phosphorous pentasulfide, lawesson’s reagent preferably, phosphorous pentasulfide, suitable solvent is selected from group comprising acetonitrile, toulene, tetrahydrofuran, ethanol, isopropyl alcohol or mixture thereof preferably tetrahydrofuran, and base is selected from group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate preferably, sodium carbonate.
The reaction of step (iii) reaction may be preferably carried out at 80-85oC, more preferably 75-80oC, and most preferably 70-75oC for 5 hours.
In an embodiment of present invention, reaction is carried out preferably at 80-85oC, more preferably 75-80oC, and most preferably 70-75oC for 5 hours.
The process of the present invention wherein in step (iv) comprising elimination of protecting group or deprotection in presence alkyl chloroformate and base to obtain compound of formula (I).
The reagent used for deprotection in step (iv) is based on type of protecting group present in compound of formula (VII). The inorganic base is used for deprotection of amide group may be selected from group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide. The organic solvent is used for deprotection of carbamate group may be selected from group comprising toluene, benzene, tetrahydrofuran, 1, 4-dioxane, dichloromethane, ethylene dichloride, chloroform preferably, catalytic hydrogenation or benzylation is used for deprotection of alkyl or benzyl derivative. The catalyst used for catalytic benzylation may be selected from group comprising raney nickel, palladium, platinium on carbon preferably Raney Ni.
In the present invention, inorganic base is selected from group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide for deprotection of amide protecting group; organic solvent is selected from group comprising toluene, benzene, tetrahydrofuran, 1, 4-dioxane, dichloromethane, ethylene dichloride, chloroform for deprotection of carbamate protecting group; deprotection of alkyl and benzyl derivative is selected from catalytic hydrogenation or debenzylation; deprotection of alkyl and benzyl derivative is selected from catalytic hydrogenation or debenzylation.
In an embodiment of present invention, catalyst for catalytic debenzylation is selected from group comprising raney nickel, palladium, platinium on carbon preferably raney nickel.
The alkylchloroformate used in step (iv) may be selected from group comprising ethyl chloroformate, chloroethylchloroformate, isopropyl chloroformate, n-propyl chloroformate preferably, ethyl chloroformate.
The base used in step (iv) may be selected from group comprising triethyl amine, diethyl amine, methyl amine, propylamine, diisopropyl ethyl amine preferably, triethylamine.
In the present invention, alkylchloroformate is selected from group comprising ethyl chloroformate, chloroethylchloroformate, isopropyl chloroformate, n-propyl chloroformate preferably, ethyl chloroformate
In the present invention, base is selected from group comprising triethyl amine, diethyl amine, methyl amine, propylamine, di-isopropyl ethyl amine preferably, triethylamine.
(B) Conversion of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I) to {2S,4S)-4-[4-[3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl)pyrrolidine-2-ylcarbonyl}thiazolidine (II)

In the process of present invention compound (I) is converted to compound of formula (II);

comprising the steps of:

i. coupling of compound (I) with compound of formula (VIII) to form N-protected compound of formula (IX) by reductive amination;

ii. deprotection of compound (IX) in presence of aqueous inorganic acid to obtain compound of formula (II) and its salt.

The compound of the formula (I) is coupled with compound of formula (VIII) through reductive amination to obtain compound of formula (IX) by reducing agent may be selected from group comprising sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride preferably, sodium triacetoxyborohydride.

In the present invention, the reducing agent is selected from group comprising sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride preferably, sodium triacetoxyborohydride.
The compound of formula (IX) is deprotected in presence of aqueous inorganic acid may be selected from group comprising hydrobromic acid, hydrochloric acid, hydroiodic acid preferably, hydrobromic acid to obtain compound of formula (II) and its salt.
In an embodiment of present invention, aqueous inorganic acid is selected from group comprising hydrobromic acid, hydrochloric acid, hydroiodic acid preferably, hydrobromic acid.

Without being limited by the theory, the process of the present invention provides a novel and efficient process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I) and {2S,4S)-4-[4-[3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl)pyrrolidine-2-ylcarbonyl} thiazolidine (II)

The process of the present invention involves the use of N- protected piperizine especially N-methyl piperizine as starting material which is available commercially and viable for industrial scale up. Moreover, deprotection of methyl group can be performed easily utilizing simple organic acids as compared to complex deprotecting agents employed in prior art. The process of present invention avoids the use protecting group like carbethoxy, amides etc. which are makes reactions unstable & interfere in yield and purity of final product by forming process related impurities like hydrazones, thioamide etc. The process of present invention also avoids the use of expensive and hazardous reagents and makes process economical and industrially feasible. The process of the present invention provides high overall yield (56-62 %) and high chemical purity (99.8 %).

The invention is now described in detail with reference to the following examples; however, the following examples should not be construed as limiting the scope of the present invention in any way.
The process explained in examples is illustrated below in the figure 2 and 3:

Example:-1 Preparation of 1-(4- methylpiperazine-1-yl) butane-1, 3-dione (V)
10.0 g of 1-methyl piperazine (IV) (0.099 mol), 17.4 g of t-butyl acetoacetate (0.11 mol) and 80 ml of toluene was heated up to 110-115 0C.The reaction mixture stirred for same temperature for 14 hr. After completion of reaction, cool the reaction mass at 60 0C.The toluene distil out under reduced pressure at 60-65 0C to obtain 17.5 g of 1-(4- methylpiperazine-1-yl) butane-1, 3-dione (V) as brown viscous oil.(M+H)+:m/z=184.9; lH-NMR(DMSO-d6, ): 2.142(s,3H), 2.173(s,3H), 2.227-2.240(t,4H), 2.253-2.266(t,4H),2.278(s,2H); IR (cm-1): 2940.9 cm-1,2799.2 cm-1,1722.1 cm-1,1635.1 cm-1,1448.3 cm-1,1295.0 cm-1,1143.6 cm-1.

Example:-2 Preparation of 1-(4- methylpiperazine-1-yl)-3-(2-phenylhydrazilidine)butane-2-one (VI)
17.5 g of 1-(4- methylpiperazine-1-yl)butane-1,3-dione (0.095 mol)was dissolved in 175 ml isopropyl alcohol and the reaction mixture cooled at 0-5 0C,10.79 g of phenyl hydrazine (0.099 mol) was added slowly to temperature not exceed 10 0C. After the addition, the reaction mixture kept at 25-300C for 12 hr. After completion of reaction, distil out solvent under reduced pressure at 50-55 0C to obtain 25.5 g of 1-(4- methylpiperazine-1-yl)-3-(2-phenylhydrazilidine)butane-2-one(VI) as brown viscous oil.(M+H)+:m/z=274.9; lH-NMR(DMSO-d6,) : 1.896(s,3H), 2.696(s,3H),3.147-3.409(t,4H),3.585-3.734(t,4H),3.889(s,1H), 6.669-7.176(m,5H),8.896(s,1H),11.337(s,1H); IR (cm-1): 3433.6 cm-1,2996.8 cm-1,2927.4 cm-1,2434.7 cm-1,1661.4 cm-1,1596.8 cm-1,1515.8, cm-1 , 1488.8 cm-1,1452.1 cm-1,974.8 cm-1,759.8 cm-1.

Figure 2

Example:-3 Preparation of 1-(methyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine (VII)
34.01 g of phosphorus pentasulfide (0.076 mol) was suspended in 200 ml tetrahydrofuran and to this added 12.17 g of sodium carbonate (0.11 mol).The reaction mixture was heated at 70 0C and kept for 1 hr. A mixture previously prepared of 20 g of (1-(4- methylpiperazine-1-yl)-3-(2-phenylhydrazilidine) butane-2-one(0.073 mol) and 40 ml of tetrahydrofuran was added for 1 hr. The reaction mixture reflux for 5 hr. After completion of reaction, 200 ml of water was added slowly at 30-35 0C.and add to it 200 ml of ethyl acetate. The separation organic layer and wash aqueous layer with 100 ml of ethyl acetate. The organic layer combined and wash with 120 ml of 5 % sodium bicarbonate solution and 120 ml water. The organic layer dry on sodium sodium sulphate and distil out solvent under reduced pressure to obtain 14.5 g of 1-(methyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine(VII) as off white solid.(M+H)+:m/z=257.1; lH-NMR(DMSO-d6,): 2.141(s,3H), 2.177(s,3H),2.356-2.759(t,4H), 2.779-1-2.782(t,4H),5.789(s,1H),7.249-7.745(m,5H); IR (cm-1): 3062.4 cm-1,2959.2 cm-1, 2927.4 cm-1,1594.8 cm-1,1559.5 cm-1, 1502.3cm-1, 1448.3cm-1, 905.4 cm-1,770.4 cm-1.

Example:-4 Preparation of1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I)
10.0 gm of 1-(methyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine(0.039 mol), 2.36 g of triethylamime (0.023 mol) and 40 ml toluene was heated at 80 0C., 4.4 g of ethyl chloroformate (0.041) was slowly added to the reaction mixture. The reaction mixture reflux for 2 hr. After completion of reaction, 100 ml of water was added slowly at 30-35 0C.The separation of organic layer and wash aqueous layer with 50 ml of toluene. The organic layer combined wash with 50 ml water. The organic layer dry on sodium sulphate and distil out solvent under reduced pressure. To distil mass was added 50 ml isopropyl alcohol and 16.56 g of potassium hydroxide (0.15 mol). The reaction mixture reflux for 4 hr .distil out solvent under reduced pressure .To distill mass 100 ml of water was added slowly at 30-35 0C and stir the reaction mass for 2-3 hr at 15-20 0C.Filter the precipitated solid and wash the solid with 20 ml water. The wet solid dry under vacuum at 50-55 0C for 5-6 hour to obtain 8.7 g of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I) as off white colored solid. HPLC purity (99.5 %)(M+H)+:m/z=242.9; lH-NMR(DMSO-d6,): 2.141(s,3H), 2.690(t,4H), 2.709(t,4H),3.4(s,1H),5.764(s,1H),7.243-7.766(m,5H)

Example:-5 Preparation of 1-(4-benzylpiperazine-1-yl)-3-(2-phenylhydrazilidine)butane-2-one (XI)
(1) Using the 17.44 g of N-benzyl piperazine (X) (0.099 mol) and 17.21 g of t-butylacetoacetate (0.11 mol), and in the same manner in the Example-1 to obtained 24.5 g of 1-(4- benzylpiperazine-1-yl) butane-1, 3-dione as an brown viscous oil.
(2) In the same manner in Example-2 and using above compound (24.5 g) the title compound obtained 32.4 g as a brown viscous oil.(XI)

Example:-6 Preparation of 1-(benzyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine (XII)
Using the product 20 g of Example -6 (XII) (0.057 mol),6.3 g of sodium carbonate(0.057) and26.32 g of Phosphorus pentasulfide(0.059) in same manner in the Example-3 to obtained 14.5 g of 1-(benzyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine (XII) as an brown viscous oil.

Figure 3

Example:-7 Preparation of1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I)
10 gm of 1-(benzyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine(XII) dissolved in 100 ml methanol at a temperature 30 0C in autoclave. The apparatus was flooded with nitrogen and 3 gm Raney Ni was suspended in methanol and added to the reaction mixture. The pressure of hydrogen of 4 kg/cm2at temperature 40-45 0C for 4-5 hour. After completion of reaction, cool the reaction mass at 30 0C.The autoclave was flooded with nitrogen and the catalyst was filtered off. The filtrate was concentrate in vacuum to obtain1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (I)off white to pale yellow solid(purity-99.2 %) and yield 92 %.(M+H)+:m/z=242.8)

Example:-8 Preparation of Teneligliptin hydrobromide hydrate (II)
10 g of 1-phenyl-1H-pyrazol-5-yl) piperazine (0.041 mol), 9.55 g of sodium triacetoxyborohydride (0.045 mol),1.2 g of acetic acid and 12.3 g of (2S)-4-oxo-2-(3-thiazolidinylcarbonyl)-1-pyrrolidinecarboxylic acid tert-butyl ester (0.041 mol) was suspended in 200 ml toluene. Stir the reaction mass for 2 hr at 30-35 0C.After completion of reaction. After completion of reaction, 100 ml of water was added slowly at 30-35 0C.The separation of organic layer and wash aqueous layer with 50 ml of toluene. The organic layer combined wash with 50 ml 10% sodium bicarbonate solution and 10 % NaCl solution. The organic layer dry on sodium sodium sulphate and distil out solvent under reduced pressure. To distil mass was added 50 ml isopropyl alcohol and 20 g of 48 % hydrobromic acid at 70-75 0C. The reaction mixture reflux for 1 hour. The reaction mixture cool slowly at 30-35 0C.and stir the reaction mass for 2-3 hr at 20-250C.Filter the resulting solid and wash the solid with 20 ml isopropyl alcohol. The wet solid dry under vacuum at 50-55 0C.for 5-6 hour to obtain Teneligliptin hydrobromide hydrate(II) as off white to pale yellow colored solid. HPLC purity (99.8 %) and yield 90%. (M+H)+:m/z=427.59; lH-NMR(DMSO-d6,): 2.164-2.17(s,3H),3.06-3.146(m,1H), 3.479-3.893(m,16H),4.058(s,1H),4.452-4.741(s,3H), 5.94(s,1H)7.30-7887(m,5H),9.15(s,1H).

Example: 9 Comparison of yield and purity with process of present invention over that of prior arts
The process of present invention provides the most optimum yield and purity as compared to other processes of the prior art. The overall yield and purity of the process of the present invention of teneligliptin is compared with the theoretical and /or exemplified over all yield of prior art at table 1 for ready reference. From the table 1, it can be seen that prior art discloses over all low yield and comparable % purity with respect to present invention.

Table 1:
S. NO. Prior art % purity % yield
1. US 7,074,794 Not Disclosed 5-10%
2. WO 12/099915 Not Disclosed 20-25%
3. WO15/019239 99.9 50-55 %
4. WO14/41560 99.7 % 6-7 %
5. Present Invention 99.8 % 56-62 %

From the table 1, it is clear that process of present invention provides good yield and high purity.