DESC:“PREPARATION OF SITAGLIPTIN PHOSPHATE MONOHYDRATE”

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Sitagliptin phosphate monohydrate (I) by using novel intermediate of (2Z)-1-[5,6-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI). The present invention is also relates to an improved and commercially viable process of Sitagliptin phosphate monohydrate with good yield.

BACKGROUND OF THE INVENTION

Sitagliptin is a glucagon-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor, which is believed to exert its action in patients with type 2 diabetes by slowing the inactivation of incretin hormones. A product containing Sitagliptin phosphate in its monohydrate form is marketed in the United States by Merck & Co., Inc. using the brand JANUVIA™. JANUVIA™ is indicated to improve glycemic control in patients with
type 2 diabetes mellitus.

Sitagliptin phosphate (1:1) monohydrate, in combination with metformin hydrochloride, is sold by Merck & Co., Inc. using the brand JANUMET™ in the form of tablets for oral administration for combination therapy in the treatment of type 2 diabetes.

The drug compound having the adopted name “Sitagliptin Phosphate” has chemical names:
7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl) -1,2,4-triazolo[4,3-a] pyrazine phosphate (1:1); or (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine phosphate; and is represented by structural Formula I.

Sitagliptin was first disclosed in US Patent 6,699,871 and can be synthesized by different synthetic approaches as mentioned below. The first synthesis of Sitagliptin appears to be set out in WO 2003/004498 (henceforth '498). This ' 498 PCT patent publication discloses a method of introducing a chiral-amine group using a chiral pyrazine derivative and to prepare Sitagliptin by Arndt-Eistert homologation using t-butoxylcarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid as a Sitagliptin intermediate. The said process as represented in scheme (I), which involves the use of unusual dihydropyarazine chiral promoters, diazomethane and silver salt which are not preferred reagent for industrial synthesis.

Another synthetic process is described in '498 PCT patent publication and Tetrahedron Asymmetry2006,17, 205 involves the use of expensive metal catalyst such as rhodium. A similar synthesis is subsequently reported in another PCT publication WO2009/064476, that involves the enantioselective hydrogenation of ?-enamino derivatives and the use of expensive precious ruthenium metal catalyst and expensive ligands such as ferrocenyl diphospine ligands -JOSIPHOS catalyst which is disclosed in several PCT publication and articles for instance such as WO2004/085378, WO2005/097733, WO2006/081151 and J.Am.Chem.Soc., 2004,126 (32), 9918-9919. The preparation of this compound is also described in J. Am. Chem. Soc., 2009, 131(25), 8798-8804; which discloses that compounds once obtained may be purified according to methods standard in the field, obtaining Sitagliptin of purity suitable for pharmaceutical applications. The said process is described in scheme (II).

According to PCT publication WO2004/085661 the described process involves the hydrogenation with cheaper achiral catalyst and chiral derivatization of enamines derived from phenylglycinamide but the enantiomeric excess (ee) values of the compounds obtained for determining the purity of chiral substance were not sufficient for the pharmaceutical use. The said process is described in scheme (III).

PCT publication WO 2004/087650 discloses the introduction of chiral center by stereoselective reduction of ß-keto acid derivatives with precious metal catalyst. But this process involves the use of (S)-BINAP-RuCl2 catalyst in the presence of hydrochloric acid. Similar process is disclosed in another article published in year 2005 by Hansen KB et al in Organic Process Research and Development (OPRD). The said process is described in scheme (IV).

Use of BINAP-RuCl2 is not preferred for industrial synthesis.
US 9938282 of Stereokem., discloses process for the preparation of Sitagliptin phosphate monohydrate, which comprises the compound of formula (III) undergoes reduction in presence of H2 / Pd/C / Ac2O and AcOH to obtain the compound of formula (VII). The compound of formula (VII) is reacted with (R)-phenylethaneamine in presence of catalytic amount of AcOH to obtain the compound of formula (VIII). The compound of formula (VIII) is reacted with H3PO4 in presence of IPA to obtain the compound of formula (IX). The compound of formula (IX) undergoes deprotection in presence of H2 / Pd/C and followed by reacted with H2O to obtain Sitagliptin phosphate monohydrate (I). The said process is described in scheme (V).

There are several disadvantages in making of Sitagliptin phosphate (I).

Aforesaid reasons above there is a need to produce Sitagliptin phosphate monohydrate (I) synthetically by industrially applicable method to ensure the availability with high purity.

Hence, there is consequently a need development for new methods to sort out prior art existing methods. So, our inventors have developed an improved process for the preparation of Sitagliptin phosphate monohydrate (I). The present invention is providing a simple, cost effective with good yield on industrial applicable process

OBJECTIVE OF THE INVENTION

The present invention relates to a process for the preparation of Sitagliptin phosphate monohydrate (I) by using novel intermediate of (2Z)-1-[5,6-Dihydro-3-(trifluoromethyl)-1,2,4 -triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl] amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI).

In yet another objective of the present invention a novel intermediate of (2Z)-1-[5,6-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI).

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Sitagliptin phosphate monohydrate (I) by using novel intermediate of (2Z)-1-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5-trifluorophenyl)-2-buten-1-one (VI). The present invention is also relates to an improved and commercially viable process of Sitagliptin phosphate monohydrate with good yield.

The one aspect of the present invention provides a process for the preparation of Sitagliptin phosphate monohydrate (I) comprising:

a) 2,4,5-trifluorophenyl acetic acid (II) is reacted with Meldrum's acid in presence of activating agent/organic base to obtain 5-[1-hydroxy-2-(2,4,5-trifluorophenyl) ethylidene ]-2,2-dimethyl-1,3-dioxane-4,6-dione (III), which is followed by reacted with 3-(trifluoro methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (IV) in presence of organic acid/organic solvent to obtain 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-1,3-dione (V),

b) the compound of formula (V) is reacted with (R)-Naphthylethylamine in presence of organic solvent and dehydrating agent to obtain (2Z)-1-[5,6-dihydro-3-(trifluoromethyl)- 1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5-trifluoro phenyl)-2-buten-1-one (VI),

c) the compound of formula (VI) is undergoes reduction in presence of reducing agent/ organic acid /organic solvent to obtain compound of formula (X),

d) the compound of formula (X) is reduced with reducing agent in presence of organic solvent to obtain Sitagliptin (XI), and

e) the compound of formula (XI) is reacted with H3PO4/H2O in presence of organic solvent to obtain Sitagliptin phosphate monohydrate (I).

In another aspect of the present invention, provides a process for the preparation of (2Z)-1-[5,6-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenyl ethyl]amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI), comprising:

a) 2,4,5-trifluorophenyl acetic acid (II) is reacted with Meldrum's acid in presence of activating agent/organic base to obtain 5-[1-hydroxy-2-(2,4,5-trifluorophenyl) ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (III), which is followed by reacted with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydro chloride (IV) in presence of organic acid/organic solvent to obtain 1-(3-(trifluoro methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl) butane-1,3-dione (V),

b) the compound of formula (V) is reacted with (R)-Naphthylethylamine in presence of organic solvent and dehydrating agent to obtain (2Z)-1-[5,6-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl] amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI),

In yet another aspect of the present invention, provides the compound of (2Z)-1-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Sitagliptin phosphate monohydrate (I) from the compound of (2Z)-1-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5-trifluorophenyl)-2-buten-1-one (VI). The present invention is also relates to an improved and commercially viable process of Sitagliptin phosphate monohydrate with good yield.

The present invention is also relates to an improved and commercially viable process of Sitagliptin phosphate monohydrate with good yield.

The one embodiment of the present invention provides a process for the preparation of Sitagliptin phosphate monohydrate (I) comprising:

a) 2,4,5-trifluorophenyl acetic acid (II) is reacted with Meldrum's acid in presence of activating agent / organic base to obtain 5-[1-hydroxy-2-(2,4,5-trifluorophenyl) ethylidene ]-2,2-dimethyl-1,3-dioxane-4,6-dione (III), which is followed by reacted with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a] pyrazine hydrochlorid (IV) in presence of organic acid / organic solvent to obtain 1-(3-(trifluoro methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl) butane-1,3-dione (V),

b) the compound of formula (V) is reacted with (R)-Naphthylethylamine in presence of organic solvent and dehydrating agent to obtain (2Z)-1-[5,6-dihydro-3-(trifluoro methyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5-trifluorophenyl)-2-buten-1-one (VI),

c) the compound of formula (VI) is undergoes reduction in presence of reducing agent / organic acid / organic solvent to obtain compound of formula (X),

d) the compound of formula (X) is reduced with reducing agent in presence of organic solvent to obtain Sitagliptin (XI), and

e) the compound of formula (XI) is reacted with H3PO4 / H2O in presence of organic solvent to obtain Sitagliptin phosphate monohydrate (I).

In another aspect of the present invention, provides a process for the preparation of (2Z)-1-[5,6-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenyl ethyl]amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI), comprising:

a) 2,4,5-trifluorophenyl acetic acid (II) is reacted with Meldrum's acid in presence of activating agent/organic base to obtain 5-[1-hydroxy-2-(2,4,5-trifluorophenyl) ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (III), which is followed by reacted with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydro chloride (IV) in presence of organic acid/organic solvent to obtain 1-(3-(trifluoro methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl) butane-1,3-dione (V), and
b) the compound of formula (V) is reacted with (R)-Naphthylethylamine in presence of organic solvent and dehydrating agent to obtain (2Z)-1-[5,6-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl] amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI).

In an according embodiment of the present invention, 2,4,5-trifluorophenyl acetic acid (II) is reacted with Meldrum's acid in presence of activating agent / organic base to obtain 5-[1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (III), which is followed by reacted with 3-(trifluoro methyl)-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a] pyrazine hydrochloride (IV) in presence of organic acid / organic solvent to obtain 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluoro phenyl)butane-1,3-dione (V). The compound of formula (V) is reacted with (R)-Naphthyl ethylamine in presence of organic solvent and dehydrating agent to obtain (2Z)-1-[5,6-dihydro -3-(trifluoro methyl)- 1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenyl ethyl]amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI). The compound of formula (VI) is undergoes reduction in presence of organic acid / organic solvent to obtain compound of formula (X), and The compound of formula (X) is reduced with reducing agent in presence of organic solvent to obtain Sitagliptin (XI). The compound of formula (XI) is reacted with H3PO4 / H2O in presence of organic solvent to obtain Sitagliptin phosphate monohydrate (I).

The process according to the embodiment of the present invention, wherein the activating agent is selected from pivaloyl chloride.

The process according to the embodiment of the present invention, wherein the organic base is selected from trimethylamine, diisopropylethylamine, methylamine, ethylamine, pyridine, dimethylaminopyridine, N-methyl morpholine and diisopropyl amine.

The process according to the embodiment of the present invention, wherein the organic acid is selected from acetic acid, formic acid, oxalic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid and p-toluene sulfonic acid.

The process according to the embodiment of the present invention, wherein the organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, diethyl ether, methyl tertiary butyl ether, toluene, 1,2-dimethoxyethane and water or mixture thereof.

The process according to the embodiment of the present invention, wherein the reducing agent is selected from Pd/C, sodium borohydride, LiAlH4, Zn powder, FeCl3, sodium triacetoxyborohydride and lithium cyanoborohydride, potassium borohydride and Pt/C.

The process according to the embodiment of the present invention, wherein the dehydrating agent is selected from acetic acid and phosphorus pentoxide.

In yet another embodiment of the present invention, provides the compound of (2Z)-1-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl] amino]-4-(2,4,5- trifluoro phenyl)-2-buten-1-one (VI).

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione (Stage-1).

100 gms of 2,4,5-trifluorophenylacetic acid, 83.4gm of Meldrum's acid, and 4-(dimethylamino) pyridine(5.14g) and 300ml of acetonitrile were charged into a three-neck flask. 148.2g of N,N-diisopropylethylamine was added in one portion at room temperature while maintaining the temperature below 40°C. Pivaloyl chloride added dropwise over 1 to 2 hrs while maintaining the temperature below 50°C. The reaction mixture was aged at 45-50°C for 4-6 hrs, 125 gms of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride added in one portion at 45-50°C. 18 gms of trifluoroaceticacid was added slowly to the reaction mass at same temperature. The reaction solution was aged at 50-55°C for 10-12 hrs. Distilled out solvent under vacuum, cool the reaction mass to room temperature, charged 500 ml of ethyl acetate and 500 ml of purified water, stir for some time, separate the layers, extract product into 200 ml of ethyl acetate again, combine both organic layers, wash with purified water and 5% sodium chloride solution. Then ethyl acetate was distilled out completely, added 200 ml of toluene. After aging 3-4 hrs at 0-5°C, filter the solid, wash with toluene to obtain title compound.
Yield: 188 (gms).

Example 2: Preparation of (Z)-7-(1-oxo-3((R)-1-Naphthylethylamino)-4-(2,4,5-trifluoro phenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a] pyrazine.

A mixture of isopropanol (100 mL), 7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoro methyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a] pyrazine (20 g), and R-1-naphthylethanamine (11.5 gms) are heated to about 40°C. Acetic acid (1.5 mL) is added and stirred for about 5 hrs. The solvent is distilled off completely to afford the title compound.
Yield: 30 (gms).

Example 3: Preparation of (Z)-7-(1-oxo-3((R)-1-Naphthylethylamino)-4-(2,4,5-trifluoro phenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a] pyrazine.

A mixture of toluene (225 mL), 7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoro methyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a] pyrazine (45 gms), R-1-naphthylethanamine (23.68 gms) and acetic acid (12.15 gms) is added, heated to about 110°C. Remove water azeotropically, stirred for about 5 hrs. Cool to 25-30°C, charged water (200 ml), stir for 1-2 hrs, filter the materials, drying to afford titled product as a dry material.
Yield: 62 (gms).

Example 4: Preparation of 7-(1-oxo-3((R)-((R)-1-Naphthylethylamino))-4-(2,4,5-trifluoro phenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine.

Charge 1,2-dimethoxy ethane (108 ml) into RBF, cool to 40-45°C, charge sodium borohydride (3 gm), add methane sulphonic acid (12.49 gms) into reaction mass at same temperature. add a mixture of 1,2-dimethoxy ethane (24 gms) and (Z)-7-(1-oxo-3((R)-1-Naphthylethylamino)-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a] pyrazine (15 gms) at same temperature and maintained for about 2-3 hrs at the same temperature. Charge ethyl acetate and add 10% sodium carbonate solution (150 ml). Separate the layers evaporate ethyl acetate to afford title compound.
Yield: 10 (gms).

Example 5: Preparation of Sitagliptin.

Methanol (90 mL), 7-(1-oxo-3((R)-((R)-1-naphthylethylamino))-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (9 gms), water (9 ml), acetic acid (2.61 gms) and 10% palladium carbon are charged in auto clave and heated to about 60-65°C. hydrogen pressure around 5-6 kg maintained for about 8-10 hrs. Catalyst is filtered. The filtrate is distilled off completely under vacuum. Water (90 ml) and ethyl acetate (50 ml) are charged to the residue, it is cooled to about 0°C. HCl (0.4 g) is added to the reaction mass, and the layers are separated. Aqueous layer is cooled to about 0°C and 5% sodium hydroxide is added till pH of the mass is attained to about 12.0. The mass is then extracted with ethyl acetate (20 mL) and the ethyl acetate layer is distilled off completely to afford the title compound.
Yield: 4 (gms).

Example 6: Preparation of Sitagliptin Phosphate Monohydrate.

7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoro methyl)-1,2,4-triazolo[4,3-a]pyrazine (3 gms), isopropanol (21 ml), water (4.9 ml) and phosphoric acid (0.84 gms) are charged and heated to about 70°C for about 3 hrs. The reaction mass is then cooled to about 30°C and stirred for about 10 hrs. The separated solid is filtered and dried at about 45°C. under vacuum for about 4 hrs to afford the title compound.

Yield: 3.45 (gms).

,CLAIMS:WE CLAIM:
1. A process for the preparation of Sitagliptin phosphate monohydrate (I) comprising:

a) 2,4,5-trifluorophenyl acetic acid (II) is reacted with Meldrum's acid in presence of activating agent/organic base to obtain 5-[1-hydroxy-2-(2,4,5-trifluorophenyl) ethylidene ]-2,2-dimethyl-1,3-dioxane-4,6-dione (III), which is followed by reacted with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (IV) in presence of organic acid/organic solvent to obtain 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-1,3-dione (V),

b) the compound of formula (V) is reacted with (R)-Naphthylethylamine in presence of organic solvent and dehydrating agent to obtain (2Z)-1-[5,6-dihydro-3-(trifluoromethyl)- 1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5-trifluoro phenyl)-2-buten-1-one (VI),

c) the compound of formula (VI) is undergoes reduction in presence of reducing agent/ organic acid /organic solvent to obtain compound of formula (X),

d) the compound of formula (X) is reduced with reducing agent in presence of organic solvent to obtain Sitagliptin (XI), and

e) the compound of formula (XI) is reacted with H3PO4 / H2O in presence of organic solvent to obtain Sitagliptin phosphate monohydrate (I).

2. The process as claimed in claim 1, wherein the reaction is carried out in the presence of activating agent is selected from pivaloyl chloride.

3. The process as claimed in claim 1, wherein the reaction is carried out in the presence of organic base is selected from trimethylamine, diisopropylethylamine, methylamine, ethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine and diisopropyl amine.

4. The process as claimed in claim 1, wherein the reaction is carried out in the presence of organic acid is selected from acetic acid, formic acid, oxalic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid and p-toluene sulfonic acid.
5. The process as claimed in claim 1, wherein the reaction is carried out in the presence of organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, diethyl ether, methyl tertiary butyl ether, toluene, 1,2-dimethoxyethane and water or mixture thereof.

6. The process as claimed in claim 1, wherein the reaction is carried out in the presence of dehydrating agent is selected from acetic acid and phosphorus pentoxide.

7. The process as claimed in claim 1, wherein the reaction is carried out in the presence of reducing agent is selected from Pd/C, sodium borohydride, LiAlH4, Zn powder, FeCl3, sodium triacetoxyborohydride and lithium cyanoborohydride, potassium borohydride and Pt/C.

8. A novel compound of (2Z)-1-[5,6-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl] amino]-4-(2,4,5-trifluorophenyl)-2-buten-1-one (VI).

9. A process for the preparation of Sitagliptin phosphate monohydrate (I) comprising by (2Z)-1-[5,6-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-[[(1R)-1-phenylethyl] amino]-4-(2,4,5-trifluorophenyl)-2-buten-1-one (VI).