Claims:1. A Sitagliptin fumarate adduct or salt thereof compound of formula-II or salt thereof

Formula-II

2. The compound of claim 1, wherein Sitagliptin fumarate adduct or salt thereof has purity more than 90%, when measured by HPLC.

3. The compound of claim 1, wherein salt is selected from the group comprising one or more of sodium, potassium, calcium and magnesium.

4. A process for the preparation of Sitagliptin fumarate adduct or salt thereof compound of formula-II

Formula-II
the process comprises the steps of
a) reacting 2-bromosuccinic acid with thionyl chloride in a alcohol solvent to obtain dimethy 2-bromosuccinate,
b) condensing 3-amino-1-(3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-triflurophenyl)butan-1-one with dimethy 2-bromosuccinate in presence of base and an aprotic solvent to obtain Sitagliptin fumarate adduct base,
c) converting Sitagliptin fumarate adduct base to acid addition salt thereof,

5. The process of claim 4, wherein step (a) is carried out in presence of catalyst, wherein catalyst is selected from group comprising one or more of potassium iodide, sodium iodide and lithium iodide.

6. The process of claim 4, wherein alcohol solvent is selected from the group comprising one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol and propylene glycol.

7. The process of claim 4, wherein aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide, N,N-diethylformamide, dimethyl sulfoxide, tetrahydrofuran and mixture thereof.

8. The process of claim 4, wherein base is selected from one or more sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

9. A Lithium salt of Sitagliptin fumarate adduct compound of formula-IIA

Formula-IIA

10. The compound of claim 1, wherein Lithium salt of Sitagliptin fumarate adduct has purity more than 90%, when measured by HPLC.
, Description:Field of Invention

The present invention provides a process for a preparation of Sitagliptin fumarate adduct or salt thereof. In particular aspect of present invention provides a Lithium salt of Sitagliptin fumarate adduct. In further aspect of present provides the use of a Sitagliptin fumarate adduct or salt thereof as reference markers and/or reference standards during the synthesis of Sitagliptin or its pharmaceutically acceptable salt thereof.

Background of the invention

Sitagliptin is chemically known as 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 and is structurally represented by Formula (I):

Formula I

Sitagliptin is an orally-active dipeptidyl peptidase-4 (DPP-IV) enzyme inhibitor that improves glycemic control in patients with Type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Sitagliptin is used as a monotherapy, as an adjunct to diet and exercise, or in combination with metformin or a PPAR? agonist (e.g., thiazolidinediones). Sitagliptin is approved under the brand name Januvia in the form of a Sitagliptin phosphate monohydrate.

U.S. patents No. 6,699,871 and 7,326,708 describe the Sitagliptin and pharmaceutically acceptable salts thereof. The process for the preparation of Sitagliptin described in several patents, U.S. Patents 7,495,123; 8,278,486; 8,293,507; 8,309,724; 8,334,385; 8,471,016; 8,471,057; 8,476,437; 8,524,936; 8,624,026; 8,710,255; 8,765,668; 8,835,679; 8,846,916; 8,889,380; 8,912,327; 8,969,558 and 9,006,436;

The object of present invention is to provide an novel compounds as 2-[[(R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluoro phenyl)butan-2-yl]amino]succinic acid or salt thereof (referred herein after “Sitagliptin fumarate adduct”). The further aspect of present invention is to provide process of preparation of Sitagliptin fumarate adduct or salt thereof, which is very simple cost effective and may be employed at commercial scale.

Summary of the Invention

The present invention provides a Sitagliptin fumarate adduct or salt thereof compound of formula-II

Formula-II

The present invention provides a use of Sitagliptin fumarate adduct or salt thereof, as reference standards in a qualitative analysis of Sitagliptin or its pharmaceutically acceptable salt thereof.

The present invention provides a process for the preparation of Sitagliptin fumarate adduct or salt thereof compound of formula-II

Formula-II
The present invention also provides a Sitagliptin fumarate adduct or salt thereof, has purity more than 99 % when measured by HPLC.

The present invention provides a Lithium salt of Sitagliptin fumarate adduct compound of formula-IIA

Formula-IIA

The present invention provides a use of Lithium salt of Sitagliptin fumarate, as reference standards in a qualitative analysis of Sitagliptin or its pharmaceutically acceptable salt thereof.

The present invention provides a process for the preparation of Lithium salt of Sitagliptin fumarate compound of formula-IIA

Formula-IIA

The present invention also provides a Lithium salt of Sitagliptin fumarate, has purity more than 99 % when measured by HPLC.

Detailed description of the Invention

For purposes of the present invention, the following terms are defined below.

The salt or pharmaceutically acceptable salt as used herein, unless otherwise defined, refers to but are not limited to sodium salts, potassium salts, calcium salts, magnesium salts and the like.

As used herein, the term “reference standard” refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. A reference marker” is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.

The present invention provides a Sitagliptin fumarate adduct or salt thereof compound of formula-II

Formula-II

One another aspect of the present invention provides a use of Sitagliptin fumarate adduct or salt thereof, as reference standards in a qualitative analysis of Sitagliptin or its pharmaceutically acceptable salt thereof.

One another aspect of the present invention provides a process for the preparation of Sitagliptin fumarate adduct or salt thereof compound of formula-II

Formula-II
the process comprises the steps of
a) reacting 2-bromosuccinic acid with thionyl chloride in a alcohol solvent to obtain dimethy 2-bromosuccinate,
b) condensing 3-amino-1-(3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-triflurophenyl)butan-1-one with dimethy 2-bromosuccinate in presence of base and an aprotic solvent to obtain Sitagliptin fumarate adduct base,
c) converting Sitagliptin fumarate adduct base to acid addition salt thereof,

The step (a) of present invention involves the reacting 2-bromosuccinic acid with thionyl chloride in a alcohol solvent to obtain dimethy 2-bromosuccinate at temperature in between range of 0°C to 5°C, wherein alcoholic solvent is selected from group comprises one or more of methanol, ethanol, isopropanol, n-propanol, butanol and isobutanol. After addition, remove cooling and reflux reaction mass for the period for 3 hour at temperature in between range of 60°C to 80 °C. After completion of reaction, concentrate reaction mass under vacuum. Residue is dissolved in dichloromethane. Wash organic layer with water and 5% solution of sodium bicarbonate and brine. Concentrate organic layer under vacuum to afford the titled as oily mass.

The step (b) of present invention involves the condensing 3-amino-1-(3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-triflurophenyl)butan-1-one with dimethy 2-bromosuccinate in presence of base, catalytic and an aprotic solvent to obtain Sitagliptin fumarate adduct base at temperature in between range of 25°C to 35°C, wherein the aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide, N,N-diethylformamide, dimethyl sulfoxide, tetrahydrofuran and mixture thereof and base is selected from one or more sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. The catalyst is selected from group comprising one or more of potassium iodide, sodium iodide, and lithium iodide.

The reaction mixture is stirred at temperature in between range of 70°C to 85°C for 24 hrs. After completion, reaction mixture is cooled room temperature, followed by reaction mixture quenched with water. The compound is extracted in dichloromethane, followed by washing the organic layer with water and brine. Concentrate organic layer under vacuum to get Sitagliptin fumarate adduct base.

The step (c) of present invention involves the converting Sitagliptin fumarate adduct base to acid addition salt thereof.

One another aspect of the present invention provides a Sitagliptin fumarate adduct or salt thereof, has purity more than 90 % when measured by HPLC.

The present invention provides a Lithium salt of Sitagliptin fumarate adduct compound of formula-IIA

Formula-IIA

The present invention provides a use of Lithium salt of Sitagliptin fumarate, as reference standards in a qualitative analysis of Sitagliptin or its pharmaceutically acceptable salt thereof.

The present invention provides a process for the preparation of Lithium salt of Sitagliptin fumarate compound of formula-IIA

Formula-IIA
the process comprises the steps of
a) reacting 2-bromosuccinic acid with thionyl chloride in a alcohol solvent to obtain dimethy 2-bromosuccinate,
b) condensing 3-amino-1-(3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-triflurophenyl)butan-1-one with dimethyl-2-bromosuccinate in presence of base and an aprotic solvent to obtain Sitagliptin fumarate adduct base,
c) converting Sitagliptin fumarate adduct base to Lithium salt of Sitagliptin fumarate,

The Sitagliptin fumarate adduct free base may be converted to its salts thereof. The conversion may be carried out by using conventional techniques, such as treating with suitable base in suitable solvent.

The present invention also provides a Lithium salt of Sitagliptin fumarate, has purity more than 90 % when measured by HPLC.

The process of the present invention is depicted in the following scheme 1:

Scheme 1

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES

Example-1: Preparation of Dimethyl 2-bromosuccinate

To the solution of methanol (50ml) and 2-bromosuccinic acid (5.0g) was added thionyl chloride (6.04g) at 0 to 50C. After addition, remove cooling and reflux reaction mass for 3hour at temperature 650C. After completion of reaction, concentrate reaction mass under vacuum. Residue was dissolved in 100ml dichloromethane. Wash organic layer with water (50ml), 5% sodium bicarbonate (50ml) and brine (50ml). Organic layer was concentrate under vacuum to get tiled compound as oily mass.
Yield: 5 g
1H NMR (400 MHz, CDCl3): 3.72, s, 3H; 3.81, s, 3H; 3.28, dd, 1H; 3.0, dd, 1H; 4.58, dd, 1H.

Example-2: Preparation of Dimethyl 2-(4-(3-(trifluromethyl)-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-triflurophenyl)-4-oxobutan-2-ylamino) succinate

To the solution of 3-amino-1-(3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-triflurophenyl)butan-1-one (6.32 g), dimethyl 2-bromosuccinate (3.5g) and dimethylformamide (60 ml) was added potassium carbonate (2.69g) and potassium iodide (0.4g) at temperature 25°C to 30°C. The reaction mixture was stirred at temperature 80 0C for 24 hours. After completion of reaction, cool the reaction mass to room temperature and quench in water (200 ml) and extract the product in Dichloromethane (200 ml). Wash organic layer with water (50ml) and brine (50ml). Organic layer was concentrate under vacuum to get tiled compound.
Yield: 3.0 g
Mass (M+1): 552.4
1H NMR (400 MHz, CDCl3): 1.82, s, 1H; 2.33-2.63, m, 4H; 2.79-2.84, m, 1H; 3.38-3.43, m, 1H; 3.57, s, 3H; 3.66, s, 3H; 3.69-3.87, m, 2H; 3.99-4.24, m, 2H; 4.27-4.34, m, 2H; 4.93-4.97, m, 2H; 5.30-6.89, m, 1H; 6.92-7.14, m, 1H.

Example-3: Preparation of 2-[[(R)-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-yl]amino]succinic acid as lithium salt

To the solution of dimethyl 2-(4-(3-(trifluromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-triflurophenyl)-4-oxobutan-2-ylamino)succinate (9.0g) and tetrahydrofuran (15 ml) was added solution of LiOH (0.52 g) in water (15 ml) at temperature 00C to 100C. The reaction mixture was stirred at temperature 250C to 300C for 12 hours. After completion of reaction, concentrate the reaction mass under vacuum to recover tetrahydrofuran at temperature 300C. Extract aqueous layer with dichloromethane (50ml) and aqueous layer was lyophilized to get titled compound.
Yield: 2.6 g
Mass (M+1): 524.4 (M+1)
1H NMR (400 MHz, DMSO-d6): 2.0-2.30, m, 4H; 2.65-2.71, m, 2H; 3.07, m, 1H; 3.14, m, 1H; 3.93- 4.17, m, 4H; 4.77-4.89, m, 2H; 7.30-7.40, m, 2H; 8.47 s, 1H.
13C NMR (400 MHz, D2O): 32.35; 33.64; 36.73; 37.95; 41.52; 43.46; 53.24; 59.16; 1045; 119; 121.41; 143.50; 143.97; 147.19; 149.58; 150.89; 170.97; 179.43; 181.21.
HPLC purity: 93.20 %