FIELD OF THE INVENTION

The present invention relates to a stereo selective process for preparing 7-[(3R)-3- amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-[l,2,4]-triazolo-[4,3-a]pyrazine of Formula I.

BACKGROUND OF THE INVENTION

Sitagliptin, chemically known as 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-[l,2,4]-triazolo[4,3-a]pyrazine marketed in the form of monohydrate of its phosphate salt in the United States under the trade name JANUVIA™. JANUVIA™ is indicated to improve glycemic control in patients with type 2 diabetes mellitus.

Sitagliptin phosphate is a glucagon-like peptide 1 metabolism modulator, hypoglycemic agent and dipeptidyl peptidase IV inhibitor (DPP-IV). Sitagliptin was disclosed for the first time in U.S. Patent No. 6,699,871 among other beta-amino-tetrahydrotriazolo [4,3-a] pyrazines that are potent inhibitors of DPP-IV. Pharmaceutically acceptable salts of this compound are generically encompassed within the scope of US Patent No. 6,699,871. It also discloses a process for the preparation of Sitagliptin and related compounds, which is as shown below:

The above process uses diazomethane, which is highly hazardous and explosive reagent, and cannot be used at industrial scale. Further, in homologation reaction Silver benzoate is used, which is a costly reagent and commercially not feasible.

US Patent No. 7,326,708 discloses the dihydrogen phosphate salt of Sitagliptin and processes for the preparation thereof.

WO 2004/083212 Al discloses a process to prepare beta-ketoamides, which is as shown below:

In this patent publication Meldrum's adduct is prepared using an acid activating agent, which is selected from pivaloyl chloride. This process suffers from less yield and low quality of compound of Formula XIII.

WO 2004/085378 discloses a process for the preparation of Sitagliptin, wherein the reduction of the Enamine amide (Sitagliptin intermediate) is carried out by using rhodium metal and a chiral ferrocenyl diphosphine. The process is as shown below:

In this patent publication diketo compound is isolated, aminated using ammonium acetate and thereafter hydrogenated. This process may result in low yield thereby increase in the cost of the production.

The present inventors have found a process for the production of Sitagliptin and its pharmaceutically acceptable salts, which involves less number of steps and which is cost effective, consistent and industrially viable.

OBJECTIVE

The objective of the present invention is to provide an improved process for preparing Sitagliptin and pharmaceutically acceptable salts thereof.

In yet another objective of the present invention is to provide a stereo selective process for preparing Sitagliptin, which is simple, industrially applicable, eco-friendly and economically viable.

In yet another objective of the present invention is to provide a safe, productive, consistent and easy to handle commercial process for preparing Sitagliptin.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparing Sitagliptin of Formula I, or acid addition salts thereof which comprises:

a) reacting 2,4,5-trifluorophenylacetic acid of Formula IX with Meldrum's acid of Formula X, in presence of a carbodiimide, in a solvent to give 2-(2-(2,4,5-trifluorophenyl)-l-hydroxyethylidene)-5,5-dimethylcyclohexane-l,3-dione [Meldrum's adduct] of Formula XI.

b) condensing compound of Formula XI, with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4- triazole[4,3-a]pyrazine of Formula XII,

in the presence of base and a solvent to give 4-oxo-4{3-(trifluoromethyl)-5,6-dihydro{ 1,2,4}triazolo-[4,3-a]pyrazine-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butane-2-one of Formula XIII,

which in situ aminated using aminating agent to give(2Z)-4-oxo-4{3-(trifluoromethyl)-5,6-dihydro-{l,2,4}triazolo-[4,3-a]pyrazine-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butane-2-en-2-amine of Formula XIV;

c) hydrogenating the compound of Formula XIV in a solvent to give Sitagliptin of Formula I;

d) optionally isolating the compound of Formula I; and

e) converting compound of formula I to its acid addition salts.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process to prepare Sitagliptin, which comprises, condensing Meldrum's adduct of Formula XI with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-a]pyrazine of Formula XII in the presence of base selected from pyridine, 4-di-(methylamino)pyridine, diisopropylethylamine, diisopropylamine, triethylamine, imidazole, lutidine and the like or mixtures thereof and a solvent selected from aromatic hydrocarbons such as toluene, xylene, or mixtures thereof; alky halides such as dichloromethane, chloroform, 1,2-dichloroethane or mixtures thereof; esters such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate or mixtures thereof; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, n-butanone or mixtures thereof; at a temperature in the range of 25 to 110°C, preferably 55 to 85°C to give 4-oxo-4{3-(trifiuoromethyl)-5,6-dihydro{ 1,2,4}triazolo-[4,3-a]pyrazine-7(8H)-yl)-l -(2,4,5-trifluoro-phenyl)butane-2-one of Formula XIII, which in situ aminated using aminating agent selected from using ammonium chloride, ammonium bromide, ammonium iodide, ammonium carbonate, ammonium formate; ammonium acetate in combination with ethanolic ammonia or methanolic ammonia or combination ammonium acetate-aqueous ammonia; formic acid-aqueous ammonia; ammonium formate-formic acid, or mixtures thereof in a solvent selected from alcohols selected from methanol, ethanol, isopropyl alcohol, butanol; nitriles selected from acetonitrile; ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, n-butanone; alkyl halides selected from dichloromethane, dichloroethane; esters selected from methyl acetate, ethyl acetate; aromatic hydrocarbons selected from toluene, xylene; amides selected from dimethylacetamide, dimethylformamide, methylpyrrolidone; ethers selected from dimethyl ether, diethyl ether, tetrahydrofuran; water or mixtures thereof to give (2Z)-4-oxo-4[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-l-(2,4,5-trifluorophenyl)but-2-en-2-amine of Formula XIV.

Hydrogenating (2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo-[4,3-a]-pyrazine-7(8H)-yl]-l-(2,4,5-trifluorophenyl)but-2-en-2-amine of Formula XIV in a solvent selected from alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol or mixtures thereof to give (2R)-4-oxo-4{3-(trifluoromethyl)-5,6-dihydro{l,2,4}-triazolo[4,3-a]pyrazine-7(8H)-yl)-l-(2,4,5-trifluoro-phenyl)butane-2-amine (Sitagliptin) of Formula I. The hydrogenation reaction can be carried out in presence of catalysts such as rhodium phosphine complex. The reaction can be carried out at a temperature in the range of 25-100°C, preferably at 50-75°C.

Sitagliptin of formula I can be further converted to its acid addition salts by reacting Sitagliptin base with an acid in a solvent. The acid can be selected from Hydrochloric acid, oxalic acid, citric acid, maleic acid, oxalic acid, phosphoric acid or methane sulphonic acid. The reaction of sitagliptin base can be carried out in a solvent selected from alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol or mixtures thereof.

In yet another embodiment, the present invention also relates to the preparation of Meldrum's adduct of Formula XI, which comprises:

a) reacting 2,4,5-trifluorophenylacetic acid of Formula IX, with Meldrum's acid of Formula X,

in presence of a carbodiimide, in a solvent to give 2-(2-(2,4,5-trifluorophenyl)-l-hydroxyethylidene)-5,5-dimethylcyclohexane-l,3-dione [Meldrum's adduct] of Formula XI.

The carbodiimides are selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and the like and mixtures thereof; solvent is selected from aromatic hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane or mixtures thereof; alkyl halide such as dichloromethane, chloroform, 1,2-dichloroethane or mixtures thereof; ester such as ethyl acetate, isopropyl acetate, n-butyl acetate or mixtures thereof; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, n-butanone or mixtures thereof; N,N-dimethylformamide, dimethylacetamide; base selected from pyridine, 4-di-(methylamino) pyridine, diisopropyl ethylamine, triethylamine, imidazole or mixtures thereof; reaction is carried out at a temperature selected from -10 to 30°C, preferably at 0 to 10°C.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE 1

PREPARATION OF 2-(2-(2,4,5-TRIFLUOROPHENYL)-l-HYDROXYETHYL-EDENE)-5,5-DIMETHYLCYCLOHEXANE-l,3-DIONE [MELDRUM'S ADDUCT]

2,4,5-Trifluorophenylacetic acid (250g, 1.316 mole) was added to methylene chloride (1250 ml) at 0-5°C, Meldrum's acid (208.4g, 1.447 mole) and 4-(dimethylamino) pyridine (160.8g, 1.316mole) were added sequentially to above suspension maintaining 0-5°C. Thereafter, N,N-dicyclohexylcarbodiimide (325.26 g, 1.579 mole) was also added slowly to reaction mass maintaining 0-5°C and stirring was continued at this temperature to complete the reaction. After completion of the reaction the reaction mass was filtered and filtrate was diluted with DM water (1250 ml) and acidified. Thereafter, separated organic layer was added to pre-cooled DM water (5000 ml) and pH of the biphasic solution was adjusted to 11 to 12 with aqueous sodium hydroxide at 25-30°C. Organic layer was separated and aqueous extract was acidified and cooled to 0-5°C. Precipitated product was filtered, washed and dried at 45-50°C under reduced pressure to give Meldrum's adduct. Yield: 400g (96%)

Chromatographic Purity (by HPLC): 99.03%

EXAMPLE 2

PREPARATION OF (2Z)-4-OXO-4{3-(TRIFLUOROMETHYL)-5,6-DIHYDRO-
{l,2,4}TRIAZOLO-[4,3-a]-PYRAZINE-7(8H)-YL)-l-(2,4,5-TRIFLUORO-PHENYL)BUTANE-2-EN-2-AMINE (ENAMINE AMIDE)

Triethylamine (15.2g, 0.150 mole) was added to a mixture of Meldrum's adduct (50g, 0.158 mole) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]-triazolo[4,3-a] pyrazine hydrochloride (36.15 g, 0.158 mole) in ethyl acetate (400 ml) at 25-30°C. Thereafter, the contents were heated to reflux at ~75°C for 5 hrs to complete the reaction. After completion of the reaction the reaction mass was cooled to 25-30°C and diluted with DM water (100 ml). The organic layer was separated and washed with saturated aqueous sodium chloride solution and then concentrated under reduced pressure to yield an oily mass. Methanol (500 ml) and ammonium acetate (60.9g, 0.79 mole) was added to the concentrated mass and heated the content to reflux at 60-65°C for 3 hrs. After completion of the reaction aqueous ammonia solution (25 ml) was added and cooled to 0-5°C and stirred for -90 min. The obtained product was filtered, washed with pre-cooled methanol and dried at 45-50°C under reduced pressure (~20mmHg) to give Enamine amide.

Yield: 57.5g

Chromatographic purity (by HPLC): 98.79%

EXAMPLE 3

PREPARATION OF (R)-3-AMINO-l-(3-(TRIFLUOROMETHYL)-5,6-DIHYDRO-[l,2,4]-TMAZOLO[4,3-a]PYRAZIN-7(8H)-YL)-4-(2,4,5-TRIFLUOROPHENYL)-BUTAN-1-ONE (SITAGLIPTIN)

Enamine amide (350 g, 0.864 moles) was suspended in degassed methanol (2450 ml) and rhodium phosphine complex was added under nitrogen atmosphere (Rhodium phosphine complex was prepared by suspending bis(l,5-cyclooctadiene)rhodium (I) (1.75g) and (R,S)-t-butyl Josiphos (4.2 g) in degassed methanol (1050 ml) under nitrogen atmosphere and stirred for 1 hr at 25-30°C). Thereafter, after degassing, reaction mass was hydrogenated under 200-280 psig at 48-50°C for -30 hrs. After completion of hydrogenation, reaction mass was concentrated at 45-50°C under reduced pressure (200-10 mm Hg) and diluted with DM water (2800 ml) and methylene chloride (1750 ml). pH of biphasic solution was adjusted to 3.5 with hydrochloric acid and organic layer was separated. Methylene chloride (1750 ml) was added to the separated aqueous layer and readjusted pH of biphasic solution to 9 with 10 %w/w aqueous sodium hydroxide. Organic layer was separated and thereafter concentrated under reduced pressure (400-100 mm Hg). Toluene (2800 ml) was added to concentrated mass and contents were stirred for ~1 h at 45-50°C. Thereafter the contents were cooled slowly to 25-30°C and stirred at this temperature for 1 h to complete the crystallization. Finally, filtered the product, washed with toluene (2x350ml) and dried at 45-50°C under reduced pressure (-20 mm Hg) to obtain titled compound.

Yield: 262.5g

Chromatographic purity (by HPLC): 99.55%
Chiral Purity (by HPLC): 99.86%

EXAMPLE 4

PREPARATION OF (R)-3-AMINO-l-(3-(TRIFLUOROMETHYL)-5,6-DIHYDRO-[l,2,4]-TRIAZOLO[4,3-a]PYRAZIN-7(8H)-YL)-4-(2,4,M5-TRIFLUOROPHENYL)-BUTAN-1-ONE DIHYDROGENPHOSPHATE MONOHYDRATE (SITAGLIPTIN PHOSPHATE MONOHYDRATE)

Sitagliptin base (50g, 0.1229 moles) was suspended in a mixture of isopropyl alcohol (100 ml) and DM water (50 ml) at 25-30°C and stirred to obtain a clear solution. Obtained solution was filtered through hyflow and residue was washed with isopropyl alcohol (25 ml). Thereafter, obtained filtrate was heated to 54-56°C and diluted phosphoric acid [87% w/w phosphoric acid (14g) is dissolved in DM water (25 ml)] was added to it at 55-60°C. Reaction mass was seeded with Sitagliptin phosphate monohydrate (0.25g) and stirring was continued for 2 hrs at this temperature. Isopropyl alcohol (525 ml) was added slowly at 45-50°C to the reaction mass, further cooled the contents slowly to 20-23°C and stirred at this temperature for 1 hr. Product was filtered, washed with 10 %v/v aqueous isopropyl alcohol and dried at 40-45 °C under reduced pressure (~20mmHg). Yield: 60g Chiral Purity (by HPLC): 100.0%

WE CLAIM

1. A process for the preparation of compound of Formula I, or acid addition salts thereof comprising:

a) condensing compound of Formula XI with compound of Formula XII,
in presence of base and a solvent to produce compound of Formula XIII;

b) aminating compound of formula XIII in situ using aminating agent to produce compound of Formula XIV:

c) hydrogenating the compound of Formula XIV in a solvent to produce compound of Formula I;

d) optionally isolating compound of Formula I; and

e) optionally converting compound of formula I to its acid addition salts.

2. The process according to claim 1, wherein the base is selected from pyridine, 4-di-(methylamino)pyridine, diisopropylethylamine, tri ethyl amine, imidazole or mixtures thereof.

3. The process according to claim 1, wherein the solvent is selected from toluene, xylene, n-hexane, n-heptane, cyclohexane, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, n-butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-butanone or mixtures thereof.

4. The process according to claim 1, wherein the hydrogenation is carried out in presence of rhodium phosphine complex.

5. The process according to claim 1, wherein aminating agent is selected from ammonium chloride, ammonium bromide, ammonium iodide, ammonium carbonate, ammonium formate, ammonium acetate in combination with ethanolic ammonia or methanolic ammonia or combination ammonium acetate-aqueous ammonia; formic acid-aqueous ammonia; ammonium formate-formic acid or mixtures thereof

6. A process for the preparation of compound of formula XI, comprising reaction of compound of Formula IX with compound of Formula X, in a solvent, characterized in that the reaction is carried out in presence of carbodiimide.

7. The process according to claim 6, further comprising conversion of compound of formula XI to compound of formula I or acid addition salts thereof.

8. The process according to claim 6, wherein the carbodiimide is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or mixtures thereof.

9. The process according to claim 6, wherein the solvent is selected from toluene, xylene, n-hexane, n-heptane, cyclohexane, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, n-butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-butanone or mixtures thereof.

10. A process for the preparation of compound of formula I or acid salts thereof substantially as described herein.