INTERMEDIATE

Field of the Invention

The present invention provides a process for the preparation of sitagliptin. The present invention also provides a process for the preparation of fert-butyl [(2i?)-4-oxo-4- [3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate, an intermediate of sitagliptin.

Background of the Invention

Sitagliptin phosphate monohydrate of Formula A, an orally -active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, chemically designated as 7-[(3i?)-3-amino-l-oxo- 4-(2,4,5 -trifluorophenyl)butyl] -5 ,6,7,8-tetrahydro-3 -(trifluoromethyl)- 1 ,2,4-triazolo [4,3 - ]pyrazine phosphate (1 : 1) monohydrate, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Formula A

Several processes are known in the literature for making fert-butyl [(2i?)-4-oxo-4- [3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate and/or sitagliptin, for example, those disclosed in U.S. Patent No. 6,699,871; PCT Publication Nos. WO 2009/064476, WO 2010/097420, WO 2010/122578, WO 2012/035549, WO 2012/099381, WO 2013/114173, WO

2013/013833, and WO 2014/023930; European Patent Nos. EP 2 423 178 and EP 2 647 624; and Indian Application No. 2575/CHE/2009.

The prior art processes reported for the preparation of fert-butyl [(2i?)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate utilize agents such as 1-hydroxybenzotriazole, N,N'- dicyclohexylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1,1 '- carbonyldiimidazole, 2-chloro-4,6-dimethoxy-l,3,5-triazine, 2-chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, or phenyl boronic acid; a base, generally diisopropylethylamine or triethylamine; and a solvent such as NN- dimethylformamide (DMF), dichloromethane, or acetonitrile.

The present inventors observed that the agents reported above such as 1- hydroxybenzotriazole, N,N'-dicyclohexylcarbodiimide, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide, Ι, Γ-carbonyldiimidazole, and 2-chloro-4,6- dimethoxy-l,3,5-triazine are costly and hazardous, and agents such as 2- chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, and phenyl boronic acid require lengthy reaction times.

The prior art processes further require a purification process to remove the unwanted side products by recrystallization, trituration, and/or preparative thin layer chromatography .

The prior art processes reported, for example, those disclosed in U.S. Patent No. 6,699,871; PCT Publication Nos. WO 2009/064476, WO 2010/122578, WO 2013/114173; Indian Application No. 2575/CHE/2009; and European Publication No. EP 2 647 624 for the preparation of sitagliptin from fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 - ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2- yl]carbamate require treating fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 - ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2- yl]carbamate with hydrochloric acid in a solvent such as methanol or isopropyl alcohol.

The present inventors have developed a process for the preparation of fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromemyl)-5,6-dihydro[l,2,4]triazol o[4,3- ]pyrazin-7(8H)-yl]-l- (2,4,5-trifluorophenyl)butan-2-yl]carbamate and sitagliptin which is less expensive, less time consuming, and more commercially viable, by avoiding the use of hazardous and costly reagents.

Summary of the Invention

The present invention provides a process for the preparation of fert-butyl [(2i?)-4- oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate which comprises reacting (3R)-3-[(tert- butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid with 3-(trifluoromethyl)- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine or a salt thereof in the presence of catalyst, wherein the catalyst is a trialkyl borate or a mixture of boric acid and a trifluoromethyl phenylboronic acid. The present invention also provides a process for the preparation of sitagliptin wherein the process comprises deprotecting fert-butyl [(2i?)-4- oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-yl]carbamate in the presence of an activated zeolite. The present inventors have found that the activated zeolite used for the deprotection of fert-butyl

[(2i?)-4-oxo-4-[3-(trifluorome l)-5,6-dmydro[l,2,4]triazolo[4,3-o]pyrazin-7(8H)-yl]-l- (2,4,5-trifluorophenyl)butan-2-yl]carbamate can be recycled.

Detailed Description of the Invention

The term "treating" includes adding, dissolving, slurrying, stirring, and combinations thereof.

The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.

The term "solvent" includes water, esters, alkanols, aromatic hydrocarbons, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, and mixtures thereof. Examples of esters include ethyl acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms, such as methanol, ethanol, «-propanol, isopropanol, and butanol. Examples of aromatic hydrocarbons include toluene and xylene. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2- dichloroethane. Examples of ketones include acetone and methyl ethyl ketone. Examples of ethers include diethyl ether and tetrahydrofuran. Examples of polar aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.

The term "base" includes organic or inorganic bases. Examples of organic bases include ethyl amine, triethylamine, diisopropyl amine, diisopropyl ethyl amine, and mixtures thereof. Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals, and the like. Examples of hydroxides, carbonates, and bicarbonates of an alkali or alkaline earth metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. A first aspect of the present invention provides a process for the preparation of sitagliptin of Formula 1

Formula 1

comprising the steps of:

treating (3R)-3 - [(fert-butoxycarbonyl)amino]

trifluorophenyl)butanoic acid of Formula 2

Formula 2

with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof

Formula 3

in the presence of a catalyst wherein the catalyst is a trialkyl borate or a mixture of boric acid and a trifluoromethyl phenylboronic acid to obtain tert- butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazo lo[4,3- ]pyrazin-7(8H)-yl] - 1 -(2,4,5-trifluorophenyl)butan-2-yl]carbamate of Formula 4: and

Formula 4

b) deprotecting the fert-butyl [(2i?)-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]carbamate of Formula 4 in the presence of an activated zeolite to obtain sitagliptin.

A second aspect of the present invention provides a process for the

preparation of fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4] triazolo [4,3 - ]pyrazin-7(8H)-yl]-l -(2,4,5 -trifluorophenyl)butan-2-yl] carbamate of Formula 4

Formula 4

which comprises treating (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid of Formula 2

Formula 2

with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof

Formula 3

in the presence of a catalyst, wherein the catalyst is trialkyl borate or a mixture of boric acid and trifluoromethyl phenylboronic acid.

A third aspect of the present invention provides a process for the preparation of sitagliptin of Formula 1

Formula 1

which comprises deprotecting fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3 - ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2 - yl] carbamate of Formula 4

Formula 4

in the presence of an activated zeolite.

The starting material, (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid of Formula 2, can be prepared by methods known in the art, including that described in European Patent No. EP 2 647 624. The starting material, 3- (trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof, can be prepared by the methods known in the art, including those described in PCT Publication Nos. WO 2004/085661 and WO 2010/122578.

(3i?)-3-[(teri-Butoxycarbonyl)amino]-4-(2,4,5-trifluoropheny l)butanoic acid of Formula 2 is treated with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 or salts thereof in the presence of catalyst, wherein the catalyst is a trialkyl borate or a mixture of boric acid and a trifluoromethyl phenylboronic acid, in a solvent at a temperature of about 25 °C to reflux for a time period of about 24 hours to about 36 hours to complete the reaction.

Examples of trialkyl borates include trimethyl borate, triethyl borate, triisopropyl borate, and triisobutyl borate. Examples of trifluoromethyl phenylboronic acids include 2- (trifluoromethyl)phenylboronic acid, 3-(trifluoromethyl)phenylboronic acid, and 4- (trifluoromethy l)phenylboronic acid .

Examples of salts of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine include acid addition salts such as hydrochloride, hydrobromide, and sulfate.

In one embodiment, 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride in toluene is treated with an aqueous sodium hydroxide solution at reflux temperature. (3i?)-3-[(fert-Butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid of Formula 2, boric acid, and 4- (trifluoromethyl)phenylboronic acid are added to 3-(trifluoromethyl)-5,6,7,8- tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of Formula 3 in toluene at a temperature of about 60°C to about 80°C to obtain a reaction mixture, then refluxed while stirring for about 24 hours to complete the reaction.

In another embodiment, boric acid, 4-trifluoromethyl(phenylboronic) acid, and triethylamine are added to a mixture of toluene, (3i?)-3-[(feri-butoxycarbonyl)amino]-4- (2,4,5 -trifluorophenyl)butanoic acid, and 3-(trifluoromethyl)-5, 6,7,8- tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride to obtain a reaction mixture, then refluxed while stirring for about 24 hours to complete the reaction.

In yet another embodiment, a mixture of (3i?)-3-[(fert-butoxycarbonyl)amino]-4- (2,4,5 -trifluorophenyl)butanoic acid, triisopropyl borate, and concentrated sulfuric acid in toluene is refluxed for about 2 hours and then cooled to 80°C to 85°C. 3-

(Trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride and triethylamine are added to the mixture at about 80°C to 85°C and refluxed while stirring for about 36 hours to complete the reaction.

After completion of the reaction, teri-butyl[(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ 1 ,2,4]triazolo [4,3- ]pyrazin-7(8H)-yl] - 1 -(2,4,5 -trifluorophenyl)butan-2- yl]carbamate can be either isolated or can be carried to the next step of the process without isolation. Suitable isolation techniques include cooling, evaporation under vacuum, washing, precipitation, filtration, filtration under vacuum, decantation, centrifugation, and combinations thereof.

Deprotection of fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3- ]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2- yl]carbamate in the presence of an activated zeolite can be performed in one or more solvents at a temperature of about 50°C to about 80°C for a time period sufficient to complete the reaction.

The activated zeolite may be obtained by treating zeolite (CBV-712) with 6N hydrochloric acid at a temperature of about 20°C to 30°C for about 30 minutes, and then filtering the mixture under vacuum.

In one embodiment, a mixture of activated zeolite and isopropyl acetate is added to fert-butyl [(2i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazo lo[4,3- ]pyrazin- 7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-yl]carbamate and heated to about 50°C to about 80°C while stirring for a time period sufficient to complete the reaction.

Sitagliptin can be isolated by cooling, precipitation, washing, filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.

While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be within the scope of the present invention.

EXAMPLES

Example 1 : Preparation of ferf-butyl r(2j?)-4-oxo-4-r3-(trifluoromethvn-5.6- dihydro[1.2.4]triazolo[4 - ]pyrazin-7(8H)-yl]-l-(2.4.5-trifluorophenyl)butan-2- yl] carbamate (Formula 4)

Water (5 mL) and sodium hydroxide (0.72 g, 1.2 equivalents) were added in a round bottom flask and dissolved at 20°C to 25°C. 3-(Trifluoromethyl)-5, 6,7,8- tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride (Formula 3; 5 g, 1.5 equivalents) and toluene (50 mL) were added at 20°C to 25 °C to the sodium hydroxide solution and stirred for 30 minutes. The temperature of the reaction mixture was raised to reflux (110°C) and refluxed for 1 hour to remove water. The reaction mixture was cooled to 70°C to 75°C and then (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid (Formula 2; 5 g, 1 equivalent), boric acid (0.93 g, 1 equivalent), and 4-(trifluoromethyl)phenylboronic acid (0.28 g; 0.1 equivalents) were added to the reaction mixture at 70°C to 75°C. The temperature of the reaction mixture was raised to reflux (110°C) and refluxed for 20 hours to 24 hours. The reaction mixture was cooled to 50°C to 55°C and toluene was recovered completely under vacuum at 50°C to 55°C to obtain a semi-solid residue. 10% Sodium hydroxide solution (50 mL) was added to the semi-solid residue at 20°C to 25°C, and the mixture was stirred for 30 minutes at 20°C to 25 °C. The solid was filtered under vacuum, washed with water (50 mL) at 20°C to 25°C, and then dried in an air drier at 50°C to 55°C for 15 hours to obtain the title compound.

Yield: 5.0 g

Example 2: Preparation of ferf-butyl [(2j?)-4-oxo-4-[3-(trifluoromethyl)-5.6- dihydro[1.2.4]triazolo[4 - ]pyrazin-7(8H)-yl]-l-(2.4.5-trifluorophenyl)butan-2- yl] carbamate (Formula 4)

Toluene (375 mL), (3i?)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid (Formula 2; 25 g, 1 equivalent), and 3-(trifluoromethyl)- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ]pyrazine hydrochloride (Formula 3; 20.5 g, 1.2 equivalents) were added in a round bottom flask. Boric acid (2.3 g, 0.5 equivalents), 4- (trifluoromethyl)phenylboronic acid (1.5 g, 0.1 equivalents), and triethylamine (9.0 g, 1.2 equivalents) were added. The temperature of the reaction mixture was raised to reflux (110°C) and refluxed for 22 hours to 24 hours. The reaction mixture was cooled to 50°C to 55°C and toluene was recovered completely under vacuum at 50°C to 55°C to obtain a semi-solid residue. 10% Sodium carbonate solution (250 mL) was added to the semi-solid residue at 20°C to 25°C, and the mixture was stirred for 1 hour at 20°C to 25°C. The solid was filtered under vacuum, washed with water (125 mL) at 20°C to 25 °C, and then dried under vacuum at 40°C to 45°C for 15 hours to obtain the title compound.

Yield: 26.5 g Example 3 : Preparation of ferf-butyl r(2j?)-4-oxo-4-r3-(trifluoromethvn-5.6- dihvdrori.2.41triazolor4 - lpyrazin-7(8H)-yll-l-(2.4.5-trifluorophenyl)butan-2- yll carbamate (Formula 4)

Toluene (300 mL) and (3i?)-3-[(teri-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoic acid (Formula 2; 20 g, 1.0 equivalent) were charged to a round bottom flask. Triisopropyl borate (12.42 g, 1.1 equivalents) and concentrated sulfuric acid (2 drops) were charged at 20°C to 25°C. The temperature was raised to reflux and refluxed for 2 hours. The reaction mixture was cooled to 80°C to 85°C. 3- (Trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- ]pyrazine hydrochloride (Formula 3; 15 g, 1.1 equivalents) and triethylamine (7.27 g, 1.2 equivalents) were charged at 80°C to 85°C to the reaction mixture and the temperature was raised to reflux and refluxed for 36 hours to 38 hours using a Dean-Stark apparatus. On completion of the reaction, toluene was recovered completely under vacuum at 50°C to 55°C. Water (100 mL) was charged to the solid residue, and the mixture was stirred for 2 hours at 20°C to 25°C. The solid was filtered under vacuum, washed with water (100 mL), and then dried in an air drier at 50°C to 55°C for 14 hours to 16 hours to obtain the title compound.

Yield: 28 g (92.10%)

Example 4: Preparation of sitagliptin (Formula 1)

Zeolite (CBV-712, 5 g) was added to 6N hydrochloric acid (25 mL) at 20°C to 25°C and the mixture was stirred for 30 minutes. The reaction mixture was filtered under vacuum and suck dried for 30 minutes to obtain activated zeolite.

The activated zeolite and isopropyl acetate (45 mL) were added to fert-butyl [(2R)- 4-0X0-4- [3 -(trifluoromethyl)-5 ,6-dihydro [ 1 ,2,4]triazolo [4,3- ]pyrazin-7(8H)-yl] - 1 -(2,4,5 - trifluorophenyl)butan-2-yl]carbamate (Formula 4; 5 g) at 20°C to 25°C. The reaction mixture was heated to 70°C, stirred for 49 hours at 70°C to 75°C, and then filtered at 70°C. The filtrate was cooled to 20°C to 25°C, then stirred for 2 hours at 20°C to 25°C. The wet solid was washed with isopropyl alcohol (5 mL), then dried under vacuum for 15 hours at 40°C to 45°C to obtain the title compound.

Yield: 3.0 g