PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND NOVEL INTERMEDIATES

Field of the Invention

The present invention relates to an improved process for the preparation of β-amino acid derivatives. More particularly, the present invention relates to an improved process for the preparation of Sitagliptin of formula lor its pharmaceutically acceptable salts.

The present invention also relates to novel intermediates used in the preparation of Sitagliptin.

Background of the Invention

Sitagliptin is an oral antihyperglycemic agent of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class. Inhibition of DPP-IV, an enzyme that inactivates both glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), represents a recent approaches to the treatment and prevention of type-2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). Sitagliptin also has an effect on appetite as it slows down gastric motility and induces a feeling of satiety. This reduction of appetite can help patients to lose weight which is also a useful effect in patients with diabetes.

Sitagliptin is chemically designated as (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trif luorophenyl)butan-2-amine and is marketed in the form of dihydrogen phosphate monohydrate under the trade name Januvia®. The empirical formula of Sitagliptin dihydrogen phosphate monohydrate is Ci ₆ H ₁₅ F ₆ N ₅ O.H ₃ PO t.H ₂ O and it has the following chemical structure:

Sitagliptin was first described and claimed in U.S. Pat. No. 6,699,871. This patent describes a class of beta-amino tetrahydrotriazolo[4,3-a]pyrazines, which are inhibitors of DPP-IV. The patent also describes a specific method for producing Sitagliptin or a salt thereof which involves coupling of intermediate compounds, namely (3R)-3-[N-(tert- butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid of formula 2 with 3- trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyr azine hydrochloride of formula 3 to afford Boc-protected Sitagliptin of formula 4, which was deprotected using methanolic hydrochloride to obtain Sitagliptin hydrochloride of formula lb. The process is shown in scheme-I given below:

Scheme-I

The process disclosed in US '871 suffers from the major disadvantage that the synthesis and purification of intermediate of formula 4 requires the use of preparative HPLC which is very expensive and not a feasible technique on industrial scale. The process also employs expensive reagents like 1-hydroxybenzotriazole (HOBT) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC). Moreover, the overall chemical yield reported is low (18%) and there is no mention of stereoisomeric yield. PCT. Pub. No. WO 2004/085661A1 discloses another process for the preparation of chiral beta amino acid derivatives including Sitagliptin. The process involves synthesis of diketone compound of formula 8 by condensation of Mel drum's adduct of formula 7 and 3- trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyra zine hydrochloride of formula 3. The intermediate compound of formula 8 was further treated with (S)-phenylglycine amide in isopropanol and acetic acid to obtain enamide of formula 9, which was further converted to compound of formula 10 by asymmetric hydrogenation at 90 psi and 22°C for 24 hours in the presence of Pt0 ₂ as catalyst. The intermediate compound of formula 10 was converted into Sitagliptin free base of formula 1 by a debenzylation reaction carried out at 40 psi at 50°C in the presence of 20% palladium hydroxide on carbon. The process is shown in the scheme-II given below:

wherein Ph is a phenyl group.

Scheme-II PCT. Pub. Nos. WO 2011/025932 and WO 2011/060213 discloses process for the preparation of Sitagliptin or its salts, which involves reacting 2,4,5 -trifluorophenyl acetic acid of formula 5 with 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid) of formula 6 in the presence of a suitable base in an organic solvent to afford compound of formula 7, which is further reacted with 3-trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]py razine hydrochloride of formula 3 in the presence of diisopropylethylamine to afford intermediate compound of formula 8. The intermediate compound of formula 8 was further treated with a chiral reagent i.e. (R)-(+)-l-phenylethylamine in the presence of an organic solvent to afford an enamide compound of formula 11, which was further converted into compound of formula 12 by reduction using sodium borohydride. The process is shown in the scheme-Ill given below:

Wherein Ph is a phenyl and R is Q-C ₄ alkyl group.

Scheme-Ill

The above two processes involves the use of metal catalysts like Pt0 ₂ and palladium hydroxide which are very expensive and require high pressure for more than 24 hours.

Hence, there is a need for an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts which is simple, eco-friendly, inexpensive, reproducible; and well suited for commercial scale.

Objective of the Invention

The main objective of the present invention is to provide cost-effective and commercially viable process for the preparation of Sitagliptin and its pharmaceutically acceptable salts. Another objective of the present invention is to provide a process for the preparation of Sitagliptin which employs less expensive, easily available and environment friendly reagents.

Summary of the Invention

Accordingly, the present invention provides an improved process for the preparation of Sitagliptin of Formula 1

7

wherein M is H, sodium or potassium;

with 3-trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]py razine of formula 3a or its salts,

in a solvent in the presence of a base to afford compound of formula 8,

ii) reacting compound of formula 8 with a compound of formula 13

13

wherein R ¹ is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C ₆ alkyl group;

in a solvent in the presence of an acid to afford enamide of formula 14,

iii) reducing the compound of formula 14 to compound of formula 15 or its salt in a solvent in the presence of a reducing agent and an acid

wherein R and m are as defined above and,

iv) deprotection of compound of formula 15 or its salts to Sitagliptin of formula 1 or its salts, in a solvent in the presence of an acid.

In another aspect, the present invention also provides novel intermediate of formula 14

wherein R is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C ₆ alkyl group. In another aspect, the present invention also provides novel intermediate of formula 15 or its salts

wherein R is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C ₆ alkyl group.

Detailed Description of the Invention

The main embodiment of the present invention provides an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts of Formula 1, which involves asymmetric synthesis using substituted phenyl alkyl amine derivatives.

In an embodiment, the present invention provides an improved process for the preparation of Sitagliptin of Formula 1

or a pharmaceutically acceptable salt thereof, which comprises:

i) reacting Mel drum's adduct of formula 7

wherein M is H, sodium or potassium;

with 3-trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]py razine or its salts of formula 3a

3a

in a solvent in the presence of a base to afford compound of formula 8,

ii) reacting compound of formula 8 with a compound of formula 13

13

wherein R ¹ is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C ₆ alkyl group; in a solvent in the presence of an acid to afford enamide of formula 14,

iii) reducing the compound of formula 14 to compound of formula 15 or its salt in a solvent the presence of a reducing agent and an acid and,

wherein R ¹ and m are as defined above and,

iv) converting compound of formula 15 or its salts to Sitagliptin or its salts of formula 1 by deprotection.

In an embodiment, the salts of compound of formula 3a are selected from HCl, HBr, HI and the like.

In another embodiment, the reaction in step (i) is carried out in a suitable solvent in the presence of a base at temperature less than about 120°, less than about 100°, less than about 80°, less than about 60° C, or any other suitable temperature for about 10 minutes to lOhours, or longer.

In accordance with the present invention, suitable solvent used in step (i) is selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate and isopropyl acetate; nitriles such as acetonitrile; halogenated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; ethers such as diethyl ether, diisopropyl ether, methylbutyl ether, tetrahydrofuran, dimethoxyethane and 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and dimethylacetamide; and or mixtures thereof.

Suitable bases used in step (i) according to the present invention is selected from organic bases such as triethylamine, diisopropyl amine, diisopropylethylamine, pyridine, dimethylamino pyridine (DMAP), diethylamino pyridine (DEAP), N- methyl morpholine, N- methyl pyrrolidone, DBU and sodium/potassium tert-butoxide, sodium methoxide and inorganic bases like sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or mixtures thereof.

In another embodiment, the reaction in step (ii) is carried out in a suitable solvent in the presence of an acid. Suitable solvents are selected from hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; ethers such as ethyl ether, isopropyl ether, methylbutyl ether, tetrahydrofuran, dimethoxyethane and 1,4- dioxane and or mixtures thereof. Suitable acids used in step (ii) according to the present invention are selected from organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulphonic acid or mixtures thereof.

In another embodiment, the reduction in step (iii) is carried out in a suitable solvent selected from ethers such as diethyl ether, diisopropyl ether, methylbutyl ether, tetrahydrofuran, dimethoxyethane and 1,4-dioxane; alcohols, such as methanol, ethanol, isopropyl alcohol and n-butanol; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethylsulfoxide (DMSO), and dimethylacetamide (DMA); and or mixtures thereof.

Suitable reducing agent used in step (iii) according to the present invention is selected from borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, zinc borohydride and the like.

Suitable acid used in step (iii) according to the present invention is selected from organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

In another embodiment, the compound of formula 15 is optionally purified by salt formation to enhance the purity. Suitable acids that can be employed for purification of compound of formula 15 are selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid or its derivatives, malic acid, maleic acid, mandelic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acidand the like.

In another embodiment, the conversion of compound of formula 15 or its salt to Sitagliptin of formula 1 in step (v) is carried out by hydrogenation using a hydrogen donor in a solvent at temperature less than about 120°, less than about 100°, less than about 80°, less than about 60°C, or any other suitable temperature for about 10 minutes to 2 hours or longer. Suitable hydrogen donors are selected from formic acid or salt thereof, acetic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid and methanesulphonic acid and the like.

The hydrogenation is carried out in suitable solvents used selected from ethers such as diethyl ether, diisopropyl ether, methylbutyl ether, tetrahydrofuran, dimethoxyethane, anisole, diphenyl ether and 1,4-dioxane; alcohols, such as methanol, ethanol, isopropyl alcohol and n- butanol; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; aprotic polar solvents such as Ν,Ν-dimethylfornnannide (DMF), dimethylsulfoxide (DMSO), and dimethylacetamide (DMA); and or mixtures thereof.

In another embodiment, Sitagliptin free base of formula 1 is converted to its pharmaceutically acceptable salts such as phosphate, hydrochloride.

The salt formation may be carried out in a suitable solvent selected from alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; ethers such as 1,4-dioxane and tetrahydrofuran; and water or mixtures thereof.

In a preferred embodiment, the present invention provides an improved process for the preparation of Sitagliptin or a pharmaceutically acceptable salt of Formula 1, which comprises:

7 wherein M is H, sodium or potassium;

with 3-trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]py razine hydrochloride formula 3 in a solvent in the presence of a base to afford compound of formula 8,

ii) reacting compound of form 13a

13a

in a solvent in the presence of an acid to afford enamide of formula 14a,

iii) reducing the compound of formula 14a to compound of formula 15a, in a solvent in the presence of a reducing agent and an acid,

iv) optionally purifying the compound of formula 15a by forming a salt, preferably tartarate salt,

v) converting compound of formula 15a or its tartarate salt to Sitagliptin of formula 1 by deprotection.

vi) optionally converting Sitagliptin free base of formula 1 to Sitagliptin phosphate of formula la by treating Sitagliptin with phosphoric acid.

In a most preferred embodiment, the present invention provides an improved process for the preparation of Sitagliptin or a pharmaceutically acceptable salt of Formula 1, which comprises:

i) reacting Meldrum's adduct of formula 7

wherein M is H, sodium or potassium;

with 3-trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]py razine hydrochloride of formula 3 in ethyl acetate in the presence of N-methyl morpholine to afford compound of formula 8,

ii) reacting compound of formula 8 with a compound of formula 13a

13a

in toluene in the presence of acetic acid to afford enamide of formula 14a,

iii) reducing the compound of formula 14a to compound of formula 15a, in dimethoxyethane in the presence of a reducing agent preferably sodium borohydride and an acid preferably methanesulphonic acid and,

iv optionally purifying the compound of formula 15a by forming a salt, preferably tartarate

v) converting compound of formula 15a or its tartarate salt to Sitagliptin of formula 1 by transfer hydrogenation in anisole in the presence of phosphoric acid and

vi) optionally converting Sitagliptin free base of formula 1 to Sitagliptin phosphate of formula la by treating Sitagliptin with phosphoric acid.

In another preferred embodiment, the present invention also provides novel intermediate of formula 14

wherein R is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C ₆ alkyl group.

In another embodiment, the present invention also provides novel intermediate of formula 15 or its salts

wherein R is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C ₆ alkyl group.

The preferred compounds of formula 15 and formula 14 of the present invention include: 7-[l-oxo-(3R)-(R-l-(4-methoxyphenyl)ethylamino)-4-(2,4,5-tri fluorophenyl)-butyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3-a]pyra zine;

(Z)-7-(l-oxo-3(R)-(4-methoxyphenyl)ethylamino)-4-(2,4,5-t rifluorophenyl)-but-2-enyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-l,2,4-triazolo [4,3-a]pyrazine 7-[l-oxo-(3R)-(R-l-(4-ethoxyphenyl)ethylamino)-4-(2,4,5-trif luorophenyl)-butyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3-a]pyra zine;

(Z)-7-(l-oxo-3(R)-(4-ethoxyphenyl)ethylamino)-4-(2,4,5-trifl uorophenyl)-but-2-enyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-l,2,4-triazolo [4,3-a]pyrazine;

7-[l-oxo-(3R)-(R-l-(4-hydroxyphenyl)ethylamino)-4-(2,4,5- trifluorophenyl)-butyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3-a]pyra zine and

(Z)-7-(l-oxo-3(R)-(4-hydroxyphenyl)ethylamino)-4-(2,4,5-trif luorophenyl)-but-2-enyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-l,2,4-triazolo [4,3-a]pyrazine.

Advantages of the present invention:

1. The process of the present invention involves use of less expensive reagents unlike the use of the expensive transition metal catalysts in the prior art.

2. The process of the present invention involves simple procedures for deprotection of p- methoxy benzyl group at penultimate step.

3. The process is commercially viable which makes the process cost effective.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limited and relate to solutions which have been particularly effective on a bench scale. Example- 1

Preparation of Sitagliptin dihydrogen phosphate

Step (i)

Preparation of 4-oxo-4-r3-(trifluoromethyl)-5,6-dihvdrori,2,41triazolor4,3, alpyrazin-7(8H)- yll-l-(2A5-trifluorophenyl)butane-2-one

To a mixture of 3-trifluoromethyl-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3a]pyr azine hydrochloride (75.7 g) and ethyl acetate (1 ltr) was added N-methylmorpholine (35.2 ml) and stirred the reaction mixture for about 10 min at room temperature. To this, 5-[l-hydroxy-2- (2,4,5-trifluorophenyl)ethyledine]-2,2-dimethyl-l,3 dioxane-4,6-dione (100 g) was added and stirred for about 10 min at room temperature and heated the reaction mixture to reflux temperature and maintained at the same temperature for about 6 hours. Cooled the reaction mixture to 25-30°C and DM water (750 ml) was added. The reaction mass was stirred for about 10 minutes and separated the organic layer from aqueous layer. Washed the organic layer with DM water and separated the organic layer. Dried the organic layer over anhydrous Na ₂ S0 ₄ and concentrated under vacuum at 50-55°C. Toluene (280 ml) was added to the residue, stirred for about 1 hour. Filtered the solid obtained, washed the cake with toluene and suck dried to get 115.0g of title compound.

Step (ii)

Preparation of (Z)-7-(l-oxo-3(R)-(4-methoxyphenyl)ethylamino)-4-(2,4,5-trif luorophenyl)- but-2-enyl)-3-trifluoromethyl-5,6J,8-tetrahydro-l,2,4-triazo lo r4,3-alpyrazine

To a mixture of toluene (1.15 ltr) and 4-oxo-4-[3-(trifluoromethyl)-5,6dihydro[l,2,4] triazolo[4,3,a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)bu tane-2-one (115.0 g) obtained in step (i) were added acetic acid (27.2 g) and (R)-(+)-4-methoxyphenylethylamine (47.0 g). The mixture was heated to reflux for 4 hours and cooled to 60-65°C. The solvent was completely distilled off under vacuum to get 150.0g of title compound.

Step (iii)

Preparation of 7-ri-oxo-(3R)-(R-l-(4-methoxyphenyl)ethylamino)-4-(2,4,5-tri fluorophenyl)- butyl)-3-trifluoromethyl-5,6J,8-tetrahydro-l,2,4-triazolor4, 3-alpyrazine

Dimethoxyethane (1.5 ltr) was cooled to -40°C, sodium borohydride (31.55 g) was added and stirred for about 5 min. Methanesulfonic acid (205.7 g) was added drop wise to the reaction mixture over a period of 30 minutes under constant stirring. The solution of (Z)-7-(l-oxo- 3(R)-4-methoxyphenylethylamino)-4-(2,4,5-trifluorophenyl)-bu t-2-enyl)-3-trifluoromethyl- 5,6,7,8-tetrahydro-l ,2,4-triazolo [4,3-a]pyrazine (150.0 g) obtained in step (ii) dissolved in Dimethoxyethane was added drop wise to the reaction mixture at -40°C over a period of 60 minutes under constant stirring. Stirred the reaction mixture for about 6 hours at the same temperature and slowly cooled down to 0-5°C. DM water (750 ml) and n-hexane (300 ml) were added and stirred the reaction mass for about 10 min. Aqueous layer was separated from organic layer and adjusted the pH of the aqueous layer to 10 with 1: 1 aq. NaOH solution and extracted the compound in to ethyl acetate (750 ml x 2). The solvent was distilled off completely under vacuum to get 109g of title compound.

Step (iv)

Preparation of 7-ri-oxo-(3R)-(R-l-(4-methoxyphenyl)ethylamino)-4-(2,4,5-tri fluorophenyl)- butyl)-3-trifluoromethyl-5,6J,8-tetrahvdro-l,2,4-triazolor4, 3-alpyrazine tartarate salt

The product obtained in step (iii) was dissolved in methanol (605.0 ml) at 25-30°C and tartaric acid (33.5 g) was added. Heated the reaction mixture to reflux temperature and stirred for about 1 hour. Distilled off the solvent completely under vacuum, toluene was added and stirred for about 1 hour. Filtered the solid obtained, washed the cake with toluene and suck dried to get 127g of title compound. [a] _D ² ° = -20.0° (C = 1.0, MeOH), HPLC chiral purity: 98% ee, HPLC purity: 98%. Step (v)

Preparation of 7-r(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)-butyll-5,6J, 8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolor4,3-alpyrazine (Sitagliptin free base)

To a mixture of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one tartarate salt (125g) obtained in step (iv) and anisole (375g), o-phosphoric acid (531.0g) was added at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and maintained at same temperature for about 1-2 hours. Cooled the reaction mixture slowly to 25-30°C, a mixture of DM water (625 ml) and MTBE (312 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (625 ml X 2). The solvent was distilled off completely under vacuum to get the 50g of title compound.

Step (vi)

Preparation of 7-r(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyll-5,6J,8 -tetrahydro-3- (trifluoromethyl)-l,2,4-triazolor4,3-alpyrazine phosphate. (Sitagliptin dihydrogen phosphate)

Sitagliptin free base obtained in step (v) 50g was dissolved in ethanol (225ml) and purified water (60ml) at 25-30°C. Heated the reaction mass to a temperature of 50°C and stirred for about 10 min. o-phosphoric acid (85% soln, 1.05 equivalents) was added to the reaction mixture at the same temperature and stirred for about 10 min. The reaction mass was heated again to a temperature of 75°C and stirred for about 10 min. Cooled the temperature of the reaction mass to 65°C, seed sample was added and stirred the reaction mass at this temperature for about 1 hour. Slowly cooled the temperature of the reaction mass to 25-30°C, ethanol (750ml) was added to the reaction mixture and stirred for about 18 hours at this temperature. The obtained solid was filtered, washed the cake with ethanol and suck dried to get 52g of the title compound. [a] _D ² ° = -20.0° (C = 1.0, H ₂ 0), HPLC chiral purity: 99% ee, HPLC purity: 99.89%. Example-2

Preparation of Sitagliptin free base

To lO.Og of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one tartarate salt was added anisole (20g) and o-phosphoric acid (8.33g) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 20-24 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of DM water (50 ml) and MTBE (25 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (50 ml X 2). The solvent was distilled off completely under vacuum to get the 2.5g of Sitagliptin base.

Example-3

Preparation of Sitagliptin free base

To lO.Og of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one tartarate salt was added anisole (30g) and 50% phosphoric acid (80.5g) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 20-24 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of DM water (50 ml) and MTBE (25 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (50 ml X 2). The solvent was distilled off completely under vacuum to get the l.Og of Sitagliptin base.

Example-4

Preparation of Sitagliptin free base

To lO.Og of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one (base from tartarate salt) was added anisole (30g) and o-phosphoric acid (62.5g) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 1 to 2 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of DM water (50 ml) and MTBE (25 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (50 ml X 2). The solvent was distilled off completely under vacuum to get the 5.0g of Sitagliptin base. Example-5

Preparation of Sitagliptin free base

To lO.Og of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one (base from tartarate salt) was added anisole (20g) and o-phosphoric acid (10.6g) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 24 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of DM water (50 ml) and MTBE (25 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (50 ml X 2). The solvent was distilled off completely under vacuum to get the 4.2g of Sitagliptin base.

Example-6

Preparation of Sitagliptin free base

To lO.Og of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one tartarate salt was added anisole (30g) and polyphosphoric acid (40. Og) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 1-1.5 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of chilled water (100 ml) and MTBE (50 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (100 ml X 2). The solvent was distilled off completely under vacuum to get the 4.5g of Sitagliptin base.

Example-7

Preparation of Sitagliptin free base To lO.Og of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one tartarate salt was added polyphosphoric acid (20.0g) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 1-1.5 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of chilled water (100 ml) and MTBE (50 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (100 ml X 2). The solvent was distilled off completely under vacuum to get the 4.2g of Sitagliptin base.

Example-8

Preparation of Sitagliptin free base

To lO.Og of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one (base from tartarate salt) was added Anisole (30g) and polyphosphoric acid (20.0g) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 1-1.5 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of chilled water (100 ml) and MTBE (50 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (100 ml X 2). The solvent was distilled off completely under vacuum to get the 5.0g of Sitagliptin base.

Example-9

Preparation of Sitagliptin free base

To lO.Og of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one (base from tartarate salt) was added polyphosphoric acid (20.0g) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 1-1.5 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of chilled water (100 ml) and MTBE (50 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (100 ml X 2). The solvent was distilled off completely under vacuum to get the 5.0g of Sitagliptin base.

Example-10

Preparation of Sitagliptin free base

To lO.Og of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one tartarate salt was added anisole (lOg) and trifluoroacetic acid (80.0g) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 10-15 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of chilled water (200 ml) and MTBE (50 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to MTBE (50 ml X 3). The solvent was distilled off completely under vacuum to get the l.Og of Sitagliptin base.

Example- 11

Preparation of Sitagliptin free base

To 5.0g of (3R)-[l-(4-methoxyphenyl)ethylamino]-l-(3-trifluoromethyl-5, 6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl )butan-l-one tartarate salt was added trifluoroacetic acid (20.0ml) at 25-30°C and stirred for about 10 min. The reaction mixture was heated to 95-100°C and stirred at same temperature for about 1-1.5 hours to complete the conversion of starting material. Cooled the reaction mixture slowly to 25-30°C, a mixture of chilled water (100 ml) and MTBE (50 ml) were added and stirred the reaction mass for about 10 minutes and separated aqueous layer from organic layer. Separated the aqueous layer, adjusted the pH of the aqueous layer to 10 with 40% aq. NaOH solution and extracted the product in to ethyl acetate (50 ml X 3). The solvent was distilled off completely under vacuum to get the 2.0g of Sitagliptin base.