DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Sitagliptin or its pharmaceutically acceptable salt.
The present invention relates to a process for the preparation of Sitagliptin Phosphate using novel intermediate of Formula II.

BACKGROUND OF THE INVENTION
Sitagliptin Phosphate is known from U.S patent No. 7,326,708 and is represented by structural Formula I.

Sitagliptin Phosphate is marketed in USA under the proprietary name “JANUVIA” and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

US patent number 7,326,708 discloses process of preparation of Sitagliptin Phosphate by process disclosed in below Scheme 1:
Scheme 1
Process disclosed in this patent involve use of costly metal catalyst and a ligand which increases the overall cost of the process and makes the process unsuitable for industrial scale production.

US patent number 8,309,724 discloses process of preparation of Sitagliptin Phosphate by preparing diasteriomeric salt and shown in below scheme 2:

Scheme 2
Diasteromeric salt in above scheme was prepared by suitable reagents like S-(+)-mandelic acid, R-(-)-mandelic acid, (1S)-(+)-camphor-10-sulfonic acid, (1R)-(-)-camphor-10-sulfonic acid, L-malic acid, D-malic acid, L-maleic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (-)-ibuprofen, (+)-ibuprofen, (1R)-(+)-3-bromocamphor-10-sulfonic acid, (1S)-(-)-3-bromocamphor-10-sulfonic acid, L-(+)-tartaric acid, D-(-)-tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dipara-tolyl-D-tartaric acid, (-)-dipara-tolyl-L-tartaric acid, L-(-)-pyroglutamic acid, L-(+)-pyroglutamic acid, (-)-lactic acid, L(+)-lactic acid, L-lysine, D-lysine, and mixtures of thereof. For example, the reagent may be (-)-di-para-tolyl-L-tartaric acid.

Preparation of intermediate diasteromeric salt in US’724 not only increases the number of steps which causes impurity level of final API to increase but also the time required to prepare final API and thus increases the overall cost of the production which makes the overall process less feasible for commercial scale of production. Further there is a decrease in yield due to resolution process.

Although there are currently many methods reported in literature for the preparation of Sitagliptin, specifically Sitagliptin Phosphate salt, still there is a continuing need to develop alternative and improved processes for the preparation of Sitagliptin Phosphate by employing intermediates which are produced through an economical process and is reproducible during scale up for achieving purity and meeting cost concerns. Present invention focused to develop simple process which reduce the number of steps as well as overall cost of the process.

The present invention focusses on the development of novel intermediates which are easy to scale up and are prepared through a cost effective process which is found to be more convenient to use, provides product in a better yield, when compared to previously known processes.

OBJECTIVE OF THE INVENTION
The main object of the present invention is to develop process for the preparation of Sitagliptin or its pharmaceutically acceptable salt by using novel intermediate of formula II.

Another object of the present invention is to provide a novel compound of Formula II.

Another object of the present invention is to provide a process for the preparation of novel compound of Formula II which can be used as an intermediate to prepare Sitagliptin or its pharmaceutically acceptable salt.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a novel compound of Formula II.

wherein, Pg is an amine protecting group selected from tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), benzyl, tosyl, benzylidene, 2-nitrophenylsulfenyl and any other protecting groups.

In another aspect, the present invention provides a process for the preparation of Sitagliptin or its pharmaceutically acceptable salt comprising the steps of:
a) reacting compound of Formula III with Meldrum's acid to give compound of Formula II;

wherein, Pg is an amine protecting group selected from tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), benzyl, tosyl, benzylidene, 2-nitrophenylsulfenyl and any other protecting groups; and
b) converting compound of Formula II to Sitagliptin or its pharmaceutically acceptable salt.

In yet another aspect, the present invention provides a process for the preparation of Sitagliptin or its pharmaceutically acceptable salt, comprising the steps of:
a) reacting compound of Formula III with Meldrum's acid to give compound of Formula II;

wherein, Pg is an amine protecting group selected from tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), benzyl, tosyl, benzylidene, 2-nitrophenylsulfenyl and any other protecting groups; and
b) treating compound of Formula II with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine or its hydrochloride followed by deprotection to give Sitagliptin or its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the preparation of Formula II, comprises the steps of:
a) reacting compound of Formula V with compound of Formula VI to give compound of Formula VII;

wherein, X is selected from halogen such as Cl, Br, I;
b) converting compound of Formula VII to give compound of Formula III; and

c) reacting compound of Formula III with Meldrum's acid to give compound of Formula II

wherein, Pg is an amine protecting group selected from tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), benzyl, tosyl, benzylidene, 2-nitrophenylsulfenyl and any other protecting groups.

DETAILED DESCRIPTION OF THE INVENTION
Definition:
The terms “pharmaceutically acceptable salt” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like or, benethamine, benzathine, diethanolamine, ethanolamine, dicyclohexyl amine, 4-(2-hydroxy-ethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.

The term “coupling agent” as used in the context of the present invention refers to pivaloyl chloride, thionyl chloride, N, N'-dicyclohexylcarbodiimide (DCC), N, N’-diisopropylcarbodiimide (DPCI), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), isobutylchloroformate, diisopropylcarbodiimide (DIC), N,N'-dicarbonyldiimidazole (CDI), benzotriazol -l-yl-Oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-l-yloxy) tripyrrolidinophosphonium hexafluorophosphate (Py AOP), hydroxybenzotriazole (HOBT) or O-benzotriazol-1-yl-1,1,3-tetramethyluronium tetrafluoroborat and the like.

The term “base” as used in the context of the present invention refers to base used for the coupling reaction of meldrum’s acid or in other step where similar coupling reaction to be performed can be selected from organic or inorganic base wherein, organic base selected from the group comprising methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine (TEA), N,N-diisopropylethylamine, tributylamine, triisopropylamine, pyridine, 1 , 8-diazabicyclo[ 5 .4.0]undec-7 -ene (DBU), 1,5- diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-dimethylaminopyridine abicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (4-DMAP), Lithium bis(trimethylsilyl)amide (LiHMDS), 1 ,8-bis-(dimethylamino)naphthalene, l-ethylpiperidine,1-methylmorpholine, lutidine or inorganic base like bicarbonates selected from the group comprising of Na2CO3, NaHCO3, KHCO3 or hydroxides selected from the group comprising of NaOH, KOH, LiOH, CsOH or mixture thereof.

The term “Solvent” as used in the context of the present invention depending on their use in different steps can be independently selected from the group comprising of nitriles, alcohols, ketones, esters, halogenated hydrocarbons, ethers, amides, dialkylsulfoxides, hydrocarbons, organic acids, water or the mixtures thereof. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like. Halogenated hydrocarbons are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like. Amides are selected from the group comprising of N, N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylformamide, N-methylpyrrolidone and the like. Dialkyl sulfoxides can be selected from the group comprising of dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide and the like.Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the group comprising of toluene, xylene or a mixture thereof.

In an embodiment, the present invention provides a novel compound of Formula II
,
wherein,
Pg is amine protecting group selected from tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), benzyl, tosyl, benzylidene, 2-nitrophenylsulfenyl and any other protecting groups.

In one embodiment, the present invention provides a process for the preparation of compound of Formula II, comprising the steps of:
a) reacting compound of Formula V with compound of Formula VI to give compound of Formula VII
,
wherein, X is selected from halogen such as Cl, Br, I;
b) converting compound of Formula VII to give compound of Formula III
,
and,
c) reacting compound of Formula III with Meldrum's acid to give compound of Formula II
.

In one embodiment, the present invention provides a process for the preparation of Sitagliptin or its pharmaceutically acceptable salt, comprising the steps of:
a) reacting compound of Formula III with Meldrum's acid to give compound of Formula II;
,
b) converting compound of Formula II to Sitagliptin or its pharmaceutically acceptable salt.

In one embodiment, the present invention provides a process for the preparation of Sitagliptin or its pharmaceutically acceptable salt, comprising the steps of:
a) reacting compound of Formula III with Meldrum's acid to give compound of Formula II
,
and,
b) treating compound of Formula II with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine or its hydrochloride followed by deprotection to give Sitagliptin or its pharmaceutically acceptable salt.

In one embodiment the present invention provides a process for the preparation of Sitagliptin or its pharmaceutically acceptable salt by the scheme 3 given below:
Scheme 3

In another embodiment, the present invention provides a process for the preparation of Sitagliptin or its pharmaceutically acceptable salt, comprising the steps of:
a) reacting compound of Formula IX with chiral amine such as (R)-phenylethanamine in the presence of base to give compound X
,
wherein X = Cl, Br, I;
b) reacting compound of Formula X with base in presence of catalyst and solvent to give compound V
;
c) reacting compound of formula V with trifluoro benzyl halide in presence of base and solvent to give compound VII
;
wherein X = Cl, Br, I;
d) hydrolysing/refluxing compound VII in presence of aqueous acid followed by protection with suitable amine protecting group in presence of base to give compound III
;
e) reacting compound III with Meldrum’s acid in presence of coupling agent, base and solvent to give adduct compound of formula II
;
f) treating compound of formula II obtained in step e) with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine or its hydrochloride (compound of Formula IV) to give compound of formula VIII
;
g) deprotecting the compound of formula VIII obtained in step f) in-situ with acid to give Sitagliptin free base
; and,
h) treating Sitagliptin free base with an acid in presence of solvent to give Sitagliptin pharmaceutically acceptable salt
.

In one embodiment, present invention is not only limited to (R)-phenylethanamine but also can be replaced with suitable chiral amine known in the literature such as (R)-(+)-1-(1-Naphthyl)ethylamine; (R)-(+)-4-Methoxy-a-methylbenzylamine; (R)-4-Fluoro-a-methylbenzylamine; (R)-(+)-a-Ethylbenzylamine; (R)-(+)-a,4-Dimethylbenzylamine.

In one embodiment, catalyst used is preferably a phase transfer catalyst selected from Triethylbenzylammonium chloride (TEBA).

In one embodiment, acid used for hydrolysing compound of formula VII or deprotecting compound of formula VIII is selected from HI, HBr, HCl, H2SO4, acetic acid, lewis acid. Preferably HI is used.

In one embodiment, coupling agent used for the formation of compound of formula II in step e) may be selected from pivaloyl chloride.

In one embodiment, compound of formula II obtained in step e) may be used in the next reaction without isolation or workup i.e. in-situ taken to next reaction.

In one embodiment, compound of formula VIII obtained in step f) may be used in the next reaction without isolation or workup i.e. in-situ taken to next reaction.

In a preferred embodiment, step h) of above process involves treating Sitagliptin free base with a phosphoric acid in the presence of solvent to give Sitagliptin Phosphate.

In another embodiment acid used in step h) for salt may selected from but not limited to hydrochloric acid, phosphoric acid, oxalic acid, hydrobromic acid, acetic acid, formic acid, succinic acid, mandelic acid, tartaric acid, fumaric acid, benzoic acid and the like.

EXAMPLES:
EXAMPLE 1: Preparation of 2,4,5-Trifluorobenzyliodide:
In a round bottom flask 2,4,5-Trifluorobenzylalcohol (2.26 g, 14 mmol) was dissolved in dry 1,4 dioxane (30 mL) and to that BF3.Et2O (1.98 g, 14 mmol) added. Potassium iodide (2.32 g, 14 mmol) was added to it and the resulting mixture was stirred for 48 h at room temperature. The reaction mixture was poured into cold water and extracted with diethyl ether. The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with 10% ethyl acetate in hexane to give 2,4,5-Trifluorobenzyliodide. Yield: 89%, Purity: 99% by HPLC.

EXAMPLE 2: Preparation of Formula X (Wherein X = Cl):
Chloroacetyl chloride (18 ml) in acetonitrile was added to (R)-phenylethanamine in a round bottom flask and added 30g sodium carbonate dissolved in water-acetonitrile (1:1) mixture at 0 o C. After completion of the reaction, the solvent was removed under pressure and the residue was acidified with 6M hydrochloric acid. The reaction mass was extracted with ethyl acetate. The solvent was removed to give title compound. Yield: 91%. Purity: 99.5% by HPLC.

EXAMPLE 3: Preparation of compound of Formula V:
To the compound (4 g) obtained in example 6 in dichloromethane in a round bottom flask was added sodium hydroxide solution (12 ml) at 30 o C. Benzyltriethyl ammonium chloride (TEBA) was then added to the reaction mixture and stirred for 48 hours. After completion of the reaction, water and 6 M hydrochloric acid were added to the reaction mixture. Solvent was removed under vacuum and aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over magnesium sulphate and filtered. The filtrate was distilled under vacuum to give title compound. Yield: 90%, Purity: 99.4% by HPLC.

EXAMPLE 4: Preparation of compound of Formula VII:
Compound V (1.64 g, 5.0 mmol) was dissolved in dry tetrahydrofuran (20 mL) in a round bottom flask and added a 1 M solution of LiHMDS (12 mL, 2.4 equiv) at -78 0C under nitrogen atmosphere to it. After 90 min, 2,4,5 trifluorobenzyl iodide (3 g, 2.2 equiv) in dry tetrahydrofuran (5 mL) was slowly added dropwise. The reaction was stirred for approximately 2 h. The reaction mixture was allowed to room temperature then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to dryness. The crude product was purified by column chromatography eluting with 10% ethyl acetate in hexane to give compound of formula VII. Yield: 82%, Purity: 99% by HPLC.

EXAMPLE 5: Preparation of compound of Formula III (Wherein Pg = tertiary butoxy carbonyl):
The compound VII (690 mg, 1.13 mmol) was refluxed in 57% HI (10 mL) for 3 h. The reaction mixture was evaporated under vacuum, after which 23 ml water containing Na2CO3 (1.6 g, 15 mmol) was added (reaction mixture pH should be basic), and cooled to 0oC. Di-tert-butyl dicarbonate (567 mg, 2.3 equiv) in 1,4-dioxane (14 mL) was added slowly and stirred for 12 h, then slowly warmed up to room temperature. Water was added to the reaction mixture and extracted with ether. The aqueous layer was acidified with aqueous citric acid solution up to pH 2 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by column chromatography eluting with 30% ethyl acetate in hexane to give title compound. Yield: 77%, Purity: 98% by HPLC.

EXAMPLE 6: Preparation of Formula II (Wherein Pg = tertiary butoxy carbonyl):
Compound of formula III (150 g, 0.789 mol) obtained in example-3, Meldrum's acid (125 g, 0.868 mol), and 4-(dimethylamino)pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. N,N-Dimethylacetamide (DMAc) (525 mL) was added in one portion at room temperature to dissolve the solids. N,N-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40° C. Pivaloyl chloride (107 mL, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5° C. The reaction mixture was aged at 5° C. for 1 h. The slurry was cooled to 0-5° C. and filtered the solid. The wet cake was washed with 20% aqueous N,N-Dimethylacetamide (300 mL), followed by an additional two batches of 20% aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature to give titled product. Yield: 95%, Purity: 99.5% by HPLC.

EXAMPLE 7: Preparation of compound of Formula VIII:
To a compound of formula II (150 g, 0.789 mol) obtained in example 4 in a round bottom flask added compound of IV (180 g, 0.789 mol) in one portion at 40-50° C. The reaction solution was maintained at 70° C. for several hours. 5% Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20-45° C. The batch was seeded and maintained at 20-30° C. for 1-2 h. Then an additional 525 mL of 5% aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h and continued for several hours at room temperature, the slurry was cooled to 0-5° C, filtered the solid. The wet cake was washed with 20% aqueous N,N-Dimethylacetamide (300 mL), followed by an additional two batches of 20% aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature to give titled product. Yield: 89%, Purity: 98% by HPLC.

EXAMPLE 8: Preparation of Sitagliptin Phosphate:
To a solution of compound VIII (100 mg, 0.19 mmol) obtained in example 7 in methanol (2 mL) was added 1 mL of conc. HCl in 2 mL of methanol at room temperature and stirred for 4 h. After stirring, the solvent was removed under vacuum followed by partitioning between ethyl acetate and 1 M aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude product was subjected to column chromatography with dichloromethane/methanol/NH4OH (900:50:2.5), to give (74 mg, 93%) of sitagliptin as a free base. To a solution of the free base sitagliptin (74 mg, 0.18 mmol) in ethanol (1 mL), phosphoric acid (85 wt %, 16.8 mg, 0.17 mmol) was added. The resulting mixture was treated at 80 0C for 30 min. The reaction mixture was allowed to cool to room temperature and filtered. The solid residue was then recrystallized in isopropanol to give the title compound. Yield: 96%, Purity: 99.5% by HPLC.
,CLAIMS:WE CLAIM:
1. A compound of formula II,

wherein, Pg is an amine protecting group selected from tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), benzyl, tosyl, benzylidene, and 2-nitrophenylsulfenyl.

2. A process for the preparation of Sitagliptin or its pharmaceutically acceptable salt comprising the steps of:
a) reacting compound of Formula V with compound of Formula VI to give compound of Formula VII

wherein, X is selected from halogen such as Cl, Br, I;
b) converting compound of Formula VII to give compound of Formula III;

c) reacting compound of Formula III with Meldrum's acid to give compound of Formula II

wherein, Pg is an amine protecting group selected from tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), benzyl, tosyl, benzylidene, and 2-nitrophenylsulfenyl; and
d) converting compound of Formula II to Sitagliptin or its pharmaceutically acceptable salt.

3. The process for the preparation of Sitagliptin or its pharmaceutically acceptable salt as claimed in claim 2, comprising the steps of:
a) reacting compound of Formula III with Meldrum's acid to give compound of Formula II;

b) treating compound of Formula II with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine or its hydrochloride followed by deprotection to give Sitagliptin or its pharmaceutically acceptable salt.

4. The process for the preparation of Sitagliptin or its pharmaceutically acceptable salt as claimed in claim 2 and 3, comprising the steps of:
a) reacting compound of Formula IX with chiral amine compound (R)-phenylethanamine in the presence of solvent and base to give compound X;

b) reacting compound of Formula X with base in presence of catalyst and solvent to give compound V;

c) reacting compound V with trifluoro benzyl halide in presence of base and solvent to give compound VII

wherein X = Cl, Br, I;
d) hydrolysing/refluxing compound VII in presence of aqueous acid followed by protection with an amine protecting group in presence of base to give compound III;

e) reacting compound III with Meldrum’s acid in presence of coupling agent, base and solvent to give adduct compound of formula II;

f) treating compound of formula II obtained in step e) with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine or its hydrochloride (compound of Formula IV) to give compound of formula VIII;

g) treating compound of formula VIII obtained in step f) in-situ with acid to give Sitagliptin free base; and

h) treating Sitagliptin free base with an acid in presence of solvent to give Sitagliptin pharmaceutically acceptable salt
.

5. The process of claim 4, wherein solvent is selected from a group comprising acetonitrile, propionitrile, butyronitrile, valeronitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane, N, N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylformamide, N-methylpyrrolidone, dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene, xylene or a mixture thereof.

6. The process of claim 4, wherein base is selected from a group comprising methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine (TEA), N,N-diisopropylethylamine, tributylamine, triisopropylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-dimethylaminopyridine abicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (4-DMAP), Lithium bis(trimethylsilyl)amide (LiHMDS), 1 ,8-bis-(dimethylamino)naphthalene, l-ethylpiperidine,1-methylmorpholine, lutidine, Na2CO3, NaHCO3, KHCO3, NaOH, KOH, LiOH, CsOH or mixture thereof.

7. The process of claim 4, wherein coupling agent is selected from a group comprising pivaloyl chloride, thionyl chloride, N, N'-dicyclohexylcarbodiimide (DCC), N, N’-diisopropylcarbodiimide (DPCI), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), isobutylchloroformate, diisopropylcarbodiimide (DIC), N,N'-dicarbonyldiimidazole (CDI), benzotriazol -l-yl-Oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-l-yloxy) tripyrrolidinophosphonium hexafluorophosphate (Py AOP), hydroxybenzotriazole (HOBT) or O-benzotriazol-1-yl-1,1,3-tetramethyluronium tetrafluoroborat.

8. The process of claim 4, wherein catalyst used is a phase transfer catalyst.

9. The process of claim 4, wherein acid used is selected from HI, HBr, HCl, H2SO4, acetic acid, lewis acid.

10. The process of claim 2, 3 and 4, wherein pharmaceutically acceptable acid is selected from hydrochloric acid, phosphoric acid, oxalic acid, hydrobromic acid, acetic acid, formic acid, succinic acid, mandelic acid, tartaric acid, fumaric acid, benzoic acid.