Field of the Invention:
The present invention relates to novel and improved processes for the preparation of sitagliptin, its pharmaceutically acceptable salts as well as their intermediates. Sitagliptin is 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 having the following structural formula

and its pharmaceutically acceptable salts thereof.
Sitagliptin phosphate is glucagon-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor. Sitagliptin phosphate is currently marketed in the United States under the brand name Januvia in its monohydrate form. Januvia is indicated to improve glycemic control in patients with type-2 diabetes mellitus.

Background of the invention:
Sitagliptin and its pharmaceutically acceptable salts as well as process for their
Preparation have been first disclosed in US 6699871. The disclosed process involves the
condensation of (3R)-3-[(l,l-dimethylethoxycarbonyl)-amino]-4-(2,4,5-trifluorophenyl)
-butanoic acid with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-I,2,4-triazolo[4,3-a]pyrazine in
the presence of HOBT in methylene chloride and then purified by preparative TLC to
provide 7-[(3R)-3-[(l,l-dimethylethoxycarbonyl)amino-4-(2,4,5-trifluorophenyl)-
butanoyl]-3(trifluoromethyI)-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3-a]pyrazine. The
obtained compound was then treated with hydrochloric acid in methanol to provide sitagliptin hydrochloride. This process involves the use of chromatographic teciinique for the purification of intermediates, also involves more number of steps and the yields are very low. Hence it is not commercially viable.

International publication number WO 2004/83212 disclosed a novel intermediates like 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-one and process for its preparation. The conversion of the said intermediate in to sitagliptin is not disclosed in this application.

International publication number WO 2004/85378 disclosed the conversion of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l.(2,4,5-trifluorophenyl)butan-2-one into sitagliptin by treating it with ammonium acetate in methanol to provide (2Z)-4-oxo-4-[3-(trifluoromethyI)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-triflurophenyl)but-2-en-2-amine, which on enantioselective hydrogenation in the presence of transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand.

International publication number WO 2005/97733 disclosed the preparation of sitagliptin by enantioselective hydrogenation of (2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-triflurophenyl)but-2-en-2-amine in the presence of rhodium metal precursor complexed with a chiral mono or biphosphine ligand.
International publication number WO 2005/72530 disclosed novel crystalline salts such as hydrochloric acid, benzene sulfonic acid, p-toluene sulfonic acid, tartaric acid, 10-camphour sulfonic acid, L-tartaric acid and D-tartaric acid salts of sitagliptin as well as its crystalline forms. The disclosed process involves treating of R-isomer of sitagliptin free base with a suitable acid as mentioned above in a suitable solvent to provide the corresponding sitagliptin salt compound.

In general all the prior art processes involve the enantioselective hydrogenation of (2Z)-4-oxo-4-[3-(trifluoromethnyl)-5,6-dihydro[ 1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1 -(2,4,5-triflurophenyl)but-2-en-2-amine in the presence of reagents like rhodium metal precursor complexed with a chiral ligand for the preparation of sitagliptin. But none involve the resolution of sitagliptin. Even though WO 2005/72530 disclosed novel crystalline salts of sitagliptin, it does not disclose or mention the possibility of resolution of sitagliptin using these salts. The process disclosed in the said patent involves the treatment of specific R-isomer of sitagliptin free base with a suitable acid in a suitable solvent.

Hence the main aspect of the present invention is to provide an alternate process which avoids the usage of costly transition metal and other chiral ligands in the preparation of sitagliptin and its pharmaceutically acceptable salts.

Summary of the Invention:
The present invention relates to novel process for the preparation of sitagliptin and its pharmaceutically acceptable salts as well as their intermediates. This invention also provides a process for the recovery of sitagliptin other isomer as well as intermediates.

The first aspect of the present invention is to provide a novel process for the preparation of sitagliptin compound of formula-1,

which comprises of the following steps,
a) Reducing alkyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of general formula-2, with a suitable stereo selective reducing agent in a suitable solvent to provide (R)-alkyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate, compound of general formula-3,

b) treating the compound of general formula-3, with a halogenating agent in a suitable solvent to provide (R)-alkyl 3-halo-4-(2,4,5-trifluorophenyl)butanoate, compound of general formula-4,

c) reacting the compound of general formula-4, with potassium phthalimide in a suitable solvent to provide (R)-alkyl 4-(l,3-dioxoisoindolin-2-yl)-3-(2,4,5-trifluorobenzyl)butanoate, compound of general formula-5,

d) reacting the compound of general formula-5 with a suitable base in a suitable solvent to provide (R)-alkyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-6,

e) treating the compound of general formula-6 with a suitable amino group protecting agent in a suitable solvent followed by hydrolysis in the presence of a base to provide (R)-3-N(protected) amino-4-(2,4,5-trifluorophenyl) butanoic acid, compound of general formula-7,

f) reacting the compound of general formula-7 with 3-(trifluoromethyI)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine compound of formula-8 or its salt, in the presence of suitable condensing agent in the presence or absence of a base, in a suitable solvent, followed by deprotection of amino protecting group provides sitagliptin compound of formula-1.

The second aspect of the present invention provides a recovery and conversion of the other isomer of Sitagliptin (S-isomer) into l-(3-(trifluoromethyl)-5,6-dihydro-[ 1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione compound of formula-10, which is a useful intermediate in the preparation of sitagliptin compound of formula-1.

a) Treating the sitagliptin other isomer of compound of formula-18 with sodium nitrite in the presence of aqueous acid followed by treating with sodium hypochlorite to provide 3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-11,

b) oxidizing the 3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[ 1,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-11 with a suitable oxidizing agent in the presence of acid to provide l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyI)butane-l,3-dione compound of formula-10,

The third aspect of the present invention provides a recovery of the methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate compound of formula-2a from (S)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-20a,

a) Treating the compound of (S)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-20a with sodium nitrite in the presence the of aqueous sulfuric acid, followed by treating with sodiimi hypochlorite to provide methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of formula-21a.

b) oxidizing the methyl 3-hydroxy-4-(2,4,5-trifluoropheny])butanoate compound of formula-21a with a suitable oxidizing agent in the presence of acid to provide methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of formula-2a,

The fourth aspect of the present invention provides a recovery of sitagliptin
intermediates from the other isomer of Sitagliptin compound of formula-18.

a) Treating the other isomer of sitagliptin with a suitable base to provide (S)-3-amino-4-(2,4,5-trifluorophenyI)butanoic acid derivative compound of general formula-19 and 3-(trifluoromethyl)-5,6,7,8-tetra hydro-[ 1,2,4]triazoIo[4,3-a]pyrazine hydrochloride compound of formula-8a,

b) (S)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid derivative compound of general formula-19 can be optionally esterified with a suitable alcoholic solvent in the presence of an acid to provide (S)-alkyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of general formula-20,

c) treating the (S)-alkyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of general formula-20 with sodium nitrite in the presence of aqueous acid, followed by treating with sodium hypochlorite to provide alkyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of formula-21,

d) oxidizing the alkyl 3-hydroxy-4-(2,4,5-trifluorophenyI)butanoate compound of general formula-21 with a suitable oxidizing agent to provide alkyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of general formula-2

The fifth aspect of the present invention provides a novel process for the preparation of sitagliptin compound of formula-1 which comprises of the following steps.

a) Reducing the l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l,3-dione compound of formula-lO with a suitable chiral reducing agent in a suitable acid in the presence or absence of solvent to provide (R)-3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1 -one compound of formula-15,

b) reacting the compound of formula-15 with a suitable halogenating agent in a suitable solvent to provide (R)-3-halo-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of general formula-16,

c) reacting (R)-3-halo-l-(3-(trifIuoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyI)butan-l-one compound of general formula-16 with potassium phthalimide in a suitable solvent to provide (R)-2-(4-oxo-4-(3-(trifluoromethyI)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-I-(2,4,5-trifluorophenyl)butan-2-yl)isoindoline-l,3-dione compound of formula-17.

d) treating the compound of formula-17 with a suitable base in a suitable compound to provide sitagliptin compound of formula-1.

The sixth aspect of the present invention provides a novel process for the preparation of sitagliptin racemic compound of formula-1 which comprises of the following steps.

a) Reacting the l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l,3-dione compound of formula-10 with hydroxylamine hydrochloride in the presence of base in the presence or absence of solvent to provide (Z)-3-(hydroxyimino)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-22,

b) reducing the compound of formula-22 with a suitable reducing agent selected from zinc in the presence of ammonium formate, zinc in the presence of ammonium chloride or Zn-Cu couple in a suitable solvent to provide racemic sitagliptin compound of formula-14.

c) Resolving the compound of formula-14 with a suitable chiral acid in a suitable solvent to provide sitagliptin compound of formula-1.

Detailed Description of the Invention:
As used herein the term "sitagliptin" refers to active isomer i.e.,7-[(3R)-3-amino-1 -oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4.3-a]pyrazine unless otherwise specifically mentioned.

Unless otherwise specified, as used herein the term "suitable solvent" refers to the solvent selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" such as to methylene chloride, chloroform, ethylene dichlonde and carbon tetra chloride; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone; "hydrocarbon solvents" such as to toluene, hexane, heptane and cyclohexane; "nitrile solvents" such as acetonitrile; "ester solvents" such as ethyl acetate, methyl acetate and isopropyl acetate; "ether solvents" such as tetrahydrofuran, diethyl ether and methyl tert-butyl ether; "polar solvents" such as water, "polar aprotic solvents" such as dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide.

As used herein the term "suitable base" refers to the bases selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate and alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal alkoxides like sodium tertiary butoxide, potassium tertiary butoxide; organic bases like methyl amine, ethyl amine, isopropyl amine, diisopropyl ethyl amine, triethyl amine, ammonia or their aqueous solution.

As used herein the term "suitable acid" refers to the acid selected from inorganic acids like hydrochloric acid, hydrobromic acid, hydroiodic acid, sulftiric acid; organic acids like acetic acid, methane sulfonic acid, para toluene sulfonic acid, trifluoro acetic acid.
As used herein the term "amino protection group" refers to a protection group which protects the amino functional group from involving in any reaction.

The present invention relates to a novel process for the preparation of sitagliptin compound of formula-1 or its pharmaceutically acceptable salts thereof. Sitagliptin is 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 having the . following structural formula-1
and its pharmaceutically acceptable salts thereof.
The first aspect of the present invention is to provide a novel process for the preparation of sitagliptin compound of formula-1, which comprises of the following steps,

a) Reducing alkyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of general formula-2,

Wherein R is C1-C6 straight or branched chain alkyl group;
with a suitable chiral reducing agent in a suitable solvent to provide (R)-alkyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate, compound of general formula-3

Wherein R is C1-C6 straight or branched chain alkyl group;

b) treating the compound of general fonnula-3, with a halogenating agent in a suitable solvent to provide (R)-alkyl 3-halo-4-(2,4,5-trifluorophenyl)butanoate, compound of
general formula-4,

Wherein R is C1C6 straight or branched chain alkyl group; and X is a halogen selected from C1, Br and I.

c) reacting the compound of general formula-4, with potassium phthalimide in a suitable solvent to provide (R)-alkyl 4-(l,3-dioxoisoindoUn-2-yl)-3-(2,4,5-
trifluorobenzyl)butanoate, compound of general formula-5,

Wherein R is C1-C6 straight or branched chain alkyl group;

d) reacting the compound of general formula-5 with a suitable base in a suitable solvent to provide (R)-alkyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-6.

Wherein R is H or C1-C6 straight or branched chain alkyl group;

e) treating the compound of general formula-6 with a suitable amino group protecting
agent in a suitable solvent followed by hydrolysis in the presence of a base to provide
(R)-3-N(protected) amino-4-(2,4,5-trifluorophenyl) butanoic acid, compound of
general formula-7,

Wherein PG is amino protecting group;

f) reacting the compound of general formula-7 with 3-(trifluoromethyl)-5,6,7,8-
tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine compound of formula-8 or its salt in the presence of suitable condensing agent in the presence or absence of base, in a suitable solvent, followed by deprotection of amino protecting group provides sitagliptin compound of formula-1.

In step a) of the above process the suitable chiral reducing agent is selected from borane DMS in the presence of R-methyl CBS or dip chloride; preferably borane DMS in the presence of R-methyl CBS and the suitable solvent is selected from ether solvents; ester solvents; hydrocarbon solvents or mixtures thereof; preferably tetrahydrofuran.

In step b) the suitable halogenating agent is selected from carbon tetra chloride, oxalyl chloride, thionyl chloride, phosphorous pentachloride, n-chloro succinamide, Phosphorus tribromide, carbon tetrabromide, N-bromo succinamide in the presence or absence of triphenyl phosphene, preferably N-bromo succinamide in the presence of triphenyl phosphene; the suitable solvent is selected from selected from hydrocarbon
solvents, chloro solvents, polar aprotic solvents or mixtures thereof preferably Methylene chloride.

In step c) the suitable solvent is selected from hydrocarbon solvents, polar aprotic solvents or mixtures thereof; preferably dimethyl formamide.

In step d) the suitable base is selected from organic amines like methyl amine, ethyl amine, tert-butyl amine, triethyl amine, N,N-diisopropyl-ethylamine, n-methyl glucamine, thiophene alkyl amine and the like and the suitable solvent is selected from alcohol solvents, ether solvents, hydrocarbon solvents, polar solvents or mixtures thereof; preferably water/toluene mixture.

In step e) the suitable amino protecting agent/group is selected from Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl, tert-Butyloxycarbonyl (BOC) group, 9-Fluorenylmethyloxycarbonyl (FMOC) group. Benzyl (Bn) group, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group and Tosyl (Ts) group, preferably tert-Butyloxycarbonyl (BOC) group, in the presence of base selected from alkali metal hydroxides; organic bases like diisopropyl ethyl amine, triethyl amine, pyridine and the like, preferably lithium hydroxide and the suitable solvent is selected from ether solvents, chloro solvents, polar solvents or mixtures thereof, preferably tetrahydrofiiran and water mixture.

In step f) the condensing agent is selected from N,N'-Dicyclohexyl carbodiimide (DCC) in the presence of hydroxybenzotriazole (HOBT), N,N'-Dicyclohexyl carbodiimide (DCC) in the presence of 4-Dimethylaminopyridine (DMAP), thionyl chloride, phosphorous pentachloride; preferably DCC in the presence of DMAP; the suitable base is selected from alkali metal hydroxides; alkali metal carbonates; alkali metal bicarbonates or the organic bases like triethyl amine, diisopropyl ethylamine; and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, ketone solvents, nitrile solvents, chloro solvents or mixtures thereof, and the deprotection is carried out in the presence of suitable acid selected from hydrochloric acid, trifluoroacetic acid and the like; in a suitable solvent is selected from alcoholic solvents, ether solvents or polar aprotic solvents or mixtures thereof; preferably dimethyl formamide.
The second aspect of the present invention provides a recovery of l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l,3-dione compound of formula-10 from the other isomer of sitagliptin (S-isomer), which comprises of the following steps,

a) Treating the sitagliptin other isomer compound of formula-18 with sodium nitrite or nitrous acid in the presence of aqueous acid followed by treating with sodium hypochlorite to provide 3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo [4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-11.

b) oxidizing the 3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-11 with a suitable oxidizing agent in a suitable solvent to provide l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione compound of formula-10,

The compound of formula-10 used as a intermediate in the preparation of Sitagliptin compound of formula-1.
In step a) of the above process, the suitable acid is selected from inorganic acids, organic acids, preferably sulfuric acid; the suitable solvent is selected from alcoholic solvents; polar solvents or mixtures thereof; preferably water.

In step b) the suitable oxidizing agent is selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium permanganate, potassium dichromate, chromic acid, chromium trioxide, selenium
dioxide, sodium hypochlorite, sodium metaperiodate, Aluminium-tert.-alcoxides like Aluminium-tert.-butoxide in presence of acetone and the like; preferably potassium dichromate in the presence of sulfuric acid and acetic acid;

The third aspect of the present invention provides a recovery of methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of formula-2a from (S)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate, which comprises of the following steps, a) Reacting the compound of (S)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-20a

with sodium nitrite in the presence of aqueous acid in a suitable solvent to provide methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of formula-21a

b) oxidizing the methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of formula-21a with a suitable oxidizing agent in the presence of acid to provide methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of general formula-2a

The obtaining compound of formula-2a using as an intermediate in the preparation of sitagliptin compound of formula-1.

In step a) of the above process, the acid is selected from inorganic acids like hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid; organic acids like acetic acid, methane sulfonic acid, para toluene sulfonic acid, trifluoro acetic acid preferably sulfuric acid; the suitable solvent is selected from alcoholic solvents, polar solvents or mixtures thereof; preferably water.

In step b) the suitable oxidizing agent is selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium peraianganate,potassium dichromate, chromic acid, chromium trioxide, selenium dioxide, sodium hypochlorite, sodium metaperiodate, Aluminium-tert.-alcoxides like Aluminium-tert.-butoxide in presence of acetone and the like; preferably potassium dichromate in the presence of sulfuric acid and acetic acid ;

The fourth aspect of the present invention provides a recovery of 3-(trifluoromethyl)-5,6,7,8-tetra hydro-[l,2,4]triazolo[4,3-a]pyrazine compound of formula-8 or its salt and alkyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate compound of general formula-2 from other isomer of sitagliptin (S-isomer), which comprises of the following steps,

a) Treating the other isomer of sitagliptin compound of formula-18

with a suitable base in a suitable solvent to provide (S)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid derivative compound of formula-19

Wherein M = H or metal salts
and 3-(trifluoromethyl)-5,6,7,8-tetra hydro-[l,2,4]triazolo[4,3-a]pyrazine compoimd of formula-8 or its salt

b) (S)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid derivative compound of general formula-19 can be optionally esterification with a suitable alcoholic solvents in the presence of acid to provide (S)-alkyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of general formula-20.

Wherein R is C1-C6 straight or branched chain alkyl group;

c) treating the (S)-alkyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of general formula-20 with sodium nitrite or nitrous acid in the presence of acid in the presence or absence of solvent to provide alkyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of general formula-21.

Wherein R is C1-C6 straight or branched chain alkyl group;
d) oxidizing the alkyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of general formula-21 with a suitable oxidizing agents to provide alkyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of general formula-2

Wherein R is C1-C6 straight or branched chain alkyl group;
In step a) of the above process, the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides, organic bases, ammonia or their aqueous solution; preferably sodium hydroxide; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, polar solvents or mixtures thereof; preferably water/methanol mixture;

In step b) the suitable alcoholic solvent is preferably methanol and the suitable acid is selected from inorganic acids, organic acids preferably sulfuric acid,

In step c) the suitable acid is selected from inorganic acids, organic acids; preferably sulfuric acid; the suitable solvent is selected from alcoholic solyents; polar solvents or mixtures thereof; preferably water.

In step d) the suitable oxidizing agent is selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium permanganate, potassium dichromate, chromic acid, chromium trioxide, selenium dioxide, sodium hypochlorite, sodium metaperiodate, Aluminium-tert.-alcoxides like Aluminium-tert.-butoxide in presence of acetone and the like; preferably potassium dichromate in the presence of sulfuric acid and acetic acid;

The fifth aspect of the present invention provides a novel process for the preparation of sitagliptin racemic compound of formula-1 which comprises of the following steps.

a) Reducing the l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l,3-dione compound of formula-10

with a suitable chiral reducing agent in a suitable solvent to provide (R)-3-hydroxy-1-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo [4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1 -one compound of formula-15,

b) reacting the compound of formula-15 with a suitable halogenating agent in a suitable solvent to provide (R)-3-halo-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of general formula-16,

Wherein X is a halogen selected from CI, Br and I

c) reacting (R)-3-halo-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of general formula-16 with
potassium phthalimide in a suitable solvent to provide (R)-2-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-yl)isoindoline-1,3-dione compound of formula-17,

d) treating the compound of formula-17 with a suitable base in a suitable solvent to provide sitagliptin compound of formula-1.

In step a) of the above process, the suitable chiral reducing agent is selected from borane DMS in the presence of R-methyl CBS or dip chloride; preferably borane DMS in the presence of R-methyl CBS and the suitable solvent is selected from ether solvents; ester solvents; hydrocarbon solvents or mixtures thereof; preferably tetrahydrofiiran.

In step b) the suitable halogenating agent is selected from carbon tetra chloride, oxalyl chloride, thionyl chloride, phosphorous pentachloride, n-chloro succinamide. Phosphorus tribromide, carbon tetrabromide, N-bromo succinamide in the presence or absence of triphenyl phosphene, preferably N-bromo succinamide in the presence of triphenyl phosphene; the suitable solvent is selected from selected from hydrocarbon solvents, chloro solvents, polar aprotic solvents or mixtures thereof preferably Methylene chloride.

In step c) the suitable solvent is selected from hydrocarbon solvents, polar aprotic solvents or mixtures thereof; preferably dimethyl formamide.

In step d) the suitable base is selected from organic amines like methyl amine, ethyl amine, tert-butyl amine, triethyl amine, N,N-diisopropyl-ethylamine, n-methyl glucamine, thiophene alkyl amine and the like and the suitable solvent is selected from alcohol solvents, ether solvents, hydrocarbon solvents, polar solvents or mixtures thereof; preferably water/toluene mixture.

The sixth aspect of the present invention provides a novel process for the preparation of sitagliptin racemic compound of formula-1 which comprises of the following steps.

a) Reacting the l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l,3-dione compound of formula-10

with hydroxylamine hydrochloride in the presence of base in the presence or absence of solvent to provide (Z)-3-(hydroxyimino)-l-(3-(trifluoromethyl)-5,6-dihydro-[ 1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l -one compound of formula-22,

b) reducing the compound of formula-22 with a suitable reducing agent selected from zinc in the presence of ammonium formate, zinc in the presence of ammonium
chloride or Zn-Cu couple in a suitable solvent provides racemic sitagliptin compound
of formula-14,

c) resolving the compound of formula-14 with a suitable chiral acid to provide
sitagliptin compound of formula-1.
In step a) of the above process, the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides, organic bases, ammonia or their aqueous solution; preferably pyridine; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, polar solvents or mixtures thereof; preferably in absence of solvent.

In step b) the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents; preferably methanol.

In step c) the suitable chiral acid for resolution is selected from S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (IS)-(+)-camphor sulfonic acid (lR)-(+)-bromocamphor-10-sulfonic acid, (IS)-(-)-bromocamphor-lO-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tataricacid, L(-)-pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine, D-lysine and the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, hydrocarbon solvents or mixtures thereof.

The present inventions schematically represented as follows Scheme-1:

Forniula-2 2a) R - CHj

''V^ HN' O I.Amino protecting' T Foniiula-7 2. hydrolysis
7a) PG ■= tert-butoxycarbonyl
Formula-8a CF,
\\ 1. deprotection
NHjp
F Formula-l'--vN^N
CF,

OR
F Forniiila-4 4a)R = CH],X-Br
:^^
Formula'
3a) R - CH,
potassium ptithalimide
XLeaving group
F 1
L O
potassium phthalimide

F Formula-9
9a) R = CHji L *' tosyl group
F
NHjO
base
OR
F Fonnula-6
6a) R " CH]
OR F Formula-5
5a)R = CH3
PG = Amino protecting group
L = Leaving group
X = Halogen
R = R is H or Ci-Cg straight or branched chain alley I group

19

Scheine-2:

NaNOj H2SO4
Oxidation ^ ^f

Formula'20
ZOa) R - CH3

CF,
Formula-8a
F Sitagliptiti other isomer Formuia-18
^ OR
^ Fomiula-21
21ii)R-CH)

OH O
NT* ^v
F
Formula-11 CFj
Oxidation
F Forniuia-2
2ii)R = CH,

Wherein R is CpCfi straight or branched chain alkyl group
Scheme-3:


OH o Reducing
halogenating
Formnla-
Lagent
O
Potassium phthalimide

O 0
Chiral Reducing F
Or> V-^N^'%
in V
CF,
Formula-10
Forniula
'* CF,

halogenating agent

' CF,
Formula-12 CF,
12a) X-Br
Formula-16
Potassium phthalimide
l«a) X - Br



N'>
JLO'*'M'**O base ^
NT* V
Formula'
CF,
Wherein X = halogen

NH,0
Formula-l4 CF.

base
N

N^'IT >
CF,
Formnla-17

Formula-1 CF,
Scheme-4:


OH
N 0

NH,0H.HC1. Base

Reducing
'V^ 'N agent
F k^N^"
CF,
Formula-22

NHj O
Formula-14 CF3

20

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:

Example-1: Preparation of (R)-methyl 3-hydroxy-4-(2,4,5-trifluoro phenyl)butanoate compound of formula-3a.
40 ml of toluene was taken in a round bottom flask and cooled to 0°C. To this added 1.55 gms of borane dimethyl sulfide and 0.55 gms of (R)-2-methyl-cbs-oxazaboroIidine under nitrogen atmosphere. To this reaction mixture slowly added 5 gms of methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate compoimd of formula-2a dissolved in 10 ml of toluene. Stirred the reaction mixture for 3 hrs at 0-5°C and quenched with methanol and followed by 1 N hydrochloric acid solution. Organic layer separated and washed with 5% hydrogen peroxide solution and 5% sodium sulfate solution and followed by with 10% sodium chloride solution. Distilled off the solvent completely under reduced pressure to get the title compoimd. Yield: 4.0 gms

Example-2: Preparation of (R)-methyl 3-bromo-4-(2,4,5-trifluorophenyl)butanoate compound of formula-4a.
To 4.0 gms of (R)-methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of formula-3a added 40 ml of methylene chloride and cooled the reaction mixture to 0-5°C. Added 4.24 gms of triphenyl phosphene and 3.17 gms of N-bromo succinamide. Raised the temperature to 25°. Stirred the reaction mixture for 2 hours at same temperature. Distilled off the solvent completely under reduced pressure. Added cyclo hexane to the obtained compoimd and stirred for 1 hr at room temperature. Filtered the unwanted precipitated solids. Filtrate was distilled off completely to get the title compound. Yield: 4.0 gms.

Example-3: Preparation of (R)-methyl 3-(l,3-dioxoisoindolin-2-yI)-4-(2,4,5-trifluorophenyl)butanoate compound of formula-5a
Potassium phthalimide (1.6 grams) was added to a mixture of (R)-methyl 3-bromo-4-(2,4,5-trifluorophenyl)butanoate compound of formula-4a (2 grams) in N,N-dimethylformamide (4 ml) and then heated to 110°C. Stirred the reaction mixture for 5 hours at same temperature, and then cooled to 25-30°C. Added water (30 ml) to the
reaction mixture. Extracted the compound with ethyl acetate, and distilled off the solvent completely to get the title compound. Yield: 1.6 grams

Exainple-4: Preparation of (R)-inethyl 3-(p-toluenesuIfonyloxy)-4-(2,4,5-trifluoro phenyI)butanoate compound of formula-9a.
A mixture of (R)-methyl 3-hydroxy-4-(2,4,5-trifIuorophenyI)butanoate compound of formula-3a (3 grams) and pyridine (7.5 ml) was cooled to 0-5°C. Para toluene sulfonyl chloride (2.88 grams) was added to the reaction mixture and raised the temperature of the reaction mixture to 22°C, Stirred the reaction mixture for 21 hours at same temperature. The reaction mixture was quenched with water followed by 18% aqueous hydrochloric acid. Methyl tert-butyl ether was added to the reaction mixture and separated the organic and aqueous layers. The organic layer was washed with 1% aqueous hydrochloric acid followed by saturated sodium bicarbonate solution and finally washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 2.9 gms.

Example-5: Preparation of (R)-methyl 3-(l,3-dioxoisoindolin-2-yl)-4-(2,4,5-trifluorophenyI)butanoate compound of formula-5a
Potassium phthalimide (1.65 grams) was added to a mixture of (R)-methyl 3-(tosyloxy)-4-(2,4,5-trifluorophenyl)butanoate compound of formuIa-9a (3 grams) in N,N-dimethyl formamide (6 ml) and then heated the reaction mixture to 110°C. The reaction mixture was stirred for 6 hours, and then cooled to 25-30°C. Water (45 ml) was added to the reaction mixture and extracted the compound with ethyl acetate. Distilled off the solvent completely to get the title compound. Yield: 1.8 grams

Example-6: Preparation of (R)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-6a
40% of methylamine solution was added to a mixture of (R)-methyl 3-(l,3-dioxoisoindolin-2-yl)-4-(2,4,5-trifluorophenyl)butanoate compound of formuIa-5a (3 grams), water (6 ml) and toluene (12 ml) at 25-30°C. The reaction mixture was heated to 40°C and stirred for 4 hours at same temperature. Separated the organic and aqueous layers and the aqueous layer was extracted with toluene. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compoimd. Yield: 1.2 grams

Example- Preparation of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluoro phenyl)butanoic acid compound of formula-7a.
To 7.5 gms of (R)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-6a added 40 ml of tetrahydrofuran and 40 ml of water. Added lithium hydroxide (2.0 gms) to the reaction mixture. Cooled the reaction mixture to 0-5°C, added di-tert-butyldicarbonate (8.0 gms) slowly to it, and stirred for 90 minutes at the same temperature. Raised the temperature to 25°C and added ethyl acetate (50 ml) and water (40 ml). Stirred the reaction mixture for 15 minutes. Separated the both aqueous and organic layers. Extracted the aqueous layer with ethyl acetate. Distilled off the solvent completely under reduced pressure. Added 55 ml of tetrahydrofuran and 55 ml of water to the obtained compound. Added lithium hydroxide(10 gms) to the reaction mixture and stirred for 4 hours at 25-30°C temperature. Acidify the reaction mixture using cone, hydrochloric acid and extracted the compound using ethyl acetate. Distilled off the solvent completely under reduced pressure. Added n-heptane (120 ml) to the obtained compound and cooled the reaction mixture to 0-5°C. Stirred the reaction mixture for 45 minutes at same temperature and filtered the precipitated solid. Dried the material to get the title compound. Yield: 10 gms.

Example-8: Preparation of 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluoroplienyI) butylj-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazoIo[4.3-a]pyrazine compound of formula-1.
To 24 ml of dimethylformamide added 4 gms of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid and cooled the reaction mixture to 0-5°C. 3.3 gms of N,N'-dicyclohexylcarbodiimide (DCC) was dissolved in 10 ml of dimethylformamide and make upto 20 ml. Added 7 ml of above prepared N,N'-dicyclohexyIcarbodiimide (DCC) solution to the above 0-5°C cooled reaction mixture. Added 3.15 gms of 3-(trifluoromethyl)-5,6,7,8-tetra hydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride and 3.3 ml of triethylamine to the reaction mixture and stirred for 15 minutes. Added 0.9 gms of dimethylaminopyridine (DMA?) and stirred the reaction mixture for 3 hrs at 0-5°C. Added 6.5 ml of N,N'-dicyclohexylcarbodiimide solution and stirred for 3 hrs. Again added 6.5 ml of N,N'-dicycIohexylcarbodiimide solution and stirred for 3 hrs at 0-5°C. Raised the temperature to 25''C and stirred the reaction mixture for 12 hrs at same
temperature. The unwanted precipitated solids were separated by filtration and to the filtrate added water and ethyl acetate. Separated the both aqueous and organic layers. Washed the organic layer with 5% hydrochloric acid solution followed by washed with 5% sodium bicarbonate solution. Distilled off the solvent completely under reduced pressure. Added 30 ml of isopropyl alcohol to the obtained compound and stirred for 45 minutes at 25-30°C temperature. Filtered the precipitated solid and dried the material. To the obtained compound added 10 ml of isopropyl alcohol and 3.8 ml of cone, hydrochloric acid. Stirred the reaction mixture for 3 hrs at 50°C. Cooled the reaction mixture to 25 °C and added water. Extracted the compound from reaction mixture with methylene chloride. Distilled off the solvent completely to get the title compound. Yield: 2.5 gms.

ExampIe-9: Preparation of 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyI) butyl]-
5,6,7,8-tetrahydro-3-(trifluoromethyI)-l,2,4-triazolo[4.3-a]pyrazine Phosphate
monohydrate.
To 2.5 gms of 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 added 5 ml of isopropyl alcohol and 1 ml of water and stirred for 10 minutes. Added 0.45 gms of phosphoric acid to the reaction mixture and heated the reaction mixture to 85°C. Slowly cooled the reaction mixture to 60°C. Added the seeding material and stirred the reaction mixture for 3 hrs at 60°C. Slowly cooled the reaction mixture to 20-25°C and filtered the precipitated solid. Dried the material to get the title compound. Yield: 2.5 gms.

Example-10: Preparation of (R)-3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-
[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one
compound of formula-15.
40 ml of toluene was taken in a round bottom fiask and cooled to 0°C. To this added 0.94 gms of borane dimethyl sulfide and 0.34 gms of (R)-2-methyl-cbs-oxazaborolidine under nitrogen atmosphere. To this reaction mixture slowly added 5 gms of l-(3-(trifluoromethyl)- 5,6-dihydro- [1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluoro phenyl)butane-l,3-dione compound of formula-10 dissolved in 10 ml of toluene. Stirred the reaction mixture for 3 hrs at 0-5 °C and quenched with methanol and followed by 1 N hydrochloric acid solution. Separated the organic layer and washed with 5% hydrogen
peroxide solution and followed by 5% sodium sulfate solution and with 10% sodium
chloride solution. Distilled off the solvent completely under reduced pressure to get the
title compoimd. Yield: 3 gms.

Example-11: Preparation of (R)-3-bromo-l-(3-(trifIuoromethyl)-5,6-dihydro-
[l,2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluoro phenyl) butan-1-one
compound of forniuIa-16a
Title compound is prepared in analogous manner to example-2 except that (R)-3-
hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-
(2,4,5-trifluorophenyl)butan-l-one compound of formula-15 is used in place of (R)-
methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate.

Example-12: Preparation of 3-bromo-l-(3-(trifluoromethyl)-5,6-dihydro-
[l,2,4]triazoIo[4,3-a]pyi'azin-7(8H)-yI)-4-(2,4,5-trifluorophenyl)butan-l-one
compound of formula-12a
To 5.0 gms of l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazinT7(8H)-yl)-
4-(2,4,5-trifluorophenyl)butane-l,3-dione compound of formula-10 added 50 ml of acetic
acid and cooled the reaction mixture to 15°C. To this reaction mixture added 1.5 gms of
sodium borohydride and stirred for 2 hrs. Quenched the reaction mixture by adding water
and extracted the compound using methylene chloride. Washed the organic layer with
water and dried over Na2S04. Cooled the organic layer to 0-5''C, added 2.90 gms of
triphenyl phosphene and 2.15 gms of N-bromo succinamide. Raised the temperature to
25 °C and stirred the reaction mixture for 2 hours at same temperature. Distilled off the
solvent completely imder reduced pressure. Added cycle hexane to the obtained
compound and stirred for 1 hr at room temperature. Filtered the unwanted precipitated
solids. The filtrate was distilled off completely to get the title compound. Yield: 4.5 gms.

Example-13: Preparation of (R)-2-(4-oxo-4-(3-(trifIuoromethyl)-5,6-dihydro-
[l,2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyI)butan-2-
yI)isoindoIine-l,3-dione compound of formula-17
Potassium phthalimide (1.4 grams) was added to a mixture of (R)-3-bromo-l-(3-
(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluoro
phenyl) butan-1-one (2 grams) in N,N-dimethylformamide (4 ml) and then heated the
reaction mixture to 110°C. Stirred the reaction mixture for 5 hours at same temperature,
and then cooled to 25-30°C. Added water to the reaction mixture (30 ml) and extracted the compound with methyl tert-butyl ether. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 1.7 grams

Example-14: Preparation of sitagliptin compound of formula-1.
40% of methylamine solution was added to a mixture of (R)-2-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[ 1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluoro phenyl)butan-2-yl)isoindoline-l,3-dione (2 grams), water (4 ml) and toluene (8 ml) at 25-30°C. The reaction mixture was heated to 40°C and stirred for 4 hours at same temperature. Separated the both organic and aqueous layers and the aqueous layer was extracted with toluene. Distilled off the solvent completely under reduced pressure from the organic layer to get the title compound. Yield: 0.8 grams

Example-15: Preparation of 3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyI)butan-1 -one compound of formula-11.
(S)-sitagliptin (20 grams) was added to the mixture of sulphuric acid. (9 grams) and water (400 ml), then heated to 55-60°C. Sodium nitrite solution (20 grams in 50 ml of water) was added to it at the same temperature. Stirred the reaction mixture for 2 hours at 55-60°C. Cooled the reaction mixture to 20-25°C and then extracted with methylene chloride. Distilled off the solvent completely from the organic layer under reduced pressure. To the obtained residue added acetic acid (100 ml) followed by sodium hypochlorite (200 ml) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 12 hours at same temperature. Cooled the reaction mixture to 20-25°C and extracted with methylene chloride. Distilled off the solvent completely from organic layer to get the title compound. Yield: 15 grams

Example-16: Preparation of l-(3-(triflnoromethyI)-5,6-dihydro-[l,2,4]triazolo[4^-a] pyrazin-7(8H)-yi)-4-(2,4,5-trifluorophenyl)butane-l,3-dione compound of formula-10.
Acetic acid (20 ml) and sulphuric acid (4 grams) was added to a mixture of 3-hydroxy-l-(3-(trifIuoromethyl)-5,6-dihydro-[l,2,4] triazolo[4,3'a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-11 (7 grams) in acetic acid (7 ml). Potassium dichromate (3 grams) was added to the reaction mixture at 25-30°C and
stirred it for 24 hours at the same temperature. Quenched the reaction mixture with water and extracted with methylene chloride. The organic layer was washed with 5% sodium bicarbonate and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 4 grams

Example-17: Conversion of (S)-sitagliptin into sodium (S)-3-amino-4-(2,4,5-trifluoro phenyl) butanoate compound of fonnula-19a and 3-(trifIuoromethyl)-5,6,7,8-tetra hydro-[l,2,4]triazoIo[4,3-a]pyrazine hydrochloride compound of formula-8a. A mixture of (S)-sitagliptin (50 grams), methanol (100 ml), water (50 ml) and sodium hydroxide (10 grams) was stirred for 10 minutes at 25-30°C and then heated to reflux temperature. Stirred the reaction mixture for 4 hours at the same temperature. Distilled off the reaction mixture under reduced pressure. Methylene chloride (200 ml) was added to the obtained residue at 20-25°C and the reaction mixture was stirred for 15 minutes. The reaction mixture was filtered to get formula-19a and washed with methylenechloride. Distilled off the solvent from the filtrate and added methanol (30 ml) followed by conc.hydrochloric acid (15 ml) to the obtained residue. The reaction mixture was stirred for 45 minutes. Distilled off the reaction mixture under reduced pressure and then acetone was added to the obtained residue at 25-30°C. The reaction mixture was cooled to 0-5°C and stirred for 2 hours. Filtered the precipitated solid, washed with acetone and dried to get the formula-8a. Yield: Formula-19a = 23 grams; Formula-8a = 22 grams; £xample-18: Preparation of (S)-methyl 3-amino-4-(2,4,S-trifluorophenyl)butanoate compound of formula-20a.
Chlorotrimethylsilane (2.8 grams) was added to the mixture of (S)-3-amino-4-(2,4,5-trifluoro phenyl)butanoic acid (3 grams) and methanol (30 ml) at 25-30°C. The reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was distilled off under reduced pressure and then water was added to the obtained residue. The reaction mixture was neutralized with sodium carbonate solution and extracted with methylene chloride. The organic layer was washed with brine solution, distilled off the solvent completely under reduced pressure to get title compound.
Yield: 2.2 grams

Example-19: Preparation of methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of formula-21a.
(S)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate (2 grams) was added to the mixture of sulphuric acid (1.9 grams) and water (85 ml), then heated to 55-60°C. Sodium nitrite solution (3.35 grams in 8 ml of water) was added to it at the same temperature. The reaction mixture was stirred for 2 hours at 55-60°C. The reaction mixture was cooled to 20-25 °C and then extracted with methylene chloride. Distilled off the solvent from the organic layer under reduced pressure and acetic acid (10 ml) followed by sodium hypochlorite (20 ml) were added to the obtained residue at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 12 hours at same temperature. The reaction mixture was cooled to 20-25°C and the compound was extracted with methylene chloride. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 1.5 grams

Example-20: Preparation of methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate compound of formula-2a.
Acetic acid (2.8 ml) and sulphuric acid (0.6 grams) were added to a mixture of methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate (1 gram) in acetic acid (1 ml). Potassium dichromate (0.6 grams) was added to the reaction mixture at 25-30°C and stirred it for 24 hours at the same temperature. The reaction mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with 5% sodium bicarbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 0.5 grams

Example-21: Preparation of 3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4] triazolo[43-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-11
A mixture of acetic acid (30 ml) and l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l,3-dione compound of formula-l0 (3 grams) was cooled to 15-20°C. Sodium borohydride (1.09 grams) was added to the reaction mixture and stirred the reaction mixture for 2 hours at same temperature. After completion of the reaction, reaction mixture was quenched with water and then extracted with methylene dichloride. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 2.2 grams

Example-22: Preparation of 3-bronio-l-(3-(trifluoroniethyl)-5,6-dihydro-[l,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyI)butan-l-one compound of formula-12a.
To 4.0 grams of 3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-11 added 40 ml of methylene chloride and cooled the reaction mixture to 0-5°C. Added 2.56 grams of triphenyl phosphine and 1.9 grams of N-bromo succinimide to the reaction mixture. Raised the temperature to 25°, stirred the reaction mixture for 2 hours at same temperature. Distilled off the solvent completely under reduced pressure. Added cyclohexane to the obtained compound and stirred for I hr at room temperature. Filtered the unwanted precipitated solids. Filtrate was distilled off completely to get the title compound. Yield: 3.6 grams.

Example-23: Preparation of 2-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-yI)isoin doline-l3-dione compound of formula-13.
Potassium phthalimide (2.1 grams) was added to a mixture of 3-bromo-l-(3-(trifluoromethyl)-5,6-dihydro-[I,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluoro phenyl) butan-1-one (3 grams) in N.N-dimethylformamide (6 ml) and then heated to 110°C. Stirred the reaction mixture for 5 hours at same temperature. Cooled the reaction mixture to 25-30°C. The reaction mixture was poured into water (45 ml). Filtered the solid, washed with water and dried to get the title compound. Yield: 2.2 grams

Example-24: Preparation of racemic sitagliptin compound of formula-14.
40% of methylamine solution was added to a mixture of 2-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluoro phenyl)butan-2-yl)isoindoline-I,3-dione (2 grams), water (4 ml) and toluene (8 ml) at 25-30°C. The reaction mixture was heated to 40°C and stirred for 4 hours. Separated the both organic and aqueous layers and the aqueous layer was extracted with toluene. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 0.9 grams

Example-25: Preparation of (Z)-3-(hydroxyimino)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyI)butan-l-one compound of formula-22.
l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l,3-dione (5 grams) and hydroxyl amine hydrochloride ( 1.28 grams) were dissolved in a mixture of ethanol (50 ml) and pyridine (50 ml) and stirred the reaction mixture for 2 hours at 25-30°C. The reaction mixture was distilled off under reduced pressure and tetrahydrofiiran was added to the obtained residue. The reaction mixture was washed with 2N hydrochloride solution. Distilled off the solvent completely from the organic layer completely to get the title compound. Yield: 3.6 grams

Example-26: Preparation of 3-amino-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4] triazoIo[4,3-a]pyrazin-7(8H)-yI)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-14. To a solution of the (Z)-3-(hydroxyimino)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one (5 grams) in methanol (50 ml) was added ammonium chloride (1.9 grams) and zinc dust (1.55 grams). The mixture was stirred under reflux. After the completion of the reaction, the reaction mixture was filtered through celite. The filtrate was distilled off under reduced pressure and then methylene chloride was added to the obtained residue at 25-30°. The reaction mixture was washed twice with 80% saturated brine solution and finally with water. The organic layer was dried over anhydrous sodium sulphate, distilled off the organic layer and gets the title compound. Yield: 3.2 grams.

Example-27: Preparation of sitaglitpin compound of formula-1:
A mixture of compound of formula-14 (8 grams), (-)-mandelic acid (2.98 grams), water (28 ml) and isopropyl alcohol was stirred for 10 minutes and heated to reflux temperature to obtain a clear solution. The reaction mixture was cooled slowly to 5-10°C and stirred for 4 hours at 5-10°C. The solid obtained was filtered, washed with isopropyl alcohol and the obtained compound was dissolved in water (15 ml) and then basified with sodium hydroxide solution. The reaction mixture was extracted with methylene chloride (45 ml). Distilled off the solvent completely from the organic layer to get the title compound. Yield: 2 grams

We claim:

1. A novel process for the preparation of sitagliptin compound of formula-1 and its pharmaceutical]y acceptable salts thereof which comprises of the following steps

a) Reducing alkyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of general
formula-2,

Wherein R is H or C1-C6 straight or branched chain alkyl group; with a suitable chiral reducing agent in a suitable solvent to provide (R)-alkyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate, compound of general formula-3,

Wherein R is H or C1-C6 straight or branched chain alkyl group;

b) treating the compound of general formula-3, with a halogenating agent in a suitable solvent to provide (R)-alkyl 3-halo-4-(2,4,5-trifluorophenyl)butanoate,compound of general formula-4,

Wherein R is H or C1-C6 straight or branched chain alkyl group;

c) reacting the compound of general formula-4, with potassium phthalimide in a suitable solvent to provide (R)-alkyl 4-(l,3-dioxoisoindolin-2-yl)-3-(2,4,5-trifluorobenzyl) utanoate, compound of general formula-5,

Wherein R is H or C1-C6 straight or branched chain alkyl group;

d) reacting the compound of general formula-5 with a suitable base in a suitable solvent to provide (R)-alkyl 3-amino-4-(2,4,5-trifluorophenyl) utanoate compound of general fonnula-6.

Wherein R is H or C1-C6 straight or branched chain alkyl group;

e) treating the compound of general formula-6 with a suitable amino group protecting agent in a suitable solvent followed by hydrolysis in the presence of a base to provide (R)-3-N(protected) amino-4-(2,4,5-trifluorophenyl) butanoic acid, compound of general formula-7,

Wherein PG is amino protecting group;

f) reacting the compound of general formula-7 with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine compound of formula-8 or its salt,in the presence of suitable condensing agent in the presence or absence of base, in a suitable solvent, followed by deprotection of amino protecting group provides sitagliptin compound of formula-1.

2. A novel process for the preparation of sitagliptin compound of formula-1, which comprises of the following steps;

a) Reducing methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of formula-2a,with borane DMS complex in the presence of R-methyl CBS in toluene to provide (R)-methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate, compound of formula-3a,

b) treating the compound of formula-3a, with N-bromo succinamide in the presence of triphenyl phosphene in methylene chloride to provide (R)-methyl 3-bromo-4-(2,4,5-trifluorophenyl)butanoate, compound of formula-4a,

c) reacting the compound of formula-4a, with potassium phthalimide in dimethyl
formamide to provide (R)-methyl 4-(l,3-dioxoisoindolin-2-yl)-3-(2,4,5-
trifluorobenzyl)butanoate, compound of formula-5a,

d) reacting the compound of formula-5a with methyl amine in water/toluene mixture to provide (R)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-6a.

e) treating the compound of formula-6a with a suitable amino group protecting agent in a suitable solvent followed by hydrolysis in the presence of a base to provide (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid compound of formuIa-7a,

f) reacting the compound of formula-7a with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride compound of formula-8a,in the presence of N,N'-Dicyclohexyl carbodiimide (DCC), dimethyl amino pyridine and triethyl amine in dimethyl formamide, followed by deprotection of amino protecting group using hydrochloric acid to provide sitagliptin compound of formula-1.

3. A novel process for the preparation of sitagliptin compound of formula-1 and its pharmaceutically acceptable salts, which comprises of the following steps, a) Reducing the l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione compound of formula-10 with a suitable chiral reducing agent in a suitable solvent provides (R)-3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-15

b) reacting the compound of formula-15 with a suitable halogenating agent in a suitable solvent provides (R)-3-halo-l-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l -one compound of general formula-16

Wherein X is a halogen selected from CI, Br and I

c) reacting (R)-3-halo-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]
pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of general
formula-16 with potassium phthalimide in a suitable solvent to provide (R)-2-(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)isoindoline-1,3-dione compound of formula-17,

d) treating the compound of formula-17 with a suitable base in a suitable solvent to
provide sitagliptin compound of formula-1.

4. A process for the recovery of sitagliptin intermediates from sitagliptin isomer compound of formula-18 which comprises of the following steps,

a) Treating the other isomer of sitagliptin compound of formula-18

with a suitable base in a suitable solvent to provide (S)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid derivative compound of general formula-19

Wherein M is metal salts,
and 3-(trifluoromethyl)-5,6,7,8-tetra hydro-[l,2,4]triazolo[4,3-a]pyrazine
compound of formula-8 or its salt,

b) optional esterification of (S)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid derivative compound of general formula-19 with a suitable alcoholic solvent in the presence of acid to provide (S)-alkyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of general formula-20,

Wherein R is Cj-Ce straight or branched chain alkyl group;

c) treating the (S)-alkyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of
general formula-20 with sodium nitrite in the presence of aqueous acid with or
without a solvent, followed by treatment with sodium hypochlorite to provide
alkyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of general

Wherein R is C1-C6 straight or branched chain alkyl group;

d) oxidizing the alkyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of
general formula-21 with a suitable oxidizing agents to provide alkyl 3-oxo-4-
(2,4,5-trifluorophenyl)butanoate, compound of general formula-2

Wherein R is C1-C6 straight or branched chain alkyl group;

5. A process for the recovery of sitagliptin intermediate compound of formula-2a from the compound of formula-20a which comprises of the following steps,

a) Reacting the compound of (S)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate
compound of formula-20a

with sodium nitrite in the presence of aqueous acid in a suitable solvent to provide methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of formula-2 la

b) oxidizing the methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of formula-2 la with a suitable oxidizing agent in the presence of acid to provide methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate, compound of formula-2a.

6. A process for the preparation of compound of sitagliptin compound of formula-1
which comprises of the following steps,

a) Reacting the I-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione compound of formula-10

with hydroxylamine hydrochloride in the presence of base and with or without a solvent to provide (Z)-3-(hydroxyimino)-l-(3-(trifluoromethyl)-5,6-dihydro-
[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-22,

b) reducing the compound of formula-22 with a suitable reducing agent selected
from zinc in the presence of ammonium formate, zinc in the presence of
ammonium chloride or Zn-Cu couple in a suitable solvent provides racemic
sitagliptin compound of formula-14,

c) resolving the compound of formula-14 with a suitable chiral acid to provide
sitagliptin compound of formula-1.

7. Compounds having the following structural formulae and their isomers.

Wherein R is H or Ci-Ce straight or branched chain alkyl group

8. A process for the recovery of sitagliptin intermediates from sitagliptin other isomer compound of formula-18, which comprises of the following steps;

a) Treating the sitagliptin other isomer compound of formula-18 with sodium nitrite in the presence of sulfuric acid in water, followed by treating with sodium hypochlorite to provide 3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[ 1,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1 -one compound of formula-11

b) oxidizing the 3-hydroxy-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-l-one compound of formula-11 with a potassium dichromate in mixture of acetic acid and sulfuric acid to provide 1 -(3-(trifluoromethyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l ,3-dione compound of formula-10

9. A process for the recovery of sitagliptin intermediates from sitagliptin other isomer compound of formula-18, which comprises of the following steps, a) Treating the other isomer of sitagliptin compound of formula-18

with a sodium hydroxide in a mixture of methanol/water to provide sodium (S)-3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-19a

and 3-(trifluoromethyl)-5,6,7,8-tetra hydro-[l ,2,4]triazolo[4,3-a]pyrazine
compound of formula-8 or its salt,

b) sodium (S)-3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-19a can be optionally esterified with methanol in the presence of sulfuric acid to
provide (S)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of formula-20a,

c) treating the (S)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate compound of
formula-20a with sodium nitrite in the presence of aqueous sulfuric acid to
provide methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of
formula-21a,

d) oxidizing the methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate compound of
formula-21a with potassium dichromate in the presence of mixture of .acetic acid
and sulfuric acid to provide methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate,
compound of formula-2a

10. Use of recovered intermediate compounds as an intermediate in the preparation of sitagliptin compound of formula-1 or its pharmaceutically acceptable salts.