Priority Claim:

This application claims the priority of our earlier provisional application number: 2652/CHE/2009, filed on 3rd November 2009.

Field of the Invention:

The present invention relates to novel and improved processes for the preparation of silagliptin, its pharmaceutically acceptable salts as well as their intermediates. Sitagliptin is chemically known as 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluoropheny1) buty1]-5,6,7,8-tetrahydro-3-(trifluoromethy1)'I,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 dipeptidy1 peptidase IV inhibitor. Sitagliptin phosphate is currently marketed in the United States under the brand name Januvia in its raonohydrate 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,]-dimethy1ethoxycarbony1)-amino]-4-(2,4,5-trifluoropheny1)
-butanoic acid with 3-(trifluoromethy1)-5,6,7,8-tetrahydro'l,2,4-tria2olo[4,3-a]pyra2ine in
presence of HOBT in methy1ene chloride and then purified by preparative TLC
to provide 7-[(3R)-3-[(i,l-dimethy1ethoxycarbony1)amino-4-(2,4,5-trifluorophenyi)-
butanoy1]-3(trifluoromethy1)-5,6J,8-tetrahydro-l,2,4-triaxolo[43-a]pyrazine.

The obtained compound was then treated with hydrochloric acid in methanol to provide sitagliptin hydrochloride, This process involves the use of chromatographic technique 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-(triftuoromethy1)-5,6-dihydro[l,2,4]triazoIo[4,3-a] pyrazin-7(8H)-y1]-l-(2,4,5-trifluoropheny1)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-(trifluoromethy1)'5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1]-l-(2,4,5-trifluoropheny1)butan-2-one into sitagliptin by treating it with ammonium acetate in methanol to provide (2Z)-4-oxo-4-[3-(trifIuoromethy1)-5,6-dihydro[l,2,4]triazoIo[4,3-a]pyrazin-7(8H)-y1]-l-(2,4,5-trifluropheny1)but-2-en-2-amine, which on enantioselective hydrogenation in presence of transition metal precursor complexed with a chiral ferroceny1 diphosphine ligand.

International publication number WO 2005/97733 disclosed the preparation of sitagliptin by enantioselective hydrogenation of (2Z)-4-oxo-4-[3-(trifluoromethy1)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1]-l-(2,4,5-trifluropheny1)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 suitable acids 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-(trifluoromethny1)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1]-l-(2,4,5-trifluropheny1)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 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 and improved processes for the preparation of sitagliptin and its pharmaceutically acceptable salts as well as their 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 alky1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate, compound of general formuia-2, with a suitable stereo selective reducing agent in a suitable solvent to provide (R)-alky1 3-hydroxy-4-(2,4,5-trifluoropheny1)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)-alky1 3-halo-4-(2,4,5-trifluoropheny1)butanoate, compound of general formula-4,

c) reacting the compound of general formula-4, with sodium azide or lithium azide in a suitable solvent to provide (R)-alky1 3-azido-4-(2,4,5-trifluoropheny1)butanoate, compound of general formula-5,

d) hydrolyzing the compound of general formula-5 with a suitable base in a suitable solvent, and in-situ reaction of the obtained compound with 3-(trifluoromethy1)-5,6,7,8-tetra hydro-[l,2,4]triazolo[4,3-a]pyrazine compound of formula-6, in the presence of a suitable condensing agent in presence or absence of base in a suitable solvent to provide (R)-3-azido-l-(3-{trifluoromethy1)-5,6-dihydro-[l,2,4]triazoIo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-tnfluoropheny1)butan-l-one, compound of formula-7, e) reducing the compound of formula-7, with a suitable reducing agent in a suitable solvent to provide sitagliptin, compound of formula-1.

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

a) treating the compound of general formula-3, with methane sulfony1 chloride or para toluene sulfony1 chloride or halogenating agent in a suitable solvent, followed by ammonia source in a suitable solvent to provide (R)-alky1 3-amino-4-(2,4,5-trifluoropheny1)butanoate, compound of general formula-8,

b) treating the compound of general formula-8, with a suitable amino group protecting agent in a suitable solvent followed by hydrolysis with a suitable base in a suitable solvent to provide (R)- 3-N(protected) amino-4-(2,4,5"trifluoro pheny1) butanoic acid, compound of general formula-9,

c) reacting the compound of general formula-9, with 3-(trifluoromethy1)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine compound of formula-6, in the presence of suitable condensing agent in presence or absence of base in a suitable solvent, followed by deprotection of amino protecting group to provide sitagliptin, compound of formula-1
The third aspect of the present invention is to provide a novel process for the preparation of sitagliptin compound of formula-1, which comprises of;

a) reducing the l-(3-(trifluoromethy1)-5,6-dihydrO'[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butane-l,3-dione compound of formula-lO with a suitable reducing agent in a suitable solvent, to provide the (R)-3-hydroxy-l-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butan-l-one compound of forraula-11,

b) treating the compound of formula-11 with methane sulfony1 chloride (MSC) or paratoluenesulfony1 chloride (PTSC) or halogenating agent in presence of a suitable base to provide corresponding derivative compound of formula-12,

c) treating the compound of formula-12 with a suitable ammonium source in a suitable solvent to provide the sitagliptin compound of formula-1.

The foixrth aspect of the present invention is to provide a novel process for the preparation of (R)-3-hydroxy-l(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyra2in-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butan-1 -one compound of formula-11, which comprise of the following steps;

a) Reducing alky1 3-oxo-4-(2,4,5-trifluorophenyi)butanoate, compound of general formula -2 with a suitable stereo selective reducing agent in a suitable solvent to provide (R)-alky1 3-hydroxy-4-(2,4,5-trifluoropheny1)butanoate, compound of general formuia-3,

b) treating the compound of formula-3 with a suitable hydroxy group protecting agent in a suitable solvent to provide the hydroxy protected compound of formula-13,

c) reacting the compound of general formula-13 with 3-(trifluoromethy1)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine compound of formula-6, in the presence of an acid or base in a suitable solvent, followed by deprotection of the hydroxy protecting group, to provide the compound of formula-11.

The fifth aspect of the present invention is to provide a novel salts of (R)-alky1 3-amino-4-(2,4,5-trifluoropheny1)butanoate, compound of general formula-8, process for their preparation and their use in the synthesis of sitagliptin and its intermediates.
Detailed Description of the Invention:

As used herein the term "sitagliptin" refers to active isomer i.e.,7-[(3R)-3-amin0' l-oxo-4-(2,4,5-trifluoropheny1)buty1]-5,6,7,8-tetrahydro-3-(tr:fluoromethy1)-l,2,4-triazoIo[4.3-a]pyrazine unless otherwise specifically mentioned.

Unless otherwise specified, as used herein the term "suitable solvent" refers to the solvents selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" such as to methy1ene chloride, chloroform, ethy1ene dichloride and carbon tetra chloride; "ketone solvents" such as acetone, methy1 ethy1 ketone, methy1 isobuty1 ketone; "hydrocarbon solvents" such as to toluene, hexane, heptane and cyclohexane; "nitrile solvents" such as acetonitrile; "ester solvents" such as ethy1 acetate, methy1 acetate and isopropy1 acetate; "ether solvents" such as tetrahydrofuran, diethy1 ether and methy1 tert-buty1 ether; "polar solvents" such as water, "polar aprotic solvents" such as dimethy1 formamide, dimethy1 acetamide and dimethy1 sulfoxide.

As used herein the term "suitable base" refers to the bases selected from alkali metal hydroxide like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate and alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; ammonia or their aqueous solution.

As used herein the term "condensing agent" refers to the condensing agent selected from N,N'-Dicyclohexy1 carbodiimide (DCC) in presence of hydroxybenzotriazole (HOBT), N,N'-Dicyclohexy1 carbodiimide (DCC) in presence of 4-Dimethy1aminopyridine (DMAP), thiony1 chloride, phosphorous pentachloride.

The present invention relates to a novel and improved processes 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-trifluoropheny1)buty1]-5,6,7,8-tetrahydro-3-(trifluoromethy1)-U2,4-triazolo[4.3-a] pyrazine having the following structural formula-1 and its pharmaceutically acceptable salts thereof

Accordingly, the first aspect of the present invention provides a novel process for the preparation of sitagliptin compound of formula-1, which comprise of a) Reducing alky1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate, compound of general formula -2,
Wherein R is H or Ci-C6 straight or branched chain alky1 group;

with a suitable stereo selective reducing agent selected from DIP chloride or Borane DMS in presence of catalyst like R-methy1 CBS, in a suitable solvent to provide (R)-alky1 3-hydroxy-4-(2»4,5-trifluoropheny1)butanoate, compound of general formula-3,

Wherein R is H or Cj-Cg straight or branched chain alky1 group;

b) treating the compound of general formula-3 with a halogenating agent in a suitable solvent to provide (R)-alky1 3-bromo-4-(2,4,5'trifluoropheny1)butanoate, compound of general formuIa-4,

Wherein R is H or Ci-Ce straight or branched chain alky1 group;

c) reacting the compound of general formula-4 with sodium azide or lithium azide in a suitable solvent to provide (R)-alky1 3-azido-4-(2,4,5-trifluoro pheny1)butanoate, compound of general formula-5.

Wherein R is H or C\-C^ straight or branched chain alky1 group;

d) hydrolyzing the compound of general formula-S using a suitable base in a suitable
solvent and in-situ reaction of the obtained compound with 3-(trifluoromethy1)-
5,6,7,8-tetrahydrO"[l,2,4]triazolo[4,3-a]pyrazine compound of formuIa-6, in the
presence of suitable condensing agent in presence or absence of base in a suitable
solvent to provide (R)-3-azido-l-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin'7(8H)-y1)-4-{2,4,5-trifluoropheny1)butan-1 -one, compound of formula-7,


e) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide sitagliptin compound of formula-1.

Wherein, in step a) the suitable solvent is selected from ester solvents, hydrocarbon solvent, chloro solvents, ether solvents or mixtures thereof, preferably toluene

In step b) the suitable halogenating agent is selected from carbon tetra chloride, oxaly1 chloride, thiony1 chloride, phosphorous pentachloride, n-chloro succinamide, Phosphorus tribromide, carbon tetrabromide, N-bromo succinamide in presence or absence of tripheny1 phosphene, preferably N-bromo succinamide in presence of tripheny1 phosphene; the suitable solvent is selected from selected from hydrocarbon solvents, chloro solvents, polar aprotic solvents or mixtures thereof preferably Methy1ene chloride.
In step c) the suitable solvent is selected from polar aprotic solvents, water, 1,3-Dimethy1-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), N-Methy1-2-pyrrolidone (NMP), hexamethy1phosphoramide (HMPA) or mixtures thereof preferably dimethy1 formamide and water mixture.

In step d) the suitable base is selected from alkali metal hydroxides; alkali metal carbonates; alkali metal bicarbonates or the organic bases like triethy1 amine, diisopropy1 ethy1amine; preferably sodium hydroxide; the condensing agent is selected from N,N'-Dicyclohexy1 carbodiimide (DCC) in presence of hydroxybenzotriazole (HOBT), N,N'-Dicyclohexy1 carbodiimide (DCC) in presence of 4'Dimethy1aminopyridine (DMAP), thiony1 chloride, phosphorous pentachloride, preferably DCC in presence of DMAP; and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, ketone solvents, nitrile solvents, chloro solvents, ether solvents, polar solvents or mixtures thereof.

In step e) the suitable reducing agent is selected from Pd/C, lithium aluminium

hydride, raney nickel, zinc in presence of ammonium chloride etc. preferably Pd/C and the suitable solvent is selected from alcohol solvents, ether solvents preferably methanol.

The second aspect of the present invention provides a novel process for the preparation of sitagliptin compound of formula-!, which comprises of;

a) treating the (R)-alky1 3-hydroxy-4-(2,4,5-trifluoropheny1)butanoate, compound of general formuta-3.

Wherein R is H or CrC6 straight or branched chain alky1 group;

with methane sulfony1 chloride or Para toluene sulfony1 chloride or halogenating
agent in a suitable solvent, followed ammonia source in suitable solvent to provide
(R)-alky1 3-amino-4-(2,4,5-trifluoropheny1)butanoate, compound of general
formula-8,

Wherein R is H or C|-C6 straight or branched chain alky1 group;

b) treating the compound of general formula-8 with a suitable amino group protecting agent in a suitable solvent followed by hydrolysis in presence of a base to provide

(R)-3-N(protected) amino-4-(2,4,5-trifluoropheny1) butanoic acid, compound of
general formula-9, Wherein R is H and PG is amino protecting group;

c) reacting the compound of general formula-9 with 3-(trifluoromethy1)-5,6,7,8-
tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine compound of fonnula-6, in the presence of
suitable condensing agent in presence or absence of base, in a suitable solvent, followed by deprotection of amino protecting group provides sitagliptin compound of
formula-1.

Wherein in step a) the suitable ammonia source was selected from ammonia, ammonium acetate and the lilce preferably ammonia and the suitable solvent was selected from alcohol solvents, ester solvents, hydrocarbon solvents, ketone solvents, nitrile solvents, chloro solvents, ether solvents or mixtures thereof, preferably methanol.

In step b) the suitable amino protecting agent/group is selected from Carbobenzy1oxy (Cbz) group, p-Methoxybenzy1 carbony1, tert-Buty1oxycarbony1 (BOC) group, 9-Fluoreny1methy1oxycarbony1 (FMOC) group, Benzy1 (Bn) group, p-Methoxybenzy1 (PMB), 3,4-Dimethoxybenzy1 (DMPM), p-methoxypheny1 (PMP) group and Tosy1 (Ts) group, preferably tert-Buty1oxycarbony1 (BOC) group, in presence of base selected from organic bases, alkali metal hydroxides; organic bases like diisopropy1 ethy1 amine, triethy1 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 tetrahydrofuran and water mixture.

In step c) the condensing agent preferably DCC in presence of DMAP; the suitable base is selected from alkali metal hydroxides; alkali metal carbonates; alkali metal bicarbonates or the organic bases like triethy1 amine, diisopropy1 ethy1amine; 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 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; preferably dimethy1 formamide.

The third aspect of the present invention provides a novel process for the preparation of sitagliptin compound of formula-1, which comprises of; a) Reducing the l-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]triazolol4,3-a]pyrazin'7(8H)-y1)-4-(2,4,5-trifluoropheny1)butane-1,3-dione compound of formula-10


with a suitable reducing agent selected from DIP chloride or Borane DMS in presence of catalyst like R-methy1 CBS in a suitable solvent to provide the (R)-3-hydroxy-l-(3-(trifluoromethy1)-5,6-dihydro-[I,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butan-l-one compound of formula-11,

b) treating the compound of formula-11 with methane sulfony1 chloride or toluene
suifony1 chloride or halogenating agent in presence of a suitable base, to provide
corresponding derivative compound of formula-12,

Where in L is a leaving group,

c) treating the compound of formula-12 with a suitable ammonium source in a suitable solvent to provide the sitagliptin compound of formula-1.

Wherein in step a) the suitable solvent is selected from chloro solvents, ether solvents or hydrocarbon solvents preferably toluene.

In step b) the suitable base is selected from alkali metal hydroxide; alkali metal carbonates; alkali metal bicarbonates; alkali metal hydrides like lithium hydride, sodium hydride or the organic bases like triethy1 amine, diisopropy1 ethy1amine, pyridine and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, ketone solvents, nitrile solvents, chloro solvents or mixtures thereof, preferably pyridine in absence of solvent.

In step c) the suitable ammonium source is selected from ammonia, ammonium acetate and the like preferably ammonia and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, ketone solvents, nitrile solvents, chloro solvents, polar solvents or mixtures thereof preferably methanol.

The fourth aspect of the present invention is to provide a novel process for the preparation of (R)-3-hydroxy-l-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5"trifluoropheny1)butan-l-one compound of formula-11,

Which comprises of the following steps,

a) Reducing alky1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate, compound of general formula -2,

Wherein R is H or C1-C6 straight or branched chain alky1 group;

with a suitable stereo selective reducing agent selected from DIP chloride or Borane
DMS in presence of a catalyst like R-methy1 CBS in a suitable solvent to provide
(R)-alky1 3-hydroxy-4-(2,4,5-tnfluoropheny1)butanoate, compound of general
formula-3,

Wherein R is H or C1-C6 straight or branched chain alky1 group;

b) treating the compound of formula-3 with a suitable hydroxy group protecting agent in a suitable solvent to provide the hydroxy protected compound of formula-13,

Wherein Pr is hydroxy protecting group and R is as defined above,

c) reacting the compound of general formuIa-13 with 3-(trifluoromethy1)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3"a]pyra2ine compound of formula-6, in the presence of an acid or base in a suitable solvent, followed by deprotection of the hydroxy protecting group, to provide the compound of formula-11.

The above obtained compound of formula-11 can be converted into sitagliptin compound of formula-1 as per the process disclosed in step b and c of third aspect of the present invention. The deprotection of hydroxy protecting group obtained in step-c can be done by the conventional methods known in the art.

Wherein, in step a) the suitable solvent is selected from ester solvents, hydrocarbon solvent, chloro solvents, ether solvents or mixtures thereof preferably toluene.

In step b) the hydroxy1 protecting group is selected from acetic anhydride or acety1 chloride, benzy1 chloride or benzy1 bromide preferably benzy1 bromide in a suitable base selected from pyridine, diisopropy1 ethy1 amine, triethy1amine preferably triethy1 amine and the suitable solvent is selected from ester solvents, hydrocarbon solvent, chloro solvents, ether solvents or mixtures thereof preferably methy1ene chloride.

In step c) the suitable base is selected from alkali metal hydroxides; alkali metal carbonates; alkali metal bicarbonates or the organic bases like triethy1 amine, diisopropy1 ethy1amine; and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, ketone solvents, nitrile solvents, chloro solvents, ether solvents or mixtures thereof.

The fifth aspect of the present invention provides novel process for the preparation of (R)-alky1 3-amino-4-(2,4,5-trifluoropheny1)butanoate, compound of general formula-8,
Wherein R is H or C1-C6 straight or branched chain alky1 group; Which comprise of the following steps.

a) Resolution of the alky1 3-amino-4-(2,4,5-trifluoropheny1)butanoate, compound of general formula-14,

Wherein R is H or C1-C6 straight or branched chain alky1 group;

with a suitable chiral acid in a suitable solvent to provide the corresponding chiral
acid salt compound of general formula-15

Wherein R is H or C1-C6 straight or branched chain alky1 group and CA is chiral acid;

b) treating the above obtained salt compound of general formula-15 with a suitable base in a suitable solvent to provide the compound of formula-8.

The obtained compound of formula-S further converted into sitagliptin compound of formula-1 as per the process steps b) and c) discussed in the second aspect of the present invention.

According to the present aspect wherein in step a) the suitable chiral acid 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, (IR)-(-)-camphor sulfonic acid, (1S)-(+)-camphor sulfonic acid (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromocamphor-10-sulfonic acid, (-)-Dibenzoy1-L-tartaric acid, (-)-Diben2oy1-L-tartaricacid monohydrate, (+)-Dibenzoy1-D -tartaric acid, (+)-Dibenzoy1-D -tartaric acid monohydrate, (+)-dipara-toly1-D-tataric acid, (-)-dipara"toly1-L-tataricacid, L(-)-pyroglutamic acid, L(+)-pyrogIutamic acid, (-)-lactic acid, L-lysine, D-Iysine and mixtures thereof; the suitable solvent is selected from "ester solvents" like ethy1 acetate, methy1 acetate, isopropy1 acetate; "ether solvents" like tetrahydrofuran, diethy1 ether, methy1 tert-buty1 ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethy1 acetamide, dimethy1 sulfoxide, acetonitrile; "ketone solvents" like acetone, methy1 ethy1 ketone, methy1 isobuty1 ketone;

and "alcoholic solvents" like methanol, ethanolj n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like methy1ene chloride, chloroform and ethy1ene dichloride; polar solvents like water; and also mixtures thereof; and the resolution is carried out at the temperature 0°C to reflux temperature of the solvent used.

In step b) the suitable base is selected from inorganic bases like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and organic bases like triethy1amine, isopropy1 ethy1amine, diisopropy1 amine, diisopropy1 ethy1amine, piperidine and pyridine.

The racemic alky1 3-amino-4-(2,4,5-trifluoropheny1)butanoate compound of formula-14 can be prepared by the following procedure, which comprises of the following steps;

a) Reacting the 2,4,5'trifluro pheny1 acetic acid compound of formula-16 with thiony1 chloride in methy1ene chloride in presence of dimethy1formamide followed by
reaction with meldrums acid in presence of triethy1 amine and finally treated with
aqueous sodium hydroxide provides sodium l'(2,2-dimethy1-4,6-dioxo-l,3-dioxan-5-
y1)-2-(2,4,5-trifluoropheny1)ethanolate compound of formula-17

b) treating the sodium l-(2,2-dimethy1-4,6'dioxo-l,3-dioxan-5-y1)-2-(2,4,5-
trifluoropheny1)ethanolate compound of formula-17 in a suitable solvent in presence
of acid provides alky1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate compound of
formula-2, Wherein R is H or Ci-Ce straight or branched chain alky1 group;

c) reacting the alky1 3-oxo-4-(2,4,5-trifIuoropheny1)butanoate compound of formula-2a with suitable ammonium source like ammonium acetate in a suitable solvent provides the (Z)-alky1 3-amino-4-(2,4,5-trifluoropheny1)but-2-enoate compound of formula-18

Wherein R is H or C|-C6 straight or branched chain alky1 group;

d) reducing the (Z)-alky1 3-amino-4-(2,4,5-trifluoropheny1)but-2-enoate with sodium borohydride in presence of acetic acid provides alky1 3-amino-4-(2,4,5-
trifluoropheny1) butanoate compound of formula-14.

Wherein R is H or Ci-Ce straight or branched chain alky1 group;

Wherein in step b) the suitable solvent is selected from alcohol solvents and the acid is selected from inorganic acid like hydrochloric acid, hydrobromic acid, sulfuric acid or organic acids like acetic acid, trifluoroacetic acid, methane sulfonic acid, Para toluene sulfonic acid;

In step c) the suitable solvent is selected from alcoholic solvents, ether solvents or mixtures thereof.

The present invention also provides the novel salts of alky1 3-amino-4-(2,4,5-trifluoropheny1)butanoate represented by the following general formula-15.

Wherein R is H or C1-C6 straight or branched chain alky1 group;

Wherein CA is an chiral acid and is selected from S-(+) mandelic acid, R"(') mandellc acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (1R)-(-)-camphor sulfonic acid, (1S)-(+)-camphor sulfonic acid

(1R)-(+)-bromocamphor-10-suIfonic acid, (1S)-(-)-bromocainphor-10-sulfonic acid, (-)-Dibenzoy1-L-tartaric acid, (")-Dibenzoy1-L-tartaricacid monohydrate, (+)-Dibenzoy1-D -tartaric acid, (+)-Dibenzoy1-D -tartaric acid monohydrate^ (+)-dipara"toly1-D-tataric acid, (')-dipara-toly1-L-tataricacid, L(-)-pyroglutamic acid, L(+)'pyroglutamic acid, (-)-Iactic acid, L-lysine, D-lysine and mixtures thereof.

The suitable solvents, wherever necessary, used in the present invention are selected from ester solvents; ether solvents, hydrocarbon solvents, polar aprotic solvents like dimethy1 acetamide, dimethy1 sulfoxide, acelonitrile; ketone solvents and alcoholic solvents, chloro solvents, polar solvents like water; and also mixtures thereof.

The suitable bases which are used in the above invention are selected from inorganic bases like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and organic bases like triethy1amine, isopropy1 ethy1amine, diisopropy1 amine, diisopropy1 ethy1amine, piperidine and pyridine.

The suitable acid which is used in the above invention is selected from hydrochloric acid, sulphuric acid, acetic acid, oxalic acid, formic acid, trifluoroacetic acid and phosphoric acid.

The pharmaceutically acceptable salts of compound of formula-1 of the present invention can be prepared by the conventional methods from the pharmaceutically acceptable non-toxic acids selected from acetic, benzenesulfonic, benzoic, citric, fumaric, gluconic, hydrochloric, hydrobromic, lactic, maleic, malic, methane sulfonic, phosphoric and nitric acids. The above aspects of the present inventions are illustrated by the following schemes;

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 l-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]triazoIo[43-
a|pyrazin-7(8H)-y1)-4-(2,4,5-trifIuoropheny1)butane-l,3-dione compound of
formula 10.

To the solution of sodium 1 -(2,2-dimethy1-4,6-dioxo-1,3-dioxan-5-y1)-2-(2,4,5-trifluoropheny1)ethanolate (50 gms) in acetonitrile (250 ml), added 3-(trifluoromethy1)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride (33.5 gms) and stirred for 10 minutes. Slowly added the methane sulfonic acid (2 ml) to the reaction mixture at 25-30°C. Heated the reaction mixture to 85°C and stirred for 90 minutes at same temperature. Distilled off the solvent from the reaction mixture and cooled to 25°C-Added ethy1 acetate (250 ml) and water (75 ml) to the residue and stirred for 20 minutes. Separated the both aqueous and organic layers. The organic layer was washed with sodium bicarbonate solution followed by sodium chloride solution. Distilled off the solvent completely from organic layer to get the title compound. Yield: 55 gms.

ExampIe-2: Preparation of sodium l-(2,2 dimethy1-4,6-dioxan-5-y1idene)-2-(2,4,5'' tnfluoropheny1)etbanoate.

To the solution of 2,4,5-trifluro pheny1 acetic acid (50 gms) in methy1ene chloride(200 ml) added dimethy1 formamide(3 ml) and stirred for 15 minutes. Added thiony1 chloride (23 ml) to the reaction mixture at 25°C, Heated the reaction mixture to 40-45°C and stirred for 3 hrs. Distilled off the solvent and added methy1ene chloride to the obtained compound. In another round bottom flask the solution of meldrum's acid (43 gms) dissolved in methy1ene chloride (200 ml) and cooled to 0-5°C. To this reaction mixture triethy1amine (72.6 ml) was added slowly. To this reaction mixture added the above acid chloride solution at 0-5 "^C and stirred for 3 hours at same temperature. Washed the reaction mixture with water and distilled off the solvent completely under reduced pressure. Cooled the obtained compound to 20°C, added aqueous sodium hydroxid solution (30 gms in 250 ml water) and stirred for 2 hours at same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 65 gms.
£xample-3: Prepflration of methy1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate compound of formula-2a.

To the solution of sodium l-(2,2-dimethy1-4,6-diojcO'l,3-dioxan-5-y1)'2-(2,4,5-trifluoropheny1)ethanolate (250 gms) in methanol (1125 ml) added methane sulphonic acid (92 gms) and heated the reaction mixture to reflux temperature. Stirred the reaction mixture for 90 minutes at same temperature. Distilled off the solvent completely under reduced pressure. Cooled the reaction mixture to 25°C and added water (150 ml) and methy1ene chloride (150 ml). Stirred the reaction mixture for 15 minutes and separated the both aqueous and organic layers. The organic layer was washed with water. Distilled off the solvent completely to get the title compound. Yield: 180 gms.

KxampIe-4; Preparation of methy1 3-amino-4-(2,4,S-trifluoropheny1)butanoate compound of formuIa-14

To the solution of methy1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate (178 gms) in methanol (375 ml) added ammonium acetate (113 ml) and heated to reflux temperature. Stirred the reaction mixture for 3 hours at same temperature. Distilled off the solvent completely from the reaction mixture and cooled to 20°C. Added toluene (1600 ml) to the obtained compound and stirred for 20 minutes. Filtered the reaction mixture. The filtrate was cooled to 0-5°C, added sodium borohydride (30 gms). Acetic acid (480 ml) was slowly added to the reaction mixture and stirred for 5 hours at 0-5°C. Quenched the reaction mixture by adding water at 0-5°C. Separated the both aqueous and organic layers. Aqueous layer was washed with toluene and basified with sodium hydroxide solution. The compound was extracted using methy1ene chloride. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 85 gms.

E\ainple-5: Preparation of (1R)-(-)-cainphor sulfonic acid salt of (R)-niethy1 3-amino-4-(2,4,5-trifluoropheny1)butaaoate compound of formula-15a:

To the solution of methy1 3-amino-4-(2,4,5-trifluoropheny1)butanoate (80 gms) in
acetonitrile (760 ml) added water(40 ml) and (R)-(-)-camphor sulphonic acid (75 gms) at
25-30°C temperature. Stirred the reaction mixture for 3 hours. Filtered the precipitated
solid and washed with acetonitrile* Recrystallized the compound from water/Acetonitrile
in 1:20 ratio to get the title compound.

Yield: 15 gms.

MR: 105 - 110°C; SOR MD" = -22° (C - 1. water)

Example-6: Process for the preparation of (R)-(-)-mandelic acid salt of (R)-methy1 3-ainlno-4-(2,4,5-trifluoropheny1)butanoate compound of formula-15b:

To the mixture of acetonitrile (540 ml) water (60 ml) added (-)-mandelic acid (37 gms) at
25-30°C temperature. Stirred the reaction mixture for 20 minutes and added compound of
formula-14(60 gms) slowly. Stirred the reaction mixture for 4 hours. Filtered the
precipitated solid and washed with acetonitrile. Recrystallized the compoimd from
water/Acetonitrile in 1:9 ratio to get the title compound.

Yield: 18 gms.

MR: 150 - 152°C; SOR MD^^ = -44° (C - 1, water)

Example-7; Preparation of (R)-3-(tert-butoxycarbony1amiEo)-4-(2,4,5-triflnoro pheny1)butanoic acid compound of formula-9a.

To 12 gms of mandelic acid salt of compound of formula-15b added 50 ml of water. Basified it using aqueous sodium carbonate solution. Extracted the reaction mixture using methy1ene chloride. Distilled off the solvent completely under reduced pressure. Added 40 ml of tetrahydrofuran and 40 ml of water to the obtained compound. Added lithium hydroxide (2.0 gms) to the reaction mixture. Cooled the reaction mixture to 0-5°C, added di-tert-buty1dicarbonate (8.0 gms) slowly and stirred for 90 minutes at the same temperature. Raised the temperature to 25°C and added ethy1 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 ethy1 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 ethy1 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-trifluoropheny1) buty1]-5,6,7,8-tetrahydro-3-(trif1uoromethy1)-l,2,4-triazolo[4.3-a]pyrazine compound of formula-1.

To 24 ml of dimethy1formamide added 4 gms of (R)-3-(tert-butoxycarbony1amino)-4-(2,4,5-trifluoropheny1)butanoic acid and cooled the reaction mixture to 0-5°C. 3.3 gms of N,N'-dicyclohexy1carbodiimide (DCC) was dissolved in 10 ml of dimethy1formamide and make upto 20 ml. Added 7 ml of above prepared N,N'-dicyclohexy1carbodiimide (DCC) solution to the above 0-5°C cooled reaction mixture. Added 3.15 gms of 3-(trifluoromethy1)-5,6,7,8-tetra hydro-[l,2,4]tria2olo[4,3-a]pyrazine hydrochloride and 3.3 ml of triethy1amine to the reaction mixture and stirred for 15 minutes. Added 0.9 gms of dimethy1aminopyridine (DMAP) and stirred the reaction mixture for 3 hrs at 0-5°C. Added 6.5 ml of N,N'-dicyclohexy1carbodiimide solution and stirred for 3 hrs. Again added 6.5 ml of N,N'-dicyclohexy1carbodiimide 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 ethy1 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 isopropy1 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 isopropy1 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 fi-om reaction mixture with methy1ene chloride. Distilled off the solvent completely to get the title compound. Yield: 2.5 gms.

Example-9: Preparation of 7-[(3R)-3-ainino-l-oxo-4-(2,4,5-trifluoropheny1) buty1]-
5,6,7,8-tetrahydro-3-(trifluoromethy1)-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-trifluorophenyi) buty1]-5,6,7,8-tetrahydro-3-(trifluoromethy1)-l,2,4-triazolo[4.3-a]pyrazine added 5 ml of isopropy1 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)-methy1 3-hydroxy-4-(2,4,5-trifluoro pheny1)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 dimethy1 sulfide and 0.55 gms of (R)-2-methy1-cbs-oxazaborolidine tmder nitrogen atmosphere. To this reaction mixture slowly added 5 gms of methy1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate compound 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 compound. Yield: 4.0 gms

Example-11: Preparation of (R)-methy1 3-bromO'4-(2,4,5-trif1uoropheny1)butanoate compound of formula-4a.

To 4.0 gms of (R)-methy1 3-hydroxy-4-(2,4,5-trifluoropheny1)butanoate added 40 ml of methy1ene chloride and cooled the reaction mixture to 0-5°C. Added 4.24 gms of triphenyi phosphene and 3.17 gms of N-bromo succinamide. Raised the temperatixre 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 compound an 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-12: Preparation of (R)-methy1 3-azido-4-(2,4,5-trifluoropbeny1)butanoate compound of formula-Sa.

To 4.0 gms of (R)-methy1 3-bromo-4-(2,4,5-trifluoropheny1)butanoate compound of formula-4a added 30 ml of dimethy1 formamide and 10 ml of water and stirred for 10 minutes. Sodium azide (2.92 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 8 hrs at same temperature. Cooled the reaction mixture to 25°C, added water and extracted with ethy1 acetate. Separated the both aqueous and organic layers. Distilled off the solvent completely from the organic layer to get the title compound. Yield; 2.5 gms.

Exaniple^l3: Preparation of (R)-methy1 3-azido-4-(2,4,5-trifIuoropheny1)butanoate compound of formula-5a.

To 4.0 gms of (R)'methy1 3-bromo-4-(2,4»5-trifluoropheny1) butanoate compound of formula-4a added 30 ml of N-methy1 pyrrolydine and 10 ml of water and stirred for 10 minutes, lithium azide (2.2 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 8 hrs at same temperature. Cooled the reaction mixture to 25°C, added water and extracted with ethy1 acetate. Separated the both aqueous and organic layers. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 2.3 gms

Example-14: Preparation of (R)-3-azido-l-(3-(trifluoromethy1)-5,6»dihydro-[l,2,4]tria2olo[4,3-a)pyrazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butan-l-one.

To 24 ml of methanol added 4 gms of (R)-methy1 3-azido-4-(2,4,5-trifluoropheny1)butanoate, 3.35 gms of 3-(trifluoromethy1)-5j6J,8-tetra hydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride and 2.3 gms of sodium hydroxide. Stirred the reaction mixture for 5 hrs at reflux temperature. Cooled the reaction mixture to 25-30''C and added water and ethy1 acetate. Separated the both aqueous and organic layers.

Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 4 gms

Example-15: Preparation of 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trinuoropheny1) buty1]-5,6,7,8-tetrahydro-3-(trifluoromethy1)-l,2,4-triazolo[4.3-aJpyrazine compound of formula-1,

To 3 gmsof(R)-3-azido-l-(3-(tnfluoromethy1)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4j5-trifluoropheny1)butan-l-one added 30 ml of methanol and 1.5 gms of palladium carbon was added. Applying 3 kgs of hydrogen pressure and maintained for 6 hours. Filtered the reaction mixture through hyflow bed and distilled off the solvent completely under the reduced pressure to get the title compound. Yield: 2 gms.
ExampIe-16;Preparation of (R)*3-hydroxy-l-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4] triazoIo(4-aJpyrazin-7(8H)-y1)-4-(2,4,5-trifluoropbeny1)butan-l-one compound of formula-11.

40 ml of toluene was taken in a round bottom flask and cooled to 0°C. To this added 0.94 gms of borane dimethy1 sulfide and 0.34 gms of (R)-2-methy1-cbs-oxazaboroUdine under nitrogen atmosphere. To this reaction mixture slowly added 5 gms of l-(3-(trifluoromethy1)- 5,6-dihydrO' [1,2,4] triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-trifIuoro pheny1)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 compound. Yield: 3 gms.

Example-17:Preparation of (R)-3-azido-l-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4] triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butan-l-one.

To 6 gms of (R)-methy1 3-azido-4-(2,4,5-trifluoropheny1)butanoatej added 30 ml of water and 30 ml of tetrahydrofuran. Added 2.0 gms of lithium hydroxide and stirred the reaction mixture for 4 hrs at 25-30*0 temperature. Acidify the reaction mixture using one, hydrochloric acid and extracted the compound using ethy1 acetate. Distilled off the solvent completely under reduced pressure. To the obtained residue added 24 ml of dimethy1formamide and cooled the reaction mixture to 0-5°C. 3.5 gms of N,N'-dicyclohexy1carbodiimide (DCC) was dissolved in 10 ml of dimethy1formamide and make upto 20 ml. Added 7 ml of above prepared N,N'-dicyclohexy1carbodiimide (DCC) solution to the above 0-5°C cooled reaction mixture. Added 3.5 gms of 3-(trifluoromethy1)-5,6,7.8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride and 3.3 ml of triethy1amine to the reaction mixture and stirred for 15 minutes. Added 0.75 gms of dimethy1aminopyridine (DMAP) and stirred the reaction mixture for 3 hrs at 0-5°C, Added 6.5 ml of N,N'-dicyclohexy1carbodiimide solution and stirred for 3 hrs. Again added 6,5 ml of N,N'-dicyclohexy1carbodiimide 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 ethy1 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 isopropy1 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 compoimd added 10 ml of isopropy1 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 methy1ene chloride. Distilled off the solvent completely to get the title compound. Yield: 4.5 gms.

Example-18:Preparation of (R)-4-oxo-4-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]
triazolo[4,3-alpyrazin-7(8H)-y1)-l-(2,4,S-trifluoropheny1)butan-2-y1 methane
sulfonate compound of formula*'12a.

To the solution of 3-hydroxy-1 -(3-(trifluoromethy1)-5,6-dihydro-[ 1,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butan-l-one (3 gms) in acetonitrile (30ml), added dimethy1 aminopyridine (1.79 gms) and diisopropy1 ethy1 amine (2,85 gms) and stirred for 10 minutes at room temperature. Cooled the reaction mixture to O-S'^C, added methane sulfony1 chloride (1.679 gms) and stirred the reaction mixture for 5 hours at same temperature. Quenched the reaction mixture with water and separated the organic and aqueous layers. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 2.5 gms.

Example-19: Preparation of 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluoropheny1) buty1]-5,6,7,8-tetrahydro-3-(trifluoromethy1)-l,2,4-triazolo[4.3-a]pyrazine compound of formula1l.

A mixture of (R)-3-hydroxy-l-(3-{trifluoromethy1)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butan-l-one (2 gms), sodium azide (0.4 gms) and PPhs (2.7 gms) in 20ml of CCU-DMF (1:4) was stirred at 90°C for 8 hours. The reaction mixture was cooled to 25°C and quenched by adding 10 ml of water. After stirring for 10 min., reaction mixture was diluted with ether (50 ml) and washed thoroughly with water. By trituration of ether fraction at 0°C, tripheny1phosphineoxide was crystallized out and ether was filtered off. The filtrate was distilled off completely to get the title compound. Yield: 1.2 gms

Example-20: Preparation of (R)-methy1 3-amino-4-(2,445-trifluoropheny1)butanoate compound of formula-8a.

A mixture of (R)-methy1 3-hydroxy-4-(2,4,5-trifluoropheny1)butanoate (5 gms), sodium azide (1.60 gms) and PPh3 (11 gms) in 50 ml of CCI4-DMF (1:4) was stirred at 90°C for 8 hours. The reaction mixture was cooled to 25°C and quenched by adding 25 ml of water. After stirring for 10 min., reaction mixture was diluted with ether (75 ml) and washed thoroughly with water. By trituration of ether fraction at 0°C, tripheny1phosphineoxide was crystallized out and ether was filtered off. The filtrate was distilled off completely to get the title compound. Yield: 3.5 gms.

Example-21: Preparation of (R)-methy1 3-amino-4-(2,4f5-trifIuoropheny1)butanoate compound of formula-8a.

To 5 gms of (R)-methy1 3'hydroxy-4-(2,4,5-trifluoropheny1)butanoate added 50 ml of pyridine and cooled the reaction mixture to . 4.2 gms of Para toluene sulphony1 chloride was added to the reaction mixture at 0°C and stirred the reaction mixture for 8 hrs at same temperature. Raised the temperature to 20°C and added water (50 ml) to the reaction mixture. Cooled the reaction mixture to 0°C and added aqueous hydrochloric acid and methy1 tert. buty1 ether. Separated the both aqueous and organic layers. The organic layer was washed with aqueous hydrochloric acid. Distilled off the solvent completely under reduced pressure. The obtained residue was dissolved in methanol and added ammonia solution to the reaction mixture. Heated the reaction mixture to reflux temperature for 3 hours. Cooled the reaction mixture to room temperature and added water to it. Extracted the reaction mixture with ethy1 acetate and distilled off the solvent completely to get the title compound. Yield: 2.5 gms.

Example-22: Preparation of 3-bromo-l-(3-(trifluoromethy1)-5,6-dihydro-[1,2,4]triazolo[43-a|pyrazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butan-l-one

To 5,0 gms of l-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]triazolo[43-a]pyTazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butane-l,3-dione compound added 50 ml of acetic acid and cooled the reaction mixture to 15°C. To this reaction mixture added L5 gms of sodium borohydride and stirred for 2 hrs. Quenched the reaction mixture by adding water and extracted the compound using methy1ene chloride. Washed the organic layer with water and dried over Na2S04. Cooled the organic layer to 0-5°C, added 2.90 gms of tripheny1 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 under reduced pressure. Added cyclo 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.

Claim:
1. A novel process for the preparation of sitagliptin compound of formula-1,

which comprises of

a) Resolution of alky1 3-amino-4-(2,4,5-trifluoropheny1) butanoate compound of
formula-14.

wherein R is H or C1-C6 straight or branched chain alky1 group;

with a suitable chiral acid in a suitable solvent provides the corresponding chiral
acid addition salt compound of general formula-15,

wherein R is H or C1-C6 straight or branched chain alky1 group and CA is chiral acid.

b) treating the compound of formula-15 with a suitable base in a suitable solvent
provides (R)-alky1-3-amino-4-(2,4,5-trifluoropheny1)butanoate compound of
formula-8

wherein R is H or C1-C6 straight or branched chain alky1 group

which on in-situ protection of amino group followed by hydrolysis in presence of

a base provides corresponding (R)-3-N(protected)-4-(2,4,5-trifluoro pheny1)butanoic acid compound of formula-9

where in PG = Amino group protecting agent and R is H

c) reacting compound of formula-9 with 3-(trifluoromethy1)-5,6,7,8-tetrahydro-[l,2,4]tna20lo[4,3-a]pyrazine compound of formula-6, in the presence of suitable condensing agent selected from N,N'-Dicyclohexy1 carbodiimide (DCC) in presence of hydroxybenzotriazole (HOBT), N,N'-Dicyclohexy1 carbodiimide (DCC) in presence of 4-Dimethy1aminopyridine (DMAP), thiony1 chloride, phosphorous pentachloride in presence or absence of base in a suitable solvent followed by deprotection of amino group using suitable acid in a suitable solvent provides 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trif]uoropheny1) buty1J-5,6,7,8-tetrahydro-3-(tnfluoromethy1)-1,2,4-triazolo[4.3-a]pyrazine compound of Formula-1

d) optionally converting the compound of formula-1 into its phosphate salt compound of formula la.

2. A novel process for the preparation of Sitagliptin compound of formula-1 comprises of
a) Reducing alky1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate, compound of general
formula-2, with a suitable stereo selective reducing agent in a suitable solvent to
provide {R)-alky1 3-hydroxy-4-(2,4,5-trifluoropheny1)butanoate, compound of
general formula-3,

wherein R is H or C1-C6 straight or branched chain alky1 group

b) treating the compound of general formula-3, with a halogenating agent in a
suitable solvent to provide (R)-alky1 3-halo-4-(2,4,5-trifluoropheny1)butanoate,
compound of general formula-4,

wherein R is H or C1-C6 straight or branched chain alky1 group and X is a halogen.

c) reacting the compound of general formula-4, with sodixim azide or lithium azide
in a suitable solvent to provide (R)-alky1 3-azido-4-(2,4,5-trifluoropheny1)
butanoate, compound of general formula-5,

wherein R is H or C1-C6 straight or branched chain alky1 group

d) hydrolyzing the compound of general fonnula-5 with a suitable base in a suitable solvent, followed by condensation with 3-(trifluoromethy1)-5,6,7,8-tetra hydro-[l,2,4]triazolo[4,3-a]pyrazine compound of fonnula-6 or its salt, in the presence of suitable condensing agent selected from N,N'-DicycIohexy1 carbodiimide (DCC) in presence of hydroxybenzotriazole (HOST), NjN'-Dicyclohexyi carbodiimide (DCC) in presence of 4-Dimethy1aminopyridine (DMAP), thiony1 chloride, phosphorous pentachloride, in presence or absence of base in a suitable solvent to provide (R)-3-azido-I-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]triazolo[43-a]pyrazin-7(8H)-y1)-4-(2,4,5-triflvioropheny1)butan-l-one, compound of formula-7

e) reducing the compoimd of formula-7, with a suitable reducing agent selected from Pd/C, lithium aluminium hydride, raney nickel, zinc in presence of ammonium chloride in a suitable solvent selected from alcohol solvents, ether solvents to provide sitagliptin, compound of formula-1.

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

a) Reducing the l-(3-(trifluoromethy1)-5,6-dihydro-[U2,4]triazolo[4,3-a]pyrazin-
7(8H)-y1)-4-(2,4,5-trifluoropheny1)butane-l,3-dione compound of formula-lO,

with a suitable reducing agent selected from DIP chloride or Borane DMS in presence of catalyst like R-methy1 CBS in a suitable solvent to provide the (R)-3-hydroxy-l-(3'(trifluoromethy1)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1) -4-(2,4,5-trifluoropheny1)butan-l-one compound of formula-11,

b) treating the compound of formula-11 with methane sulfony1 chloride or toluene
sulfony1 chloride or halogenating agent in presence of a suitable base, to provide
corresponding derivative compound of formula-12,

Wherein L is a leaving group as defined in detailed description,

c) treating the compound of formula-12 with a suitable ammonium source in a
suitable solvent to provide the sitagliptin compound of formula-1.

4. A novel process for the preparation of (R)-3-hydroxy-l-(3-(trifluoromethy1)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-trifluoropheny1)butan-]-one compound of formula-11, which comprises of the following steps,

a) Reducing alky1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate, compound of general
formula -2,

Wherein R is H or C1-C6 straight or branched chain alky1 group;

with a suitable stereo selective reducing agent selected from DIP chloride or Borane DMS in presence of a catalyst like R-methy1 CBS in a suitable solvent to provide (R)-alky1 3-hydroxy-4-(2,4,5''trifluoropheny1)butanoate, compound of general formula-3,

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

b) treating the compound of formuIa-3 with a suitable hydroxy group protecting
agent in a suitable solvent to provide the hydroxy protected compound of formula-13,

Wherein PR is H or hydroxy protecting group and R is H or as defined above,

c) reacting the compound of general formula-13 with 3-(trifluoro]riethy1)-5,6,7,8-
tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine compound of formula-6, in the presence
of an acid or base in a suitable solvent, followed by deprotection of the hydroxy
protecting group, to provide the compound of formula-11.

5. A novel process for the preparation of (R)-alky1 3-ammo-4-(2,4,5-trifluoro pheny1)butanoate, compound of general formula-S,

Wherein R is H or C1-C6 straight or branched chain alky1 group which comprise of the following steps,

a) Reacting the 2,4,5-trifluro pheny1 acetic acid compound of formula-16 with
thiony1 chloride in methy1ene chloride in presence of dimethy1formamide catalyst
followed by reaction with meldrums acid in presence of triethy1 amine and finally
treated with aqueous sodium hydroxide provides sodium l-(2,2-dimethy1-4j6-
dioxo-l,3-dioxan-5-y1)-2-(2,4,5-trifluoropheny1)ethanolate compound of
formula-17

b) treating the sodium l-(2,2-dimethy1-4,6-dioxo-l,3-dJoxan-5-y1)-2-(2,4,5-trifluoropheiiy1)ethanolate compound of formula-17 in a suitable alcoholic solvent in presence of acid provides alky1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate compound of formula-2a.

c) reacting the methy1 3-oxo-4-(2,4,5-trifluoropheny1)butanoate compound of fonnula-2a with suitable ammonia source like ammonium acetate in a suitable alcoholic solvent provides the (Z)-methy1 3-amino-4-(2,4,5-trifluoropheny1)but-2-enoate compound of formula-18

d) reducing the (Z)-methy1 3-amino-4-(2,4,5-trifluoropheny1)but-2-enoate with
sodium borohydride In presence of acetic acid provides methy1 3-amino-4-(2,4,5'
trifluoropheny1) butanoate compound of formula-14a.

e) resolving the alky1 3-amino-4-(2,4,5-trifluoropheny1)butanoate, compound of
general formula-14, with a suitable chiral acid 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, (1R)-(-)-camphor sulfonic acid,
(1S)-(+)-camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (IS)-(-
)-bromocamphor-10-sulfonic acid, (-)-Dibenzoy1-L-tartaric acid, (-)-Dibenzoy1-L-
tartaricacid monohydrate, (+)-Dibenzoy1-D -tartaric acid, (+)-Dibenzoy1-D -
tartaric acid monohydrate, (+)-dipara-toly1-D-tataric acid, (-)-dipara-toly1-L-
tataricacid, L(-)-pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid,
L-lysine and D-lysine in a suitable solvent selected from"alcoholic solvents" such
as methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro
solvents" such as to methy1ene chloride, chloroform, ethy1ene dichloride and
carbon tetra chloride; "ketone solvents" such as acetone, methy1 ethy1 ketone,
methy1 isobuty1 ketone; "hydrocarbon solvents" such as to toluene, hexane,
heptane and cyclohexane; "nitrile solvents" such as acetonitrile; "ester solvents"
such as ethy1 acetate, methy1 acetate and isopropy1 acetate; "ether solvents" such
as tetrahydrofuran, diethy1 ether and methy1 tert-buty1 ether; "polar solvents"
such as water, "polar aprotic solvents" such as dimethy1 formamide, dimethy1
acetamide, dimethy1 sulfoxide and mixtures thereof, at a suitable temperature
ranges from 0°C to reflux temperature of the solvent used, to provide the
corresponding chiral acid salt compound of general formula-15,


f) treating the above obtained salt compound of general formula-15 with a suitable base in a suitable solvent to provide the compound of formula-8.

6. Compounds having following structures

Wherein R is H or C1-C6 straight or branched chain alky1 group.

7. Compounds having the following structural formula

Wherein R is H or C1-C6 straight or branched chain alky1 group and CA is chiral acid as defined above

with the proviso that the chiral acid is not (1S)-(+)"camphor sulfonic acid.

8. The crystalline (R)-methy1 3-amino-4-(2,4,5-trifluoropheny1)butanoate (R)-(-) mandelic acid having melting point 150 - 152°C.

9. The crystalline (R)-methy1 3-aniino-4-(2,4,54rifluoropheny1)butanoate (1R)-(-)-camphor sulfonic acid having melting point 105 - 110°C.

10. Resolution of racemic alky1 3-amino-4-(2,4,5-trifluoropheny1) butanoate compounds of formula-14 using the chiral acid 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, (1R)-(-)-camphor sulfonic acid, (1S)-(+)-camphor
sulfonic acid (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromocamphor-10-
sulfonic acid, (-)-Dibenzoy1-L-tartaric acid, (-)-Dibenzoy1-L-tartaricacid
monohydrate, (+)-Dibenzoy1-D -tartaric acid, (+)-Dibenzoy1-D -tartaric acid
monohydrate, (+)-dipara'toly1-D-tataric acid, (-)-dipara-toly1-L-tataricacid, L(-)-
pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine and D4ysine.

11. Usage of compounds claimed in claims 6 to 9 in the preparation of sitagliptin
compound of formula-1 and its pharmaceutically acceptable salts thereof.