Priority Claim:

This application claims the priority of our earlier provisional application number: 901/CHE/2009, filed on 20 April 2009.

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 and hydrates thereof.

Sitagliptin phosphate is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, which is believed to treat patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIF), are released by the intestine throughout the day. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-l also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.

Sitagliptin phosphate is currently marketed in the United States under the brand name Januvia in its monohydrate form and 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 Scondensation of (3R)-3-[(1,1-dimethylethoxycarbonl)-amino]-4-(2,4,5-trifluorophenyl)-butanoic acid with 3-(trifluoromethyl)-5,67,8-tetrahydro-l,2,4-triazolo[4,3-a]pyrazine in presence of HOBT in methylene chloride and then purified by preparative TLC to provide 7-[(3R)-3-[(1,1-dimethylethoxycarbonl)amino-4-(2,4,5-trifIuorophenyl)-butanoyl]-3(trifluoromethyl)-5,6,8-tetrahydro-U2,4-triazolo[4,3-a]pyrazine. The obtained compound 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-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a] pyrazin-7(8H)-y1]-1-(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[1,2,4]triazolo[4,3-a] pyrazin-7(8H)-y1]-l-(2,4,5-trifluorophenyI)butan-2-one into sitagliptin by treating it with ammonium acetate in methanol to provide (2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyra2in-7(8H)-yl]-l-(2,4,5-triflurophenyl)but-2-en-2-amine, which on enantioselective hydrogenation in 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]tria2olo[4,3-a]pyrazin-7(8H)-y1]-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 suitable salts 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-(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 reagents like rhodium metal precursor complexed with a chiral ligand for the preparation of sitagliptin and do not 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 first aspect of the present invention provides an improved process for the preparation of sitagliptin compound of formula-1 or its pharmaceutically acceptable salts, which comprises of the following steps;

a) condensing the 1 -(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-(2,4,5-trifluorophenyl)ethanolate derivative compound of formula-3, with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2.4]triazolo[4,3-a]pyrazine hydrochloride compound of formula-4 in presence of a suitable acid in a suitable solvent to provide the condensed compound of formula-5,

b) treating the condensed compound of formula-5 with ammonia source in a suitable solvent to provide the compound of formula-6,

c) reducing the compound of formula-6 with suitable reducing agent in a suitable solvent to provide the racemic sitagliptin compound of formula-7,

d) resolving the racemic sitagliptin compound of formula-7 with suitable resolving agent in a suitable solvent to provide salt of sitagliptin compound of formula-8,

e) treating the salt compound of formula-8 with suitable base followed by treatment with phosphoric acid in a suitable solvent to provide sitagliptin hydrogen phosphate compound of formula-1 a.

The second aspect of the present invention is to provide an improved process for the preparation of hydrochloride salt 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4] triazolo[4,3-a]pyrazine hydrochloride compound of formula-4, Which comprises of,

a) treating hydrazine hydrate compound of formula-16 with ethyltrifluoroacetate in acetonitrile to provide a product which on in-situ acylation in presence of a suitable base followed by reaction with suitable cyclizating agent to provide 2-(chloromethyl)-5-(trifluoromethyl)-l,3,4-oxadiazole compound of formula-19,

b) reacting the compound of formula-19 with ethylene diamine in a suitable solvent to provide (Z)-2,2,2-trifluoro-N'-(piperazin-2-ylidene)acetohydrazide compound of formula-20,

c) treating the compound of formula-20 with a suitable acid in a suitable solvent and isolating the compound in acetone to provide of 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride compound of formula-4,

The third aspect of the present invention is to provide a novel process for the preparation of sodium l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-2-(2,4,5-trifluofophenyl) ethanolate, compound of formula-3b,

a) Reacting the trifluorophenyl acetic acid compound of formula-2 with thionyl chloride, followed by treating with meldrums acid in a suitable solvent,

b) adding aqueous sodium hydroxide solution,

c) filtering the compound to provide compound of formula-3b.

The fourth aspect of the present invention is to provide a novel process for the preparation of (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid compound of formula-13.

a) reacting the 2,4,5- trifluoro phenylacetonitrile compound of formula-9 with diisobutylaluminium hydride in a suitable solvent followed by reaction with allyl magnesium halide in a suitable solvent provides 1 -(2,4,5-trifluorophenyl)pent-4-en-2-amine compound of formula-12,

b) resolving the compound of formula-12 with a suitable chiral acid in a suitable solvent at a suitable temperature provides (S)-l-(2,4,5-trifluorophenyl)pent-4-en-2-amine compound of formula-21,

c) oxidizing the compound of formula-21 with a suitable oxidizing agent selected from ruthenium tri chloride in presence of sodium metaperiodate or osmium tetroxide, in a suitable solvent provides (R)0-amino 4-(2,4,5-trifluorophcnyl)butanoic acid compound of formula-l5.

The compound of formula-13 can be used for the preparation of dipeptidyl peptidase IV inhibitor like sitagliptin.

The fifth aspect of the present invention is to provide a novel process for the preparation of (Z)-alkyl-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate compound of formula-15,

a) Reacting the 2,4,5-trifIuoro phenyl acetonitrile compound of formula-9 with a halo ester compound of formula-22 in presence of zinc in a suitable solvent provides compound of formula-14,

b) treating the compound of formula-14 with a suitable ammonia source provides (2)-alkyl 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate compound of formula-is.

Detailed Description of the Invention:

As used herein the term "sitagliptin" refers to active isomer i.e.,7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,84etrahydro-3-(trifluoromethyl)-(2,4-triazolo[4,3-a]pyrazine unless otherwise specifically mentioned.

The present invention relates to an improved process for the preparation of sitagliptin compound of formula-1 or its pharmaceutically acceptable salts thereof. The sitagliptin is chemically known as 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl) butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-U2,4-triazolo[4.3-a]pyrazine having the following structural formula-1 and its phamiaceutically acceptable salts thereof.

The suitable solvents, wherever necessary, used in the present invention are selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents*' like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, elhanol, n-propanol, isopropnol, n-butanol and isobutanol; "chloro solvents" like dichloromethane, chloroform and ethylene dichloride; 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 lithium hydroxide, sodium hydroxide, potassium hydroxide and alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, piperidine and pyridine.

The suitable chiral acids which are used in the above invention are 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, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)'dipara-tolyl-D-tartaric acid, (-)-dipara-tolyl-L-tartaricacid, L(-)-pyroglutamic acid, L(+)-pyrogIutamic acid, (-)-lactic acid, L-lysine and D-lysine.

The first aspect of the present invention provides an improved process for the preparation of sitagliptin hydrogen phosphate compound of formula-1 a, which comprises of the following steps;

a) condensing the l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-2-(2,4,5-trifluorophenyl)ethanolate derivative compound of formula-3,

With 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyra2ine hydrochloride compound of formula-4 in presence of a suitable acid in a suitable solvent provides the condensed compound of formula-5,

b) treating the condensed compound of formula-5 with a suitable ammonia source in a suitable solvent to provide the compound of formula-6,

c) reducing the compound of formula-6 with a suitable reducing agent in a suitable
solvent to provide the racemic sitagliptin compound of formula-7,


Formula-7

d) resolving the racemic sitagliptin compound of formula-7 with a suitable resolving
agent in a suitable solvent to provide salt of sitagliptin compound of formula-8,

e) treating the salt compound of formula-8 with a suitable base followed by treatment with phosphoric acid in a suitable solvent to provide sitagliptin hydrogen phosphate compound of formula-la.

Wherein, in step a) the suitable acid is selected form methane sulphonic acid, trifluoro acetic acid, p-toluene sulphonic acid, hydrochloric acid, sulphuric acid, nitric acid and a suitable solvent selected from nitrile solvents, alcohol solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents.

In step b) the suitable ammonia source was selected from ammonia, ammonium acetate and the like preferably ammonium acetate 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 c) the suitable reducing agent is selected from sodium borohydride, sodium cyano borohydride, Raney Nickel, Palladium/carbon; preferably sodium borohydride and the suitable solvent is selected from alcoholic solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, acetic acid or their mixtures thereof preferably toluene/acetic acid mixture.

In step d) the suitable resolving agent is selected from chiral acid preferably (-) mandelic acid and the suitable solvent is selected from alcoholic solvents, chloro solvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents, polar solvents, polar aprotic solvents and mixtures thereof; preferably aqueous isopropyl alcohol mixture.

In step e) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, and
organic bases preferably sodium hydroxide; the suitable solvent is selected from alcoholic solvents, chloro solvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents, polar solvents, polar aprotic solvents and mixtures thereof

Further the present invention also provides a recovery of mandelate salt of sitagliptin compound of formula-8a from the mother liquors, which comprises of the following steps.

a. Take the mother liquors obtained at step d) of above aspect, distilling off the solvent completely under reduced pressure,

b. adding polar solvent and chloro solvent to the obtained compound,

c. basifying the reaction mixture with a suitable base and separating the organic layer,

d. distilling off the solvent completely under reduced pressure,

e. adding mixture of polar solvent and alcohol solvent to the obtained,

f. adding (+)-mandelic acid to the reaction mixture, cooling down the reaction mixture,

g. filtering the precipitated solid and washing with alcohol solvent,

h. taking the filtrate and distilling off the solvent completely under reduced pressure,

i. adding mixture of polar solvent and chloro solvent to the obtained compound,

j. basifying the reaction mixture with a suitable aqueous base and separated the organic
layer,

k. distilling off the solvent completely under reduced pressure,

l. adding mixture of polar solvent and alcohol solvent to the obtained compound, m. adding (-)-mandelic acid to the reaction mixture, cooling down the reaction mixture,

n. filtering the precipitated solid and washed with alcoholic solvent,

o. recrystallizing from polar solvent and alcohol solvent mixture to get the pure
mandelic acid salt of sitagliptin compound of formula-8a.

The preferred embodiment provides a recovery of compound of formula-8a from the mother liquors. Which comprises of following steps.

a) Taking the mother liquors and distilled off the solvent completely under reduced pressure,

b) adding water and methylene chloride to the obtained compound.

c) basifying with aqueous sodium hydroxide and separated the organic layer,

d) distilling off the solvent completely under reduced pressure,

e) adding water and IPA to the obtained compound and stirred for 10 minutes,

f) adding (+)-mandelic acid to the reaction mixture, cooling down the reaction mixture to \0A5°C and stirred for 1 hr,

g) filtering the precipitated solid and washed with IPA,

h) taking the filtrate and distilled off the solvent completely under reduced pressure,

i) adding water and methylene chloride to the obtained compound,

j) basifying with aqueous sodium hydroxide and separated the organic layer,

k) distilling off the solvent completely under reduced pressure,

1) adding water and IPA to the obtained compound and stirred for 10 minutes,

m) adding (-)-mandelic acid to the reaction mixture, cooling down the reaction mixture
to l0-l5˚C and stirred for 1 hr,

n) filtering the precipitated solid and washed with IPA,

o) recrystallizing from water/IPA mixture to get the pure title compound.

The second aspect of the present invention provides an improved process for the preparation of 3'(trifluoromethyl)-5,6,7,8-tetrahydro-[l ,2,4]triazolo[4,3-a] pyrazine hydrochloride compound of formula-4. The process comprises of;

a) Treating hydrazine hydrate compound of formula-16 with ethyltrifluoroacetate in acetonitrile to provide a product which on in-situ acylation in presence of a suitable
base followed by reaction with suitable cyclizating agent to provide 2-(chloromethyl)-
5-(trifluoromethyl)-l,3,4-oxadiazole compound of fonnula-19,
N-N

Formula-19

b) reacting the compound of formula-19 with ethylene diamine in a suitable solvent to provide (Z)-2,2,2-trifluoro-N'-(piperazin-2-ylidene)acetohydrazide compound of
formula-20,

Formula-20

c) treating the compound of formula-20 with a suitable acid in a suitable solvent and isolating the compound in acetone to provide of 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyra2ine hydrochloride compound of fonnula-4,

The third aspect of the present invention provides a novel process for the preparation of sodium 1 -(2,2-dimethyl-4,6'dioxo-1,3-dioxan'5-yIidene)-2-(2,4,5-trifluoro phenyl)ethanolate compound of formula-3b.

Which comprises the following steps

a) Reacting the trifluorophenyl acetic acid compound of formula-2 with thionyl chloride, followed by treating with meldrums acid in a suitable solvent,

b) adding aqueous sodium hydroxide solution,

c) filtering the compound to provide compound of formula-3b.

The compound of formula-3b of the present invention is used an intermediate for the preparation of dipeptidyl peptidase IV inhibitors like sitagliptin and its pharmaceutically acceptable salts.

The fourth aspect of the present invention provides a novel process for the
preparation of (R)0'amino-4-(2,4,5-trifluorophenyl)butanoic acid compound of formula-
which comprises of,

a) reacting the 2,4,5- trifluoro phenylacetonitrile compound of formula-9

with diisobutylaluminium hydride in a suitable solvent followed by reaction with allyl magnesium halide in a suitable solvent provides l-(2,4,5-trifluorophenyl)pent-4-en''2-amine compound of formula-12,

b) resolving the compound of formula-12 with a suitable chiral acid in a suitable solvent
at a suitable temperature provides (S)-l-(2,4,5-trifluorophenyl)pent-4-en-2-amine
compound of formula-21,

c) oxidizing the compound of formula-21 with a suitable oxidizing agent selected from ruthenium tri chloride in presence of sodium metaperiodate or osmium tetroxide in
presence of sodium metaperiodate, in a suitable solvent provides (R)-3-amino-4-
(2,4,5-trifluorophenyI)butanoic acid compound of formula-13.

The compound of formula-13 of the present invention is used as intermediate for the preparation of dipeptidyl peptidase IV inhibitor like sitagliptin.

Wherein in step a) the suitable solvent is selected from ether solvents, ester solvents, hydrocarbon solvents preferably tetrahydrofuran.

In step b) resolving the l-(2,4,5-trifluorophenyl)pent-4-en-2-amine compound of formula-12 with a suitable chiral acid in a suitable solvent selected from alcoholic solvents, chloro solvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents, polar solvents, polar aprotic solvents, and mixtures thereof, at a suitable temperature ranges from 0°C to reflux temperature of the solvent used, to provide (S)-l-(2,4,5'trifluorophenyl)pent-4-en-2-amine compound of formula-21,

In step c) the suitable oxidizing agent is selected from ruthenium trichloride in presence of sodium metaperiodate and the suitable solvent is selected from nitrile solvents, ester solvents, polar solvents or mixtures thereof preferably acetonitrile/water mixture.

The fifth aspect of the present invention provides a novel process for the preparation of (Z)-alkyl-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate compound of formula-15,
which comprises of the following steps;

a) Reacting the 2,4,5-trifluoro phenyl acetonitrile compound of formula-9 with a halo ester compound of formula-22 in presence of zinc in a suitable solvent provides compound of formula-14,

b) treating the compound of formula-14 with a suitable ammonia source provides (Z)- alkyl-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate compound of formula-15,

The compound of formula-15 of the present invention is used an intermediate for the preparation of dipeptidyl peptidase IV inhibitor like sitagliptin and its pharmaceutically acceptable salts.

The sitagliptin phosphate prepared as per the present invention is either anhydrous or hydrated form.

The pharmaceutically acceptable salts of compound of formula-1 of the present invention can be prepared from the pharmaceutically acceptable non-toxic acids selected from phosphoric, acetic, benzenesulfonic benzoic, citric, fumaric, gluconic, hydrochloric, hydrobromic, lactic, maleic, malic, methane sulfonic and nitric acids.

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 compound of formula-3a:

Thionyl chloride (44 ml) was added to a solution of trifluorophenyl acetic acid in a mixture of methylene chloride (600 ml) and dimethyl formamide (6 ml), heated to reflux temperature and then stirred for 2 hours. The solvent from the reaction mixture distilled off completely under atmospheric pressure and methylene chloride (100 ml) was added to the obtained residue. This reaction mixture was added to another round bottomed flask containing mixture of meldrums acid (86 grams), methylene chloride (600 ml) and triethyl amine (106 ml) at 0-5°C then stirred for 3 hours. The temperature of the reaction mixture was adjusted to 25-35°C and stirred for 12 hours and then acidified with hydrochloric acid. The organic and aqueous layers separated, organic layer extracted with aqueous sodium hydroxide. The extracted aqueous layer was acidified and then filtered the solid formed. The obtained solid dissolved in methylene chloride. The methylene chloride from the organic layer was distilled off completely under reduced pressure to get the title compound. Yield: 130 grams

Example-2: Preparation of 4-oxo-4-[3-(trif1uoromethyl)-5,6-dihydro[l,2,4] triazolo 14,3-a]pyrazin-7(8H)-yl-1-(2,4,5-trifluoropheyl)butan-2-one compound of formula-5:
A mixture of compound of formula-3a (50 grams), acetonilrile (500 ml), isopropyl ethyl amine (75.5 ml), compound of formula-4(36 grams) and trifluoroacetic acid (36 ml) was heated to reflux temperature and stirred for 8 hours at reflux. The reaction mixture was cooled to 25-30°C, water (500 ml) and ethyl acetate was added to it then stirred for 15 min. The organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate. The solvent from ethyl acetate layer was distilled off under reduced pressure to get the title compound. Yield: 45 grams

Example-3: Preparation 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-trifluorophenyl)butan-2-en-2-amine compound of formula-6:

Ammonium acetate (22 grams) was added to a mixture of compound of formula-5 (38,5 grams) and methanol (19.25 ml). Aqueous ammonia (11.9 ml) and methanol (70 ml) was added to it and heated to reflux temperature. The reaction mixture was stirred for
5 hours at reflux and then cooled to 15-20°C then stirred for 1.5 hours at 15-20°C. The solid obtained was filtered, washed with methanol and dried to get the title compound Yield: 32.5 grams

Example-4: Preparation of racemic sitagliptin compound of formula-7:
Sodium borohydride (2.34 grams) was added to a mixture of compound of formula-6 (25 grams) in toluene at 5-10°C. Acetic acid (75 ml) was added to it and stirred for 3 hours. The reaction mixture was quenched with water and then layers were separated. The aqueous layer was basified with aqueous sodium hydroxide and then the reaction mixture extracted into methylene chloride. The extracted methylene chloride dried over sodium sulphate and then solvent from it distilled off completely to get the title compound. Yield: 24 grams

Example 5: Preparation of (-) mandelic acid salt of sitaglitpin compound of formuIa-8a:
Mixture of compound of formula-7 (8 grams), (-)-mandelic acid (2.98 grams), water (28 ml) and aqueous 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 dried to get the crystalline title compound. Yield: 2.17 grams

Example-6: Preparation of sitagliptin hydrogen phosphate monohydrate compound:
(-) mandelic acid salt of sitagliptin compound of formula-8a (3 grams) was dissolved in water (15 ml) and then basified with sodium hydroxide solution. The reaction mixture is extracted with methylene chloride (45 ml). The solvent was then distilled off completely and isopropyl alcohol (4 ml), water (1.5 ml) and phosphoric acid (0.27 ml) was added to the obtained residue. The reaction mixture was stirred for 10 minutes then heated to 75-80'°C for dissolution, cooled to 20-25°C and stirred for 12 hours. The solid formed is filtered, washed with isopropyl alcohol and dried to get the title compound. Yield: 1,8 grams

Example 7: Preparation of N-[(2Z)-piperazin-2-ylidene]trifluoroacetohydrazide compound of formula-20.

A solution of hydrazine hydrate compound of formula-16 (100 grams) in acetonitrile (500ml) was cooled to 10-15°C and then ethyltrifluoroacetate (274 grams)
was added slowly to the reaction mixture and stirred for 1.5 hours at same temperature. After the completion of the reaction, the reaction mixture was cooled to -5 to 5°C, and triethylamine (272 grams) and chloroacetyl chloride (199 grams) were added simultaneously to the reaction mixture. The reaction mixture was stirred for 3 hrs at the same temperature. After completion of the reaction, filtered the unwanted solids precipitated and washed with acetonitrile (200 ml). Distilled off the solvent form the filtrate under reduced pressure. Acetonitrile (200 ml) was added to the obtained residue at 20-30°C, stirred for 15 minutes and the reaction mixture was cooled to 0-5°C. Phosphorus oxytrichloride (220 ml) was added to the reaction mixture at 0-5°C, slowly raised the temperature to 20-25°C and then heated the reaction mixture to 80-85°C. The reaction mixture was stirred for 26 hrs at same temperature and then the reaction mixture was cooled to 25-35˚C. The reaction mixture was added to pre 0-5°C cooled aqueous methyl tertiarybutyl ether and stirred it for 45 minutes. The organic and aqueous layers were separated and aqueous layer was extracted with methyl tertiarybutyl ether. The organic layers were combined and washed with sodium bicarbonate solution followed by sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure to get 2-chloro-5-(trifluoromethyl)-l,3,4-oxadiazole compound of fonnula-19. The obtained compound of formula-19 was added to the mixture of methanol (800 ml) and ethylenediamine (284 grams) at -30 to -20°C. The reaction mixture was stirred for 4 hours at the same temperature and then raised the temperature of the reaction mixture to -10 to 5°C. The reaction mixture was stirred for 2 hours at -10 to -5°C. The solid obtained was filtered, washed with methanol and dried to get the title compound. Yield: 100 grams

Example-8: Preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo [4,3-a]pyrazine hydrochloride compound of formula-4

A mixture of N-[(2Z)-piperazin-2-ylidene]trifluoroacetohydrazide compound of formuIa-20 (50 grams) and methanol (200 ml) was heated to 50-55°C. Cone, hydrochloric acid (25 ml) was added to the reaction mixture and stirred for 3 hours same temperature. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure and cooled to 25-30''C. Acetone (50 ml) was added to the obtained residue, cooled the reaction mixture to 0-5°C and stirred for 1.5 hours at same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 42 grams; M.P: 260-264°C

Example-9: Preparation of sodium l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-2-
(2,4,5-trifluorophenyl)ethanolate compound of formula-3b

To the solution of 2,4,5-trifluro phenyl acetic acid (50 gms) in methylene chloride(200 ml) added dimethyl formamide(3 ml) and stirred for 15 minutes. Added thionyl 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 methylene chloride to the obtained compound. In another round bottom flask the solution of meldrum's actd (43 gms) dissolved in methylene chloride (200 ml) and cooled to 0-5˚C. To this reaction mixture triethylamine (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 hydroxide 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.

Exampie-10: Preparation of (2Z)-4-oxo-4-(3-(trifIuoromethyl)-5,6-dihydro[l,2,41 triazolo[4,3-a]pyrazine-7(8H)-y]]-l-(2,4,5-trif1uorophenyI)but'2-en-2-amine compound of formula-6

A mixture of sodium l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-2-(2,4,5-trifluorophenyl)ethanolate compound of formula-3a (50 grams), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[ 1,2,4] triazolo[4,3-a]pyrazine hydrochloride compound of formula-4 (33.5 grams) and acetonitrile (250 ml) was stirred for 15 minutes at 25-30°C. Methane sulphonic acid (2 ml) was added to the reaction mixture at same temperature and then heated it to 80-85˚C. The reaction mixture was stirred for 1.5 hours. After completion of the reaction, the solvent from the reaction mixture was distilled off under reduced pressure. Ethyl acetate (250 mi) followed by water (75 ml) was added to the obtained residue at 25-30°C and stirred for 20 minutes. The organic and aqueous layers were separated. The organic layer was washed with aqueous sodium bicarbonate solution followed by sodium chloride solution and dried with sodium sulphate. Distilled off the solvent from the organic layer under reduced pressure. Methanol (85 ml), ammonium
acetate (20 grams) and ammonia (10 ml) was added to the obtained residue at 20-30˚C
and then heated the reaction mixture to reflux. The reaction mixture was stirred for 4
hours at same temperature. The reaction mixture was cooled to 20-25°C and then water
(100 ml) was added to it. Stirred it for 1.5 hours at 20-25°C. The obtained solid was
filtered, washed with water and dried to get the title compound. Yield: 48 grams.

Example-11; Preparation of 7-((3R)-3-aiiiino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]-
S,6,7,8-tetrabydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-alpyra2ine mandelate compound of formula-8a

A mixture of (2Z)-4-oxo-4-[3-(trifIuoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazine-7- (8H)-yl]-l-(2,4,5-trifluorophenyI)but'2-en-2-amine (60 grams) and toluene (600 ml) was cooled to 0-5°C and then sodium borohydride (7.3 grams) was added to the reaction mixture. Acetic acid (180 ml) was added to the reaction mixture at 0-5°C and stirred it for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with water (600 ml) and separated both aqueous and organic layers. The aqueous layer was washed with toluene at l0-l5˚C. Basified the aqueous layer using sodium hydroxide solution. The reaction mixture was extracted with dichloromethane. The solvent from organic layer was distilled off under reduced pressure. Isopropyl alcohol (495 ml) and water (55 ml) were added to the obtained residue at 20-30°C and then (-)-mandelic acid (20.5 grams) was added to it. The reaction mixture was stirred for 30 minutes at 20-30°C. Then cooled it to 11-16°C and the reaction mixture was stirred for an hour at same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound. The obtained compound was recrystallized from aqueous isopropanol, to get the pure title compound. Yield: 17 grams.

Example-12: Preparation of Sitagliptin Phosphate (1:1) monohydrate compound of formula-la

A mixture of 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-I.2,4-triazolo[4,3-a]pyrazine mandelate (25 grams), water (250 ml) and dichloromethane (125 ml) was stirred for 5 minutes at 20-30°C. Basified the reaction mixture with aqueous sodium carbonate solution and stirred for 20 minutes at 20-30°C. The aqueous and organic layers were separated and the aqueous layer was extracted with dichloromethane (125 ml). Combined the both organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. Isopropyl alcohol (40 ml) and water (16 ml) was added to the obtained solid at 20-30°C and stirred for 15 minutes. The reaction mixture was filtered through hollow bed and washed with aqueous isopropyl alcohol. Orthophoshoric acid (3.2 ml) was added to the filtrate at 20-35°C and stirred for 30 minutes. Heated the reaction mixture to reflux temperature, and cooled to 55-60°C. The reaction mixture was seeding with sitagliptin phosphate monohydrate and then stirred the reaction mixture for 3 hours at 55-60°C. The above reaction mixture was cooled to 20-25'°C slowly and isopropyl alcohol (125 ml) was added to it. Stirred the reaction mixture for 2 hours at same temperature. The solid obtained was filtered, washed with aqueous isopropyl alcohol and dried to get the title compound. Yield: 22 grams

Example-13; Recovery process of 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazoIo[4,3-a] pyrazine tnandelate compound of formula-Sa from mother liquors.

The filtrate obtained in example-11 was distilled under reduced pressure and cooled to 20-30°C. Water (250 ml) and dichloromethane (100 ml) were added to the reaction mixture and then basified with sodium hydroxide solution. The aqueous and organic layers were separated. The solvent from organic layer was distilled off under reduced pressure. Isopropyl alcohol (540 ml) and water (60 ml) were added to the obtained solid at 20-25°C and stirred for 10 minutes. (+)-Mandelic acid (22 grams) was added to the reaction mixture, cooled to 11-16°C and the reaction mixture was stirred for 1 hour at same temperature. Filtered the reaction mixture and washed with isopropyl alcohol. The solvent form filtrate was distilled off under reduced pressure and the obtained compound was cooled to 20-30°C. Water (200 ml) and dichloromethane (100 ml) were added to the obtained compound and then basified with sodium hydroxide solution. The aqueous and organic layers were separated. The solvent from organic layer was distilled off under reduced pressure, Isopropyl alcohol (360 ml) and water (40 ml) were added to the obtained solid at 20-25°C and stirred for 10 minutes. (-)-maidenly acid (15 grams) was added to the reaction mixture, cooled to 11-16°C and the reaction mixture was stirred for 1 hour at same temperature. Filtered the precipitated solid, washed with
isopropyl alcohol and dried to get title compound, Recrystallized the obtained compound from mixture of isopropanol and water to get the pure title compound.

Yield: 9 grams

Example 14: Preparation of (S)-l-(2,4,5-trif1uorophenyl)pent-4-en-2-aniine:
DIBAL-H (30 ml) was added to a solution of 2-(2,4,5-trifluorophenyl)acetonitrile (5 grams) in tetrahydrofuran (50 ml) at 0°C and the reaction mixture was stirred for an hour.

The reaction mixture was added to (-)-p-allyidiisopinocamphenylborane (10 ml) in tetrahydrofuran (60 ml) and then cooled to -78˚C. Methanol (1 ml) was added to the reaction mixture and the reaction mixture was stirred for 4 hours at -78°C. After completion of the reaction, treated the reaction mixture with hydrogen peroxide followed by sodium hydroxide at -78°C and then temperature of the reaction mixture was raised to 25-30°C. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. The organic layer was treated with aqueous hydrochloric acid, stirred it for 30 minutes and then water was added to the reaction mixture. Both organic and aqueous layers were separated. The aqueous layer was washed with ethyl acetate and then neutralized the aqueous layer with sodium hydroxide solution. The reaction mixture was extracted with dichloromethane. Distilled off the solvent completely from organic layer to get the title compound. Yield: 3.96 grams

Example 15: Preparation of l-(2,4,5-trifluorophenyl)pent-4-en-2-aniine compound of formula-12;

DIBAL-H (30 ml) was added to a solution of 2-(2,4,5-trifluorophenyl)acetonitrile (5 grams) in tetrahydrofuran (50 ml) at 0°C and the reaction mixture was stirred for an hour. The reaction mixture was added to allylmagnesiumbromide (12 ml) in tetrahydrofuran (60 ml) and then cooled to -78C. Methanol (1 ml) was added to the reaction mixture and the reaction mixture was stirred for 4 hours at -78°C. After completion of the reaction, hydrogen peroxide followed by sodium hydroxide was added to the reaction mixture at -78°C and then temperature of the reaction mixture was raised to 25-30°C. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. The organic layer was treated with aqueous hydrochloric acid„ stirred it for 30 minutes and water was added to the reaction mixture. Both organic and aqueous layers were separated. The aqueous layer was washed with ethyl acetate and
then neutralized the aqueous layer with aqueous sodium hydroxide solution. The reaction mixture was extracted with dichloromethane, distilled off the solvent from organic layer and gets the title compound. Yield: 3.0 grams

Example 16: Preparation of (S)-l-(2,4,5-trifluorop]ethyl)pent-4-en-2-amme

Mixture of compound of l-(2,4,5-trifluorophenyl)pent-4-en-2-amine (4 grams), (+)-mandelic acid (2.8 grams), water (16 ml) and aqueous 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 stined for 4 hours at 5-10°C, The solid obtained was filtered, washed with isopropyl alcohol. Added water (40 ml) to the obtained compound and basified the compound using aqueous sodium carbonate solution and extracted the compound using methylene chloride. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 1.37 grams

Example 17: Preparation of (R)-3-amino-4-(2,4,5-trinuorophenyl)butanoic acid

A mixture of (S)-1 -(2,4,5-trifluorophenyl)pent-4-en-2-amine (3 grams), acetonitrile (30 ml)and water were cooled to 16°C. Sodium periodate (11 grams) was added to the reaction mixture-1 followed by ruthenium chloride (0.005 grams) hydrate at 12-20˚C. The reaction mixture was stirred for 2 hours at same temperature and then ethyl acetate was added to the reaction mixture. The obtained solid was removed from the reaction mixture by filtration. The organic layer was washed with aqueous hydrochloric acid followed by saturated sodium thiosulfate solution and brine solution. The solvent was distilled off under reduced pressure and get title compound. The obtained compound was recrystallized from hexane or hexane/ Ethylacetate and get pure title compound. Yield: 1.5 grams

We claim:

1. A process for the preparation of sitagliptin compound of formula-1 or its pharmaceutically acceptable salts, which comprises of the following steps;

a) condensing the l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-2-(2,4,5-trifIuoro-
phenyl)ethanolate derivative compound of formula-3,
Frmula-3

Wherein M=H, Na & K; 3a) M=H; 3b) M=Na; 3c)M=K

with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride compound of formula-4
Frmula-4

in presence of a suitable acid in a suitable solvent provides the condensed compound of formula-5,
Frmula-5

b) treating the condensed compound of formula-5 with ammonia source in a suitable solvent to provide the compound of fonnula-6,
Frmula-6

c) reducing the compound of formula-6 with suitable reducing agent selected from
sodium borohydride, sodium cyano borohydride, Raney Nickel, Palladium/carbon in a suitable solvent to provide the racemic sitagliptin compound of formula-?,
Frmula-7

d) resolving the racemic sitagliptin compound of formula-? with suitable chiral acid in a suitable solvent to provide corresponding acid addition salt of sitagliptin compound of formula-8,
Frmula-8

e) treating the salt compound of formula-S with suitable base followed by treatment with phosphoric acid in a suitable solvent to provide sitagliptin hydrogen phosphate compound of formula-1 a.

2. A process for the preparation of sitagliptin compound of formula-1 or its pharmaceutically acceptable salts, which comprises of the following steps;

a) condensing the sodium l-(2,2-dimethyl'4,6-dioxo-1,3-dioxan-5-ylidene)-2-(2,4,5-trifluoro-phenyl)ethanolate compound of formula-3b, with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride compound of formula-4 in presence of methane sulphonic acid in acetonitrile provides the condensed compound of formula-5,

b) treating the condensed compound of formula-5 with ammonium acetate in methanol to provide the compound of formuIa-6,

c) reducing the compound of formula-6 with sodium borohydride, sodium cyano borohydride, in toluene in presence of acetic acid provides the racemic sitagliptin compound of formuIa-7,

d) resolving the racemic sitagliptin compound of formula-7 with (-)mandelic acid in a suitable solvent to provide mandelic acid salt of sitagliptin compound of formula-8,
Frmula-8a

e) treating the salt compound of fonnula-8 with sodium carbonate in dichloromethane followed by treatment with phosphoric acid in a mixture of water/isopropanol provides sitagliptin hydrogen phosphate compound of formula-la.

3. A process for the preparation of 3-(tnfluoromethyl)-5,6,7,8-tetrahydro-
[l,2,4]triazolo[4,3-a] pyrazine hydrochloride compound of formula-4, which
comprises of;

a) Treating hydrazine hydrate compound of formula-16 with ethyltrifluoroacetate in acetonitrile to provide a product which on in-situ acylation in presence of triethyl amine followed by reaction with phosphorous oxychloride to provide 2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole compound of formula-19,

b) reacting the compound of formula-19 with ethylene diamine in methanol to provide (Z)-2,2,2-trifluoro-N'-(piperazin-2-ylidene)acetohydrazide compound of formula-20,

c) treating the compound of formula-20 with cone, hydrochloric acid in a methanol and isolating the compound in acetone to provide 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride compound of formula-4,

4. A novel process for the preparation of (Z)-aikyl-3-amino-4-(2,4,5-
trifluorophenyl)but-2-enoate compound of formula-15 which comprises of

a) Reacting the 2,4,5-trifluoro phenyl acetonitrile compound of formula-9 with a halo ester in presence of zinc in a suitable solvent provides compound of formula-14.

b) treating the compound of formula-10 with a suitable ammonia source provides (Z)-alkyl-3-amino"4-(2,4,5-tnfluorophenyI)but-2-enoate compound of formula-15

5. A novel process for the preparation of (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid compound of formula-13 which comprises of the following steps,

a) reacting the 2,4,5-trifluoro phenyl acetonitrile compound of formuIa-9 with diisobutylaluminium hydride in a suitable solvent followed by reaction with allyl magnesium halide in a suitable solvent provides l-(2,4,5-trifluorophenyI)pent-4-en-2-amine compound of formula-12.

b) resolving the compound of formula-12 with a suitable chiral acid in a suitable solvent at a suitable temperature provides (S)-l-(2,4,5-trifluorophenyl)pent-4-en-2-amine compound of formula-21.

c) oxidizing the compound of formula-21 with a suitable oxidizing agent selected
from ruthenium tri chloride in presence of sodium metaperiodate or osmium
tetroxide in presence of sodium metaperiodate, in a suitable solvent provides (R)-
3-amino-4-(2,4,5-trifluorophenyl)butanoic acid compound of formula-13.

6. A process for the preparation of sodium l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-2-(2,4,5-trifluoro phenyl)ethanolate compound of formula-3b,

which comprises the following steps,

a) Reacting the trifluorophenyl acetic acid compound of formula-2

with thinly chloride, followed by treating with meld rums acid in a suitable solvent,

b) adding aqueous sodium hydroxide solution,

c) filtering the compound to provide compound of formula-3b.

7. Use of sodium l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-2-(2,4,5-trifluoro phenyl)ethanolate compound of formula-3b for the preparation of sitagliptin or its pharmaceutically acceptable salts.

8. A process for recovery of (-)-mandelate salt of sitagliptin compound of formula-8a from the mother liquors, which comprises of the following steps.

a) Take the mother liquors obtained at step d) of claim-1, distilling off the solvent completely under reduced pressure,

b) adding polar solvent and chloro solvent to the obtained compound,

c) basifying the reaction mixture with a suitable base and separating the organic layer,

d) distilling off the solvent completely under reduced pressure,

e) adding mixture of polar solvent and alcohol solvent to the obtained,

f) adding (+)-mandelic acid to the reaction mixture, cooling down the reaction mixture,

g) filtering the precipitated solid and washing with alcohol solvent,

h) taking the filtrate and distilling off the solvent completely under reduced pressure,

i) adding mixture of polar solvent and chloro solvent to the obtained compound,

j) basifying the reaction mixture with a suitable aqueous base and separated the
organic layer,
k) distilling off the solvent completely under reduced pressure,

I) adding mixture of polar solvent and alcohol solvent to the obtained compound,

m) adding (-)-mandelic acid to the reaction mixture, cooling down the reaction mixture, n) filtering the precipitated solid and washed with alcoholic solvent, o) recrystallizing from polar solvent and alcohol solvent mixture to get the pure mandelic acid salt of sitagliptin compound of formula-8a.

9. A process for recovery of mandelate salt of sitagliptin compound of formula-8a from the mother liquors, which comprises of the following steps.

a) Take the mother liquors and distilled off the solvent completely under reduced pressure,

b) adding water and methylene chloride to the obtained compound,

c) basifying with aqueous sodium hydroxide and separated the organic layer,

d) distilling off the solvent completely under reduced pressure.

e) adding water and IPA to the obtained compound and stirred for 10 minutes,

f) adding (+)-mandelic acid to the reaction mixture, cooling down the reaction mixture to l0-l5°C and stirred for 1 hr,

g) filtering the precipitated solid and washed with IPA,

h) taking the filtrate and distilled off the solvent completely under reduced pressure,

i) adding water and methylene chloride to the obtained compound,

j) basifying with aqueous sodium hydroxide and separated the organic layer,

k) distilling off the solvent completely under reduced pressure,

1) adding water and IPA to the obtained compound and stirred for 10 minutes,

m) adding (-)-mandelic acid to the reaction mixture, cooling down the reaction mixture
to 10-15°C and stirred for 1 hr,

n) filtering the precipitated solid and washed with IPA,

o) recrystallizing from water/IPA mixture to get the pure title compound.

10. The compound having following structural formula