FIELD OF THE INVENTION:
The present invention relates to cost-effective and industrial feasible purification process for l-(3-(trifluoromethyl)-5)6-dihydro-[ls2)4]triazolo[4,3-a]pyra2in-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione.
BACKGROUND OF THE INVENTION:
Sitagliptin, 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 phosphate of formula-1, is dipeptidyl peptidase-4 inhibitor class and used for treatment of diabetes mellitus type-2.
Sitagliptin is white, crystalline, slightly hygroscopic solid.
US 6699871 discloses class of beta-amino tetrahydrotriazolo [4,3-a] pyrazines. It also describes process for preparation of sitagliptin or a salt thereof comprises coupling of (3R)-3-[N-(tert- butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid with 3-trifluoromethyl-S^JjS-tetrahydro-tl^^Jtriazolo^^-aJpyrazine hydrochloride to afford Boc-protected Sitagliptin, which was deprotected using methanolic hydrochloride to obtain Sitagliptin hydrochloride.
The process is given below scheme.

WO2006081151 describes a process for preparation of Sitagliptin via enamine compound which is reduced by employing a rhodium metal precursor complexed to a ferrocenyl diphosphine ligand, followed by treatment with phosphoric acid to obtain Sitagliptin phosphate.
WO2009064476 describes process for preparing sitagliptin comprises reacting (R)-3-(t-butoxycarbonylamino)-4-(234,5-trifluorophenyl)butanoic acid with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride in the presence of N,N'-dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine(DMAP)3 and triethylamine in dimethylformamide to give sitagliptin.
WO 2005097733 discloses the process of asymmetric hydrogenation is carried out in the presence of a rhodium metal precursor complexed with a chiral mono- or biphosphine ligand.
Most of the prior art process involves use of costly metal catalyst makes process uneconomical. Further tedious workups make process more complex at industrial scale. The major disadvantages of above said processes are using hazardous chemicals such as butyl lithium, diazomethane and silver benzoate. Moreover, the processess involves multiple step synthesis which results in lower yield.
It is required to develop cost-effective and safe process for purification of l-(3-
(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-
trifluorophenyl)butane-l,3-dione.

The present invention provides economical, safe and industrially feasible process for purification of 1 -(3-(trifluoromethyl)-5,6-dihydro-[ 1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-1,3-dione.
OBJECT OF THE PRESENT INVENTION:
(1) The main object of the present invention is that the purification process is improved which results in high purity of the product as compare to prior art process.
(2) The other object of the present invention is that the improved purification process is applicable at commercial scale and easy to operate.
(3) Another object of the present invention is that the present invention process reduces atom economy and environment friendly.
SUMMARY OF THE INVENTION:
The present invention relates to easy, safe and commercially viable process for purification of l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyra2in-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione of formula-2
One embodiment of the present invention provides purification process for l-(3-(trifluoromethyl)-5]6-dihydro-[l,234]triazolo[4)3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione.
One another embodiment of the present invention is provides process for preparing l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione.
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to improved, robust and effective purification process for l-(3-(trifluoromethyl)-5)6-dihydro-[l52J4]triazolo[4)3-a]pyrazin-7(8H)-yl)-4-(2,4)5-trifluorophenyl)butane-1,3-dione of formula-2
One aspect of the present invention provides purification process for l-(3-(trif!uoromethyl)-S^-dihydro-tl^^triazolo^^-aJpyrazin-TCSH)^!)^^^^- trifluorophenyl)butane-l,3-dione comprises;
(a) dissolving crude l-(3-(trifluoromethyl)-5,6-dihydro-[l32)4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-l,3-dione into solvent
(b) adding solvent and stirred the solution
(c) isolating pure l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4}3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-l ,3-dione.
The solvent used for step (a) and (b) is selected from the group consisting of isopropyl acetate, n-heptane, ethyl acetate, cyclohexane, n-hexane, hexane or mixture thereof.
The temperature for said process is ambient temperature.

One aspect of the present invention is provides process for preparing l-(3-(trifluoromethyl)-5,6-dihydro-[l,2J4]triazoto[4,3-a]pyrazin-7(8H)-yl)-4-(2,4)5- trifluorophenyl)butane-l,3- , dione of formula-2 comprises;
(a) reacting. 2,4,5-trifluorophenyl acetic acid with MeLdrum acid in presence of an acid activating agent, solvent and base to obtain
(b) adding acid to reaction mixture
(c) isolating l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-
(2,4,5- trifluorophenyl)butane-1,3-dione
The acid activating agent for step (a) is selected from the group consisting of 1,1'-
carbonyldiimidazole, 1,1 '-thiocarbonyldiimidazole, tri methyl acetyl (pi valoyl) chloride,
isovaleryl chloride, oxalyl chloride, phosphorus pentachloride, isobutyl chloroformate ,
diethylcyanophosphate, diethylchlorophosphate.
The solvent for step (a) is selected from the group consisting of THF, dimethoxymethane,
DME, DMF, DMAc,.NMP, DMSO, IP Ac, EtOAc, MTBE, toluene, MeCN or mixture
thereof.
The base for the step (a) is selected from the group consisting of triethylamine, N,N-
diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, NN-
dimethylaniline, DMAP, DABCO, DBU, diethylmethylamine, di-isobutylethylamine, n-
butylethylamine, n-propylethylamine.
The present invention provides improved process for purification of l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyI)butane-l,3-dione which results in high purity with good yield. In present invention, before purification the purity of -(3-(trifluoromethyl)-5,6-dihydro-[l)2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-

(2,4,5- trifluorophenyl)butane-l,3-dione was 98.94% with any unknown impurity 0.55%. Whereas, with improved purification process the purity of -(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-l,3-dione results in 99.92% with reduced any unknown impurity 0.08%. Hence, the present invention provides high purity with good yield makes the invention robust, effective and economical.
The following examples explain various other embodiments without limiting the scope of the present invention.
Example-1: Purification of l-(3-(trifluoromethyI)-5,6-dihydro-[l,2,41triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-l,3-dione
To a solution of IPAc (16 L) and SM (16 Kg) was stirred initially at room temperature for 30
min and 60 - 65 6C for 1 h. The reaction mixture was slowly cooled to 40 - 50 oC and n-
Hepatane (16 L) was added and stir for 30 min. The reaction mixture was further cooled to 25
- 30 oC and n-Hepatane (16 L) was added and stirred at room temperature for 1 h. The
resultant slurry was filtered and repeat above operation twice, followed by dried to yielded
pure l-(3-(trifluorbmethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-
trifluorophenyl)butane-1,3-dione. HPLC purity: 99.92% A [Any unknown impurity < 0.1 %]
Example-2: Preparation of l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-l,3-dione
In a clean RBF, 2,4,5-trifluorophenyl acetic "acid, Meldrum acid, DMAP and DIPEA dissolved in DMAc. Slowly added pivaloyl chloride over 1-2 hrs at room temperature, followed by heated the mass at 45-65°C for 2 - 4 h. The progress of reaction checked by TLC/HPLC. After completion of reaction, triazole hydrochloride was added and followed by drop wise addition of Trifluoroacetic acid at below 60°C. The reaction mass maintained at 45- 60 °C for 7 - 8 h. Then, 5% sodium bicarbonate solution added dropwise over 1 - 2 h at 20 - 40 °C. Additional 5% sodium bicarbonate solution added over 2 - 3 h and cooled the mass at 0 - 10 °C, stirred for 1 h. Filtered the slurry and washed with water to get l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2J4,5-trifluorophenyl)butane-l,3-dione.

Claims:
(1) An improved purification process for l-(3-(trifluoromethyl)-5,6-dihydro-
[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-l,3-dione of
formula-2 comprises;
(a) dissolving crude l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-l,3-dione into solvent
(b) adding solvent and stirred the solution at preferred temperature
(c) isolating pure l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-1,3-dione.
(2) The process according to claim 1, wherein the solvents for (a) and (b) are selected from
the group consisting of isopropyl acetate, n-heptane, ethyl acetate, cyclohexane, n-hexane,
hexane or mixture thereof.
(3) The process according to claim 1, wherein the preferred temperature is ambient
temperature.
(4) An advantageous process for preparing l-(3-(trifluoromethyl)-5,6-dihydro-
[ 1,254]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2)4,5- trifluorophenyl)butane-1,3-dione of
formula-2 comprises;

Formula-2
(a) reacting 2,4,5-trifluorophenyl acetic acid with Meldrum acid in presence of an acid activating agent, solvent and base to obtain
(b)'adding acid to reaction mixture
(c) isolating l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)butane-l,3-dione
(5) The process according to claim 4, wherein the acid activating agent is selected from the group consisting of l,r-carbonyldiimidazole, 13 l'-thiocarbonyldiimidazole, trimethylacetyl (pivaloyl) chloride, isovaleryl chloride, oxalyl chloride, phosphorus pentachloride, isobutyl chloroformate , diethylcyanophosphate, diethylchlorophosphate.
(6) The process according to claim 4, wherein the solvent is selected from the group consisting of THF, dimethoxymethane, DME, DMF, DMAc, NMP, DMSO, IP Ac, EtOAc, MTBE, toluene, MeCN or mixture thereof.
(7) The process according to claim 5, wherein the base is selected from the group consisting of triethylamine, N3N-diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, NN-dimethylaniline, DMAP, DABCO, DBU, diethylmethylamine, di-isobutylethylamine, n-butylethylamine, n-propylethylamine.
(8) The process according to claim 1, wherein the HPLC purity is 99.92 % with reduced any unknown impurity < 0.1 %.