DESC:FIELD OF THE INVENTION
The present application provides a novel and cost effective process for the preparation of Sitagliptin intermediate (3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride) which is suitable to manufacture in commercial scale.

BACKGROUND OF THE INVENTION
Dipeptidyl peptidase 4 (DPP-4 inhibitors) inhibitors are generally called as gliptins a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4) and used to treat diabetes mellitus type 2. Sitagliptin, is an anti-diabetic medication used to treat type 2 diabetes, which is safe and most potent gliptin in DPP-4 class of inhibitors. FDA approved Sitagliptin 2006, Merck sold under the brand name JANUVIA (Sitagliptin alone) and JANUMET (Sitagliptin /Metformin-Fixed dose combination). Sitagliptin having the IUPAC name (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine and has the following chemical structure.

The triazolo intermediate having IUPAC name 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride plays a major role in the process for the preparation of Sitagliptin. The intermediate has the following structure with CAS no: 762240-92-6

US 6699871 discloses the below processes for the preparation of Sitagliptin triazolo intermediate. The process involves the costly raw materials like 2- chloropyrazine and
2,3-Dichloropyrazine. The process mainly uses polyphosphoric acid at elevated temperatures for cyclization, reducing agents like palladium and Platinum. So, the process is not commercially viable and not environment eco-friendly.

US 7468459 discloses the below process for the preparation of Sitagliptin triazolo intermediate. The process involves hydrazine reacts with trifluoroacetic acid and chloro acetyl chloride which gives substituted acetyl substituted hydrazide which undergoes dehydrative cyclization in presence of POCl3 at higher temperature gives substituted oxadiazole. Oxadiazole derivative further reacts with ethylenediamine transforms to substituted pyrazine derivative which finally undergoes cyclization in presence of acid gives the corresponding Sitagliptin intermediate.

The main disadvantages of the process are, in stage 1 after completion of the reaction, lot of acetonitrile (nearly 60 volumes) was used to remove the water which is present in hydrazine and ethanol the by-product formed in stage 1. The inventors of the present application are observed formation of dihydrazide impurity (2,2,2-trifluoro-N'-(2,2,2-trifluoroacetyl)acetohydrazide) if we try to distil the ethanol and water at higher temperatures. In stage 2 POCl3 was used for dehydrative cyclization and the obtained yield are only 72%. So, the process was commercially not viable to produce the corresponding intermediate in tonnage levels.

Organic Process Research & Development 2005, 9, 634-639 discloses the below process for the preparation of Sitagliptin triazolo intermediate. The process involves hazardous reagents like superphosphoric acid for cyclization and metal reagents like Pd/C which is not eco-friendly for reduction and gives overall yield of 51%, which is not a commercially viable process.

CN101973997 B patent discloses the below process for the preparation of Sitagliptin triazolo intermediate. The process involves piperazin-2-one reacts with Lawessons reagent to form piperazine-2-thione, which further reacts with trifluorohydrazide to form corresponding intermediate. The disadvantage of the below process is Lawessons is not eco-friendly reagent and lot hypochlorite solution is required to destroy the foul smell. Apart from this preparation of starting material 2-Oxopiperazine obtains in very low yields and the overall conversion yields are low.

Therefore, still there is need for the development of commercially viable, eco-friendly, and cost-effective process for the preparation of Sitagliptin triazolo intermediate.

SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of Sitagliptin intermediate of formula (I) which is cost effective and suitable for industrial production.
In an aspect the present application provides a process for preparation of compound of formula I

formula (I)
which comprises
a) hydrazine hydrate reacts with ethyl trifluoroacetate to form compound of formula (II); wherein the compound of formula II is not isolated;

formula (II)
b) reacting compound of formula (II) with chloroacetyl chloride in presence of base and solvent to form compound of formula (III); wherein the solvents are selected from DCM, Chloroform, acetonitrile, MTBE, ethanol, methanol, THF and 2-methy THF and the bases are selected from Na2CO3, K2CO3, NaHCO3, NaOH or KOH to form compound of formula (III);

formula (III)
c) compound of formula (III) undergoes dehydrative cyclization in presence of stronger acidic reagents like Oleum or Conc. H2SO4 to form compound of formula (IV);

formula (IV)
d) reacting compound of formula (IV) with ethylene diamine in suitable solvent at lower temperature to form compound of formula (V);

formula (IV)
e) compound of formula (V) undergoes cyclization in presence of acid in suitable solvent to form compound of formula (I);

formula (I)
f) optionally purifying the compound of formula (I) in a suitable solvent.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment the present invention particularly describes process for the preparation of Sitagliptin intermediate compound of formula (I)

Formula (I)
In another embodiment the following scheme (A) describe the process for the preparation of Sitagliptin intermediate compound of formula (I).
Scheme (A)

In another embodiment stage (a) of the present process involves, ethyl trifluoro acetate reacts with hydrazine hydrate in presence of solvents like DCM, Chloroform, MTBE, ethanol, methanol, THF and 2-methy THF and the bases are selected from Na2CO3, K2CO3, NaHCO3, NaOH or KOH to form trifluorohydrazide in situ it reacts with chloroacetyl chloride in presence of bases like Na2CO3, K2CO3, NaHCO3, NaOH or KOH to form N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide. The formation of below mentioned di hydrazide impurity ((2,2,2-trifluoro-N'-(2,2,2-trifluoroacetyl) acetohydrazide)) is drastically reduced.

(Impurity)
In another embodiment stage (b) of the present process involves, dehydrative cyclization of N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide happens with oleum or Conc.H2SO4 at 60-700C forms 2,5 di substituted oxadiazole in higher yields with purity. The oleum used for dehydrative cyclization is 23% oleum or 65 % oleum.

In another embodiment the inventors of the present application found that oleum is working as best dehydrative cyclizing agent compared to POCl3 in terms of getting yield and pure compound of 2,5 di substituted oxadiazole.

In another embodiment stage (c) of the present process involves, 2,5-disubstituted-1,3,4-oxadiazole compound of formula (IV) reacts with ethylene diamine in presence of suitable solvents at lower temperatures to form trifluorohydrazide substituted piperazine compound of formula (V); wherein the suitable solvent is selected from methanol, ethanol, propanol, isopropanol, or n-butanol; wherein the suitable lower temperature is -40 0C to 0 0C.

In another embodiment stage (d) of the present process involves, cyclization of trifluorohydrazide substituted piperazine compound of formula (V) to sitagliptin intermediate compound of formula (I) in presence of an acid and a suitable solvent at favourable temperature; wherein the acid is selected from aq HCl, methanolic HCl, ethanolic HCl, IPA.HCl or gaseous HCl and the solvents are methanol, ethanol, propanol, isopropanol di isopropyl ether or MTBE; wherein the favourable temperature is 40 0C. to 55 0C.

In another embodiment Sitagliptin intermediate compound of formula (I) is optionally purified by using a suitable solvent; wherein the suitable solvent is selected form diethyl ether, methyl tertiary butyl ether, acetone, cyclohexane, ethyl acetate, acetonitrile, ethanol, methanol, hexane, water, or mixtures thereof.

In another embodiment the below are the abbreviations are used in the specification.
THF-Tetrahydrofuran, DCM- Dichloromethane, MTBE-Methyl tertiary butyl ether, Na2CO3-Sodium carbonate, K2CO3-potassium carbonate, KOH-potassium hydroxide, NaOH- sodium hydroxide, NaHCO3-Sodium bicarbonate, HCl- Hydrochloric acid, g- Grams, mL-millilitres, °C- degrees centigrade, Eq-Equivalent, HCl-Hydrochloric acid, Na2SO4-Sodium Sulphate, IPA- Isopropyl alcohol, TLC-Thin layer Chromatography, and HPLC-High performance Liquid Chromatography.

EXAMPLES
Example 1
Preparation of N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide:

Method 1:
To s solution of 80% Hydrazine hydrate (46 gm, 1.25 eq) in MTBE (400 mL) was added ethyl trifluoroacetate (100 gm, 1 eq) at 0 0C. Maintain the reaction at the same temperature for 2 hrs. The progress of the reaction was monitored by TLC, after completion of the reaction at the same temperature chloroacetyl chloride (100 gm, 0.95 eq), and sodium carbonate (46 gm, 0.5 eq), were added lot wise simultaneously. The reaction was maintained at the same temperature for 2 hrs. The progress of the reaction was monitored by TLC, after the completion of the reaction the temperature of the reaction was raised to 25-30 0C and maintain at the same temperature for 1 hr. The reaction mass was filtered to remove the formed side product sodium chloride. The filtrate was washed with brine solution (200 mL). The organic layer was dried over Na2SO4 concentrated under reduced pressure to obtain the crude product. The crude product was triturated with dichlromethane or hexane to obtain the pure desired product (142 gm, 98.6% HPLC purity-98%).
Example 2:
Preparation of 2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole

Method 1:
To 25% oleum (100mL, 1 Volume) at a temperature 25 – 35 0C was added N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide (100 gm) portion wise. The reaction mass was heated to 70-75 0C. The reaction was maintained at same temperature for 48 hrs. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass poured portion wise into a mixture of crushed ice and dichloromethane (400 mL). The organic layer was separated dried over Na2SO4 and concentrated under vacuum to obtain the desired product. (77g, Yield: 85% HPLC purity: 98%)
Method 2:
To 25% oleum (200 mL, 2 Volumes) at a temperature 25 – 35 0C was added N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide (100 gm) portion wise. The reaction mass was heated to 70-75 0C. The reaction was maintained at same temperature for 48 hrs. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass poured portion wise into a mixture of crushed ice and dichloromethane (400 mL). The organic layer was separated dried over Na2SO4 and concentrated under vacuum to obtain the desired product. (79g, Yield: 87% HPLC purity: 98.3%).
Method 3:
To 25% oleum (300 mL, 3 Volumes) at a temperature 25 – 35 0C was added N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide (100 gm) portion wise. The reaction mass was heated to 70-75 0C. The reaction was maintained at same temperature for 48 hrs. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass poured portion wise into a mixture of crushed ice and dichloromethane (400 mL). The organic layer was separated dried over Na2SO4 and concentrated under vacuum to obtain the desired product. (87g, Yield: 95% HPLC purity: 98.7%).
Method 4:
To 25% oleum (400 mL, 4 Volumes) at a temperature 25 – 35 0C was added N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide (100 gm) portion wise. The reaction mass was heated to 70-75 0C. The reaction was maintained at same temperature for 48 hrs. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass poured portion wise into a mixture of crushed ice and dichloromethane (400 mL). The organic layer was separated dried over Na2SO4 and concentrated under vacuum to obtain the desired product. (87.6g, Yield: 95% HPLC purity: 98.2%).

Example 3
Preparation of Trifluoroacetic acid(2Z)-piperazinylidenehydrazide

Method-1:
To solution of ethylenediamine (91 gm, 2.8 eq) in 1000 mL methanol at -20 0C was added 2-(Chloromethyl)-5-(trifluromethyl)-1,3,4-oxadiazole (100 g, 1.0 eq). The reaction was maintained at same temperature for 1 hr. To the reaction mass 1000 mL of methanol were then charged, and the reaction mass was slowly warmed to -5 0C. The reaction was maintained at -5 0C for 1 hr. The reaction mass was filtered at -50C. The solid was collected to obtain Trifluoroacetic acid(2Z)-piperazinylidenehydrazide. The wet material proceeded as such for the next step (110.5 gm, 97.7% yield and purity by HPLC 99.5%.

Method-2:
To solution of ethylenediamine (65 gm, 2 eq) in 1000 mL methanol at -20 0C was added 2-(Chloromethyl)-5-(trifluromethyl)-1,3,4-oxadiazole (100 g, 1.0 eq). The reaction was maintained at same temperature for 1 hr. To the reaction mass 1000 mL of methanol were then charged, and the reaction mass was slowly warmed to -5 0C. The reaction was maintained at -5 0C for 1 hr. The reaction mass was filtered at -50C. The solid was collected to obtain Trifluoroacetic acid(2Z)-piperazinylidenehydrazide. The wet material proceeded as such for the next step (110 gm, 97% yield and purity by HPLC 99.5%.

Method-3:
To a solution of ethylenediamine (39 gm, 1.2 eq) in 1000 mL methanol at -20 0C was added 2-(Chloromethyl)-5-(trifluromethyl)-1,3,4-oxadiazole (100 g, 1.0 eq). The reaction was maintained at same temperature for 1 hr. To the reaction mass 1000 mL of methanol were then charged, and the reaction mass was slowly warmed to -5 0C. The reaction was maintained at -5 0C for 1 hr. The reaction mass was filtered at -50C. The solid was collected to obtain Trifluoroacetic acid(2Z)-piperazinylidenehydrazide. The wet material proceeded as such for the next step (108 gm, 95% yield and purity by HPLC 99.5%.
Example 4:
Preparation of 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazole[4,3-a]pyrazine hydrochloride:

To a solution of Trifluoroacetic acid(2Z)-piperazinylidenehydrazide (100 gm, 1 eq) in isopropyl alcohol (300 mL) and was added 20% IPA. HCl (100 g) for a period of 1 hr. The reaction mass was heated to 60-70 0C and maintained at same temperature for 3 hr. The reaction mass was cooled to 0 to 50C. The reaction mass was filtered to obtain 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazole[4,3-a]pyrazine hydrochloride 101 gm, yield 93.5% and purity by HPLC 99.9%, M.P:264 0C.
,CLAIMS:1. A process for the preparation of compound of formula (I)

formula (I)
which comprises
a) hydrazine hydrate reacts with ethyl trifluoroacetate to form compound of formula (II); wherein the compound of formula II was not isolated;

formula (II)
b) reacting compound of formula (II) with chloroacetyl chloride in presence of base and solvent to form compound of formula (III); wherein the solvents are selected from DCM, Chloroform, acetonitrile, MTBE, ethanol, methanol, THF and 2-methy THF and the bases are selected from Na2CO3, K2CO3, NaHCO3, NaOH or KOH to form compound of formula (III);

formula (III)
c) compound of formula (III) undergoes dehydrative cyclization in presence of stronger acidic reagents like Oleum or Conc. H2SO4 to form compound of formula (IV);

formula (IV)
d) reacting compound of formula (IV) with ethylene diamine in suitable solvent at lower temperature to form compound of formula (V);

formula (IV)
e) compound of formula (V) undergoes cyclization in presence of acid in suitable solvent to form compound of formula (I);

formula (I)
f) optionally purifying the compound of formula (I) in a suitable solvent.

2. A process for the preparation of compound of formula (IV)

which comprises compound of formula (III) undergoes dehydrative cyclization in presence of oleum or conc. H2SO4.

3. The process as claimed in claim 2, the said oleum is either 25% or 65%.

4. The process as claimed in claim 1, wherein the solvent is selected from DCM, Chloroform, acetonitrile, MTBE, ethanol, methanol, THF and 2-methy THF or mixture thereof.

5. The process as claimed in claim 1, wherein the base selected from Na2CO3, K2CO3, NaHCO3, NaOH or KOH or mixture thereof.

6. The process as claimed in claim 2, wherein the dehydrative cyclization reagent is selected from oleum or conc. H2SO4 or mixture thereof.