DESC:Field of the Invention
The present invention relates to an improved process for the preparation of sitagliptin and intermediates thereof.

Background of the Invention
(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, generically known as Sitagliptin, belongs to therapeutic class of dipeptidyl 4-peptidase inhibitors and globally marketed under the tradename Januvia® for the treatment of diabetes mellitus.
Sitagliptin, structurally represented as Formula (A),

was first reported and disclosed in the US Patent No. 6,699,871 and its marketed dihydrogen phosphate salt was disclosed in the US Patent No. 7,326,708.

The process for preparing sitagliptin disclosed in the ‘871 patent involves coupling of (3R)-3-[1,1-dimethylethoxycarbonylamino]-4-(2,4,5)-trifluorophenyl)-butanoic acid (BOC acid) with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a] pyrazine hydrochloride in presence of hydroxybenzotriazole (HOBt) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) in methylene dichloride (MDC). BOC sitagliptin thus obtained was converted to sitagliptin using methanolic HCl.

Patent applications WO2009064476, IN338/CHE/2012, WO2015114657 disclose the de-protection of protected sitagliptin in iso-propyl alcohol solvent. The BOC sitagliptin was dissolved at 40°C- 60°C and treated with concentrated HCl to form sitagliptin hydrochloride.

BOC sitagliptin (BOC protected sitagliptin) is not soluble in alcoholic solvent and hence the reaction of deprotection of tert-butoxy carbonyl is carried out at higher temperature 40°C-60°C. At higher temperature, the BOC sitagliptin is solubilized and de-protected efficiently. However, it was observed that at higher temperature the molecule hydrolyzed and converted to deprotected BOC acid and pyrazine hydrochloride and hence there was yield loss as well as deterioration in quality. A repeated purification was required to get desired quality.

IN293562 discloses coupling of (3R)-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazole[4,3-a] pyrazine in presence of dicyclohexyl carbodiimide (DCC) and 1-hydroxybenzotriazole in methylene chloride (MDC) at room temperature. The reaction was carried out in presence of diisopropylethylamine. As mentioned in the patent itself, the time required for completion of reaction was 15-16 hours. Thus, the process was troublesome at commercial scale. The use of chlorinated solvent MDC is not suitable with DCC. DCC is lachrymatic and solution of DCC in MDC causes severe problems in large scale operations due to high vapor pressure of MDC.

Also, another problem associated with the process is that the carbodiimide used in the reaction acts as dehydrating agent. The carbodiimide itself gets hydrated to form urea impurity which is carried over in the further steps in final product if not removed at this stage.

Dicyclohexyl carbodiimide used in the reaction is converted to dicyclohexylurea (DCU) impurity, which is nearly insoluble in most organic solvents and insoluble in water. Majority of the DCU is removed by filtration, although it is very difficult to remove last traces that are carried over in the next steps for preparation of sitagliptin and salts thereof. Although the traces of DCU in the final API are not detectable, if present solubility issue is observed in final API.

Thus, there is a need for an improved process for synthesis of sitagliptin, which is scalable, environmentally safe and provides higher yield with better purity.

Summary of the invention
An aspect of the present invention relates to a process for preparation of sitagliptin (Formula (A)) and salts thereof. The process comprises reacting a compound of Formula (I) with a first acid and a substituted alcohol having electron withdrawing groups.

Another aspect of the invention relates to a process for preparation of compound of Formula (I). The process comprises reacting (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (BOC acid) of Formula (II) with triazolopyrazine compound of Formula (III), in presence of dicyclohexylcarbodimide (DCC), hydroxybenzotriazole (HOBt) and an organic base in a solvent.

Detailed Description of the Invention
In an aspect, the present invention relates to a process for preparation of salt of sitagliptin (Formula (A)). The process comprises reacting a compound of Formula (I) with a first acid and a substituted alcohol having electron withdrawing groups (also referred as “substituted alcohol”).

The reaction is carried out by solubilizing the compound of Formula (I) in the substituted alcohol and then adding the first acid. The reaction results in de-protection of compound of Formula (I).

The substituted alcohol is selected from 2-chloroethanol, 2,2-dichloroethanol, 2,2,2-trichloroethanol, 2-fluoroethanol, 2,2-difluoroethanol, 2,2,2-trifluroethanol, 2-nitroethanol, 3-hydroxy propionitrile and mixture thereof.

The first acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, hydro bromic acid, trifluoroacetic acid, trichloroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, benzenesulfonic acid, nitric acid, hydroiodic acid, lactic acid citric acid and combination thereof.

The process is carried out at ambient temperature. Optionally, the solution can be heated at a low temperature.

The substituted alcohol described above enhances the solubility of compound of Formula (I) at ambient temperature. An enhanced solubility of the compound of Formula (I) aids in complete utilization of the compound of Formula (I) in the reaction, thus leading to an enhanced yield of sitagliptin.

In an embodiment, the invention relates to a process for preparation of sitagliptin base. The process comprises de-protection of compound of Formula (I), in presence of a first acid in a substituted alcohol to form salt of sitagliptin. The reaction is carried out at ambient temperature. Further, the reaction mixture is diluted by addition of water, treated with an alkali and the pH of the reaction mixture is adjusted to be in a range of 10.0 to 11.0 to form sitagliptin base. The sitagliptin base is extracted with an organic solvent.

The first acid and substituted alcohol are described above.

The alkali is an inorganic base and is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and combination thereof. The alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide; alkali metal alkoxide is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide; alkali metal carbonate is selected from sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonates is selected from sodium bicarbonate, potassium bicarbonate, and combination thereof.

In the aforesaid process, the compound of Formula (I) is treated with the substituted alcohol and the temperature of the solution is raised if required to dissolve compound of Formula (I) completely. The reaction mixture is filtered to remove any undissolved matter. The first acid is added to the filtrate and the mixture is stirred at ambient temperature for sufficient time for completion of the reaction to form salt of sitagliptin. The reaction mixture is diluted by at least 3-4 volumes of water and filtered. Then, the alkali is added or charged to the reaction mass (filtrate) and the pH is adjusted to be in a range of 10.0 to 11.0 to form sitagliptin base.

Sitagliptin base obtained in the process as described above is extracted with an organic solvent. The organic solvent is selected from an organic ester or organic chlorinated solvent. The organic solvent is selected from methylene dichloride (MDC), ethylene dichloride (EDC), chloroform, carbon tetrachloride, isopropyl acetate, ethyl acetate and mixture thereof. Preferably, the solvent for extraction is MDC. The organic layer obtained after solvent extraction step is distilled off and sitagliptin base is isolated with higher purity.

The isolated sitagliptin base can be further converted to a salt by reacting with a second acid.

Alternatively, sitagliptin salt can also be formed directly without isolation of sitagliptin base by treating the organic layer obtained after solvent extraction process with the second acid.

The second acid is selected from hydrochloric acid, phosphoric acid, maleic acid, fumaric acid, acetic acid, succinic acid, benzene sulfonic acid, D-tartaric acid, L-tartaric acid, DL-tartaric acid methanesulfonic acid, L-malic acid, D-malic acid , (R)-(-) mandelic acid, (S)- (+) mandelic acid, adipic acid, lactic acid, glycolic acid, citric acid, oxalic acid, (S)-(+) O-acetyl mandelic acid, isonicotinic acid, 4-methylsalicylic acid, salicylic acid, myristic acid, orotic acid, isophthalic acid, gentisic acid, butenedioic acid, p-toluenesulfonic acid, (1S)- (+)-camphorsulfonic acid, benzoic acid, hydrobromide, di-p-tolyl-L-tartaric acid, di-p-tolyl-D-tartaric acid, di-p-tolyl-DL-tartaric acid, pyroglutamic acid, glutaric acid, L-aspartic acid, D-gluconic acid, galactaric acid, ethanesulfonic acid, malonic acid, carpric acid, 1-hydroxy naphthoic acid, D-glucronic acid, quinic acid, formic acid, nicotinic acid, picolinic acid, cinnamic acid, nitric acid, trifluoromethanesulfonic acid, boric acid, trifluoroacetic acid, caffeic acid, ferulic acid, coumaric acid, (R)-(+)-1,2-dithiolane-3-pentanoic acid, (S)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid, isethionic acid, thioglycolic acid, or naphthalenesulfonic acid.

In another aspect, the invention relates to a process for preparation of compound of Formula (I). The process comprises coupling reaction of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (BOC acid) of Formula (II) with triazolopyrazine compound of Formula (III), in presence of dicyclohexylcarbodimide (DCC), hydroxybenzotriazole (HOBt), and an organic base in a solvent.

DCC is present in an amount of 1.1-1.5 mol equivalent of compound of Formula (III). The organic base is selected from di-isopropyl ethylamine (DIPEA), triethylamine (TEA) and the like and combination thereof.

The solvent is selected from dimethylformamide, dimethyl sulphoxide, N-methyl pyrrolidone, methylene dichloride, acetonitrile and ethereal solvents like diethyl ether, diiospropyl ether, diglyme, monoglyme, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, cylopentyl methyl ether, dimethoxy methane, methyl tertiary butyl ether, ethyl tertiary butyl ether tetrahydropyran, morpholine toluene and mixture thereof. The solvent preferably is toluene. The reaction is completed within 1-2 hours with a higher yield of compound of Formula (I).

DCC used is in molar excess in the coupling reaction and hence the time required for the completion of the reaction is considerably reduced. The isolated compound of Formula (I) contains dicyclohexyl urea impurity, however it is removed completely by filtration.

The process of the present invention enhances the yield of intermediates of sitagliptin while completely eliminating the impurity due to carbodiimide and also gets completed in a short duration of time. As methylene dichloride is not used as a solvent with carbodiimide in the preparation of compound of Formula (I), the process is carried out safely.

The process also enhances the solubility of intermediates of sitagliptin thereby increasing yield of sitagliptin. As the process to prepare sitagliptin is carried out at ambient temperature there is no degradation of the Formula (I). As the process is simple and processing time is short, the process can be easily scaled up.

In a preferred embodiment, the process for preparing sitagliptin and salts thereof comprises a coupling reaction (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (BOC acid) of Formula (II) with triazolopyrazine compound of Formula (III), in presence of DCC (1.0-1.4 mol equivalent), hydroxybenzotriazole (HOBt) and an organic base in a solvent to form compound of Formula (I). The compound of Formula (I) is isolated and then solubilized or dissolved in a substituted alcohol. The solution is filtered and concentrated hydrochloric acid (first acid) is charged to the filtrate to deprotect compound of Formula (I) to form salt of sitagliptin (Formula (A)). Subsequently, the reaction mixture is diluted by adding at least 3-4 volumes of water, followed by filtration of the mixture. The pH of the filtrate is adjusted in a range of 10.0 to 11.0 by addition of an alkali to form sitagliptin base. Subsequently, the sitagliptin base is extracted by solvent extraction using a suitable organic solvent selected from an organic ester or organic chlorinated solvent. The sitagliptin base so obtained is either isolated or converted into a salt by reacting it with a second acid.

In this embodiment, DCC used in the coupling reaction, is in molar excess and hence the time required for the completion of the reaction is considerably reduced. Organic base used in the coupling reaction is selected from di-isopropyl ethylamine (DIPEA), triethylamine (TEA) and the like and combination thereof. The isolated compound of Formula (I) contains dicyclohexyl urea impurity, however it is removed completely in the next steps. The compound of Formula (I) is soluble in the substituted alcohol at room or ambient temperature. However, dicyclohexylurea impurity being insoluble in the substituted alcohol is removed by filtration. After completion of the de-protection reaction, the sitagliptin formed is further converted to sitagliptin hydrochloride simultaneously in-situ. Water added during dilution of the reaction mixture solubilizes sitagliptin hydrochloride. Dicyclohexyl urea being insoluble in water, thus all the remaining traces are completely removed by filtration. The pH of the filtrate is adjusted to 10.0-11.0 by the alkali to precipitate out sitagliptin base which is extracted with the organic solvent. The organic solvent is preferably selected from methylene dichloride, ethylene dichloride, chloroform carbon tetrachloride, ethyl acetate and isopropyl acetate. The sitagliptin base thus obtained is pure and free from dicyclohexyl urea impurity.

Sitagliptin base thus obtained is optionally isolated and further converted to its acid addition salt. Organic layer obtained from the solvent extraction step can be distilled off and the second acid is added to the residue to obtain the sitagliptin acid addition salt without isolation of the base.

The solvent, alkali, second acid are same as already described in above paragraphs.

Examples
The following examples illustrate the invention and are not limiting thereof. Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of tert-butyl N-[(1R)-3-oxo-3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-1-[(2,3,5-trifluorophenyl)methyl]propyl]carbamate (BOC Sitagliptin) (Compound of Formula I)
3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (Formula III) (75.44 g) was charged to toluene (300 ml) at room temperature. The mixture was stirred and cooled to 15° C-20° C. N, N-Diisopropylethylamine (DIPEA) (85.31 g) was charged slowly followed by addition of hydroxybenzotriazole (HOBt) (16.2 g). The mixture was stirred at 15° C-20° C for 5-10 minutes. (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (Formula II) (100 gm) was charged to the mixture at 15° C -20° C. The mixture was stirred for further 5-10 minutes.

The solution of DCC (86.6 gm) in toluene was prepared separately and charged to the above reaction mass slowly at 15° C -20° C. The temperature of the mixture was raised to 25° C -30° C. The reaction mixture was stirred for at least for 1 hour and filtered to yield wet cake.

The BOC Sitagliptin obtained above was slurried in sodium carbonate (2M) solution (600 ml). The mass was stirred for 30-40 minutes and filtered. The wet cake was washed with water (100 ml) and suck dried. The compound was further dried at 60° C -65° C under vacuum.
The titled compound was isolated (230 gm) (HPLC purity: 89.5%).

Example 2
Preparation of Sitagliptin Hydrochloride
BOC Sitagliptin (100 g) obtained in Example 1 was charged to 2,2,2-trifluoroethanol (170 ml) at 25° C-30° C. The temperature of the reaction mixture was raised to 40° C -45°C and the mixture was stirred. The mixture was cooled and filtered. The precipitate was washed with 2,2,2-trifluoroethanol (50 ml) and concentrated HCl was charged to the filtrate obtained. The mixture was stirred at 25° C -30° C for at least 1 hour. The mass was cooled to 5° C -10°C. Water (350 ml) was added and stirred at 5° C -10°C for 10-15 minutes. The mass was filtered and washed with water (400 ml). pH of the filtrate obtained was adjusted to 10.0-11.0 using 20% sodium hydroxide (90 ml) to form sitagliptin base.

The reaction mass was extracted with MDC (100 ml) at 30° C -35° C and the layers were separated, and the aqueous layer was extracted with MDC (100 ml x 4). MDC layers were collected, and temperature was raised to 40° C -50° C. MDC was distilled out at atmospheric pressure at 40° C -50° C. IPA (isopropyl alcohol) (450 ml) was charged and temperature was raised to 70° C -75° C. Concentrated HCl (18.7 gm) was charged slowly and the mixture was cooled to 65° C -70° C. The mass was stirred at least for 1 hour. Further, the mass was cooled to 50° C -55° C and stirred for 2-3 hours. The mass was cooled to 25° C -30° C and filtered and the cake was washed with IPA (50 ml). Sitagliptin hydrochloride obtained was dried under vacuum at 70° C -75° C for 8-10 hours.
Dry wt. 50 gm (82.5%), HPLC purity 100%.

Example 3
Preparation of Sitagliptin Hydrochloride monohydrate
Sitagliptin Hydrochloride (100 gm) obtained in Example 2 was charged to di-isopropyl ether (DIPE) (400 ml) in dry conditions at room temperature. The mass was cooled to 5° C -10° C. Water (8.1 ml) was charged to the reaction mixture and stirred for 5 hours. The reaction mass was filtered, and wet cake was washed with DIPE (100 ml). The cake obtained was suck dried and further dried under vacuum below 45° C. When the moisture content of the material is achieved between 3.5-5% the drying is stopped and the dry sitagliptin hydrochloride monohydrate is obtained.
Dry wt. 99 gm (95.1%). HPLC purity 99.98%

Example 4
Isolation of Sitagliptin Base
BOC protected Sitagliptin (100 gm) was charged to 2,2,2-trifluoroethanol (170 ml) at room temperature. The temperature of the reaction mixture was raised to 40° C-45° C and mixture was stirred for 30 minutes. The reaction mass obtained was cooled to 25° C -30° C and filtered. Concentrated hydrochloric acid (46.7 gm) was charged to the filtrate at 25 ° C -30° C and stirred for 2 hours. The mass was cooled to 5° C -10° C and water (400 ml) was charged. The mass was filtered, and the filtrate was cooled to 5° C -10° C. pH of the solution was adjusted to 10-11 using 20% sodium hydroxide (90 ml). The mass was extracted with MDC (100 ml x 5). The layers were separated, and the MDC layer was distilled out completely under vacuum at 45° C -50° C. Toluene (50 ml) was charged to the mass obtained and distilled out under vacuum to yield sitagliptin base.
Yield (46.3 gm, 83%); HPLC purity: 97.58%

Example 5
Preparation of Sitagliptin phosphate anhydrous
BOC Sitagliptin (100 g) obtained in Example 1 was charged to 2,2,2-trifluoroethanol (170 ml) at 25° C -30° C. The temperature of the reaction mixture was raised to 40° C -45° C. The mixture was stirred for 25-30 minutes. The mixture was cooled, filtered and washed with 2,2,2-trifluoroethanol (50 ml) and concentrated HCl was charged to the filtrate obtained. The mixture was stirred at 25° C -30° C for 2 hours. The mass was cooled to 5° C -10° C. Water (400 ml) was added and stirred at 5° C -10° C for 10-15 minutes. The mass was filtered and washed with water (100 ml). pH of the filtrate obtained was adjusted to 10.0-11.0 using 20% sodium hydroxide (90 ml) to form sitagliptin base.

The reaction mass was extracted with MDC (100 ml) at 30° C -35° C. The layers were separated, and the aqueous layer was extracted again with MDC (100 ml x 4). All the MDC layers were collected, and temperature was raised to 40° C -50° C. MDC was distilled out at atmospheric pressure at 40° C -50° C. IPA (100 ml) was charged and temperature was raised to 70° C -75° C. O-phosphoric acid (88%) (13.7 gm) was charged slowly and the mixture was stirred for 15-20 minutes. Water (47.8 ml) was charged, and the mass was stirred for 1 hour at 70° C -75° C. The mass was cooled to 50° C -55° C.

IPA (200 ml) was charged, and the mass was stirred for 2 hours. The mass was cooled to 25° C -30° C and stirred at least for 1 hour. The mass was filtered, and the cake was washed with IPA (50 ml). Sitagliptin phosphate anhydrous obtained was dried under vacuum at 70° C -75° C for 8-10 hours.
Dry wt. 53 gm (76.78%). HPLC purity 99.99%.

Example 6
Preparation of Sitagliptin phosphate monohydrate
BOC Sitagliptin (100 g) obtained in Example 1 was charged to 2,2,2-trifluoroethanol (170 ml) at 25° C -30° C. The temperature of the reaction mixture was raised to 40° C -45° C. The mixture was stirred for 25-30 minutes. The mixture was cooled, filtered and washed with 2,2,2-trifluoroethanol (50 ml) and concentrated HCl (46.7 gm) was charged to the filtrate obtained. The mixture was stirred at 25° C -30° C for 2 hours. The mass was cooled to 5° C -10° C. Water (400 ml) was added and stirred at 5° C -10° C for 10-15 minutes. The mass was filtered and washed with water (100 ml). pH of the filtrate obtained was adjusted to 10-10.5 using 20% sodium hydroxide (90 ml) to form sitagliptin base.

The reaction mass was extracted with MDC (100 ml) at 30° C -35° C. The layers were separated, and the aqueous layer was extracted with MDC (100 ml x 4). All the MDC layers were collected, and temperature was raised to 40° C -50° C. MDC was distilled out at atmospheric pressure at 40° C -50° C. IPA (150 ml) was charged and temperature was raised to 50° C -55° C. The mass was cooled to 25° C -30° C. The mixture of ortho phosphoric acid (88%) (15.5 gm) and water (50 ml) was charged slowly and the temperature was raised to 70° C -75° C. The mixture was stirred for 15-20 minutes.

The mixture was gradually cooled to 40° C -45° C and further to 25 ° C -30° C with constant stirring. IPA (250 ml) was charged, and the mass was stirred for 4-5 hours. The mass was cooled to 25° C -30° C and stirred at least for 30 minutes. The mass was filtered, and the cake was washed with IPA (50 ml). Sitagliptin phosphate monohydrate obtained was dried under vacuum at 70° C -75° C for 5-6 hours.
Dry wt. 58 gm (81.10 %). HPLC purity 99.99%.

Example 7
Preparation of Sitagliptin Maleate
BOC Sitagliptin (100 g) obtained in Example 1 was charged to 2,2,2-trifluoroethanol (170 ml) at 30° C -35° C. The temperature of the reaction mixture was raised to 40° C -45° C. The mixture was stirred for 25-30 minutes. The mixture was cooled, filtered and washed with 2,2,2-trifluoroethanol (50 ml) and concentrated HCl (46.7 gm) was charged to the filtrate obtained. The mixture was stirred at 25° C -30° C for 2 hours. The mass was cooled to 5° C -10° C. Water (350 ml) was added and stirred at 5° C -10° C for 10-15 minutes. The mass was filtered and washed with water (100 ml). pH of the filtrate obtained was adjusted to 10-10.5 using 20% sodium hydroxide (90 ml) to form sitagliptin base.

The reaction mass was extracted with MDC (100 ml) at 5° C -10° C and the temperature was raised to 30° C -35° C. The layers were separated, and the aqueous layer was extracted with MDC (100 ml x 4). All the MDC layers were collected, and temperature was raised to 40° C -50° C. MDC was distilled out at atmospheric pressure at 40° C -50° C. Ethanol (50 ml) was charged and temperature was maintained less than 50° C. Ethanol (350 ml) was charged for 15-20 minutes. The mass was gradually cooled to 15° C -20° C and maleic acid (13.5 g) was charged slowly and mass was stirred for 1-2 hours. The precipitate was filtered and washed with ethanol (50 ml). The precipitate was suck dried. Sitagliptin maleate obtained was dried under vacuum at 55° C -60° C for 8-10 hours.
Dry wt. 55 gm (76.92%). HPLC purity 99.99%.

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.

,CLAIMS:
1. A process for preparation of sitagliptin (Formula (A)) and salts thereof, the process comprising,
reacting a compound of Formula (I) with a first acid and a substituted alcohol having electron withdrawing groups.

2. The process as claimed in claim 1, wherein compound of Formula (I) is solubilized in the substituted alcohol followed by addition of the first acid.

3. The process as claimed in claim 1 or 2, wherein the reaction is carried out at ambient temperature.

4. The process as claimed in claim 1, wherein the substituted alcohol is selected from 2-chloroethanol, 2,2-dichloroethanol, 2,2,2-trichloroethanol, 2-fluoroethanol, 2,2-difluoroethanol, 2,2,2-trifluroethanol, 2-nitroethanol, 3-hydroxy propionitrile and mixture thereof.

5. The process as claimed in claim 1, wherein the first acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, benzenesulfonic acid, nitric acid, hydroiodic acid, lactic acid, citric acid and combination thereof

6. The process as claimed in claim 1 comprising
adding water to the reaction mixture;
treating the reaction mixture with an alkali and adjusting the pH to be in a range of 10.0-11.0 to form sitagliptin base; and
extracting sitagliptin base with an organic solvent.

7. The process as claimed in claims 6, wherein the alkali is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and combination thereof.

8. The process as claimed in claim 7, wherein the alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide; alkali metal alkoxide is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide; alkali metal carbonate is selected from sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonates is selected from sodium bicarbonate, potassium bicarbonate, and combination thereof.

9. The process as claimed in claim 6, wherein the organic solvent is selected from an organic ester or organic chlorinated solvent.

10. The process as claimed in claim 9, wherein the organic solvent is selected from methylene dichloride (MDC), ethylene dichloride (EDC), chloroform, carbon tetrachloride, isopropyl acetate, ethyl acetate and mixture thereof.

11. The process for preparation of salt of sitagliptin, the process comprising
preparing a reaction mixture as claimed in claim 1;
treating the reaction mixture with the alkali and adjusting the pH to be in a range of 10.0-11.0 to form sitagliptin base; and
treating the sitagliptin base with a second acid.

12. The process as claimed in claim 11, wherein the second acid is selected from hydrochloric acid, phosphoric acid, maleic acid, fumaric acid, acetic acid, succinic acid, benzene sulfonic acid, D-tartaric acid, L-tartaric acid, DL-tartaric acid methanesulfonic acid, L-malic acid, D-malic acid, (R)-(-) mandelic acid, (S)- (+) mandelic acid, adipic acid, lactic acid, glycolic acid, citric acid, oxalic acid, (S)- (+) O-acetyl mandelic acid, isonicotinic acid, 4-methylsalicylic acid, salicylic acid, myristic acid, orotic acid, isophthalic acid, gentisic acid, butenedioic acid, p-toluenesulfonic acid, (1S)- (+)-camphorsulfonic acid, benzoic acid, hydro bromide, di-p-tolyl-L-tartaric acid, di-p-tolyl-D-tartaric acid, di-p-tolyl-DL-tartaric acid, pyroglutamic acid, glutaric acid, L-aspartic acid, D-gluconic acid, galactaric acid, ethanesulfonic acid, malonic acid, carpric acid, 1-hydroxy naphthoic acid, D-glucronic acid, quinic acid, formic acid, nicotinic acid, picolinic acid, cinnamic acid, nitric acid, trifluoromethanesulfonic acid, boric acid, trifluoroacetic acid, caffeic acid, ferulic acid, coumaric acid, (R)-(+) 1,2-dithiolane-3-pentanoic acid, (S) 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid, isethionic acid, thioglycolic acid, or naphthalenesulfonic acid.

13. A process for preparation of compound of Formula (I) comprising,
reacting (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (BOC acid) of Formula (II) with triazolopyrazine compound of Formula (III), in presence of dicyclohexylcarbodimide (DCC), hydroxybenzotriazole (HOBt) and an organic base in a solvent.

14. The process as claimed in claim 13, wherein dicyclohexylcarbodimide is present in an amount of 1.1-1.5 mol equivalent of compound of Formula (III).

15. The process as claimed in claim 13, wherein the organic base is selected from di-isopropyl ethylamine (DIPEA), triethylamine (TEA) and combination thereof.

16. The process as claimed in claim 13, wherein the solvent is selected from dimethylformamide, dimethyl sulphoxide, N-methyl pyrrolidone, methylene dichloride, acetonitrile and ethereal solvents like diethyl ether, diiospropyl ether, diglyme, monoglyme, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, dimethoxy methane, methyl tertiary butyl ether, ethyl tertiary butyl ether tetrahydropyran, morpholine, toluene and mixture thereof.

17. The process as claimed in any one of claims 13 to 16, wherein the solvent is toluene.

18. A process for preparation of sitagliptin and salts thereof comprising,
i) reacting (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (BOC acid) of Formula (II) with triazolopyrazine compound of Formula (III), in presence of 1.0-1.4 mol equivalent of dicyclohexylcarbodimide (DCC), hydroxybenzotriazole (HOBt) and an organic base in a solvent to form compound of Formula (I);
ii) isolating compound of Formula (I);
iii) dissolving compound of Formula (I) in a substituted alcohol having electron withdrawing groups and filtering the solution;
iv) adding a first acid, concentrated hydrochloric acid, to the filtrate;
v) adding at least 3-4 volumes of water and filtering the mixture;
vi) adding an alkali to the filtrate and adjusting the pH of the mixture to 10.0-11.0 to form sitagliptin base; and
vii) extracting sitagliptin base with an organic solvent.

19. The process as claimed in claim 18, wherein the solvent is selected from dimethylformamide, dimethyl sulphoxide, N-methyl pyrrolidone, methylene dichloride, acetonitrile and ethereal solvents like diethyl ether, diiospropyl ether, diglyme, monoglyme, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, dimethoxy methane, methyl tertiary butyl ether, ethyl tertiary butyl ether tetrahydropyran, morpholine, toluene and mixture thereof;

the organic base is selected from di-isopropyl ethylamine (DIPEA), triethylamine (TEA) and combination thereof;

the substituted alcohol is selected from 2-chloroethanol, 2,2-dichloroethanol, 2,2,2-trichloroethanol, 2-fluoroethanol, 2,2-difluoroethanol, 2,2,2-trifluroethanol, 2-nitroethanol, 3-hydroxy propionitrile and mixture thereof;

the alkali is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and combination thereof;
wherein the alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide; alkali metal alkoxide is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide; alkali metal carbonate is selected from sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonates is selected from sodium bicarbonate, potassium bicarbonate, and combination thereof;

the organic solvent is selected from methylene dichloride (MDC), ethylene dichloride (EDC) chloroform, carbon tetrachloride, isopropyl acetate, ethyl acetate and mixture thereof.

20. The process as claimed in claim 18 comprising forming a salt of sitagliptin by reacting sitagliptin with a second acid selected from hydrochloric acid, phosphoric acid, maleic acid, fumaric acid, acetic acid, succinic acid, benzene sulfonic acid, D-tartaric acid, L-tartaric acid, DL-tartaric acid methanesulfonic acid, L-malic acid, D-malic acid , (R)-(-) mandelic acid, (S)- (+) mandelic acid, adipic acid, lactic acid, glycolic acid, citric acid, oxalic acid, (S)- (+) O-acetyl mandelic acid, isonicotinic acid, 4-methylsalicylic acid, salicylic acid, myristic acid, orotic acid, isophthalic acid, gentisic acid, butenedioic acid, p-toluenesulfonic acid, (1S)- (+)-camphorsulfonic acid, benzoic acid, hydro bromide, di-p-tolyl-L-tartaric acid, di-p-tolyl-D-tartaric acid, di-p-tolyl-DL-tartaric acid, lactic acid, pyroglutamic acid, glutaric acid, L-aspartic acid, D-gluconic acid, galactaric acid, ethanesulfonic acid, malonic acid, carpric acid, 1-hydroxy naphthoic acid, D-glucronic acid, quinic acid, formic acid, nicotinic acid, picolinic acid, cinnamic acid, nitric acid, trifluoromethanesulfonic acid, boric acid, trifluoroacetic acid, caffeic acid, ferulic acid, coumaric acid, (R)-(+) 1,2-dithiolane-3-pentanoic acid, (S) 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid, isethionic acid thioglycolic acid, or naphthalenesulfonic acid.