DESC:Field of the Invention
The present invention generally relates to the field of process chemistry, and more particularly relates to process for the preparation of sitagliptin. The present invention also relates to novel intermediates used in the process to prepare sitagliptin.

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. 6,669,871 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 with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyrazine in presence of hydroxybenzotriazole (HOBt) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) in methylene dichloride (MDC). (3R)-3-[1,1-dimethylethoxy carbonylamino]-4-(2,4,5)-trifluorophenyl)-butanoic acid is prepared by reacting (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine with 2,4,5-trifluoromethyl benzyl bromide in presence of Butyl lithium followed by reaction with Di-BOC.

Various processes for synthesis of sitagliptin and its pharmaceutically acceptable salts are well known. WO2015120111 teaches process for preparation of sitagliptin by reacting 1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4] triazolo[4,3-a]pyrazin-7-yl]-4-(2,3,5-trifluorophenyl)but-2-en-1-one with a Michael donor. However, there are no specific processes disclosed in the prior art for achieving diasteromeric purity without seeding.

It would be desirable to provide process having enantiomeric excess greater than 99.5 and also suitable for manufacturing scale production.

Summary of the Invention
The present invention provides an industrially viable and scalable process for the preparation of sitagliptin. The present invention further provides intermediates used to prepare sitagliptin and pharmaceutically acceptable salts thereof.

Detailed Description of the Invention
In one embodiment, the present invention provides a process for the preparation of an intermediate enamine compound of formula (I):

wherein,
R1 is selected from alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cyloalkyl, C(O)R1, -C(O)OR1, -O-C(O)-R1, -S(O)2R1, Si(R1)3 and O-Si(R1)3;

each R1 is independently selected from substituted benzyl, substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

wherein the process comprises steps of:
A1) reacting intermediate of formula (VI) with suitable amine of formula (VII), .
The enamine preparation proceeds through formation of imine of formula V’. The imine being unstable is converted to enamine of formula (V).

The reaction is carried out in presence of catalytic amount of an acid selected from acetic acid, formic acid, methane sulfonic acid, trifluoroacetic acid, phosphoric acid, oxalic acid, benzene sulfonic acid, succinic acid, preferably acetic acid.

The reaction is carried out in a solvent preferably selected from 1-4C alcohol and at 0-50°C, preferably at 20-30°C.

In another embodiment, the present invention provides a process for the preparation of compound of formula (II)

wherein
R1 is as defined above and wavy bond represents that the compound is in R-, S- or racemic form;
wherein the process comprises,
A2) chiral reduction of enamine compound of formula (I) using sodium cyanoboro hydride. The diastereoisomeric excess of compound (II) obtained is 70:30.

The reaction is carried out in an ethereal solvent selected from di-ethyl ether, di-iso-propyl ether, diglyme, cyclopentylmethylether, dimethoxyethane, dimethoxymethane, 1,4-dioxane, ethyl tert butyl ether, methyl tert butyl ether, 1,4-dioxane, 2-methyl tetrahydrofuran, tetrahydrofuran, preferably THF.

The reaction is carried out at 0-70°C, preferably at 0-10°C.

In another embodiment, the present invention provides a process for the preparation of compound of formula (II)

wherein R1 is as defined above and wavy bond represents that the compound is in R-, S- or racemic form;

the process comprises the step of:
A2) chiral reduction of enamine compound of formula (I) using sodium borohydride. The diastereoisomeric excess of compound (II) obtained is 90:10.

The reaction is carried out in a solvent selected from monoglyme, diglyme, toluene and mixtures thereof.

The reaction is carried out in presence of suitable sulphonate derivatives selected from benzene sulfonic acid selected from p-toluene sulfonic acid, camphor sulfonic acid, benzophenone sulfonic acid, naphthalene sulfonic acid, trifluoromethane sulfonic acid and sodium dodecyl sulfate.

The reaction is carried out at -50 to -80°C, preferably at -60-75°C, especially at -65 to -70°C.

In yet another embodiment, the present invention a process for achieving diastereo-isomeric excess of compound of formula (II) from 70:30 to 99.5-99.9:0.5-0.1,

wherein the reaction comprises steps of:
A3) reacting compound (II) with a suitable chiral acid resolving agent;
B3) isolating corresponding chiral acid salt of formula (IIIa);
C3) treating (IIIa) with suitable alkali under suitable conditions to form compound (III) with diastereoisomeric excess 99.5:0.5 - 99.9:0.1.

The chiral resolving agents used in stage A3) is selected from S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (1R)-(-)-camphor sulfonic acid, (1S)-(+)-camphor sulfonic acid (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromo camphor-10-sulfonic acid, (-)-dibenzoyl-L-tartaric acid, (-)-dibenzoyl-L-tartaricacid monohydrate, (+)-dibenzoyl-D -tartaric acid, (+)-dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-diparatolyl-L-tataricacid, L(-)-pyroglutamic acid, L(+)-pyrogIutamic acid, (-)-lactic acid, L-lysine, D-Iysine.

Step A3) is carried out in a solvent selected from "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" such as toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" such as dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone.

The diastereoisomeric purity is achieved by purifying the salt in an alcoholic solvent at reflux. Further, the diastereoisomeric purity>99.5 is achieved, by repeating the steps A3) to C3).

In the reaction before maintaining of the mass, the seeds of chiral resolving acid salt may be added to achieve the desired chiral purity. The seed compound can be obtained by re-resolution of compound of formula (III).

In yet another embodiment, the present invention provides a process for preparation of seed crystal of compound of formula (IV-S) having diastereoisomeric purity>99.5

wherein
HX is pharmaceutically acceptable acid selected from phosphoric, acetic, methane sulfonic, benzenesulfonic, benzoic, citric, fumaric, hydrochloric, hydrobromic; R1 is as defined above; comprising the steps of:
A4) reacting compound of formula (III) with suitable acid;
B4) isolating salt of formula (IV-S) with diastereoisomeric excess>99.5.
The reaction is preferably carried out in an alcoholic solvent at 20-80°C.

In another embodiment, the present invention provides a process for preparation of compound of formula (IV)

wherein
HX and R1 is as defined above, comprising the steps of:
A5) reacting compound of formula (III) with suitable acid;
B5) seeding the corresponding salt (IV-S) with enantiomeric purity>99.5;
C5) isolating compound of formula (IV) with diastereoisomeric excess>99.5.

In another embodiment, the present invention provides a process for the preparation of sitagliptin salt of formula (V)

wherein the process comprises the steps of:
A6) hydrogenation of compound of formula (IV) in a suitable solvent;
B6) reacting the salt with suitable alkali.
The reaction is preferably carried out in an alcoholic solvent, preferably (1-4C) alcohol.

In yet another embodiment, the present invention provides a process for the preparation of sitagliptin phosphate of formula (V), comprising the steps of:
P1) reacting intermediate of formula (VI) with suitable amine of formula (VIII) to form enamine compound of formula (I),
P2) chiral reduction of enamine compound of formula (I) using sodium cyanoborohydride,
P3) reacting compound of formula (II) with suitable chiral resolving agent form salt of formula (IIIa),
P4) reacting (IIIa) salt with suitable alkali to isolate compound of formula (III),
P5) reacting compound of formula (III) with an acid,
P6) seeding the corresponding acid salt having diastereoisomeric purity>99.5;
P7) isolating acid salt of formula (IV) with diastereoisomeric excess>99.5;
P8) hydrogenation of compound of formula (IV) in a suitable solvent to isolate sitagliptin salt,
P9) if the salt obtained in step P8) is other than phosphate salt, the salt is reacted with suitable alkali; and
P10) reacting sitagliptin base with phosphoric acid in a suitable solvent to form sitagliptin phosphate of formula (Va).

Step P1) is carried out in presence of catalytic amount of an acid selected from acetic acid, formic acid, methane sulfonic acid, trifluoroacetic acid, phosphoric acid, oxalic acid, benzene sulfonic acid, succinic acid, preferably acetic acid.

Step P1) is carried out in a solvent preferably selected from 1-4C alcohol and at 0-50°C, preferably at 20-30°C.

Step P2) is carried out in an ethereal solvent selected from di-ethyl ether, di-iso-propyl ether, diglyme, cyclopentyl methyl ether, dimethoxy ethane, dimethoxy methane, 1,4-dioxane, ethyl tertbutyl ether, methyl tert butyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, preferably THF.

Step P2) is carried out at 0-70°C, preferably at 0-10°C.

The chiral resolving agents used in stage P3) is selected from S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (1R)-(-)-camphor sulfonic acid, (1S)-(+)-camphor sulfonic acid (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromo camphor-10-sulfonic acid, (-)-dibenzoyl-L-tartaric acid, (-)-dibenzoyl-L-tartaricacid monohydrate, (+)-dibenzoyl-D-tartaric acid, (+)-dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tataricacid, L(-)-pyroglutamic acid, L(+)-pyrogIutamic acid, (-)-lactic acid, L-lysine, D-Iysine.

Step P3) is carried out in a solvent selected from "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" such as toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" such as dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone.

Acid used in step P5) is selected from phosphoric, acetic, methane sulfonic, benzenesulfonic, benzoic, citric, fumaric, hydrochloric, hydrobromic acid.

Hydrogenation in step P8) is carried out in a metal catalyst selected from palladium, platinum, nickel, iron and the like.

The reaction is carried out under hydrogen pressure and in a suitable acid selected from alcoholic solvent, preferably 1-4C alcohol.

The compound of formula (VI) used in the reaction is prepared by
a) reacting 2,4,5-trifluorophenylacetic acid with Meldrum's acid to form Meldrum’s adduct of formula (VIII). The reaction is preferably carried out in presence of dimethyl aminopyridine and EDC.HCl;
b) coupling Meldrum’s adduct with triazole hydrochloride in presence of di-isopropylamine.

Examples
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 2,2-dimethyl-5-[2-(2,4,5-trifluorophenyl)acetyl]-1,3-dioxane-4,6-dione (Meldrum’s adduct) (VIII)
2,4,5-Trifluoro phenyl acetic acid (100 g) was charged to MDC (1000 ml) at 25-30°C. Meldrums acid (83.4 gm) was added and the reaction mixture was stirred for 10-15 minutes at 25-30°C. The mass was chilled to 5-10°C. 4-dimethyl amino pyridine was charged at 5-10°C and mass was stirred for 10-15 minutes to get clear solution.

EDC.HCl solution was prepared by adding EDC.HCl (131.2 gm) to MDC (1500 ml). EDC.HCl solution (1500 ml) was charged slowly to above reaction mass at 5-10°C. The temperature was gradually raised to 10-15°C and the mass was stirred for 4 hours at 10-15°C. After completion of reaction, pH of the solution was adjusted to 2-3 using dilute HCl. The temperature was raised to 25-30°C and stirred for 10-15 minutes. The layers were separated and aqueous layer was extracted with MDC. MDC layers were combined and treated with sodium sulfate. MDC was distilled out under vacuum below 40-45°C. The mass was stripped with acetone (50 ml) under vacuum below 40-45°C. Acetone (50 ml) was charged to the mass and stirred for 1hour at 25-30°C. The mass was cooled to 10-15°C and stirred for 1 hour at 10-15°C. The product was filtered and washed with cold acetone (25 ml). The meldrum’s adduct obtained was suck dried and further dried at 55-60°C (102 gm) Yield: 102 gm.

Example 2
Preparation of 1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butane-1,3-dione (VI)
2,2-dimethyl-5-[2-(2,4,5-trifluorophenyl)acetyl]-1,3-dioxane-4,6-dione (100 g) was charged to acetonitrile (600 ml) at 25-30°C. Pyrazine hydrochloride (72.15 gm) was charged to the reaction mixture at 25-30°C and di-isopropyl ethylamine was added drop wise at 25-30°C. The mass was stirred for 25-30°C. TFA was added slowly drop wise at 25-30°C. The reaction mass was heated to 50-55°C and stirred for 3 hours. After completion of the reaction, the mass was cooled to 25-30°C and further chilled to 0-10°C. The pH of the mass was adjusted to 9-10 using 20% NaOH solution. The temperature was raised to 25-30°C and ethyl acetate was charged and stirred for 10-15 minutes. The mass was settled, and layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 100 ml). All the ethyl acetate layers were combined and washed with water (200 ml) and treated with sodium sulfate (10 gm). Ethyl acetate layer was distilled out under vacuum at 50-55°C. 1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butane-1,3-dione was obtained as oil (153 gm).

Example 3
Preparation of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)but-2-en-1-one (V)
1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butane-1,3-dione obtained from example 2 (100 g) was charged to isopropyl alcohol (200 ml) at 25-30°C. (R)-naphthyl ethylamine (37.90 gm) and acetic acid (7.38 gm) was charged to the reaction mixture at 25-30°C. Isopropyl alcohol (100 ml) was charged and mixture was stirred for 17 hours. The reaction mass was chilled to 0-5°C and stirred for 2 hours. The precipitate was filtered and washed with chilled IPA (50 ml). The precipitate was suck dried and further dried at 55-60°C to yield 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)but-2-en-1-one (88 gm).

Example 4
Preparation of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (IV)
3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4] triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)but-2-en-1-one obtained in example 3 (100 g) was added to THF (900 ml) at 25-30°C. The mixture was stirred for 15-20 minutes to get clear solution. The solution was cooled to 0-5°C and sodium cyanoborohydride (13.79 gm) was charged in one lot under inert atmosphere at 0-5°C. The mixture was stirred for 3 hours at 0-5°C and pH was adjusted to 2-4 using dil. HCl . The mass was stirred for 15-20 minutes at 0-5°C. pH of the mass was adjusted to 6-7 using 10% sodium carbonate solution at 0-5°C. Ethyl acetate (300 ml) was charged and temperature was raised to 25-30°C. The mass was stirred for 15-20 minutes and layers were separated. Aqueous layer was extracted with ethyl acetate and all the combined ethyl acetate layers were treated with sodium sulfate. Ethyl acetate was distilled out under vacuum at 45-50°C and stripped with di-isopropyl ether. 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (93g) with an diastereoisomeric excess 70:30 (S:R) was obtained.

Example 5
Preparation of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (IV)
Mixture of solvent toluene (90 ml) and monoglyme (305 ml) was chilled to -65 to -70°C. Sodium borohydride (7.4 gm) was charged and the mixture was stirred for 10 minutes. P-toluene sulfonic acid (95 gm) was charged in 3 lots after interval of 10 minutes. The mixture was stirred for 1 hour at -65 to -70°C. IPA (50 ml) was added dropwise to the reaction mass and 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoro methyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)but-2-en-1-one (50 gm) obtained in example 3 was charged in three lots at -65 to -70°C within 20-25 minutes. The reaction mixture was maintained at -65 to -70°C for 6-7 hours.

After completion of the reaction acetone was charged to the reaction mass at -65 to -70°. Ammonium chloride solution was prepared separately by adding 10 gm ammonium chloride in water (25 ml). The solution was charged to the reaction mass at -45 to -50°C. Water (250 ml) was charged at -10°C. The pH of the solution was adjusted to 7-8 using ammonia. The temperature was gradually raised to 25-30°C. Toluene (200 ml) was charged and the layers were separated. Toluene (70ml x 2) was charged to the aqueous layer and extracted. Toluene layers were separated and dried over sodium sulphate. Toluene was distilled out under vacuum to get thick mass. To this mass dilute HCl was added and heated to 55 to 60°C for 2 hours. The solid was precipitated and cooled to 25-30°C and filtered. MDC (100 ml) was charged and pH was adjusted to 8 using sodium bicarbonate solution. The layers were separated. MDC was distilled out under vacuum to get thick mass.
Chiral purity: 93.7:6.30 and HPLC rel purity: 92.58%.

Example 6
Preparation of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (IV)
Using the procedure described in example 5, compound 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one is prepared using sodium borohydride as a reducing agent and in presence of camphor sulphonic acid, benzene sulphonic acid, naphthalene-1-sulphonic acid, trifluoromethane sulphonic acid, sodium dodecyl sulphate.

Activating agent Chiral Purity (EE) Relative HPLC purity % Yield
Camphor sulphonic acid 90.07:9.93 95.92% 81.75%
Benzene sulphonic acid 81.23:18.77 80.08%
Naphthalene-1-sulphonic acid 92.93:7.07 76.7%
Trifluoromethane sulphonic acid 85.43:14.57 85.8%
Sodium dodecyl sulphate 9.81:8.19 86%

Example 7
Preparation of tartarate salt of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
Methanol (210 ml) was charged to the reaction mass obtained in example 6 and the mixture was heated to 60-65°C. D(-)-tartaric acid (9.35 g) was charged in one lot and 50 mg seeds were added. The mixture was maintained for 2 hours at 60-65°C. The mass was gradually cooled to 25-30°C. The mass was filtered and washed with methanol (35 ml) and dried in oven at 50-55°C. Tartarate salt of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluoro phenyl)butan-1-one (38.3 gm, 86.3% yield) was isolated as white solid.
Chiral purity: 99.71% and HPLC purity is 98.91%.

Example 8
Preparation of tartarate salt of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
D-(-)-tartaric acid (5.34 gm) was charged to water (31 ml) and methanol (24 ml) and heated to 60-65°C. A crude solution of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (20 gm) in methanol (10 ml) was charged drop wise at 60-65°C. The mixture was stirred for 10-15 minutes at 60-65°C and solid precipitated. The reaction mixture was maintained for 2-3 hours. The solid was filtered in hot condition and washed with methanol (5 ml) and water (5 ml) to yield tartarate salt of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (13 gm) with diastereoisomeric Purity: 88.41% was isolated.

The D-(-)-tartarate salt was taken in methanol (20 ml) and heated to reflux at 60-65°C for 1 hour. The mass was cooled to 40-45°C and filtered in hot conditions. The precipitate was washed with hot methanol (10 ml) to isolate (D)-tartarate salt (7 gm) with diastereoisomeric purity 98.2%.

Example 9
Preparation of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
Tartarate salt obtained in example 5 (10gm) was charged to purified water (70 ml) under stirring at 25-30°C and stirred for 15 minutes.

Toluene (10 ml) was charged at 25-30°C to the reaction mixture and stirred for 15 minutes. Toluene layer was separated and pH of the aqueous layer was adjusted to 11-12 using 5% NaOH solution at 25-30°C over a period of 1 hour. The reaction mass was stirred for 1 hour at 25-30°C. The mass was filtered and the wet cake was washed with water (450 ml) until the pH of the solution becomes neutral. The solid obtained was dried at 50-55°C under vacuum. 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (7.8 gm) was isolated with diastereoisomeric purity 98.20%.

Example 10
Preparation of tartarate salt of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
D-(-)-tartaric acid (5.34 gm) was charged in mixture of water (31 ml) and methanol (24 ml) and heated to 60-650C. A solution of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluoro phenyl)butan-1-one (20 g) in 25 ml methanol was added drop wise in above reaction mixture within 10-15 minutes at 60-65°C. Solid precipitation was observed at 60-65°C after 40-45 minute. The mass was maintained for 2-3 hours at 60-65°C. Precipitated solid was filtered in hot condition at 40-45°C and washed with methanol (5 ml) and water (5 ml). The solid obtained was dried (19.4 gm)
Diastereomeric purity: 99.7%.

Example 11
Preparation of Phosphate salt of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
IPA (600 ml) was charged to 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoro methyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one (100 gm) isolated from example 6. The mixture was heated to 55-60°C and stirred for 15-20 minutes to get clear solution. Phosphoric acid (20.55 gm) was slowly added to the reaction mixture at 55-60°C and stirred for 2 hours. IPA was distilled under vacuum at 45-50°C and stripped with DIPE (2x100 ml). Phosphate salt of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (115 gm) was isolated as white residue.

Example 12
Preparation of Sitagliptin phosphate
Phosphate salt of 3-[[(1S)-1-(1-naphthyl)ethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (100 gm) was charged to IPA (600 ml). Water (150 ml) and 5%Pd/C was charged and the reaction mixture was hydrogentaed in an autoclave under inert atmosphere at 70-75°C and under 12 kg/Cm2 pressure. The mixture was stirred at 70-75°C for 2 hours and the mass was cooled to 25-30°C. The catalyst was filtered and IPA was distilled under vacuum at 50-55°C. IPA (600 ml) and water (60 ml) was charged to the residue and heated to 70-75°C to get clear solution. The mass was stirred for 1 hour at 70-75°C and cooled to 25-30°C. The mass was further chilled to 5-10°C and stirred. The product was filtered and washed with chilled IPA. The precipitate was suck dried and further dried under vacuum at 55-60°C to yield Sitagliptin Phosphate (32 gm).
,CLAIMS:1. A process for the preparation an intermediate enamine compound of formula (I)

wherein,
R1 is selected from alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cyloalkyl, C(O)R1, -C(O)OR1, -O-C(O)-R1, -S(O)2R1, Si(R1)3 and O-Si(R1)3;

each R1 is independently selected from substituted benzyl, substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,

the process comprising the step of:

A1) reacting intermediate of formula (VI) with a suitable amine of formula (VII).

2. The process as claimed in claim 1, where the reaction is carried out in the presence of catalytic amount of an acid selected from the group comprising of acetic acid, formic acid, methane sulfonic acid, trifluoroacetic acid, phosphoric acid, oxalic acid, benzene sulfonic acid, and succinic acid.
3. The process as claimed in any of the preceding claims, wherein the reaction is carried out in the presence of acetic acid.
4. The process as claimed in claim 1, wherein the reaction is carried out in a solvent from 1-4C alcohol.
5. The process as claimed in claim 1, wherein the reaction is carried out at 0-50°C.
6. The process as claimed in claim 1, wherein the reaction is carried out at 20-30°C.
7. A process for the preparation of compound of formula (III),

the process comprising the steps of:
A2) chiral reduction of enamine compound of formula (I) using sodium cyanoborohydride to achieve diastereoisomeric excess of compound (II) to 70:30;
A3) reacting compound (II) with a suitable chiral acid resolving agent;
B3) isolating corresponding chiral acid salt of formula (IIIa);
C3) treating (IIIa) with a suitable alkali under suitable conditions to form compound (III) with diastereoisomeric excess 99.5:0.5 – 99.9:0.1.
8. The process as claimed in claim 7, wherein step A2) is carried out in an ethereal solvent selected from the group consisting of di-ethyl ether, di-iso-propyl ether, diglyme, cyclopentyl methyl ether, dimethoxy ethane, dimethoxymethane, 1,4-dioxane, ethyl tertbutyl ether, methyl tert butyl ether, 1,4-dioxane, tetrahydrofuran and 2-methyl tetrahydrofuran.
9. The process as claimed in claim 7, wherein step A2) is carried out in tetrahydrofuran.
10. The process as claimed in claim 7, wherein step A2) is carried out at 0-70°C.
11. The process as claimed in claim 7, wherein step A2) is carried out at 0-10°C.
12. The process as claimed in claim 7, wherein the chiral resolving agent of step A3) is selected from the group consisting of S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (1R)-(-)-camphor sulfonic acid, (1S)-(+)-camphor sulfonic acid (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromocamphor-10-sulfonic acid, (-)-dibenzoyl-L-tartaric acid, (-)-dibenzoyl-L-tartaricacid monohydrate, (+)-dibenzoyl-D -tartaric acid, (+)-dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tataricacid, L(-)-pyroglutamic acid, L(+)-pyrogIutamic acid, (-)-lactic acid, L-lysine, D-Iysine.
13. The process as claimed in claim 7, wherein step A3) is carried out in a solvent selected from the group of ester solvent, ether solvent, hydrocarbon solvent, polar aprotic solvent, and ketone solvent.
14. The process as claimed in claim 13, wherein the ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, and isopropyl acetate.
15. The process as claimed in claim 13, wherein the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.
16. The process as claimed in claim 13, wherein the hydrocarbon solvent is selected from the group consisting of toluene, hexane, heptane, and cyclohexane.
17. The process as claimed in claim 13, wherein the polar aprotic solvent is selected from the group consisting of dimethyl acetamide, dimethyl sulfoxide and acetonitrile.
18. The process as claimed in claim 13, wherein the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, and methyl isobutyl ketone.
19. The process as claimed in claim 7, wherein the diastereoisomeric purity of greater than 99.5 is achieved by purifying the salt in an alcoholic solvent at reflux.
20. The process as claimed in claim 19, wherein the alcoholic solvent is selected from (1-4C) alcohol.
21. A process for the preparation of compound of formula (IV)

wherein HX is pharmaceutically acceptable acid selected from phosphoric, acetic, methane sulfonic, benzenesulfonic, benzoic, citric, fumaric, hydrochloric, hydrobromic and R1 is as defined above; the process comprising the steps of:
A5) reacting compound of formula (III) with a suitable acid;
B5) seeding the corresponding salt (IV-S) with enantiomeric purity > 99.5;
C5) isolating compound of formula (IV) with diastereoisomeric excess 99.5.
22. The process as claimed in claim 21, wherein preparing seed crystal of compound of formula (IV-S) in step B5) having diastereoisomeric purity greater than 99.5 comprising the steps of:
A4) reacting compound of formula (III) with a suitable acid;
B4) isolating salt of formula (IV-S) with diastereoisomeric excess greater than 99.5.
23. The process as claimed in claim 23, wherein step A4) is carried out in an alcoholic solvent at 20-80°C.
24. A process for the preparation of sitagliptin salt of formula (V)

the process comprises the steps of:
A6) hydrogenation of compound of formula (IV) in a suitable alcoholic solvent;
B6) reacting the salt with a suitable alkali.
25. A process for the preparation of sitagliptin acid salt of formula (V),

the process comprising the steps of:
P1) reacting intermediate of formula (VI) with a suitable amine of formula (VII) to form enamine compound of formula (I),
P2) chiral reduction of enamine compound of formula (I) using a reducing agent to form compound of formula (II) having diastereoisomeric excess 70:30,
P3) reacting compound of formula (II) with a suitable chiral resolving agent form salt of formula (IIIa),
P4) reacting salt of formula (IIIa) with a suitable alkali to isolate compound of formula (III) with diastereoisomeric excess 99.5:0.5 – 99.9:0.1,
P5) reacting compound of formula (III) with an acid,
P6) seeding the corresponding acid salt having diastereoisomeric purity greater than 99.5%,
P7) isolating acid salt of formula (IV) with diastereoisomeric excess greater than 99.5,
P8) hydrogenation of compound of formula (IV) in a suitable alcoholic solvent to isolate sitagliptin salt.
26. The process as claimed in claim 25, wherein the reducing agent used in step P2) is selected from the group consisting of sodium cyanoborohydride and sodium borohydride.