DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS INTERMEDIATES

We, Stereokem Pvt. Ltd.,
a company incorporated under the companies act, 1956 having address at Plot No. 36/A, IDA Uppal, Hyderabad-500039, Telangana, INDIA.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of novel intermediates useful for the preparation of Sitagliptin or its pharmaceutically acceptable salts.

The present invention relates to an efficient process for the preparation of Sitagliptin intermediates.

The present invention relates to an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION
Sitagliptin is an oral antihyperglycemic agent of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class. Inhibition of DPP-IV, an enzyme that inactivates both glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), represents a recent approaches to the treatment and prevention of type-2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). Sitagliptin also has an effect on appetite as it slows down gastric motility and induces a feeling of satiety. This reduction of appetite can help patients to lose weight which is also a useful effect in patients with diabetes.

Sitagliptin which exists as its phosphate salt is chemically described as 7-[(3R)-3-amino-1-oxo-4-(2,4,5 trifluorophenyl)butyl]5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4- triazolo [4,3-a]pyrazine phosphate (1:1) monohydrate. The empirical formula for phosphate salt is C16H15F6N5O.H3PO4.H2O: the molecular weight is 523.32. The structural formula is shown below:

Sitagliptin is currently marketed in its phosphate salt in the United States under the tradename JANUVIA™ in its monohydrate form. JANUVIA™ is indicated to improve glycemic control in patients with type 2 diabetes mellitus.

Sitagliptin can be obtained by condensation of 2 key intermediates. The first intermediate is (3R)-amino-4-(2,4,5-trifluorophenyl)butanoic acid (“Synthon I”). Synthon I has the following formula:

Synthon I
where R = H.

The second intermediate is 3-(trifluoromethyl)-5,6,7,8-tetrahydro [1,2,4]triazolo[4,3-a]pyrazine (“Synthon II”), having the following formula:

Synthon II

Sitagliptin was first described and claimed in US 6,699,871 and describes the preparation of Sitagliptin hydrochloride salt, while US 7,326,708 claims the phosphate salt of Sitagliptin or a hydrate thereof. The key step in the synthesis of Sitagliptin is the condensation of synthon I and synthon II. This being a peptide bond formation, according to the prior art, standard peptide coupling conditions and reagents are used.

Several other processes for the synthesis of Sitagliptin are known. For example, WO2004/085661 discloses the preparation of Sitagliptin using S-phenylglycine amide as a chiral auxiliary.
WO2004/085378, WO2005/097733, and WO2006/081151 disclose the preparation of Sitagliptin which involves an enantioselective reduction of the intermediate chiral enamine in the presence of specific catalysts.

WO2009/085990 discloses the preparation of Sitagliptin using various chiral auxiliaries, such as chiral resolving agents.

US 8,471,016 B2 discloses another process for the preparation of Sitagliptin and its intermediates as shown below:

In the above process, compound of Formula IIa or its enantiomer of Formula IIb are condensed with compound of Formula III or its salt thereof, to form a compound of Formula IVa, or its enantiomer of Formula IVb respectively. This is followed by hydrogenolysis of compound of Formula IVa or its enantiomer of a compound of Formula IVb to the give corresponding compound of Formula Ia or compound of Formula Ib. Optionally the compounds of Formula Ia or Ib are further converted to Sitagliptin or pharmaceutically acceptable salts.

While these methods are useful for preparing Sitagliptin, alternative methods of the preparation, particularly for manufacturing scale production, are desirable. Hence, there still exists a need for an efficient and economical synthesis of Sitagliptin or its pharmaceutically acceptable salts, which provides highly pure final product with high yield.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for preparation of novel intermediates of Sitagliptin or its pharmaceutically acceptable salts.
Another objective of the present invention is to provide novel intermediates of Sitagliptin or its pharmaceutically acceptable salts.

Another objective of the present invention is to provide an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts.

Another objective of the present invention is to provide an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts which is commercially feasible.

Yet another objective of the present invention is to provide a feasible and commercially viable process for preparation Sitagliptin or its pharmaceutically acceptable salts employing the novel intermediates.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of intermediate compound of Formula (IV)

Formula (IV)
where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (I)

Formula (I)
with R-NH2 to obtain an intermediate compound of Formula (II)

Formula (II)
where R is as defined above,
b) condensing the intermediate compound of Formula (II) with michael donor represented below

where Ph is substituted or unsubstituted, to obtain intermediate compound of Formula (III)

Formula (III)
where R and Ph are as defined above, and
c) reducing the intermediate compound of Formula (III) to obtain intermediate compound of Formula (IV)

Formula (IV)
where R and Ph are as defined above.

In another aspect, the present invention provides process for the preparation of intermediate compound of Formula (III)

Formula (III)
where R and Ph are as defined above, wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (I)

Formula (I)
with R-NH2 to obtain an intermediate compound of Formula (II)

Formula (II)
where R is as defined above,
b) condensing the intermediate compound of Formula (II) with michael donor represented below

where Ph is substituted or unsubstituted, to obtain intermediate compound of Formula (III)

Formula (III)
where R and Ph are as defined above.

In another aspect, the present invention provides process for the preparation of intermediate compound of Formula (II)

Formula (II)
where R is as defined above, by reacting the intermediate compound of Formula (I)

Formula (I)
with R-NH2 to obtain an intermediate compound of Formula (II)

Formula (II)
where R is as defined above.

In yet another aspect, the present invention provides the compound of Formula (II)

Formula (II)
where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

In yet another aspect, the present invention provides the compound of Formula (III)

Formula (III)
where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and Ph is substituted or unsubstituted.

In yet another aspect, the present invention provides an improved process for the preparation of compound of Formula (IV) which comprises reduction of the compound of Formula (III) with various reducing agents.

In yet another aspect, the present invention provides an improved process for the preparation of compound of Formula (VI)

Formula (VI)
comprising the step of:
a) converting intermediate compound of Formula (IV)

Formula (IV)
where R is as defined above; in the presence of metal catalyst to give compound of Formula (V)

where R is as defined above, and
b) hydrolysis followed by protection of amine group to give compound of Formula (VI).
In another aspect of the present invention provides an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (VI)

Formula (VI)
with acid halide of the following formula

where R1 represents alkyl and Hal represents halogen, in presence of base and solvent to give carbamate compound of Formula (VII)

Formula (VII)
where R1 is as defined above,
b) condensing the carbamate compound of Formula (VII) with Synthon (II)

Synthon II
optionally in situ to give compound of Formula (VIII), and

Formula (VIII)
c) hydrolysis of compound of Formula (VIII) to give Sitagliptin or its pharmaceutically acceptable salts.

In another aspect of the present invention provides an improved process for the preparation of intermediate compound of Formula (VIII)

Formula (VIII)
wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (VI)

Formula (VI)
with acid halide of the following formula

where R 1 represents alkyl and Hal represents halogen, in presence of base and solvent to give carbamate compound of Formula (VII)

Formula (VII)
where R1 is as defined above, and
b) condensing the carbamate compound of Formula (VII) with Synthon (II)

Synthon II
optionally in situ to give compound of Formula (VIII).

In another aspect of the present invention provides an improved process for the preparation of intermediate compound of Formula (VII)

Formula (VII)
where R1 is as defined above, wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (VI)

Formula (VI)
with acid halide of the following Formula

where R1 represents alkyl and Hal represents halogen, in presence of base and solvent to give carbamate compound of Formula (VII).

In yet another aspect, the present invention provides use of intermediate compounds of Formula (II), Formula (III), Formula (VII) and Formula (VIII) in the preparation of Sitagliptin or its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts.

The present invention provides an improved process for the preparation of intermediate compound of Formula (IV) starting from compounds of Formula (I).

The present invention also provides novel intermediate compounds of Formula (II) and Formula (III).

These intermediate compounds of Formula (II) and Formula (III) are used in the preparation of Sitagliptin or its pharmaceutically acceptable salts.

The present invention also provides process for the preparation of novel intermediate compound of Formula (II) and Formula (III).

The present invention also provides an improved process for the preparation of novel intermediate compound of Formula (IV), Formula (V), Formula (VI), Formula (VII) and Formula (VIII).

These intermediate compounds of Formula (IV), Formula (V), Formula (VI),
Formula (VII) and Formula (VIII) are used in the preparation of Sitagliptin or its pharmaceutically acceptable salts.

The compound of Formula (I) is converted to compound of Formula (II) by treating with an amine derivative R-NH2 in an organic solvent. After completion of the reaction, the organic solvent was distilled off and the obtained solid was washed with an appropriate solvent.

The obtained novel intermediate compound of Formula (II) is further converted to compound of Formula (III). In a specific embodiment, the obtained compound of Formula (II) is treated with substrate (R)-Phenylethylamine in presence of an organic acid in an organic solvent. After completion of the reaction, solvent was distilled off completely under vacuum to obtain compound of Formula (III).

The intermediate compounds of Formula (II) and intermediate compounds of Formula (III) may be isolated or not. Any of the above reactions may be carried out in-situ to obtain Sitagliptin or its pharmaceutically acceptable salts. The above compounds may be isolated as salts or free bases. If the above compounds are isolated as salts, they are converted to their free bases first and used for further reactions.

The intermediate compound of Formula (III) is reduced to intermediate compound of Formula (IV) using a reducing agent in an organic solvent. The reduction is carried out in the presence of an acid.

The hydrogenolysis of compound of Formula (IV) is converted in to compound of Formula (V) using metal catalysts with hydrogen pressure in the range of 8-12 kg/cm2 followed by hydrolysis and protection of amine group to give compound of Formula (VI).

The hydrogenolysis is carried out in an alcohol solvent using a catalyst followed by hydrolysis and protection of amine group to give compound of Formula (VI). This hydrogenolysis is carried out in presence of an acid and subsequent protection of the amine group which is carried out in situ. The appropriate amine protecting group are selected from acetyl, di-tert-butyl dicarbonate, benzoyl tert-butyloxycarbonyl (BOC), carbobenzyloxy, p-methoxybenzyl carbonyl, 9-fluorenylmethyloxycarbonyl, benzyl group, 3,4-dimethoxybenzyl, p-methoxyphenyl etc. more preferably di-tert-butyl dicarbonate.

The amine protection reaction is carried out in ether solvents. After completion of the reaction, solvent was removed and the crude product was washed with an appropriate solvent followed by pH adjustment with HCl. The organic layer and aqueous layer was washed with an organic solvent. The combined organic layer was again washed with water and distilled off completely under vacuum. The obtained crude was washed with an appropriate solvent and the obtained solid was filtered to give compound of Formula (VI).

The compound of Formula (VI) is further converted to carbamate compound of Formula (VII) using appropriate reactive acid derivatives, wherein the conversion may be optionally carried in-situ which in turn is condensed with Synton II to give compound of Formula (VIII).

The term reactive acid derivatives means halides like branched aliphatic carboxylic acid halides, such as e.g. 2-ethylbutyryl chloride, cyclohexanecarboxylic acid chloride, 2,2-dimethyl-propionyl chloride, pivaloyl chloride and isovaleroyl chloride and more preferably, acid derivatives are pivaloyl chloride, isovaleroyl chloride and ethyl chloroformate.

The intermediate compound of Formula (IV) is further converted to Sitagliptin or its pharmaceutically acceptable salts in a number of steps.

The compound of Formula (VI) further converted to Sitagliptin or its pharmaceutically acceptable salts.

The conversion of compound of Formula (VI) to compound of Formula (VIII) is carried out using any conventional bases. The conversion of compound (VI) to compound of Formula (VIII) is carried out in suitable solvent. Thus, obtained compound of Formula (VII) is coupled with Synthon II to obtain intermediate compound of Formula (VIII), wherein the carbamate and coupling process may be optionally carried out in-situ. The compound of Formula (VII) along with reactive acid halide is dissolved in suitable solvent and in a suitable base; then Synthon II is added portion wise. The reaction mixture is stirred for 4 hrs and after completion of the reaction, solvent is distilled off under vacuum and the obtained solid was dried to give compound of Formula (VIII) directly.

The obtained compound of Formula (VIII) is hydrolyzed to give Sitagliptin or its pharmaceutically acceptable salts. The hydrolysis is carried out by adding appropriate acid. The reaction mixture was stirred for 2 hrs and water was added. The reaction mixture was cooled and pH adjusted to 11-12. The reaction mixture was extracted with appropriate solvent and dried to give Sitagliptin.

Compound of Formula (I) can be prepared by any known methods in the art.

In another embodiment of present invention, alkyl group as used herein is a straight or branched, substituted or unsubstituted alkyl. The substituents on alkyl group are selected from C1-C6 alkyl, halogen such as chloro, bromo, fluoro, iodo; nitro, hydroxyl, 6 to 10 member aryl ring such as phenyl, napthyl.

In another embodiment of present invention, aryl group as used herein is substituted or unsubstituted selected from phenyl, naphthyl, anthryl, phenanthryl or biphenyl. The substituents on aryl group are selected from halogen such as chloro, bromo, fluoro, iodo; nitro, hydroxyl, cyano, amino.
In another embodiment of present invention, heteroaryl group as used herein is substituted or unsubstituted2,3-dihydroindene, indene, indoline, 3H-indole, 1H-indole, 2H-isoindole, indolizine, 1H-indazole, benzimidazole, 7-azaindole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindazole, pyrazolo[1,5-a] pyrimidine, purine, benzofuran, isobenzofuran, benzo[c]thiophene, benzo[b]thiophene, 1,2-benzisoxazole, 2,1-benzisoxazole, 1,2-benzisothiazole, 2,1-benzisothiazole, benzoxazole, benzthiazole, benzo[c][1,2,5]thiadiazole, 2-benzisothiazole-3(2H)-One, adenine, guanine. The substituents on heteroaryl group are selected from halogen such as chloro, bromo, fluoro, iodo, nitro, hydroxyl, (C1-C6) alkyl group, which may further be substituted, alkoxyalkyl, 6 to 10 member aryl ring such as phenyl, napthyl.

In yet another embodiment, solvent used in the present invention are selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, diethylether, pet-ether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane; amides such as dimethyl formamide, N-methyl acetamide, N,N-dimethyl acetamide; N-methyl pyrrolidone, dimethyl sulfoxide and/or mixtures thereof, preferably the solvent is alcoholic solvent and more preferably methanol.

In yet another preferred embodiment, base used in the present invention is selected from either inorganic base like ammonium hydroxide; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), aniline, triethylamine, triethanolaminetributylamine, N-alkyl morpholines, N-methylmorpholine, N-ethylmorpholine, dimethylaniline, N,N,N',N'-tetramethylethylenediamine, pyridines, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.

Reducing agent as used herein is and not limited to NaHg, ZnHg, ZnCl2, MgCl2, diborane, lithium borohydride, sodium borohydride, potassium borohydride, cesium borohydride iron sulfate, tin chloride, dithionates, DIBAL-H, phosphonic acid, hypophosphite, phosphite, tetrakis{3,5-trifluoromethyl}phenyl borate and 1,4-Dithio-D-threitol.

Acid used in hydrogenation herein is and not limited to inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, poly phosphoric acid, conc. H2SO4, organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid.

In another preferred embodiment, the present invention is to provide an improved process for the preparation of intermediate compound of Formula (IV)

Formula (IV)
where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (I)

Formula (I)
with R-NH2 in presence of organic solvent to obtain an intermediate compound of Formula (II)

Formula (II)
where R is as defined above,
b) condensing the intermediate compound of Formula (II) with michael donor represented below

in presence of an acid in an organic solvent, where Ph is substituted or unsubstituted, to obtain intermediate compound of Formula (III)

Formula (III)
where R and Ph are as defined above, and
c) reducing the intermediate compound of Formula (III) using an alkalimetal borohydride in presence of an acid in organic solvent to obtain intermediate compound of Formula (IV)

Formula (IV)
where R and Ph are as defined above.

In yet another preferred embodiment, the present invention is to provide an improved process for the preparation of compound of Formula (VI)

Formula (VI)
where R is as defined above; comprising the step of:
a) converting intermediate compound of Formula (IV)

Formula (IV)
in the presence of metal catalyst in an organic solvent to give compound of Formula (V), and

b) hydrolysis of compound Formula (V) in presence of an acid followed by protection of amine group in presence of solvent to give compound of Formula (VI).

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1: Preparation of 4-(2,4,5-trifluorophenyl)-3-oxo-N-phenylbutanamide (Formula II):
A stirred suspension of 5-(2-(2,4,5-trifluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Formula I) (150 g, 0.47 mol) was dissolved in toluene (600 ml) and heated to 50-55 °C. Aniline (43 g, 0.46 mol) was added drop wise over a period of 45 min to the reaction mixture. After addition of aniline, the reaction mixture was stirred at the same temperature for 18 hrs. After completion of the reaction as monitored by TLC, approximately half of the toluene was distilled under vacuum and the slurry was cooled to 0-5 °C. The obtained cake was filtered and washed with 50 ml of chilled toluene to obtain (135 g, 92%) the title product.
Purity by HPLC: >99%.

Example 2: Preparation of (Z)-3-((R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-N-phenylbut-2-enamide (Formula III):
A stirred mixture of 4-(2,4,5-trifluorophenyl)-3-oxo-N-phenylbutanamide (Formula II) (135 g, 0.43 mol) was dissolved in toluene (560 ml). (R)-Phenylethylamine (67 g, 0.55 mol) was added followed by acetic acid (4 ml) addition at room temperature. The reaction mixture was heated to 40-45 °C and maintained at the same temperature for 16 hrs. After completion of the reaction, toluene was completely distilled under vacuum to obtain the title compound (180 g, 100%) as dark yellow liquid.
Purity by HPLC: >99%.

Example 3: Preparation of (R)-3-((R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-N-phenyl butanamide (Formula IV):
The pre cooled solution of (Z)-3-((R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-N-phenylbut-2-enamide (Formula III) (180 g, 0.43 mol) was stirred in methylene dichloride (1800 ml) followed by addition of acetic acid (537 ml) at -20 °C over a period of 20 min. The reaction mixture was further cooled to -45 °C and sodium borohydride (17.5 g, 0.46 mol) added portion wise in 1 hr. Subsequently, the reaction temperature was allowed to reach to room temperature and quenched with 1000 ml of water slowly at below 20 °C. The pH of the reaction mixture was adjusted to 9 with 50% lye solution at below 20 °C. The organic layer was separated and washed with another 300 ml of water. The organic layer was distilled off completely and cooled to room temperature. Then Di isopropyl ether (300 ml) was added to the residue and stirred for 1 hr. The obtained solid was filtered and washed with diisopropyl ether again to obtain title compound (140 g, 80%).
Purity by HPLC: >99%, de : 99.7%.

Example 4: Preparation of (R)-Boc-3-amino-4-(2,4,5-trifluorophenyl) butanoic acid (Formula VI):
To a solution of (R)-3-((R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-N-phenyl butanamide (Formula IV) (50 g, 0.12 moles) was subjected to hydrogenolysis in methanol (500 ml) employing 5% Palladium on charcoal (6 g) as catalyst at 70 °C at a hydrogen pressure of 8 kg/cm2. After completion on reaction, the catalyst was removed by filtration and reaction mixture was concentrated under vacuum. Hydrochloric acid (100 ml) was added to the obtained reaction mixture and heated at 90 °C until the reaction was complete. The resulting reaction mixture was cooled to room temperature and 50% sodium hydroxide was added to the solution at below 35 °C. Then methylene dichloride (100 ml) was added under stirring for 10 min and organic layer was separated. The aqueous layer was cooled to 10 °C and tetrahydrofuran (100 ml) was added followed by DIBOC (21 g, 0.09 moles).The reaction mass stirred at 10-15 °C for 2 hrs and then the temperature was allowed to reach room temperature and further stirring was continued for 18 hrs. After completion of the reaction, tetrahydrofuran was distilled off under vacuum and the crude product was extracted with ethyl acetate (100 ml). The pH of the reaction mixture was adjusted to 2-3 with hydrochloric acid at 0-5 °C. The organic layer was separated and aq. layer was washed with another 100 ml of ethyl acetate. Combined organic layers were washed with water (100 ml) and distilled off completely under vacuum. n-Hexane (150 ml) was added to the crude product and stirred for 30 min at room temperature.
The obtained solid was filtered to obtain the title compound (23 g, 88%).
HPLC: 99.2% and Chiral purity by HPLC: >99%.

Example 5: Preparation of (3R)-3-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 (Formula VIII):
To a solution of (R)-Boc-3-amino-4-(2,4,5-trifluorophenyl) butanoic acid (Formula VI) (25 g, 0.084 moles) in methylene chloride (250 ml) was added morpholine (19.3 g, 0.221 moles) at 25 °C in 15 min. Then pivaloylchloride (10 g, 0.083 moles) was added slowly at 0-5 °C over a period of 1 hr. the reaction mixture was stirred at the same temperature for another 1 hr. Temperature was raised to 25-30 °C and stirred for 1 hr at the same temperature. Reaction mixture was cooled to 0 °C and added 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (Synthon II) (18.50 g, 0.081 moles) lot wise. The obtained reaction mixture was stirred at the same temperature for 4 hrs. Temperature was raised to room temperature and stirring was continued for another 12 hrs. The reaction completion was monitored by HPLC. Methylene chloride was distilled off and added 200 ml of DM water. The reaction mixture was stirred at room temperature for 30 min. The solid was filtered to obtain the title compound (35 g, 82%).
HPLC purity: 98%

Example 6: Preparation of Sitagliptin:
Conc. Hydrochloric acid was added to (3R)-3-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 (Formula VIII) (30 g, 0.059 moles) (45 ml) in 4 lots at 25-30 °C. The reaction mixture was stirred at the same temperature for another 2 hrs. 30 ml of water was added after completion of the reaction at 25-30 °C and the reaction mixture was cooled to 0-5 °C and pH was adjusted to 11-12 with ammonium hydroxide solution. Product was extracted with methylene chloride (2 x 150 ml) and dried over anhydrous sodium sulphate. The solvent was distilled off to obtain the title compound (22 g, 91%).
HPLC purity : 99%. Chiral purity by HPLC: >99% ,CLAIMS:We Claim:

1. An improved process for the preparation of intermediate compound of Formula (IV)

Formula (IV)
where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (I)

Formula (I)
with R-NH2 to obtain an intermediate compound of Formula (II)

Formula (II)
where R is as defined above,
b) condensing the intermediate compound of Formula (II) with michael donor represented below

where Ph is substituted or unsubstituted, to obtain intermediate compound of Formula (III)

Formula (III)
where R and Ph are as defined above, and
c) reducing the intermediate compound of Formula (III) to obtain intermediate compound of Formula (IV)

Formula (IV)
where R and Ph are as defined above.

2. The process as claimed in claim 1 for the preparation of intermediate compound of Formula (III)

Formula (III)
where R where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and Ph is substituted or unsubstituted, wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (I)

Formula (I)
with R-NH2 to obtain an intermediate compound of Formula (II)

Formula (II)
where R is as defined above,
b) condensing the intermediate compound of Formula (II) with michael donor represented below

where Ph is substituted or unsubstituted, to obtain intermediate compound of Formula (III)

Formula (III)
where R and Ph are as defined above.

3. The process as claimed in claim 1 for the preparation of intermediate compound of Formula (II)

Formula (II)
where R where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
by reacting the intermediate compound of Formula (I)

Formula (I)
with R-NH2 to obtain an intermediate compound of Formula (II)

Formula (II)
where R is as defined above.

4. Novel intermediate compound of Formula (II)

Formula (II)
where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

5. Novel intermediate compound of Formula (III)

Formula (III)
where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and Ph is substituted or unsubstituted.

6. An improved process for the preparation of compound of Formula (VI)

Formula (VI)
comprising the steps of:
a) converting intermediate compound of Formula (IV)

Formula (IV)
in the presence of metal catalyst to give compound of Formula (V)

where R where R = H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and
b) hydrolysis followed by protection of amine group to give compound of Formula (VI).

7. The process for the preparation of Sitagliptin or its pharmaceutically acceptable salts, wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (VI)

Formula (VI)
with acid halide of the following formula

where R1 represents alkyl and Hal represents halogen, in presence of base and solvent to give carbamate compound of Formula (VII)

Formula (VII)
where R1 is as defined above,
b) condensing the carbamate compound of Formula (VII) with Synthon (II)

Synthon II
optionally in situ to give compound of Formula (VIII), and

Formula (VIII)
c) hydrolysis of compound of Formula (VIII) to give Sitagliptin or its pharmaceutically acceptable salts.

8. The process as claimed in claim 7 for the preparation of intermediate compound of Formula (VIII)

Formula (VIII)

wherein the process comprises the steps of:
a) reacting the intermediate compound of Formula (VI)

Formula (VI)
with acid halide of the following formula

where R 1 represents alkyl and Hal represents halogen, in presence of base and solvent to give carbamate compound of Formula (VII)

Formula (VII)
where R1 is as defined above, and
b) condensing the carbamate compound of Formula (VII) with Synthon (II)

Synthon II
optionally in situ to give compound of Formula (VIII).

9. The process as claimed in claim 7 for the preparation of intermediate compound of Formula (VII)

Formula (VII)
where R1 is as defined above; wherein the process comprises:
reacting the intermediate compound of Formula (VI)

Formula (VI)
with acid halide of the following Formula

where R1 represents alkyl and Hal represents halogen, in presence of base and solvent to give carbamate compound of Formula (VII).

10. The process for preparation of Sitagliptin or its pharmaceutically acceptable salts comprising the process for preparing compounds of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) and Formula (VIII) as claimed in any of claims 1-9.

11. The process as claimed in claim 7, wherein the metal catalyst is selected from nickel, platinum and palladium; more preferably palladium.

12. The process as claimed in claim 1, wherein the reducing agent is selected from NaHg, ZnHg, ZnCl2, MgCl2, diborane, lithium borohydride, sodium borohydride, potassium borohydride, cesium borohydride iron sulfate, tin chloride, dithionates, DIBAL-H, phosphonic acid, hypophosphite, phosphite, tetrakis{3,5-trifluoromethyl}phenyl borate and 1,4-Dithio-D-threitol.

13. The process as claimed in claims 1-9, wherein the acid used in any of the claims is selected from inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, poly phosphoric acid, Conc. H2SO4, organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid.
14. The process as claimed in claims 7-8, wherein base is selected from either inorganic base like ammonium hydroxide; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), aniline, triethylamine, triethanolaminetributylamine, N-alkyl morpholines, N-methylmorpholine, N-ethylmorpholine, dimethylaniline, N,N,N',N'-tetramethylethylenediamine, pyridines, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

15. The process as claimed in claims 1-9, wherein the solvent used in any of claims is selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, diethylether, pet-ether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane; amides such as dimethyl formamide, N-methyl acetamide, N,N-dimethyl acetamide; N-methyl pyrrolidone, dimethyl sulfoxide and/or mixtures thereof, preferably the solvent is alcoholic solvent and more preferably methanol.

Dated this Thirty First (31st) day of October, 2019

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883