FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF SITAGLIPTIN
2. APPLICANT:
(a) NAME: Centaur Pharmaceuticals Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956.
(c) ADDRESS:Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai, Maharashtra India Pin Code: 400055.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
Present invention relates to aprocess for preparation of sitagliptin compound represented by structural formula (I)through a novel mix anhydride compound represented by structural formula (IX).

whereinR is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl, phenyl or substituted phenyl.
BACKGROUND OF THE INVENTION:
Sitagliptin is chemically defined as (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazole [4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine and is known from the US patent number6,699,871 and is represented by structural formula (I).

Sitagliptin is approved in the US as sitagliptin phosphate as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus and is marketed by brand name Januvia.Sitagliptin phosphate is also approved in the US in combination with Metformin hydrochloride which is marketed by the brand name Janumet and sitagliptin phosphateis also approved in the US in combination with Ertugliflozin which is marketed by the brand name Glyxambi.

U.S. Patent No.6,699,871 discloses process for preparation of sitagliptin compound represented by structural formula (I) wherein (3R)—N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid compound represented by structural formula (II) is coupled with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyrazine compound represented by structural formula (III) using l-ethyl-3-(3-dimethylaminopropyl)carbodimide (EDC), 1-hydroxy-benzotriazole (HOBT) and a base diisopropylethylamine to provide compound represented by structural formula (IV) which is further treated with methanol saturated with hydrochloric acid to provide sitagliptin compound represented by structural formula (I).

The above process is disadvantageous as it involves use of hazardous reagents like HOBT which is potentially explosive in anhydrous form and not safe to handle at commercial scale. Further, synthesis of intermediate compound represented by structural formula (IV) requires purification by the use of preparative HPLC which is very expensive and not a feasible technique on commercial scale.
PCT Publication No. 2009/064476 discloses process for the preparation of Sitagliptin compound represented by structural formula (I) wherein (3R)—N-(tert-butoxycarbonyl)-3-

amino-4-(2,4,5-trifluorophenyl)butanoic acid compound represented by structural formula (II) is coupled with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]-pyrazine compound represented by structural formula (III) using N, N'-dicyclohexylcarbodiimide (DCC) and a base triethylamine to provide compound represented by structural formula (IV) which is further treated inlPA with concentrated hydrochloric acid to provide sitagliptin compound represented by structural formula (I).

The above process is disadvantageous as it involves use of hazardous reagents like DCC.DCC vapours are extremely hazardous to inhalation and to the eyes and hence it is not safe to handle at commercial scale. Further, DCC is waxy solid that is often difficult to remove from a bottle or container.
PCT Publication No. 2004/085661 discloses process for the preparation of
sitagliptincompound represented by structural formula (I) wherein compound represented by
structuralformula (V) is condensed with 3-trifluoromethyl-5,6,7,8-
tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride compound represented by structural formula (III) to provide diketone compound compound represented by structural formula (VI) which is further treated with (S)-phenylglycine amide in isopropanol and acetic acid to obtain compound of formula (VII) which on asymmetric hydrogenation at 90 psi and 22°C for 24

hours in the presence of PtO2 as catalyst was converted to compound of formula (VIII) followed by debenzylation reaction carried out at 40 psi at 50°C in the presence of 20% palladium hydroxide on carbon to providesitagliptin compound represented by structural formula (I):

wherein Ph is a phenyl group.
The above process is disadvantageous as it involves the use of metal catalysts like PtO2 and palladium hydroxide which are very expensive and require high pressure for more than 24 hours which is not recommended on commercial scale.
In view of the above the inventors of present invention have designed an efficient, economical and eco-friendly process for the preparation of sitagliptin compound of structural

formula (I). Sitagliptin compound of structural formula (I) can be converted in to Sitagliptin phosphate salt by method disclosed in U.S. Patent No.7,326,708.
OBJECT OF THE INVENTION:
An object of the present invention is to provide a simple, cost efficient and environment friendly process for preparation of sitagliptin compound represented by structural formula (I).

Another object of present invention is to provide a novel mix anhydridecompound represented by structural formula (IX):

whereinR is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl, phenyl or substituted phenyl.

SUMMARY OF THE INVENTION:
First aspect of the present invention is to provide an efficient, economical, less hazardous and eco-friendly process for the preparation of sitagliptin compound represented by structural formula (I) comprising:
i. reacting compound represented by structural formula (II) with compound represented
by structural formula (X)to obtainmix anhydride compound represented by structural
formula (IX);

whereinR is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl, phenyl or substituted phenyl;
ii. reacting mix anhydridecompound represented by structural formula (IX) with compound represented by structural formula (III) to obtain compound represented by structural formula (IV);

III. treating compound represented by structural formula (IV) with acid to obtain sitagliptin compound represented by structural formula (I);

iv. optionally converting sitagliptin compound represented by structural formula (I) to pharmaceutically accepted salts, polymorphs, hydrates thereof.

Second aspect of the present invention is to provide process for the preparation of sitagliptin compound represented by structural formula (I) comprising:
i. reacting compound represented by structural formula (II) with compound represented by structural formula (X) in organic solvent in presence of base to obtain mix anhydride compound represented by structural formula (IX);

whereinR is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl, phenyl or substituted phenyl;
iii. treating compound represented by structural formula (IV) with acid to obtain sitagliptin compound represented by structural formula (I);

ii. reacting mix anhydridecompound represented by structural formula (IX) with compound represented by structural formula (III) to obtain compound represented by structural formula (IV);

iv. optionally converting sitagliptin compound represented by structural formula (I) to pharmaceutically accepted salts, polymorphs, hydrates thereof.
Third aspect of the present invention is to provide one pot process for the preparation of sitagliptin compound represented by structural formula (I) comprising:

i. reacting compound represented by structural formula (II) with compound represented by structural formula (X) in organic solvent in presence of base to obtainmix anhydridecompound represented by structural formula (IX) which is used for next step without isolation;

wherein R is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl, phenyl or substituted phenyl;
ii. reacting mix anhydridecompound represented by structural formula (IX) obtained in step (i) with compound represented by structural formula (III) to obtain compound represented by structural formula (IV) which is used for next step without isolation;

iii. treating compound represented by structural formula (IV)obtained in step (ii) with acid to obtain sitagliptin compound represented by structural formula (I);

iv. optionally converting sitagliptin compound represented by structural formula (I) to pharmaceutically accepted salts, polymorphs, hydrates thereof.
Fourth aspect of the present invention is to provide a novel mix anhydride compound represented by structural formula (IX):


whereinR is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl, phenyl or substituted phenyl.
DETAIL DESCRIPTION OF THE INVENTION:
Compound represented by structural formula (II) is prepared by method known in the art such as those described in U.S.Patent No. 6,699,871.
According to an aspect present invention provides process for preparation of sitagliptin compound represented by structural formula (I) as depicted in scheme below:

wherein R is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl,phenyl or substituted phenyl.
Compound represented by structural formula (II) is reacted with compound represented by structural formula (X) in organic solvent in the presence of base at a temperature in the range

of -10°C to 90°C for a period of 1 to 12 hours to obtain compound represented by structural formula (IX).
The examples of compoundrepresented by structural formula (X) may include but not limited to methyl chloroformate ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, phenyl chloroformate
Organic solvent is selected from the group consisting of toluene, xylene, mesitylene, anisole, heptane, hexane, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), dimethyl acetamide (DMA), tetrahydrofuran or mixture of thereof.
Base is selected from the group selected from triethylamine, trimethylamine, diisopropyl amine, diisopropyl ethyl amine, N-methyl morpholine or mixture thereof.
Compound represented by structural formula (IX) is optionally isolated by method of concentration, filtration, centrifugation or combination thereof or used without isolation for next step.
Compound represented by structural formula (IX) is reacted with compound represented by structural formula (III) in organic solvent at a temperature in the range of -10°C to 90°C for a period of 1 to 12 hours to obtain compound represented by structural formula (IV).
Organic solvent is selected from the group consisting of toluene, xylene, mesitylene, anisole, heptane, hexane, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), dimethyl acetamide (DMA), tetrahydrofuran or mixture of thereof.
Compound represented by structural formula (IV) is optionally isolated by method of concentration, filtration, centrifugation or combination thereof or used without isolation for next step,
Compound represented by structural formula (IV) is treated with acid at a temperature in the range of 0°C to 90°C for a period of 1 to 12 hours to obtain sitagliptin compound represented by structural formula (I).

Acid is hydrochloric acid dissolved in alcoholic solvent selected from the group consisting of methanolicHCl, ethanolic HCL, IPA.HC1.
Sitagliptin compound represented by structural formula (I)can be converted to pharmaceutically accepted salts, polymorphs, hydrates thereof by methods known in the art such as those described inU.S. Patent No.7,326,708.
EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example-1: Synthesis of Sitagliptin:
To a solution of (3R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid represented bystructural formula (II) (10 g) in Dimethyl formamide (50 mL) was added Triethyl amine (16.8 mL) and then Ethyl chloroformate (ECF) (4.56 g) was added to the resulting mixture at a temperature in the range of 0°C to 5°C within a period of 35-40 minutes. The resulting reaction mixture was stirred for a period of 2 hours at a temperature in the range of 0°C to 5°C to get mix anhydride compound represented bystructural formula (IX) (wherein R= -ethyl). The resulting reaction mixture containing mix anhydride compound represented bystructural formula (IX) (wherein R= -ethyl) was added 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo[4s3-a]pyrazine HC1 (7.20 g) in lot wiseand then the reaction mixture was stirred for a period of 2 hours at a temperature in the range of 0°C to 5°C and further stirred ata temperature in the range of 25°C to 35°C for a period of 2 hours. The resulting reaction mixture was then cooled to a temperature in the range of 0°C to 5°C and then water (200 mL) was added to the reaction mixture and stirred for a period of 2 hours to get solid. The resulting solid was filtered and washed with water (40 mL) andwet solidwas charged into RBF and then IPA-HCI solution (50mL) was added to RBF. The resulting reaction mixture was heated to a temperature in the range of 45°C to 50°C and was maintained for a period of 2 hours. Then IPA was distilled out completely under vacuum from reaction mixture.MDC (50 mL) and water (20 mL) was charged to the concentrated reaction mixture at a temperature in the range of 20°C to 35°C. Added 20% NaOH solution to maintain pH of reaction mixture in the range of 11-12 and stirred the reaction mixture for a

period of 30 minutes. Separated the organic layer and washed with saturated aqueous NaHC03 solution (20 mL), brine (30 mL) and dried over with anhydrous Na2S04. The solvent was evaporated from organic layer and the residue was dissolved in isopropanol (20 mL). The resulting solution was maintained at a temperature in the range of 50°C to 55°C for a period of 1 hour and then cooled down to a temperature in the range of 20°C to 35°C. Heptane (50 mL) was added to the solution to get solid. The resulting solid was filtered and washed with 20% isopropanol in heptane and dried over vacuum to getSitagliptin free base. Yield: (9.0 g) [74.0%]; HPLC Purity: 98.5%.

We Claim:
1. Process for the preparation of sitagliptin compound represented by structural formula
(I) comprising:
i) reacting compound represented by structural formula (II) with compound
represented by structural formula (X) to obtainmix anhydride compound
represented by structural formula (IX);

wherein R is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl, phenyl or substituted phenyl;
ii) reacting mix anhydride compound represented by structural formula (IX) with compound represented by structural formula (III) to obtain compound represented by structural formula (IV);

iii) treating compound represented by structural formula (IV) with acid to obtain sitagliptin compound represented by structural formula (I);

iv) optionally converting sitagliptin compound represented by structural formula (I) to pharmaceutically accepted salts, polymorphs, hydrates thereof.

2. The process as claimed in claim 1 (i) wherein Compound represented by structural formula (II) is reacted with compound represented by structural formula (X) in an organic solvent in the presence of baseat a temperature in the range of -10°C to 90°C.
3. The process as claimed in claim 2 wherein organic solvent is selected from the group consisting of toluene, xylene, mesitylene, anisole, heptane, hexane, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), dimethyl acetamide (DMA), tetrahydrofuran or mixture of thereof.
4. The process as claimed in claim 2 wherein base is selected from the group consisting of triethylamine, trimethylamine, diisopropyl amine, diisopropyl ethyl amine, N-methyl morpholine or mixture thereof.
5. The process as claimed in claim 1 (ii) wherein compound represented by structural formula (IX) is reacted with compound represented by structural formula (III) in organic solvent at a temperature in the range of-10°C to 90°C.
6. The process as claimed in claim 5 wherein organic solvent is selected from the group consisting of toluene, xylene, mesitylene, anisole, heptane, hexane, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), dimethyl acetamide (DMA), tetrahydrofuran or mixture of thereof.
7. The process as claimed in claim 1 (iii) wherein compound represented by structural formula (IV) is treated with acid at a temperature in the range of 0°C to 90°C for a period of 1 to 12 hours to obtain sitagliptin compound represented by structural formula (I).
8. The process as claimed in claim 7 wherein acid is hydrochloric acid dissolved in alcoholic solvent selected from the group consisting of methanolicHCl, ethanolic HCL, IPAHC1.
9. Amix anhydride compound represented by structural formula (IX):


wherein R is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl, phenyl or substituted phenyl.
10. Process for the preparation of mix anhydride compound represented by structural formula (IX) comprising reacting compound represented by structural formula (II) with compound represented by structural formula (X) to obtain mix anhydride compound represented by structural formula (IX);

wherein R is group selected from C1 to C5 alkyl, substituted C1 to C5 alkyl, phenyl or substituted phenyl;