CLIAMS:We Claim:
1. A process for the preparation of Sitagliptin or pharmaceutically acceptable salt thereof comprising the following steps:
a) reacting N-protected-3-((R)-amino)-4-(2,4,5-trifluorophenyl)-butyric acid of formula III

with pyrazine intermediate of formula IV or its salt

using acyl chloride in presence of base and solvent to provide N-protected-sitagliptin; and

b) treating the compound of formula II of step a)

with an acid at elevated temperature to provide Sitagliptin or pharmaceutically acceptable salt.

2. The process of claim 1, wherein said N-protection with PG is selected from acetyl, tert-butyl carbonyl, benzyloxy, benzyl, Fmoc and trifluoracetyl.

3. The process of claim 1, wherein said acyl chloride of step a) is selected from alkyl carbonyl chloride, alkyloxy carbonyl chloride, unsubstituted or substituted benzyloxy carbonyl chloride, for example, 4-nitrobenzyloxycarbonyl.

4. The process of claim 1, wherein said base of step a) is selected from inorganic base, for example, sodium carbonate.

5. The process of claim1, wherein said solvent is selected from ester solvent, for example, isopropyl acetate, alcohol, for example methanol, water or combination thereof.

6. The process of claim 1, wherein said acid is phosphoric acid.

7. A process for the preparation of Sitagliptin phosphate, comprising the steps of:
a) condensation of compound of formula IIIA or its salt

Formula IIIA
with compound of formula IVA or its salt

Formula IVA
using pivaloyl chloride in presence of base and solvent to provide Boc-sitagliptin of formula IIA;

Formula IIA
b) deprotecting the compound of formula IIA of step a) to Sitagliptin by the treatment with an acid at elevated temperature; and

c) treating Sitagliptin of step b) with alcoholic phosphoric acid in presence of alcohol to provide Sitagliptin phosphate.

8. The process of claim 7, wherein said Sitagliptin phosphate may prepared in one-pot synthesis.

9. The process of claim 7, wherein said alcoholic phosphoric acid is selected from alcohol saturated with phosphoric acid, for example, methanolic phosphoric acid, isopropanolic phosphoric acid and the like.

10. The process of claim 7, wherein said base is sodium carbonate, solvent is isopropyl acetate and acid is phosphoric acid.

Dated this 28th day of Jan, 2013 For Wockhardt Limited
(Dr Mandar Kodgule) Authorized Signatory
,TagSPECI:DESCRIPTION

The present invention provides a process for the preparation of Sitagliptin or its salt. The present invention also provides simple and cost effective process for intermediate of Sitagliptin.

Sitagliptin of Formula I is chemically known 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.

Formula I

Sitagliptin is an orally-active dipeptidyl peptidase-4 (DPP-IV) enzyme inhibitor that improves glycemic control in patients with Type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Sitagliptin is used as a monotherapy, as an adjunct to diet and exercise, or in combination with metformin or a PPARγ agonist (e.g., thiazolidinediones). Sitagliptin is approved under the brand name Januvia in the form of a Sitagliptin phosphate monohydrate.

U.S. patent No. 6,699,871 describes Sitagliptin and pharmaceutically acceptable salts thereof. It also discloses a process for the preparation of Sitagliptin hydrochloride which involves reaction of (3R)-3-[(1,1-dimethylethoxy-carbonyI)-amino]-4-(2,4,5-trifiuorophenyl)butanoic acid and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3- a]pyrazine using expensive reagents EDC and HOBT to provide 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4(2,4,5-trifiuorophenyl)-butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-α]pyrazine and then purified by expensive preparative TLC technique to provide its solid, which is then treated with methanol saturated with HCl to provide Sitagliptin hydrochloride.

PCT application No. 2004/087650 discloses a process for preparing Sitagliptin in which N-benzyloxy-3-((R)-amino)-4-(2,4,5-trifluorophenyl)-butyric acid reacted with pyrazine intermediate in presence of expensive reagents EDC.HCl and NMM to provide N-benzyloxy protected amide compound, which is deprotected with Pd/C to provide Sitagliptin.

U.S. Pat. No. 7,326,708 discloses Sitagliptin dihydrogenphosphate monohydrate and process for the preparation thereof using aqueous phosphoric acid.

Another synthetic approach asymmetric hydrogenation of β-enamino acid intermediate to provide Sitagliptin using expensive metal catalysts like ruthenium metal catalysts, rhodium diphosphine chiral catalysts, platinum oxide and sodium borohydride disclosed in following patent/non-patent literature: WO 09/064476, WO 04/085378, WO 05/097733, WO 06/081151, WO 04/085661, WO 2007/050485, WO 2010/122578, US 2009/0192326, WO 2005/03135 Hansen, K. B.; et. al. Journal of American Chemical Society 2009, 131, 8798-8804.; Hansen K. B.; et. al. Organic Process Research Development 2005, 9, 634-639.

Christopher K. Savile et.al. in Science, 2010, Vol. 329 no. 5989, Pages 305-309 discloses another route of synthesis for Sitagliptin which involves expensive and cumbersome biocatalytic asymmetric synthesis.

The processes for preparing Sitagliptin disclosed in the prior art suffer from one or more drawbacks such as involving the use of expensive and hazardous regents, like palladium, platinum oxide, rhodium catalyst, etc., expensive reagents like EDC, DCC, HOBT, etc.., and involves number of steps like formation of Hunig’s base intermediate, diketo intermediate and β-enamino intermediate, isolation of intermediates and purification of intermediates. Hence, there is an ongoing need for simple, cost effective, and industrially viable processes for the production of Sitagliptin and pharmaceutically acceptable salt thereof.

The present inventors developed a short, cost effective and industrially feasible process for Sitagliptin or pharmaceutically acceptable salt thereof. Further, the present inventors developed simple and cost effective process for intermediate of Sitagliptin.

In an aspect of the present invention is to provide a process for the preparation of Sitagliptin or pharmaceutically acceptable salt thereof. The process includes the steps of:
a) reacting N-protected-3-((R)-amino)-4-(2,4,5-trifluorophenyl)-butyric acid of formula III

with pyrazine intermediate of formula IV or its salt

using acyl chloride in presence of base and solvent to provide N-protected-Sitagliptin; and

b) treating the compound of formula II of step a)

with an acid at elevated temperature to provide Sitagliptin or pharmaceutically acceptable salt.

The step a) may involve activation of the acid compound of formula III first with acyl chloride in presence of base and solvent, and then reacting with the compound of formula IV for the formation of N-protected Sitagliptin:

The N-protection with PG (protecting group) is selected from acetyl, tert-butyl carbonyl, benzyloxy, benzyl, Fmoc, trifluoracetyl, and the like.

The acyl chloride is used as coupling agent for the formation of boc-sitagliptin. The acyl chloride is selected from alkyl carbonyl chloride, alkyloxy carbonyl chloride, unsubstituted or substituted benzyloxy carbonyl chloride, for example, 4-nitrobenzyloxycarbonyl and the like. The alkyl is selected from straight or branched alkyl such as C1-C5 alkyl. In embodiment of the present invention involves use of C4-branched alkyl such as tert-butyl.

The base used for the formation of N-protected-sitagliptin of step (a) is selected from inorganic base, for example,sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like or organic base for example triethyl amine, methyl amine, N-Methylmorpholine (NMM), di-isopropylethylamine (DIPEA) and the like.

The solvent used for the formation of N-protected Sitagliptin includes but are not limited to ester solvent, such as ethyl acetate, isopropyl acetate, 2-methoxyethyl acetate, n-butyl acetate and the like; alcohol such as methanol, ethanol, isopropyl alcohol and the like; water or combination thereof.

The reaction may be conducted at below room temperature, for example, 0-15°C, for a period of 1 hour to 6 hours or more for the activation of acid compound of formula III and converting it into the compound of formula II.

After completion of the reaction, the reaction mixture may be quenched with quenching agents, for example, water at any temperature depending on the reagents, for example, from 50 to about 80°C.

The resultant organic layer comprising the compound of Formula II may be separated and subjected for further reaction without isolation of solid.

The step b) involves addition of acid, for example, phosphoric acid, to the resultant organic layer of step a) at elevated temperature, for example, 50 to about 80°C to provide Sitagliptin or pharmaceutically acceptable salt. The reaction may be performed for a certain period, for example, 30 minutes to 3 hours.

After completion of the reaction between the compound of formula II and acid, the reaction mixture is diluted with water and then directed to basification of aqueous layer comprising Sitagliptin or pharmaceutically acceptable salt thereof by treating with base, for example, potassium hydroxide.

The resultant product, Sitagliptin, is extracted into chlorinated solvent, for example, dichloromethane, chloroform, and the like. The organic layer may be concentrated to residue and used directly for further reaction or it may be subjected to isolation of Sitagliptin base using ether solvent, for example, diethyl ether, diisopropyl ether or methyl tert-butyl ether (MTBE).

The term “salt" in the phrase of "Sitagliptin or its salt," "Sitagliptin or pharmaceutically acceptable salt" and other similar phrases encompass hydrochloride salt, phosphate salt, tartarate salt, mandalate salt and the like.

The Sitagliptin or pharmaceutically acceptable salt thereof obtained from the present invention has purity greater than or equal to 99.9% and yield greater than 80%.

In another aspect of the present invention is to provide a process for the preparation of Sitagliptin phosphate, include the steps of:
a) condensation of compound of formula IIIA or its salt

Formula IIIA
with compound of formula IVA or its salt

Formula IVA
using pivaloyl chloride in presence of base and solvent to provide Boc-sitagliptin of formula IIA;

Formula IIA

b) deprotecting the compound of formula IIA of step a) to Sitagliptin by the treatment with an acid at elevated temperature; and

c) treating Sitagliptin of step b) with alcoholic phosphoric acid in presence of alcohol to provide Sitagliptin phosphate.

In an embodiment, the compound of formula IIA of present invention may be prepared in-situ.

In another embodiment, the present invention also involves a one pot process for Sitagliptin phosphate by preparing the compound of Formula IIA and Sitagliptin base in-situ.

The base used for conducting the step a) is selected from inorganic base, for example, sodium carbonate.

The solvent used for preparing the compound of formula IIA of step a) is a selected from ester solvent, for example, isopropyl acetate, n-butyl acetate and the like; water or combination thereof. In an embodiment, the use of isopropyl acetate of the present invention provides an efficient reaction conditions due to its stability in both acidic and basic conditions for step a) as well as for step b).

The acid used for the deprotection of compound of formula IIA of step b) is selected from inorganic acid, for example, phosphoric acid.

The suitable temperature for the deprotection of step b) is elevated temperature, for example, 50 to about 80°C. The reaction may be performed for a certain period of time, for example, 30 minutes to 3 hours.

After completion of the reaction of step b), the reaction mixture is diluted with water and then directed to basification of aqueous layer with base, for example, potassium hydroxide.

The resultant product, Sitagliptin, is extracted into chlorinated solvent, for example, dichloromethane, chloroform, and the like. The organic layer may be concentrated to residue and used directly for further reaction or it may be subjected to isolation of Sitagliptin base using ether solvent, for example, diethyl ether, diisopropyl ether or methyl tert-butyl ether (MTBE).

The resultant Sitagliptin of present invention is converted to Sitagliptin phosphate having purity greater than 99.9% using alcoholic phosphoric acid in presence of alcohol. The alcohol used for the preparation of alcoholic phosphoric acid and as a solvent for the reaction is selected from methanol, ethanol, isopropyl alcohol, n-butanol and the like.

The Sitagliptin phosphate obtained from the present invention has particle size d(0.9) less than 250 microns or less than 150 microns or less than 50 microns, d(0.5) less than 150 or less than 100 or less than 20 microns and d(0.1) less than 50 microns or less than 10 microns or less than 5 microns .

The resultant pure Sitagliptin phosphate may be utilized for the preparation of pharmaceutical composition by using known process of the prior art.

In another aspect of the present invention is to provide a process for the preparation of intermediate of Sitagliptin, the compound of formula IIA, comprising condensing the compound of formula IIIA with hydrochloride salt of formula IVA using pivaloyl chloride in presence of base and solvent to provide Boc-sitagliptin of formula IIA.

The base used for conducting the step a) is selected from inorganic base, for example, sodium carbonate.

The solvent used for preparing the compound of formula IIA of step a) is selected from water, ester solvent, for example, isopropyl acetate, n-butyl acetate and the like or combination thereof.

The boc-sitagliptin obtained from the present invention can be converted to sitatagliptin or pharmaceutically acceptable salt thereof

The present invention is further illustrated by the following example, which does not 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 application.

EXAMPLES
Example -1: One pot process for preparing Sitagliptin phosphate:

Boc-Butanoic acid of formula IIIA (100 gm) was dissolved in isopropyl acetate (1500ml). Sodium carbonate solution was added (70 gm in 350 ml water) and cooled to 0-5 0C. Pivaloyl chloride ( 45 gm ) was added, maintained for 3 hours at 5-10 0C and then triazole (85 gm) of formula IVA was added and maintained for additional 3 hours. After completion of the reaction, the reaction mixture was quenched with water (800 ml), heated 65-70 0C to dissolve the materials and separated the layers. The organic layer contains Boc-Sitagliptin of formula IIA was directly taken into next step.

Phosphroic acid (140 gm) was added to the above organic layer and heated to 65-70 0C for 3 hr. After completion of the reaction, water was added. The aqueous layer contains compound was basified with potassium hydroxide solution (200 gm in 600 ml water). The product is extracted with DCM (1000 ml) and then concentrated to residue.

The residue was dissolved in IPA (500 ml) at 50-60 0C and then phosphoric acid solution was added (23.8 gm in 90 ml IPA) at 50 -60 0C slowly. After completion of the addition, cooled to 10-15 0C, filtered and dried to get Sitagliptin Phosphate.

Yield: 120 gm (80%).
HPLC purity: 99.9 %;
Single largest impurity: below 0.05%.

Example-2:

Stage-I: Preparation of Sitagliptin:
Boc-Butanoic acid (100 gm) of formula IIIA was dissolved in isopropyl acetate (1500ml) and then sodium carbonate solution was added (70 gm in 350 ml water). The reaction mixture was cooled to 0-5 0C and then pivaloyl chloride ( 45 gm ) was added. The reaction mixture was maintained for 3 hours at 5-10 0C and then triazole (85 gm) was added and maintained for additional 3 hours. After completion of the reaction, the reaction mixture was quenched with water (800 ml), heated 65-70 0C to dissolve the materials and then separated the layers. The organic layer contains Boc Sitagliptin was directly is taken into next step.

Phosphroic acid (140 gm) was added to the above organic layer and heated to 65-70 0C for 3 hr. After completion of the reaction, water was added. The aqueous layer contains compound was basified with potassium hydroxide solution (200 gm in 600 ml water). The product was extracted with DCM (1000 ml) and then concentrated to residue and isolated from MTBE (500 ml) to get Sitagliptin Base.

Yield: 110 gm (90%).
HPLC purity: >99.5%, single largest impurity NMT 0.1%.

Stage-II: Preparation of Sitagliptin Phosphate
Sitagliptin Base (90 gm) was dissolved in methanol (450 ml) at 50-60 0C and then phosphoric acid solution was added (23.8 gm in 90 ml methanol) at 50 -60 0C slowly. After completion of the addition, the reaction mixture was cooled to 10-15 0C, filtered and dried to get Sitagliptin Phosphate.

Yield: 103 gm (94%).
HPLC purity: 99.9 %.
Single largest impurity: below 0.05%.