DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“A PROCESS FOR PURIFICATION OF SITAGLIPTIN OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF”

Laurus Labs Limited, an Indian company of DS-1, IKP Knowledge Park, Genome valley, Turkapally, Shameerpet Mandal, Medchal-Malkajgiri District, Hyderabad-500 101, 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 generally relates to a process for purification of sitagliptin or pharmaceutically acceptable salts thereof. In particular, the present invention relates to a process for purification of sitagliptin hydrochloride and sitagliptin phosphate salts.

BACKGROUND OF THE INVENTION:

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 may be used as a monotherapy, as an adjunct to diet and exercise, or in combination with metformin or a PPARy agonist (e.g., thiazolidinediones).

Sitagliptin is chemically designated as (3R)-3-amino-l-[9-(trifluoromethyl)-1,4,7,8- tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-l-one, is represented by the following structural Formula I:

Sitagliptin phosphate monohydrate, in combination with metformin hydrochloride, is sold by Merck & Co., Inc. using the brand JANUMET™ in the form of tablets for oral administration, for combination therapy in the treatment of type 2 diabetes.

U.S. Patent No. 6,699,871 discloses various DPP-IV inhibitors including sitagliptin and their pharmaceutically acceptable salts, a pharmaceutical composition and method of treatment and a process for preparation of sitagliptin hydrochloride by treating Boc-protected sitagliptin with methanol saturated with HCl.

U.S. Patent No. 7,326,708 (“the ‘708 patent”) discloses dihydrogen phosphate salt of sitagliptin and crystalline hydrate thereof, in particular a crystalline monohydrate and processes for the preparation thereof. The process mainly involves treatment of sitagliptin free base (I) with 85% phosphoric acid in a mixture of isopropanol (IPA) and water in the presence of seed crystals of sitagliptin phosphate monohydrate followed by adding further isopropanol and isolating sitagliptin phosphate monohydrate after drying on frit with open to air.

Since the discovery of Sitagliptin, a number of processes described in the literature. Most processes consist of the reaction of protected amino acid (compound of formula II) with a triazolopyrazine intermediate (Compound of formula III) to form protected sitagliptin (compound of formula IV) using well-established amide coupling procedures followed by deprotection to get sitagliptin (compound I). Later, more sophisticated procedures including asymmetric reductive aminations, chiral auxiliary transformations, and enzymatic transamination have also been described.

Predominant amide coupling and deprotection synthesis is represented as follows:

It is well known to a skilled person that most chemical reactions are not completely finished, may be reversible or are driven simultaneously with some other parallel reactions. Starting materials, side reaction products or degradation products are usually found as impurities in the isolated main product which should therefore be further purified. Therefore, intermediate products such as Compounds of formula II and III used in the manufacturing process of Sitagliptin are also potential impurities of the active pharmaceutical ingredient (API) of Sitagliptin.

Recently, a nitrosamine impurity, Nitroso-STG-19 (also known as NTTP impurity), has been found in trace amounts in sitagliptin products which may be formed during product manufacturing and during subsequent storage of the drug product. Structure of the NTTP impurity is as follows:

The present inventors have found that preparation of sitagliptin or pharmaceutically acceptable salts thereof especially the hydrochloride and phosphate salts resulted in contamination of the product with higher levels of its starting materials and genotoxic impurities such as compound of formula III and NTTP impurity which makes the process unsuitable. Further, requires extensive purification techniques to get pure sitagliptin or pharmaceutically acceptable salts thereof free from the genotoxic impurities.

PCT publication No. WO2023/181076 (The ‘076 publication) disclosed Sitagliptin or a salt thereof having less than about 100 ppm of compound of Formula III or salt thereof and/or having less than about 1 ppm of NTTP impurityand a process for its preparation by providing a solution of Sitagliptin or a pharmaceutically acceptable salt thereof in a suitable solvent, optionally, adding an anti-solvent to the obtained solution and isolating Sitagliptin or a pharmaceutically acceptable salt thereof.

Typically, most cases of N-nitrosamine contamination can be attributed to the presence of nitrites and relevant amines during the manufacturing process and appropriate conditions (for example elevated temperatures, acidic conditions, and liquid phase). In the case of Sitagliptin, compound III, either as carry forwarded impurity or as degradation impurity, is able to undergo a nitrosation reaction in the presence of any nitrosating agent (such as nitrites) to form NTTP impurity, which might have carcinogenic potential because it belongs to the class of N-nitrosamines.

Regulatory authorities worldwide require the drug manufacturers to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present at the lowest possible levels, even if structural determination is not possible. Due to the new requirements of Health Agencies on genotoxic compounds, the presence of genotoxic impurities make the use of such sitagliptin salts unsuitable for human if these contain impurities beyond set exposure limits. Thus, the active ingredient as well as pharmaceutical preparations made therefrom requires the presence of impurities well within the limitsor as low as possible in order to comply with regulatory guidance.

In this view, there is a dire need for an efficient and improved process for the purification of sitagliptin or pharmaceutically acceptable salts thereof eliminating or minimizing to acceptable limit of genotoxic impurities, particularly NTTP and compound of formula III.

SUMMARY OF THE INVENTION:

Accordingly, the present invention provides simple, cost effective and reproducible process for the preparation of Sitagliptin or pharmaceutically acceptable salts thereof, especially Sitagliptin phosphate or sitagliptin hydrochloride substantially free of genotoxic impurities.

In accordance with another embodiment, the present invention provides Sitagliptin or pharmaceutically acceptable salts thereofhaving less than about 1 ppm of NTTP impurity or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides Sitagliptin or pharmaceutically acceptable salts thereofhavingless than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides Sitagliptin or pharmaceutically acceptable salts thereofhaving less than about 10ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides Sitagliptin or pharmaceutically acceptable salts thereof havingless than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides Sitagliptin or pharmaceutically acceptable salts thereofhaving less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides Sitagliptin or pharmaceutically acceptable salts thereof havingless than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm, or less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides processes for the preparation of Sitagliptin or pharmaceutically acceptable salts thereofhaving less than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; comprising treating sitagliptin hydrochloride having compound of formula III or salt thereof and/or NTTP impurity with a base to get sitagliptin of formula I and converting it into sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin Hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS, the process comprising:
a) providing a solution of sitagliptin hydrochloride having a compound of formula III or salt thereof and/or NTTP impurity in water;
b) adding a base to the step a) reaction mass to get sitagliptin of formula I,
c) providing a solution or suspension of sitagliptin of formula I in a suitable solvent or mixture of solvents;
d) adding hydrochloric acid to the step c) reaction mass; and
e) isolating sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin Hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS, the process comprising:
a) providing a solution of sitagliptin hydrochloride having a compound of formula III or salt thereof and/or NTTP impurity in water;
b) adding a base to the step a) reaction mass;
c) extracting the reaction mass with a suitable water immiscible organic solvent;
d) removing the organic solvent to obtain sitagliptin of formula I;
e) dissolving the sitagliptin of formula I in a suitable solvent or mixture of solvents;
f) adding hydrochloric acid to the step e) solution; and
g) isolating sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS, the process comprising:
a) providing a solution of sitagliptin phosphate having a compound of formula III or salt thereof and/or NTTP impurity in water;
b) adding a base to the step a) reaction mass to get sitagliptin of formula I,
c) providing a solution or suspension of sitagliptin of formula I in a suitable solvent or mixture of solvents;
d) adding phosphoric acid to the step c) reaction mass; and
e) isolating sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS, the process comprising:
a) providing a solution or suspension of Sitagliptin or pharmaceutically acceptable salts thereof having a compound of formula III or salt thereof and/or NTTP impurity in a suitable solvent or mixture of solvents;
b) stirring the step a) reaction mass; and
c) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS:

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS, the process comprising:
a) providing a solution or suspension of Sitagliptin hydrochloride having a compound of formula III or salt thereof and/or NTTP impurity in a suitable solvent or mixture of solvents;
b) stirring the step a) reaction mass; and
c) isolating sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; comprising providing a solution or suspension of Sitagliptin phosphate having compound of formula III or salt thereof and/or NTTP impurity with a suitable solvent or mixture of solvents and isolating the Sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing a solution or suspension of Sitagliptin phosphate having a compound of formula III or salt thereof and/or NTTP impurity in a suitable solvent or mixture of solvents;
b) stirring the step a) reaction mass; and
c) isolating Sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing a solution or suspension of sitagliptin phosphate having a compound of formula III or salt thereof and/or NTTP impurity in a suitable solvent or mixture of solvents;
b) stirring the step a) solution or suspension at a temperature from about 40°C to about 80°C;
c) optionally adding a suitable solvent or mixture of solvents to step b) solution or suspension;
d) cooling the step b) solution or suspension to a temperature from about 5°C to about 35°C; and
e) isolating Sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing sitagliptin or pharmaceutically acceptable salts thereof in a suitable solvent;
b) treating the step a) reaction mass with a suitable nitrite scavenger; and
c) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing sitagliptin hydrochloride in a suitable solvent;
b) treating the step a) reaction mass with a suitable nitrite scavenger; and
c) isolating sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing sitagliptin phosphate in a suitable solvent;
b) treating the step a) reaction mass with a suitable nitrite scavenger; and
c) isolating sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing a solution or suspension of sitagliptin or pharmaceutically acceptable salts thereof in a suitable solvent;
b) adding an anti-solvent to step a) reaction mass; and
c) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing a solution or suspension of sitagliptin hydrochloride in a suitable solvent;
b) adding an anti-solvent to step a) reaction mass; and
c) isolating sitagliptin hydrochloride having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing a solution or suspension of sitagliptin phosphate in a suitable solvent;
b) adding an anti-solvent to step a) reaction mass; and
c) isolating sitagliptin phosphate having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides pharmaceutical compositions comprising Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm, less than about 0.5 ppm less than about 0.1 ppm or less than less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS and at least one pharmaceutically acceptable excipient.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising Sitagliptin hydrochloride having less than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS and at least one pharmaceutically acceptable excipient.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising Sitagliptin phosphate having less than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS and at least one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION:

As used herein, the term “genotoxic impurity or impurities” refers to compound of formula III or NTTP impurities either alone or in combination.

The term “Sitagliptin or pharmaceutically acceptable salts thereof”used as starting material throughout the present invention is known in the art and can be prepared by any known method, for example itmay be synthesized as disclosed in U.S. Patent Nos. 6,699,871, 7,326,708; PCT publication Nos. WO2005072530 & WO2015170340 or any suitable methods resulting in formation of sitagliptin or pharmaceutically acceptable salts thereof, which are incorporated herein by reference. Further, Sitagliptin or pharmaceutically acceptable salts thereof used as starting material may be in any form such as crude obtained directly from the reaction mass, crystalline, amorphous or other forms of Sitagliptin or pharmaceutically acceptable salts thereof, including various solvates and hydrates known in the art.

The term "Sitagliptin hydrochloride or sitagliptin phosphate" used throughout the specification refers to not only Sitagliptin hydrochloride or sitagliptin phosphate per se, but also its pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

Sitagliptin or pharmaceutically acceptable salts thereof used as starting material may contain any quantity of compound of formula III or salt thereof and/or NTTP impurity, for example Sitagliptin or pharmaceutically acceptable salts thereof used as starting material may contain more than about 0.05 ppm, 0.1 ppm, 0.5 ppm, 1 ppm, 1.5 ppm, 5 ppm of NTTP impurity or salt thereof by LC-MS and/or above about 5 ppm, 10 ppm, 20 ppm, 40 ppm, 50 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with one embodiment, the present invention provides processes for the preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides processes for the preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than about0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm of compound or less than about 5 ppm of formula III or salt thereof by LC-MS.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS, the process comprising:
a) providing a solution of Sitagliptin or pharmaceutically acceptable salts thereof having a compound of formula III or salt thereof and/or NTTP impurity in water;
b) adding a base to the step a) reaction mass to get sitagliptin of formula I,
c) providing a solution or suspension of sitagliptin of formula I in a suitable solvent or mixture of solvents;
d) adding suitable acid to the step c) reaction mass; and
e) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

Step a) of the foregoing process involves stirring Sitagliptin or pharmaceutically acceptable salts thereof in water at a suitable temperature such as 0°C to reflux temperature for a period of time from about 5 minutes to until complete dissolution. Preferably, stirring may be carried out at a temperature of about 10°C to about 50°C for about 5 minutes to about 30 minutes.

Then the reaction solution may be treated with a base, which is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, preferably sodium hydroxide.

In another embodiment, the step b) of the above embodiment further comprises
i) extracting the reaction mass with a suitable water immiscible organic solvent; and
ii) removing the organic solvent to obtain sitagliptin of formula I.

In another embodiment, the resulting reaction mass obtained after step b) of the above embodiment containing sitagliptin base may be extracted with a suitable water immiscible organic solvent and then the organic layer may be separated and distilled under vacuum to obtain a residue containing sitagliptin of formula I.

The water immiscible organic solvent includes, but are not limited to esters such as ethyl acetate, isopropyl acetate and the like; ethers such as methyl tertiary butyl ether, diethyl ether and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like and mixtures thereof, preferably dichloromethane.

The residue so obtained after the solvent distillation step is either suspended or dissolved in a suitable organic solvent or a mixture of solvents at a suitable temperature of about 30°C to about reflux temperature, preferably about 40°C to about 60°C, to provide a solution or suspension of sitagliptin of formula I.

The suitable organic solvent used in the step c) include, but are not limited to alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol, t-butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol, ethylene glycol, and the like; ethers such as diethyl ether, 1,4-dioxane, DIPE, MTBE, THF and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, and the like; water; and suitable mixtures of one or more of the solvents, preferably the organic solvent is selected from methanol, isopropanol or water and mixtures thereof.

Then, the resulted suspension or solution containing the sitagliptin of formula I is treated with suitable acid such as for e.g. hydrochloric acid or phosphoric acid. The acid can be added either as a solution in one or more solvents as herein before defined or it may be added directly to the solution. The reaction mixture may be stirred at a temperature from about 30°C to about reflux temperature, preferably about 40°C to about 90°C.

Thereafter, the reaction mass may be gradually cooled to a temperature of about 0°C to about 50°C and stirred for a period of time from about 5 mins to about 24 hrs prior to isolation of the product. Preferably, the reaction mass may be cooled to a temperature of about 10°C to about 40°C and stirred for 30 mins to about 5 hrs.

Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 20°C to about 80°C. The resultant product may optionally be exposed to relative humidity, water, or atmospheric environment for a sufficient period suitable for the complete formation of sitagliptin or pharmaceutically acceptable salts thereof.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS;the process comprising:
a) providing a solution or suspension of Sitagliptin or pharmaceutically acceptable salts thereof having a compound of formula III or salt thereof and/or NTTP impurity in a suitable solvent or mixture of solvents;
b) stirring the step a) reaction mass; and
c) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

Step a) of the foregoing process involves adding sitagliptin or pharmaceutically acceptable salts thereof to a suitable solvent or mixture of solvents or vice versa. Typically, the process involves slurrying sitagliptin or pharmaceutically acceptable salts thereof in a suitable solvent or mixture of solvents at a suitable temperature such as 25°C to reflux temperature of the solvent, preferably about 30°C to about 70°C and stirring for a period of time from about 5 minutes to 12 hours, preferably 1 hr to about 5 hrs.

The suitable organic solvent used in the step a) include but are not limited to alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol, t-butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol, ethylene glycol, Propylene glycol, isoamyl alcohol and the like; ketones such as acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone and the like; ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, cyclopentyl methyl ether, propylene glycol methyl ether and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, and the like; halogenated solvents such as methylene chloride, chloroform, and the like; aliphatic hydrocarbon solvents such as hexane, heptane and the like; cyclic hydrocarbon solvents such as cyclohexane and the like; aromatic hydrocarbon solvents such as toluene and the like; nitriles such as acetonitrile, propionitrile, and the like; amides such as dimethylformamide, dimethyl acetamide and the like; and water and mixtures thereof. Preferably, the suitable solvent is selected from isopropanol, water and mixtures thereof.

Step b) involves stirring sitagliptin or pharmaceutically acceptable salts thereof at a suitable temperature such as 25°C to reflux temperature of the solvent, preferably about 30°C to about 70°C for a period of time from about 5 minutes to 12 hours, preferably 1 hr to about 5 hrs. If required additional amount of solvent selected from the aforementioned list may be added to completely precipitate out the product.

The resultant reaction mass may be cooled to a temperature in the range of from about 0°C to about 50°C, preferably about 10°C to about 40°C and stirred for a period of about 10 mins to about 15 hrs, preferably about 1 hr to about 12 hrs.

Isolation of Sitagliptin or pharmaceutically acceptable salts thereof may be carried out by employing conventional techniques, for example filtration, and the resultant wet product may optionally be dried at a temperature of about 20°C to about 80°C for a period of about 1 hour to 15 hours. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS;the process comprising:
a) providing sitagliptin or pharmaceutically acceptable salts thereof in a suitable solvent;
b) treating the step a) reaction mass with a suitable nitrite scavenger; and
c) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

Step a) of the foregoing process involves providing sitagliptin or pharmaceutically acceptable salts thereof in a suitable solvent. Typically, this step involves adding a suitable solvent or mixture of solvents to sitagliptin or pharmaceutically acceptable salts thereof, for e.g. sitagliptin hydrochloride or phosphate salts, and stirring at a suitable temperature such as 10°C to reflux temperature, preferably about 30°C to about 70°C.

The suitable organic solvent used in the step a) include but are not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons such as hexane, heptane, pentane and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like and mixtures thereof, preferably selected from methanol, isopropanol and mixtures thereof.

Step b) involves treating the resultant reaction mass with a suitable nitrite scavenger at a temperature of about 10°C to about reflux temperature, preferably about 30°C to about 70°C and stirring for about 5 minutes to about 10hrs, preferably 1 hr to about 5 hrs.

Suitable nitrite scavenger is selected from the group ascorbic acid, sodium ascorbate, ascorbyl palmitate, maltol, propyl gallate, para-aminobenzoic acid (PABA), L-cysteine, resveratrol, butylated hydroxyanisole, butylated hydroxytoluene, glycine, Arginine, lysine, Histidine, urea, sodium sulfite, ammonium sulfate, ammonium chloride, sulfamic acid, hydrazoic acid, and tocopherol and mixtures thereof, preferably propyl gallate.

Thereafter, isolation of the product can be carried out by conventional technique known in the art, for example isolation can be carried out by distilling the reaction mass or by cooling the reaction mass to a temperature of about 0°C to 40°C, preferably 20°C to about 40°C and stirred for a period of time from 5 mins to 10 hrs, preferably about 5 hrs to about 9 hrs. The reaction mass may be filtered and further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

In accordance with another embodiment, the present invention provides a process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS;the process comprising:
a) providing a solution or suspension of sitagliptin or pharmaceutically acceptable salts thereof in a suitable solvent;
b) adding an anti-solvent to step a) reaction mass; and
c) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

Step a) of the foregoing process involves providing a solution or suspension of sitagliptin or pharmaceutically acceptable salts thereof in a suitable solvent at a suitable temperature such as 25°C to reflux temperature of the solvent, preferably about 30°C to about 70°C for a period of time from about 5 minutes to 10hrs, preferably about 30 mins to about 2hrs to form a solution or suspension.

The suitable organic solvent used in the step a) include but are not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons such as hexane, heptane, pentane and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like and mixtures thereof. Preferably, the suitable solvent is methanol or isopropanol.

Step b) of the foregoing process involves adding the step a) reaction mass into an anti-solvent or vice versa. The anti-solvent used for step b) includes solvent selected from aforementioned step. Typically, the anti-solvent is added to reaction mass and stirred at a temperature from about 25°C to reflux temperature of the solvent, preferably about 30°C to about 70°C for a period of time from about 5 minutes to 5 hrs, preferably about 30 mins to about 2 hrs.

Isolation of the product can be carried out by conventional technique known in the art, for example by cooling the reaction mass to a temperature of about 0°C to 50°C, preferably about 10°C to about 40°C and stirring for a period of time from about 5 minutes to 10 hrs, preferably 1 hr to about 4 hrs followed by filtration. The resultant wet product may be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

The resulting Sitagliptin or pharmaceutically acceptable salts thereof as obtained by the process described herein is having a chemical purity of at least about 98%, as measured by HPLC, preferably at least about 99%, as measured by HPLC, and more preferably at least about 99.8%, as measured by HPLC and free of genotoxic impurities.

The resulting Sitagliptin or pharmaceutically acceptable salts thereof as obtained by the process described herein is having less than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS.

The resulting Sitagliptin or pharmaceutically acceptable salts thereof as obtained by the process described herein is having less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS.

The resulting Sitagliptin or pharmaceutically acceptable salts thereofhaving less than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS.

The Sitagliptin or pharmaceutically acceptable salts thereof, especially sitagliptin hydrochloride or phosphate salt obtained in the present invention may be stable for period of from 1 month to 12 months or longer when stored under pharmaceutically acceptable conditions under normal or accelerated storage conditions.

In accordance with another embodiment, the present invention provides pharmaceutical compositions comprising Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS and at least one pharmaceutically acceptable excipient.

In accordance with another embodiment, the present invention provides pharmaceutical compositions comprising Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS and at least one pharmaceutically acceptable excipient.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising Sitagliptin hydrochloridehaving less than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS and at least one pharmaceutically acceptable excipient.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising Sitagliptin phosphatehaving less than about 1 ppm, less than about 0.5 ppm, less than about 0.1 ppm or less than about 0.05 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm, less than about 8 ppm or less than about 5 ppm of compound of formula III or salt thereof by LC-MS and at least one pharmaceutically acceptable excipient.

The present invention provides Sitagliptin or pharmaceutically acceptable salts thereof such as Sitagliptin hydrochloride and sitagliptin phosphate, obtained by the above processes, are analyzed using high performance liquid chromatography ("HPLC") with the conditions as tabulated below:

Column Kromasil 100-5-C18, (250 x 4.6 ) mm, 5.0 µm
Column/sample temperature 50ºC / 5ºC
Mobile phase Mobile phase-A: Buffer and Methanol (85:15v/v).
Mobile phase-B: Water and Acetonitrile (20:80 v/v).
Buffer Dissolved about 1.77 g of disodium hydrogen phosphate dihydrate and 1.38 g of sodium dihydrogen phosphate monohydrate in 1L Milli-Q Water. Adjusted pH to 6.0±0.05 with diluted phosphoric acid (10%, v/v).
Diluent Mixture of Methanol, Acetonitrile and water in a ratio of 80:10:10 (v/v/v).
Flow rate 0.8 mL/min
Wavelength By UV at 210 nm
Injection volume 10 µL
Elution Gradient

Gradient program:
Time in min. Mobile phase-A (% v/v) Mobile phase-B (% v/v)
0 90 10
40 60 40
55 50 50
70 15 85
80 15 85
82 90 10
90 90 10

The content of the NTTP impurity and compound of formula III in Sitagliptin or pharmaceutically acceptable salts thereof such as Sitagliptin hydrochloride and sitagliptin phosphate, obtained by the above processes, are measured by LC-MS method with the conditions as tabulated below:

LC Conditions:
For NTTP For compound III
Column Zorbax RX C-18 (100 x 4.6) mm, 3.5 µm YMC pack ODS AQ (150 x 4.6) mm, 3.0 µm
Flow rate 0.8 mL/min 0.5 mL/min
Detection MS MS
Injection volume 10 µL 10 µl
Column oven temp. 40°C 40°C
Sample temperature 5°C 5°C
Elution Gradient Gradient
Runtime 15 mins 15 mins
Retention time About 4.5 mins for Sitagliptin Phosphate
About 5 mins for Sitagliptin hydrochloride About 4.3 mins for SitagliptinPhosphate
About 4.3 mins for Sitagliptin hydrochloride
Needle wash Acetonitrile and water (50:50% v/v) Acetonitrile and water (50:50% v/v)
Mobile Phase Mobile Phase A: Formic acid (1 mL), water (1 L);
Mobile Phase B: Methanol Mobile Phase A: Formic acid (1 mL), water (1 L);`
Mobile Phase B: Methanol
Gradient program Time in min. Mobile phaseA (%) Mobile phase-B (%)
0 95 5
6 85 15
8 40 60
12 40 60
12.1 95 5
15 95 5
Time in min. Mobile phase-A (%) Mobile phase-B (%)
0 98 2
6 85 15
8 40 60
12 40 60
12.1 98 2
15 98 2

MS Conditions:
LC Conditions for NTTP LC Conditions for compound III
Ionization AJS ESI (+ve) AJS ESI (+ve)
Detection MRM (polarity +ve) MRM (polarity +ve)
Gas temp. 350°C 350°C
Gas flow 12 L/min 12 L/min for Sitagliptin Phosphate
5 L/min for Sitagliptin hydrochloride
Nebulizer 35 psi 50 psi
Sheath gas heater 300°C 250°C
Sheath gas flow 12 L/min 11 L/min
Capillary voltage 3000 V 4000 V
V charging 500 500
Delta EMV (+ve) 400 100

The following non-limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLES:

Example 1: Preparation of Sitagliptin HCl monohydrate:
Compound IV (Boc-Sitagliptin; 100 gms) was added to DCM (300 mL) and stirred the reaction mass for 15-30 min at 25-35°C. Conc. HCl (115 mL) was added slowly over a period of 30-60 min at 25-35°C and stirred for 1-2hrs at 25-35°C. Water (500 mL) was added to the reaction mass, stirred for 15-30 min and separated the layers. The aqueous layer was washed with DCM (200 mL), adjusted pH to 9-10 with 20 % aqueous NaOH solution at 25-35°C (80 gms NaOH dissolved in 400 mL water) and extracted with DCM. Washed the resulting organic layer with water (200 mL), distilled out the solvent completely and degassed for 45-60 min under vacuum at below 40°C.

IPA (300 mL) and methanol (68 mL) were added and stirred at 50-56°C for 20-40 mins. Conc. HCl solution (20 mL Conc. HCl diluted with 228 mL IPA) was added to the reaction mass over 30-60 min at 50-56°C and stirred for 60-80 min at 50-56°C. The reaction mass is gradually cooled to 25-35°C, stirred for 60-120 min, filtered and washed with IPA (2x100 mL). Dried the product in vacuum oven initially at 25-35°C for 1-2hrs and later at 57-63°C for 10-12hrs. Exposed the dried material to water /RH/atmosphere for 4-8hrs to get the title compound. Yield= 75 gms.
Purity by HPLC= >99.9%, NTTP content= 0.17 ppm, Compound III content= 19 ppm.

Example 2: Purification of Sitagliptin HCl monohydrate:
Sitagliptin HCl monohydrate (100 gms; NTTP content= 0.17 ppm; compound III content= 19 ppm) was dissolved in DM water (500 mL) at 25-35°C and washed with DCM (200 mL). pH of the resulting aqueous layer was adjusted to 9-10 with 20% NaOH solution (20 gms NaOH dissolved in 100 mL DM water) at 25-35°C, extracted with DCM and washed the resultant organic layer with DM water. The solvent was distilled out completely and to the resulting residue, IPA (300 mL) and methanol (68 mL) were added and stirred at 50-56°C for 20-40 mins. Conc. HCl solution (20 mL Conc. HCl diluted with 228 mL IPA) was added to the reaction mass over 30-60 min at 50-56°C and stirred for 60-80 min at 50-56°C. The reaction mass is gradually cooled to 25-35°C, stirred for 60-120 min, filtered and washed with IPA (2x100 mL). Dried the product in vacuum oven initially at 25-35°C for 1-2hrs and later at 57-63°C for 10-12hrs. The dried material was exposed to water /RH/atmosphere for 4-8hrs to get the title compound. Yield= 88 gms.
Purity by HPLC= >99.9%, NTTP content= 0.004 ppm, Compound III content= 0.5 ppm.

Examples 3 and 4: Purification of Sitagliptin HCl monohydrate:
The process disclosed in Example 2 was repeated by using Sitagliptin HCl monohydrate contaminated with varying NTTP and compound III contents as tabulated below:

The invention is best understood from the comparative table as illustrated below, which validates that purification of the Sitagliptin hydrochloride salt is highly effective.
Ex. No. Impurity Before purification After purification
Ex 2 NTTP impurity 0.17 0.004
Compound III 19 0.5
Ex 3 NTTP impurity 0.15 0.004
Compound III 14.8 0.5
Ex 4 NTTP impurity 1.36 0.05
Compound III 18 4.2

Example 5: Purification of Sitagliptin HCl monohydrate:
Sitagliptin HCl monohydrate (176 Kg; NTTP content= 0.17 ppm; compound III content= 19 ppm) was dissolved in DM water (880 Lt) at 25-35°C and washed with DCM (350 Lt). pH of the resulting aqueous layer was adjusted to 9-10 with 20% NaOH solution (35 Kg NaOH dissolved in 700 Lt DM water) at 25-35°C, extracted with DCM and washed the resultant organic layer with DM water. The solvent was distilled out completely and to the resulting residue, IPA (530 Lt) and methanol (120 Lt) were added and stirred at 50-56°C for 20-40 mins. Conc. HCl solution (35 Lt Conc. HCl diluted with 400 Lt IPA) was added to the reaction mass over 30-60 min at 50-56°C and stirred for 60-80 min at 50-56°C. The reaction mass is gradually cooled to 25-35°C, stirred for 60-120 min, filtered and washed with IPA (2x180 Lt). Dried the product in vacuum oven initially at 25-35°C for 1-2hrs and later at 57-63°C for 12-16hrs. The dried material further dried in fluidized bed dryer for 4hrs to get the title compound. Yield= 149 Kgs.
Purity by HPLC= >99.9%, NTTP content= 0.0058 ppm, Compound III content= 1 ppm.

Example 6: Purification of Sitagliptin HCl monohydrate:
Sitagliptin Hydrochloride (50 gms; NTTP content= 0.17 ppm; compound III content= 19 ppm) was dissolved in methanol (300 mL) at 48-58°C. Gradually added isopropanol (900 mL) to the reaction mass and stirred at 50-55°C for 1 hr. Cooled the reaction mass to 25-35°C and maintained for 2-3 hrs, filtered, washed with Isopropanol (100 mL) and dried under vacuum at 60?C to get the title compound. Yield= 40 gms.
Purity by HPLC= 99.9%, NTTP content= 0.004 ppm, Compound III content= 2.1 ppm.

Example 7: Purification of Sitagliptin HCl monohydrate:
Sitagliptin Hydrochloride (500 gms; NTTP content= 0.17 ppm; compound III content= 19 ppm) was stirred in isopropanol (4000 mL) at 45-55°C for 4 hrs. Cooled the reaction mass to 25-35°C and stirred overnight at the same temperature. The resultant reaction mass was filtered, washed with isopropanol (500 mL) and dried under vacuum at 60?C to afford the title compound. Yield= 450 gms.
Purity by HPLC= 99.9%, NTTP impurity= 0.05 ppm, Compound III= 9 ppm.

Example 8: Purification of Sitagliptin HCl monohydrate:
Sitagliptin Hydrochloride (50 gms; NTTP content= 0.10 ppm; Compound III content= 5.8 ppm) was stirred in a mixture of methanol (25 mL), propyl gallate (2 gms) and isopropanol (900 mL) at 45-55°C and stirred for 4 hrs. Cooled the reaction mass to 25-35°C and maintained for 8 hrs. The resultant reaction mass was filtered, washed with isopropanol (100 mL) and dried under vacuum at 60?C to afford the title compound. Yield= 45gms.
Purity by HPLC= 99.9%, NTTP content= <0.01 ppm, Compound III content= 0.2 ppm.

Example 9: Preparation of Sitagliptin phosphate monohydrate:
Compound IV (Boc-Sitagliptin; 100 gms) was added to DCM (300 mL) and stirred the reaction mass for 15-30 min at 25-35°C. Conc. HCl (115 mL) was added slowly over a period of 30-60 min at 25-35°C and stirred for 1-2hrs at 25-35°C. Water (500 mL) was added to the reaction mass, stirred for 15-30 min and separated the layers. The aqueous layer was washed with DCM (200 mL), adjusted pH to 9-10 with 20 % aqueous NaOH solution at 25-35°C (80 gms NaOH dissolved in 400 mL water) and extracted with DCM. Washed the resulting organic layer with water (200 mL), distilled out the solvent completely and degassed for 45-60 min under vacuum at below 40°C.

IPA (170 mL) and water (72 mL) were added to the obtained residue and stirred for 15 to 30 mins at 25-35°C. 85% Phosphoric acid (22.7 gms) was added slowly and temperature of the reaction mass was raised to 72-78°C till clear solution is obtained. The reaction mass was cooled to 65-71°C, seed crystals of sitagliptin phosphate monohydrate (0.5 gms) was added and maintained at 65-71°C for 120 to 135 mins. The reaction mass was gradually cooled to 17-23°C over a period of 8 to 10hrs and maintained for further 10-12 hrs. Precooled IPA (560 mL) was added to the mass and stirred at 17-23°C for 1-2 hrs. The precipitated material was filtered, washed with 5% Aq. IPA and dried initially at 25-35°C for 1-2 hrs and later at 51-55°C for 10-12hrs to afford the title compound. Yield: 85 gms.
Purity by HPLC= >99.9%, NTTP content= 0.08ppm, Compound III content= 43.7 ppm.

Example 10: Purification of Sitagliptin phosphate monohydrate:
Sitagliptin Phosphate monohydrate (100 gms; NTTP content= 0.08 ppm; compound III content= 43.7 ppm) was slurred in IPA (500 mL) and water (100 mL) at 57-63°C for 120 to 135 mins. To the reaction mass, IPA (200 mL) was added at 57-63°C and stirred for 60 to 75 mins. Cooled the reaction mass gradually to 17-23°C, stirred for 120 to 135 mins, filtered and washed with 5% aqueous IPA. Dried the material under vacuum initially at 25-35°C for 1-2hrs and later at 50-55°C for 10-12hrs to get the tile compound. Yield: 92.5 gms.
Purity by HPLC= 100%, NTTP content= 0.01 ppm, Compound III content= 2.4 ppm

Example 11: Purification of Sitagliptin phosphate monohydrate:
Sitagliptin Phosphate monohydrate containing NTTP content= 0.12 ppm; compound III content= 32.3 ppm was used as starting material and further purified according to the example 6 process to get the title compound.
Purity by HPLC= >99.9%, NTTP content= 0.02 ppm, Compound III content= 2.3 ppm

Further, the invention is best understood from the comparative table as illustrated herein below which validates that purification of the Sitagliptin phosphate salt is highly effective:
Ex. No. Impurity Before purification After purification
Ex 10 NTTP impurity 0.08 ppm 0.01 ppm
Compound III 43.7 ppm 2.4 ppm
Ex 11 NTTP impurity 0.12 ppm 0.02 ppm
Compound III 32.3 ppm 2.3 ppm

Example 12: Purification of Sitagliptin phosphate monohydrate:
Sitagliptin Phosphate monohydrate (150 Kg; NTTP content= 0.12 ppm; compound III content= 32.3 ppm) was slurred in IPA (750 Lts) and water (150 Lts) at 57-63°C for 120 to 135 mins. To the reaction mass, IPA (300 Lt) was added at 57-63°C and stirred for 60 to 75 mins. Cooled the reaction mass gradually to 17-23°C, stirred for 120 to 135 mins, filtered and washed with 5% aqueous IPA. Dried the material under vacuum initially at 25-35°C for 1-2hrs and later at 50-55°C for 10-12hrs to get the tile compound.
Yield: 142.2 Kg.
Purity by HPLC= 100%, NTTP content= <0.0009ppm, Compound III content= 4 ppm.

Example 13: Purification of Sitagliptin phosphate monohydrate:
Sitagliptin phosphate monohydrate (50 gms; NTTP content= 0.12 ppm & Compound III content= 32.3 ppm) was stirred in a mixture of isopropanol (500 mL) and water (100 mL) at 55-65°C for 4 hrs. Cooled the reaction mass to ambient temperature, stirred for 4hrs, filtered and washed with Isopropanol (100 mL). Dried the material under vacuum at 60?C to afford title compound. Yield= 44.6gms.
Purity by HPLC= 99.9%, NTTP impurity= <0.01ppm, Compound III= 2 ppm.

Example 14: Purification of Sitagliptin phosphate monohydrate:
Sitagliptin Phosphate monohydrate (25 gms; NTTP content= 0.15 ppm; compound III content= 23.9 ppm) was dissolved in DM water (125 mL) at 25-35°C and washed with DCM (50 mL). pH of the resulting aqueous layer was adjusted to 9-10 with 20% NaOH solution (10gms NaOH dissolved in 50 mL DM water) at 25-35°C, extracted with DCM and washed the resultant organic layer with DM water. The solvent was distilled out completely and IPA (90 mL) and water (16 mL) were added to the obtained residue and stirred for 15 to 30 mins at 25-35°C. 85% Phosphoric acid (5.8 gms) was added slowly and temperature of the reaction mass was raised to 72-78°C till clear solution is obtained. The reaction mass was cooled to 65-71°C, seed crystals of sitagliptin phosphate monohydrate (0.1 gms) was added and maintained at 65-71°C for 120 to 135 mins. The reaction mass was gradually cooled to 17-23°C over a period of 8 to 10 hrs and maintained for further 10-12 hrs. Precooled IPA (110 mL) was added to the mass and stirred at 17-23°C for 1-2 hrs. The precipitated material was filtered, washed with IPA (25 mL) and dried the material under vacuum at 60?C to afford title compound. Yield= 21.7 gms.
Purity by HPLC= >99.9%, NTTP content= 0.03 ppm, Compound III content= 8 ppm.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Those skilled in the art may implement other arrangements and methods without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
,CLAIMS:We claim:

1. A process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS, the process comprising:
a) providing a solution of Sitagliptin or pharmaceutically acceptable salts thereof having a compound of formula III or salt thereof and/or NTTP impurity in water;
b) adding a base to the step a) reaction mass to get sitagliptin of formula I,
c) providing a solution or suspension of sitagliptin of formula I in a suitable solvent or mixture of solvents;
d) adding suitable acid to the step c) reaction mass; and
e) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

2. The process as claimed in claim 1, wherein the step b) further comprises:
i) extracting the reaction mass with a suitable water immiscible organic solvent; and
ii) removing the organic solvent to obtain sitagliptin of formula I.

3. A process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing a solution or suspension of Sitagliptin or pharmaceutically acceptable salts thereof having a compound of formula III or salt thereof and/or NTTP impurity in a suitable solvent or mixture of solvents;
b) stirring the step a) reaction mass; and
c) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

4. The process as claimed in claims1 to 3, wherein the Sitagliptin or pharmaceutically acceptable salts thereof are selected from sitagliptin hydrochloride or sitagliptin phosphate.

5. The process as claimed in claims1 or 4, wherein the isolated Sitagliptin hydrochloride contains less than about 0.33 ppm of NTTP impurity by LC-MS and/or less than about 5 ppm of compound of formula III or salt thereof by LC-MS.

6. The process as claimed in claims1 or 4, wherein the isolated Sitagliptin phosphate contains less than about 0.29 ppm of NTTP impurity by LC-MS and/or less than about 5 ppm of compound of formula III or salt thereof by LC-MS.

7. A process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing sitagliptin or pharmaceutically acceptable salts thereof in a suitable solvent;
b) treating the step a) reaction mass with a suitable nitrite scavenger; and
c) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

8. The process as claimed in claim 7, wherein the suitable nitrite scavenger is selected from the group ascorbic acid, sodium ascorbate, ascorbyl palmitate, maltol, propyl gallate, para-aminobenzoic acid (PABA), L-cysteine, resveratrol, butylated hydroxyanisole, butylated hydroxytoluene, glycine, Arginine, lysine, Histidine, urea, sodium sulfite, ammonium sulfate, ammonium chloride, sulfamic acid, hydrazoic acid, and tocopherol and mixtures thereof.

9. A process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS; the process comprising:
a) providing a solution or suspension of sitagliptin or pharmaceutically acceptable salts thereof in a suitable solvent;
b) adding an anti-solvent to step a) reaction mass; and
c) isolating sitagliptin or pharmaceutically acceptable salts thereof having less than about 1 ppm of NTTP impurity or salt thereof by LC-MS and/or less than about 10 ppm of compound of formula III or salt thereof by LC-MS.

10. The process as claimed in claims 1 to 9, wherein the base is sodium hydroxide;the suitable solvent is selected from isopropanol, methanol, water and mixtures thereof; the suitable acid is hydrochloric acid or phosphoric acid and the anti-solvent is isopropanol.