DESC:Field of the invention
The present invention provides substantially pure teneligliptin hydrobromide or its hydrate and a process for its preparation.

Background and the prior art
Teneligliptin hydrobromide hydrate is chemically known as {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}(1,3-thiazolidin-3-yl)methanone hemipentahydrobromide hydrate and represented by formula (1). It belongs to the class of anti-diabetic drugs known as dipeptidyl peptidase-4 inhibitors or "gliptins".

wherein n is 0 to 3.

US patent no. 7,074,794 discloses teneligliptin, its pharmaceutically acceptable salt and process for the preparation of the same. US patent no. 8,003,790 discloses teneligliptin hydrobromide hydrate and process for the preparation of the same. Each of these references is hereby incorporated herein by reference in its entirety.

Other processes for the preparation of teneligliptin hydrobromide or its hydrate are also known in the art. However, neither of these documents describes a method for preparing substantially pure teneligliptin hydrobromide or its hydrate having decreased content of teneligliptin sulfoxide impurity as per regulatory norms.

So there exists a scope of developing an improved process that consistently yields substantially pure teneligliptin hydrobromide or its hydrate meeting regulatory norms.

The term "substantially pure Teneligliptin hydrobromide" as used herein shall be understood to mean Teneligliptin hemipentahydrobromide hydrate having little or no content of the impurities. Further, the term “substantially pure Teneligliptin hemipentahydrobromide hydrate” shall be understood to mean Teneligliptin hemipentahydrobromide hydrate having the sulfoxide impurity content equal to 0.1% or less, when measured by HPLC.

Object of the invention
Objective of the present invention is to provide a cost effective and industrially viable process for obtaining substantially pure teneligliptin hydrobromide or its hydrate having higher purity and higher yield.

Another objective of the present invention is to provide a substantially pure teneligliptin hydrobromide or its hydrate having reduced content of undesired by-products or impurities.

One more objective of the present invention is to provide a process for the purification of teneligliptin hydrobromide or its hydrate having content of teneligliptin sulfoxide impurity of formula (2) more than 0.1% in it, to obtain substantially pure teneligliptin hydrobromide or hydrate thereof.

Summary of the Invention:

In one embodiment, the present invention provides substantially pure teneligliptin hydrobromide or hydrate thereof.

In another embodiment, the present invention provides a substantially pure teneligliptin hydrobromide or its hydrate having 0.1% or less content of teneligliptin sulfoxide impurity of formula (2)

wherein n is 0 to 3.

In one more embodiment, the present invention provides a substantially pure teneligliptin hemipentahydrobromide hydrate of formula (1) having 0.1% or less content of teneligliptin sulfoxide impurity of formula (2).

In one more embodiment, the present invention provides a process for the preparation of substantially pure teneligliptin hemipentahydrobromide hydrate of formula (1) having reduced content of the compound of formula (2), comprising:
a) dissolving teneligliptin hemipentahydrobromide hydrate having more than 0.1% content of teneligliptin sulfoxide impurity of formula (2) in a suitable solvent; and
b) isolating substantially pure teneligliptin hemipentahydrobromide hydrate by crystallization or precipitation.

Description of the invention

In one aspect, present invention provides a Teneligliptin sulfoxide compound of formula (2)

wherein n is 0 to 3.

In one aspect of the present invention, compound of formula (2) is prepared by subjecting Teneligliptin hydrobromide or hydrate thereof to an oxidation reaction using oxidizing agents such as hydrogen peroxide in a suitable solvent. The suitable solvent used in the oxidation of Teneligliptin hydrobromide is water or water miscible organic solvent such as methanol.

In one more aspect of the present invention, the present inventors have found that during the synthesis of KSM of Teneligliptin viz. 3-[(2S)-1-(1,1-dimethyl ethyloxycarbonyl)-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (1,3-PTH) of formula (3), which involves oxidation step, corresponding 1,3-PTH sulfoxide impurity of formula (4) is formed. It is observed that the said sulfoxide impurity of formula (4) is formed due to sulfide oxidation; and formation of the impurity of formula (4) may not be avoided at this step. Hence, the 1,3-PTH sulfoxide impurity is potential impurity in the synthesis of 1,3-PTH. The 1,3-PTH sulfoxide of formula (4) leads to formation of Teneligliptin sulfoxide impurity of formula (2) during the preparation of Teneligliptin hydrobromide.

The formation of the 1,3-PTH sulfoxide impurity of formula (4) and teneligliptin sulfoxide impurity of formula (2) during the preparation of teneligliptin hemipentahydrobromide hydrate is described as per below reaction scheme.

Accordingly, the present invention provides a process for the preparation of substantially pure teneligliptin hemipentahydrobromide hydrate having reduced content of the teneligliptin sulfoxide impurity of formula (2), which comprises steps of:
a) dissolving teneligliptin hemipentahydrobromide hydrate having more than 0.1% content of teneligliptin sulfoxide impurity of formula (2) in a suitable solvent at a suitable temperature; and
b) isolating substantially pure teneligliptin hemipentahydrobromide hydrate by crystallization or precipitation at suitable temperature.

According to the present invention, the preferred suitable solvent is water or water miscible organic solvent or a mixture thereof. The water miscible organic solvent of the present invention is selected from alcohols such as methanol, ethanol, isopropanol, etc., ketones such as acetone and a mixture thereof.

According to the present invention, the teneligliptin hemipentahydrobromide hydrate having more than 0.1% content of teneligliptin sulfoxide impurity, is dissolved into the solvent at suitable temperature range selected from the 25oC to the boiling point of the solvent, preferably at the temperature range of 30oC to 90oC.

According to the present invention, the reaction mass is cooled gradually to about -10 oC to 30oC temperature, preferably to -5oC to 30oC temperature to obtain wet cake.

According to the present invention, the obtained wet cake is slurried with the solvent, filtered and dried under vacuum to afford substantially pure teneligliptin hemipentahydrobromide hydrate having 0.1% or less content of the teneligliptin sulfoxide impurity.

According to the present invention, the substantially pure teneligliptin hemipentahydrobromide hydrate of the present invention is dried by the techniques known in the art, such that the residual solvents in the drug substance are within the scope of the regulatory guidelines.

Accordingly, the substantially pure teneligliptin hemipentahydrobromide hydrate of the present invention is dried using drying equipment known in the art such as oven tray, rotary cone, paddle and tumble dryers or rotary evaporators wherein the drying typically is carried out at reduced pressure.

According to the present invention, the substantially pure teneligliptin hemipentahydrobromide hydrate of the present invention is dried at 50-100oC, preferably at 50-80oC under vacuum.

According to the present invention, the obtained substantially pure teneligliptin hydrobromide or its hydrate is substantially free of teneligliptin sulfoxide impurity ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1-oxidothiazolidin-3-yl)methanone hemipentahydrobromide hydrate of formula (2)

wherein m is 0 to 3.

According to one aspect of the present invention, substantially pure teneligliptin hemipentahydrobromide hydrate produced by a method according to present invention is characterized by the content of the teneligliptin sulfoxide impurity of formula (2) in it is 0.1% or less.

In another preferred aspect, the product obtained by the process of the present invention is substantially pure teneligliptin hemipentahydrobromide hydrate having purity >99.7% measured as area percentage by HPLC.

According to the present invention, substantially pure teneligliptin hydrobromide or its hydrate of the present invention contains 0.1% or less content of the teneligliptin sulfoxide impurity of formula (2).

The content of teneligliptin sulfoxide impurity in the substantially pure teneligliptin hemipentahydrobromide hydrate is detected and measured by following method.

High Performance Liquid chromatography (HPLC): The method of measuring area percentage of the teneligliptin sulfoxide impurity in teneligliptin hemipentahydrobromide hydrate is carried out by using HPLC with the following conditions:
• Detector : ultraviolet absorptiometer (detection wavelength: UV at 254 nm)
• Column : Inertsil ODS-3V (150 x 4.6)mm, 5µm
• Flow rate : 1.0 mL/min
• Column oven temperature: 40 oC
• Mobile phase :
A. Mix and degas 30mL Acetonitrile, 970mL water and 1.0mL Trifluoroacetic acid;
B. Mix and degas 1000mL Acetonitrile and 1.0mL Trifluoroacetic acid

A representative example of the process for purification of teneligliptin hemipentahydrobromide hydrate having more than 0.1% of teneligliptin sulfoxide impurity, is illustrated in examples.

Present invention is further illustrated by the following non-limiting examples.

Example-1: Preparation of teneligliptin hemipentahydrobromide hydrate
To a mixture of 3-[(2S)-1-(1,1-dimethylethyloxycarbonyl)-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (1,3-PTH) (1.0 mole) and 1-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine (3-MPPP) (1.0 mole) in DCM (5.0 volume), sodium triacetoxyborohydride (2.56 mole) was added at 10-18°C. Once the reaction complies, DCM (5.0 volume) was added followed by water addition (5.0 volume). The organic layer was separated and washed with aq. HCl solution and aq. sodium bicarbonate solutions. The organic layer was distilled out solvent under vacuum. To the residue of BOC protected Teneligliptin, ethanol (14.0 volume) was added and heated up to 50-60°C and 48% HBr solution (3.35 mole) was added at 50-60°C, After reaction completion, the reaction mass was cooled to 0-5°C, filtered and dried at 60-70oC under vacuum to obtain teneligliptin hemipentahydrobromide hydrate having the teneligliptin sulfoxide impurity 0.18%.

Example-2: Purification of teneligliptin hemipentahydrobromide hydrate
The teneligliptin hemipentahydrobromide hydrate (5.0 gm) (having the sulphoxide impurity 0.18%) was dissolved in water (1.0 volume) at 42-50oC and acetone (10 volume) was slowly added at 42-50oC. The reaction mixture was cooled at 20-25oC, filtered, washed with acetone and dried at 60-70oC under vacuum to yield pure teneligliptin hemipentahydrobromide hydrate having the teneligliptin sulfoxide impurity 0.06%.
Purity = 99.81%
Yield = 72%.

Example-3: Purification of teneligliptin hemipentahydrobromide hydrate
The teneligliptin hemipentahydrobromide hydrate (8.0 gm) (having the teneligliptin sulphoxide impurity 0.18%) was suspended in 5% aq. ethanol (10 Volume), heated up to 55-60°C to get clear solution. The reaction mixture was slowly cooled to at 20-25oC, filtered, washed with ethanol and dried at 60-70oC under vacuum to yield pure teneligliptin hemipentahydrobromide hydrate having the teneligliptin sulfoxide impurity 0.07%.
Purity = 99.78%
Yield = 78%.

Example-4: purification of teneligliptin hemipentahydrobromide hydrate
The teneligliptin hemipentahydrobromide hydrate (25.0 gm) (having the teneligliptin sulphoxide impurity 0.17%) was dissolved in water (1.0 volume) at 50-55°C and isopropanol (10 volume) was slowly added at 50-55°C. The reaction mixture was cooled at 0-5°C, filtered, washed with isopropanol and dried at 60-70oC under vacuum to yield pure teneligliptin hemipentahydrobromide hydrate having the teneligliptin sulfoxide impurity 0.04%.
Purity = 99.85%
Yield = 79%.

Example-5: Preparation of teneligliptin sulfoxide impurity
Teneligliptin hydrobromide hydrate (5.0 g) and 1% Hydrogen peroxide solution (25 mL) was added in RB Flask. The reaction mass was stirred at room temperature. After 2 hours, the reaction mass was neutralized with 1% sodium thiosulfate solution and concentrated the reaction mass under reduce pressure to obtain the semisolid mass. The obtained semisolid mass was dissolved in methanol (50 mL), water (5 mL) and then neutralized with aqueous hydrochloric acid (2 mL) and filtered the solution to separate the undissolved solid. The obtained filtrate was lyophilized to obtain title compound. The obtained product was characterized by Infra-red and mass spectroscopy.
Infra-Red Spectra: 414.7, 447.49, 468.7, 478.35, 497.63, 524.64, 586.36, 603.72, 632.65, 696.3, 771.53, 918.12, 1012.63, 1033.85, 1099.43, 1222.87, 1242.16, 1323.17, 1357.89, 1365.6, 1444.68, 1502.55, 1550.77, 1595.13, 1627.92, 1658.78, 2574.97, 2625.12, 2682.98, 2704.2, 2951.09, 3007.02 cm-1.
Mass Spectra: 443.05 (m/Z).
,CLAIMS:1. Substantially pure teneligliptin hemipentahydrobromide hydrate containing 0.1% or less teneligliptin sulfoxide impurity of formula (2)
,
wherein n is 0 to 3.

2. A process for the preparation of substantially pure teneligliptin hemipentahydrobromide hydrate having reduced content of teneligliptin sulfoxide impurity of formula (2), comprising:
a) dissolving teneligliptin hemipentahydrobromide hydrate having more than 0.1% of teneligliptin sulfoxide impurity of formula (2) in a suitable solvent at 25oC to the boiling point of the solvent; and
b) isolating substantially pure teneligliptin hemipentahydrobromide hydrate by crystallization or precipitation at -10oC to 30oC temperature.

3. The process according to claim 2, wherein the suitable solvent is water or water miscible organic solvent or a mixture thereof.

4. The process according to claim 3, wherein the water miscible organic solvent is selected from alcohol, ketone and a mixture thereof.

5. The process according to claim 4, wherein the alcohol is methanol, ethanol, isopropanol and a mixture thereof.

6. The process according to claim 4, wherein the ketone is an acetone.

7. Substantially pure teneligliptin hemipentahydrobromide hydrate containing 0.10% or less of the teneligliptin sulfoxide impurity, produced by method according to claim-2.

8. Substantially pure teneligliptin hemipentahydrobromide hydrate containing 0.09% or less of the teneligliptin sulfoxide impurity, produced by method according to claim-2.

9. A compound of the formula:

or salt thereof.