DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application IN 202041046238 filed on October 23, 2020 which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention provides a process for preparation of amorphous Teneligliptin 2.5 hydrobromide. The present invention also provides a process for preparation of crystalline form A and form C of Teneligliptin 2.0 hydrobromide

BACKGROUND OF THE INVENTION
Teneligliptin hydrobromide hydrate known chemically as {(2S,4S)-4-[4-(3- methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl} (1,3-thiazolidin3-yl) methanone hemipenta hydrobromide hydrate which belongs to Dipeptidyl peptidase IV (DPP-IV) inhibitors. Teneligliptin hydrobromide hydrate is approved for the treatment of type 2 diabetes and is being marketed under the brand name Tenelia®.

U.S. Patent No. 7,074,794 B2 discloses Teneligliptin as L-proline derivative and its pharmaceutically acceptable salts which exhibits a Dipeptidyl peptidase IV (DPP-IV) inhibitory activity, which is useful for the treatment or prophylaxis of diabetes. The example-222 of the US ‘794 discloses the process for the preparation of teneligliptin as trihydrochloride salt

U.S. Patent No. 8,003,790 B2 discloses salts of proline derivative, solvate thereof and production method thereof. In particular, the US ‘790 discloses 2.0 hydrochloride or 2.5 hydrochloride; 2.0 hydrobromide or 2.5 hydrobromide, and hydrates thereof Teneligliptin.

U.S. Patent No. 8,604,198 B2 discloses crystalline form A, form B and form C of Teneligliptin 2.0 hydrobromide

International patent application WO 2019/205021 discloses an amorphous form of Teneligliptin 2.5 hydrobromide and a process for the preparation thereof.

The present invention provides methods for the preparation of amorphous Teneligliptin 2.5 hydrobromide. The present invention also provides a process for preparation of crystalline form A and form C of Teneligliptin 2.0 hydrobromide

SUMMARY OF THE INVENTION
One aspect of the present invention provides a process for preparation of amorphous Teneligliptin 2.5 hydrobromide comprising the steps of:

a. dissolving Teneligliptin 2.0 hydrobromide in a polar solvent;
b. adding aqueous hydrobromic acid; and
c. isolating amorphous form of Teneligliptin 2.5 hydrobromide

Another aspect of the present invention provides a process for preparation of crystalline form A of Teneligliptin 2.0 hydrobromide comprising the steps of:

a. dissolving Teneligliptin in mixture of alcohol and water;
b. adding aqueous hydrobromic acid;
c. seeding Teneligliptin 2.0 hydrobromide form A;
d. adding an anti-solvent; and
e. isolating form A of Teneligliptin 2.0 hydrobromide.

Another aspect of the present invention provides a process for preparation of crystalline form C of Teneligliptin 2.0 hydrobromide comprising the steps of:

a. dissolving Teneligliptin 2.0 hydrobromide form A in a mixture of alcohol and water;
b. seeding Teneligliptin 2.0 hydrobromide form C; and
c. isolating form C of Teneligliptin 2.0 hydrobromide.

BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:
Figure 1 shows a powder X-ray diffraction pattern of the amorphous Teneligliptin 2.5 hydrobromide
Figure 2 shows a powder X-ray diffraction pattern of the form A of Teneligliptin 2.0 hydrobromide
Figure 3 shows a powder X-ray diffraction pattern of the form C of Teneligliptin 2.0 hydrobromide
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

One embodiment of the present invention provides a process for preparation of amorphous Teneligliptin 2.5 hydrobromide comprising the steps of:

a. dissolving Teneligliptin 2.0 hydrobromide in a polar solvent;
b. adding aqueous hydrobromic acid; and
c. isolating amorphous form of Teneligliptin 2.5 hydrobromide

According to the present embodiment, the term “polar solvent,” unless otherwise indicated, refers to an alcohol solvent, ketone solvent, nitrile solvent, water or a mixture thereof.
As used herein, alcohol solvents include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, t-butanol, pentanol, or mixtures thereof; ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone, or mixtures thereof; nitrile solvents include acetonitrile, propionitrile, or mixtures thereof; Within the context of this embodiment methanol or water are preferably used.
According to this embodiment, Teneligliptin 2.0 hydrobromide may be dissolved particularly in methanol under heating, heating may be carried out at a temperature of about 25°C to about reflux. In some embodiments of the present invention, a temperature of about 40°C to about 50°C was found to be particularly useful for dissolving Teneligliptin 2.0 hydrobromide in methanol. As used herein, the term “about” means 10% above or below the value recited.
Further, the above resulted clear solution may be cooled to 25±2°C and may be maintained under stirring for about 10 to 15 minutes.
In another context of this embodiment, Teneligliptin 2.0 hydrobromide may be dissolved particularly in water at a temperature of about 25°C to about reflux. In some embodiments of the present invention, a temperature of about 23°C to about 25°C was found to be particularly useful for dissolving Teneligliptin 2.0 hydrobromide in water as used herein, the term “about” means 10% above or below the value recited.
Next, according to this embodiment, an aqueous hydrobromic acid may be added to the reaction mass and maintained under stirring for about 10 to 15 minutes. Further, the reaction mass may be filtered through hyflo to remove any undissolved particulates and followed by washing methanol. Amorphous form of Teneligliptin 2.5 hydrobromide may be formed in-situ.
Amorphous form of Teneligliptin 2.5 hydrobromide may then be isolated from this solution. Isolation may be carried out by methods well known in the art. According to the present embodiment, the solvent may be removed by known techniques which may include, but are not limited to, evaporation, distillation, spray drying, filtration, lyophilization, or agitated thin film drying.
Another embodiment of the present invention provides a process for preparation of crystalline form A of Teneligliptin 2.0 hydrobromide comprising the steps of:

a. dissolving Teneligliptin in mixture of alcohol and water;
b. adding aqueous hydrobromic acid;
c. seeding Teneligliptin 2.0 hydrobromide form A;
d. adding an anti-solvent; and
e. isolating form A of Teneligliptin 2.0 hydrobromide.

According to the present embodiment, as used herein, alcohol solvents include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, t-butanol, pentanol, or mixtures thereof; Within the context of this embodiment mixture of ethanol and water is preferably used.
According to this embodiment, Teneligliptin may be dissolved particularly in ethanol and water under heating, heating may be carried out at a temperature of about 25°C to about reflux. In some embodiments of the present invention, a temperature of about 50°C to about 80°C was found to be particularly useful for dissolving Teneligliptin in ethanol and water mixture. As used herein, the term “about” means 10% above or below the value recited.
Next, according to this embodiment, an aqueous hydrobromic acid may be added slowly to the reaction mass and maintained under stirring for about 30 to 60 minutes at a temperature of 50°C to about 80°C. Further, the reaction mass may be cooled to 25°C, followed by further cooling to 5±2°C.
Next, according to this embodiment, seeding of Teneligliptin 2.0 hydrobromide form A may be added to the reaction mass at a temperature of about 5°C and maintained under stirring for about 60 minutes.
Next, according to this embodiment, an anti-solvent may be added to the reaction mass at a temperature of about 5°C and maintained under stirring for about 60 minutes.
Within the context of this embodiment, anti-solvent may be polar protic solvents include, but not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, the use of n-butanol as anti-solvent was found to be particularly effective.
Form A of Teneligliptin 2.0 hydrobromide may then be isolated from this solution. Isolation may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by suck-drying.
Another embodiment of the present invention provides a process for preparation of crystalline form C of Teneligliptin 2.0 hydrobromide comprising the steps of:

a. dissolving Teneligliptin 2.0 hydrobromide form A in a mixture of alcohol and water;
b. seeding Teneligliptin 2.0 hydrobromide form C; and
c. isolating form C of Teneligliptin 2.0 hydrobromide.

According to the present embodiment, as used herein, alcohol solvents include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, t-butanol, pentanol, or mixtures thereof; Within the context of this embodiment mixture of ethanol and water is preferably used.
According to this embodiment, Teneligliptin 2.0 hydrobromide form A may be dissolved particularly in ethanol and water under heating, heating may be carried out at a temperature of about 25°C to about reflux. In some embodiments of the present invention, a temperature of about 50°C to about 80°C was found to be particularly useful for dissolving Teneligliptin in ethanol and water mixture. As used herein, the term “about” means 10% above or below the value recited.
Further, the above resulted reaction mass may be maintained under stirring for about 30 to 60 minutes, followed by cooled to 25±2°C.
Next, according to this embodiment, seeding of Teneligliptin 2.0 hydrobromide form C may be added to the reaction mass at a temperature of about 25°C and maintained under stirring for about 10 hours.
Further, the above resulted reaction mass may be cooled to 0±2°C and followed by maintained under stirring for about 4 hours
Form C of Teneligliptin 2.0 hydrobromide may then be isolated from this solution. Isolation may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by suck-drying
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES

Example1: Preparation of amorphous Teneligliptin 2.5 hydrobromide

Teneligliptin 2.0 Hydrobromide (14g) was dissolved in methanol (280mL) at 45±2°C. The resulting clear solution was cooled to 25±2°C and aqueous hydrobromic acid (2.04g) was added. Then the reaction mass was filtered through hyflo to remove any undissolved particulates and washed with methanol (20mL) and subjected to spray drying to yield amorphous form of Teneligliptin 2.5 hydrobromide.

Example 2: Preparation of amorphous Teneligliptin 2.5 hydrobromide

Teneligliptin 2.0 Hydrobromide (15g) was dissolving in water (150mL) at 25±2°C and aqueous hydrobromic acid (2.194g) was added. Then the reaction mass was filtered through hyflo to remove any undissolved particulates and washed with methanol (20mL) and subjected to spray drying to yield amorphous form of Teneligliptin 2.5 Hydrobromide.

Example 3: Preparation of amorphous Teneligliptin 2.5 hydrobromide

Teneligliptin 2.0 Hydrobromide (20g) was dissolved in water (190mL) at 25±2°C and aqueous hydrobromic acid (dissolved 2.655g Aq. HBr in 10mL water) was added. Then the reaction mass was filtered through 0.45micron filter to remove any undissolved particulate matter and resulting clear solution was subjected to spray drying to yield amorphous form of Teneligliptin 2.5 Hydrobromide.

Example 4: Preparation of amorphous Teneligliptin 2.5 hydrobromide

Teneligliptin 2.0 Hydrobromide (20g) was dissolved in water (190mL) at 25±2°C and aqueous hydrobromic acid (dissolved 2.80g Aq. HBr in 10mL water) was added. Then the reaction mass was filtered through 0.45micron filter to remove any undissolved particulate matter and resulting clear solution was subjected to spray drying to yield amorphous form of Teneligliptin 2.5 Hydrobromide.

Example 5: Preparation of crystalline Teneligliptin 2.0 Hydrobromide Form A

Teneligliptin (39.0g) was dissolving in a mixture of ethanol (175mL) and water (20mL) at 70±5°C and slowly aqueous hydrobromic acid was added (31.4g). Then the reaction mass was stirred for 30min at 70±5°C and slowly cooled to 25±5°C and further cooled to 5±2°C. Seeds of Teneligliptin 2.0 Hydrobromide Form A (100mg) was added at 5±2°C and stir for 1hour. To this suspension 2-Butanol (378mL) was added at 5±2°C and stirred for 1h. Filter the reaction mass, wash with 2-Butanol (20mL) and suck dried for 30min. The material obtained was dried under vacuum at 30°C for 15h. The product obtained was tested by PXRD and identified as crystalline Teneligliptin 2.0 Hydrobromide Form A.
Example 6: Preparation of crystalline Teneligliptin 2.0 Hydrobromide Form C

Teneligliptin 2.0 Hydrobromide Form A (50g) obtained as per example 3 was dissolving in a mixture of ethanol (394mL) and water (3.9mL) at 70±5°C. Then the reaction mass was stirred for 30min at 70±5°C and slowly cooled to 25±5°C. Added seeds of Teneligliptin 2.0 Hydrobromide Form C (100mg) at 25±2°C and stirred for 10h. Then the reaction mass was cooled to 2±2°C and stirred for 4h. Filter the reaction mass, wash with Ethanol (24mL) and suck dried for 30min. The material obtained was dried under vacuum at 30°C for 15h. The product obtained was tested by PXRD and identified as crystalline Teneligliptin 2.0 Hydrobromide Form C.
,CLAIMS:1. A process for preparing amorphous Teneligliptin 2.5 hydrobromide comprising the steps of:
a. dissolving Teneligliptin 2.0 hydrobromide in a polar solvent;
b. adding aqueous hydrobromic acid; and
c. isolating amorphous form of Teneligliptin 2.5 hydrobromide

2. The process as claimed in claim 1, wherein the polar solvent is selecting from the group consisting alcohol solvent, water and/or mixtures thereof.

3. The process as claimed in claim 2, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, 1-pentanol, 2-pentanol, or mixtures thereof.

4. The process as claimed in claim 2, wherein the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone, or mixtures thereof.

5. The process as claimed in claim 2, wherein the nitrile solvent is selected from the group consisting of acetonitrile, propionitrile or mixtures thereof.

6. A process for preparing crystalline form A of Teneligliptin 2.0 hydrobromide comprising the steps of:
a. dissolving Teneligliptin in mixture of alcohol and water;
b. adding aqueous hydrobromic acid;
c. seeding Teneligliptin 2.0 hydrobromide form A;
d. adding an anti-solvent; and
e. isolating form A of Teneligliptin 2.0 hydrobromide.

7. The process as claimed in claim 6, wherein the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, 1-pentanol, 2-pentanol and mixtures thereof.
8. The process as claimed in claim 6, wherein the anti-solvent is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
9. A process for preparing crystalline form C of Teneligliptin 2.0 hydrobromide comprising the steps of:
a. dissolving Teneligliptin 2.0 hydrobromide form A in a mixture of alcohol and water;
b. seeding Teneligliptin 2.0 hydrobromide form C;
c. isolating form C of Teneligliptin 2.0 hydrobromide.

10. The process as claimed in claim 9, wherein the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, 1-pentanol, 2-pentanol and mixtures thereof.