Claims:WE CLAIM:

1. A purification process of stable form A Linagliptin, comprising;

a) Linagliptin is refluxed in isopropyl alcohol,
b) cooling the solution obtained in step a), and
c) isolating the stable pure Linagliptin form A.

2. The process as claimed in claims 1, wherein the cooling reaction is carried out at 20-25ºC for 2 hrs.

3. The process as claimed in claim 1, stable form A Linagliptin having a powder X-ray diffraction pattern substantially in accordance with Figure-1.

4. The process as claimed in claim 1 and 3, stable form A Linagliptin having powder X-ray diffraction pattern characterised by the peaks at 7.0, 7.5, 8.3, 9.8, 10.3, 11.0, 11.5, 12.2, 15.1, 19.7, 22.3, 22.9, 24.7, 25.0, 25.6, 0.2º 2θ values.

5. The process as claimed in claim 1, stable form A Linagliptin having a differential scanning calorimetry substantially in accordance with Figure-2.

6. The process as claimed in claim 1 and 5, Stable form A Linagliptin is further characterized by differential scanning calorimetry (DSC) melts at 206.87ºC.

7. The process as claimed in claim 1, the purity of the form A Linagliptin is 99.9%.
, Description:PURIFICATION PROCESS OF STABLE FORM A LINAGLIPTIN

FIELD OF THE INVENTION

The present invention relates to improved, commercially viable and industrially applicable purification process of stable form A Linagliptin with high purity and yield.

BACKGROUND OF THE INVENTION

Linagliptin, sold under the brand name Tradjenta among others, is a medication used to treat diabetes mellitus type 2. It is generally less preferred than metformin and sulfonylureas as an initial treatment. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth. Common side effects include inflammation of the nose and throat. Serious side effects may include angioedema, pancreatitis, joint pain. Use in pregnancy and breastfeeding is not recommended. Linagliptin is a dipeptidyl peptidase-4 inhibitor. It works by increasing the production of insulin and decreasing the production of glucagon by the pancreas.

Chemically, Linagliptin is 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione. The empirical formula is C25H28N8O2. Its molecular weight is 472.54 g/mol, and its chemical structure is represented below:

Linagliptin is marketed by Boehringer and Eli Lilly under the trade names Tradjenta (in the United States) Trajenta (in Europe).

U.S. Patent No. 7,407,955 discloses Linagliptin, related compounds, and their pharmaceutical compositions. It also describes a process for the preparation of Linagliptin, wherein tert-butyloxycarbonyl (Boc) protected Linagliptin is deprotected using 5-6 M isopropanolic hydrochloric acid, followed by purification using chromatography. The patent does not mention the polymorphic form obtained.

WO 2013128379 of Dr. Reddy’s describes Linagliptin polymorph form I & II and it’s process.

WO 2007/128721 A1 describes crystalline Forms A, B, C, D, and E of Linagliptin, and processes for the preparation of the polymorphic forms. The publication also describes polymorphic forms A, B, D, and E as being anhydrous, and polymorphic form C as a hydrate with a stoichiometry somewhere in the region of a hemihydrate or monohydrate.
The process of anhydrous polymorph A comprises refluxing Linagliptin in absolute ethanol, cooling the hot solution and diluting with a solvent methyl tert butyl ether. Drying the polymorph A at 4º5C melts at 206±3ºC.

In view of the foregoing, the present inventors have provided herewith the purification process of stable form A Linagliptin with commercially suitable reaction conditions with high yield and purity. The process is simple, efficient more economical and eco-friendly for the stable pure purification process of Linagliptin form A.

SUMMARY OF THE INVENTION

The present invention relates to improved, commercially viable and industrially applicable purification process of stable form A Linagliptin with high purity and yield.

One aspect of the present invention provides a purification process of stable form A Linagliptin, comprising;

a) Linagliptin is refluxed in isopropyl alcohol,
b) cooling the solution obtained in step a), and
c) isolating the stable form A Linagliptin.

Another aspect of the present invention provides a high pure stable form A Linagliptin (99.9%).

In Another aspect of the present invention relates to the purification process of stable form A Linagliptin, characterized by the X-ray powder diffraction patterns (XRPD) and Differential scanning calorimetry (DSC).

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: X-ray powder diffraction (PXRD) of stable pure Linagliptin form A

Figure 2: Differential scanning calorimetry (DSC) of stable pure Linagliptin form A.
DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to improved, commercially viable and industrially applicable purification process of stable form A Linagliptin with high purity and yield.

In one embodiment of the present invention provides a purification process of stable form A Linagliptin, comprising;

a) Linagliptin is refluxed in isopropyl alcohol,
b) cooling the solution obtained in step a), and
c) isolating the stable pure Linagliptin form A.

According to the embodiment of the present invention, a purification process of stable form A Linagliptin. which comprises crude Linagliptin is refluxed in isopropyl alcohol until to dissolve solid completely. Gradually cool the reaction mass to 20-25°C, stirred for 2 hours at 20-25°C. Filter and washed the solid with methyl tert butyl ether. Dry the material at 60-65°C under atmospheric pressure obtained stable pure Linagliptin form A.

According to the embodiment of the present invention, the obtained solution cooling at 20-25ºC and stirred for 2 hrs.
Another embodiment of the present invention provides a high pure stable form A Linagliptin (99.9%).
In another embodiment of the present invention provide, pure stable form A Linagliptin XRPD patterns of the figures have a vertical axis that is intensity unit and a horizontal axis that is 2 angle in degrees.
According to the present invention, the stable pure form A Linagliptin is characterized by X-ray powder diffraction pattern having peaks at 7.0, 7.5, 8.3, 9.8, 10.3, 11.0, 11.5, 12.2, 15.1, 19.7, 22.3, 22.9, 24.7, 25.0, 25.6, 0.2º 2θ values.
According to the present invention, the stable pure form A Linagliptin is further characterized by Differential scanning calorimetry (DSC) melts at 206.87ºC.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
EXAMPLES

Example-1:

Purification process of stable form A Linagliptin:

100 gm of Linagliptin is refluxed in 1000 ml of isopropyl alcohol until to dissolve solid completely. Gradually cool the reaction mass to 20-25°C, stirred for 2 hours at 20-25°C. Filter the solid and wash the solid with 200 ml of methyl tert butyl ether. Dry the material at 60-65°C under atmospheric pressure obtained pure stable form A Linagliptin.

Purity: 99.9%

Yield: 81 gm

Example-2:

Purification process of stable form A Linagliptin:

100 gm of Linagliptin is refluxed in 1000 ml of isopropyl alcohol until to dissolve solid completely. Gradually cool the reaction mass to 20-25°C, stir for 60 minutes. Further cool the mixture to 0-5°C, stir for 60 minutes at 0-5°C. Filter the solid and wash the solid with 200 ml of methyl tert butyl ether. Dry the material at 60-65°C, to obtained pure Linagliptin form A.

Purity: 99.7%

Yield: 86 gm

Example-3:

Purification process of stable form A Linagliptin:

100 gm of Linagliptin is refluxed in 1000 ml of isopropyl alcohol until to dissolve solid completely. Distilled off 500 ml of solvent under reduced pressure at below 55°C. Then cool the reaction mass to 30-35°C, stirred for 60 minutes. Filter the compound and wash with 200 ml of methyl tert butyl ether. Dried the material at 60-65°C to obtained 85 gm of pure Linagliptin form A.

Purity: 99.8%

Yield: 85 gm

Example-4:

Process for Stable pure purification process of Linagliptin form A:

100 gm of Linagliptin was charged in 1200 ml of isopropyl alcohol, heat to reflux temperature (80-85°C), stir for 60 to 120 minutes to get clear solution. Gradually cool the reaction mass to 20-25°C, stirred for 2 hours. Filter the compound and wash with 200 ml of methyl tert butyl ether. Dried the material at 60-65°C to obtained pure Linagliptin form A.

Purity: 99.8%

Yield: 80 gm