CLIAMS:1. A process for the preparation of Anagliptin:

Formula I
comprising:
a) treating 2-methyl-1,2-propane diamine of formula II:

Formula II

with 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid of formula III:

Formula III

with N,N’-carbonyldiimadazole in suitable organic solvent to provide N-(2-amino-2-methylpropyl)2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide of formula IV

Formula IV
b) condensation of N-(2-amino-2-methylpropyl)2-methylpyrazolo[1,5-a] pyrimidine-6-carboxamide of formula IV with 1-(2-chloroacetyl)-2S-pyrrolidine carbonitrile of formula V

Formula V
in the presence of base and a catalyst in organic solvent to give Anagliptin.

2. The process of claim 1, wherein the suitable organic solvent in step (a) is
a mixture of halogenated solvent and ether.

3. The process of claim 1, wherein the suitable organic solvent in step (a) is
dichloromethane.

4. The process of claim 1, wherein the halogenated solvent in step (b) is dichloromethane.

5. The process of claim 1, wherein the base in step (b) is diisopropylamine.

6. The process of claim 1, wherein the catalyst in step (b) is sodium iodide.

7. The process of claim 1,wherein the condensation step (a) is carried at 0°C-10°C.

8. The process of claim 1, wherein the condensation step (b) is carried at 35°C -40°C.
,TagSPECI:Field of Invention

Aspects of the present invention relates to an industrially advantageous, short process for the preparation of Anagliptin.

Background of the invention

The drug compound having the adopted name “Anagliptin” has chemical name: N-[2-({2-[(2S)-2-Cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo [1,5-a] pyrimidine-6-carboxamide; and has the structural formula I:

Formula I

The pharmaceutical product Suini® tablets contain Anagliptin as active ingredient. Anagliptin is a DPP-4 (dipeptidyl peptidase-4) inhibitor useful for the treatment of diabetes.

U.S. Pat. No. 7,345,180 describes Anagliptin and process for the preparation thereof. The process of US’180 involves reaction of 2-methylpyrazolo [1, 5-a] pyrimidin-6-yl with (S)-1-(2′-Chloroacetyl) pyrrolidine-2-carbonitrile in presence of potassium carbonate and sodium iodide in acetone for a period of 8 hours at room temperature.

Noriyasu Kato etal in Bioorganic and Medicinal Chemistry 19(23), 2011, 7221-7227 reported synthesis of anagliptin hydrochloride. The process involves selective protection of 2-amino-2-methylpropylamine with di-tert-butyl dicarbonate and condensation with (S)-1-(2-chloroacetyl) pyrrolidine-2-carbonitrile. After deprotection of the BOC group, the amino pyrrolidine is then condensed with pyrimidine acid in tetrahydrofuran solvent using N, N-carbonyldiimidazole to give Anagliptin which is converted to Anagliptin hydrochloride using hydrochloric acid and 1, 4-dioxan solvent.

The reported processes involve protection and deprotection which are tedious and increases the steps and the cost of process, making it lengthy and cumbersome. Hence there is a need to develop a simple and short process which would be cost effective and commercially viable.

The inventors of the present invention found that the reaction of 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid proceeds easily with 2-methyl-1,2-propane diamine, which reacts further with 1-(2-chloroacetyl)-2S-pyrrolidine carbonitrile to get Anagliptin.

Summary of the Invention

The present invention provides a short, industrially advantageous process for the preparation of Anagliptin.

In an aspect, the present invention is to provide a process for the preparation of Anagliptin of formula I:

Formula I
which includes steps of:
a) treating 2-methyl-1,2-propane diamine of formula II:

Formula II

with 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid of formula III:

Formula III

with N,N’-carbonyldiimadazole in suitable organic solvent to provide N-(2-amino-2-methylpropyl)2-methylpyrazolo[1,5-a] pyrimidine-6-carboxamide of formula IV; and

Formula IV

b) condensing N-(2-amino-2-methylpropyl)2-methylpyrazolo[1,5-a] pyrimidine-6-carboxamide of formula IV with 1-(2-chloroacetyl)-2S-pyrrolidine carbonitrile of formula V

Formula V

to give Anagliptin in the presence of an organic base and a catalyst in an organic solvent.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The term “catalyst” includes metal halides like potassium iodide, sodium bromide, sodium iodide and the like.

The term “suitable organic solvent” includes a mixture of one or more halogenated solvent and ethers, where the preferred solvent is a halogenated solvent.

The term “organic solvent” includes halogenated solvent.

The intermediates and starting materials of the present invention may be used as free bases.

In an aspect, the present invention is to provide a process for the preparation of Anagliptin of formula I:

Formula I

which includes steps of:
a) treating 2-methyl-1,2-propane diamine of formula II:

Formula II

with 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid of formula III:

Formula III

with N,N’-carbonyldiimidazole in suitable organic solvent to provide N-(2-amino-2-methylpropyl)2-methylpyrazolo[1,5-a] pyrimidine-6-carboxamide of formula IV; and

Formula IV

b) ) condensing N-(2-amino-2-methylpropyl)2-methylpyrazolo[1,5-a] pyrimidine-6-carboxamide of formula IV with 1-(2-chloroacetyl)-2S-pyrrolidine carbonitrile of formula V

Formula V
in the presence of an organic base and a catalyst in an organic solvent to give Anagliptin.
The reaction between 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid and N,N’-carbonyldiimidazole may be carried out in an inert atmosphere at a temperature range of 20°C to 40°C. The solvent may be selected from a suitable organic solvent. The suitable organic solvent may be a mixture of one or more halogenated solvent and ethers. The halogenated solvent may be selected from dichloromethane, dichloroethane, chloroform, chlorobenzene and the like. Further, the ether solvent may be selected from dimethyl ether, diethyl ether, dioxane and the like.

The obtained 2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid-N,N’-carbonyl
diimidazole mixture may be added to 2-methyl-1,2-propane diamine at a temperature range of -10°C to 10°C. After completion of reaction, water may be added and N-(2-amino-2-methylpropyl)2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide may be isolated from the suitable organic solvent.

In the condensation reaction, 1-(2-chloroacetyl)-2S-pyrrolidine carbonitrile may be added to N-(2-amino-2-methylpropyl)2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide at a temperature range of 20°C to 30°C in an organic solvent. The organic solvent may be halogenated solvent. The halogenated solvent is selected from dichloromethane, dichloroethane, chloroform, chlorobenzene and the like.
After completion of reaction, water may be added and crude anagliptin may be isolated from the organic solvent.

The condensation reaction may be conducted in the presence of an organic base which includes but is not limited to triethylamine, 4-dimethylaminopyridine, diisopropylamine and the like and in the presence of a catalyst which includes, but is not limited to sodium iodide, potassium iodide, sodium bromide.

The crude Anagliptin may be purified using solvents like esters for example isopropyl acetate.
The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example 1: Process for preparation of N-(2-amino-2-methylpropyl)-2-methyl- pyrazolo [1, 5-a] pyrimidine-6-carboxamide

N, N’-carbonyldiimidazole (9.6g) was added to a solution of 2-methylpyrazolo [1, 5-a] pyrimidin-6–carboxylic acid (10.0g) in dichloromethane under nitrogen at 25°C-30°C and stirred the reaction mixture for 1 hour. The reaction mixture was added slowly to a solution of 2-methyl-1,2-propanediamine (5.5g) in dichloromethane at 0°C-10°C. The reaction mixture was maintained till completion of reaction. Water was added to the reaction mixture and dichloromethane layer was separated. The combined dichloromethane layers were concentrated to get N-(2-amino-2-methylpropyl)-2-methyl-pyrazolo [1,5-a]pyrimidine-6-carboxamide (8.8g)

Example-2: Process for preparation of Anagliptin

Diisopropylamine (3.8g), sodium iodide (5.2g) and (S)-1-(2’-chloroacetyl) pyrrolidine-2-carbonitrile (6.0g) was added to solution of N-(2-amino-2-methylpropyl)-2-methyl-pyrazolo [1,5-a] pyrimidine-6-carboxamide (8.0g) in dichloromethane. The reaction mixture was heated to 35°C-40°C and maintained till completion of reaction. Water was added and the dichloromethane layer was separated and concentrated to get crude Anagliptin. The crude Anagliptin was purified using Isopropyl acetate to get pure Anagliptin.

HPLC purity: 99.6%.

Yield: 3.0 g.