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

Formula I
or pharmaceutically acceptable salt thereof, which comprises: reaction of amino pyrrolidine of formula II:

Formula II
with pyrazole acid of formula III:

Formula III

using carbonyldiimadazole in presence of base and chlorinated solvent to provide Anagliptin or a pharmaceutically acceptable salt thereof having purity greater than or equal to 99%.

2. The process of claim 1, wherein the chlorinated solvent is dichloromethane.

3. The process of claim 1, wherein the reaction is carried out at a temperature of about 25 to about 35 °C.

4. The process of claim 1, wherein the base is triethylamine.

5. The process of claim 1, wherein the purity of anagliptin or a pharmaceutically acceptable salt thereof is greater than or equal to 99.3%.

6. A crystalline form of Anagliptin or a pharmaceutically acceptable salt thereof, which is characterized by characteristic peaks of X-ray powder diffraction pattern comprises two or more peaks of 9.9, 11.1, 12.9, 17.5, and 18.7 ± 0.2° 2 theta.

7. The compound of claim 6, wherein the crystalline form is further characterized by differential scanning calorimetry (DSC) has an endotherm peak at about 118 °C and Thermogravimetric analysis (TGA) represented as Fig. 2.

8. A process for the preparation of crystalline Anagliptin or a pharmaceutically acceptable salt thereof, comprising crystallization of a solid from the suspension or solution of Anagliptin or a pharmaceutically acceptable salt thereof in a solvent.

9. The process of claim 8, wherein the solvent is ester, for example, isopropyl acetate.

10. An amorphous form of Anagliptin or a pharmaceutically acceptable salt thereof.
,TagSPECI:Field of Invention

Aspects of the present invention relates to a process for the preparation of Anagliptin or a pharmaceutically acceptable salt thereof. Further aspects of the present invention relates to a polymorph of Anagliptin or a pharmaceutically acceptable salt thereof and a method for the preparation thereof.

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 contains Anagliptin as active ingredient. Anagliptin is 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 (S)-1-[(2-amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride with 2-methylpyrazole [1,5-a]pyrimidin-6-yl acid in presence of Diimidazolyl ketone, triethylamine and tetrahydrofuran for a period of overnight.

The reported process suffers one or the other problems like yield and purity due to the reagents and reaction condition. Hence, there is a need for a simple process for making large scale quantities of Anagliptin or a pharmaceutically acceptable salt thereof.

Additionally, the present inventors discovered unexpected physical characterizations for Anagliptin or a pharmaceutically acceptable salt, for example, different polymorphs and specific particle size distribution, which will provide stable formulations.

Summary of the Invention

The present invention provides a process for the preparation of Anagliptin or pharmaceutically acceptable salt thereof. Further, the present invention provides polymorph to Anagliptin or a pharmaceutically acceptable salt thereof and a method for the preparation thereof.

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

Formula I

or pharmaceutically acceptable salt thereof, which comprises: reaction of amino pyrrolidine of formula II:
Formula II

with pyrazole acid of formula III:

Formula III

using carbonyldiimadazole in presence of base and chlorinated solvent to provide Anagliptin or a pharmaceutically acceptable salt thereof having purity greater than or equal to 99%.

In another aspect, the present invention provides Anagliptin or a pharmaceutically acceptable salt thereof having purity greater than or equal to 99%.

In another aspect, the present invention provides a polymorph of Anagliptin or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a crystalline form of Anagliptin or a pharmaceutically acceptable salt thereof having an X-ray diffraction pattern, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K α-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 9.9, 11.1, 12.9, 17.5, 18.7 ± 0.2°.

In another aspect, the present invention provides a process for the preparation of crystalline Anagliptin or a pharmaceutically acceptable salt thereof, which comprises crystallization of a solid from the suspension or solution of Anagliptin or a pharmaceutically acceptable salt thereof in a solvent.

In another aspect, the present invention provides an amorphous form of Anagliptin hydrochloride, which is characterized by an X-ray diffraction pattern shown as Fig. 4.

In another aspect, the present invention provides composition of Anagliptin or a pharmaceutically acceptable salt thereof comprising 90 percent or more of particle have particle size less than or equal to 500 microns or less than or equal to 250 microns or less than or equal to 210 microns.

In another aspect, there is provided a composition comprises anagliptin or a pharmaceutically acceptable salt thereof of the present invention and at least one pharmaceutically acceptable carrier or excipient.

Brief Description of the Drawings

FIG. 1 shows an illustrative example of X-ray powder diffraction pattern of a crystalline form of Anagliptin prepared according to Example 1.

FIG. 2 shows an illustrative example of thermogravimetric analysis curve (TGA) thermogram pattern of a crystalline form of Anagliptin prepared according to Example 1.

FIG. 3 shows an illustrative example of differential scanning calorimetry (DSC) thermogram pattern of a crystalline form of Anagliptin prepared according to Example 1.

FIG. 4 shows an illustrative example of X-ray powder diffraction pattern of an amorphous form of anagliptin hydrochloride prepared according to Example 2.

Description of the Invention

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

The term “pure” as used herein, unless otherwise defined, the compound that has purity of greater than about 99 % or greater than about 99.3 %.

The term “polymorph”, unless otherwise defined, includes amorphous, crystalline and solvate of Anagliptin or a pharmaceutically acceptable salt thereof.

The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical product that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The salt or pharmaceutically acceptable salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoracetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

The term “composition” includes, but is not limited to, a powder, a suspension, an emulsion and/or mixtures thereof.

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Kα radiation, having the wavelength 1.54 Å.

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

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

Formula I

or pharmaceutically acceptable salt thereof, which comprises: reaction of amino pyrrolidine of formula II:

Formula II

with pyrazole acid of formula III:

Formula III

using carbonyldiimadazole in presence of base and chlorinated solvent to provide Anagliptin or a pharmaceutically acceptable salt thereof having purity greater than or equal to 99%.

The reaction may be conducted at a temperature of about 25 to about 60°C or about 25 to about 40 °C in presence of solvent. The reaction may be carried out for a period of about 1 to 5 hours or more.

The chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform, chlorobenzene and the like. Further, the chlorinated solvent may be mixture of solvent with ethers such as dimethyl ether, diethyl ether, dioxane and the like.

The process for Anagliptin or a pharmaceutically acceptable salt thereof comprises:
i) reaction between pyrazole acid and carbonyldiimadazole in presence of solvent; and
ii) addition of a mixture of aminopyrrolidine and base in a solvent to the mixture of step i) to afford Anagliptin or a pharmaceutically acceptable sat thereof.

The mixture of aminopyrrolidine, base and solvent may be prepared at a temperature of less than 25 °C or less than 15 °C. The mixture may be stirred for a period of 30 minutes 3 hours or more at a lower temperature. The solvent may be selected from the group of chlorinated solvent, for example, dichloromethane. The base may be selected from inorganic base or organic base. The inorganic base includes but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, potassium bicarbonate and the like; the organic base may be selected from triethyl amine, diisopropyl amine, methyl amine, pyridine, N-methyl pyrrolidine and the like.

The obtained aminopyrrolidine mixture is added to the reaction mixture of pyrazole acid derivative of step (i) at a temperature of about 20 to about 60 °C or at 25 to about 35 °C. Then the reaction mixture may be stirred for a period of 30 minutes to 2 hours or more for the completion of the reaction.

After completion of the reaction, the reaction mixture may be subjected for isolation of solid by using suitable techniques such as column chromatography and concentration.

In another aspect, the present invention provides Anagliptin or a pharmaceutically acceptable salt thereof having purity greater than or equal to 99%.

The anagliptin or a pharmaceutically acceptable salt obtained from the present invention contains greater than or equal to 99.3%. The inventors of the present invention found that the reaction of pyrazole acid derivative and amino pyrrolidine and other conditions like crystallization of solid gives higher purity.

In another aspect, the present invention provides a polymorph of Anagliptin or a pharmaceutically acceptable salt thereof.

Further, the present invention provides polymorphs of anagliptin or a pharmaceutically acceptable salt thereof includes crystalline anagliptin, amorphous anagliptin, crystalline pharmaceutically acceptable salt of anagliptin and amorphous pharmaceutically acceptable salt of anagliptin and solvate thereof.

In another aspect, the present invention provides a crystalline form of Anagliptin or a pharmaceutically acceptable salt thereof having an X-ray diffraction pattern, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K α-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 9.9, 11.1, 12.9, 17.5, 18.7 ± 0.2°.

The XRPD characteristic peaks of the crystalline form of anagliptin or a pharmaceutically acceptable salt further defined from the Table 1:

°2 Theta d-spacing Rel. Intensity [%]
8.89 9.93 21.15
9.99 8.85 43.03
11.22 7.88 26.73
13.03 6.79 22.40
15.20 5.82 20.21
16.50 5.37 30.17
16.77 5.28 19.32
17.54 5.05 86.29
18.75 4.73 100.00
19.29 4.59 39.01
20.17 4.40 32.42
20.34 4.36 10.92
25.29 3.52 44.85
25.47 3.49 38.85
25.99 3.42 39.91

The crystalline form of Anagliptin or a pharmaceutically acceptable salt thereof, which is characterized by thermogravimetric analysis (TGA) represented as Fig. 2. The TGA shows that the compound contains less than 0.5 % of water/solvent.

The crystalline form of Anagliptin or a pharmaceutically acceptable salt thereof, which is characterized by differential scanning calorimetry (DSC) has an endotherm peak at about 118 °C and the same is shown by the Fig.3.

In another aspect, the present invention provides a process for the preparation of crystalline Anagliptin or a pharmaceutically acceptable salt thereof, comprising crystallization of a solid from the suspension or solution of Anagliptin or a pharmaceutically acceptable salt thereof in a solvent.

The starting material used for the preparation of crystalline may be amorphous, syrup mass obtained from the reaction, solution obtained from the reaction, solvate.

The solvent used for the crystallization of solid includes and is not limited to alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; chlorinated solvent such as dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; ether such as tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, dioxane and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbon such as n-hexane, cyclohexane, heptane, toluene and the like; water or in combination thereof.

The techniques for crystallization include recrystallization, anti-solvent technique, crash cooling, and the like. In an embodiment, the present invention produces crystalline anagliptin or a pharmaceutically acceptable salt thereof from the recrystallization technique.

In an embodiment, the present invention provides a process for the preparation of crystalline anagliptin or a pharmaceutically acceptable salt thereof, comprises:
a) providing solution of anagliptin or a pharmaceutically acceptable salt in an ester solvent;
b) cooling the solution of step a);
c) recovering the crystal solid from the step b).

The solution may be provided by the dissolution of compound in an ester or may be directly obtained from the reaction. The dissolution may be carried out at a temperature of about 30 to about 90 °C or of about 50 to 85 °C. The solution may be treated with carbon and may be filtered through hyflo to provide clear solution.

The resultant solution is cooled to a temperature of less than 30 °C or less than 15 °C and stirred for a period of about 30 minutes to 1 hour or more to influence the yield of the solid and crystallinity.

The resultant solid of step b) may be separated / recovered by using suitable techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with suitable solvent such as isopropyl acetate.

The wet solid 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 may be carried out at temperatures of about 35 °C. to about 60° C or of about 40 to about 45 °C. The drying can be carried out for any time periods necessary for obtaining a desired weight consistent, such as from about 1 to about 8 hours, or longer.

In another aspect, the present invention provides an amorphous form of Anagliptin or a pharmaceutically acceptable salt thereof. In an embodiment, the present invention provides an amorphous form of anagliptin hydrochloride which is characterized by an X-ray diffraction pattern shown as Fig. 4.

In another aspect, the present invention provides composition of Anagliptin or a pharmaceutically acceptable salt thereof comprising 90 percent or more of particle have particle size less than or equal to 500 microns or less than or equal to 250 microns or less than or equal to 210 microns.

The determined particle size D90 less than or equal to 500 microns shows high solubility, good powder flowability and uniform particle distribution which are advantages characteristic for stable formulation.

In an embodiment, the present invention provides composition of anagliptin or a pharmaceutically acceptable salt thereof comprising 50 percent (D50) or more of particles have particle size less than 200 or less than 100 microns.

In an embodiment, the present invention provides composition of anagliptin or a pharmaceutically acceptable salt thereof comprising 10 percent (D10) or more of particles have particle size less than 100 or less than 50 microns or less than 25 microns.

In another aspect, there is provided a pharmaceutical composition comprises anagliptin or a pharmaceutically acceptable salt thereof of the present invention and at least one pharmaceutically acceptable excipient or carrier.

The polymorphs of the present invention can be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product according to the invention is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including for example solutions, suspensions, syrups, elixirs and emulsions, containing inert diluents, solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin, may be used.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous, sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients that are of use in the present invention include but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

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: A process for preparing Anagliptin and its crystalline form

To the mixture of pyrazole acid (40 gm) in dichloromethane (1200 ml) carbonyldiimadazole (43.9 gm) was added and stirred for 4 hours at 25-35 °C. In another RBF added amino pyrrolidine (67.1 gm) and DCM (400 ml) and cooled the reaction mass to 10-15°C and then Triethyl amine (114.2 gm) was added. This reaction mass was added to above pyrazole acid mass and maintained the reaction at 25-35 °C for 2 hours. After completion of the reaction, the reaction mixture was washed with water (2x640 ml). Then the organic layer was distilled to get syrupy mass. The product was dissolved in isopropyl acetate (200ml) at 50-85 °C and then cooled to room temperature followed by cooled to 10-15 °C. The resultant solid was filtered and dried to get anagliptin (53.2 gm) as white color crystalline powder.
HPLC purity: 99.38%
XRD: Crystalline form represented as Fig.1
TGA: represented as Fig.2
DSC: 118.5 0C represented as Fig. 3
M.P:118.2 to 118.6 0C
Particle size distribution: d(0.9): 205.291 microns;
d(0.5) : 95.024 microns;
d(0.1) : 21.658 microns.

Example-2: Préparation Anagliptin Hydrochloride

To the solution of Anagliptin (5.0 gm) in dioxane (15 ml) isopropyl alcohol.hydrochloride (2.0 gm) was added. To this suspension diethyl ether (50 ml) was added and stirred for 1 hour at 25-30 °C. Filtered the solid and washed with diethyl ether, and dried to get anagliptin hydrochloride (4.0 gm).

XRD: Amorphous and is represented as Fig.4
Moisture content: 6.46% w/w
HPLC purity: 99.10 %