CLIAMS:We Claim:

1. A process for the purification of Boc-aminopyrrolidine of formula III or a pharmaceutically acceptable salt thereof

Formula III
substantially free from its dimer impurity of Formula A:

Formula A
which comprises:
a) providing suspension or solution of Boc-aminopyrrolidine in ether solvent;
b) cooling the reaction mixture of step a) to below 15 °C; and
c) recovering the pure Boc-aminopyrrolidine or a pharmaceutically acceptable salt thereof substantially free from its dimer impurity of formula A.

2. The process of claim 1, wherein the ether is methyl tertiary butyl ether, diethyl ether, dimethyl ether, methyl ethyl ether, anisole, tetrahydrofuran or mixtures thereof.

3. The process of claim 1, wherein the temperature below 15 °C is about 5 to 10 °C.

4. The process of claim 1, wherein the Boc-aminopyrrolidine having greater than or equal to 95% of purity.

5. The process of claim 1, wherein the Boc-aminopyrrolidine having less than or equal to 1% of dimer impurity of formula A.

6. The process of claim 1, wherein the Boc-aminopyrrolidine is further converted to Anagliptin.

Dated this 31st day of December 2013 For Wockhardt Limited (Dr Mandar Kodgule)
Authorized Signatory
,TagSPECI:Field of Invention

Aspects of the present invention relates to a process for the purification of intermediate of Anagliptin, Boc-aminopyrrolidine of formula III:

Formula III
or a pharmaceutically acceptable salt thereof from ether solvent.

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 triethylamine and tetrahydrofuran.

Reported processes for preparing Boc-aminopyrrolidine of formula III in the prior art, for example, Kato Noriyasu et al., in Bioorganic & Medicinal Chemistry, 19(23), 7221-7227; 2011 and US 7,345,180, involves condensation using potassium carbonate in presence of acetone. However, the prior art process has disadvantages including formation of dimer of pyrrolidine of Formula A more than 10%. The prior art process neither isolated the impurity nor provided any process to purify the compound of formula III from its dimer impurity.

The use of impure intermediate of formula III for the preparation of Anagliptin make the process expensive and industrially unviable.

Therefore, there is a need to develop a simple and industrially feasible purification process for preparing pure Boc-aminopyrrolidine, which is key intermediate for the preparation of Anagliptin or a pharmaceutically acceptable salt thereof.

Summary of the Invention

The present invention provides a process for the purification of Boc-aminopyrrolidine and its conversion to Anagliptin or pharmaceutically acceptable salt thereof.

In an aspect, the present invention relates to a process for the purification of Boc-aminopyrrolidine of formula III or a pharmaceutically acceptable salt thereof

Formula III

substantially free from its dimer impurity of Formula A:

Formula A
which comprises:
a) providing suspension or solution of Boc-aminopyrrolidine in ether solvent;
b) cooling the reaction mixture of step a) to below 15 °C; and
c) recovering the pure Boc-aminopyrrolidine or a pharmaceutically acceptable salt thereof substantially free from its dimer impurity of formula A.

In another aspect, the present invention relates to a process for the preparation of Anagliptin substantially free of impurity A, which comprises:
a) providing suspension or solution of Boc-aminopyrrolidine in ether solvent;
b) cooling the reaction mixture of step a) to below 15 °C;
c) recovering the pure Boc-aminopyrrolidine or a pharmaceutically acceptable salt thereof substantially free from its dimer impurity of formula A; and
d) conversion of pure Boc-aminopyrrolidine of formula III to pure Anagliptin.

Description of the Invention

The term “substantially free” as used herein, unless otherwise defined, refers to Anagliptin, an intermediate thereof, or salt thereof that contains dimer pyrrolidine impurity less than 1%.

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

The term “pure” as used herein, unless otherwise defined, the compound that has purity of greater than or equal to 90 % or greater than or equal to 95%.

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 slat may include acetate, mesylate, tosylate and the like.

In an aspect, the present invention relates to a process for the purification of Boc-aminopyrrolidine of formula III or a pharmaceutically acceptable salt thereof

Formula III

substantially free from its dimer impurity of Formula A:

Formula A
which comprises:
a) providing suspension or solution of Boc-aminopyrrolidine in ether solvent;
b) cooling the reaction mixture of step a) to below 15 °C; and
c) recovering the pure Boc-aminopyrrolidine or a pharmaceutically acceptable salt thereof substantially free from its dimer impurity of formula A.

The step a) involves providing suspension or solution of Boc-aminopyrrolidine in ether solvent.

A suspension or solution of Boc-aminopyrrolidine in ether solvent can be provided from the chemical reaction by which the compound is prepared, or by combining isolated Boc-aminopyrrolidine with ether solvent. Ether solvent may comprise methyl tertiary butyl ether, diethyl ether, dimethyl ether, methyl ethyl ether, anisole, tetrahydrofuran or mixtures thereof. The suspension includes syrup of the reaction mass.

The suspension or solution of Boc-aminopyrrolidine may be provided at temperatures ranging from about 20 °C up to the boiling point of the solvent.

The suspension or solution of Boc-aminopyrrolidine may also be provided by dissolving Boc-aminopyrrolidine in a desired solvent, followed by concentration to a desired extent to produce a suspension or syrup.

The step b) involves cooling the reaction mixture of step a) to below 15 °C.

The resultant suspension or solution may be cooled to lower temperature, for example, below 15 °C or below 10 °C or about 5 to 10 °C. The obtained suspension may be maintained at the same temperature for a period of about 30 minutes to 2 hours or more to increase the precipitation of solid with purity greater than or equal to 95%.

The step c) involves recovering the pure Boc-aminopyrrolidine or a pharmaceutically acceptable salt thereof substantially free from its dimer impurity of formula A.

The pure Boc-aminopyrrolidine may be isolated by the techniques known in the art. For example, it may be isolated by using filtration by gravity or by suction, centrifugation, decantation, and the like. For example, the Boc-aminopyrrolidine may be isolated by filtering the cold suspension obtained in (b) at below 15 °C.

After isolation, the solid may optionally be washed. A wet solid obtained from (c) may be dried in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures about 30 °C to about 85 °C, optionally under reduced pressure. The drying may be carried out for any time periods, such as, for example, for about 1 to about 10 hours, or longer, to give the desired compound of Formula III or a pharmaceutically acceptable salt.

In another aspect, the present invention relates to a process for the preparation of Anagliptin substantially free of impurity A, which comprises:
a) providing suspension or solution of Boc-aminopyrrolidine in ether solvent; and
b) cooling the reaction mixture of step a) to below 15 °C; and
c) recovering the pure Boc-aminopyrrolidine or a pharmaceutically acceptable salt free from its dimer impurity of formula A.
d) conversion of pure Boc-aminopyrrolidine of formula III to pure Anagliptin.

The resultant compound of formula III is useful for the preparation of aminopyrrolidine of formula II and Anagliptin, or a pharmaceutically acceptable salt thereof. The process of Anagliptin is schematically presented in the following scheme 1:

SCHEME-1

The resultant Anagliptin or a pharmaceutically acceptable salt thereof obtained from the present invention is useful for pharmaceutical composition.

In another aspect, the present invention relates to pharmaceutical composition comprising Anagliptin or a pharmaceutically acceptable salt, which is substantially free from its dimer pyrrolidine impurity, and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically for the treatment of type 2 diabetes in a mammal in need thereof.

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 Boc-aminopyrrolidine

To the mixture of 1-amino-2-methyl propanamine (500 gm) in dichloromethane (2.5 L) at 5-10 °C was added Boc-anhydride solution slowly (310 gm in 0.5 L dichloromethane). The reaction mixture was maintained at the same temperature for 1 hour. After 1 hour, reaction mixture was brought to 25-30 °C and maintained for 3 hours. To the reaction mixture, water (1.5 L) was added and continued stirring. After 30 minutes, separated organic layer and distilled the solvent to get 1-tert-butoxycarbonylamino-2-methyl-2-propanamine residue in dichloromethane.

To the above residue, dichloromethane (3.5 L), (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (chloro pyrrolidine) (400 gm), sodium iodide (334 gm), and diisopropyl amine (226 gm) were added. The reaction mixture was heated to 35-40 °C and maintained for 5 hours. The reaction mixture was cooled to 25-30 °C and water (2.5 L) was added and stirred the solution for 30 minutes. The organic layer was separated and distill-off the solvent till syrupy mass was observed.

Dimer impurity: 2.5%

Example-2: A process purification of Boc-aminopyrrolidine of Formula III

Methyl tertiary butyl ether (2.5 L) was added to the Boc-aminopyrrolidine and cooled the reaction mixture to 5-10 °C. The reaction mixture was maintained for 2 hours at 5-10 °C, filtered the solid and washed with chilled methyl tertiary butyl ether (500 ml) to get pure Boc-aminopyrrolidine (620 gm).

HPLC purity: 98.5%; dimer impurity: 0.62%

Example-3: A process for preparing amino pyrrolidine

To the mixture of Boc-aminopyrrolidine (100 gm) obtained from the example-2 in isopropyl alcohol (1000 ml), aqueous hydrochloric acid (80.4 gm) were added. The reaction mixture was heated to 60-65 °C and maintained for 5 hours. The mixture was cooled to 40-45 °C and then added isopropyl alcohol (200 ml). The mixture was further cooled to 5-10 °C and maintained for 2 hours. The solid was filtered and washed with chilled isopropyl alcohol to get pure amino pyrrolidine dihydrochloride (72.1 gm).

HPLC purity: 99.1%, dimmer impurity: 0.08%.