CLIAMS:
1. A process for the preparation of Teneligliptin or pharmaceutically acceptable salt thereof of Formula I

Formula-I
the process comprises the steps of
a) condensing 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine formula II

Formula-II
or salt thereof with 3-[(2S)-1-(1,1-dimethylethyloxycarbonyl)-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine formula III

Formula-III
in a halogenated solvent in presence of base and acid to obtain of Boc-teneligliptin formula IV,

Formula-IV
b) deprotecting Boc-teneligliptin in presence of acid in aqueous alcohol,
c) purification of reaction mixture of step b) to obtain Teneligliptin base,
d) converting Teneligliptin base to pharmaceutically acceptable salt.

2. The process of claim 1, wherein the halogenated solvent is selected from the group comprising one or more of dichloromethane, chloroform, carbon tetrachloride and mixture thereof.

3. The process of claim 2, wherein the suitable halogenated solvent is dichloromethane.

4. The process of claim 1, wherein aqueous alcohol is mixture of alcohol and water, wherein ratio alcohol and water is about 10:1 to 10.3.

5. The process of claim 4, wherein alcohol is selected from the group comprising one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, propylene glycol and mixtures thereof.

6. The process of claim 1, wherein reducing agent is selected from group comprising one or more sodium borohydride and sodium triacetoxyborohydride.

7. The process of claim 6, wherein reducing agent is sodium triacetoxyborohydride.

8. The process of claim 5, wherein acid is selected from group comprising one or more of acetic acid and hydrochloric acid.

9. The process of claim 5, wherein purification is carried out by acid base treatment.

10. The process of claim 1, wherein the purity of Teneligliptin or salt thereof, has purity more than 99 % by as measured HPLC.

,TagSPECI:Field of Invention

The present invention relates to process for the preparation of Teneligliptin or its pharmaceutically acceptable salt thereof, has purity more than 99% as measured by HPLC. The present invention particularly directs to an insitu process of Teneligliptin or a pharmaceutically acceptable salt thereof. In the further aspect of present invention involves the purification of Teneligliptin base by acid base treatment.

Background of the invention

Teneligliptin is chemically known 3-[[(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl] carbonyl] thiazolidine or its pharmaceutical acceptable salt thereof and is structurally represented by formula (I):

Formula I
Teneligliptin is indicated for the treatment of type 2 diabetes mellitus. US Pat. No. 7,074,794 (referred to herein as ‘794) and 8,003,790 (referred to herein as ‘790) describe Teneligliptin and its process for the preparation thereof.

The US '790 describes the process of preparation of Teneligliptin or pharmaceutically acceptable salt thereof, which involve the preparation 3-[(2S)-1-(1,1-dimethyl ethyloxycarbonyl)-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine (referred to herein as Boc-pyrrolidinone thiazolidine) and 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine, which is subsequently condensed to prepare Boc-Teneligliptin and Teneligliptin or a pharmaceutically acceptable salt thereof.
The reported process suffers various drawbacks like it requires multiple steps of isolation of intermediate, which subsequently reduces the yield as well as reaction takes longer time to complete, thus reported process is not industrially feasible.

Thus, an object of the present invention is to provide a process to overcome aforesaid problems and to provide simple, less time consuming insitu process, which very cost effective and industrially feasible.

Summary of the Invention

The present invention provides process for the preparation of Teneligliptin or pharmaceutically acceptable salt thereof, has purity more than 99 % as measured by HPLC.

The present invention provides a process for the preparation of Teneligliptin or pharmaceutically acceptable salt thereof of Formula I,

Formula-I
the process includes the steps of;
a) condensing 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine or its salt thereof with 3-[(2S)-1-(1,1-dimethylethyloxycarbonyl)-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine or its salt thereof in a halogenated solvent in presence of base and acid to obtain Boc-teneligliptin or its salt thereof,
b) deprotecting Boc-teneligliptin in presence of acid in aqueous alcohol,
c) purification of reaction mixture of step b) to obtain Teneligliptin base,
d) converting Teneligliptin base to its pharmaceutically acceptable salt thereof.

In another aspect of the present invention Teneligliptin or pharmaceutically acceptable salt thereof has purity more than 99% as measured by HPLC.

Description of the Invention

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

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

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

The present invention provides a process for the preparation of Teneligliptin or pharmaceutically acceptable salt thereof of Formula I

Formula-I
which includes steps of ;
a) condensing 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine formula II

Formula-II
or salt thereof with 3-[(2S)-1-(1,1-dimethylethyloxycarbonyl)-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine formula III

Formula-III
or its salt thereof in a halogenated solvent in presence of base and acid to obtain of Boc-teneligliptin formula IV

Formula-IV
b) deprotecting Boc-teneligliptin in presence of acid in aqueous alcohol
c) purification of reaction mixture of step b) to obtain Teneligliptin base
d) converting Teneligliptin base to pharmaceutically acceptable salt thereof

The step a) of the present invention involves the condensing of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine with 3-[(2S)-1-(1,1-dimethylethyloxycarbonyl)-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine in a halogenated solvent at temperature in between range of 20C to 30C, followed by addition of acid and reducing agent at temperature in between range of 30C to 40C, for period of 4 to 5 hour. The reducing agent is selected from group comprising one or more sodium borohydride and sodium triacetoxyborohydride. The acid is selected from group comprising one or more hydrochloric acid and acetic acid. After completion of reaction, reaction mixture washed with water. The solvent is removed under reduced pressure to get Boc-Teneligliptin as syrupy mass.

The halogenated solvent is selected from the group comprising one or more of dichloromethane, chloroform, carbon tetrachloride and mixture thereof.
The step b) of the present invention involves deprotection of Boc-teneligliptin by means of addition of Boc-teneligliptin in aqueous alcoholic solvent, followed by addition concentrated hydrochloric acid, the reaction mixture heated at temperature in between range of 60°C to 70°C for period of 2 to 4 hours. After completion of reaction, reaction mixture cooled at temperature in between range of 20°C to 35°C, followed by washing with dichloromethane solvent.

The aqueous alcohol is the mixture alcohol and water in the ratio of 10:1, wherein alcohol solvent is selected from the group comprising one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, propylene glycol and mixtures thereof.

The step c) of the present invention involves purification of reaction mixture of step b) to obtain purified Teneligliptin base by means of acid base treatment. The reaction mixture treated with aqueous solution of base to get pH in between range of 8 to 9. The reaction mixture extracted with extracted in dichloromethane. The dichloromethane solvent is distilled out under vacuum to get Teneligliptin base as syrupy mass.

The step d) of the present invention involves converting Teneligliptin base to pharmaceutically acceptable salt such as hydrobromide. The reaction involves dissolving Teneligliptin base in alcoholic solvent. The alcohol solvent is selected from the group comprising one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, propylene glycol and mixtures thereof, followed by addition of hydrobromic acid. The reaction mixture is cooled at temperature in between range of 10°C to 20°C. The reaction mixture is filtered and dried to get Teneligliptin Hydrobromide.

In another aspect of the present invention involves the step (a) to (d) of the present invention may be carried out without the isolation of intermediates.

In another aspect of the present invention Teneligliptin or pharmaceutically acceptable salt thereof has purity more than 99% as measured by HPLC.
The process of the present invention is depicted in the following Scheme 1:

Scheme 1

The present invention is further illustrated by the following example, which does not limit the scope of the invention. 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 application.
Examples

Example-1: Preparation of Boc-Teneligliptin
Charged 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (80.0 gm) and 3-[(2S)-1-(1,1-dimethyl ethyloxycarbonyl)-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine (100.0 gm) in dichloromethane (1000 ml) at temperature about 25C to 35C, followed by addition of acetic acid (30.0 gm) and sodium triacetoxyborohydride (140.0 gm). Reaction mixture was stirred at temperature 30C to 35°C for 4 hours. After completion of reaction, reaction mixture washed with water (2L). The dichloromethane was distilled out under vacuum to get the titled compound as syrupy mass.
Yield: 180g
HPLC purity: 92%

Example-2: Preparation of Teneligliptin Base
Charged Boc-Teneligliptin syrup 180g in water (500 ml) and isopropyl alcohol (50 ml), followed by addition of concentrated hydrochloric acid (140.0 gm). Reaction mixture was heated at 60°C to 65 °C for 2 hours. After completion of reaction, the reaction mixture was cooled to 25°C to 35°C, followed by washing with dichloromethane (300x2 ml). The pH of the reaction mixture was adjusted to 8-9 by sodium carbonate solution. The title compound was extracted from the reaction mass in dichloromethane (1600 ml). The dichloromethane was distilled out under vacuum to obtain the title compound as syrupy mass.
Yield: 130g
HPLC Purity: 97%

Example-3: Preparation of Teneligliptin hydrobromide
Charged Teneligliptin base 130g in ethanol (600.0 ml), followed by addition of hydrobromic acid (172.0 gm). The reaction was seeded with Teneligliptin hydrobromide. The reaction was cooled to 10-15°C. The reaction mixture was filtered & dried to get titled compound.
Yield: 150 g
HPLC purity: 99.82%.