CLIAMS:1. A process for the preparation of substantially pure Boc-piperazine pyrazole or salt thereof of Formula IB, which comprises

Formula-IB
a) reacting compound of formula (II)

Formula-II
or salt thereof with condensing reagent in presence of inorganic base in suitable solvent obtain compound of formula-IB
b) isolation of obtained compound of formula-IB from reaction mixture thereof.
c) purification of compound of formula-IB in the suitable solvent.

2. The process of claim 1, wherein condensing reagent is Lawesson’s reagent.

3. The process of claim 1, wherein substantially pure Boc-piperazine pyrazole or salt thereof is substantially free of impurities, such as tert-butyl piperazine-1-carboxylate, Formula-A and 3-methyl-1-phenyl-1H-pyrazole, Formula-B.

4. The process of claim 1, wherein the inorganic base is selected from the group comprising sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide and potassium bicarbonate.

5. The process of claim 1, wherein the suitable solvent is selected from the group comprising halogenated solvent, amides, water or mixture thereof.

6. The process of claim 1, wherein the purity of Boc-piperazine pyrazole Formula (IB), having the purity more than 99 % by HPLC.

7. The process of claim 1, wherein compound of formula-IB subsequently converted to Teneligliptin or a pharmaceutically acceptable salt thereof.

8. A process for the preparation of Teneligliptin or pharmaceutically acceptable salt thereof of Formula I,

Formula-I
which comprises
a) reacting compound of formula (II)

Formula-II
or salt thereof with condensing reagent in presence of inorganic base in suitable solvent obtain compound of formula-IB

Formula-IB
b) isolation of obtained compound of formula-IB in the suitable solvent.
c) purification of compound of formula-IB in the suitable solvent.
d) subsequently converted compound of formula-IB to Teneligliptin or a
pharmaceutically acceptable salt thereof.

9. The process of claim 8, wherein the inorganic base is selected from the group comprising sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide and potassium bicarbonate.
10. The process of claim 8, wherein the suitable solvent is selected from the group comprising halogenated solvent, amides, water or mixture thereof
,TagSPECI:Field of Invention

The present invention relates to an improved process for the preparation of substantially pure key intermediate of Teneligliptin, e.g. Boc-piperazine pyrazole, having purity more than 99%. A further aspect of the present invention relates to subsequently conversion of said key intermediate to Teneligliptin. The new process is directed to improvement in the manufacture of teneligliptin, which would be industrially feasible and facilitate simple and cost effective manufacture of teneligliptin and salts thereof, having better purity and yield.

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 2.5 hydrobromide hydrate and is structurally represented by formula (I):

Formula I
Teneligliptin is indicated for the treatment of type 2 diabetes mellitus. US Patent Numbers 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 '794 describes the process of preparation of tri-hydrochloride salt of compound I. The process described in the US '794 employs the use of phosphorus oxychloride for the synthesis of Boc-piperazine pyrazole, which is one of the key intermediate in the synthesis of compound I. There are several known drawbacks of the process, which includes very low yield and purity. The carcinogenic nature of phosphorus oxychloride, makes the process industrial non feasible.

The intermediates tert-butyl 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine-1-carboxylate (referred to herein as “Boc-piperazine pyrazole”) can be used to prepare highly pure Teneligliptin in the subsequent reaction steps.

Thus, an object of the present invention is to provide a process to overcome aforesaid problems and to provide simple, cost effective and industrially feasible processes for manufacture of teneligliptin and pharmaceutically acceptable salt or solvate thereof. Teneligliptin and pharmaceutically acceptable salt or solvate thereof prepared by the process of present invention provides both enhanced yield and purity.

Summary of the Invention

The present invention provides an improved process for the preparation of Boc-piperazine pyrazole or salt thereof, having purity more than 99 %. A further aspect of the present invention relates to conversion of said key intermediate Teneligliptin to Teneligliptin.

The present invention provides a process for the preparation of Boc-piperazine pyrazole or salt thereof of Formula IB, which includes steps of
a) reacting compound of formula (II) or salt thereof with condensing reagent in presence of inorganic base in suitable solvent obtain compound of formula-IB
b) isolation of obtained compound of formula-IA in the suitable solvent.
c) purification of compound of formula-IB in the suitable solvent.

In another aspect, the present invention provides Boc-piperazine pyrazole or salt thereof, having purity greater than or equal to 99%.

In another aspect, the present invention provides highly pure Boc-piperazine pyrazole or salt thereof, substantially free of impurities, e.g. tert-butyl piperazine-1-carboxylate, compound of Formula-A and 3-methyl-1-phenyl-1H-pyrazole, compound of Formula-B.

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 present invention provides a process for the preparation of Boc-piperazine pyrazole or salt thereof of Formula IA, which includes steps of

Formula-IB
a) reacting compound of formula (II)

Formula-II
or salt thereof with condensing reagent in presence of inorganic base in
suitable solvent obtain compound of formula-IB
b) isolation of obtained compound of formula-IA from reaction mixture thereof.
c) purification of compound of formula-IB in the suitable solvent.

In another aspect, the present invention provides Boc-piperazine pyrazole or salt thereof having purity greater than or equal to 99% when measured by HPLC.

The condensing reagent used for the reaction is Lawesson’s reagent, which is chemically 2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide, represent herein as compound of Formula-C

Formula-C

Suitable solvent used for the reaction includes but are not limited to ether, alcohol, acetates, water or mixture thereof. The ether such as methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether and the like; The alcohol such as methanol, ethanol, isopropyl alcohol and the like; the acetate such as ethyl acetate, propyl acetate, butyl acetate and the like;

The inorganic base includes but is not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, potassium bicarbonate and the like.

In another aspect, the present invention provides Boc-piperazine pyrazole or salt thereof having purity greater than or equal to 99% measured by HPLC.

In another aspect, the present invention provides highly pure Boc-piperazine pyrazole or salt thereof, substantially free of impurities, such as tert-butyl piperazine-1-carboxylate, compound of Formula-A and 3-methyl-1-phenyl-1H-pyrazole, compound of Formula-B.

The process of the present invention is depicted in the following scheme:

The compounds of formula IA can be converted into Teneligliptin according to known methods known to person skill in the art via US Patent Number 7,074,794.

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-piperazine pyrazole:

To the solution of Boc-piperazine imine (50 gm) in tetrahydrofuran (700 ml) Lawesson’s reagent (65 gm) was added at 0 to 10 °C. After completion of reaction, ethyl acetate (500 ml) was added to the reaction mixture and washed with aqueous sodium bicarbonate. The ethyl acetate was distilled off under reduced pressure to get the crude Boc-piperazine pyrazole, which was purified in methanol-water mixture to get pure Boc-piperazine pyrazole (38 gm). The product was confirmed by spectral data, Mass: 343 [m+1] and 1H NMR
Yield: 80%
HPLC Purity: 99%