CLIAMS:1. A process for the preparation of Boc-piperazine dione or salt thereof of Formula IA, which comprises

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

Formula-II
or salt thereof with compound of formula (III)

Formula-III
or salt in the suitable solvent,
b) Isolation of formula-IA from reaction mixture thereof.
2. The process of claim 1, wherein the suitable solvent is selected from the group comprising halogenated solvent, amides, water or mixture thereof.

3. The process of claim 2, wherein halogenated solvents and amide are one or mixture of chloroform, dichloromethane, dimethyl acetamide and dimethyl formamide

4. The process of claim 1, wherein the purity of Boc-Piperazine dione Formula IA, having the purity more than 99 % by as measured HPLC.

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

6. A process for the preparation of Teneligliptin or salt thereof of Formula I,

which comprises
a) reacting compound of formula (II)

Formula-II
or salt thereof with compound of formula (III)

Formula-III
or salt in the suitable solvent to

Formula-IA
obtain compound of formula-IA.
b) isolation of obtained compound of formula-IA in the suitable solvent.
c) subsequently converted compound of formula-IA to Teneligliptin or a
pharmaceutically acceptable salt thereof.
,TagSPECI:Field of Invention

The present invention relates to an improved process for the preparation of substantially pure intermediate of Teneligliptin ,Tert-butyl-4-acetoacetylpiperazine-1-carboxylate or salt, having purity more than 99%. A further aspect of the present invention relates to conversion of said 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 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 '794 describes the process of preparation of tri-hydrochloride salt of compound I. The process described in the US '794 employs diketene for the synthesis of tert-butyl-4-acetoacetylpiperazine-1-carboxylate (referred to herein as “Boc-Piperazine dione), which is one of the intermediate in the synthesis of Teneligliptin, compound of formula I. There are several known drawbacks of the process, which includes inter alia the instability of the diketene making it difficult to handle. Furthermore, “diketene” starting material is not available commercially, which makes the prior art process industrially, not feasible.

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 intermediate, tert-butyl-4-acetoacetylpiperazine-1-carboxylate or salt thereof. The Intermediates 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 dione or salt thereof, having purity more than 99 %. A further aspect of the present invention relates to conversion of said intermediate Teneligliptin to Teneligliptin.

The present invention provides a process for the preparation of Boc-piperazine dione or salt thereof of Formula IA, which includes steps of reacting compound of formula (II) or salt thereof with compound of formula (III) or salt in the suitable solvent to obtain compound of formula-IA.

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

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 dione or salt thereof of Formula IA,

Formula-IA
which includes steps of
a) reacting compound of formula (II)

Formula-II
or salt thereof with compound of formula (III)

Formula-III
or salt in the suitable solvent,
b) Isolation of compound of formula-IA from reaction mixture thereof.

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

Suitable solvent used for the reaction includes but are not limited to halogenated solvent, amides, water. The halogenated solvent include of chloroform, dichloromethane and amides solvents such as dimethyl acetamide and dimethyl formamide and the like.

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 given in 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 dione
To the solution of Boc-piperazine (100 gm) in dimethyl acetamide (200 ml) tert-butyl acetoacetate (93 gm) was added at 25-30 °C. Reaction mixture was heated to 110-115 °C and maintained for 10 hour. The reaction mixture cooled to 25-30 °C, added dichloromethane (500 ml) and washed with water (1000 ml). The dichloromethane layer was distilled under the reduced pressure to get Boc-piperazine dione (143 gm).
Yield: 98 %
Purity: 99 %