This application claims priority to Indian patent application No. 1339/CHE/2009 filed on June 08, 2009, the contents of which are incorporated by reference in their entirety.

Field of the Invention

The present invention relates to hydrogenation of benzyl perindopril in the presence of a catalyst and solvent at atmospheric pressure to give perindopril free acid, which is further converted to perindopril erbumine. The invention also relates to a process for the purification of perindopril erbumine alpha crystalline form, which yields substantially pure alpha crystalline form of Perindopril erbumine.

Background of the Invention

Angiotensin-converting enzyme (ACE) inhibitors are used to treat high blood pressure and some types of heart failure. Perindopril, (2S)-2-[(IS)-l-carbethoxybutylaminoj-l-oxopropyl-(2S, 3aS, 7aS)-perhydroindole-2-carboxylic acid, is a potential (ACE) inhibitor. Perindopril erbumine is marketed under the brand name ACEON® and structurally represented as formula I

US patent 4,508,729 and EP 004965881 patents have disclosed Perindopril erbumine or pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt is selected from the group comprising mineral or organic base or acid such as the sodium salt or maleate salt. This patent also disclosed the stability of maleate and sodium salts of Perindopril. In the course of stability studies towards temperature and humidity, it is found that sodium salt is not suitable for making the formulation because it is immediately converted into oil on contact with the atmosphere. With respect to the maleate salt, it degrades rapidly under such conditions (approximately 25 to 30% of product degraded in 8 days at 50° C).

US patent 4,914,214 discloses a process for the preparation of Perindopril and its tert-butylamine salt (Perindopril erbumine). The process comprises condensation of a protected ester of (28, 3aS,7aS)-2-carboxyperhydroindole with the (S, S) diastereoisomer of N-[(S)-1 - carbethoxybutyl]-(S)-alanine, followed by deprotection employing 5% Palladium carbon under hydrogen pressure in a solvent. After completion of the hydrogenation, Palladium carbon is removed by filtration then treated with tertiary-butylamine to give perindopril erbumine. It is subjected to crystallization in ethyl acetate to give perindopril erbumine.

US patent 7,351,840 discloses a process for the preparation of perindopril erbumine comprising the steps of a) benzyl perindopril is subjected to hydrogenation in the presence of Palladium carbon, b) added t-butyl amine under hydrogen pressure in isopropanol. After completion of the hydrogenation, reaction mass is filtered to remove the catalyst and solvent and the solid is then crystallized in ethyl acetate to give perindopril erbumine.

U.S. Patent Publication No. 200510059609 disclosed a process for the preparation of perindopril erbumine polymorphic form alpha, wherein perindopril erbumine is subjected to crystallization by dissolving perindopril erbumine in ethyl acetate at reflux temperature followed by cooling to yield perindopril erbumine form alpha.

U.S. Patent Publication No. 2005/0250706 disclosed a process for the preparation of perindopril erbumine alpha form. According to US’706, Perindopril erbumine is dissolved in acetone, isopropyl alcohol and acetonitrile at 70°C, the resulting solution is cooled to room temperature to yield perindopril erbumine alpha crystalline form.

According to the prior art processes, hydrogenation reaction is carried out in the presence of hydrogen gas under pressure, this reaction required a special equipment like a pressure reactor and safety precautions.

According to prior art processes, perindopril erbumine is crystallized in different solvents or mixture of solvents at reflux temperatures, in this process perindopril erbumine is dissolved at reflux temperature and product is exposed to the higher temperature, while this period the formation of impurities are more at reflux temperature and it yield the impure perindopril erbumine.

The above obtained perindopril erbumine need to be crystallized in different solvents or mixture of solvents at number of times to get the desire quality of the final product.

In view of the above prior disadvantageous, there is a need to develop a process for the preparation of Perindopril erbumine, which is prepared by an efficient, economic and reproducible process, particularly to large scale preparation.
Objective of the Invention:

The main object of the present invention relates to reduction of benzyl Perindopril in the presence of a catalyst, hydrogen gas at atmospheric pressure in a solvent to give perindopril free acid, which is further converted to perindopril erbumine

Another object of the present invention relates to a process for the purification of perindopril erbumine alpha crystalline form, which yields substantially pure alpha crystalline form of Perindopril erbumine.

Summary of the Invention:

The main aspect of the present invention provides an improved process for the preparation of perindopril erbumine.

According to the present invention, the process for the preparation of perindopril comprises the steps of: (a) reducing benzyl perindopril in the presence of catalyst using hydrogen gas at atmospheric pressure (b) removing the catalyst and (c) isolating perindopril.

Another aspect of the present invention provides an improved process for the preparation of perindopril erbumine which comprising the steps of (a) reducing benzyl Perindopril in the presence of catalyst and solvent using hydrogen gas at atmospheric pressure (b) optionally removing the catalyst (c) adding t-butyl amine and (d) isolating perindopril erbumine.

Yet another aspect of the present invention provides an improved process for the preparation of perindopril erbumine which comprising the steps of (a) reducing benzyl Perindopril in the presence of catalyst, solvent and t-butyl amine using hydrogen gas at atmospheric pressure (b) removing the catalyst and (d) isolating perindopril erbumine.

Yet another aspect of the present invention provides an improved process for the preparation of perindopril erbumine which comprising the steps of (a) reducing benzyl Perindopril in the presence of catalyst and solvent using hydrogen gas at atmospheric pressure (b) optionally removing the catalyst (c) treating with t-butyl amine (d) adding anti-solvent and (e) isolating perindopril erbumine.

Yet another aspect of the present invention provides purification of perindopril erbumine alpha crystalline form which comprising the steps of (a) dissolving the perindopril erbumine in a solvent (b) adding anti-solvent and (c) isolating perindopril erbumine alpha crystalline form.

Yet another aspect of the present invention provides substantially pure alpha crystalline form of Perindopril erbumine.

Detailed Description of the Invention:

The present invention relates to an improved process for the preparation of perindopril erbumine, wherein the benzyl perindopril is subjected to hydrogenation reaction in the presence of a catalyst and solvent using hydrogen gas at atmospheric pressure to give perindopril, which is further converted into perindopril erbumine by conventional method. The present invention also relates to process for the purification of Perindopril erbumine, which yields substantially pure alpha crystalline form of Perindopril erbumine,
The main embodiment of the present invention relates a process for the preparation of perindopril comprising the steps of: (a) reducing benzyl Perindopril in the presence of a catalyst and solvent using hydrogen gas at atmospheric pressure (b) removing the catalyst and (c) isolating perindopril.

According to the present invention, benzyl perindopril is dissolved in a solvent selected from ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate or methanol, ethanol, isopropanol, followed by addition of a catalyst selected from Palladium carbon, Raney Nickel. Hydrogenation is carried out in the presence of hydrogen bubbling. After completion of the reaction, remove the catalyst by filtration to give Perindopril.

Another embodiment of the present invention relates to an improved process for the preparation of Perindopril erbumine which comprising the steps of: (a) reducing benzyl Perindopril in the presence of catalyst and solvent using hydrogen gas at atmospheric pressure (b) optionally removing the catalyst (C) adding t-butyl amine and (d) isolating Perindopril erbumine.

According to the present invention, benzyl Perindopril is dissolved in a solvent selected from ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate or methanol, ethanol, isopropanol; addition of catalyst is selected from Palladium carbon, Raney Nickel.

Hydrogen gas is bubbled till the completion of the reaction. After completion of the reaction remove the catalyst and followed by addition of t-butyl amine to give Perindopril erbumine.

Yet another embodiment of the present invention relates to an improved process for the preparation of perindopril erbumine which comprising the steps of: (a) reducing benzyl Perindopril in the presence of catalyst, solvent and t-butyl amine using hydrogen gas at atmospheric pressure (b) removing the catalyst and (d) isolating perindopril erbumine.

According to the present invention, benzyl perindopril is dissolved in a solvent selected from ethyl acetate, n-propyl acetate, n-butyi acetate, t-butyl acetate or methanol, ethanol, isopropanol, followed by addition of the catalyst and t-butyl amine to the above solution, wherein the catalyst is selected from Palladium carbon, Raney Nickel. Hydrogen gas is bubbled till the completion of the reaction. After completion of the reaction, remove the catalyst to afford perindopril erbumine.

Yet another embodiment of the present invention relates to an improved process for the preparation of perindopril erbumine which comprising the steps of: (a) reducing benzyl Perindopril in the presence of catalyst and solvent using hydrogen gas at atmospheric pressure (b) optionally removing the catalyst (c) adding t-butyl amine (d) adding anti-solvent and (e) isolating perindopril erbumine.

According to the present invention, benzyl perindopril is dissolved in a solvent selected from ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate or methanol, ethanol, isopropanol; preferred solvent is ethyl acetate or methanol. The catalyst is added to the above solution, wherein catalyst is selected from Palladium carbon, Raney Nickel.

Hydrogen gas is purged till the completion of the reaction. After completion of the reaction remove the catalyst, addition of t-butyl amine. Stir the reaction mass, followed by addition of anti-solvent, wherein anti-solvent is selected from ethers such as diethyl ether, dimethyl ether, and diisopropyl ether to afford perindopril erbumine.

In another embodiment, the present invention relates to a process for the purification of perindopril erbumine alpha crystalline form comprising the steps of a) dissolving perindopril erbumine in an alcoholic solvent (b) adding anti-solvent and (c) isolating Perindopril erbumine alpha crystalline form.

According to the present invention, Perindopril erbumine is dissolved in a solvent selected form methanol, ethanol, and isopropanol. The obtained clear solution is treated with carbon, followed by addition of anti-solvent selected from ethers such as diethyl ether, dimethyl ether, and diisopropyl ether to afford pure perindopril erbumine alpha crystalline form.

In yet another embodiment, the present invention relates to substantially pure alpha crystalline form of Perindopril erbumine.

According to the present invention, “substantially pure” refers to Perindopril erbumine alpha crystalline form having acetyl impurity of less than about 0.3% by HPLC, more preferably less than about 0.1%. Acetyl impurity is (2s,3as,7as) - 1-acetyloctahydro-1H-indole-2-carboxylic acid, structurally represented as formula II.

The examples mentioned below explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.

Example 1:

The benzyl perindopril (100g) was dissolved in 1 500ml of ethyl acetate and hydrogenated by bubbling hydrogen gas in presence of 20 gm of 5% Palladium on carbon at 0-30°C for 2-6 hrs. The catalyst was removed by filtration after completion of reaction. Perindopril base was added to 16 g t-butyl amine at 10-25°C. Heat the mass up to reflux temperature, cool the reaction mass, filtered the mass and dried at 40-45°C under vacuum to get 68 gm of perindopril erbumine.

Example 2:

The benzyl perindopril (bOg) was dissolved in 200 ml methanol, hydrogenated by bubbling hydrogen gas in presence of 20 gm of 5% Palladium on carbon at 0-30°C for 2-6 hrs. The catalyst was removed by filtration after completion of reaction. To the filtrate added 16 g t-butyl amine at 10-25°C, to the clear solution added 1500m1 diisopropyl ether to get white precipitate and stirred for 1 hr, filtered and dried at 40-45°C under vacuum to get 46 gm of perindopril erbumine.

Example 3:

The 80 gm crude perindopril erbumine was dissolved in 160 ml of methanol at 25-30C.The resulting solution was diluted with 1200 ml of diisopropyl ether. The resulting mass was cooled to 0-5°C and stirred for 1 hr. Filtered the product and dried at 40°C under vacuum to give 68 gm of perindopril erbumine a- crystalline form.

We claim

1) A process for the preparation of perindopril erbumine comprising the steps of:

(a) dissolving benzyl perindopril in a solvent and adding catalyst;

(b) purging hydrogen gas at atmospheric pressure;

(c) isolating crude perindopril;

(d) adding t-butyl amine; and

(e) isolating perindopril erbumine.

2) A process of hydrogenating benzyl perindopril comprising the steps of:

(a) dissolving benzyl perindopril in a solvent and adding catalyst;

(b) purging hydrogen gas at atmospheric pressure;

(C) isolating crude perindopril;

3) The process according to claims 1 and 2, wherein the catalyst is selected Palladium
carbon, Raney Nickel.

4) The process according to claims 1 and 2, wherein the solvent is selected from ethyl acetate, npropyl acetate, n-butyl acetate, t-butyl acetate or methanol, ethanol or isbpropanol.

5) The process according to claims 1 and 2, wherein the hydrogenation is carried out using hydrogen bubbling at atmospheric pressure.

6) A process for the purification of perindopril erbumine alpha crystalline form comprising the
steps of

a) dissolving perindopril erbumine in an alcoholic solvent selected from methanol or ethanol;

(b) adding anti-solvent selected from diethyl ether or diisopropyl ether; and

(c) isolating Perindopril erbumine alpha crystalline form.

7) (2s, 3as,7as) - 1 -acetyloctahydro-1 H-indole-2-carboxylic acid of formula II

8) Substantially pure alpha crystalline form of Perindopril erbumine having (2s,3as,7as) - 1- acetyloctahydro-1 H-indole-2-carboxylic acid of less than about 0.1%.

9) A process for the preparation of perindopril erbumine comprising the steps of:

(a) reducing benzyl Perindopril in the presence of solvent and catalyst;

(b) purging hydrogen gas at atmospheric pressure;

(c) adding t-butyl amine;

(d) adding anti-solvent; and

(e) isolating perindopril erbumine.

10) The process according to claim 9, wherein the solvent is selected from ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, methanol, ethanol or isopropanol and the anti-solvent is selected from diethyl ether, dimethyl ether or diisopropyl ether.