This application claims priority to Indian patent application No. 1756/CHE/2008 filed on July 22,2008, the contents of which are incorporated by reference in their entirety

Field of the invention
The present invention relates to a novel process for preparation of Perindopril-(L)-Arginine salt from protected perindopril.

Background of the invention
US 4,508,729 patent is first disclosed the perindopril and its pharmaceutically acceptable salts. Perindopril is active as Angiotensin Converting Enzyme (ACE) inhibitors and which is commercially important anti-hypertensive agent. Perindopril is chemically described as (2S, 3aS, 7aS)-l [(2S)-2-[[(l S)-l-ethoxycarbonyl) -butyl] amino] propionyl] octahydro-1 H-indole-2-carboxylic acid (Formula-I)
H
a
>*COOH
° U A

Formula I
It has proved very difficult to find a pharmaceutically acceptable salt having not only good bioavailability but also adequate stability to be suitable for the preparation and storage of pharmaceutical compositions.

In the course of temperature and humidity stability studies, it is found that the sodium salt is not suitable for handling because it is immediately converted into an oil on contact with the atmosphere. Both the sodium and the maleate salts degrade rapidly under such conditions (approximately 25 to 30% of product degraded in 8 days at 50° C), hence not suitable for pharmaceutical compositions.

The arginine salt of perindopril is preferentially the salt of natural arginine (L-arginine). The basic characteristic of this salt is having good stability to heat and to humidity compared to the tert-butylamine salt. Perindopril arginine is 50 % more stable than Perindopril tert-butylamine salt.

Perindopril-(L)-Arginine, represented by formula II, and its hydrate and pharmaceutical composition and a method of treatment were first disclosed in US 6,696,481. However, this patent did not specify the process details and conditions for obtaining the (L)-Arginine salt of perindopril and its hydrates.

•C02H
^N OH

„ /NH NH2V^ NH2
COOEt \H

Formula II

Keeping in view of the above mentioned shortcomings, now, we have developed a new process for the preparation of Perindopril-(L)-Arginine starting from readily accessible starting materials with improved yield and quality as compared to prior art.

Objective of the invention

The main object of the present invention is to provide a novel process for the preparation of Perindopril-(L)-Arginine salt from protected perindopril.

Another object of the present invention is to provide in-situ process for the preparation of Perindopril-(L)-Arginine salt from protected perindopril.

Summary of the Invention

The main aspect of the present invention is to provide a novel process for the preparation
of Perindopril-(L)-Arginine salt by using protected perindopril.
In another aspect, the process according to the present invention includes deprotection of
the protected perindopril by spurging hydrogen gas in the presence of a catalyst and
suitable organic solvent. The free based thus obtained is treated with L-Arginine.
Optionally an antisolvent is added followed by isolation of crude Perindopril-(L)-
Arginine.

In another aspect, the present invention is to provide an in-situ process for the preparation
of Perindopril-(L)-Arginine salt by using protected perindopril.

In another aspect, the process according to the present invention includes deprotection of
the protected perindopril by spurging hydrogen gas in the presence of a catalyst and
suitable organic solvent. The free based thus obtained is treated with L-Arginine without
isolation. Optionally an antisolvent is added followed by isolation of crude Perindopril-
(L)-Arginine.

In another aspect, the process according to the present invention includes deprotection of
the protected perindopril by spurging hydrogen gas in the presence of a catalyst and
suitable organic solvent. The free based thus obtained is treated with L-Arginine.
Optionally an antisolvent is added and filtered. Slurring the resultant wet mass followed
by isolation of Perindopril-(L)-Arginine.

In yet another aspect, the present invention is to provide a process for the purification of
Perindopril-(L)-Arginine.

Detailed description of the invention

The present invention relates to novel process for the preparation of Perindopril-(L)-
Arginine salt.

In one embodiment, the present invention relates to process for the preparation of
Perindopril-(L)-Arginine as depicted in Scheme I

Scheme I
o
C02H
H3C.
p-rf H rH v
N 7
CH3

Formula I
0

Formula III
H3C-
L - Arginine

(L) - Arginine
H3C-
O
CH'(tf»

Formula II
In another embodiment, the process for the preparation of Perindopril-(L)-Arginine comprises the steps of: (a) de-protecting the protected perindopril of formula (III) using hydrogen spurging in the presence of a catalyst and suitable organic solvent (b) removing the catalyst (c) treating with (L)-Arginine (d) optionally adding antisolvent and (e) isolating the Perindopril-(L)-Arginine with improved yield and quality.

According to the present invention, protected perindopril is dissolved in an organic solvent selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, cyclohexane, water or mixtures thereof. The resulting solution is subjected to hydrogenation in the presence of a catalyst selected from Palladium, Raney nickel, preferably palladium on charcoal. The hydrogenation is carried out under hydrogen pressure at ambient temperature. After completion of the hydrogenation reaction, the reaction mass is filtered to separate the catalyst. The clear filtrate is treated with L-Arginine at ambient temperature and optionally added with an anti solvent selected from acetone, diisopropyl ether, preferred solvent is acetone to give Perindopril-(L)-Arginine with improved yield and quality.

In yet another embodiment, the present invention relates to novel process for the preparation of Perindopril-(L)-Arginine salt without isolating the perindopril free base. In yet another embodiment, the present invention relates to process for the preparation of Perindopril-(L)-Arginine as depicted in Scheme II
Scheme II

COOCH2C6H5
H2/Pd-C
Formul* III

L - Arginine

0
•th:
\H )
Formula I

H,C
0
CH3

C02H
(L) - Arginine

Formula II
In yet another embodiment, the process for the preparation of Perindopril-(L)-Arginine comprises the steps of: (a) de-protecting the protected perindopril of formula (III) in the presence of catalyst under hydrogen pressure and adding L-Arginine in a solvent (b) removing the catalyst (c) optionally adding antisolvent and (d) Isolating the Perindopril-(L)-Arginine with improved yield and quality.

According to the present invention, protected perindopril and L-Arginine is dissolved in a solvent selected from methanol, ethanol, cyclohexane or mixtures thereof, preferably methanol. Resulting solution is subjected to hydrogenation in the presence of a catalyst selected from Palladium, Raney nickel; preferably palladium on charcoal. The hydrogenation is carried out under hydrogen pressure at ambient temperature. After completion of the hydrogenation reaction, the catalyst is separated by filtration. Adding anti solvent selected from acetone, diisopropyl ether or mixtures thereof, preferably diisopropyl ether, isolating the Perindopril-(L)-Arginine with improved yield and quality. In another embodiment, the process for the preparation of Perindopril-(L)-Arginine comprises the steps of: (a) de-protecting the protected perindopril of formula (III) using hydrogen spurging in the presence of a catalyst and suitable organic solvent (b) removing the catalyst (c) treating with (L)-Arginine (d) optionally adding anti solvent (e) slurring the resultant mass with non polar solvent and (f) isolating the Perindopril-(L)-Arginine with improved yield and quality.

According to the present invention, the slurring of the wet mass with a non polar solvent such as hydrocarbons selected from heptane or hexane and the like results in the improved purity of the final compound. The slurring may optionally remove some of the possible impurities.

In yet another embodiment, the present invention relates to purification of Perindopril-(L)-Arginine salt wherein the crude Perindopril-(L)-Arginine is dissolved in organic solvent such as ethyl acetate and isolate pure Perindopril-(L)-Arginine. In yet another embodiment, the present invention relates to purification of Perindopril-(L)-Arginine salt wherein, crude Perindopril-(L)-Arginine is dissolved in C1-C4 alcohol, adding anti solvent followed by gradual cooling and isolating the pure Perindopril-(L)-Arginine.

In yet another embodiment, the process for the purification of Perindopril-(L)-Arginine comprising the steps of: (a) dissolving or suspending crude Perindopril-(L)-Arginine in a suitable solvent C1-C4 alcohol, (b) adding an anti solvent, followed by gradual cooling and (c) isolating the pure Perindopril-(L)-Arginine..
According to our present invention, crude Perindopril-(L)-Arginine is dissolved in C1-C4 alcohol solvent is selected form methanol, ethanol etc. The most preferred solvent is methanol. Adding anti solvent selecting from ketones such as acetone, ethers such as

diisopropyl ether or mixtures and the preferred anti solvent is diisopropyl ether, followed by gradual cooling and isolating the pure Perindopril-(L)-Arginine with improved yield and quality.

Examples:

Example 1: Prepration of Perindopril-(L)-Arginine
Benzyl perindopril (lOOg) was added 400 ml of cyclohexane and 300 ml of water at 20 to
25 °C. Stirred the reaction mixture for 15 minutes at 20 to 25 °C. Added 10 g of 10 %
Palladium on carbon at 20 to 25 °C under nitrogen. The reaction mass was surged with
hydrogen gas at atmospheric pressure up to the completion of the reaction. Filtered the
catalyst under nitrogen atmosphere. Washed the bed with 100 ml of water. Transferred
the filtrate to a separating funnel and separated the lower aqueous layer and preserved.
Extracted the organic layer with 50 ml of water. Combined all the aqueous layers and
(L)-Arginine (40 g) was added to the combined aqueous layer and stirred for one hour.
Acetone 4 litres is added to this clear solution and stir overnight, filtered and dried for 40
to 45 °C under vacuum to get 86 g Perindopril-(L)-Arginine.
Purity (by HPLC): 99.3%

Example 2: Prepration of Perindopril-(L)-Arginine
Ben2yl perindopril (106g) was dissolved in 1530 ml of ethyl acetate and hydrogenated at
10 psi of hydrogen pressure in presence of 15.9 gm of 5% Palladium on carbon at 10 to
15°C for 6 hours. The catalyst was removed by filtration after completion of reaction. To
the filtrate containing perindopril base was added 55.6 gm (L)-Arginine at 10 to 15°C.
Cooled to 0 to 5 °C and stirred for one hour. Filtered the solid and dried under vacuum
for 40 to 45 °C to get 90 gm of Perindopril-(L)-Arginine.
Purity (by HPLC): 98.9%

Example 3: Purification of Perindopril-(L)-Arginine:
The 84 gm Perindopril-(L)-Arginine (having less purity) was dissolved in 200 ml of
methanol at 25 to 30°C and diluted with 1560 ml of diisopropyl ether. The resulting
mass was cooled to 0 to 5 °C and stirred for one hour. Filtered the product and dried
under vacuum at 40°C to give 55.4 gm Perindopril-(L)-Arginine.
Purity (by HPLC): 99.2%

Example 4: Purification of Perindopril-(L)-Arginine:
40 gm of crude Perindopril (L)-Arginine was suspended in 2000 ml of ethyl acetate at 25
to 30 °C and refluxed for 2 hours. Cooled the resultant mass, filtered and dried at 40°C
under vacuum to give 35 gm Perindopril-(L)-Arginine .
Purity (by HPLC): 99.8 %

Example 5: Prepration of Perindopril (L)-Arginine
Benzyl perindopril (lOg) was dissolved in 90 ml of methanol at 20 to 25 °C. 10 %
Palladium on carbon was added (2 g) at 20 to 25 °C under nitrogen. The reaction mass
was surged with hydrogen gas at atmospheric pressure up to the completion of the
reaction. Filtered the catalyst under nitrogen atmosphere. Washed the bed with 20 ml of
methanol. Added (L)-Arginine (2 g) and stirred for one hour. Diisoprolyl ether 300 ml
was added to this clear solution and stirred overnight, filtered and dried for 40-45°C
under vacuum to get 9.4 g Perindopril-(L)-Arginine.
Purity (by HPLC): 99%

Example 6: Prepration of Perindopril-(L)-Arginine
Benzyl perindopril (lOg) & (L)-Arginine (2 g) was suspended in 100 ml of methanol at
20 to 25 °C. 10 % Palladium on carbon (2 g) was added of at 20 to 25 °C under nitrogen.
The reaction mass was surged with hydrogen gas at atmospheric pressure up to the
completion of the reaction. Filtered the catalyst under nitrogen atmosphere. Washed the
bed with 10 ml of methanol. Diisoprolyl ether 300 ml was added to this clear solution and
stirred for overnight, filtered and dried for 40-45°C under vacuum to get 5. 4 g
Perindopril-(L)-Arginine.

Example 7: Prepration of Perindopril-(L)-Arginine
Benzyl perindopril (lOg) & (L)-Arginine (2 g) added to 60 ml of cyclohexane & 300 ml
of water at 20 to 25 °C. The reaction mixture was stirred for 15 minutes at 20 to 25 °C.
10 % Palladium on carbon (2 g) was added at 20 to 25 °C under nitrogen. The reaction
mass was surged with hydrogen gas at atmospheric pressure up to the completion of the
reaction. Filtered the catalyst under nitrogen atmosphere. Washed the bed with 100 ml of
water. Transferred the filtrate to a separating funnel and separated the lower aqueous.
layer and preserved, extracted the organic layer with 50 ml of water. Combined all the
aqueous layers and added 500ml of acetone to the clear solution and stirred for overnight,
filtered and dried for 40 to 45 °C under vacuum to get 3 g Perindopril-(L)-Arginine .

Example 8: Prepration of Perindopril (L)- Arginine
Benzyl perindopril (lOOg) added to 600 ml of cyclohexane & 500 ml of water at 20 to 25°C. Stirred the reaction mixture for 15 minutes at 20 to 25 °C. 5 % Palladium on carbon (20 g) was added at 20 to 25 °C under nitrogen. The reaction mass was surged with hydrogen gas at atmospheric pressure till the completion of the reaction. Filtered the catalyst under nitrogen atmosphere. Washed the bed with 100 ml of water. Transferred the filtrate to a separating funnel and separated the lower aqueous layer and preserved. Extracted the organic layer with 50 ml of water. Combined all aqueous layers and washed with cyclohexane. L-ARGININE (20 g) is added to the combined aqueous layer and stirred for one hour. Clear aqueous layer is filtered & added slowly to acetone 5 Lt and stirred for overnight, filtered and washed with acetone (2 x 100ml). Wet mass was added to heptanes, stirred at 40-60 for one hour, filtered and dried at 40 to 65°C under reduced pressure (0-50 torr) to get 66 g PERINDOPRIL L- ARGININE (I). Purity (by HPLC): 99.9 %

We claim
1. Process for the preparation Perindopril-(L)-Arginine comprising the steps of:
(a) de-protecting the protected perindopril in the presence of a catalyst and organic solvent under hydrogen pressure,
(b) removing the catalyst,
(c) treating with (L)-Arginine,
(d) optionally adding anti solvent and
(e) isolating Perindopril-(L)-Arginine.

2. Process for the preparation Perindopril-(L)-Arginine comprising the steps of:
(a) de-protecting the protected perindopril in the presence of a catalyst and organic solvent under hydrogen pressure and treating with (L)-Arginine
(b) removing the catalyst,
(c) optionally adding anti solvent and
(d) isolating Perindopril-(L)-Arginine.

3. Process for the preparation Perindopril-(L)-Arginine comprising the steps of:
(a) de-protecting the protected perindopril in the presence of a catalyst and organic solvent under hydrogen pressure
(b) removing the catalyst,
(c) treating with (L)-Arginine,
(d) optionally adding anti solvent,
(e) slurring with a non polar solvent and
(f) isolating Perindopril-(L)-Arginine.

4. The process according to claims 1 to 3, wherein the organic solvent is selected from the group of alcohols, esters, ethers, ketones, water, hydrocarbons and mixtures thereof.

5. The process according to claim 4, wherein the alcohol is methanol, ester is ethyl acetate, hydrocarbon is cyclohexane.

6. The process according to claims 1 to 3, wherein the anti solvent is selected from ketones such as acetone or ethers such as diisopropyl ether.

7. The process according to claim 3, wherein the non polar solvent is selected from hydrocarbons such as heptane or hexane.

8. Process for the purification of Perindopril-(L)-Arginine comprising the steps of: a) dissolving or suspending crude Perindopril-(L)-Arginine in a organic solvent,

b) optionally adding an antisolvent and
c) isolating pure Perindopril-(L)-Arginine.

9. The process according to claim 8, wherein the organic solvent is selected from alcohols
such as methanol, esters such as ethyl acetate.

10. The process according to claim 8, wherein the anti solvent is selected from ethers
such as diisopropyl ether.
Dated this the Twenty First (21th) day of July, 2009