PROCESS FOR THE PREPARATION OF PERINDOPRIL ERBUMINE
TECHNICAL FIELD This patent application encompasses an improved process for the preparation of perindopril erbumine.
INTRODUCTION Perindopril erbumine is chemically known as (2S, 3aS, 7aS)-1-[(S)-N-[(S)-1-carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, tert-butylamine (1:1) and is represented by the structural Formula I:

Perindopril erbumine is the ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor useful for the treatment of hypertension and commercially available under the brand name "ACEON" as tablets in 2 mg, 4 mg and 8 mg strengths for oral administration.
Vincent et al., in U.S. Patent No. 4,508,729 discloses perindopril, its pharmaceutically acceptable salts, a pharmaceutical composition and preparation thereof, and its use in the treatment of hypertension. US 4,508729 also disclose a process for preparing perindopril mono ammonium salt, which is schematically summarized in scheme-1.


Scheme 1: Process for preparing perindopril as per US 4,508729 The above process comprises the use of ethyl ester of (2S,3aS,7aS)-2-carboxyperhydroindole as a starting material to prepare perindopril.
Vincent et al., in U.S.Patent No.4,914,214 discloses another process for the preparation of perindopril erbumine as shown below in the scheme-2.


The above process comprises the use of benzyl ester of (2S,3aS,7aS)-2-carboxyperhydroindole.p-toluenesulfonate salt as a starting material to prepare perlndopril.
Langlois et al., In U.S. Patent No. 6835843 discloses Improved process for the preparation of perlndopril erbumlne, wherein the chemistry Is essentially similar to that as described under scheme-2. The process as per US 6835843, comprises of reacting benzyl ester of (2S,3aS,7aS)-2-carboxyperhydrolndole, p-toluenesulfonate salt with N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine in the presence of 1-hydroxy benzotrlazole (HOBT) (In molar proportions In the range of 0.4 to 0.6 moles with respect to benzyl ester of (2S,3aS,7aS)-2-carboxyperhydrolndole, p-toluenesulfonate salt) ; dicyclohexyl carbodlimide (DCC) (in molar proportions in the range of 1 to 2 moles with respect to benzyl ester of (2S,3aS,7aS)-2-carboxyperhydroindole, p-toluenesulfonate salt) presence or absence of triethylamine in the ethylacetate solvent medium to provide benzyl-(2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]-1-oxopropyl]octahydro-1H-lndole-2-carboxylate, wherein it was disclosed by inventors that the impurities in perlndopril were reduced to less than 0.2 % w/w levels.

U.S. Patent Application Publication No. 2006/0178422 A1 describes another improved process for the preparation of benzyl-(2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxy carbonyl)butyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylate, wherein the chemistry is essentially similar to that as described under scheme-2. The process as per US 6835843, comprises of reacting p-toluene sulfonate of benzyl ester of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid with N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine, using dicyclohexyl carbodiimide (DCC), and 1-hydroxy benzotriazole (HOBT) in the presence of the base triethylamine and methylene chloride as a solvent instead of ethyl acetate, wherein it was disclosed by inventors that the N-acetyl impurity in perindopril was removed.
WO 2006/097941 discloses purification of perindopril dicyclohexyl amine salt using acetonitrile as solvent, which is further converted into perindopril tert-butyl amine salt wherein the purity is 99.9 % by HPLC.
Inspite of various process disclosers for the preparation of perindopril however, there is still a need of improvement in the process to provide simple and commercially viable process for preparing perindopril.
SUMMARY The present invention encompasses process for the preparation of perindopril erbumine of Formula I.
In an embodiment, the present invention provides an improved process for the preparation of perindopril erbumine, which process comprises;
a) reacting the compound benzyl (2S,3aS,7aS)-octahydroindole-2-carboxylate hydrochloride of Formula V


V with the compound N-[1-(S)-ethoxycarbonyl-butylHS)-alanine of Formula IV

using HOBT, DCC and a inorganic base in presence of a halo alkane solvent to
provide the compound benzyl-(2S,3aS,7aS)-1[(2S)-2-[[(1S)-1-(ethoxy
carbonyl)butyl)]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylate of
Formula III;

b) reacting the compound benzyl-(2S,3aS,7aS)-1[(2S)-2-[(1S)-1-
(ethoxycarbonyl)butyl)]amino]-1 -oxopropyl]octahydro-1 H-indole-2-carboxylate of
Formula III with a hydrogenating agent in the presence of toluene to afford the
compound (2S,3aS,7aS)-1[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl)]amino]-1-
oxopropyl]octahydro-1H-lndole-2-carboxylic acid of Formula II;

c) reacting the compound (2S, 3aS, 7aS)-1[(2S)-2-[[(1S)-1-(ethoxy carbonyl) butyl)] amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid of Formula II with the compound tertiary butyl amine in the presence of toluene to afford perindopril erbumine of Formula I; and
d) purifying perindopril erbumine of Formula I as obtained in step (c) optionally, using an organic solvent or mixture of water miscible solvents to afford the pure perindopril erbumine of Formula I.

DETAILED DESCRIPTION In their endeavor, there is provided an improved process for the preparation of perindopril erbumine that includes:
a) reacting the compound benzyl (2S,3aS,7aS)-octahydroindole-2-
carboxylate hydrochloride of Formula V

with the compound N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine of Formula IV

using HOBT; DCC and a inorganic base in presence of a halo alkane solvent to
provide the compound benzyl-(2S,3aS,7aS)-1[(2S)-2-[[(1S)-1-(ethoxy
carbonyl)butyl)]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylate of
Formula III;

b) reacting the compound benzyl-(2S,3aS,7aS)-1[(2S)-2-[(1S)-1-
(ethoxycarbonyl)butyl)]amino]-1 -oxopropyl]octahydro-1 H-indole-2-carboxylate of
Formula III with a hydrogenating agent in the presence of toluene to afford the
compound (2S,3aS,7aS)-1[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl)]amino]-1-
oxopropyl]octahydro-1H-indole-2-carboxylic acid of Formula II;


c) reacting the compound (2S, 3aS, 7aS)-1[(2S)-2-[[(1S)-1-(ethoxy carbonyl) butyl)] amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid of Formula II with the compound tertiary butyl amine in the presence of toluene to afford perindopril erbumine of Formula I; and
d) purifying perindopril erbumine of Formula I as obtained in step (c) optionally, using an organic solvent or mixture of water miscible solvents to afford the pure perindopril erbumine of Formula I.
Each step is separately contemplated.
Step a) involves reacting the compound benzyl (2S, 3aS, 7aS)-octahydro indole-2-carboxylate hydrochloride of Formula V with the compound N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine of Formula IV using HOBT, DCC and a inorganic base in presence of a halo alkane solvent to provide the compound benzyl-(2S,3aS,7aS)-1[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl)]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylate of Formula III;
Inorganic base, which is used in step a) include but are not limited to sodium hydroxide, sodium carbonate, potassium hydroxide, and potassium carbonate, preferably sodium carbonate.
Halo alkane solvents, which are useful in step a) include but are not limited to dichloromethane, ethylene dichloride, and chloroform, preferably dichloromethane.
Suitable temperatures for conducting the reaction range from about 0 °C to about 50 °C, or from about 10 °C to about 40 °C.
The molar ratios of the compound benzyl (2S,3aS,7aS)-octahydroindole-2-carboxylate hydrochloride of Formula V, when the reaction is carried out using dichloromethane as a solvent, to the compound of Formula IV can be in the range of about 1:1 to about 1:1.2.
The molar ratio of DCC to the compound of Formula V, when the reaction is carried out using dichloromethane, can be in the range of about 1 to about 1.2 per molar equivalent of Formula IV.

The molar ratio of HOBT to the compound of Formula V, when the reaction is carried out using dichloromethane, can be in the range of about 0.1 to 1.
The molar ratio of inorganic base to the compound of V, when the reaction is carried out using dichloromethane, can be in the range of about 0.5 to about 1.
After completion of the reaction, the reaction mixture is filtered to remove byproducts like dicylohexyl urea (DCU) and then the compound of Formula III is extracted into organic solvent from the filtrate.
Organic solvent which is used to extract the compound of Formula III include but are not limited to dichloromethane, ethyl acetate, toluene, diethyl ether, and diisopropyl ether.
The solvent is removed from the obtained solution by using dry distillation, spray drying, freeze drying (lyophilization), and agitated thin film drying ("ATFD").
Optionally, the compound of Formula III is isolated or directly proceeded to further step to prepare the corresponding compound of Formula I.
The compound of Formula III obtained after removal of solvent is free from the process related impurities.
Step b) involves reacting the compound benzyl-(2S,3aS,7aS)-1[(2S)-2-
[(1S)-1-(ethoxycarbonyl)butyl)]amino]-1-oxopropyl]octahydro-1H-indole-2-
carboxylate of Formula III with hydrogenating agent in the presence of toluene to
afford the compound (2S,3aS,7aS)-1[(2S)-2-[[(1S)-1-
(ethoxycarbonyl)butyl)]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid of Formula II.
Hydrogenating agents include but are not limited to hydrogen with a palladium catalyst such as palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, and palladium hydroxide on carbon.
Suitable temperatures for conducting the reaction range from about 15 °C to about 50 °C, or from about 10 °C to about 40 °C.

Hydrogenating agent used can be 5% to 10% palladium on any substrate.
Hydrogen pressures used during reduction can be from about atmospheric pressure to about 3 kg/cm^.
The compound of Formula II is optionally isolated or directly proceeded in further step to prepare the corresponding compound of Formula I.
Step c) involves reacting the compound (2S,3aS,7aS)-1[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl)]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid of Formula II v\/ith the compound tertiary butyl amine in the presence of toluene to afford perindopril erbumine of Formula I.
Suitable temperatures for conducting the reaction range from about 35 °C to about 75 °C, or from about 25 °C to about 55 °C, or the reflux temperature of the solvent used.
The molar ratio of tertiary-butyl amine to the compound of Formula II can be in the range of about 1:1 to about 1:2.
After completion of the reaction, the reaction mixture is cooled to below 10 °C to obtain the solid.
Step d) purifying perindopril erbumine of Formula I optionally, using a suitable organic solvent or mixture of water miscible solvents to afford the pure perindopril erbumine of Formula I.
Purification involves providing a solution of crude perindopril erbumine in a solvent or mixture of solvents and then crystallizing the solid from the solution.
Suitable solvents for purification include but are not limited to: nitrile solvents such as acetonitrile, and propionitrile; alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; ketones such as acetone, 2-butanone, methyl ethyl ketone, and methyl isobutyl ketone; and mixtures thereof or their miscible combinations with water in various proportions without limitation.
Suitable temperatures for conducting the reaction are range from about -10 °C to about 80 °C, or from about 20 °C to about 40 °C, or the reflux temperature of the solvent used.

The concentration of the perindopril erbumine in the solvent can range from about 30 to 80% or more. The solution can be prepared at an elevated temperature if desired to achieve a higher solute concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the perindopril erbumine is obtained and is not detrimental to the drug substance chemically or physically. The solution may be brought down to a lower temperature for further processing if required or an elevated temperature may be used. A higher temperature for dissolution will allow the precipitation from solutions with higher concentrations of perindopril erbumine, resulting in better yields.

The perindopril erbumine of Formula I produced by the above process is free from impurities, including process, structural, and isomeric impurities. Typically the perindopril erbumine is of high purity, such as at least about 99.5 wt %, or at least about 99.9 wt % purity. Correspondingly, the level of impurities

may be less than about 0.5 wt %, or about 0.1 wt %, as determined by high performance liquid chromatography ("HPLC").
Similarly, the perindopril erbumine of Formula I produced by the above processes is substantially free from residual solvents such as solvents used in making the perindopril erbumine. The residual solvent content may be less than about 1, or less than about 0.5 wt %, or about 0.1 wt %, as determined by gas chromatography (GC).
In yet another embodiment, the present invention encompasses pharmaceutical compositions comprising perindopril erbumine made by the process of the present invention and at least one pharmaceutically acceptable carrier.
The drug substance can be formulated as solid compositions for oral administration, tablets, pills, powders or granules may be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents such as sucrose, lactose or starch. These compositions can also comprise substances other than diluents, e.g. a lubricant such as magnesium stearate.
The drug substance can be formulated as liquid compositions for oral administration, solutions, suspensions, syrups, elixirs and pharmaceutically acceptable emulsions, containing inert diluents such as water or liquid paraffin, may be used. These compositions can also comprise substances other than diluents, e.g. wetting, sweetening or flavouring products.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous, sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These

compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable carriers that are of use in the present invention are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, and sugar; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and pregelatinized starch; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, and colloidal silicon dioxide; lubricants such as stearic acid, magnesium stearate, and zinc stearate; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
The process of the present invention is simple, cost effective, eco-friendly, commercially suitable, and reproducible on an industrial scale.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are

provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES EXAMPLE 1: PREPARATION OF BENZYL- (2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-1-
(ETHOXYCARBONYL) BUTYL] AMIN0]-1-0X0PR0PYL] 0CTAHYDR0-1H-
INDOLE-2- GARBOXYLATE (FORMULA III)
Benzyl-(2S,3aS,7aS)octahydroindole-2-carboxylate hydrochloride of
Formula V (25 g), dichloromethane (250 ml) and 5% sodium carbonate solution
(150 ml) were charged into a clean and dry 4 neck round bottom flask followed
by stirring for about 15 minutes. Organic and aqueous layers were separated
followed by extraction of the aqueous layer with dichloromethane (100 ml). Both
the organic layers were combined and the total organic layer was washed with
water (2x125 ml). Organic and aqueous layers were separated followed by
drying the organic layer over anhydrous sodium sulphate (5 g). N-[1-(S)-
ethoxycarbonyl-butyl]-(S)-alanine (19.3 g) was charged followed by cooling to
about 3 °C. 1-hydroxy benzotriazole (2.6g) was charged followed by addition of
dicyclohexylcarbodiimide (17.4 g) dissolved in dichloromethane (25 ml) over
about 1 hour. The resultant reaction mixture was stirred for about 30 minutes
followed by allowing the reaction mixture to reach the temperature of about 10
°C. The reaction mass was stirred at about 10 °C for about 3 hours. After
completion of the reaction, the reaction mass was cooled to about -5 °C followed
by stirring for about 1 hour. The reaction mass was filtered through a celite bed
and the celite was washed with dichloromethane (50 ml). The resultant filtrate
was washed with 5% sodium carbonate solution (3x125 ml) followed by
separation of organic and aqueous layers. Organic layer was washed with'water
(3x125 ml) followed by washing with 1% hydrochloric acid solution (2x125 ml).
Organic and aqueous layers were separated followed by washing the organic
layer with water (4x125 ml). Organic layer was evaporated at atmospheric
pressure. To the crude toluene (75 ml) was charged followed by cooling to about
-5 °C. The reaction solution was stirred for about 2 hours followed by filtration of

the solution through a celite bed and the celite was washed with toluene (25 ml) to afford a solution containing 108.6 g (approx) of title compound. Compound purity by HPLC: 95.18%. Dicylohexyl urea content: 0.03%.
EXAMPLE 2: PREPARATION OF (2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-1-(ETHOXYCARBONYL) BUTYL] AMIN0]-1-0X0PR0PYL] 0CTAHYDR0-1H-INDOLE-2- CARBOXYLIC ACID TERTIARY BUTYL AMINE (FORMULA I)
Organic layer obtained from Example 1, toluene (25 ml) and 10% palladium on charcoal (50% water content; 5 g) were charged into a clean and dry autoclave vessel followed by cooling to about 15 °C. Anhydrous hydrogen gas pressure (3 kg/cm^) was applied to the reaction suspension for about 2 hours. After completion of the reaction, the resultant reaction suspension was filtered through a celite bed followed by washing the celite with toluene (25 ml). The resultant filtrate was charged into a clean and dry 4neck round bottom flask followed by charging of tertiary-butyl amine (8 g) dissolved in toluene (25 ml). The resultant reaction mixture was stirred for about 1 hour followed by heating to about 60 °C for about 1 hour. The reaction solution was cooled to about 0 °C followed by stirring for about 1 hour. Separated solid was filtered and the solid was washed with precooled toluene (25 ml). The solid obtained was dried at about 35 °C under vacuum for about 10 hours to afford 22.3 g of the title compound. Purity by chiral HPLC: 99.88%
EXAMPLE 3: PURIFICATION OF PERINDOPRIL ERBUMINE USING 25 VOLUMES OF ACETONITRILE
Perindopril erbumine (10 g) and acetonitrile (250 ml) were charged into a clean and dry 4 neck round bottom flask followed by heating to about 78 °C. The resultant reaction suspension was stirred at about 78 °C for about 10 to about 20 minutes. The resultant reaction solution was cooled to about 30 °C for about 1 hour. Separated solid was filtered and the solid was washed with acetonitrile (10

ml). Solid obtained was dried at 30 °C under vacuum for about 4 hours to afford 9.1 g of the title compound in pure form. Purity by HPLC: 99.53%. Purity by chiral HPLC: 100%.
EXAMPLE 4: PURIFICATION OF PERINDOPRIL ERBUMINE USING MIXTURE OF ACETONITRILE AND METHANOL
Perindopril erbumine (5 g), acetonitrile (50 ml) and methanol (5 ml) were charged into a clean and dry 4 neck round bottom flask followed by heating to about 74 °C. The resultant reaction suspension was stirred at about 74 °C for about 5 to 10 minutes to form a solution, followed by cooling to about 5 °C for about 40 minutes. Separated solid was filtered and the solid was washed with acetonitrile (10 ml). Solid obtained was dried at about 30 °C for about 4 hours to afford 4.4 g of the title compound in pure form. Purity by HPLC: 99.36%. Purity by chiral HPLC: 100%.
EXAMPLE 5: PURIFICATION OF PERINDOPRIL ERBUMINE USING MIXTURE OF ISOPROPYLALCOHOL AND ACETONITRILE
Perindopril erbumine (5 g) and isopropyl alcohol (25 ml) were charged into a clean and dry 4 neck round bottom flask followed by heating to about 64 °C. The resultant reaction suspension was stirred at about 64 °C for about 10 minutes to form a solution, followed by cooling to about 35 °C. Acetonitrile (50 ml) was charged followed by cooling to about 5 °C for about 35 minutes. Separated solid was filtered and the solid was washed with acetonitrile (10 ml). Solid obtained was dried at about 30 °C for about 4 hours to afford 3.8 g of the title compound in pure form. Purity by HPLC: 99.44%. Purity by chiral HPLC: 100%.

EXAMPLE 6: PURIFICATION OF PERINDOPRIL ERBUMINE USING MIXTURE OF ACETONITRILE AND WATER
Perlndopril erbumine (5 g), acetonitrile (125 ml) and water (1.25 ml) were charged into a clean and dry 4 neck round bottom flask followed by heating to a temperature of about 78 °C. The resultant reaction suspension was stirred at about 78 °C for about 15 minutes to form a solution, followed by cooling to about 30 °C for about 50 minutes. Separated solid was filtered and the solid was washed with acetonitrile (10 ml). Solid obtained was dried at about 30 °C for about 4 hours to afford 4.2 g of the title compound in pure form. Purity by HPLC: 99.52%. Purity by chiralHPLC: 100%.
EXAMPLE 7: PURIFICATION OF PERINDOPRIL ERBUMINE USING MIXTURE OF ACETONITRILE AND 1% WATER
Perlndopril erbumine (5 g), acetonitrile (50 ml) and water (0.5 ml) were charged into a clean and dry 4neck round bottom flask followed by stirring for about 5 minutes. The resultant reaction mixture was heated to about 78 °C for about 35 minutes. The reaction mass was cooled to about 30 °C for about 60 minutes. Separated solid was filtered and the solid was washed with acetonitrile (10 ml). Solid obtained was dried at about 30 °C under vacuum to afford 3.6 g of pure of form of perlndopril erbumine. Purity by HPLC: 99.55%.
EXAMPLE 8: PURIFICATION OF PERINDOPRIL ERBUMINE USING MIXTURE OF ACETONITRILE AND METHANOL
Perindopril erbumine (5g), acetonitrile (50 ml) and methanol (7.5 ml) were charged into a clean and dry 4neck round bottom flask followed by stirring for about 10 minutes. The resultant reaction mixture was heated to about 72 °C for about 20 minutes. The reaction solution was cooled to a temperature of about 0 °C for about 1 hour. Separated solid was filtered and the solid was washed with

acetonitrile (10 ml). Solid obtained was dried at about 35 °C under vacuum for
about 5 hours to afford 3.6 g of the title compound in pure form.
Purity by HPLC: 99.6%.
EXAMPLE 9: PURIFICATION OF PERINDOPRIL ERBUMINE USING MIXTURE
OF IPA AND ACETONE
Perindopril erbumine (5 g), acetone (138 ml) and isopropyl alcohol (25 ml) were charged into a clean and dry 4neck round bottom flask followed by heating to reflux and stirred for about 15 to 30 minutes. The reaction solution was cooled to about 25 to about 35 °C and further cooled to about -5 to about 0 °C. The obtained reaction mass was stirred for about 30 to about 60 minutes. Separated solid was filtered and the solid was washed with acetone (10 ml). Solid obtained was dried at about 35 °C under vacuum for about 5 hours to afford 4.5 g of the title compound in pure form.

Claims:
1. An improved process for preparing perindopril erbumine of Formula I:

Step b) reacting tiie compound of Formula II obtained from step a) with tertiary butyl amine in the presence of toluene to afford perindopril erbumine of Formula I; and
Step c) purifying perindopril erbumine of Formula I optionally, using a suitable organic solvent or mixture of water miscible solvents to afford the pure perindopril erbumine of Formula I.
2. The process according to claim 1, wherein said hydrogenating agent in step a) is palladium on carbon.

3. The process according to claim 1, wlierein said organic solvent in step c)
is alcohol, nitrile, combination thereof or their miscible combination with water.
4. The process according to claim 1, wherein the purity of perindopril erbumine is more than 99.5 % as measured by HPLC.
5. The process according to claim 1, wherein the chiral purity of perindopril erbumine is more than 99.5 % as measured by chiral HPLC.

using HOBT, DCC and an inorganic base in presence of a halo alkane solvent.
7. The process according to claim 6, wherein said inorganic base is sodium hydroxide, sodium carbonate, potassium hydroxide, or potassium carbonate.

8. The process according to claim 6, wlierein the molar equivalent of
inorganic base is used in step a) in range between 0.5 and 1 per molar
equivalent of Formula V.
9. The process according to claim 7, wherein said inorganic base is sodium carbonate.
10. The process according to claim 6, wherein said halo alkane solvent is dichloromethane, ethylene dichloride, or chloroform.