FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF PERINDOPRIL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

"AN IMPROVED PROCESS FOR THE PREPARATION OF PERINDOPRIL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
FIELD OF THE INVENTION:
The present invention relate to pharmaceutically acceptable salts of perindopril with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine and there use in the purification of perindopril and its pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION:
Perindopril is chemically (2S)-2-[(1S)-carbethoxybuty(amino]-1-oxo-propyi-(2S, 3aS, 7aS) perhydroindole carboxylic acid and is known previously from US Patent No. 4,508,729 and is represented by structural formula I.

Perindopril, an angiotensin I converting enzyme inhibitor (CEI) is indicated for the treatment of arterial hypertension and heart failure.
U.S Patent no. 4,508,729 describe that the compounds of the invention may be presented in the form of addition salts with a pharmaceutically acceptable mineral or organic base or acid. The compounds described in the patent are in a non-salt form and primarily, when addition salts with a pharmaceutically acceptable base or acid are mentioned by way of example, the sodium salt or the maleate salt are described. Perindopril sodium is not suitable for handling because it is immediately converted into oil on contact with the

atmosphere. Perindopril maleate is unstable and degraded rapidly in the course of temperature and humidity stability studies.
V.S Patent no. 6,696,481 describes an arginine salt of perindopril and its hydrates,
PCT publication no. 2006/097941 describes dicyclohexylamine salt of perindopril and its use for the purification of perindopril.
PCT publication no. 2009/000909 describes calcium salt of perindopril or a solvate thereof and an alkyl amine salts (RNH2) of perindopril represented by the compound of structural formula I, wherein R represents C5-C7 cycloalkyl or sec-butyl or a solvate thereof.
The prior art processes for preparing perindopril compound of structural formula I always produces compound of structural formula II as a key impurity in the debenzylation of compound of structural formula III by catalytic hydrogenation.

The applicant of the patent has investigated different salts of perindopril compound of structural formula I with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine. L-tryptophan or L-tyrosine and has found that the crude perindopril containing the compounds of structural formula 1/ may be purified by forming the salts of perindopril compound of structural formula I with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine.

Accordingly there is provided a process of purifying crude perindopril and its pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide L-tyrosine salt of perindopril.
A second aspect of the present invention is to provide a process for the purification of crude perindopril through the formation of L-tyrosine salt of perindopril.
A third aspect of the present invention is to provide a process for the preparation of L-tyrosine salt of perindopril.
A fourth aspect of the present invention is to provide crystalline polymorphic form of L-tyrosine salt of perindopril.
A fifth aspect of the present invention is to provide amorphous form of L-tyrosine salt of perindopril.
A sixth aspect of the present invention is to provide a pharmaceutical composition comprising L-tyrosine salt of perindopril.
A seventh aspect of the present invention is to provide a pharmaceutical composition comprising L-tyrosine salt of perindopril used for the manufacture of medicament for the treatment of arterial hypertension and heart failure.
A eighth aspect of the present invention is to provide a process for the preparation of pure perindopril or its pharmaceutically acceptable salts thereof comprising the steps of (a) treating crude perindopril with L-tyrosine base (b) isolating perindopril L-tyrosine salt and, (c) converting perindopril L-tyrosine salt into perindopril and its pharmaceutically acceptable salts thereof.

A ninth aspect of the present invention is to provide pharmaceutically acceptable salts of perindopril with L-glutamine, L-glutamic acid, L-histidine, L-fysine, methionine, phenylalanine or L-tryptophan.
A tenth aspect of the present invention is to provide a process for the purification of crude perindopril or its pharmaceutically acceptable salts thereof through the formation of pharmaceutically acceptable salts of perindopril with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine or L-tryptophan.
Another aspect of the present invention is to provide crystalline and amorphous form of pharmaceutically acceptable salts of perindopril with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine or L-tryptophan.
Another aspect of the present invention is to provide a process for the preparation of pharmaceutically acceptable salts of perindopril with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine or L-tryptophan.
Another aspect of the present invention is to provide pharmaceutically acceptable salts of perindopril with L-tyrosine L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine or L-tryptophan, for which bioavailability is under review compare with perindopril tertiary butyl amine and perindopril L-arginine.
DETAILED DESCRIPTION OF THE INVENTION
The crude perindopril and its pharmaceutically acceptable salts thereof may be prepared by methods known in the art such as those described in U.S. Patent nos 6,835,843; 7,223,872, which are incorporated herein by reference only.
The crude perindopril and its pharmaceutically acceptable salts thereof may contain up to the 5% weight/weight of compound of structural formula II


The salts of perindopril compound of structural formula I with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine may be formed by reacting perindopril compound of structural formula I with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine in an organic solvent at a temperature in the range of 30°C to 85°C.
The examples of organic solvent may include alcohols, alkyl acetates, ethers, nitriles, halogenated aliphatic hydrocarbons or aromatic hydrocarbons.
The examples of alcohol solvents may include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol ort-butyl alcohol.
The examples of alkyl acetate solvents may include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate.
The examples of ether solvents may include diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane.
The examples of nitrile solvents may include acetonitrile, propionitrile, butyronitrile or isobutyronitrile

The examples of halogenated aliphatic hydrocarbons solvents may include dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
The examples of aromatic hydrocarbons solvents may include benzene, toluene or xylene.
The salts of perindopril compound of structural formula I with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine may be isolated by the steps of filtration, centrifugation, washing drying and the combinations thereof.
The salts of perindopril compound of structural formula I with L-glutamine, L-glutamic acid, L-histidine, L-fysine, methionine, phenylalanine, L-tryptophan or L-tyrosine may be further converted into perindopril erbumine.
The salts of perindopril compound of structural formula I with L-glutamine, L-glutamic acid, L-histidine, L-iysine, methionine, phenylalanine, L-tryptophan or L-tyrosine may be neutralized with acid to get substantially pure perindopril compound of structural formula
I
The examples of acid may include hydrochloric acid, hydrobromic acid, acetic acid or
formic acid.
The substantially pure perindopril compound of structural formula I may contain less than 0.1% weight /weight of compound of structural formula II.


The limit of detection (LOD) of compound of formula II in perindopril compound of structural formula I is 0.01% weight / weight.
The limit of quantitation (LOQ) of compound of formula II in perindopril compound of structural formula I is 0.05% weight / weight.
The pharmaceutical^ acceptable salts of perindopril compound of structural formula I may include perindopril erbumine.
The substantially pure perindopril compound of structural formula I may be further reaction with tertiary butyl amine to get perindopril erbumine.
The substantially pure perindopril erbumine may be dried at a temperature in the range of 40°C to 45°C under reduced pressure.

EXAMPLES
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of substantially pure perindopril erbumine
The crude perindopril (lOgm) was treated with L-tyrosine-(5gm) in toluene solvent (200ml) at 50°C for 4 hours. The resulting reaction mixture was cooled to 0°C and then resulting solid were filtered, washed with toluene (20ml) and then it was treated with dilute hydrochloric acid (5%, 25ml) at 25°C in dimethoxy ethane (50ml). The organic layer was separated and then it was treated with tertiary butyl amine (2gm) at 30°C and then resulting reaction mixture was stirred for 4 hours at 0°C and then resulting solids were filtered, washed with dimethoxy ethane (20ml). The solid was dried under reduced pressure at 40°C. Yield: 12gm Purity: 99.98% (By HPLC); Compound of formula IJ: 0.01% (weight/weight by HPLC)
Example 2: Preparation of substantially pure perindopril erbumine
The crude perindopril (lOgm) was treated with L-glutamine (4gm) in toluene solvent (200ml) at 60°C for 3 hours. The resulting reaction mixture was cooled to 0°C and then resulting solid were filtered, washed with toluene (20ml) and then it was treated with dilute hydrochloric acid (5%, 25ml) at 25°C in ethyl acetate (50ml). The organic layer was separated and then it was treated with tertiary butyl amine (2gm) at 30°C and then resulting reaction mixture was stirred for 4 hours at 0°C and then resulting solids were filtered, washed with ethyl acetate (20ml). The solid was dried under reduced pressure at 40°C.
Yield: 1 Igm Purity: 99.98% (By HPLC): Compound of formula II: 0.01% (weight/weight by HPLC)

Example 3: Preparation of substantially pure perindopril erbumine
The crude perindopril (l0gm) was treated with L-glutamic acid (4gm) in dichloro-methane solvent (200ml) at 55°C for 4 hours. The resulting reaction mixture was cooled to 0°C and then resulting solid were filtered, washed with dichloromethane (20ml) and then it was treated with dilute hydrochloric acid (5%. 25ml) at 25°C in acetonitrile (50ml). The organic layer was separated and then it was treated with tertiary butyl amine (2gm) at 30°C and then resulting reaction mixture was stirred for 3 hours at 0°C and then resulting solids were filtered, washed with acetonitrile (20ml). The solid was dried under reduced pressure at 40-45°C. Yield: 11 gm Purity: 99.97% (By HPLC); Compound of formula II: 0.01% (weight/weight by HPLC)
Example 4: Preparation of substantially pure perindopril erbumine
The crude perindopril (10gm) was treated with L-histidine (4.2gm) in acetonitrile solvent (200ml) at 65°C for 3.5 hours. The resulting reaction mixture was cooled to 0°C and then resulting solid were filtered, washed with acetonitrile (20ml) and then it was treated with dilute hydrochloric acid (5%, 25ml) at 25°C in ethyl acetate (50ml). The organic layer was separated and then it was treated with tertiary butyl amine (2gm) at 35°C and then resulting reaction mixture was stirred for 3.5 hours at 0°C and then resulting solids were filtered, washed with ethyl acetate (20ml). The solid was dried under reduced pressure at 45°C.
Yield: 11.8gm
Purity: 99.98% (By HPLC); Compound of formula II: 0.01% (weight/weight by HPLC)
Example 5: Preparation of substantially pure perindopril erbumine
The crude perindopril (l0gm) was treated with L-lysine (4gm) in toluene solvent (200ml) at 50°C for 4.5 hours. The resulting reaction mixture was cooled to 0°C and then resulting solid were filtered, washed with toluene (20ml) and then it was treated with dilute acetic acid (30%, 25ml) at room temperature in acetonitrile (50ml). The organic

layer was separated and then it was treated with tertiary butyl amine (2gm) at 30°C and
then resulting reaction mixture was stirred for 4 hours at 0°C and then resulting solids
were filtered, washed with acetonitrile (20ml). The solid was dried under reduced
pressure at 40°C.
Yield: 11.6gm
Purity: 99.98% (By HPLC); Compound of formula II: 0.01% (weight/weight by HPLC)
Example 6: Preparation of substantially pure perindopri| erbumine
The crude perindopril (l0gm) was treated with methionine (4gm) in dichloroethane solvent (200ml) at 55°C for 4 hours. The resulting reaction mixture was cooled to 0°C and then resulting solid were filtered, washed with dichloroethane (20ml) and then it was treated with dilute acetic acid (10%, 25ml) at room temperature in ethyl acetate (50ml). The organic layer was separated and then it was treated with tertiary butyl amine (2gm) at 30-35°C and then resulting reaction mixture was stirred for 3.5 hours at 0°C and then resulting solids were filtered, washed with ethyl acetate (20m1), The solid was dried under reduced pressure at 40-45°C. Yield: 11.7gm Purity: 99.97% (By HPLC); Compound of formula II: 0.01% (weight/weight by HPLC)
Example 7: Preparation of substantially pure perindopril erbumine
The crude perindopril (l0gm) was treated with phenylalanine (4.5gm) in ethyl acetate (200ml) at 60°C for 3 hours. The resulting reaction mixture was cooled to 0°C and then resulting solid were filtered, washed with ethyl acetate (20ml) and then it was treated with dilute hydrochloric acid (5%, 25ml) at 25°C in acetonitrile (50ml). The organic layer was separated and then it was treated with tertiary butyl amine (2gm) at 30°C and then resulting reaction mixture was stirred for 4 hours at 0°C and then resulting solids were filtered, washed with acetonitrile (20ml). The solid was drieq under reduced pressure at 40°C.
Yield: 12gm Purity: 99.98% (By HPLC); Compound of formula 11: 0.01% (weight/weight by HPLC)

Example 8: Preparation of substantially pure perindopril erbumine
The crude perindopril (10gm) was treated with L-tryptophan (5.5gm) in methanol (200ml) at 50°C for 4 hours. The resulting reaction mixture was cooled to 0°C and then resulting solid were filtered, washed with methanol (20ml) and then it was treated with dilute hydrochloric acid (5%, 25ml) at 25°C in ethyl acetate (50ml). The organic layer was separated and then it was treated with tertiary butyl amine (2gm) at 30°C and then resulting reaction mixture was stirred for 3.5 hours at 0°C and then resulting solids were filtered, washed with ethyl acetate (20ml). The solid was dried under reduced pressure at 40-45°C. Yield: 12.9gm Purity: 99.98% (By HPLC); Compound of formula II: 0.01% (weight/weight by HPLC)

WE CLAIM:
1. A process for the preparation of substantially pure perindopril compound of structural formula I or its pharmaceutically acceptable saits thereof comprising the steps of
a. treating crude perindopril with L-glutamine, L-glutamic acid, L-histidine, L-
lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine,
b. isolating salts of perindopril with L-glutamine, L-glutamic acid, L-histidine,
L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine
c. converting salts of perindopril with L-glutamine* L-glutamic acid, L-histidine,
L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine into
perindopril and its pharmaceutical^ acceptable Salts thereof.
2. The process according to claim no. 1, wherein crude perindopril is having up to 5%
weight /weight of a compound of structural formula II

3. The process according to claim no. 1, wherein crude perindopril is reacted with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine in an organic solvent at a temperature in the range of 30°C to 85°C.
4. The process according to claim no. 3, wherein organic solvent is selected from the group comprising of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol; alky I acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether,

methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronltrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride or aromatic hydrocarbons such as benzene, toluene or xylene.
5. The process according to claim no. 1, wherein salts of perindopril with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine is isolated by the steps of filtration, centrifugation, washing, drying and the combinations thereof.
6. The process according to claim no.l, wherein salts of perindopril with L-glutamine, L-glutamic acid, L-histidine, L-lysine, methionine, phenylalanine, L-tryptophan or L-tyrosine is treated with acid to get substantially pure perindopril compound of structural formula I.
7. The process according to claim no 1 and 6, wherein substantially pure perindopril compound of structural formula I contain less than 0.1% weight / weight of compound of structural formula II.

8. The process according to claim no.I wherein the pharmaceutically acceptable salts of perindopril compound of structural formula I is perindopril erbumine.
9. The process according to claim no.] wherein perindopril compound of structural formula J is reacted with tertiary butyl amine to get perindopril erbumine.
10. The process according to claim no 1, wherein pharmaceutically acceptable salts of
perindopril compound of structural formula I such as perindopril erbumine contain less
than 0.1% weight / weight of compound of structural formula II.