FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
"PERINDOPRIL"
CIPLA LIMITED of 289 Bellasis Road, Mumbai Central, Mumbai 400 008, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

WO 2004/046172 2 PCT/GB2003/004981
PERINDOPRIL
This invention relates to a process for preparing a pharmaceutically acceptable salt of perindopril, and a novel polymorphic form thereof.
Perindopril is the international non-proprietary name of (2S,3aS,7aS)-l-{2-[l-
(ethoxycarbonyl)-(S)-butylamino]-(S)-propionyl}-octahydroindole-2-carboxylic acid
Perindopril is known to have therapeutic application as an angiotensin - converting enzyme (ACE) inhibitor. ACE is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to angiotensin n, as well as causing the degradation of bradykinin. Angiotensin II is a vasoconstrictor which also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE has, therefore, been shown to have therapeutic utility in patients suffering from disease states such as hypertension and congestive heart failure. In addition, it has been discovered that ACE inhibitors are useful m treating cognitive disorders.
Perindopril has me following structural formula (I)

a)
Perindopril is described in US patent no. 4508729. Preparative processes described in this US patent are carried out in an alcoholic medium, and in the presence of a neutral dehydrating agent and an organic or inorganic cyanoborohydride. Deprotection processes can be carried out where necessary, for example with reference to hydrolysis and/or hydrogenolysis.
US patent no. 4914214 describes a process for the preparation of perindopril and its t-butylamine salt The process comprises condensation of a protected ester of (2S,3aS,7aS)-2-carboxyperhydroindole with me (S,S) diastereoisomer of N-[(S)-l-carbemoxybutyl]-(S)-

WO 2004/046172 PCT/GB2003/004981
2>
alanine, followed by deprotection employing charcoal containing 5% palladium and water. Tertiary-butylamine is then added to yield the t-butylamine salt of perindopril.
PCT patent application WO 01/87835 describes a novel crystalline form, namely a crystalline form, of the t-butylamine salt of perindopril, processes of preparing the same and pharmaceutical formulations containing the same.
PCT patent application WO 01/87836 describes a novel crystalline form, namely 3 crystalline form, of the t-butylamine salt of perindopril, processes of preparing the same and pharmaceutical formulations containing the same.
PCT patent application WO 01/87835 describes a novel crystalline form, namely y crystalline form, of the t-butylamine salt of perindopril, processes of preparing the same and pharmaceutical formulations containing the same.
PCT patent application WO 01/58868 describes a process of preparing perindopril or pharmaceutically acceptable salts thereof, which process provides perindopril, or a salt thereof, with improved purity. More particularly, the level of known impurities associated with perindopril or a salt thereof, prepared according to PCT patent application WO 01/58868, is described as being less than 0.2 or 0.1% by weight Intermediate process steps are carried out in the presence of 1-hydroxybenzotriazole, dicyclohexylcarbodiimide and optionally triethylamine, and at a temperature in the range of 20 to 77EC, followed by Deprotection and where required salt conversion.
Prior art processes for the preparation of perindopril, or pharmaceutically acceptable salts thereof, have generally tended to be time-consuming and have often resulted in undesirable associated impurities, such as diketopiperazine analogues. There is, therefore, a need for an improved process for preparing perindopril, or pharmaceutically acceptable salts thereof, which alleviates the above mentioned problems.
We have now developed a process for preparing a pharmaceutically acceptable salt of perindopril, which is advantageous in terms of a faster reaction time compared to known processes for the preparation of a pharmaceutically acceptable salt of perindopril, and also in obviating the production of undesirable impurities so as to achieve a highly pure product
In accordance with one aspect of the present invention, there is provided a process for preparing a pharmaceutically acceptable salt of perindopril of formula (I) from a protected precursor compound of formula (Q)

WO 2004/046172 PCT/GB2003/004981

COOR COOH
H \ 6-miH I \ H"'"y y""H = *
CH3 COOEt - » / \ CH3 COOEt

(H) (I)
wherein R represents a carboxyl protecting group, which process comprises subjecting a compound of formula (II) to deprotection of the carboxylic group COOR attached to the heterocyclic ring so as to yield the corresponding free acid, which deprotection is carried out in the presence of a base which forms a pbannaceutically acceptable salt with said free acid formed by said deprotection.
Typically, R can represent any suitable carboxyl protecting group that can be selectively removed by a process according to the present invention. Preferably, R can represent optionally substituted aralkyl, especially optionally substituted benzyl R can, therefore, typically represent unsubstituted benzyl; alternatively substituted benzyl can be employed, such as 4-halo substituted, or 4-C1-4alkoxy substituted benzyl, especially 4-C1 benzyl, or 4-methoxy benzyl.
Suitably, deprotection as employed in a process according to the present invention can comprise bydrogenolysis in the presence of a noble metal catalyst, preferably palladium-on-chacoal.
The process of the present invention is advantageous in achieving a highly pure product A pharmaceutically acceptable salt of perindopril prepared by a process according to the present invention is preferably more than about 99% w/w pure, and more preferably more man about 99.5% w/w pure. The purity of a pharmaceutically acceptable salt of perindopril prepared by a process according to the present invention can be further enhanced by an optional crystallisation step in a suitable solvent, such as ethyl acetate, isopropanol or the like, so as to obtain a pharmaceutically acceptable salt of perindopril which is preferably about 99.8% w/w pure.

WO 2004/046172 5 PCT/GB2003/004981
Preferably, the base employed in the process of the present invention is selected so as to form a pharmaceutically acceptable salt with the tree acid formed by the deprotection as indicated above, whereby it is possible to obtain a pharmaceutically acceptable salt of perindopril directly from such a reaction work-up. In a particularly preferred embodiment according to the present invention the base comprises t-butylamine and as such a preferred process according to the present invention can provide a highly pure t-butylamine salt of perindopril directly from the reaction process.
According to the above preferred embodiment of the present invention, mere is provided a process for preparing perindopril t-butylamine (which is well known to those of skill in the art as being perindopril erbumine) from a protected precursor compound of formula (D) substantially as hereinbefore described (preferably a benzyl protected precursor compound of formula (D) where R represents benzyl), which process comprises subjecting a compound of formula (IT) to deprotection (preferably hydrogenolysis in the presence of a noble metal catalyst such as palladium-on-chacoal) of the carboxylic group COOR attached to the heterocyclic ring so as to yield the corresponding free acid, which deprotection is carried out in me presence of t-butylamine so as to form the t-butylamine salt of perindopril
Suitably a precursor compound of formula (II) is initially dissolved in an alkanol solvent, such as isopropanol or the Kke, followed by addition of the base thereto. This is further followed by the deprotection of the carboxylic group COOR, suitably by the addition of palladium-on-charcoal and hydrogenation for several hours. The alkanol solvent is suitably concentrated under vacuum and replaced by a water immiscible solvent, such as ethyl acetate or the like. The resulting solids can then be cooled and filtered to yield a pharmaceutically acceptable salt of perindopril.
The process according to the present invention substantially as hereinbefore described may further comprises hydrating a pharmaceutically acceptable salt of perindopril obtained by the process so as to yield a pharmaceutically acceptable salt of hydrated perindopril of formula (la)

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PCT/GB2003/004981

CH3 COOEt
COOH

nH20

(la)
wherein n is an integer of 1 to 5, or a reciprocal of integers 2 to 5. Hydration can be by way of the addition of water or by drying in air.
Preferably n is 1, whereby a phannaceutically acceptable salt of perindopril monohydrate is formed by a process according to the present invention.
The present invention also provides a process for preparing a monohydrate of a phannaceutically acceptable salt of perindopril, which process comprises hydrating a phannaceutically acceptable salt of perindopril so as to yield said monohydrate. Hydration can be by way of the addition of water or by drying in air, and preferably perindopril t-burylamine is hydrated to yield perindopril t-butylamine monohydrate.
The present invention farther provides a pharmaceutically acceptable salt of perindopril optionally in hydrated form, prepared by a process substantially as hereinbefore described In particular, a pharmaceutically acceptable salt of hydrated perindopril of formula (la) is provided
COOH

(la)

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wherein n is an integer of 1 to S, or a reciprocal of integers 2 to 5. Preferably, n is 1. A preferred phannaceutically acceptable salt of hydrated perindopril of formula (la) is the t-butylamine salt In a particularly preferred embodiment, the present invention provides perindopril t-butylamine (or erbumine) monobydrate.
The present invention also provides perindopril t-butylamine monobydrate having an X-ray diffractogram, or substantially the same X-ray diffractogram, as set out in Figure 1. More particularly, perindopril t-butylamine monobydrate according to the present invention can be characterised as having an X-ray powder diffraction pattern with characteristic peaks (26): 9.5504,14.8600,15.7486,16.5400, 20.0400,21.0499,22.0600, 24.1744,26.3300 and 27.1600.
Further characterising data for perindopril t-butylamine monobydrate according to the present invention as obtained by X-ray diffraction is shown in following Table 1.
Table 1

Peak No. 20 (deg) d (A) I/II FWHM (deg) Intensity (Counts) Integrated I (Counts)
1 8.6400 10.22611 10 0.57600 151 6899
2 9.5504 925324 73 0.50470 1090 28204
3 10.5940 8.34394 5 0.97200 79 4071
4 13.6000 6.50569 6 0.42860 91 2112
5 14.1400 6.25844 14 0.47120 215 5210
6 14.8600 5.95678 22 0.59000 332 10293
7 15.7486 5.62262 75 0.14270 1111 49244
8 16.5400 5.35533 30 0.72500 450 15749
9 17.5400 5.05220 16 0.67120 231 9128
10 18.6100 4.76406 17 0.56000 249 7981
11 20.0400 4.42722 31 0.51660 458 13471
12 21.0499 4.21704 100 0.90700 1488 63860
13 22.0600 4.02618 50 0.59480 747 23998
14 23.1600 3.83738 17 0.71720 253 12014

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15 24.1744 3.67860 47 0.50030 705 17912
16 24.8000 3.58721 5 0.26000 73 1463
17 26.3300 3.38213 31 0.94000 468 19402
18 27.1600 3.28062 20 0.68500 292 9230
19 28.4444 3.13534 15 0.96890 223 11023
20 30.8000 2.90071 7 0.59340 99 3196
21 31.8000 2.81173 9 0.65600 130 4356
22 32.5600 2.74782 11 0.61340 163 4411
23 33.2400 2.69314 6 0.75000 95 3116
24 34.1800 2.62120 4 0.64000 61 2155
25 35.4728 2.52857 7 0.85430 104 4353
26 36.8838 2.43502 6 0.61900 93 2985
27 38.7340 2.32285 4 0.50800 55 1432
Perindopril as provided by the present invention has therapeutic utility as an ACE inhibitor.
In addition, the present invention farther provides a method of inhibiting ACE in a patient in need thereof comprising administering to said patient an effective ACE inhibitory amount of perindopril (preferably perindopril t-butylamine monohydrate) as provided according to the present invention.
The present invention also provides use of perindopril as provided according to the present invention (preferably perindopril t-butylamine monohydrate) in the manufacture of a medicament for inhibiting ACE.
A patient can be in need of treatment to inhibit ACE, for example when the patient is suffering from hypertension, chronic congestive heart failure, or the like. Inhibition of ACE reduces levels of angiotensin H and thus inhibits the vasopressor, hypertensive and hyperaldosteronemic effects caused thereby. Inhibition of AGE would also potentiate endogenous levels of bradykinin. An effective ACE inhibitory amount of perindopril as provided according to the present invention is mat amount which is effective in inhibiting ACE in a patient in need thereof which results, for example, in a hypotensive effect
In effecting treatment of a patient, perindopril as provided according to die present invention can be administered in any form or mode which makes the compound bioavailable

WO 2004/044172 9 PCT/GB2003/004981
in effective amounts, including oral and parenteral routes. For example, perindopril as provided according to the present invention can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, and the like. Oral administration is generally preferred. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the disease state to be treated and the stage of the disease.
Perindopril as provided according to the present invention can be administered in the form of pharmaceutical compositions or medicaments which are prepared by combining the perindopril according to the present invention with pharmaceutical^ acceptable carriers, diluents or excipients therefor, the proportion and nature of which are determined by the chosen route of administration, and standard pharmaceutical practice.
In another embodiment, the present invention provides pharmaceutical compositions comprising an effective ACE inhibitory amount of perindopril as provided according to the present invention (preferably perindopril t-butylarnine monohydrate), together with one or more pharmaceutically acceptable carries, dilsents or excipients therefor.
By "pharmaceutically acceptable" it is meant be compatible with perindopril as provided according to the present invention, and not be deleterious to a recipient thereof
The pharmaceutical compositions or medicaments are prepared in a manner well known in the pharmaceutical art The carrier, diluent or excipient may be a solid, semi-solid, or liquid material, which can serve as a vehicle or medium for the active ingredient Suitable carriers, diluents or excipients are well known in the art Pharmaceutical compositions according to the present invention may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions or the like.
The pharmaceutical compositions may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, a monohydrate according to the present invention may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups and the tike.
The tablets, pills, capsules, and the like may also contain one or more of the following adjuvants: binders, such as microcrystalline cellulose, gum tragacanth or gelatin; excipients,

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such as starch or lactose; disintegrating agents such as alginic acid, corn starch and the like; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; and sweetening agents, such as sucrose or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives. Materials used in preparing these various compositions should be phannaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral administration perindopril as provided according to the present invention may be incorporated into a solution or suspension. The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; and buffers such as acetates, citrates or phosphates. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
The present invention will now be further illustrated by the following Figure and Examples, which do not limit the scope of the invention in any way.
Figure 1: X-ray diffraction pattern of perindopril erbumine monohydrate according to the present invention. The sample was analysed using a Shimadzu-6000 x-ray diffractometer. The source used was K« monochromatic radiation of Cu having wavelength of 1.5406 A°. The Divergent Slit used was 1°. The Receiving Slit was 0.30mm. The Scintillation counter was used as the detector, with the range being from 3° to 40° (20) with a scan speed of 2° per minute.
F.xample 1
The benzyl ester of (2S,3aS,7aS>l-{2-[l-(ethoxycarbonyl)-{S>butylamino]-{S)-propionyl}-octahydroindole-2-carboxylic acid, namely benzyl perindopril, (l0gms) was dissolved in isopropanol (100ml). To the clear solution, t-butylamine (2.5gms) and 10% w/w

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palladium on charcoal (2gms) was added. The reaction mixture was hydrogenated at a pressure of lkg/cm2 for 2 hours.
The reaction mass was filtered to remove the catalyst The solvent was concentrated under vacuum and isopropanol was replaced by simultaneous addition of ethyl acetate. The solids obtained were cooled to OEC and filtered to obtain perindopril erbumine (7.8gms).
Example 2
Perindopril erbumine (l0gms) was suspended in acetone (80ml). To mis was added water (0.4ml) and the contents heated to dissolve the solids and cooled to ambient The resulting slurry was filtered to obtain perindopril erbumine monohydrate (9.4gms).
P.Yflmple 3
Perindopril erbumine (20gms) was suspended in ethyl acetate (300ml). To mis was added water (1.5ml) and me contents heated to dissolve the solids and cooled to 10EC. The resulting shiny was filtered to obtain perindopril erbumine monohydrate(17gms).
Example 4
Perindopril erbumine (5gms) was suspended in acetonitrile (75ml). To mis was added water (0.4ml) and the contents heated to dissolve the solids and cooled to OEC. The resulting slurry was filtered to obtain perindopril erbumine monohydrate (2.9gms).
Example 5
Perindopril erbumine (20gms) was suspended in ethyl acetate (300ml). The contents were heated to dissolve the solids and cooled to 10EC. The resulting slurry was filtered and dried in air having a relative humidity of at least 75% to give perindopril erbumine monohydrate (17gms).
Example 6
Preparation of perindopril erbumine monohydrate
Raw Materials :-
1. Perindopril erbumine anhydrous =10gm.
2. Isopropyl alcohol =70 ml.

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3. Water =2 ml.
4. Ethyl acetate =85 ml.
Procedure :-
1. Charge 10 gm of perindopril erbumine (anhydrous) in round bottom flask. Add 70 ml isopropyl alcohol. Stir for Vi hr. (around 95% product dissolved).
2. Add 2 ml of water. Stir for 15 min (clear solution obtained).
3. Stir reaction mass at 38-40'C for 2 hrs.
4. Distill out isopropyl alcohol completely under vacuum (below 600 mm) below 40°C. (Gel type material observed)
5. Charge 30 ml ethyl acetate. Stir for 15 min below 40°C (clear solution observed). Distill under vacuum below 40°C (semi-solid observed).
6. Charge 40 ml ethyl acetate at 36-38*C Stir for 15 min (firee solid observed).
7. Stir l hr at room temperature (25-30*0). (Free crystalline solid observed)
8. Cool to lO'C. Stir for 2 hrs.
9. Filter solid and wash with 15 ml ethyl acetate. Suck dry for 2 hrs.
10. Dry under vacuum below 40°C for 12 hrs.
Water Content =3.2-3.8% MJP = 145-150*C.
F.xample 7
The following tablets were prepared: (a) Formulation I:

Strengths
2mg 4 me 8mg
Ingredients 2mg 4mg 8mg
Perindopril Erbumine Monohydrate
Maize starch 5mg 10 mg 20 mg
Lactose anhydrous 12.5 mg 25.0 mg 100.0 mg
Microcrystalline cellulose 25.10 mg 50.20 mg 100.40 mg

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Magnesium stearate 0.4 0.8 1.6
Total weight 45.0 mg 90.0 mg 180.0 mg
Procedure: Sift the above ingredients through respective sieves. Mix the ingredients in a suitable blender. Compress the tablets in the suitable toolings.
(b) Formulation II:

Strengths
2 me 4 me 8 me
Ingredients 2mg 4mg 8mg
Periiidopril Erbumine Monohydrate
Maize starch 10 mg 10 mg 10 mg
Lactose anhydrous 25 mg 25.0 mg 25.0 mg
Microcrystalline cellulose 52.2 mg 49.20 mg 45.20 mg
Yellow oxide of Iron - 1.0 -
Red oxide of Iron - - 1.0
Hydrogenated castor oil 0.8 mg 0.8 mg 0.8 mg
Total weight 90.0 mg 90.0 mg 90.0 mg
Procedure:
1) Dissolve Perindopril Erbumine Monohydrate ethanol
2) Granulate the above ingredients except hydrogenated castor oil with the above solution. Dry the granules and size.
3) Lubricate with hydrogenated castor oil in suitable blender. Compress the granules in the suitable tooling
Pharmaceutical composition prepared according to present invention is a synergistic composition exhibiting surprising results.

14
We claim:
1. A pharmaceutically acceptable salt of hydrated perindopril of formula (la).

nHzO

COOR o

(la)
wherein n is an integer of 1 to 5, or a reciprocal of integers 2 to 5.
2. A pharmaceutically acceptable salt according to claim 1, wherein n is 1.
3. A pharmaceutically acceptable salt according to claim 1 and 2, which is the t-butylamine salt.
4. Perindopril t-butylamine monohydrate.
5. Perindopril t-butylamine monohydrate having an X-ray diffractogram, or substantially the same X-ray diffractogram, as set out in Figure 1.
6. Perindopril t-butylamine monohydrate characterised as having an X-ray powder diffraction pattern with characteristic peaks (20): 9.5504, 14.8600, 15.7486, 16.5400, 20.0400, 21.0499, 22.0600, 24.1744, 26.3300 and 27.1600.
7. A pharmaceutically acceptable salt of perindopril in hydrated form prepared by a process comprising:
Preparing a pharmaceutically acceptable salt of perindopril of formula (I) from a protected precursor compound of formula (II)



HII ••) Ir IH CHs COOEt

(II)

(I)

15
wherein R represents a carboxyl protecting group, which process comprises subjecting a compound of formula (II) to de-protection of carboxylic group COOR attached to the heterocyclic ring so as to yield the corresponding free acid, which deproptection is carried out in presence of which forms a pharmaceutically acceptable salt with said free acid formed by said deprotection, and hydrating the compound of formula (I) so as to yield the pharmaceutically acceptable salt of hydrated perindopril of formula (la).
8. A pharmaceutical composition comprising an effective ACE inhibitory amount of a pharmaceutically acceptable salt of perindopril according to any of the claims 1 to 7, together with one or more pharmaceutically acceptable carrier, diluents or excipients therefore.
9. A process for preparing a monohydrate of a pharmaceutically acceptable salt of perindopril, which process comprises hydrating a pharmaceutically acceptable salt of perindopril so as to yield said monohydrate.
10. A process according to claim 9 wherein perindopril t-butylamine is hydrated to yield perindopril t-butylamine monohydrate.
Dated this 2nd day of December 2006 VIBHA SHUKLA
Of K & S Partners Agent for the Applicant

16
ABSTRACT
Title: "PERINDOPRIL"
A pharmaceutically acceptable salt of perindopril of formula (I) is made from a protected precursor compound of formula (II) wherein R represents a carboxyl protecting group, which process comprises subjecting a compound of formula (II) to deprotection of the carboxylic group COOR attached to the heterocyclic ring so as to yield the corresponding free acid, which deprotection is carried out in the presence of a base which forms a pharmaceutically acceptable salt with said free acid formed by said deprotection.