COMPETE AFTER PROVTSTONAI LEFT ON 7/7/06

FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION
"PROCESS FOR THE PREPARATION OF CILAZAPRIL"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

PRIORITY
This application claims the benefit under Indian Provisional Application 813/MUM/2005, filed on July 7, 2005, and entitled "PROCESS FOR THE PREPARATION OF CILAZAPRIL", the contents of which are incorporated by reference herein.
BACKGROUND OF INVENTION
1. Field of Invention
The present invention generally relates to a process for the preparation of cilazapril and pharmaceutical^ acceptable salts thereof.
2. Description of the Related Art
The present invention relates to a process for the preparation of cilazapril (also known as (IS, 9S)-9-[[(lS)-l-ethoxycarbonyl)-3-phenylpropyl] amino] octahydro-10-oxo-6H-pyridazino [1, 2-a] [1,2] diazepine-1-carboxylic acid) of the general formula I:

Cilazapril is an angiotensin converting enzyme inhibitor for inhibiting the formation of angiotensin II from angiotensin I via inhibiting the angiotensin converting enzyme, thereby reducing the systolic and diastolic blood pressure.
It would be desirable to provide a process for preparing cilazapril in relatively high yields and with high purity.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of cilazapril, the process comprising isolating an organic or inorganic acid salt of (IS, 9S) tert butyl 9-[[(lS) ethoxycarbonyl-3-phenylpropyl] amino] octahydro- 10-oxo-6H-pyridazino [1, 2-a] [1, 2] diazepine-1-carboxylate and (b) converting the organic or inorganic acid salt to cilazapril.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
One aspect of the present invention provides a process for preparing cilazapril. In one embodiment, the process involves (a) isolating (IS, 9S) tert butyl 9-[[(lS) ethoxycarbonyl-3-phenylpropyl] amino] octahydro-10-oxo-6H-pyridazino [1, 2-a][l,2] diazepine-1-carboxylate in a solid form as its organic or inorganic acid salt and (b) converting the organic or inorganic acid salt to cilazapril. Generally, the organic or inorganic acid salt of (IS, 9S) tert butyl 9-[[(lS) ethoxycarbonyl-3-phenylpropyl] amino] octahydro-10-oxo-6H-pyridazino [1, 2-a] [1,2] diazepine-1-carboxylate of formula II:


O COOt Bu
HA

(II)
can be obtained by (i) condensation of (1S,9S) tert butyl octahydro-10-oxo-9-amino-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate of formula III


H,N
0 COOt Bu

(HI)

with ethyl (R)-2-(trifluoromethanesulfonyloxy)-4-phenyl butyrate of formula IV:

(IV); and
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(ii) treating the resulting product with an organic or inorganic acid to obtain the organic or inorganic salt of formula II. Suitable organic acids used to isolate the salt include, but are not limited to, substituted or unsubstituted aliphatic mono carboxylic acids, substituted or unsubstituted aliphatic di carboxylic acids, substituted or unsubstituted aromatic mono carboxylic acids, substituted or unsubstituted aromatic di carboxylic acids, substituted or unsubstituted alkyl sulfonic acids, substituted or unsubstituted aryl sulfonic acids and the like and mixtures thereof. Suitable inorganic acid include, but are not limited to, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid and the like and mixtures thereof with hydrochloric acid being preferred.. Step (a) of the process of the present invention can be carried out under general conditions and at temperature ordinarily ranging from about 0 to about 50°C, and preferably from about 20°C to about 40°C.
In step (b) of the process of the present invention, the organic or inorganic acid salt is treated with an organic and/or inorganic acid to obtain cilazapril. Suitable organic acids used to isolate the salt include, but are not limited to, substituted or unsubstituted aliphatic mono carboxylic acids, substituted or unsubstituted aliphatic di carboxylic acids, substituted or unsubstituted aromatic mono carboxylic acids, substituted or unsubstituted aromatic di carboxylic acids, substituted or unsubstituted alkyl sulfonic acids, substituted or unsubstituted aryl sulfonic acids and the like and mixtures thereof. The preferred acid is trifluoroacetic acid. In another embodiment, the organic acids are alkyl sulfonic acids, and substituted alkyl sulfonic acids with substituted alkyl sulfonic acids being preferred. The preferred alkyl sulfonic acid is trifluoromethane sulfonic acid. Suitable inorganic acid include, but are not limited to, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid and the like and mixtures thereof.
Another aspect of the present invention provides a substantially pure cilazapril. In one embodiment, cilazapril has a purity of greater than or equal to about 95%. In another embodiment, cilazapril has a purity of greater than or equal to about 98%. In yet another embodiment, cilazapril has a purity of greater than or equal to about 99%.
Yet another aspect of the present invention is directed to pharmaceutical compositions containing at least cilazapril of the present invention. Such pharmaceutical compositions may
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be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. Cilazapril of the present invention also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The dosage forms may contain the cilazapril of the present invention as is or, alternatively, may contain cilazapril as part of a composition. The pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinabove.
Capsule dosages will contain the cilazapril of the present invention within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.
Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and
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unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
In one embodiment, cilazapril for use in the pharmaceutical compositions of the present invention can have a D50 and D90 particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 15 microns. For example, the particle sizes of cilazapril can be obtained by any milling, grinding, and micronizing or other particle size reduction method known in the art to bring the solid state form of the cilazapril of the present invention into any of the foregoing desired particle size range. As also used herein, cilazapril particles with reduced size are referred to as "micronized particles of cilazapril "or" cilazapril".
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
EXAMPLE
1 Preparation of (IS, 9S) tert butyl 9-[[(lS) ethoxycarbonyl-3-phenylpropyl] amino] octahydro-10-oxo-6H-pyridazino [1, 2-a][l,2] diazepine-1-carboxylate trifluoromethane sulfonate salt.
A solution of (IS, 9S) tert butyl octahydro-10-oxo-9-amino-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate (50 gm) in dichloromethane (100 ml) was added to a
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solution of ethyl (R)-2-(trifluoromethanesulfonyloxy)-4-phenyl butyrate (25 gm) in dichloromethane(100 ml) over a period of 2 to 3 hours at 20 to 25°C. Next, the reaction mixture was stirred for an additional 2 hours at the same temperature. Following the completion of the reaction, a solution of trifluoromethane sulfonic acid (30 gm) in water (150 gm) was added to the reaction mass, and stirred for 30 minutes. The organic layer was separated, washed with water (100 ml) and concentrated under reduced pressure. The oily residue obtained was recrystallized from a mixture of methanol and di isopropyl ether to get (IS, 9S) tert butyl 9-[[(lS) ethoxycarbonyl-3-phenylpropyl] amino] octahydro-10-oxo-6H-pyridazino [1, 2-a][l,2] diazepine-1-carboxylate trifluoromethane sulfonate salt as a solid ( 40 gm,75%). Purity more than 99%.
EXAMPLE 2
Preparation of Cilazapril
(IS, 9S) tert butyl 9-[[(lS) ethoxycarbonyl-3-phenylpropyl] amino] octahydro-10-oxo-6H-pyridazino [1, 2-a] [1,2] diazepine-1-carboxylate trifluoromethane sulfonate salt (25 gm) obtained in Example 1 was added to trifluoroacetic acid (100 ml) and the reaction mass was stirred at 20 to 30°C. After completion of the reaction, the excess trifluoroacetic acid was distilled off under vacuum and isolated after water work up to provide cilazapril (15 gm .HPLC purity greater than 99%).
Dated this Sixth (06th) day of July, 2006

TARANPREET SINGH LAMBA
SENIOR MANAGER-IPM GLENMARK PHARMACEUTICALS LIMITED

7

WE CLAIM:
1. A process for the preparation of cilazapril of formula I

(i);
the process comprising (a) isolating an organic acid or inorganic acid salt of (IS, 9S) tert butyl 9-[[(lS) ethoxycarbonyl-3-phenylpropyl] amino] octahydro- 10-oxo-6H-pyridazino [1, 2-a][l,2] diazepine-1-carboxylate of formula II as a solid:



O COOl Bu
"COOC2H5

HA

(II); and
(b) converting the organic or inorganic acid salt to cilazapril.
2. The process according to claim 1, wherein in step (a) the organic acid is selected from the group consisting of a substituted or unsubstituted aliphatic mono carboxylic acid, a substituted or unsubstituted aliphatic di carboxylic acid, a substituted or unsubstituted aromatic mono carboxylic acid, a substituted or unsubstituted aromatic di carboxylic acid, a substituted or unsubstituted alkyl sulfonic acid, a substituted or unsubstituted aryl sulfonic acid and mixtures thereof.
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3. The process according to claim 1, wherein in step (a) the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid and mixtures thereof.
4. The process according to claim 1 and 2, wherein in step (a) the organic acid is selected from the group consisting of a substituted or unsubstituted alkyl sulfonic acid, a substituted or unsubstituted aryl sulfonic acid and mixtures thereof.

5. The process according to claims 1-4, wherein in step (a) the organic acid is trifluoromethanesulfonic acid.
6. The process according to claims 1-5, wherein step (b) comprises treating the product of step (a) with an organic acid selected from the group consisting of a substituted or unsubstituted aliphatic mono carboxylic acid, a substituted or unsubstituted aliphatic di carboxylic acid, a substituted or unsubstituted aromatic mono carboxylic acid, a substituted or unsubstituted aromatic di carboxylic acid and mixtures thereof.
7. The process according to claims 1-6, wherein step (b) comprises treating the product of step (a) with trifluoroacetic acid.
8. The process according to claims 1-7, wherein step (b) comprises treating the product of step (a) with an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid and mixtures thereof.
9. The process of claims 1-8, wherein the cilazapril has a purity of grater than or equal
to about 95%.
10. The process of claims 1-8, wherein the cilazapril has a purity of grater than or
equal to about 98%.
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11. The process of claims 1-8, wherein the cilazapril has a purity of grater than or equal to about 99%.
12. A pharmaceutical composition comprising a therapeutically effective amount of Cilazapril of claims 1-11

13. The pharmaceutical composition of claim 12, wherein the cilazapril is a micronized cilazapril having a particle size of less than about 400 microns.
14. The pharmaceutical composition of claim 12, wherein the cilazapril is a micronized cilazapril having a particle size of less than about 200 microns.
15. The pharmaceutical composition of claim 12, wherein the cilazapril is a micronized cilazapril having a particle size of less than about 150 microns.
16. The pharmaceutical composition of claim 12, wherein the cilazapril is a micronized cilazapril having a particle size of less than about 50 microns.
17. The pharmaceutical composition of claim 12, wherein the cilazapril is a micronized cilazapril having a particle size of less than about 15 microns.
Dated this Sixth (06th) day of July, 2006

TARANPREET SINGH LAMBA
SENIOR MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED
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ABSTRACT
A process for the preparation of cilazapril is provided comprising isolating an organic or inorganic acid salt of (IS, 9S) tert butyl 9-[[(lS) ethoxycarbonyl-3-phenylpropyl] amino] octahydro- 10-oxo-6H-pyridazino [1, 2-a] [1, 2] diazepine-1-carboxylate and (b) converting the organic or inorganic acid salt to cilazapril.