FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - AN IMPROVED PROCESS FOR THE PREPARATION OF
POLYMORPHIC FORM A OF ENTACAPONE
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY: An Indian Company.
(C) ADDRESS: Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of the Invention
The present invention relates to an improved process for the preparation of highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer less than 0.1%, particularly less than 0.02%.
Background of the Invention
The chemical name of Entacapone is N, N-diethyl-2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) acrylamide or (E)-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide of formula (I) and molecular formula is C14H15N3O5 and molecular weight is 305.29. Entacapone is marketed by Orion Corporation under tradename Comtan® and is indicated for the treatment of Parkinson's disease.

Entacapone is a potent and specific peripheral catechol-O-methyltransferase (COMT) inhibitor. It is used in combination with levodopa/carbidopa to treat Parkinson's disease, sometime referred to as shaking palsy. Entacapone enhances the effect of levedopa/carbidopa by improving muscle control.
US Patent No. 4,963,590 describes a process for the preparation of Entacapone of formula (I). The synthetic process disclosed in this patent comprises the condensation of 3, 4-dihydroxy-5- nitrobenzaldehyde of formula (II) and N, N-diethylcyanoacetamide of formula (III) in anhydrous ethanol as shown below in Scheme-I
2


In the above process piperidine acetate was used as catalyst. Entacapone thus synthesized was obtained in 73 % yield having a mixture of two geometrical isomeric forms, i.e., (E) and (Z). Moreover, the reaction is lengthy and takes long time which makes the process operation difficult.
Subsequently it is described in the US Patent No 5,135,950 about preparing E-isomer and polymorphism-A from the mixture obtained from the reaction is reported in the GB patent No 2200109. It also discloses about the (E) and (Z)-isomers having the structural formula:

are obtained as mixture in the ratio of about 70-80 % to about 30-20 %,
respectively. (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)
acrylamide may exist at least in two polymorphic forms A and B as shown by X-ray crystallography. The Z-isomer as well as the polymorphic form B of the E-isomer have been shown to be unstable. The Z-isomer is transformed readily into the E-isomer under the influence of heat or acids. Similarly the polymorphic form B of the E-isomer isomerizes slowly to the polymorphic form A on standing at
3

room temperature. On recrystallization of the crude synthesis product from conventional solvents such as lower aliphatic alcohols, esters or hydrocarbons, e.g., ethanol, 2-propanol, ethyl acetate or toluene, a very complicated mixture of different geometric isomers and/or polymorphic forms are generally obtained which interfere with the characterization and standardization of the drug substance. The polymorphism and geometrical isomerism may also influence the bioavailability of the drug.
US Patent 5,135,950 discloses that "crystallographically essentially pure" and stable polymorphic form A of (E)-N, N-diethyl-2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) acrylamide is prepared by recrystallizing crude Entacapone from lower aliphatic carboxylic acids such as formic acid or acetic acid with a catalytic amount of hydrochloric or hydrobromic acid as shown below in Scheme-II

However, this process of isomerization using HBr /Acetic acid suffers with major drawback of operation difficulty as it requires specifically designed glass reactor because of the use of corrosive material. Moreover, it also involves high degree of temperature in highly acidic medium. Further, because of the low reaction volume, it is operationally difficult to transfer the final compound from the reactor.
In summary, process disclosed in prior art for the preparation of form A of Entacapone, are tedious, time consuming and operationally difficult at industrial
4

scale. Moreover, form A of Entacapone obtained by prior art process, involves the formation of (Z)-isomer, which causes low yield and affects the purity of the final product.
Therefore, there is a need to develop a process which provides highly pure polymorphic form A of Entacapone, which is operationally simple at an industrial scale and provides high yield and purity of final product.
With an objective of providing an improved process for the preparation of highly pure polymorphic form A of Entacapone, the present inventors has directed the research work towards developing a process for preparing of highly pure polymorphic form A of Entacapone which devoid the drawback of the prior art.
Surprisingly, when the present inventors carried out the recrystallization of crude Entacapone in specific condition in a solvent selected from methanol, ethanol, propanol, butanol, t-butanol, toluene, chloroform, methylene dichloride, ethylacetate, butyl acetate, methylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone and acetonitrile to obtain polymorphic form A of Entacapone, the compound obtained by this process having high yield and good isomeric purity. Moreover, the present invention provides highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer of Entacapone less than 0.1%.
Moreover, this makes the process for the preparation of highly pure polymorphic form A of Entacapone operationally simple and easily applicable at an industrial scale.
5

Object of the Invention
Therefore, it is an object of the invention is to provide highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer of Entacapone less than 0.1%.
Another object of the invention is to provide highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer of Entacapone less than 0.02%.
Another object of the invention is to provide an improved process for the preparation of highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer of Entacapone less than 0.1%, which is operationally simple, cost-effective, easy to handle and feasible at commercial scale.
Yet another object of the present invention is to provide an improved process for the preparation of highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer of Entacapone less than 0.1% comprising steps of,
a) dissolving crude Entacapone in solvent selected from methanol, ethanol, propanol, butanol, t-butanol, toluene, chloroform, methylene dichloride, ethylacetate, butyl acetate, methylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or mixture, optionally at 50°C-75°C
b) treating the solution of step (a) with charcoal
c) stirring the reaction mixture of step (b) at 25°C to 80°C
d) filtering the reaction mixture of step (c) through hyflo bed
e) cooling the reaction mixture of step (d) at 0°C to 40°C
f) filtering the material of step (e), wherein material is washed the same solvent
g) drying the material of step (f)
6

Furthermore object of the invention is to provide highly pure polymorphic form A of Entacapone having purity of at least 99.5%.
Yet another object of the invention is to provide an improved process for the preparation of highly pure polymorphic form A of Entacapone having purity of at least 99.5% comprising steps of,
a) dissolving crude Entacapone in solvent selected from methanol, ethanol, propanol, butanol, t-butanol, toluene, chloroform, methylene dichloride, ethylacetate, butyl acetate, methylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or mixture, optionally at 50°C-75°C
b) treating the solution of step (a) with charcoal
c) stirring the reaction mixture of step (b) at 25°C to 80°C
d) filtering the reaction mixture of step (c) through hyflo bed
e) cooling the reaction mixture of step (d) at 0°C to 40°C
f) filtering the material of step (e), wherein material is washed the same solvent
g) drying the material of step (f)
Summary of this invention
According to one aspect of the present invention, there is provided an improved process for the preparation of highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer less than 0.1% comprising steps of,
a) dissolving crude Entacapone in solvent selected from methanol, ethanol, propanol, butanol, t-butanol, toluene, chloroform, methylene dichloride, ethylacetate, butyl acetate, methylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or mixture, optionally at 50°C-75°C
b) treating the solution of step (a) with charcoal
c) stirring the reaction mixture of step (b) at 25°C to 80°C
7

d) filtering the reaction mixture of step (c) through hyflo bed
e) cooling the reaction mixture of step (d) at 0°C to 40°C
f) filtering the material of step (e), wherein material is washed the same solvent
g) drying the material of step (f)
According to another aspect of the present invention, there is provided a highly pure polymorphic form A of Entacapone having purity of at least 99.5%
Brief description of the drawing
Figure-1 shows the X-ray powder diffraction pattern of polymorphic form A of Entacapone.
Detailed description of the Invention
Accordingly, the present invention relates to provide an improved process for the preparation of highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer less than 0.1% comprising steps of,
a) dissolving crude Entacapone in solvent selected from methanol, ethanol, propanol, butanol, t-butanol, toluene, chloroform, methylene dichloride, ethylacetate, butyl acetate, methylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or mixture, optionally at 50°C-75°C
b) treating the solution of step (a) with charcoal
c) stirring the reaction mixture of step (b) at 25 °C to 80°C
d) filtering the reaction mixture of step (c) through hyflo bed
e) cooling the reaction mixture of step (d) at 0°C to 40°C
f) filtering the material of step (e), wherein material is washed the same solvent
g) drying the material of step (f)
8

The present invention also provides an improved process for the preparation of highly pure polymorphic form A of Entacapone having purity of at least 99.5% comprising steps of,
a) dissolving crude Entacapone in solvent selected from methanol, ethanol, propanol, butanol, t-butanol, toluene, chloroform, methylene dichloride, ethylacetate, butyl acetate, methylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or mixture, optionally at 50°C-75°C
b) treating the solution of step (a) with charcoal
c) stirring the reaction mixture of step (b) at 25°C to 80°C
d) filtering the reaction mixture of step (c) through hyflo bed
e) cooling the reaction mixture of step (d) at 0°C to 40°C
f) filtering the material of step (e), wherein material is washed the same solvent
g) drying the material of step (f)
The term 'highly pure' incorporated herein means polymorphic form A of Entacapone with no individual impurity including Z-isomer less than 0.1%, preferably less than 0.05% and more preferably less than 0.02%.
The term "dissolving" as used hereinabove refers to suspending, mixing and treating Crude Entacapone in any of the solvent described above.
After dissolving Crude Entacapone in solvent, activated charcoal is added to it. After stirring for 30 min, the reaction mixture is filtered through hyflow supercell bed. The filtrate is allowed to cool to 25-30°C and stirred for l hr. The material is filtered and washed with solvent. Finally, the material is dried at 40-45°C under vacuum to get highly pure polymorphic form A of Entacapone.
The present invention provides process of preparation of highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer less than

0.1% which is simple, environment friendly, economical and leads to an enhanced isomeric purity.
The process of the present invention has following advantages:
• It provides a process which is economical, operational on and industrially applicable.
• The process does not involve the use of corrosive material.
• The process is simple and easy to handle and does not require special handling care or critical temperature conditions.
• It eliminates the use of HBr which is harmful for health.
The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example 1
Preparation of polymorphic form A of Entacapone
Crude Entacapone (2.0 g) was dissolved in ethanol (40 ml) at 50-55°C and activated charcoal was added to it. After stirring for 30 min, the reaction mixture was filtered through hyflow supercell bed. The filtrate was allowed to cool to 25-30°C and stirred for lhr. The material was filtered and washed with ethanol.
10

Finally, the material was dried at 40-45 °C under vacuum to get form A of
Entacapone (1.5 g).
Yield: 75%
HPLC purity: 99.33%
Content of Z isomer: 0.02%
XRD Analysis confirmed for Form A
Example 2
Preparation of polymorphic form A of Entacapone
Crude Entacapone (5.0 g) was dissolved in acetone (60 ml) at 50-55°C and
activated charcoal was added to it. After stirring for 30 min, the reaction mixture
was filtered through hyflow supercell bed. The filtrate was allowed to cool to 25-
30°C and stirred for 30 min. The material was filtered and washed with acetone.
Finally, the material was dried at 40-45°C under vacuum to get form A of
Entacapone (3.2 g).
Yield: 64%
HPLC purity: 98.75%
Content of Z isomer: 0.16%
XRD Analysis confirmed for Form A
Example 3
Preparation of polymorphic form A of Entacapone
Crude Entacapone (6.0 g) was charged with ethyl acetate (60 ml) and raised the
temperature to 70-78°C and refluxed for 30 min. The reaction mixture was
allowed to Cool to 25-30°C and stirred for 1 hr. The material was filtered and
washed with ethyl acetate (6ml). Finally, the material was dried at 50-55°C under
vacuum to get form A of Entacapone (5.5 g)
Yield: 91%
XRD Analysis confirmed for Form A
11

Example 4
Preparation of polymorphic form A of Entacapone
Crude Entacapone (22 g) was dissolved in methanol (220 ml) at 60- 65°C and
activated charcoal was added to it. After stirring for 30 min, the reaction mixture
is filtered through hyflow supercell bed. The filtrate was allowed to cool to 25-
30°C and stirred for 30 min. The material was filtered and washed with methanol.
Finally, the material was dried at 40-45°C under vacuum to get form A of
Entacapone (19.2 g)
Yield: 87%
HPLC purity: 99.89%
Content of Z isomer: 0.02%
XRD Analysis confirmed for Form A
Example 5
Preparation of polymorphic form A of Entacapone
Crude Entacapone (22 g) was dissolved in methanol (220 ml) at 60- 65°C and
activated charcoal was added to it. After stirring for 30 min, the reaction mixture
was filtered through hyflow supercell bed. The filtrate was allowed to cool to 25-
30°C and stirred for 30 min. The material was filtered and washed with methanol.
Finally, the material was dried at 40-45 °C under vacuum to get form A of
Entacapone (19 g)
Yield: 86%
HPLC purity: 99.89%
Content of Z isomer: 0.02%
XRD Analysis confirmed for Form A
12

We Claim
1. Highly pure polymorphic form A of Entacapone.
2. A process for the preparation of highly pure polymorphic form A of Entacapone comprising steps of,

a) dissolving crude Entacapone in solvent selected from methanol, ethanol, propanol, butanol, t-butanol, toluene, chloroform, methylene dichloride, ethylacetate, butyl acetate, methylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or mixture, optionally at 50°C-75°C
b) treating the solution of step (a) with charcoal
c) stirring the reaction mixture of step (b) at 25°C to 80°C
d) filtering the reaction mixture of step (c) through hyflo bed
e) cooling the reaction mixture of step (d) at 0°C to 40°C
f) filtering the material of step (e), wherein material is washed the same solvent
g) drying the material of step (f)

3. Polymorphic form A of Entacapone having purity of at least 99.5%.
4. A process for the preparation of highly pure polymorphic form A of Entacapone having purity of at least 99.5% comprising steps of,

a) dissolving crude Entacapone in solvent selected from methanol, ethanol, propanol, butanol, t-butanol, toluene, chloroform, methylene dichloride, ethylacetate, butyl acetate, methylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or mixture, optionally at 50°C-75°C
b) treating the solution of step (a) with charcoal
c) stirring the reaction mixture of step (b) at 25°C to 80°C
d) filtering the reaction mixture of step (c) through hyflo bed
13

e) cooling the reaction mixture of step (d) at 0°C to 40°C
f) filtering the material of step (e), wherein material is washed the same solvent
g) drying the material of step (f)

5. Polymorphic form A of Entacapone with no individual impurity including Z-isomer of Entacapone less than 0.02%.
6. A process for the preparation of highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer of Entacapone less than 0.02% comprising steps of,

a) dissolving crude Entacapone in solvent selected from methanol, ethanol, propanol, butanol, t-butanol, toluene, chloroform, methylene dichloride, ethylacetate, butyl acetate, methylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or mixture, optionally at 50°C-75°C
b) treating the solution of step (a) with charcoal
c) stirring the reaction mixture of step (b) at 25°C to 80°C
d) filtering the reaction mixture of step (c) through hyflo bed
e) cooling the reaction mixture of step (d) at 0°C to 40°C
f) filtering the material of step (e), wherein material is washed the same solvent
g) drying the material of step (f)


Dated this 11th day of October 2006

14

Abstract
The present invention relates to provide an improved process for the preparation of highly pure polymorphic form A of Entacapone with no individual impurity including Z-isomer of Entacapone less than 0.1%.
15