FORM 2
THE PATENTS ACT: 1970 (39 OF 1970)
& PATENTS RULES. 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)


"AN IMPROVED PROCESS FOR THE PREPARATION OF ENTACAPONE"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED


"AN IMPROVED PROCESS FOR THE PREPARATION OF ENTACAPONE
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Entacapone.
BACKGROUND OF THE INVENTION
Entacapone. an inhibitor of catechol-O-methyltransferase (COMT), is a nitro-catechol-structured compound with a molecular weight of 305.3. Entacapone is a potent and specific peripheral catechol-O-methytransferase (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.
The chemical name of entacapone is (E)-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C14H15N305, and its structural formula is:

U.S. Patent No. 4,963.590 discloses a pharmaceutical composition comprising entacapone and pharmaceutically acceptable carrier.
US Patent 5,446.194 describes a process for the preparation of Entacapone. The synthetic process disclosed in this patent comprises Knovenagel condensation of 3. 4-dihydroxy-5- nitrobenzaldehyde and N, N-diethylcyanoacetamide in the presence of
2

catalytic amount of Piperidine acetate in anhydrous ethanol as shown below in Scheme-I.
Scheme-I

Entacapone thus synthesized was obtained in 73 % yield having a mixture of two geometrical isomeric forms, i.e.. (E) and (Z).
US Patent 5,135,950 teaches that (E)-N, N-Diethyl-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl) acryl amide (I) 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 has 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 room temperature. The polymorphism and geometrical isomerism may also influence the bioavailability of the drug. Subsequently preparation of E-isomer is described.
Internationa] publication number WO 2005/063693 claims the improved process for the preparation of Entacapone by condensation of 3-alkoxy-4-hydroxy-5-nitro benzaldehyde with N, N-diethylaminocyanoacetamide in presence of mild acid catalyst followed by de-alkylation as depicted in Scheme-II.
3

Scheme-II

Another application WO/2005 070881 claims an efficient procedure for the preparation of (E) Entacapone stable polymorphic Form A by simple extraction of E-isomer from the mixture of E and Z isomer from aqueous acidic media at pH 3.5 to 4.0.
WO/2008 023380A1 claims a process for the preparation of Entacapone by condensation of 3,4-dihydroxy -5-nitro benzaldehyde with N'N- diethyl cyanoacetamide in presence of catalyst in an organic solvent selected from toluene and Xylene and azeotropic distillation; and isolating entacapone from acidic alcoholic solution of pH around 0.5 to 2 with Z-isomer NMT 0.2%.
All the above mentioned patents are incorporated by reference. The prior art processes described above discloses process for the preparation of Entacapone, which have been prepared by the various processes.
Despite various processes disclosed in the prior art for the preparation of Entacapone, still there is a need for producing Entacapone in high purity and yield. The present invention provides a process for the preparation of Entacapone in high yields and purity by using Ion exchange resin as catalyst. This process is also suitable for large-scale manufacturing, which helps to overcome some of the deficiencies of the prior art.
4

The process disclosed in prior art for the preparation of Entacapone, are tedious, time consuming and operationally difficult at industrial scale. The prior art procedures involved acidic and basic catalysts i.e., piperidineacetate, p-toluene sulphonic acids resulting in the formation of gummy products. The tendency of the sticky reaction mass to stick to the sides of the reactor during the course of the reaction posed serious hindrance in achieving uniform stirrability of the reaction mass thereby affecting the homogeneity of the reaction mixture. These processes involved messy workup and difficult cleaning procedures.
Entacapone obtained by prior art process, involves the formation of (Z)-isomer, which causes low yield and affects the purity of the final product. Surprisingly, present invention carried out the condensation of 3-alkoxy-4-hydroxy-5-nitro benzaldehyde or 3, 4-dihydroxy-5-nitro benzaldehyde of Formula (Ha) and (lib) with N, N-diethylcyanoacetamide in the presence of Ion Exchange resin as catalyst in organic solvent to obtain Entacapone of high yield and good isomeric purity, The process of the present invention is also an economical and industrially advantageous manufacturing method of Entacapone which is substantially free of the (Z)-isomer.
SUMMARY OF THE INVENTION
According to first aspect of the present invention, there is provided an improved process for the preparation of Entacapone of Formula (I)

Formula (I) (E)-Entacapone
comprising the steps of condensation of 3-alkoxy-4-hydroxy-5-nitro benzaldehyde of formula (Ha)
5


Formua Ma
Wherein. R is Ci- Ce cyclic alkyl, straight or branched Cr Q alkyl
*



with N, N-diethylcyanoacetamide of Formula (III)
comprising the steps of condensation of 3,4-dihydrc)Xy_5-nitro benzaldehyde of formula (lib)
6

with N. N-diethylcyanoacetamide of Formula (III)


in the presence of an ion exchange resin as catalyst in an organic solvent to give Entacapone of formula (I) substantially free from the Z-isomer.
According to another aspect of the present invention is provided a process for preparation of Entacapone of formula 1, wherein the ion exchange resin is selected from the group comprising weakly basic, strongly basic, neutral, weakly acidic and strongly acidic resins such as IRA 67, IRA 96, Amberlist IR 120, Amberlyst A 21, Amberfyst A 26, Amberlyst 200 C, Amberlyst 16, and the like or mixtures thereof.
According to another aspect of the present invention is provided a process for preparation of Entacapone of Formula I, wherein the solvent is selected from the group comprising alcohols, hydrocarbons, esters, ethers and chlorinated solvents, or mixtures thereof.
Yet another aspect of the present invention is provided a pharmaceutical composition comprising Entacapone of formula I.
In still yet another aspect of the present invention is to provide a pharmaceutical composition that comprises the Form A of Entacapone according to the first object of the invention, together with one or more excipients or other auxiliary agents pharmaceutical^ acceptable.
7

The following are the advantages in the process of the present invention:
• It provides a process which is economical, operational on and industrially applicable.
• The process employs Ion exchange resin as catalyst instead of the conventional acidic and basic catalysts of the like of p-toluenesulphonic acid. Piperidine acetate, thus avoiding messy workup procedures.
• The process is an eco-friendly process as it does not generate effluents otherwise formed using conventional bases.
• The resin is re-usable making the process economically viable.
• The mildly basic nature of the resin minimizes major side reactions.
• The process does not require critical temperature conditions thereby making it simple and easy to handle.
• It provides a homogenous reaction mixture with uniform stirrability and gives increased yield of over 90-95% of the crude and 80-85% of the desired E-isomer.
The invention can be summarized as follows:
A. A process for the preparation of Entacapone of Formula (1)

comprising the steps of condensation of 3-alkoxy-4-hydroxy-5-nitro benzaldehyde of formula (Ha)
8


Wherein. R is Cj- C$ cyclic alkyl, straight or branched Ci- Cg alkyl with N, N-diethylcyanoacetamide of Formula (III)

in the presence of an ion exchange resin as catalyst in an organic solvent to give 3-0-alkylated entacapone which is de-alkylated to give Entacapone of formula (I) substantially free from the Z-isomer.
B. A process for the preparation of Entacapone of Formula (I)

comprising the steps of condensation of 3,4-dihydroxy-5-nitro benzaldehyde of formula (lib)
9

with N, N-diethylcyanoacetamide of Formula (III)


in the presence of an ion exchange resin as catalyst in an organic solvent to give Entacapone of formula 0) substantially free from the Z-\$omer,
C. The process according to A and B above, wherein the Ion exchange resin is
selected from the group comprising of weakly basic, strongly basic, weakly acidic,
strongly acidic and neutral resins.
D. The process according to C above, wherein the Ion exchange resin is selected from
the group comprising of IRA 67, IRA 96, Amberlist IR 120, Amberlyst A 21,
Amberlyst A 26, Amberlyst 200 C, Amberlyst 16, and the like or mixtures thereof.
E. The process according to D above, wherein the ion exchange resin is selected from
the group comprising of IRA 67 or IRA 96 and the like.
F. The process according to A and B above, wherein the condensation is carried out in
an organic solvent selected from a group comprising of alcohols, hydrocarbons,
esters, ethers and chlorinated solvents, or mixtures thereof.
G. The process according to F above, wherein the solvent is selected from the group
comprising hydrocarbon such as Toluene, Xylene or mixtures thereof.
H. The process according to G above, wherein the solvent is toluene.
10

I. The process according to A and B above, wherein the Entacapone obtained is E-isomer substantially free from the Z- isomer.
J. The process according to A and B above, wherein the E-isomer of Entacapone has a purity of at least 99%
K. Use of E-isomer of Entacapone of formula (I) according to in A and B above, in
the manufacture of a medicament for treating Parkinson's disease in animals and humans.
BRIEF DESCRIPTION OF DRAWINGS
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in ihe accompanying drawing figures wherein:
[Scheme I] is a schematic representation of an embodiment for condensation of 3, 4-dihydroxy-5- nitrobenzaldehyde and N, N-diethylcyanoacetamide in anhydrous ethanol
[Scheme II] is a schematic representation of a process for the preparation of Entacapone starting from 3-alkoxy-4-hydroxy-5-iiitrobenzaldehyde and its condensation with other intermediate N, N-diethylaminocyanoacetamide in presence of mild acid catalyst followed by de- alkylation
[Scheme III] is a schematic representation of process of the present invention for the preparation of the compound (E)-N, N- Diethyl-2-Cyano-3-(3, 4-Dihydroxy-5-Nitrophenyl) acryl amide in the presence of Ion exchange resin as catalyst in an organic solvent using 3-alkoxy-4-hydroxy-5-nitro benzaldehyde of formula (Ha)
[Scheme IV] is a schematic representation of process of the present invention for the preparation of the compound (E)-N, N- DiethyI-2-Cyano-3-(3, 4-Dihydroxy-5-
11

Nitrophenyl) acryl amide in the presence of Ion exchange resin as catalyst in an organic solvent using 3, 4-dihydroxy-5-nitro benzaldehyde of formula (lib)
DETAILED DESCRIPTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such
12

compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
In accordance with present embodiment, there is provided an improved process for the preparation of the compound Entacapone having the structure of Formula-I as described in Scheme (III) and (IV):
[SCHEME III]

CHO
,17
HO
N02
3,4-d i hy d rox y-5-nitro benzaldehyde

k
CN
~CH<
CH-.
N,N-diethylcyano acetamide

Ion exchange resin

13

The starting material 3-alkoxy-4-hydroxy-5-nitrobenzaldehyde and 3, 4-dihydroxy~5-nitrobenzaldehyde is prepared as per the process described in prior art.
In accordance with present embodiment, there is provided an improved process for the preparation of Entacapone of Formula (I)

Formula (I) (E)-Entacapone
comprising the steps of condensation of 3-alkoxy-4-hydroxy-5-nitro benzaldehyde of formula (Ila)

Wherein. R is Ci- Ce cyclic alkyl, straight or branched d- C$ alkyi with N, N-diethylcyanoacetamide of Formula (III)
O

in the presence of an ion exchange resin as catalyst in an organic solvent to give 3-0-alkylated entacapone which is de-alkylated to give Entacapone of formula (I) substantially free from the Z-isomer.
14

In the process of the present invention. Entacapone was prepared by condensation of 3-alkoxy-4-hydroxy-5-nitro benzaldehyde of Formula (TTa) with N, N-diethylaminocyanoacetamide in the presence of an ion exchange resin as catalyst in an organic solvent to give 3-Oalkylated entacapone which is de-alkylated to give Entacapone of formula (I) substantially free from the Z-isomer. In one embodiment of the present invention the 3-alkoxy-4-hydroxy-5-nitro benzaldehyde compound used was 3-methoxy-4-hydroxy-5-nitro benzaldehyde and in another embodiment it was 3, 4-dihydroxy-5-nitrobenzaldehyde of formula (Hb).
According to a preferred aspect the step of condensation is carried out in presence of Ion-exchange resin as a catalyst.The use of Ion exchange resins as catalyst for the synthesis of Entacapone has been discovered for the first time by the inventors. None of the prior art suggests the use of Ion Exchange Resin as a catalyst in the Knovenagel condensation step of Entacopone synthesis. The Ion exchange resin catalyst used in the present embodiment is selected from a group comprising of weakly basic, strongly basic, weakly acidic, strongly acidic and neutral resins.
The anion exchange resin may be selected from a group comprising of strongly basic and weakly basic resins comprising of Amberlyst A 26, IRA 67, IRA 96, Amberlyst A 21 and the like or mixtures thereof. For the purpose of the process the preferred resin may be selected from a group comprising of IRA 67 and IRA 96 as they gave similar results in terms of yield and purity. For the purpose of the process the more preferred resin is IRA 96 due to its economic advantage. The cation exchange resin is selected from a group comprising of strongly acidic and weakly acidic resins comprising of Amberlyst IR 120, Amberlyst 200C, Amberlyst 16 and the like or mixtures thereof.
In accordance with present embodiment, (here is provided an improved process for the preparation of Entacapone of Formula (I) wherein the solvent is selected from the group comprising alcohols, hydrocarbons, esters, ethers and chlorinated solvents, and the like or mixtures thereof. The solvent used in the present invention is selected from the group consisting of substituted, unsubstituted, cyclic, bicyclic, saturated, or unsaturated, straight or branched hydrocarbon but not limited to aliphatic or aromatic
16

hydrocarbon, having C6-Cio atoms, Suitable solvents are generally alcohols, such as methanol, ethanol, isopropanol, hydrocarbon such as toluene, ester, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethers such as tetrahydrofuran, and dioxane, chlorinated solvents such as methylene chloride, or mixtures of these solvents preferably hydrocarbon or mixtures thereof, even more preferably toluene, xylene, or mixtures thereof.
The reaction is carried out at reflux temperature. The reaction period is between 12 to 16 hours. In the step of isolation in the process of the invention, the resin is removed by simple filtration. The solvent is removed completely by distillation. Preferably, the solvent is distilled under vacuum. The reaction mass is cooled to room temperature and the product is filtered and dried.
In the said step of isolation, the (E)-Entacapone that is isolated is a mixture of E and Z isomer. The (E)-Entacapone is isolated by dissolution of the crude Entacapone in a 1% solution of HBr in Acetic acid at about 100°C, preferably at 90-95°C and maintained at this temperature under stirring for 1 hour. The reaction mixture is then cooled to room temperature and maintained under stirring at this temperature for 20-24 hours. The said (E)-Entacapone isolated is recrystalised from alcohol. The finally recrystallized (E)-Entacapone is substantially free from Z-isomer having the purity of at least 99%.
A process according to the present invention provides Entacapone as polymorph Form A of E-isomer of Entacapone, substantially free of Z-Entacapone and having an improved yield as compared to prior art process techniques.
There is further provided by the present invention, therefore, E-isomer of Entacapone, preferably as polymorph Form A, having an isomeric purity of at least about 99%, more preferably at least about 99.5%, more preferably more than about 99.7% and even more preferably at least about 99.8%. In a particularly preferred embodiment, the present invention provides Entacapone having an isomeric purity of more than about 99.7%.
17

Entacapone prepared by a process substantially as hereinbefore described, or present in a reaction product substantially as hereinbefore described, as provided by the present invention, has therapeutic utility in inhibition of catechol-O-methyltransferase and as such in the treatment of diseases prevented, ameliorated or eliminated by such enzyme inhibition, in particular Parkinson's disease.
The present invention further provides, therefore, a pharmaceutical composition comprising a therapeutically effective dose of Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, together with a pharmaceutically acceptable carrier, diluent or excipient thereof. Excipients are chosen according to the pharmaceutical form and the desired mode of administration.
Pharmaceutical compositions according to the present invention may contain Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, alone or combined with some other medicines. For the treatment of Parkinson's disease Entacapone as provided by the present invention is administered with levodopa, each as separate compositions or combined in one composition.
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.
18

EXAMPLE 3
Preparation of (E)-N, N-diethyI-2-cyano-3-(3, 4-dihydroxy-5-nitro) acryl amide [(E)-Entacapone]
In a Round Bottomed flask equipped with a stirrer, thermo well and a Dean-Stark condenser was charged with 1.83 g of 3, 4-dihydroxy 5-nitrobenzaldehyde. 1.54 g of N.N-diethyl-2-cyano acetamide, 150mg of IRA 120 resin and 15ml of toluene and refluxed at 108-112°C and the formed water removed azeotropically until the disappearance of starting material for 12-16 hours. The resin was removed by filtration and the reaction mass concentrated by distillation of the solvent completely under vacuum. The concentrated mass was treated with a solution of 1 %HBr in acetic acid and maintained under stirring at 90-95°C for 1 hour. The reaction mixture was cooled to room temperature and stirred for 20-24 hours. The reaction mixture was filtered and recrystallised from alcohol to give 2.1g of Pure (E)-Entacapone having 99.8% purity.
EXAMPLE 4
Condensation of 5-nitrovaniIline (3-methoxy-4-hydroxy-5-nitro benzaldehyde) with NN-diethylcyanoacetamide to give Entacapone.
In a Round Bottomed flask equipped with a stirrer, thermo well and a Dean-Stark condenser was charged with lOg of 5-nitrovaniline, toluene 100ml, IRA 96 (1.0 g), N, N-diethyl cyanoacetamide (7.1) and refluxed with azeotropic removal of water till the completion of the reaction. The resin was filtered off and the solvent removed completely. To the flask was added methylene chloride (80ml) and cooled to 5° C. Aluminium chloride (16 g) and pyridine (20mJ) added at the same temperature and stirred under reflux for 2-3 hrs. Reaction mixture was quenched with dil. Hydrochloric acid stirred for 1 hr and filter the solid. It was then recrystallised from alcohol to give 13 g of E isomer having a purity of 99.4%.
20

Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Applicants Patent Agent
Dated this 30lh day of January, 2009
To:
21
The Controller of Patents. Patent Office, Mumbai 400 037