FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR THE PREPARATION OF STABLE POLYMORPHIC
FORM-D OF ENTACAPONE.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of stable polymorphic form-D of Entacapone.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides a process for the preparation of stable polymorphic form-D of entacapone.
Entacapone of formula I is chemically known as (E)-N, N-Diethyl-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide.
HO o
HO-f y- C=C CHSCH3
Formula I
British patent No. 8,727,854 describes entacapone as a potent inhibitor of catechol-O-methyl- transferase (COMT) enzyme. The product is indicated for the treatment of Parkinson's disease.
US Patent 4,963,590 discloses a process for the preparation of entacapone (Formula I) by the condensation of 3,4-Dihydroxy-5- nitrobenzaldehyde and N,N-diethylcyanoacetamide in anhydrous ethanol.
US Patent 5,135,950 discloses crystallographically essentially pure and stable polymorphic form A of entacapone.
The processes of preparation of entacapone and different polymorphic forms are also disclosed in PCT patent application WO 2005063693; WO 2005063695; WO 2005063696; WO 2005066117 and WO 200507088.
The inventors have surprisingly found that polymorphic form-D of entacapone can be directly isolated by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N,N-diethyl acetamide in alcohol solvent in presence of base.
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In the aspect of present invention there is provided a process for the preparation of stable polymorphic form-D of entacapone, wherein the said process comprises of
a) Reacting 3,4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N,N-diethyl acetamide in alcohol solvent in presence of base
b) isolating the stable polymorphic form-D of Entacapone from reaction mass thereof.
The process involves reacting 3, 4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N,N-diethyl acetamide using alcohol solvent in presence of acetic acid and base such as piperidine, pyridine, alkyl amines (such as methyl amine, diethyl amine, triethyl amine and the like) at temperature below 100 °C. After completion of reaction, the reaction mixture was concentrated and residue obtained was treated with mixture of alcohol and acetic acid. The precipitated product was then re-suspended in mixture of water and acetic acid and the polymorph form-D of Entacapone was isolated from the reaction mass thereof.
The non-limiting examples of alcohol include straight chain and branched chain CrC6 alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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EXAMPLE Preparation of stable polymorph form-D of Entacapone
Charged isopropyl alcohol (5 litre) 3, 4-dihydroxy-5-nitrobenzaldehyde (500 gm), 2-cyano-N,N-diethyl acetamide (640 gm), piperidine (620 gm) and acetic acid (400 gm). The reaction mixture was refluxed for 15-24 hours. After completion of the reaction, reaction mixture was concentrated and concentrated mass treated with mixture of isopropyl alcohol (700 ml) and acetic acid (640 ml). The reaction mixture is further stirred for 22-25 hours to get the complete precipitation. Precipitated product was filtered and washed with mixture of water (90%) -acetic acid (10%) and dried to get the titled product. Yield: 449 gm. Purity (by HPLC): 99.31%.
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WE CLAIM:
1. A process for the preparation of stable polymorphic form-D of (E)-Entacapone,
wherein the said process comprises of
a) reacting 3,4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N,N-diethyl
acetamide in alcohol solvent in presence of base
b) isolating the stable polymorphic form-D of (E)-Entacapone from reaction mass
thereof.
2. A process of claim 1 wherein the alcohol was selected from the group of straight chain and branched chain C1-C6 alcohols.
3. A process of claim 1 wherein the base was selected from the group of piperidine, pyridine, alkyl amines.

Dated this 30th day of October, 2006

For Wockhardt Limited

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(Mandar Kodgule) Authorized Signatory