FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone) of Formula
(I).

BACKGROUND OF THE INVENTION
(E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (I) is generically icnown as Entacapone.
Entacapone is a selective and reversible inhibitor of catechol-0-methyl transferase (COMT). COMT is distributed throughout various organs with the highest activities in the liver, kidney, heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells, and neuronal tissues, especially in glial cells. COMT catalyses the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contains a catechol structure. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.
Entacapone is marketed under the Trade name Comtan®. It has been approved for the treatment of Parkinson's disease.

Orion Corporation disclosed generically Entacapone and its pharmaceutically acceptable salts in US 5,446,194 and disclosed specifically Entacapone Form A in US 5,135,950. US 5,446,194 also discloses a process for the preparation of 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (la) by refluxing a solution containing 3,4-dihydroxy-5-nitrobenzaldehyde (II), N,N-diethyl-2-cyanoacetamide (III) and a catalytic amount of piperidine acetate in dry ethanol. The product has a melting point of about 153-156°C.

The major disadvantage with the above process is that 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (la) produced by the above process is the mixture of E and Z isomers (70-80% of E-isomer and 30-20% of Z-isomer). Crystallization of pure E isomer, using conventional solvents such as lower aliphatic

alcohols, esters or hydrocarbons from the complicated mixture of E and Z geometrical isomers is difficult.
US 5,135,950 discloses a process for the preparation of a stable and crystallographically essentially pure polymorphic Form A of (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (I) (Entacapone) having a melting point of 162°C-163°C. The process comprises crystallization of the above described crude mixture of the E and Z isomers of 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (la) from a lower aliphatic carboxylic acid containing a catalytic amount of hydrochloric or hydrobromic acid.


However, the major disadvantage with the above process is that the process involves use of HBr or HCl, which requires specifically designed glass reactor because of the use of corrosive material.
Further, there are many latter patent applications such as US 2006/0258877 Al, WO 2006/064296 A I, US 2007/0004935 Al, US 2007/0060767 A I, WO 2007/094007 Al, US 2008/0319226 Al, US 2008/0300420 A I, WO 2008/007093 Al, US 2008/0146829 Al, US 2009/0012176 Al, WO 2009/084031 A2, which disclosed purification of 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (la) having both geometrical isomers (E) - and (Z) using different methods. However, none of the references discloses the process, which provides exclusively (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide(I) (Entacapone).
Hence, there is a need to develop a process which provides (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (I), which is operationally simple at an industrial scale and provides high purity of final product.
The present invention is specifically directed towards a process, wherein 3,4-dihydroxy-5-nitrobenzaldehyde (II) is condensed with cyanoacetic acid (IV) to produce exclusively (E)-2-cyano-3-(3-dihydroxy-5-nitrophenyl)-2-propenoic acid (V), which is further converted to Entacapone (I) with high purity and yield, without any further purification.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple and effective process for the preparation of Entacapone (I) with high purity and good yields on a commercial scale.

SUMMARY OF THE INVENTION
The present application provides an improved process for tlie preparation of (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone) of Formula I,


(ii) reacting compound (V) or its reactive derivative, with N,N-diethylamine (VI),

wherein reactive derivative is selected from an acid chloride, acid anhydride, mixed acid anhydrides, reactive esters, and reactive amides; in the presence of base in a solvent to produce (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone) of Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone) of Formula (I), by reacting 3,4-dihydroxy-5-nitrobenzaldehyde (II) with cyanoacetic acid (IV) in the presence of a suitable catalyst to produce (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoic acid (Entacapone acid) (V).
The suitable catalyst is selected from inorganic base and organic base or salt thereof. The base is selected from organic base such as piperidine, pyridine, N-methylmorpholine, morpholine, piperazine and the like or mixture thereof The base is selected from inorganic base such as ammonium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, magnesium carbonate, calcium carbonate and the like or mixture thereof; The inorganic and organic salt of base mentioned include but not limited sodium acetate, potassium t-butoxide, cesium t-butoxide, piperidinium acetate, pyridine acetate, piperidiniumpropionate and pyridinium

para toluene sulfonate and or mixture thereof. Preferred catalyst is the piperidinium acetate.
The reaction is carried out in a solvent selected from ethers such as dioxane, tetrahydrofuran, ethylene glycol, dimethyl ether and the like or mixture thereof; aromatic hydrocarbons such as toluene, xylene and the like or mixture thereof; lower alcohols such as methanol, ethanol, isopropanol, glycols and the like or mixture thereof; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide; esters such as methylacetete, ethylacetate, butylacetate, t-butylacetate; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; ketones such as acetone, methyl isobutyl ketone, methylethyl ketone and the like or mixture thereof. Preferred solvent is the ethanol.
The reaction is performed at a temperature ranging from about 15°C to about 100°C based on the solvents used for the reaction. More preferably from about 60°C to about 90°C. A preferred reaction time is from about 3 to about 15 hours, more preferably from about 5 to about 8 hours.
After completion of the reaction, Entacapone acid (V) can be isolated by removing the solvent from the reaction mixture and subsequently adding a sufficient amount of aqueous base in a solvent to the reaction mixture to basify the reaction mass. The aqueous layer containing product is separated and sufficient amount of acid is added to acidify the reaction mass to precipitate the Entacapone acid (V), which is isolated by filtration followed by drying. The preferable base used for basification is selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxides, calcium hydroxide. The preferable acid used for acidification is selected from the group consisting of inorganic acids such as hydrochloric acid, hydriodic acid, hydrobromic acid, phosphoric acid and sulfuric acid, and more preferably the acid is

hydrochloric acid. Preferably, the solvent used in the extraction is selected from methylene chloride, ethyl acetate or toluene.
Reacting Entacapone acid (V) or its reactive derivative with N,N-diethylamine (VI) in the presence of a suitable base in a solvent to produce Entacapone (I).
The suitable base is selected from inorganic or organic bases. The organic base is a cyclic and acyclic amines selected from piperidine, pyrrolidine, diisopropyl amine, 4-(dimethylamino)pyridine, diethyl amine, di-n-butyl amine, di-tert-butyl amine, diisobutyl amine. The inorganic base is selected from sodium or potassium hydroxide or an alkali hydrogen carbonate or alkali carbonate such as potassium or sodium hydrogen carbonate.
The reaction is carried out in a solvent selected from ethers such as dioxane, tetrahydrofuran, ethylene glycol, dimethyl ether and the like or mixture thereof; aromatic hydrocarbons such as toluene, xylene and the like or mixture thereof; lower alcohols such as methanol, ethanol, isopropanol, glycols and the like or mixture thereof; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide; esters such as methylacetete, ethylacetate, butylacetate, t-butylacetate; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; ketones such as acetone, methyl isobutyl ketone, methylethyl ketone and the like or mixture thereof. Preferred solvent is the methylene dichloride.
The reaction may be performed at a temperature ranging from about -10°C to about 30°C based on the solvents used for the reaction. A preferred reaction time is from about 1 to about 10 hours, more preferably from about 3 to about 5 hours. Entacapone (I) can be isolated from the reaction removing the solvent form the reaction mixture, followed by addition of another solvent and water. The organic layer is separated and removed.

Crude Entacapone produced by the above is process is furtiier purified by recrystallization with solvents selected from ethyl acetate, acetone, alcohol, ester or hydrocarbon or mixture thereof and product is dried to obtain pure Entacapone (I).
When the reaction is carried out with the reactive derivative of Entacapone acid (V), the
reactive derivative is selected from an acid chloride, acid anhydride, mixed acid
anhydrides, reactive esters, and reactive amides. The activation is carried with thionyl
chloride, PCI5, oxalyl chloride, ethyl chloroformate, methyl chloroformate or pivaloyl
chloride in presence or absence of organic solvent in presence of an organic base
selected from pyridine, triethylamine, diethylamine, tributylamine, N-alkylanilines, 1,8-
diazabicyclo[5.4.2]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, N-
methylmorpholine, l,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine or mixtures thereof
It has been observed that Entacapone (I) produced by the above described process having (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide less than l%byHPLC.
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLES: EXAMPLE 1
Stage 1:
Preparation of (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoic acid
(Entacapone acid) (V).
3,4-Dihydroxy-5-nitrobenzaldehyde (II) (lOOg, 547mmol), cyanoacetic acid (IV)
(69.67g, 820mmol), piperidine (86. Ig, 1013 mmol) and acetic acid (42g, VOOmmol)
were added in ethanol (900 ml) at 25-30''C. The contents were heated to reflux at 78-

80°C and reflux was continued for 8hrs. Ethanol was removed completely under reduced pressure. The resulting reduced mass was diluted with ethyl acetate (100 ml) and water (100ml) at 25-30°C. The solution was basified with 10% w/v aqueous sodium hydroxide solution (~200ml). The aqueous layer was separated and thereafter the aqueous layer was acidified with concentrated HCl (~50ml). The Entacapone acid was precipitated in aqueous layer and the slurry was stirred for 1 hrs at 5-10°C. The product was filtered and dried to get 66.4g of (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoic acid (Entacapone acid) (V).
Chromatographic purity: 99.47% (by HPLC, by area normalization)
Stage-2:
Preparation of (E)-2-cyano-3-(3,4-diliydroxy-5-nitrophenyl)-2-propenoyl chloride
(Entacapone acid chloride) .
(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoic acid (V) (5g, 20 mmol) was added in thionyl chloride (25ml) at 25-30°C and refluxed for 4hrs at 77-80°C. The reaction mass was concentrated by distillation under reduced pressure to get 5.17g of (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoyl chloride.
Stage-3:
Preparation of Entacapone (I)
(E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoyl chloride (Va) (5g, 18.62 mmol) was diluted with (50 ml) methylene dichloride at 25-30°C under nitrogen and the solution was added to a mixture of diethylamine (VI) (2.92g, 40 mmol) in methylene dichloride (50ml) at -5 to O^C in 20min. The reaction mass was stirred for 2 hrs at -5 to O^C. Dichloromethane was removed completely under reduced pressure and diluted with ethyl acetate (50ml) and water (50ml). The solution was stirred for 30min at 5 to lO^C. The organic layer was separated. The organic layer was concentrated under reduced pressure. Ethyl acetate (15ml) was added to the residue. The slurry was stirred for Ihrs

at 5-10°C. The product was filtered and dried to yield 2.50 g of (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide(Entacapone)(I).
Chromatographic purity: 97.03% (by HPLC, by area normalization)

WE CLAIM
1. A process for the preparation of (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone) of Formula I,

in the presence of catalyst in a solvent to produce (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoic acid (Entacapone acid) (V) containing (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoic acid less than 1%,


wherein reactive derivative is selected from an acid chloride, acid anhydride, mixed acid anhydrides, reactive esters, and reactive amides; in the presence of base in a solvent to produce (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone) of Formula (I).
2. The process according to claim 1, wherein the catalyst is selected from inorganic
base and organic base or salt thereof.
3. The process according to claim 1, wherein the catalyst is organic base selected
from piperidine, pyridine, N-methylmorpholine, morpholine, piperazine and
mixture thereof, or inorganic base selected from ammonium hydroxide, sodium
hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide,
calcium hydroxide, sodium carbonate, potassium carbonate, barium carbonate,
magnesium carbonate, calcium carbonate and mixture thereof
4. The process according to claim 1, wherein the catalyst is selected from sodium
acetate, potassium t-butoxide, cesium t-butoxide, piperidinium acetate, pyridine

acetate, piperidiniumpropionate and pyridinium para toluene sulfonate and or mixture thereof.
5. The process according to claim 1, wherein the solvent is selected from ethers such as dioxane, tetrahydrofuran, ethylene glycol, dimethyl ether or mixture thereof; aromatic hydrocarbons such as toluene, xylene or mixture thereof; lower alcohols such as methanol, ethanol, isopropanol, glycols or mixture thereof; solvent is selected from polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide; solvent is selected from esters such as methylacetete, ethylacetate, butylacetate, t-butylacetate or mixtures there of; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; ketones such as acetone, methyl isobutyl ketone, methylethyl ketone or mixture thereof.
6. The process according to claim I, wherein activation is carried using thionyl chloride, PCI5, oxalyl chloride, ethyl chloroformate, methyl chloroformate or pivaloyl chloride.
7. The process according to claim 1, wherein the activation is carried in an organic
solvent.
8. The process according to claim 1, wherein the activation is carried in presence of an organic base selected from pyridine, triethylamine, diethylamine, tributylamine, N-alkylanilines, l,8-diazabicyclo[5.4.2]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine and mixtures thereof.
9. The process according to claim 1, wherein base used in step (ii) is selected from inorganic base such as ammonium hydroxide, sodium hydroxide, potassium

hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, magnesium carbonate, calcium carbonate and mixtures thereof, or organic base such as pyridine, piperidine, pyridine, N-methylmorpholine, morpholine, piperazine and mixtures thereof.
10. The process according to claim 1, wherein solvent used in step (ii) is selected from ethers such as dioxane, tetrahydrofuran, ethylene glycol, dimethyl ether or mixture thereof; aromatic hydrocarbons such as toluene, xylene or mixture thereof; lower alcohols such as methanol, ethanol, isopropanol, glycols or mixture thereof; solvent is selected from polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide; solvent is selected from esters such as methylacetete, ethylacetate, butylacetate, t-butylacetate or mixtures there of; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; ketones such as acetone, methyl isobutyl ketone, methylethyl ketone or mixtures thereof.