FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
A PROCESS FOR THE PREPARATION OF 2-CYANO-3- (3,4-DIHYDROXY-5-NITROPHENYL)-N, N-DIETHYL-2-PROPENAMIDE)
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

The invention relates to a process for the preparation of 2-Cyano-3- (3,4-dihydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide), compound of Formula 1, or its pharmaceutically acceptable salts.

N02 '
Formula I
The E-isomer of compound of formula I is called Entacapone (INN name) which is useful in the treatment of Parkinson's disease.
BACKGROUND OF THE INVENTION
United States patent No. 4,963,590 (Indian reference not available, referred to herein as '590) disclosed a process for the preparation of N, N-Diethyl-2-cyano-3- (3,4-dihydroxy-5-nitrophenyl) acrylamide compound of Formula I by condensation of 3,4-Dihydroxy-5-nitrobenzaldehyde (Formula II) with N,N-Diethylcyanoacetamide (Formula III) overnight. Example 100 prepares compound of formula I with the aid of catalytic amount of piperidine acetate by refluxing in dry ethanol overnight. However, when we carried out the process by using catalytic amount of piperidine acetate i.e. less than 1 molar equivalent, huge amount of starting material remains unreacted. Added to this is the fact that the reaction has to be carried out under anhydrous conditions for longer periods. This makes the process commercially unviable.
The yield of compound of formula I, mixture of two geometric isomeric forms, i.e., (E)-and (Z), synthesized by adopting the patented process was about 73 % yield with no disclosure on the separation techniques to obtain the substantially pure (E) isomer.
2

United States patent No. 5,135,950 (Indian reference not available, referred to herein as '950) discloses the (E)-and (Z)-isomers having the structural formulae as follows:

(E)-isomer

(Z)-isomer

As revealed by X-Ray crystallography (E)-N, N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro-phenyl) acrylamide may exist at least in two polymorphic forms A and B. The (Z)-isomer and polymorphic Form B of the (E)-isomer have been shown to be unstable 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. Crude entacapone thus synthesized from conventional solvent such as hydrocarbons viz. benzene or toluene, is a mixture of different geometric isomers and/or polymorphic forms which interfere with the characterization and standardization of the drug substance.
However, in the above mentioned patents / patent application the reaction is carried out for 10-20 hours making the process commercially unviable and the product obtained is not in pure isomeric form. When we carried out the patented process we obtained a mixture of (E) to (Z) isomer in the ratio of about 70-80 % to about 30-20 %, respectively.
OBJECT OF THE INVENTION
The present invention relates to the process of preparation of compound of formula I, which is suitable for use on an industrial scale.
Particularly, the present invention relates to process of preparation of compound of formula I, within 2 to 5 hours by reacting compound of formula II with formula III.
3

More particularly, the present invention relates to process of preparation of entacapone i.e. the E-isomer of compound of formula I within 2 to 5 hours by reacting compound of formula II with III.
SUMMARY OF THE INVENTION
According to the present invention the process for the preparation of compound of formula I comprises reacting compound 3,4-Dihydroxy-5-nitrolenzaldehyde (Formula II) with N, N-Diethylcyanoacetamide (Formula III) in presence of base and catalyst, compound of formula IV, in shorter reaction time.

wherein R1, R2; R3, R4 are independently selected from hydrogen, substituted or unsubstituted C1-C12 linear or branched or cyclic alkyl, aryl and aralkyl groups; and X is hydroxy!, to obtain compound of formula I in about 2 to 5 hours.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to process for the preparation of compound of Formula I, in shorter reaction time, by reacting compound of formula II with formula III.
4

Particularly, the present invention provides process for the preparation of E-isomer of compound of formula I, in shorter reaction time substantially free from Z-isomer.
More particularly, process for the preparation of E-isomer of compound of formula I, which has HPLC purity equal to or greater than 99.5% by area.
According to the present invention the process comprises reacting compound of Formula II with compound of Formula III

wherein the reaction can be completed in less time with higher purity of entacapone i.e. E-isomer of compound of formula I, by carrying out the reaction in the presence of base and catalyst, compound of Formula IV

wherein R1, R2, R3, R4 are independently selected from hydrogen, C1-C12 linear or branched or cyclic alkyl, aryl and aralkyl groups; and X is hydroxyl; to obtain compound of formula I in about 2 to 5 hours.
5

The compound of formula IV may be selected from monoalkyl. dialkyl. trialkyl tertraalkyl or
aralkyl ammonium hydroxide such as tetramethylammonium hydroxide, tetraethylammonim
hydroxide, tetrapropylammonium hydroxide, trimethylethylammonium hydroxide.
Trimethylethylammonium hydroxide, dimethylethylammonium hydroxide,
methylethylammonium hydroxide, phenyltrimethylammonium hydroxide,
phenyltriethylammonium hydroxide, benzyltrimethylammonium hydroxide and the like.
The preferred compound of formula IV is benzyltrimethylammonium hydroxide.
The process of the present invention is carried out in presence of suitable base selected from organic or inorganic base selected from amine, Piperidine, N-methylmorpholine, morpholine, pyridine or piperazine more preferable piperidine.
A process as describe above, wherein the reaction time is about 2 to 5 hours, preferably about 3 hours.
The compound of Formula I of the present invention is characterized by an endotherm of about 159 °C in diffraction scanning calorimetric analysis (DSC). (Temperature range: 35-140 °C. heating rate: 10°C/min & 140-175 °C, heating rate: 1.0 °C/min)
The E-isomer of compound of Formula I prepared by the process of the present invention has HPLC purity equal to or greater than 99.5% by area.
The E-isomer of compound of Formula I prepared by the process of the present invention has less than about 0.1% by area of the Z-isomer by HPLC.
The invention is illustrated but not restricted by the description in the following examples.
6

EXAMPLES
Example 1
50 ml of methanol was added to 25 gms of 3,4-dihydroxy-5-nitrobenzaldehyde at 20-25o C and 13.5 ml of piperidine, 6.1 ml of benzyltrimethyl ammonium hydroxide solution in methanol (40%) and 22.95 gm of 2-cyano-N,N-diethylacetamide was added to reaction mixture in a reactor and heated to reflux (65-75 C). The reaction mixture was maintained at reflux for 3.0 hrs, cooled to 10-15 o C, pH adjusted to 5 using acetic acid and 140 ml of D.M. water was added, stirred. The material was filtered at 0-5°C and washed with D.M. water and methanol mixture.
The above crude product was dissolved in 250 ml methanol at 60-70°C, activated charcoal
added and the solvent distilled under vacuum at below 65 C till 75 ml of the reaction material
remained behind in the flask. The material was gradually cooled to 0-5°C, filtered and the
solids dried in air oven at 50-60°C, till the LOD is less than 0.5%.
Weight of E-isomer of compound of formula I: 20.8 gm.
HPLC purity: E-isomer of compound of formula 1 is 99.8% with Z-isomer content as 0.07%
Example 2
50 liters of methanol was added to 20.0 kg of 3,4-dihydroxy-5-nitrobenzaldehyde at 20-25°C and 9.3 kg of piperidine was added and stirred for 30 minutes. 4.6 kg of benzyltrimethyl ammonium hydroxide solution in methanol (40%) and 18.4 kg of 2-cyano-N,N-diethylacetamide was added to reaction mixture in a reactor and heated to reflux (65-75 C). The reaction mixture was maintained at reflux for 3.0 hrs. The reaction was monitored by HPLC and methanol was distilled and degassed with vacuum. 50.0 liters of acetic acid was added and the reaction material heated to 75-80°C to get a clear solution and 45 liters D.M. water was added, stirred and filtered the material at 0-5 C and washed with D.M. water.
7

The above crude product was dissolved in 250 liters methanol at 60-70 C, activated charcoal
added and solvent distilled under vacuum at below 65°C till 75 liters of the reaction material
remained behind in the reactor. The material was gradually cooled to 0-5°C, filtered and the
solids dried in air oven at 50-60°C, till the LOD is less than 0.5%.
Weight of E-isomer of compound of formula I is 20.3 kg.
HPLC purity of E-isomer of compound of formula I is 99.6% with Z-isomer content as 0.04%
Example 3
Details of HPLC analysis
Column : Inertsil ODS-3V, 250 x 4.6mm, 5|i
Wavelength : 275 nm.
Flow rate : 1.5ml/min
Buffer : ammonium dihydrogen orthophosphat, pH = 3.0 ± 0.1
Mobile phase : buffer and acetonitrile 650 : 350
Retention Time : (E)-isomer : 13.48, (Z)-isomer : 11.77
The solubility characteristic of compound of formula I are:
Solvent Solubility
Acetone 10 to 30 vol
Methanol 10 to 30 vol
Ethyl acetate 30 to 100 vol
Methylene dichloride 30 to 100 vol
Isopropyl alcohol 100 to 1000 vol or > = 100 vol
8

COMPARATIVE EXAMPLES : (As per process of Example 100 of product patent United States patent No. 4,963,590)
Example A :
0.31 ml of acetic acid is added to 0.55 ml piperidine and to the formed piperidine acetate 220
ml of absolute alcohol is added. 10.0 gm of 3,4-dihydroxy-5-nitrobenzaldelhyde and 8.18 gm
of 2-cyano-N-, N-diethylacetamide is added to the ethanol solution, heated and maintained
reflux for 14.0 hrs. Solvent distilled and degassed with vacuum at 65° C to obtain brown
coloured degassed mass. 20 ml aceticacid is added and the reaction mass heated to 75-80X to
get a clear solution followed by addition of 30 ml DM water, stirred and filtered the material at
0-5°C, washed with DM water and dried.(wt 3.8 gm)
HPLC purity: entacapone: 0.44%, 3,4-dihydroxy-5-nitrobenzaldehyde : 99.28%
Example B :
1.56 ml of acetic acid is added to 2.74 ml piperidine and to the formed piperidine acetate 220
ml of absolute alcohol is added. 10.0 gm of 3,4-dihydroxy-5-nitrobenzaldelhyde and 8.18 gm
of 2-cyano-n-, n-diethylacetamide is added to the ethanol solution, heated and maintained the
reflux for 14.0 hrs. Solvent distilled and degassed with vacuum at 65°C to obtain brown
coloured degassed mass. 20 ml aceticacid is added and heated the reaction mass to 75-80°C to
get a clear solution and 30 ml DM water is added, stirred and filtered the material at 0-5°C and
washed with DM water and dried the product.(wt 3.4 gm)
HPLC purity : entacapone: 97.78%, 3,4-dihydroxy-5-nitrobenzaldehyde : 1.86%
Example C :
3.2 ml of acetic acid is added to 5.47 ml piperidine and to the formed piperidine acetate 220
ml of absolute alcohol is added. 10.0 gm of 3,4-dihydroxy-5-nitrobenzaldelhyde and 8.18 gm
of 2-cyano-n-, n-diethylacetamide is added to the ethanol solution, heated and maintained the
reflux for 14.0 hrs. Solvent distilled and degassed with vacuum at 65°C to obtain brown
coloured degassed mass. 20 ml aceticacid is added and heated the reaction mass to 75-80°C to
get a clear solution and 30 ml DM water is added, stirred and filtered the material at 0-5°C and
washed with DM water and dried the product.(wt 8.2 gm)
HPLC purity : entacapone: 99.38%, 3,4-dihydroxy-5-nitrobenzaldehyde : 0.22%
9

WE CLAIM

1. A process for the preparation of compound of Formula I,

Formula I
comprising reacting compound of Formula II with compound of Formula III in

Formula II Formula III
presence of base and catalyst, compound of Formula IV

Formula IV.
wherein R1; R2, R3, R4 are independently selected from hydrogen, C1-C12 linear or branched or cyclic alkyl, aryl and aralkyl groups; and X is hydroxy!, to obtain compound of formula I in about 2 to 5 hours.
2. A process as claimed in claim 1 wherein compound of formula I is obtained as an E-isomer in substantially pure form.
3. A process as claimed in claim 1 wherein compound of formula I is obtained as an E-isomer in greater than 99.5% area by HPLC.
4. A process as claimed in claim 3 wherein compound of formula I is obtained as an E-isomer with Z-isomer less than about 0.1% area by HPLC.
5. A process as claimed in claim 1 wherein compound of formula IV is selected from .
10

6. A process as claimed in claim 5 wherein compound of formula IV benzyltrimethylammonium hydroxide.
Dated this 27th day of April 2007

11

ABSTRACT

A process for the preparation of compound of Formula I,

Formula I
comprising reacting compound of Formula II with compound of Formula III in

Formula II Formula III
presence of base and catalyst, compound of Formula IV

Formula IV.
wherein R1; R2; R3, R4 are independently selected from hydrogen, C1-C12 linear or branched cyclic alkyl, aryl and aralkyl groups; and X is hydroxyl; to obtain compound of formula I about 2 to 5 hours.
To
The Controller of Patents, The Patent Office, Mumbai-400037

12