EP1701937A1

EP1701937A1 - Stable polymorphs of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide

Info

Publication number: EP1701937A1
Application number: EP03768046A
Authority: EP
Inventors: Siddiqui Mohammed Wockhardt Ltd JAWEED MUKARRAM; Rashid Abdul Rehman Wockhardt Ltd. KHAN; Ram Prasad Wockhardt Ltd. YADAV; Zakir Gafoor Wockhardt Ltd. SHAIKH
Original assignee: Wockhardt Ltd
Current assignee: JAWEED MUKARRAM, SIDDIQUI MOHAMMED; Khan Rashid Abdul Rehman; Shaikh Zakir Gafoor; YAVAD, RAM PRASAD; Wockhardt Ltd
Priority date: 2003-12-29
Filing date: 2003-12-29
Publication date: 2006-09-20
Also published as: WO2005066117A1; EP1701937A4; CA2551791A1; AU2003292465A1; BR0318690A

Abstract

The present invention relates to stable crystalline polymorphic forms C and D of (E)-N,N-diethyl-2-cyan-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (Entacapone) and their preparation processes. (E)-Entacapone Form C is obtained by condensing 3,4-Dihydroxy-5-nitrobenzaldehyde and N,N-Diethylcyanoacetamide in presence of a base followed by addition of acetic acid after the reaction is over and crystallization step. (E)-Entacapone Form D is prepared from Entacapone Form C, Crystallographically pure (E)-Entacapone Form A or Crystallographically essentially pure From A. Polymorphic forms C and D of (E)-Entacapone are characterized by specific Infra Red (IR) and X-ray powder diffraction peak values.

Description

STABLE POLYMORPHS OF (EVN.N-DIETHYL-2-CYANO-3- .4- DIHYDROXY-5-NITROPHENYL^ACRYL AMIDE

FIELD OF THE INVENTION

The present invention relates to stable crystalline polymorphic forms C and D of (E)- N,N- iethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (Entacapone) and their efficient preparation processes. Polymorphic Form C of Entacapone (E)-isomer is obtained by simple work-up procedure while Form D by converting Form A or Form C of Entacapone. Polymorphic form C and D of (E)-Entacapone are characterized by specific Jjnfra Red (IR) and X-ray powder diffraction peak values. (E)- isomer of Entacapone is an excellent inhibitor of Catechol-O-methyl transferase (COMT) enzyme.

BACKGROUND OF THE INVENTION

The chemical name of Entacapone is N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophe- nyl)acrylamide. British patent application 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. Catechol-O-methyltransferase (COMT) catalyzes the methyl group from s-adenosyl-L-methionine to a number of compounds with catechol structures. This enzyme is important in the extraneuronal inactivation of catecholamines and drugs with catechol structures. COMT is one of the most important enzyme involved in the metabolism of catecholamines. It is find in the most tissues, both in periphery and the central nervous system. The highest activities are found in the liver, intestine and kidney.

US Patent No. 4,963,590 describes a process for the preparation of crude N,N-Diethyl-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (Formula I). The synthetic process disclosed in the US patent "590" comprises the condensation of 3,4-Dihydroxy-5- nitrobenzaldehyde (Formula LI) and N,N-Diethylcyanoacetamide (Formula III) in anhydrous ethanol as shown below: Formula IV Formula II Piperidine Anhyd. Ethanol (E)- & (Z)- Isomers of Entacapone

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). About the separation of (E)- and (Z)- isomers no techniques is discussed so for in US Patent No. 4,963,590. On the other hand US Patent No. 5,131,950 discloses about the (E)- and (Z)- isomers having the structural formula:

(E)-isomer (Z)-isomer m.p.162-163°C m.p. 148-151 °C

are^* obtained as mixture in the ratio of about 70-80 % to about 30-20 %, respectively. As revealed by X-Ray crystallography (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro- phenyrjacrylamide may exist at least in two polymorphic forms A and B. The (Z)-isomer as well as 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, e.g., benzene, toluene etc. a 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 bioavailability of the drug may be also influenced by polymorphism and geometrical isomensm. 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 may be obtained in good yield, when the crude product of Entacapone is re-crystallized from lower aliphatic carboxylic acids such as formic acid or acetic acid with a catalytic amount of hydrochloric hydrobromic acid as shown below:

(E)- and (Z)-isomers of Entacapone (E)-isomer of Entacapone

The said method allows large scale production of homogeneous and crystallographically essentially pure polymorphic form A of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)acrylamide. In this context "Crystallographically essentially pure" means the polymorphic form A of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide containing a maximum of 3 % and preferably a maximum of 2 % of the Z-isomer.

Entacapone is widely used as an excellent potent inhibitor of Catechol-O-methyl transferase enzyme. The present invention discloses manufacturing processes of new polymorphic Forms C and D of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)- acrylamide. Form C may be obtained in high purity without isolating crude solid of isomeric mixture of N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nirrophenyl)acrylamide, directly by simple crystallization technique.

SUMMARY OF THE INVENTION The present invention is directed to an anti-Catechol-O-methyl-transferase compound having therapeutic value and processes for their manufacture. In a first embodiment, the invention is directed to the new crystallographically pure polymoφhic Form C and D of (E)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (Entacapone) having Formula I,

In a second embodiment, the invention is directed to a process for the manufacture of (E)-Entacapone Form C, comprising reacting 3,4-dihydroxy-5-nitrobenzaldehyde withN,N- Diethylcyanoacetamide in presence of a base in alcohol followed by treatment with acetic acid and crystallization with a mixture of alcohols.

In a third embodiment, the invention is directed to the preparation process of (E)- Entacapone Form D. The polymrohic Form D is prepared by converting polymorphic form A or C of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide. The purity of these new polymoφhic forms C and D has been assessed by HPLC while characterized by Infra Red Spectroscopy and X-Ray powder diffraction (XRD) techniques.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an anti-Catechol-O-methyl transferase compound in different polymoφhic forms having therapeutic value and processes for their manufacture. In particular the present invention is directed to the new polymoφhic Forms C and D of (E)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide and processes for the preparation of such compound in different polymoφhic forms.

The present invention provides a method for the manufacture of new polymoφhic Form C of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide. The product is obtained in highly pure form using absolute alcohol without isolating crude solid. In another embodiment, the present invention provides a number of methods to develop polymoφhic Form D of (E)-Entacapone using different solvent combinations. The processes comprise by dissolving "crystallographically pure Form A" or "crystallographically essentially pure Form A" or "Form C" in lower carboxylic acid or highly polar water miscible organic solvent or mixtures thereof.

In one embodiment a process is provided for the manufacture of (E)-N,N-Diethyl-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide which comprises the condensation of 3,4- Dihydroxy-5-nitrobenzaldehyde (Formula II) with N,N-Diethylcyanoacetamide (Formula III) in presence of a base in alcoholic solution.

The schematic presentation of synthetic process of (E)-Entacapone is shown as follows:

Formula I Formula I Formula IV

(E)- and (Z)- Isomers of Entacapone

(E)- and (Z)-lsomers of Entacapone (E)-lsomer of Entacapone

According to another embodiment the present invention, (E)-N,N-Diethyl-2-cyano-3- (3,4-dihydroxy-5-nitrophenyl)acrylamide and its polymoφhic Forms C and D are prepared according the following synthetic reaction scheme:

(a) Reaction of 3.4-Dihydroxy-5-nitrobenzaldehyde and N.N-Diethylcvanoacetamide to form (EVEntacapone Form C 3,4-Dihydroxy-5-nitrobenzaldehyde (Formula II) is reacted with N,N-Diethylcyano- acetamide (Formula III) in a solvent in presence of a base, to form a mixture of (E)- and (Z)- isomers ofN,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide. Suitable solvent for this synthetic stage include, but are not limited to, aliphatic alcohols, e.g., methanol, ethanol, isopropanol, isobutanol or n-butanol more particularly in isopropanol or ethanol. Suitable bases include, but not limited to, amines, e.g., piperidine, N- methylmoφholine, moφholine, pyridine or piperazine more preferably piperidine. After completion of the reaction aliphatic acid more preferably acetic acid is added to the reaction mixture. After diluting the reaction mixture with alcohol and cooling between about 0 °C to 35 °C affords the required stable and pure polymoφhic Form C of pure (E)-isomer (essentially without Z- isomer contamination) in 99.45 % HPLC purity. In the present invention product is not isolated in its crude form, it is rather crystallized in reaction mixture itself containing ethyl alcohol. The present invention is quite interesting since the US Patent No. 5,135,950 emphasizes that crude mixture cannot afford desired purity product using lower aliphatic alcohols, esters or hydrocarbons, e.g., ethanol, 2-propanol, ethyl acetate or toluene and a very complicated mixture of different geometrical isomers and/or polymoφhic forms are generally obtained. But surprisingly, we get the new polymoφhic form of Entacapone, i.e., Form C with high purity by very simple operation. HPLC purity of the product of invention is more than 99% while (Z)- isomer in less than 0.3 % (Figure 1). The specification of HPLC profile of the present invention is mentioned below:

Column HICHROM HIRPB (250 x 4.6 m, 5 μ) Wavelength 210 nm Flow rate 1.0 ml /minute Temperature Ambient Buffer 1 ml H₃PO₄ in 1000 ml distilled water

Mobile phase Buffer (65) : Acetonitrile (35) Sample preparation 0.5 mg/ml in mobile phase Retention Time (E)-Isomer = 11.5 minutes, (Z)-Isomer = 10.3 minutes

(b) Preparation of Polvmoφhic Form D of (E -N.N-Diethyl-2-cyano-3-(3.4-dihydroxy- 5 -nitrophenyDacrylamide Crystallographically pure Form A of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)acrylamide is dissolved in polar organic solvents. Suitable polar solvents include, aliphatic organic amides more preferably N,N-dimethylformamide or N,N-Dimethyl acetamide. Entacapone solution is added slowly and carefully to vigorously stirred chilled water. The reaction mixture is stirred additionally for about 1 to about 5 hours. Finally, polymoφhic Form D of Entacapone is washed with water and isopropyl ether. The product obtained is dried under vacuum to get crystalline title product in 90 % yield.

In the next embodiment, Crystallographically pure Form C of (E)-N,N-Diethyl-2-cyano- 3-(3,4-dihydroxy-5-nitrophenyl)acrylamide is dissolved in aliphatic alcohol more preferably in ethanol to get the clear solution. The solution is added to vigorously stirred chilled water and stirred additionally for about 1 to about 5 hours. Title product is isolated by filtration, washing with water and isopropyl ether followed by vacuum drying. (E)-Entacapone Form D thus obtained is crystalline in nature in 88 % yield.

In another embodiment, Crystallographically essentially pure Form A of (E)-N,N- Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide is dissolved in sulfoxides preferably in Dimethylsulfoxide. The solution is added to vigorously stirred chilled water and stirred additionally for about 1 to about 5 hours additionally. Title product is isolated by filtration, washing with water and isopropyl ether followed by vacuum drying. (E)- Entacapone Form D thus obtained is crystalline form in about 91 % yield and in more than 99 % HPLC purity.

(c) Characterization of (E)-N. N-Diethyl-2-cyano-3-(3 ,4-dihydroxy-5-nitrophenyl acrylamide Form C and D

Crystalline Form C and D of (E)-N, N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrop- henyl)acrylamide has been characterized by Infra Red (LR) Spectrum, X-Ray powder diffraction (XRD)and melting points and their purity is tested HPLC. For comparison puφoses, certain of these analyses have also been performed for the corresponding polymoφhic form A of Entacapone.

Infra Red Spectrum Figures 2 and 3 show Infra Red absoφtion bands for the polymoφhic forms C and D of (E)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide, respectively. IR Pealcs for Entacapone Form A is referred from US Patent 5,135,590 for comparison purpose. A comparison of IR peak values of polymoφhic forms of (E)-Entacapone is set forth in Table 1. TABLE 1 : Infra Red Peaks (in cm^"1) for the Polymoφhic Forms A, C and D of (E> N,N- Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide

X-Ray Powder Diffraction Figures 4 and 5 show X-ray powder diffraction pattern for the polymoφhic form C and D of (E)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide, respectively. A comparison of the complete diffraction peaks, designated by "2Θ" and expressed in degrees, is set forth in Table 2.

TABLE 2: XRD Peaks for the Polymoφhic Form A, C and D of (E)- N,N-Diethyl-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide

Examples

The following example illustrates the invention, but is not limiting thereof.

EXAMPLE 1

Crystallographically pure (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)- acrylamide Form C 3,4-Dihydroxy-5-nitrobenzaldehyde (10.0 gm), N,N-Diethylcyanoacetamide (15.5 gm) and piperidine (15.0 gm) is charged to isopropanol (200 ml). The reaction mixture is refluxed for 12 to 15 hours till the starting material is disappeared. The solution is slowly cooled to room temperature and acetic acid glacial (15 ml) is added to it thereafter reaction mixture is concentrated followed by dilution with ethyl alcohol (50 ml). The mixture is stirred overnight and filtered. Isolated product thus obtained is dried under vacuum to afford crystallographically pure Form C of crystalline (E)-N, N-Diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitrophenyl)acrylamide with melting point between 156 - 160 °C. The title product is obtained as crystalline solid in 75.5 % yield. HPLC Purity = 99.45% (Z-isomer 0.24%). Mass Spectra = m+1 306.1 (100%).

EXAMPLE 2

Crystallographically pure (E)-N,N-Diethyl-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)- acrylamide Form D Crystallographically pure form A of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)acrylamide ( 5.0 gm) is dissolved in N,N-dimethylformamide (25 ml) to make a clear solution. The solution is added slowly and carefully to vigorously stirred chilled water (200 ml). Stirring is continued for further two hours to get the precipitate. Precipitated product is isolated by filtration followed by washing with water and isopropyl ether. The title product thus obtained is dried under vacuum to obtain in crystalline form. (E)-N,N-Diethyl- 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide Form D is obtained as crystal in 90 % yield having melting point 158 - 162 °C in 90.0 % yield.

EXAMPLE 3

Cjγstallographically pure (E)-N,N-Diethyl-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)~ acrylamide Form D Crystallographically pure form C of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)acrylamide ( 5.0 gm) is dissolved in ethanol (45 ml). Clear solution is added to vigorously stirred chilled water (200 ml) and stirring is continued for further two hours. Precipitated product is isolated by filtration followed by washing with water and isopropyl ether. (E)-Entacapone Form D thus obtained is dried under vacuum. Title product is obtained in crystalline form in 88.0 % yield.

EXAMPLE 4

Crystallographically pure (E)-N,N-Diethyl-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)- acrylamide Form D "Crystallographically essentially pure form A" of (E)-N,N-Diethyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)acrylamide ( 5.0 gm) is dissolved in N,N-dimethyl acetamide (25 ml). Clear solution is added slowly and carefully to vigorously stirred chilled water (200 ml). Stirring is continued for further two hours. Precipitated product is isolated by filtration followed by washing with water and isopropyl ether. The product obtained is dried under vacuum. Title compound is obtained in crystalline form in 91.0 % yield.

EXAMPLE 5

Crystallographically pure (E)-N,N-Diethyl-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)- acrylamide Form D "Crystallographically essentially pure form A" of (E)-N,N-Diethyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)acrylamide (5.0 gm) is dissolved in dimethylsulphoxide (25 ml) to make solution. Clear solution is added to vigorously stirred chilled water (200 ml). Stirring is continued for further two hours and precipitated product is isolated by filtration followed by washing with water and isopropyl ether. The (E)-Entacapone obtained by this method is dried under vacuum. Title compound is obtained in crystalline form in 90 % yield.

Claims

We Claim:

1 A compound of Formula I

(E)-Entacapone Form C and its pharmaceutically acceptable salts.

2 A pharmaceutical composition comprising compound of claim 1.

3 A process for the manufacturing (E)-Entacapone Form C having the Formula I

the said method comprising:

(a) contacting 3,4-Dihydroxy-5-nitrobenzaldehyde with N,N-Diethylcyanoacetamide in a solvent and in presence of a base; and

(b) isolating the (E)-isomer of N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)- acrylamide Form C.

4 The process of claim 3, wherein step (a) is carried out in organic solvent.

5 The process of claim 4, wherein organic solvent selected from the alcohols.

6 The process of claim 5, wherein more preferably selected alcohol is isopropanol.

7 The process of claim 3, wherein step (a) is carried out in the presence of a base.

8 The process of claim 7, wherein base is selected from piperidine, N-methylmoφholine, N-methylmoφholine, pyridine or piperazine.

9 The process of claim 8, wherein more particularly base is piperidine.

10 The process of claim 3, wherein step (a) is conducted at reflux temperature. The process of claim 3, wherein reaction time in step (a) is from about 8 to about 20 hours. The process of claim 11 , wherein more preferably reaction time is between about 10 to about 18 hours. The process of claim 3, wherein aliphatic acid is added to the reaction mixture after the reaction is completed. The process of claim 13, wherein said aliphatic acid is acetic acid. The process of claim 3, wherein reaction mixture in step (b) is slightly concentrated after the addition of acid. The process of claims 13-15, wherein alcohol is added to the reaction mixture. The process of claim 16, wherein said alcohol is ethanol. The process of claim 15-17, wherein crystalline (E)-Entacapone Form C is collected after stirring for about 10 to about 14 hours. A crystalline (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide Form C, as claimed in claim 1 and characterized by an Infra Red Spectrum having the following peaks at about 3043, 2972, 2821, 2721, 2644, 2544, 2451, 2340, 2199, 2124, 2002, 1896, 1767, 1629, 1605, 1539, 1477, 1435, 1385, 1359, 1346, 1317, 1263, 1219, 1153, 1124, 1072, 1016, 947, 866, 833, 802,781, 739,681,637, 608, 561 and 511 cm^"1. A crystalline (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide Form C, as claimed in claim 1 and characterized by an X-Ray powder diffraction (XRD) having the following peaks at about 6.040, 6.360, 8.960, 10.600, 11.620, 12.420, 12.960, 13.220, 15.260, 16.180, 16.960, 17.400, 18.080, 18.600, 19.980, 20.380, 20.900, 21.360, 22.960, 24.500, 25.040, 25.600, 26.820, 28.640, 29.680, 29.880, 30.880, 31.480, 31.740, 32.460, 33.000, 33.820, 34.560, 35.380, 36.600, 37.140, 37.520, 37.960 and 39.260°. The process of claim 2, wherein isolated crystalline (E)-N,N-Diethyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)acrylamide Form C is obtained in more than 99.4 % HPLC purity. The process of claim 2, wherein (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)acrylamide contains (Z)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)acrylamide in less than 0.25 %.

A compound of Formula I

(E)-Entacapone Form D and pharmaceutically acceptable salts.

24 A pharmaceutical composition comprising compound of claim 23.

25 A process for the manufacturing (E)-Entacapone Form D having the Formula I

the said method comprising:

(a) dissolving (i) Crystallographically pure Form A or (ii) Crystallographically pure Form C or (iii) Crystallographically essentially pure Form A, of (E)-isomer of N,N-Diethyl-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide;

(b) pouring the solution into water;

(c) and isolating (E)-isomer of N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)- acrylamide Form D.

26 The process of claim 25, wherein organic solvent selected for step (a)-(i) comprises N,N-Dimethylformamide.

27 The process of claim 25, wherein organic solvent selected for step (a)-(ii) comprises ethanol.

28 The process of claim 25, wherein organic solvent selected for step (a)-(iii) comprises N,N-Dimethylformamide or Dimethylsulfoxide.

29 The process of claim 26-28, wherein (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)acrylamide solution is poured into chilled water.

30 The process of claim 27-29, wherein solution is stirred for about 1 to about 5 hours. The process of claim 30, wherein precipitate is filtered and washed with water and isopropyl ether, respectively. A crystalline (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide Form D, as claimed in claim 23 and characterized by an Infra Red Spectrum having the following peaks at about 3186, 3091, 2982, 2941, 2883, 2750, 2648, 2390, 2208, 1884, 1736, 1632, 1611, 1583, 1539, 1490, 1475, 1445, 1381, 1360, 1310, 1281, 1252, 1196, 1140, 1165, 1084, 1070, 1024, 991, 945, 891, 870, 804, 764, 746, 681, 637, 610, 567 and 530 cm^"1. A crystalline (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide Form D, as claimed in claim 23 and characterized by an X-Ray powder diffraction (XRD) having the following peaks at about 6.820, 11.800, 12.080, 13.500, 14.780, 15.540, 16.540, 16.880, 17.960, 18.760, 19.020, 20.760, 21.400, 21.540, 22.200, 23.360, 23.960, 24.600, 25.320, 26.500, 27.440, 28.100, 28.260, 29.940, 31.360, 32.020, 32.420, 33.520, 34.020, 36.760, 37.380, 37.960 and 38.700°. The process of claim 25, wherein crystalline (E)-N,N-Diethyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)acrylamide Form D is obtained in about 88 to about 91 % yield. The process of claim 25, wherein crystalline (E)-N,N-Diethyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)acrylamide Form D is obtained in about more than 99.4 % purity.