AU2003292465A1 - Stable polymorphs of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide - Google Patents

Description

WO 2005/066117 PCT/IB2003/006200 1 STABLE POLYMORPHS OF (E)-NN-DIETHYL-2-CYANO-3-(34 DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE 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 Infra 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 meth yi 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 NN-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 II) and N,N-Diethylcyanoacetamide (Formula III) in anhydrous ethanol as shown below: CONFIRMATION COPY WO 2005/066117 PCT/IB2003/006200 2 Formula IV Formula O ~ HO CHO H N CH 3 Piperidine I HO N H 3 HO CN CH Anhyd. Ethanol HO / CN CH3 NO2

NO

2 (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: HO HO HO HO C,=O C 0 2 N NC ,N-Et 0 2 N EN-Et Et Et 1 (E)-isomer (Z)-isomer m.p.162-163 0 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 phenyl)acrylamide 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 isomerism.

WO 2005/066117 PCT/IB2003/006200 3 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: 0 0 HO HO H N CH 3 HCOOH or CH 3 COOH HO N OH 3 HO CN CH 3 HCI or HBr HO

CH

3

NO

2

NO

2 (E)- and (Z)-isomers of Entacapone (E)-isorner of Entacapone The said method allows large scale production of homogeneous and crystallographically essentially pure polymorphic form A of (E)-NN-Diethyl-2-cyano-3-(3,4-dihydroxy-5 nitrophenyl)acrylamide. In this context "Crystallographically essentially pure" means the polymorphic form A of (E)-NN-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-nitrophenyl)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 polymorphic Form C and D of (E) N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (Entacapone) having Formula

I,

WO 2005/066117 PCT/IB2003/006200 4 Formula I 0 HOO HO N CH 3 CN HO

CH

3

NO

2 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 with NN 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 polynrohic 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 polymorphic 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 polymorphic forms having therapeutic value and processes for their manufacture. In particular the present invention is directed to the new polymorphic 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 polymorphic forms. The present invention provides a method for the manufacture of new polymorphic 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 polymorphic Form D of (E)-Entacapone using different solvent combinations. The processes comprise by dissolving "crystallographically pure Form A" or "crystallographically essentially pure Form WO 2005/066117 PCT/IB2003/006200 5 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 NN-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 il Formula III Formula IV HO CHO O 0 NO HOI + N OH 3 HO N H 3 NO CN CH 3 HO N CN CH 3

NO

2 (E)- and (Z)- Isomers of Entacapone Formula IV 0 FormulalI HO N CH 3 HO N CH HO:[[;) CN CHN HO CN CH 3 HO CN CH 3

NO

2

NO

2 (E)- and (Z)-Isomers of Entacapone (E)-Isomer of Entacapone According to another embodiment the present invention, (E)-NN-Diethyl-2-cyano-3 (3,4-dihydroxy-5-nitrophenyl)acrylamide and its polymorphic Forms C and D are prepared according the following synthetic reaction scheme: (a) Reaction of 3,4-Dihydroxy-5-nitrobenzaldehyde and NN-Diethylcvanoacetamide to form (El-Entacapone 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 of N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylanide. Suitable WO 2005/066117 PCT/IB2003/006200 6 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 methylmorpholine, morpholine, 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 polymorphic 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 polymorphic forms are generally obtained. But surprisingly, we get the new polymorphic 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 p) Wavelength : 210 nm Flow rate : 1.0 ml /minute Temperature : Ambient Buffer : 1 ml H 3

PO

4 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 Polymorphic Form D of (E)-N.N-Diethyl-2-cvano-3-(3,4-dihydroxy 5-nitrophenyl)acrvlamide 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 WO 2005/066117 PCT/IB2003/006200 7 water. The reaction mixture is stirred additionally for about 1 to about 5 hours. Finally, polymorphic Fonn 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)-NN 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-cvano-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 (IR) Spectrum, X-Ray powder diffraction (XRD)and melting points and their purity is tested HPLC. For comparison purposes, certain of these analyses have also been performed for the corresponding polymorphic form A of Entacapone. Infra Red Spectrum Figures 2 and 3 show Infra Red absorption bands for the polymorphic forms C and D of (E)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide, respectively. IR Peaks for Entacapone Form A is referred from US Patent 5,135,590 for comparison purpose. A comparison of IR peak values of polymorphic forms of (E)-Entacapone is set forth in Table 1.

WO 2005/066117 PCT/IB2003/006200 8 TABLE 1: Infra Red Peaks (in enfi) for the Polymorphic Forms A, C and D of (E)- N,N Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide 1 3339 3043 3186 2 3092 2972 3091 3 3066 2821 2982 4 3039 2721 2941 5 2981 2644 2883 6 2938 2544 2750 7 2217 2451 2648 8 1628 2340 2390 9 1607 2199 2208 10 1580 2124 1884 11 1544 2002 1736 12 1512 1896 1632 13 1441 1767 1611 14 1377 1629 1583 15 1298 1605 1539 16 1281 1539 1490 17 1210 1477 1475 18 1165 1435 1445 19 1150 1385 1381 20 800 1359 1360 21 779 1346 1310 22 740 1317 1281 23 1263 1252 24 1219 1196 25 1153 1140 26 1124 1165 27 1072 1084 28 1016 1070 29 947 1024 WO 2005/066117 PCT/IB2003/006200 9 30 866 991 31 833 945 32 802 891 33 781 870 34 739 804 35 681 764 36 637 746 37 608 681 38 561 637 39 511 610 40 567 530 X-Ray Powder Diffraction Figures 4 and 5 show X-ray powder diffraction pattern for the polymorphic 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 "20" and expressed in degrees, is set forth in Table 2. TABLE 2: XRD Peaks for the Polymorphic Form A, C and D of (E)- N,N-Diethyl-2 cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide S. No. Form A Form C Form D 1 3.680 6.040 6.820 2 9.040 6.360 11.800 3 11.840 8.960 12.080 4 13.541 10.600 13.500 5 14.060 11.620 14.780 6 15.820 12.420 15.540 7 16.320 12.960 16.540 8 18.220 13.220 16.880 9 18.459 15.260 17.960 WO 2005/066117 PCT/IB2003/006200 10 10 18.720 16.180 18.760 11 18.940 16.960 19.020 12 20.041 17.400 20.760 13 20.380 18.080 21.400 14 21.140 18.600 21.540 15 21.939 19.980 22.200 16 22.901 20.380 23.360 17 23.340 20.900 23.960 18 23.960 21.360 24.600 19 24.480 22.960 25.320 20 26.343 24.500 26.500 21 25.040 27.440 22 25.600 28.100 23 26.820 28.260 24 28.640 29.940 25 29.680 31.360 26 29.880 32.020 27 30.880 32.420 28 31.480 33.520 29 31.740 34.020 30 32.460 36.760 31 33.000 37.380 32 33.820 37.960 33 34.560 38.700 34 35.380 35 36.600 36 37.140 37 37.520 38 37.960 39 39.260 WO 2005/066117 PCT/IB2003/006200 11 Examples The following example illustrates the invention, but is not limiting thereof. EXAMPLE 1 Crystallographically pure (E)-NN-Diethyl-2-cyano-3-(3,4-dilydroxy-5-nitrophelyl) 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)-NN-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 NN-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 Crystallographically pure (E)-NN-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide Form D WO 2005/066117 PCT/IB2003/006200 12 Crystallographically pure form C of (E)-NN-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 Cystallographically pure (E)-NN-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide Form D "Crystallographically essentially pure form A" of (E)-NN-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)-NN-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 (4)

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

39.2600. 21 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. 22 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 %. 23 A compound of Formula I WO 2005/066117 PCT/IB2003/006200 15 Formula I HO N CH3 CN HO CH 3 NO 2 (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 Formula I HO N CH 3 CN HO CH 3 NO 2 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. WO 2005/066117 PCT/IB2003/006200 16 31 The process of claim 30, wherein precipitate is filtered and washed with water and isopropyl ether, respectively. 32 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 . 33 A crystalline (E)-NN-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 38.7000. 34 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. 35 The process of claim 25, wherein crystalline (E)-NN-Diethyl-2-cyano-3-(3,4 dihydroxy-5-nitrophenyl)acrylamide Form D is obtained in about more than 99.4 % purity.