STABLE POLYMORPHS OF (E)-N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE

POLYMORPHES STABLES DE (E)-N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE

English 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.

French Abstract

L'invention concerne les polymorphes cristallins stables C et D de (E)-N,N-diéthyl-2-cyan-3-(3,4-dihydroxy-5-nitrophényl)acrylamide (Entacapone) et leur préparation. (E)-Entacapone de forme C est obtenue par condensation de 3,4-dihydroxy-5-nitrobenzaldehyde et N,N-diéthylcyanoacetamide en présence d'une base suivi par l'addition de l'acide acétique après la réaction et une cristallisation subséquente. (E)-Entacapone de forme D est obtenue à partir de l'entacapone de forme C, (E)-entacapone de forme A pur ou sensiblement pur d'un point de vue cristallographique. Les polymorphes C et D de (E)-entacapone sont caractérisées par valeurs crêtes d'infra rouge (IR) et diffraction des rayons X sur poudre.

Claims

13
We Claim:
1 A compound of Formula I
<IMG>
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
<IMG>
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.
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-
methylmorpholine,
N-methylmorpholine, pyridine or piperazine.
9 The process of claim 8, wherein more particularly base is piperidine.
The process of claim 3, wherein step (a) is conducted at reflux temperature.

14
11 The process of claim 3, wherein reaction time in step (a) is from about 8
to about 20
hours.
12 The process of claim 11, wherein more preferably reaction time is between
about 10 to
about 18 hours.
13 The process of claim 3, wherein aliphatic acid is added to the reaction
mixture after the
reaction is completed.
14 The process of claim 13, wherein said aliphatic acid is acetic acid.
15 The process of claim 3, wherein reaction mixture in step (b) is slightly
concentrated after
the addition of acid.
16 The process of claims 13-15, wherein alcohol is added to the reaction
mixture.
17 The process of claim 16, wherein said alcohol is ethanol.
18 The process of claim 15-17, wherein crystalline (E)-Entacapone Form C is
collected
after stirring for about 10 to about 14 hours.
19 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.
20 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°.
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

15
<IMG>
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
<IMG>
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.

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)-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°.
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)-N,N-Diethyl-2-cyano-3-(3,4-
dihydroxy-5-nitrophenyl)acrylamide Form D is obtained in about more than 99.4
%
purity.

Description

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STABLE POLYMORPHS OF (El-N,N-DIETHYL-2-CYANO-3-(3 4-
DIHYDROXY-5-NITROPHENYL1ACRYLAMIDE
FIELD OF THE INVENTION
The present invention relates to stable crystalline polyrnorphic 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.
Polymorpluc form C and D of (E)-Entacapone are characterized by specific Infra
Red (TR)
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-
yl 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 fznd 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 II) and N,N-Diethylcyanoacetamide (Formula III) in
anhydrous
ethanol as shown below:
CONFIRMATION COPY

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Formula IV
Formula I I . . . - . , . ...
O O
HO \ CHO
~N~CH Piperidine _ HO I \ \ N~CH3
HO ~ + CN ' 3 Anhyd. Ethanol / CN
CH3 HO ~CH3
NOZ N02
(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
O~N , NC N-Et O~N N-Et
Et Et~
(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-
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.

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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 ~ ~ ~ ~ CH3 HCOOH or CH3COOH HO ~ ~ \ N~CH3
/ ~ I
HO CN CH3 HCI or HBr HO ~ CN ~CH3
N02 NOz
(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-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,

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Formula I
O
HO ( \ \ N~CH3
I l
HO ~ CN \CH3
NOZ
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 N,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
polyrnorphic 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

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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 II Formula III Formula IV
HO ~ CHO O O
+ ~N~CH3 ~ HO ~ \ \ N~CH3
HO CN HO ~ CN ~CH3
NOa ~CH3
NO~
(E)- and (Z)- Isomers of Entacapone
Formula IV
O Formula I
O
HO ~ \ \ N~CH3 HO ~ ~ N/WCH3
HO CN ~CH3 HO ~ / ~ N ~CH
3
N02 NOz
(E)- and (~)-Isomers of Entacapone (E)-Isomer of Entacapone
According to another embodiment the present invention, (E)-N,N-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 N N-
Diethylcyanoacetamide 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)acrylamide.
Suitable

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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 ~.)
Wavelength : 210 rnn
Flow rate : 1.0 ml /minute
Temperature : Ambient
Buffer : 1 ml H3P04 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 Polvmorahic Form D of fEl-N N-Diethyl-2-cyano-3-(3,4-
dihydroxy-
5-nitrophen~lacr~amide
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

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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)-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
clulled 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 (El-N, N-Dieth~yano-3-(3,4-dihydroxy-5-nitrophenyll
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 Pealcs
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.

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TABLE 1: Infra Red Peaks (in cm 1) 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
2981 2644 2883
6 2938 2544 2750
7 2217 2451 2648
8 1628 2340 2390
9 1607 2199 2208
1580 2124 1884
11 1544 2002 1736
12 1512 1896 1632
13 1441 1767 1611
14 1377 1629 1583
1298 1605 1539
16 1281 1539 1490
17 1210 1477 1475
18 1165 1435 1445
19 1150 1385 1381
800 1359 1360
21 779 1346 1310
22 740 1317 1281
23 1263 1252
24 1219 1196
1153 1140
26 1124 1165
27 1072 1084
28 1016 1070
29 947 1024

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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
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

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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
21.939 19.980 22.200
16 22.901 20.380 23.360
I7 23.340 20.900 23.960
18 23.960 21.360 24.600
19 24.480 22.960 25.320
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
29.680 31.360
26 29.880 32.020
27 30.880 32.420
28 31.480 33.520
29 31.740 34.020
32.460 36.760
31 33.000 ~ 37.380
32 33.820 37.960
33 34.560 38.700
34 35.380
36.600
36 37.140
37 37.520
38 37.960
39 39.260

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11
Examples
The following example illustrates the invention, but is not limiting thereof.
EXAMPLE 1
Czystallograplzically pure (E)-N,NDiethyl-2-cyano-3-(3,4-dilzydroxy-S-
nitrophenyl)-
aczylanzide 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
Czystallographically puz"e (E)-N,NDiethyl-2-cyano-3-(3,4-dihydroxy-S-
nitrophenyl)-
aczylanzide Form D
Crystallograplucally 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 f~r fiu~ther 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
CfystallogYaphically pure (E)-N,NDiethyl-2-cyano-3-(3,4-dilzydf-oxy-5-
nitroplzenyl)-
acfylamide For-rn D

CA 02551791 2006-06-27
WO 2005/066117 PCT/IB2003/006200
12
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 stirnng 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,NDiethyl-2-cyano-3-(3,4-dihydr~xy-5-
nitrophetayl)-
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
Cfystallographically pure (E)-N,NDiethyl-~-cyano-3-(3,4-dihydroxy-5-
nitropherayl)-
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.