- Synthesis of entacapone by Pd-catalyzed heck coupling reaction
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Synthesis of entacapone from 4-iodo-2-methoxy-phenol with 2-cyano-N,N-diethylacrylamide by palladium-catalyzed Heck reaction, as a key step, is described.
- Veerareddy, Arava,Reddy, Gogireddy Surendra
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Read Online
- Method for producing entacapone
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The present invention relates to an entacapone production method, which comprises a nitration reaction, a de-methylation reaction and a condensation reaction. The nitration reaction is completed by glacial acetic acid, vanillin and 65% nitric acid within 3-5 hours; the de-methylation reaction is completed by reaction among nitrovanillin, dichloromethane, tetrabutyl ammonium bromide, anhydrous aluminum chloride and pyridine; and the condensation reaction is completed by reaction among isopropanol, 3,4-dihydroxyl-5-nitro benzaldehyde, N,N-diethyl cyanoacetamide and piperidine. The entacapone production method provided by the invention is high in yield, high in purity and stable in quality.
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- Entacapone preparation method
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The invention relates to an entacapone preparation method, which comprises: carrying out condensation on 3-alkoxy-4-hydroxybenzaldehyde and cyanoacetic acid to generate an intermediate 2-cyano-acrylicacid (III), carrying out a reaction on the compound (III) and a halogenating agent to generate an acyl halide (IV), carrying out a reaction on the acyl halide (IV) and diethylamine to generate the salt (V) of entacapone alkyl ether, and carrying out acidolysis demethylation on the salt (V) in a suitable solvent to generate entacapone (I). According to the present invention, the method has characteristics of convenient operation, mild reaction conditions and high in yield, and is suitable for large-scale industrial production. The formulas (I), (III), (IV) and (V) are defined in the specification.
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- A new synthesis of Entacapone and report on related studies
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A new synthesis of the catechol-O-methyltransferase (COMT) inhibitor, entacapone (E-isomer) has been achieved under mild conditions by amine-mediated demethylation of the precursor 2-Cyano-3-(3- hydroxy-4-methoxy-5-nitrophenyl) prop-2-eneamide, wherein the methoxyl group adjacent to a nitro group gets demethylated under nucleophilic attack. Similar demethylation was achieved on ethyl 2-cyano-3-(3, 4-dimethoxy-5-nitrophenyl) prop-2-enoate, 2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethylprop-2-enamide, ethyl 2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl) prop-2-enoate and ethyl 2-cyano-3-(4-methoxy-3-nitrophenyl) prop-2-enoate. The scope of demethylation has been studied. Analogues of ethyl 2-cyano-3-(3, 4-dimethoxy-5-nitrophenyl) prop-2-enoate wherein a methoxyl group is not adjacent to a NO 2 group are unaffected and phenolic derivatives yield the amine salts. Entacapone has been converted to salts with organic bases. The crystal structure of the isomer of entacapone (Z-isomer), a significant human metabolite of E-isomer has been established. NMR methods for deriving E and Z geometry and other similar molecules have been successfully established, mainly by studying the proton coupled 13C spectra. Preliminary studies reveal in vitro activity for some compounds against tuberculosis (TB) and dengue. [Figure not available: see fulltext.]
- Harisha, Attimogae Shivamurthy,Nayak, Suresh Parameshwar,Pavan,Shridhara,Sundarraja Rao,Rajendra,Pari, Koteppa,Sivaramkrishnan,Guru Row,Nagarajan, Kuppuswamy
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p. 1977 - 1991
(2015/12/30)
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- Novel triethylamine mediated thermal reactions of 3-aryl-2-cyanoprop-2-enoic acid derivatives - Demethylation, reduction and vinylogation
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3-Aryl-2-propenoic acid derivatives undergo interesting reactions with hot triethylamine. Substrates like 6 having a methoxyl with a nitro in the ortho and cyanoacrylic derivatives in the para positions give O-demethylated products, for example, entacapone 7. On the other hand compounds like 16 having the NO2 in the para and cyanoacrylic in the ortho position undergo reduction and vinylogation. The latter phenomenon is observed in the absence of the NO2 group also.
- Harisha, Attimogae Shivamurthy,Nayak, Suresh Parameshwar,Nagarajan, Kuppuswamy,Guru Row, Tayur Narasingarow,Hosamani, Amar A.
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supporting information
p. 1427 - 1431
(2015/03/04)
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- DENGUE AND WEST NILE VIRUS PROTEASE INHIBITORS
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Compounds and methods of treating or preventing a Flavivirus infection in a subject are provided. The methods comprise administering to the subject a therapeutically effective amount of a compound as described herein. The methods are useful in treating and/or preventing Flavivirus infections such as, for example, West Nile Virus, Dengue Virus, and Japanese Encephalitis Virus. Methods of inhibiting a Flavivirus protease in a cell are also provided.
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Page/Page column 28; 29
(2014/10/18)
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- PROCESS FOR THE PREPARATION OF ENTACAPONE AND ITS INTERMEDIATE THEREOF
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Provided herein are processes for preparing a compound of Formula (V), comprising nitrating a compound of Formula (IV), with a nitrating agent in the presence of a catalyst.
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- Efficient approach to pure entacapone and related compounds
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A new and efficient process through a new intermediate, (2E)-2-cyano-3-(3,4-dihydroxy-5-nirtrophenyl)prop-2-enoic acid 15, has been described for preparing substantially pure entacapone 1. This new intermediate 15 was prepared by Knoevenagel condensation of 3,4-dihydroxy-5-nitrobenzaldehyde 2 with 2-cyanoacetic acid 14 and was further condensed with diethylamine to get pure entacapone 1. Some of the important process-related impurities of entacapone (17, 18, 19, and 20) were also prepared easily from this intermediate 15. Copyright Taylor & Francis Group, LLC.
- Srikanth,Ray, Uttam Kumar,Srinivas Rao,Gupta, P. Badarinadh,Lavanya,Islam, Aminul
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p. 1359 - 1366
(2012/04/04)
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- Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases
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The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a Ki-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.
- Nitsche, Christoph,Steuer, Christian,Klein, Christian D.
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p. 7318 - 7337
(2012/01/05)
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- PROCESS FOR THE PREPARATION OF ENTACAPONE
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The present invention relates to an improved process for the preparation of Entacapone of formula (I) comprising a step of, condensation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula (II) with N,N-diethylcyanoacetamide of formula (III) in the presence of two component solvent system, a catalyst and optionally a phase transfer catalyst to give Entacapone of formula (I).
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Page/Page column 4
(2010/09/18)
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- AN IMPROVED PROCESS FOR PREPARATION OF (2E)-2-CYANO-3-(3,4- DIHYDROXY-5-NITROPHENYL)N,N-DIETHYL-2-PROPENAMIDE POLYMORPHIC FORM A
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The present invention relates to an improved, cost effective, eco-friendly and easy t handle process to manufacture substantially pure form of (2E)-2-Cyano-3-(3,4-dihydroxy-5 nitrophenyl)-N,N-diethyl-2-propenamide or (E)- N,N-diethyl-2-cyano-3-(3,4-dihyroxy-5 nitroρhenyl)-acrylamide polymorphic form A commonly known as (E)-Entacapone represente by Formula I, using ammonium acetate as a base.
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Page/Page column 7-8
(2009/08/14)
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- PROCESS AND PRODUCT
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The present invention relates to an improved process for isolation and purification of Entacapone, pharmaceutical compositions and therapeutic uses thereof. The process provides an improved yield and improved isomeric purity of produced Entacapone.
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Page/Page column 9
(2008/06/13)
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- Process for the preparation of entacapone and intermediates thereof
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New preparation process for the preparation of entacapone which comprises converting the 3,4-dimethoxy-5-nitrobenzoic acid into an activated derivative which is reacted with 2-cyano-N,N-diethylacetamide in the presence of a base to give 2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyacrylamide; reacting the resulting compound with MHB(OCOR)3 where R is (C1-C4)-alkyl, phenyl, or CF3; and M is a sodium, potassium or ((C1-C4)-alkyl)4N, in the presence of an appropriate solvent to give E-2-cyano-3-3,4-dimethoxy-5-nitrophenyl)-N,N-diethylacrylamide; and finally submitting the compound obtained to a demethylation reaction to yield entacapone. Both 2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyacrylamide and E-2-cyano-3-3,4-dimethoxy-5-nitrophenyl)-N,N-diethylacrylamide are new. Entacapone has industrial applicability as antiparkinson's agent.
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Page/Page column 6; 10-11
(2008/12/08)
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- PROCESS FOR PREPARING ENTACAPONE SUBSTANTIALLY FREE OF Z-ISOMER, SYNTHESIS INTERMEDIATES THEREOF AND A NEW CRYSTALLINE FORM
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The present invention relates to a new process for preparing Entacapone substantially free of Z-isomer from 3, 4-dihydroxy-5-Nitrobenzaldehyde and N, N-Dimethylcyano acetamide, or directly from a mixture of (E) - and (Z) - isomers of Entacapone, by formation of organic or inorganic salts, specially piperidine and sodium ones. A new crystalline form G of Entacapone can be obtained from this method in a fast, efficient, and simple way and substantially free of Z-isomer. Another object of the invention is a pharmaceutical composition comprising it.
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Page/Page column 12-13
(2008/12/08)
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- PROCESS FOR THE PREPARATION OF ENTACAPONE
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A process for the preparation of entacapone, in particular as the polymorphic form A, comprising the preparation of a compound of formula (V), as herein defined, by condensation of N,N-diethyl-cyano-acetamide with a compound of formula (IV), as herein defined, in the presence of a strong basic agent; the dealkylation of said compound of formula (V) to obtain entacapone and the crystallization thereof to the polymorphic form A.
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Page/Page column 4
(2008/12/06)
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- A process for the preparation of entacapone
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A process for the preparation of entacapone, in particular as the polymorphic form A, comprising the preparation of a compound of formula (V), as herein defined, by condensation of N,N-diethyl-cyano-acetamide with a compound of formula (IV), as herein defined, in the presence of a strong basic agent; the dealkylation of said compound of formula (V) to obtain entacapone and the crystallization thereof to the polymorphic form A.
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Page/Page column 6
(2008/12/06)
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- ENTACAPONE-DERIVATIVES
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Pharmaceutical composition comprising one or more entacapone derivatives and one or more pharmaceutically acceptable carriers, a process for producing the pharmaceutical composition, specific entacapone derivatives, a process for the preparation of entacapone derivatives, and the use of the entacapone derivatives for the preparation of a medicament.
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Page/Page column 17
(2008/06/13)
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- Stable polymorphs of (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide
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The present invention provides stable crystalline polymorphic Form C and Form D of (E)-Entacapone, (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-henyl)acrylamide and processes for their preparation. The polymorphic Form C and Form D of (E)-Entacapone are characterized by specific Infra Red (IR) and X-ray powder diffraction peak values.
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Page/Page column 5
(2008/06/13)
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- IMPROVED AND SIMPLIFIED PROCEDURE FOR THE PREPARATION OF (E) N,N-DIETHYL-2-CYANO-3(3,4-DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE
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Process for the preparation of N,N-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)acrylamide having the structure of Formula -IV by condensing 3,4-dihydroxy-5-nitrobenzaldehdye with N,N-diethyl cyanoacetamide in toluene in the presence of a catalyst piperadine acetate at reflux temperature for a period of 5-6 hours; and isolating (E) isomer of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide after removing the solvent completely by distillation at temperature of between 60-90°C followed by acidification to pH 0.5 to 1.5 preferably 1.0. The isolated (E)-N,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl) acrylamide is substansially free from Z-isomer , preferably NMT 0.20%.
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Page/Page column 7-8
(2008/06/13)
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- PROCESSES FOR THE PREPARATION OF A STABLE POLYMORPHIC FORM OF ENTACAPONE
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The invention relates to processes for the preparation of a stable polymorphic form of entacapone. More particularly, it relates to the preparation of stable polymorphic form designated as Form D. The invention also relates to an improved process for the preparation of 2-cyano-N,N-diethylacetamide, and to the use of this compound as an intermediate for the preparation of entacapone.
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Page/Page column 5
(2008/12/05)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF ENTACAPONE
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The invention relates to Novel Z form of ENTACAPONE-( Z N1N- Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide . This invention also relates to a process for the preparation of Novel Z form of ENTACAPONE- by treating pure 3- O- alkylated Entacapone with aluminium chloride and pyridine with dichloromethane as solvent to get crude Entacapone with no impurity and dissolving the crude entacapone in one or more solvents selected from soluble or partially soluble solvents or their mixtures filtering . and concentrating by distillation
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Page/Page column 15
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF HIGHLY PURE (E) N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY- 5-NITRO PHENYL) ACRYLAMIDE (ENTACAPONE)
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A process for the preparation of highly pure (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide (Entacapone). It comprises condensing3,4-dihydroxy-5-nitro benzaldehyde with N,N-diethyl cyano acetamide in an organic solvent in the presence of an organic base and an acid under reflux conditions followed by distilling off the solvent under vacuum and treating the residue with a lower aliphatic carboxylic acid at 40 - 8O0C. The resulting residue is extracted with a chlorinated solvent and the solvent is distilled off under vacuum. The resulting residue is extracted with an organic solvent to obtain crude N,N-diethyl-2-cyano-3-3,4-dihydroxy-5-nitrophenyl)acrylamide. The crude product N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide formed is treated with a mixture of organic alcohol and organic acid in the molar ratio of the crude product to organic alcohol 1:5 to 15 and crude product to organic acid 1:1 to 3 under reflux conditions.
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- PROCESS FOR MANUFACTURING ENTACAPONE
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A new process for manufacturing entacapone comprising reacting 3,4-dihydroxy-5-nitrobenzaldehyde with N,N-diethyl-2-cyanoacetamide in the presence of a catalyst in a C 4 to 8 alcohol at reduced pressure and at a temperature of at least 70 °C, cooling the mixture to a temperature of 30 °C or below, seeding the mixture with N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide comprising at least 10 % of the Z-isomer by weight in the seeding crystals, cooling the mixture to a temperature of 5 °C or below, isolating the crystallized product and converting the obtained mixture of the E- and Z-isomers of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide to the E-isomer (entacapone).
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Page/Page column 9-11
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF ENTACAPONE FORM-A
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A process to prepare (2E) -2-cyano-3- (3 , 4-dihydroxy-5-nitrophenyl) -N, N-diethyl-2- propenamide (Entacapone) eliminating corrosive acids in the purification, with more than 99.5 % purity with a Z-isomer content of less than 0.1% comprising condensation of 3, 4-Dihydroxy{5-nitrobenzaldehyde with N,N-diethyl cyanoacetamide in the presence of a base selected from cyclic and acyclic secondary amines and a mixture of solvents, to obtain a crude product, stirring the crude product in a halogenated solvent, filtering and finally crystallization of polymorph A of Entacapone in a solvent.
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Page/Page column 5-6
(2008/06/13)
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- Process for the preparation of (E)-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide (entacapone)
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The present invention relates to an improved process for the preparation of (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide formula (I) comprising steps of, (a) condensation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula (II) with N,N-diethylcyanoacetamide of formula (III) in the presence of a catalyst and optionally in the presence of phase transfer catalyst in a solvent selected from the group comprising of ethylacetate, acetonitrile, hydrocarbon such as toluene, xylene and like or mixture thereof to give mixture of (E) and (Z)-isomer of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide of formula (IV). b) treating an isomeric mixture of (E) and (Z)-isomer of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide of formula (IV) obtained in step (a) with a halogen in catalytic amounts, in a solvent to give (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide formula (I).
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Page/Page column 4
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF (E)-N,N-DIETHYL-2-CYANO-3(3,4-DIHYDROXY-5-NITRO-PHENYL)-ACRYLAMIDE IN STABLE POLYMORPHIC FORM AND INTERMEDIATES OF THE PROCESS
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The invention relates to a process for the preparation of pure E isomer of N1N- diethyl-2-cyano-3-(3,4-dihydrìxy-t5-nitro-phenyl)-acryIamide of formula (1 ) ( D in stable polymorphic form. According to the invention _ (a) (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro-phenyl)-acryl- amide is demethylated; or (b) (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide is nitrated, and the. resulting (E)-N-, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro- phenyl)-acrylamide is demethylated; or - (c) vanillin is reacted with N.N-diethyl-cy.anoacetamide in the presence of a weak organic acid and of an amine compound used as catalysts, the resulting (E)- N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide is nitrated, and the resulting (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro-phenyl)-acrylamide is demethylated. The invention also relates to (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy- phenyl)-acrylamide and (E)-N, N-diethyl-2-cyano-3-(3-rhethoxy-4-hydroxy-5-nitro- phenyl)-acrylamide and to their preparation.
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Page/Page column 7-8
(2008/06/13)
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- IMPROVED PROCESS FOR THE PREPARATION OF ENTACAPONE
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The invention disclosed in this application relates to an improved process for the preparation of the Entacapone which comprises. (i)reacting 3-alkoxy- 4-hydroxy-5-nitrobenzadehyde with N,N-diethylaminocyanoactamide in the presence of mild acid catalyst and a solvent at a temperature in the range of 50-115 °C, to get the 3-O-alkylated (methyl or ethyl) Entacapone and treating with acid catalysts in the presence of organic base and solvents at temperature in the range of 20-60 °C to get Entacapone.
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Page/Page column 9
(2008/06/13)
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- STABLE POLYMORPHS OF (E)-N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE
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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.
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Page/Page column 11
(2008/06/13)
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- NOVEL CRYSTALLINE FORMS OF ENTACAPONE, AND PRODUCTION THEREOF
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Disclosed are two novel crystalline forms of entacapone, form C and form D, which represent peripheral and selective COMT inhibitors that can be used for the treatment of Parkinson's disease in combination with levodopa and a decarboxylase inhibitor. Form C is produced by crystallizing entacapone from a mixture of at least one aromatic and at least one aliphatic hydrocarbon. Form D is produced by a) dissolving entacapone in a water-miscible solvent and introducing said solution into water or a mixed aqueous system, or b) dissolving entacapone in a polar aprotic or alcoholic solvent and adding said solution to an aliphatic hydrocarbon which can be mixed with said solvent and in which entacapone is insoluble, or c) crystallizing entacapone in a non-acidic solvent or a solvent mixture containing at least one non-acidic component in the presence of a strong acid, the entacapone being usable as a raw product or, in variant c), as the Knoevenagel condensation product of 3,4-dihydroxy-5-nitro-benzaldehyde and N,N-diethyl-2-cyano-acetamide, which is used in situ. Also disclosed are improvements of said Knoevenagel condensation regarding the catalyst used and regarding the production of the two components thereof, 3,4-dihydroxy-5-nitro-benzaldehyde and N,N-diethyl-2-cyano-acetamide.
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Page/Page column 11
(2008/06/13)
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- AN EFFICIENT PROCESS FOR THE MANUFACTURE OF (E)-ENTACAPONE POLYMORPHIC FORM A
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The present invention describes an improved process for the manufacture of (E)-N, N-Diethyl-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl) acrylamide (Entacapone) polymorphic Form A, which is an excellent inhibitor of Catechol-O-methyltransferase (COMT) enzyme. 3, 4-Dihydroxy-5-nitrobenzaldehyde is condensed with N, N-Diethylcyanoacetamide in presence of a base in alcoholic solution to get the Entacapone. After the disappearance of reactants the crude reaction mixture is poured into aqueous ethyl acetate solution followed by adjusting pH between 3.5 to 4.0 with acetic acid. Simple extraction process provides 99.7% HPLC pure (E)- isomer of Entacapone Form A.
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Page/Page column 7
(2008/06/13)
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- Synthesis and in-vitro/in-vivo evaluation of orally administered entacapone prodrugs
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Entacapone is a new inhibitor of catechol-O-methyltransferase (COMT) that is used as an adjunct to L-dopa therapy in the treatment of Parkinson's disease. The bioavailability of orally administered entacapone is, however, relatively low (29-46%). In this study we have prepared more lipophilic acyl and acyloxyacyl esters, an acyloxy alkyl ether and an alkyloxycarbonyl ester of entacapone, and we have evaluated them as potential prodrugs to enhance the oral bioavailability of entacapone. All the derivatives fulfilled prodrug criteria and released entacapone in human serum in-vitro. The oral bioavailability of monopivaloyl (1a) and dipivaloyl (1b) esters of entacapone were investigated further in rats. The lipophilicity of 1b was high (log Papp 4.0 at pH 7.4) but its oral bioavailability was low (F = 0.6%), most probably due to its low aqueous solubility. The monopivaloyl ester of entacapone (1a) had a higher lipophilicity (log Papp 0.80) than entacapone (log Papp 0.18) at pH 7.4 while maintaining an aqueous solubility equal to entacapone. However, oral bioavailability was not increased when compared with the parent drug entacapone (F = 7.0% and 10.4%, respectively).
- Leppaenen,Savolainen,Nevalainen,Forsberg,Huuskonen,Taipale,Gynther,Maennistoe,Jaervinen
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p. 1489 - 1498
(2007/10/03)
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- PHARMACOLOGICALLY ACTIVE COMPOUNDS, METHODS FOR THE PREPARATION THEREOF AND COMPOSITIONS CONTAINING THE SAME
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Pharmacologically active catechol derivatives of formula I I wherein R1 and R2 independently comprise hydrogen, alkyl, acyl, optionally substituted aroyl, lower alkylsulfonyl or alkylcabamoyl or taken together form a lower alkylidene or cycloalkylidene, X comprises an electronegative substituent such as halogen, nitro, cyano, lower alkylsulfonyl, sulfonamido, aldehyde, caboxyl or trifluoromethyl and R3 comprises hydrogen, halogen, hydroxy alkyl, amino, nitro, cyano, trifluoromethyl, lower alkylsulfonyl, sulfonamide, aldehyde, alkyl carbonyl, aralkylidene carbonyl or carboxyl or a group selected from wherein R4 comprises hydrogen, alkyl, cyano, carboxyl or acyl and R5 comprises hydrogen, cyano, carboxyl, alkoxycarbonyl, carboxyalkenyl, nitro, acyl, optionally substituted aroyl or heteroaroyl, hydroxyalkyl or carboxyalkyl or R4 and R5 together form a five to seven membered substituted cycloalkanone ring; -(CO)n(CH2)m-COR wherein n is 0-1 and m is 0-7 and R comprises hydroxy, alkyl, carboxyalkyl, optionally substituted alkene, alkoxy or optionally substituted amino; wherein R8 and R9 independently comprise hydrogen or one of the following optionally substituted groups; alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or together form an optionally substituted piperidyl group; -NH-CO-R10 wherein R10 comprises a substituted alkyl group
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