WO2007054950A1 - A process for the preparation of highly pure (e) n,n-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitro phenyl) acrylamide (entacapone) - Google Patents
A process for the preparation of highly pure (e) n,n-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitro phenyl) acrylamide (entacapone) Download PDFInfo
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- WO2007054950A1 WO2007054950A1 PCT/IN2005/000363 IN2005000363W WO2007054950A1 WO 2007054950 A1 WO2007054950 A1 WO 2007054950A1 IN 2005000363 W IN2005000363 W IN 2005000363W WO 2007054950 A1 WO2007054950 A1 WO 2007054950A1
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- Prior art keywords
- acid
- organic
- dihydroxy
- diethyl
- cyano
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- JRURYQJSLYLRLN-BJMVGYQFSA-N CCN(CC)C(/C(/C#N)=C/c(cc1O)cc([N+]([O-])=O)c1O)=O Chemical compound CCN(CC)C(/C(/C#N)=C/c(cc1O)cc([N+]([O-])=O)c1O)=O JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
Definitions
- the invention relates to a process for the preparation of highly pure (E) N,N-diethyl-2-cyano- 3-(3,4-dihydroxy-5-nitro phenyl) acrylamide (Entacapone) of the formula I:
- Process for the preparation of N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide comprises condensation of 3,4-dihydroxy-5-nitro benzaldehyde and N 9 N- hydrochloric diethyl cyanoacetamide in the presence of piperidine-acetate in dry ethanol (Example 100).
- the condensation reaction and yield are reported to be very long (overnight) and 73%, respectively.
- the process is not, therefore, commercially viable for industrial scale production of entacapone and economical.
- N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide is a mixture of two geometric isomers namely E- and Z-isomers (70 - 80% E-isomer and 30-20% Z-isomer) of the following formulae I and II, respectively :
- This patent relates to a stable and crystallographically essentially pure polymorphic form A of E- isomer of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide obtained by purifying the crude product by recrystallisation from lower aliphatic carboxylic acid such as formic acid or acetic acid with catalytic amount of hydrochloric or hydrobromic acid.
- the purification procedure increases the process duration and renders it commercially unviable for industrial scale production.
- WO 2005/063693 describes a process for the preparation of entacapone using 3-alkoxy-4- hydroxy-5-nitrobenzaldehyde.
- WO 2005/070881 describes a process for the production of (E)-entacapone polymorphic form A.
- 3,4Dihydroxy-5-nitrobenzaldehyde is condensed with N,N-diethylcyanoacetamide in the presence of a base like piperidine in alcohol like isopropanol.
- the reaction mixture is poured into a mixture of aqueous ethyl acetate and water followed by pH adjustment with acetic acid.
- the product is separated from the organic layer to yield (E) isomer of entacapone having 99.7% purity.
- the condensation reaction itself is reported to be quite long (10 - 15 hours).
- Novel polymorphic forms C and D of entacapone are disclosed in WO2005/066117.
- 3,4Dihydroxy-5-nitrobenzaldehyde is condensed with N,N-diethylcyanoacetamide in the presence of a base like piperidine in isopropanol followed by addition of acetic acid and crystallization with a mixture of alcohols to obtain polymorphic form C.
- Polymorphic form D is obtained from form C or form A by dissolution in solvents such as polar organic solvents aliphatic alcohols or sulfoxides.
- WO 2005/063695 and WO 2005/063696 also disclose novel polymorphs C 5 D and E of Entacapone by crystallisation.
- An object of the invention is to provide a process for the preparation of (E)-N, N-diethyl-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide, which gives the product in high purity and good yield.
- Another object of the invention is to provide a process for the preparation of (E)-N, N-diethyl- 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide, which reduces the process duration and is simple, easy and convenient to carry out and is commercially viable and economical.
- Another object of the invention is to provide (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl) acrylamide in very high purity and good yield.
- Formula I comprising i) condensing 3,4-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 - 8O 0 C;
- the organic solvent used in step (i) is selected from lower aliphatic alcohol like methanol, ethanol, n-propanol, isopropanol or mixtures thereof or is preferably ethanol.
- the organic base used in step (i) is selected from piperidine morpholine, N-methyl morpholine or pyrrolidine or is preferably piperidine.
- the acid used in step (i) is organic acid selected from lower aliphatic carboxylic acid or inorganic acid selected from sulfuric acid or hydrochloric acid.
- the lower aliphatic carboxylic acid used in step (i) is preferably acetic acid or formic acid.
- the residue in step (i) is treated at 65 0 C,
- the chlorinated solvent used in step (ii) is selected from methylene chloride or chloroform or is preferably methylene chloride.
- the organic solvent used in step (iii) is selected from polar and non-polar solvents such as alcohols, ketones, esters or mixtures thereof.
- the organic solvent is preferably ester selected from methyl acetate, ethyl acetate, propyl acetate or mixtures thereof or is preferably ethyl acetate.
- the mixture of organic alcohol and organic, acid used in step (iv) is selected from aliphatic alcohol like methanol, ethanol, n-propanol or isopropanol and lower aliphatic carboxylic acid like acetic acid, formic acid, methane sulfonic acid or trifluoro acetic acid or is preferably, methanol and acetic acid.
- the molar ratio of the crude product to organic alcohol is 1: 8 and the crude product to organic acid is 1 :2.
- the product namely N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide is recovered from the reaction mixture of step (iv) by filtering the reaction mixture, precipitating the product from the filtrate by gradually cooling the filtrate at 0-30 0 C preferably 10 - 50° C and drying the precipitate at 60 - 70° C preferably in an electric oven.
- the process of the invention affords (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide in high purity ( > 99.8%) and in good yield (about 53.68%) with Z- isomer content ⁇ 0.5%.
- the process duration is reduced and the process is simple, easy and convenient to carry out and is commercially viable and economical.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
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.
Description
A process for the preparation of highly pure (E) N,N-Diethyl-2-Cyano-3-(3,4-dihydroxy- 5-nitro phenyl) acrylamide (Entacapone)
Technical Field
The invention relates to a process for the preparation of highly pure (E) N,N-diethyl-2-cyano- 3-(3,4-dihydroxy-5-nitro phenyl) acrylamide (Entacapone) of the formula I:
Formula I
Background and Prior Art
US 4,963, 590 describes catechol derivatives including N, N-diethyl-2-cyano-3-(3,4- dihydroxy-5-nitro phenyl) acrylamide as being useful in the treatment of diseases like central or peripheral nervous system disorders, Parkinson's disease or parkinsonian disorders.
Process for the preparation of N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide comprises condensation of 3,4-dihydroxy-5-nitro benzaldehyde and N9N- hydrochloric diethyl cyanoacetamide in the presence of piperidine-acetate in dry ethanol (Example 100). The condensation reaction and yield are reported to be very long (overnight) and 73%, respectively. The process is not, therefore, commercially viable for industrial scale production of entacapone and economical.
US 5,135,950 reports that N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide is a mixture of two geometric isomers namely E- and Z-isomers (70 - 80% E-isomer and 30-20% Z-isomer) of the following formulae I and II, respectively :
Formula II
This patent relates to a stable and crystallographically essentially pure polymorphic form A of E- isomer of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide obtained by purifying the crude product by recrystallisation from lower aliphatic carboxylic acid such as formic acid or acetic acid with catalytic amount of hydrochloric or hydrobromic acid. The purification procedure increases the process duration and renders it commercially unviable for industrial scale production.
WO 2005/063693 describes a process for the preparation of entacapone using 3-alkoxy-4- hydroxy-5-nitrobenzaldehyde.
WO 2005/070881 describes a process for the production of (E)-entacapone polymorphic form A. 3,4Dihydroxy-5-nitrobenzaldehyde is condensed with N,N-diethylcyanoacetamide in the presence of a base like piperidine in alcohol like isopropanol. The reaction mixture is poured
into a mixture of aqueous ethyl acetate and water followed by pH adjustment with acetic acid. The product is separated from the organic layer to yield (E) isomer of entacapone having 99.7% purity. The condensation reaction itself is reported to be quite long (10 - 15 hours).
Novel polymorphic forms C and D of entacapone are disclosed in WO2005/066117.
3,4Dihydroxy-5-nitrobenzaldehyde is condensed with N,N-diethylcyanoacetamide in the presence of a base like piperidine in isopropanol followed by addition of acetic acid and crystallization with a mixture of alcohols to obtain polymorphic form C. Polymorphic form D is obtained from form C or form A by dissolution in solvents such as polar organic solvents aliphatic alcohols or sulfoxides.
WO 2005/063695 and WO 2005/063696 also disclose novel polymorphs C5 D and E of Entacapone by crystallisation.
Objects of the Invention
An object of the invention is to provide a process for the preparation of (E)-N, N-diethyl-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide, which gives the product in high purity and good yield.
Another object of the invention is to provide a process for the preparation of (E)-N, N-diethyl- 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide, which reduces the process duration and is simple, easy and convenient to carry out and is commercially viable and economical.
Another object of the invention is to provide (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl) acrylamide in very high purity and good yield.
Detailed Description of invention
According to the invention there is provided a process for the preparation of highly pure (E)- N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide (Entacapone) of the formula I
Formula I comprising i) condensing 3,4-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;
ii) extracting the residue with a chlorinated solvent and distilling off the solvent under vacuum;
iii) extracting the residue with an organic solvent to obtain crude N,N-diethyl-2- cyano-3-3,4-dihydroxy-5-nitrophenyl)acrylamide; and
iv) treating the crude product N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl) acrylamide 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.
The organic solvent used in step (i) is selected from lower aliphatic alcohol like methanol, ethanol, n-propanol, isopropanol or mixtures thereof or is preferably ethanol. The organic base used in step (i) is selected from piperidine morpholine, N-methyl morpholine or pyrrolidine or is preferably piperidine. The acid used in step (i) is organic acid selected from lower aliphatic
carboxylic acid or inorganic acid selected from sulfuric acid or hydrochloric acid. The lower aliphatic carboxylic acid used in step (i) is preferably acetic acid or formic acid. Preferably, the residue in step (i) is treated at 650C,
The chlorinated solvent used in step (ii) is selected from methylene chloride or chloroform or is preferably methylene chloride.
The organic solvent used in step (iii) is selected from polar and non-polar solvents such as alcohols, ketones, esters or mixtures thereof. The organic solvent is preferably ester selected from methyl acetate, ethyl acetate, propyl acetate or mixtures thereof or is preferably ethyl acetate.
The mixture of organic alcohol and organic, acid used in step (iv) is selected from aliphatic alcohol like methanol, ethanol, n-propanol or isopropanol and lower aliphatic carboxylic acid like acetic acid, formic acid, methane sulfonic acid or trifluoro acetic acid or is preferably, methanol and acetic acid.
Preferably, the molar ratio of the crude product to organic alcohol is 1: 8 and the crude product to organic acid is 1 :2.
The product namely N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide is recovered from the reaction mixture of step (iv) by filtering the reaction mixture, precipitating the product from the filtrate by gradually cooling the filtrate at 0-300C preferably 10 - 50° C and drying the precipitate at 60 - 70° C preferably in an electric oven.
The process of the invention affords (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide in high purity ( > 99.8%) and in good yield (about 53.68%) with Z- isomer content < 0.5%. The process duration is reduced and the process is simple, easy and convenient to carry out and is commercially viable and economical.
The following experimental example is illustrative of the invention but not limitative of the scope thereof :
Example 1
A mixture of 3,4-dihydroxy-5-nitro benzaldehyde (50Og), N,N-diethyl cyano acetamide
(575ml), acetic acid (375ml) and piperidine (500ml) in ethanol (4.51) were refluxed for 6 hrs. Ethanol was distilled off under vacuum and 1.5 1 of formic acid was added to the residue at
65° C and stirred for 30 mins at 65° C. The reaction mixture was cooled to R T and charged with methylene dichloride. The organic layer was separated and washed twice with 2 x 3.5 1 water. Methylene dichloride was distilled off under vacuum from the organic layer and the residue was treated with ethyl acetate 1.25 1. The yellow solid was filtered out from the solvent, washed with 1.25 1 ethyl acetate and dried in an electric oven at 60-70° C to obtain crude N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide.
Yield of crude entacapone 495g (59.63 %), Purity 99.2++
Z- isomer 0.5%
The crude product (495 g), methanol (3960ml) and acetic acid (990ml) were refluxed for lhr.
The clear solution was filtered and the product was precipitated by gradually cooling the filtrate to 10-15° C. The solid was filtered out, washed twice with cold ethyl acetate
(2 x 990 ml) at 15°C_and dried in an electric oven at 60-70° C.
Yield of entacapone based on the crude product 445.5g (90 %). Purity 99.8%.
Z-isomer 0.02 %
Claims
1. A process for the preparation of highly pure (E)-N,N-diethyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl) acrylamide (Entacapone) of the formula I
Formula I
comprising i) condensing 3,4-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 - 800C;
ii) extracting the residue with a chlorinated solvent and distilling off the solvent under vacuum;
iii) extracting the residue with an organic solvent to obtain crude N,N-diethyl-2- cyano-3-3,4-dihydroxy-5-nitrophenyl)acrylamide; and
iv) treating the crude product N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl) acrylamide 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.
2. The process as claimed in claim 1, wherein the organic solvent used in step (i) is selected from lower aliphatic alcohol like methanol, ethanol, n-propanol, iso-propanol or mixtures thereof or is preferably ethanol.
3. The process as claimed in claim 1, wherein organic base used in step (i) is selected from piperidine, morpholine, N-methyl morpholine or pyrrolidine or is preferably piperidine and the acid used in step (i) is selected from lower aliphatic carboxylic acid like acetic acid or formic acid or inorganic acid selected from hydrochloric acid or sulphuric acid or is preferably acetic acid or formic acid.
4. The process as claimed in claim 1, wherein the residue in step (i) is treated 65° C.
5. The process as claimed in claim 1, wherein the chlorinated solvent used ins tep (ii) is selected from chlorofom or methylene dichloride or is preferably methylene dichloride.
6. The process as claimed in claim 1, wherein the organic solvent used in step (iii) is selected from polar and non-polar solvents such as alcohols, ketones or esters or mixtures thereof or is preferably ester, preferably ethyl acetate.
7. The process as claimed in claim 1 wherein the mixture of organic alcohol and organic acid used in step (iv) is selected from aliphatic alcohol like methanol, ethanol, n- propanol or iso-propanol and lower aliphatic carboxylic acid like acetic acid, formic acid or trifluoro acetic acid or is preferably methanol and acetic acid.
8. The process as claimed in claim 1, wherein molar ratio of the crude product to alcohol is 1:8 and the crude product to organic acid is 1: 2.
9 N,N-diethyl-2-cyano-3-)3,4-dihydroxy-5-nitrophenyl) acrylamide of the formula 1
Formula I in high purity (> 99.8%) and in good yield (53.68%) prepared by the process as claimed in claim 1.
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IN2005/000363 WO2007054950A1 (en) | 2005-11-09 | 2005-11-09 | A process for the preparation of highly pure (e) n,n-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitro phenyl) acrylamide (entacapone) |
DE602005017204T DE602005017204D1 (en) | 2005-11-09 | 2005-11-09 | PROCESS FOR PREPARING HIGH-PURITY (E) -N, N-DIETHYL-2-CYANO-3- (3,4-DIHYDRO-5-NITROPHENYL) ACRYLAMIDE (ENTACAPONE) |
US12/092,657 US20080319226A1 (en) | 2005-11-09 | 2005-11-09 | Process For the Preparation of Highly Pure (E) N,N-Diethyl-2-Cyano-3-(3,4-Dihydroxy-5-Nitro Phenyl) Acrylamide (Entacapone) |
EP05826478A EP1945607B1 (en) | 2005-11-09 | 2005-11-09 | A process for the preparation of highly pure (e) n,n-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitro phenyl) acrylamide (entacapone) |
AT05826478T ATE445591T1 (en) | 2005-11-09 | 2005-11-09 | METHOD FOR PRODUCING HIGH PURITY (E)-N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDRO-5-NITROPHENYL)ACRYLAMIDE (ENTACAPONE) |
Applications Claiming Priority (1)
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PCT/IN2005/000363 WO2007054950A1 (en) | 2005-11-09 | 2005-11-09 | A process for the preparation of highly pure (e) n,n-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitro phenyl) acrylamide (entacapone) |
Publications (1)
Publication Number | Publication Date |
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WO2007054950A1 true WO2007054950A1 (en) | 2007-05-18 |
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PCT/IN2005/000363 WO2007054950A1 (en) | 2005-11-09 | 2005-11-09 | A process for the preparation of highly pure (e) n,n-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitro phenyl) acrylamide (entacapone) |
Country Status (5)
Country | Link |
---|---|
US (1) | US20080319226A1 (en) |
EP (1) | EP1945607B1 (en) |
AT (1) | ATE445591T1 (en) |
DE (1) | DE602005017204D1 (en) |
WO (1) | WO2007054950A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009084031A2 (en) * | 2007-12-03 | 2009-07-09 | Neuland Laboratories Ltd | An improved process for preparation of (2e)-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)n,n-diethyl-2-propenamide polymorphic form a |
EP2251323A1 (en) * | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Method for the purification of entacapone |
CN104402764A (en) * | 2014-11-26 | 2015-03-11 | 千辉药业(安徽)有限责任公司 | Preparation method for entacapone |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105061259A (en) * | 2015-08-25 | 2015-11-18 | 重庆植恩药业有限公司 | Preparing method for entacapone A-type crystals |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2200109A (en) * | 1986-11-28 | 1988-07-27 | Orion Yhtymae Oy | Catechol derivatives |
US5135950A (en) * | 1989-11-03 | 1992-08-04 | Orion-Yhtyma Oy | Stable polymorphic form of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide and the process for its preparation |
WO2005066117A1 (en) * | 2003-12-29 | 2005-07-21 | Wockhardt Limited | Stable polymorphs of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide |
WO2005070881A1 (en) * | 2003-12-24 | 2005-08-04 | Wockhardt Limited | An efficient process for the manufacture of (e)-entacapone polymorphic form a |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2003288712B2 (en) * | 2003-12-29 | 2010-11-04 | Suven Life Sciences Ltd | Alternative process for the preparation of entacapone |
US20080076825A1 (en) * | 2003-12-31 | 2008-03-27 | Thomas Bader | Novel Crystalline Forms of Entacapone and Production Thereof |
-
2005
- 2005-11-09 US US12/092,657 patent/US20080319226A1/en not_active Abandoned
- 2005-11-09 EP EP05826478A patent/EP1945607B1/en not_active Not-in-force
- 2005-11-09 DE DE602005017204T patent/DE602005017204D1/en active Active
- 2005-11-09 AT AT05826478T patent/ATE445591T1/en not_active IP Right Cessation
- 2005-11-09 WO PCT/IN2005/000363 patent/WO2007054950A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2200109A (en) * | 1986-11-28 | 1988-07-27 | Orion Yhtymae Oy | Catechol derivatives |
US5135950A (en) * | 1989-11-03 | 1992-08-04 | Orion-Yhtyma Oy | Stable polymorphic form of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide and the process for its preparation |
WO2005070881A1 (en) * | 2003-12-24 | 2005-08-04 | Wockhardt Limited | An efficient process for the manufacture of (e)-entacapone polymorphic form a |
WO2005066117A1 (en) * | 2003-12-29 | 2005-07-21 | Wockhardt Limited | Stable polymorphs of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009084031A2 (en) * | 2007-12-03 | 2009-07-09 | Neuland Laboratories Ltd | An improved process for preparation of (2e)-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)n,n-diethyl-2-propenamide polymorphic form a |
WO2009084031A3 (en) * | 2007-12-03 | 2010-11-25 | Neuland Laboratories Ltd | An improved process for preparation of (2e)-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)n,n-diethyl-2-propenamide polymorphic form a |
EP2251323A1 (en) * | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Method for the purification of entacapone |
CN104402764A (en) * | 2014-11-26 | 2015-03-11 | 千辉药业(安徽)有限责任公司 | Preparation method for entacapone |
Also Published As
Publication number | Publication date |
---|---|
EP1945607B1 (en) | 2009-10-14 |
DE602005017204D1 (en) | 2009-11-26 |
US20080319226A1 (en) | 2008-12-25 |
EP1945607A1 (en) | 2008-07-23 |
ATE445591T1 (en) | 2009-10-15 |
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