WO2008023380A1 - Improved and simplified procedure for the preparation of (e) n,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)acrylamide - Google Patents
Improved and simplified procedure for the preparation of (e) n,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)acrylamide Download PDFInfo
- Publication number
- WO2008023380A1 WO2008023380A1 PCT/IN2006/000310 IN2006000310W WO2008023380A1 WO 2008023380 A1 WO2008023380 A1 WO 2008023380A1 IN 2006000310 W IN2006000310 W IN 2006000310W WO 2008023380 A1 WO2008023380 A1 WO 2008023380A1
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- WO
- WIPO (PCT)
- Prior art keywords
- process according
- solvent
- dihydroxy
- diethyl
- cyano
- Prior art date
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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
-
- 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
Definitions
- the present invention relates to an improved process for the preparation of the compound (E) N,N-DffiTHYI ⁇ 2-CYANOO(3,4-DIHYDROXY-5-NrrROPHENYL) ACRYLAMIDE having the structure of Formula -IV.
- the invention relates to a process for the preparation of (E) N,N-DIETHYL-2-CYANO-3(3,4-DIHYDROXY- 5-NITROPHENYL)ACRYLAMIDE which is efficient and Industrial advantageous.
- the said compound of the present invention is known as Entacapone.
- COMT Catechol-O-methyltransferase
- GB 8.727854 teaches (E) N,N-DIETHYL-2-CYANO-3(3,4-DIHYDROXY-5- NITROPHENYL)ACRYLAMIDE [ ENTACAPONE] for the treatment of Parkinson's disease as a potential inhibitor of catechol-O-methyl- transferase (COMT) enzyme.
- the process of innovator is disadvantageous in that it requires isolation of mixture of E and Z isomers and further treatment with formic acid or acetic acid in presence of hydrobromic acid to get pure E isomer.
- the organic solvent used in the step of condensation is selected from toluene and xylene.
- the preferred solvent is toluene.
- the step of condensation is carried out in presence of catalyst.
- the catalyst is selected from peperidine acetate, pyridine acetate, Para toluene sulphonic acid.
- the catalyst is piperidine acetate.
- the condensation reaction is preferably carried out at reflux temperature.
- the reflux temperature is 100-120 0 C, and most preferably between 108-112 0 C.
- the reaction period is between 4 to 8 hours, preferably between 5 to 6 hours.
- the reaction mass is acidified using hydrochloric acid or sulphuric acid although hydrochloric acid is preferred.
- the reaction mass is refluxed in presence of aqueous hydrobromic acid at reflux temperature of between 108-112 0 C for about 1-4 hours and preferably 1.5 to 2.0 hours.
- the solvent is removed completely by distillation.
- the solvent is distilled under vacuum and the distillation is carried out at temperatures between 60-90 0 C, preferably 70-80 0 C.
- a protic solvent is added.
- the said protic solvent is selected from methanol and ethanol, preferably methanol.
- the solvent is removed completely by distillation.
- the solvent is distilled under vacuum and at temperatures between 60-90 0 C, preferably 70-80 0 C.
- the solvent is concentrated to about 50% by vacuum distillation.
- the reaction mass is acidified to pH 0.5 to 1.5 preferably 1.0 by the use of hydrochloride acid or sulphuric acid preferably hydrochloric acid.
- the (E)-N,n-diethyl-2-cyano-3(3,4-dihydroxy-5- nitrophenyl) acrylamide that is isolated is mixture of E and Z isomer.
- the said isolated (E)-N,n- diethyl-2-cyano-3(3,4-dihydroxy-5- nitrophenyl) acrylamide is recrystalised in solvent selected from methanol, ethyl acetate or a mixture of toluene and methanol.
- the finally recrystallized (E)-N,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl) acrylamide is substantially free from Z-isomer , preferably NMT 0.20%.
- Mass was filtered through hyflow bed in hot condition. Filtrate was cooled to 10 0 C, pH of the filtrate adjusted to 1.0 to 2.0 with Con HCl. Mass was cooled to 5-10 ° C and product (E) -entacapone with Z-isomer content NMT 0.20% is isolated, dried at 70-80C was found to be stable polymorph A with melting point 162-164 0 C.
- the advantages of the process of the present invention are the following: 1) Reduction of reaction time by increasing the temperature of the reaction mass and driving the reaction fast by removing water formed in the reaction azeotropically. Reaction time was reduced to 6 hours from maximum of 100 hours and minimum of 20 hours of prior art. 2) Avoiding use of excess amount of one of the intermediate as also hazardous chemicals and number of solvents.
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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
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IN2006/000310 WO2008023380A1 (en) | 2006-08-24 | 2006-08-24 | Improved and simplified procedure for the preparation of (e) n,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)acrylamide |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IN2006/000310 WO2008023380A1 (en) | 2006-08-24 | 2006-08-24 | Improved and simplified procedure for the preparation of (e) n,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)acrylamide |
Publications (1)
Publication Number | Publication Date |
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WO2008023380A1 true WO2008023380A1 (en) | 2008-02-28 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/IN2006/000310 WO2008023380A1 (en) | 2006-08-24 | 2006-08-24 | Improved and simplified procedure for the preparation of (e) n,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)acrylamide |
Country Status (1)
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WO (1) | WO2008023380A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2251323A1 (en) | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Method for the purification of entacapone |
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 (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
-
2006
- 2006-08-24 WO PCT/IN2006/000310 patent/WO2008023380A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2251323A1 (en) | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Method for the purification of entacapone |
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 |
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