WO2006064296A1 - 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 - Google Patents
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 Download PDFInfo
- Publication number
- WO2006064296A1 WO2006064296A1 PCT/HU2005/000131 HU2005000131W WO2006064296A1 WO 2006064296 A1 WO2006064296 A1 WO 2006064296A1 HU 2005000131 W HU2005000131 W HU 2005000131W WO 2006064296 A1 WO2006064296 A1 WO 2006064296A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diethyl
- formula
- cyano
- acrylamide
- hydroxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000000543 intermediate Substances 0.000 title description 6
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 title description 5
- 150000007524 organic acids Chemical class 0.000 claims abstract description 9
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims abstract description 9
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 235000012141 vanillin Nutrition 0.000 claims abstract description 9
- DBTGDJLRURNRLD-XYOKQWHBSA-N (e)-2-cyano-n,n-diethyl-3-(4-hydroxy-3-methoxyphenyl)prop-2-enamide Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC=C(O)C(OC)=C1 DBTGDJLRURNRLD-XYOKQWHBSA-N 0.000 claims abstract description 7
- MAZRYCCTAIVEQP-IZZDOVSWSA-N 3-O-methylentacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(OC)=C(O)C([N+]([O-])=O)=C1 MAZRYCCTAIVEQP-IZZDOVSWSA-N 0.000 claims abstract description 7
- -1 amine compound Chemical class 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 229940117913 acrylamide Drugs 0.000 claims abstract 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 4
- RYSHIRFTLKZVIH-UHFFFAOYSA-N N,N-diethylcyanoacetamide Chemical compound CCN(CC)C(=O)CC#N RYSHIRFTLKZVIH-UHFFFAOYSA-N 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- 238000006396 nitration reaction Methods 0.000 claims description 2
- JRURYQJSLYLRLN-UHFFFAOYSA-N 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide Chemical compound CCN(CC)C(=O)C(C#N)=CC1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-UHFFFAOYSA-N 0.000 claims 1
- 239000003377 acid catalyst Substances 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000000047 product Substances 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229940074355 nitric acid Drugs 0.000 description 5
- 229960003337 entacapone Drugs 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 230000017858 demethylation Effects 0.000 description 3
- 238000010520 demethylation reaction Methods 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RNQBKZQLNUBWCE-UHFFFAOYSA-N 2-cyano-n,n-diethylacetamide;hydrochloride Chemical compound Cl.CCN(CC)C(=O)CC#N RNQBKZQLNUBWCE-UHFFFAOYSA-N 0.000 description 1
- BBFJODMCHICIAA-UHFFFAOYSA-N 3,4-dihydroxy-5-nitrobenzaldehyde Chemical compound OC1=CC(C=O)=CC([N+]([O-])=O)=C1O BBFJODMCHICIAA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZEHYRTJBFMZHCY-UHFFFAOYSA-N 5-nitrovanillin Chemical compound COC1=CC(C=O)=CC([N+]([O-])=O)=C1O ZEHYRTJBFMZHCY-UHFFFAOYSA-N 0.000 description 1
- 102000006378 Catechol O-methyltransferase Human genes 0.000 description 1
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012649 demethylating agent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 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
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU0402573A HUP0402573A2 (en) | 2004-12-15 | 2004-12-15 | Process for producing stable polymorph form of (e)-n,n-diethyl-3-cyano-3-(3,4-dihydroxi-5-nitrophenyl)-acrylamide and the intermediates of the process |
HUP0402573 | 2004-12-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006064296A1 true WO2006064296A1 (en) | 2006-06-22 |
Family
ID=89985687
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/HU2005/000131 WO2006064296A1 (en) | 2004-12-15 | 2005-12-13 | 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 |
Country Status (2)
Country | Link |
---|---|
HU (1) | HUP0402573A2 (de) |
WO (1) | WO2006064296A1 (de) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007077572A1 (en) * | 2006-01-02 | 2007-07-12 | Actavis Group Ptc Ehf | A process for the preparation of entacapone form-a |
WO2008007093A1 (en) * | 2006-07-12 | 2008-01-17 | Pliva Hrvatska D.O.O. | Process and product |
EP1935873A1 (de) | 2006-12-19 | 2008-06-25 | Dipharma Francis S.r.l. | Verfahren zur Herstellung von Entacapon |
EP2251323A1 (de) | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Verfahren zur Reinigung von Entacapon |
WO2011008675A2 (en) * | 2009-07-15 | 2011-01-20 | Chadeayne Andrew R | Catecholamine compounds, compositions, and formulations, and methods of using the same |
WO2013149566A1 (en) * | 2012-04-01 | 2013-10-10 | Sunshine Lake Pharma Co., Ltd. | Process for the preparation of entacapone and its intermediate thereof |
CN105061259A (zh) * | 2015-08-25 | 2015-11-18 | 重庆植恩药业有限公司 | 一种恩他卡朋a型晶的制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5446194A (en) * | 1986-11-28 | 1995-08-29 | Orion-Yhtyma Oy | Pharmacologically active catechol derivatives |
WO2005063693A1 (en) * | 2003-12-29 | 2005-07-14 | Suven Life Sciences Ltd | Improved process for the preparation of entacapone |
-
2004
- 2004-12-15 HU HU0402573A patent/HUP0402573A2/hu unknown
-
2005
- 2005-12-13 WO PCT/HU2005/000131 patent/WO2006064296A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5446194A (en) * | 1986-11-28 | 1995-08-29 | Orion-Yhtyma Oy | Pharmacologically active catechol derivatives |
WO2005063693A1 (en) * | 2003-12-29 | 2005-07-14 | Suven Life Sciences Ltd | Improved process for the preparation of entacapone |
Non-Patent Citations (1)
Title |
---|
WIKBERG ET AL.: "Identification of Major Metabolites of the Catechol-O-Methyl Transferase Inhibitor Entacapone in Rats and Humans", DRUG METABOLISM AND DISPOSITION , 21(1), 81-92 CODEN: DMDSAI; ISSN: 0090-9556, vol. 21, no. 1, 1993, pages 81 - 92, XP009064899 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007077572A1 (en) * | 2006-01-02 | 2007-07-12 | Actavis Group Ptc Ehf | A process for the preparation of entacapone form-a |
WO2008007093A1 (en) * | 2006-07-12 | 2008-01-17 | Pliva Hrvatska D.O.O. | Process and product |
EP1935873A1 (de) | 2006-12-19 | 2008-06-25 | Dipharma Francis S.r.l. | Verfahren zur Herstellung von Entacapon |
US7750177B2 (en) | 2006-12-19 | 2010-07-06 | Dipharma Francis S.R.L. | Process for the preparation of entacapone |
EP2251323A1 (de) | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Verfahren zur Reinigung von Entacapon |
WO2011008675A2 (en) * | 2009-07-15 | 2011-01-20 | Chadeayne Andrew R | Catecholamine compounds, compositions, and formulations, and methods of using the same |
WO2011008675A3 (en) * | 2009-07-15 | 2011-04-28 | Chadeayne Andrew R | Catecholamine compounds, compositions, and formulations, and methods of using the same |
WO2013149566A1 (en) * | 2012-04-01 | 2013-10-10 | Sunshine Lake Pharma Co., Ltd. | Process for the preparation of entacapone and its intermediate thereof |
CN105061259A (zh) * | 2015-08-25 | 2015-11-18 | 重庆植恩药业有限公司 | 一种恩他卡朋a型晶的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
HU0402573D0 (en) | 2005-02-28 |
HUP0402573A2 (en) | 2006-07-28 |
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