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
Definitions
- the invention relates to a new process for the preparation of pure E isomer of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro-phehyl)-acrylamide of formula (1)
- the invention also relates to new intermediates formed in the process:
- the crude product which also comprises the Z isomer and form "B" of the E isomer, is treated at 9O 0 C with formic acid or acetic acid also comprising hydrogen bromide or hydrogen chloride, the mixture is cooled then slowly to 2O 0 C, maintained at this temperature for 20 hours, thereafter it is cooled to 15 0 C and maintained at this temperature for further 6 hours.
- the resulting product comprises up to 3 % by -weight ⁇ of undesired " components (Z isomer and/or form -"B"); its melting point is 162-163 0 C. -
- Entacapone is prepared by a new process through intermediates which have not been disclosed before in the literature, achieving thereby that even the first intermediate is obtained practically solely in the form of the desired E geometric isomer.
- the undesired Z isomer which is in fact a ballast, does not appear in the further steps.
- the preferred forms of the process according to the invention enable one to use mild reaction conditions and short reaction times, thus the side reactions are suppressed and excellent yields can be obtained.
- N.N-diethyl-cyanoacetamide is reacted with N.N-diethyl-cyanoacetamide in the presence of a weak organic acid and of an amine compound used as catalysts.
- weak organic acid preferably an aliphatic carboxylic acid can be used, of which acetic acid is particularly preferred; whereas as amine compound suitably a secondary amine, preferably piperidine or diethyl amine, particularly preferably diethyl amine can be applied.
- the reaction can be performed in an aprotic solvent, preferably in acetonitrile or toluene, suitably at the boiling point of the solvent utilized.
- Nitration can be performed by conventional methods under conventional conditions.
- nitric acid is used as nitrating agent and the reaction is performed in an organic acid or in an aqueous medium; under these conditions the reaction can also be performed at temperatures close to room temperature (at 15-3 ' 5 0 C, preferably a_t 25 0 C).
- nitric - acid with a strength of 55-63 % by weight, particularly of -58 % by weight, is used as reactant.
- the resulting compound of formula (4) also comprises the Z geometric isomer in amounts of less than 1 % by weight; thus it does not require further purification and can be directly transferred to the next reaction. .
- Demethylation can be performed by conventional methods under conventional conditions: According to a particularly preferred method demethylation is performed in a dipolar aprotic solvent, in the presence of a Lewis acid and of an organic base. Under such conditions demethylation proceeds within a short period of time (about 1 hour at a temperature of about 100 0 C), whereas when other conven- . tional demethylating agents (such as hydrogen bromide) are used, longer - sometimes much longer - reaction times and/or temperatures exceeding 10O 0 C are required.
- dipolar aprotic solvent e.g.
- the resulting end product can be purified further.
- the end product is recrystallized first from isopropanol and then from a mixture of acetone and acetic acid.
- the compounds of formulae (3) and (4), formed " as intermediates in the above process, are new.
- the invention also relates to these new compounds and to the preparation of the new compounds. .
- the separated product is filtered off, washed acid-free with water and dried in air, 25.1 g of the title compound, comprising less than 1. % by weight of Z geometric isomer as determined by HPLC, are obtained; m.p.: 105-107 0 C.
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 (es) |
| WO (1) | WO2006064296A1 (es) |
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 (en) | 2006-12-19 | 2008-06-25 | Dipharma Francis S.r.l. | A process for the preparation of entacapone |
| EP2251323A1 (en) | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Method for the purification of entacapone |
| 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 (en) | 2006-12-19 | 2008-06-25 | Dipharma Francis S.r.l. | A process for the preparation of entacapone |
| US7750177B2 (en) | 2006-12-19 | 2010-07-06 | Dipharma Francis S.R.L. | Process for the preparation of entacapone |
| EP2251323A1 (en) | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Method for the purification of entacapone |
| 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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