WO2008055849A1 - Process for the preparation of trifluoroethoxytoluenes - Google Patents

Process for the preparation of trifluoroethoxytoluenes Download PDF

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Publication number
WO2008055849A1
WO2008055849A1 PCT/EP2007/061818 EP2007061818W WO2008055849A1 WO 2008055849 A1 WO2008055849 A1 WO 2008055849A1 EP 2007061818 W EP2007061818 W EP 2007061818W WO 2008055849 A1 WO2008055849 A1 WO 2008055849A1
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Prior art keywords
trifluoroethoxy
toluene
formula
preparation
trifluoroethanol
Prior art date
Application number
PCT/EP2007/061818
Other languages
French (fr)
Inventor
Daina Zicane
Janis Jaunbergs
Original Assignee
Grindeks, A Joint Stock Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Grindeks, A Joint Stock Company filed Critical Grindeks, A Joint Stock Company
Priority to JP2009535081A priority Critical patent/JP2010508330A/en
Priority to AT07847103T priority patent/ATE514670T1/en
Priority to US12/312,323 priority patent/US20100063292A1/en
Priority to MX2009004647A priority patent/MX2009004647A/en
Priority to EP07847103A priority patent/EP2079674B1/en
Priority to EA200900357A priority patent/EA200900357A1/en
Priority to PL07847103T priority patent/PL2079674T3/en
Priority to BRPI0714991-3A priority patent/BRPI0714991A2/en
Priority to CA002660358A priority patent/CA2660358A1/en
Priority to AU2007316690A priority patent/AU2007316690A1/en
Publication of WO2008055849A1 publication Critical patent/WO2008055849A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00Ethers; Compounds having groups, groups or groups
    • C07C43/02Ethers
    • C07C43/20Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01Preparation of ethers
    • C07C41/09Preparation of ethers by dehydration of compounds containing hydroxy groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00Ethers; Compounds having groups, groups or groups
    • C07C43/02Ethers
    • C07C43/20Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C07C43/2055Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond

Definitions

  • the present invention relates to an novel process for the preparation a substituted 1 ,4-£/s(2,2,2-trifluoroethoxy)benzene of the formula (I)
  • 2,5-6/s(2,2,2-trifluoroethoxy)toluene is a derivative of 1 ,4-6/5(2,2,2- trifluoroethoxy)benzene, which as well is used as intermediate for synthesis of Flecainide.
  • £/s(2,2,2-trifluoroethoxy)benzene is that the process requires the reaction of 8 equivalents of 2,2,2-trifluoroethanol while only 2 equivalents are theoretically needed.
  • the use of less than 8 equivalents of 2,2,2- trifluoroethanol results in incomplete conversion to 1 ,4-£/s(2,2,2- trifluoroethoxy)benzene, with the starting material and 1-bromo-4-(2,2,2- trifluoroethoxy)benzene as the main impurities. Isolation and purification of desired product from this mixture is not practical on an industrial scale.
  • Another method involves the process to obtained the 1 ,4-£/s(2,2,2- trifluoroethoxy)benzene (III) is by the reaction of 4-fluoro-1-bromobenzene with 2,2,2-trifluoroethanol in the presence of sodium hydride, N 1 N- dimethylformamide and CuBr 2 at about 100-105 0 C WO 02/066413 (NARCHEM CORPORATION) 2002.02.20. .
  • the method of the present invention involves the novel initial preparation of 2,5-£/s(2,2,2-trifluoroethoxy)toluene by reaction 2,5-dihalotoluene with 2,2,2-trifluoroethanol in the presence alkali metal and copper containing material.
  • the 2,2,2-trifluoroathanol reacts in about 2-10 fold molar excess of the 2,5-dihalotoluene to replace the 2,5-dihalotoluene aromatic halogen substituents with trifluoroethoxy groups.
  • Bases that enable the reaction include alkali metals, e.g., metallic sodium.
  • a copper containing material is used as a catalyst in the reaction, e.g., copper (II) sulphate.
  • ⁇ /, ⁇ /-dimethylformamide can be used as an dipolar aprotic solvent.
  • the best mode for carrying out the reaction is a temperature of about 85 to 105 0 C.
  • the 2,5-£/s(2,2,2-trifluoroethoxy)toluene [II] can be used as intermediate in pharmaceutical industry.
  • 2,5-b/s ⁇ 2, 2, 2-trifluoroethoxy)toluene as intermediate yield of Flecainide [III] and pharmaceutically acceptable salts can be increased to 86%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Catalysts (AREA)

Abstract

The present invention relates to a process for the preparation of 2,5-bis(2,2,2-trifluoroethoxy)toluene (II). The compound 2,5-bis(2,2,2-trifluoroethoxy)toluene is useful as intermediate for pharmaceutical industry, especially useful as an intermediate for the preparation of Flecainide and pharmaceutically acceptable salts.

Description

Description
Process for the preparation of trifluoroethoxytoluenes Technical Field
[0001] The present invention relates to an novel process for the preparation a substituted 1 ,4-£/s(2,2,2-trifluoroethoxy)benzene of the formula (I)
Figure imgf000002_0001
m wherein R is methyl
[0002] 2,5-b/s{2, 2, 2-trifluoroethoxy)toluene of the formula [II] is useful as a novel intermediate in the pharmaceutical industry.
Figure imgf000002_0002
[0003] For example use as novel intermediate for the synthesis of the antiarrhythmic drug-Flecainide [III] and pharmaceutically acceptable salts thereof.
Figure imgf000003_0001
Background Art
[0004] 2,5-6/s(2,2,2-trifluoroethoxy)toluene is a derivative of 1 ,4-6/5(2,2,2- trifluoroethoxy)benzene, which as well is used as intermediate for synthesis of Flecainide.
[0005] It is known that 1 ,4-£/s(2,2,2-trifluoroethoxy)benzene can be obtained by the reaction of 1 ,4-dibromobenzene with 2,2,2-trifluoroethanol in the presence of sodium hydride, Λ/,Λ/-dimethylformamide and cuprous iodide GB 2045760 (RIKER LABORATORIES) 1980.03.18.
[0006] A serious disadvantage of using 1 ,4-dibromobenzene to form 1 ,4-
£/s(2,2,2-trifluoroethoxy)benzene is that the process requires the reaction of 8 equivalents of 2,2,2-trifluoroethanol while only 2 equivalents are theoretically needed. The use of less than 8 equivalents of 2,2,2- trifluoroethanol results in incomplete conversion to 1 ,4-£/s(2,2,2- trifluoroethoxy)benzene, with the starting material and 1-bromo-4-(2,2,2- trifluoroethoxy)benzene as the main impurities. Isolation and purification of desired product from this mixture is not practical on an industrial scale.
[0007] Another method involves the process to obtained the 1 ,4-£/s(2,2,2- trifluoroethoxy)benzene (III) is by the reaction of 4-fluoro-1-bromobenzene with 2,2,2-trifluoroethanol in the presence of sodium hydride, N1N- dimethylformamide and CuBr2 at about 100-1050C WO 02/066413 (NARCHEM CORPORATION) 2002.02.20. .
[0008] As disadvantage of this process is that the system NaH with the N,N- dimethylformaide has a high safety risk for large-scale industrial synthesis since this system can decompnose exothermically in an uncontrollable manner. BUCKLEY, J.. Report on thermal reaction. Chem. Eng. News. 1982, vol.60, no.28, p.5. , POND, D.. Sodium hydride and DMF. Chem.
Eng. News. 1982, vol.60, no.37, p.5,43. [0009] Both of these processes involve three steps to obtain the main intermediate 2,5-£/s(2,2,2-trifluoroethoxy)benzoic acid, for preparation
Flecainide. Disadvantage of multi steps process disclosed in that, what yield of 2,5-£/s(2,2,2-trifluoroethoxy)benzoic acid is reducing. Disclosure of Invention [0010] The above object is attained by present invention which provides a novel process for the preparation of 2,5-£/s(2,2,2-trifluoroethoxy)toluene of the formula [II] [0011]
Figure imgf000004_0001
|ϊi|
[0012] which process comprises reacting a 2,5-dihalotoluene of formula [IV] [0013]
Figure imgf000004_0002
[0014] wherein Xi and X2 is halogen, the Xi and X2 substituents may be the same or different, R is methyl. [0015] With 2,2,2-trifluoroethanol in the presence alkali metal and a copper containing material. [0016] The process of preparation of 2,5-bis(2,2,2-trifluoroethoxy)toluene by using as starting material 2,5-dihalotolunes has a following advantages:
[0017] 1. use of metallic sodium instead of sodium hydride and as dipolar aprotic solvent using N,N-dimethylformamide is attempt safer method in industrial production;
[0018] 2. production of desired final product in high yields;
[0019] 3. amenability for large scale production which does not require specialized equipment.
[0020] The method of the present invention involves the novel initial preparation of 2,5-£/s(2,2,2-trifluoroethoxy)toluene by reaction 2,5-dihalotoluene with 2,2,2-trifluoroethanol in the presence alkali metal and copper containing material. The 2,2,2-trifluoroathanol reacts in about 2-10 fold molar excess of the 2,5-dihalotoluene to replace the 2,5-dihalotoluene aromatic halogen substituents with trifluoroethoxy groups. Bases that enable the reaction include alkali metals, e.g., metallic sodium. A copper containing material is used as a catalyst in the reaction, e.g., copper (II) sulphate. For performing reaction Λ/,Λ/-dimethylformamide can be used as an dipolar aprotic solvent. The best mode for carrying out the reaction is a temperature of about 85 to 1050C.
As it is mentioned above 2,5-£/s(2,2,2-trifluoroethoxy)toluene can be used as a novel intermediate for preparation Flecainide and pharmaceutically acceptable salts in high yields up to 82%. The preparation of Flecainide can be released by a sequential combination of four process steps, starting from 2,5-dibromotoluene:
1. replacement of the 2,5-dibromotoluene aromatic bromine substituents by trifluoroethoxy groups, and, thus, preparation of 2,5-£/s(2,2,2- trifluoroethoxy)toluene or any of the intermediate substitution products 2-bromo-5-trifluorethoxytoluene and 5-bromo-2-trifluorethoxytoluene,
2. oxidation of 2,5-£/s(2,2,2-trifluoroethoxy)toluene with potassium or sodium permanganate, to produce 2,5-£/s(trifluorethoxy)benzoic acid,
3. activation of 2,5-£/s(2,2,2-trifluorethoxy)benzoic acid in-situ with a chloroformate, and substitution of the leaving carbonate group with 2- (aminomethyl)pyridine, and 4. hydrogenation of 2,5-i6»/s(2,2,2-trifluorethoxy)-Λ/-(pyrid-2-yl- methyl)benzamide to obtain Flecainide acetate.
Best Mode for Carrying Out the Invention
[0021] The present invention will be described in more detail with the aid of the following examples, which are merely representative and should not serve to limit the scope of the invention.
[0022] Preparation of 2,5-£/s(2,2I2-trifluoroethoxy)toluene from 2,5- dibromotoluene
[0023] 2,2,2-trifluoroethanol (55.0 g, 0.550 mol) was added to dioxane (125 ml_) in a glass vessel fitted with a reflux condenser. Sodium metal (11.5 g, 0.500 mol) was added in portions of 2-3 grams to the solution, resulting in a temperature increase from 22°C to 90°C. The solution was stirred at 85- 105°C until the sodium dissolution was completed, then N, N- dimethylformamide (100 ml_) was added, followed by 2,5-dibromotoluene (I) (42.5 g, 0.170 mol) and anhydrous copper (II) sulphate (2.9 g, 0.018 mol). The reaction mixture was stirred at 95-1000C for 4 hours, and then cooled to 25-3O0C and poured into 900 ml of a cold (5-1O0C) 40% aqueous methanol solution.
[0024] Concentrated hydrochloric acid was added (-25 ml_, 0.300 mol), until pH=1-2. The crystallization suspension was stirred for 1 hour at -5 to O0C, the solid white precipitate was filtered, after which the reaction vessel and the product cake on the filter were rinsed with 50 ml_ of water. The intermediate 2,5-£/s(2,2,2-trifluoroethoxy)toluene (II) was dried at ambient temperature and pressure for 5 hours, then at 22 to 240C and at a reduced pressure for 4 hours. The 2,5-b/s{2, 2, 2-trifluoroethoxy)toluene was obtained as a white or off-white powder (45.5 g, 92%) having a melting point of 370C to 420C.
Industrial Application
[0025] The 2,5-£/s(2,2,2-trifluoroethoxy)toluene [II] can be used as intermediate in pharmaceutical industry. For example, can be used as useful intermediate for obtaining Flecainide [III] and pharmaceutically acceptable salts. By using 2,5-b/s{2, 2, 2-trifluoroethoxy)toluene as intermediate yield of Flecainide [III] and pharmaceutically acceptable salts can be increased to 86%.

Claims

Claims
1. A substituted 1 ,4-£/s(2,2,2-trifluoroethoxy)benzene of the formula (I)
Figure imgf000008_0001
wherein R is methyl
2. A compound according to claim 1 , which is 2,5-£/s(2,2,2-trifluoroethoxy) toluene.
3. The process for the preparation of 2,5-£/s(2,2,2-trifluoroethoxy)toluene of the formula [II]
Figure imgf000008_0002
[Hi which process comprises reacting a 2,5-dihalotoluene of the formula [IV]
Figure imgf000008_0003
ilVf wherein Xi and X2 is halogen, the X-i, X2 substituents may be the same of different, R is methyl; with 2,2,2-trifluoroethanol in the presence of a alkali metal and a copper containing material.
4. The process of claim 3 wherein Xi and X2 preferably is Br, i.e. the compound of formula [IV] is 2,5-dibromotoluene.
5. The process of claim 3 wherein the reaction is carried out in the presence of copper (II) sulphate.
6. The process of claim 3 wherein the 2,2,2-trifluoroethanol is reacted in a first step with a strong base to form a 2,2,2-trifluoroethoxide and, which is reacted in a second step with a 2,5-dihalotoluene of formula [IV] in the presence of copper containing material.
7. The process of claim 3 wherein the alkali metal is metallic sodium.
8. The process of claim 3 wherein the reaction is conducted is an aprotic solvent.
9. The process of claim 8 wherein said aprotic solvent is a dipolar aprotic solvent or an N-containing heterocycle or mixtures thereof.
10. The process of claim 9 wherein the dipolar aprotic solvent is N, N- dimethylformamide.
11. The process of claim 3 wherein the molar ratio, between 2,5-dihalotoluene and 2,2,2-trifluoroethanol is comprised from 1 :2 to 1 :10, molar ration 1 :6 is preferably.
PCT/EP2007/061818 2006-11-06 2007-11-02 Process for the preparation of trifluoroethoxytoluenes WO2008055849A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
JP2009535081A JP2010508330A (en) 2006-11-06 2007-11-02 Preparation of trifluoroethoxytoluenes
AT07847103T ATE514670T1 (en) 2006-11-06 2007-11-02 METHOD FOR PRODUCING TRIFLUORETHOXYTOLUENES
US12/312,323 US20100063292A1 (en) 2006-11-06 2007-11-02 Process for the preparation of trifluoroethoxytoluenes.
MX2009004647A MX2009004647A (en) 2006-11-06 2007-11-02 Process for the preparation of trifluoroethoxytoluenes.
EP07847103A EP2079674B1 (en) 2006-11-06 2007-11-02 Process for the preparation of trifluoroethoxytoluenes
EA200900357A EA200900357A1 (en) 2006-11-06 2007-11-02 METHOD OF OBTAINING TRIFTOROETOXYTOLUOLES
PL07847103T PL2079674T3 (en) 2006-11-06 2007-11-02 Process for the preparation of trifluoroethoxytoluenes
BRPI0714991-3A BRPI0714991A2 (en) 2006-11-06 2007-11-02 process for the preparation of trifluroethoxytoluenes
CA002660358A CA2660358A1 (en) 2006-11-06 2007-11-02 Process for the preparation of trifluoroethoxytoluenes
AU2007316690A AU2007316690A1 (en) 2006-11-06 2007-11-02 Process for the preparation of trifluoroethoxytoluenes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06123547.9 2006-11-06
EP06123547A EP1918280A1 (en) 2006-11-06 2006-11-06 Process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide and salts thereof

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WO2008055849A1 true WO2008055849A1 (en) 2008-05-15

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PCT/EP2007/061818 WO2008055849A1 (en) 2006-11-06 2007-11-02 Process for the preparation of trifluoroethoxytoluenes
PCT/EP2007/061820 WO2008055851A1 (en) 2006-11-06 2007-11-02 Process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-n-(2-piperidylmethyl)-benzamide and salts thereof

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US (2) US20100056794A1 (en)
EP (3) EP1918280A1 (en)
JP (2) JP2010508331A (en)
KR (2) KR20090055638A (en)
CN (2) CN101516817A (en)
AT (1) ATE514670T1 (en)
AU (2) AU2007316692A1 (en)
BR (2) BRPI0714989A2 (en)
CA (2) CA2660364A1 (en)
EA (2) EA200900356A1 (en)
MX (2) MX2009004648A (en)
PL (1) PL2079674T3 (en)
WO (2) WO2008055849A1 (en)
ZA (2) ZA200902183B (en)

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Publication number Priority date Publication date Assignee Title
CN102977003A (en) * 2012-11-28 2013-03-20 郑州大明药物科技有限公司 Preparation method of flecainide acetate
CN111018694A (en) * 2019-12-12 2020-04-17 贵州省欣紫鸿药用辅料有限公司 Production method of flecainide
CN115368786B (en) * 2022-08-15 2023-05-09 江阴市华昌不锈钢管有限公司 Preparation process of super austenitic high-temperature-resistant corrosion-resistant stainless steel welded pipe

Citations (6)

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US3900481A (en) * 1974-04-01 1975-08-19 Riker Laboratories Inc Derivatives of pyrrolidine and piperidine
WO1998047853A1 (en) * 1997-04-21 1998-10-29 Finetech Ltd. Process for the preparation of trifluoroethoxyarenecarboxylic acids
WO2001090062A2 (en) * 2000-05-26 2001-11-29 Merck Patent Gmbh Method for the production of trifluoroethoxy-substituted benzoic acids
WO2002004419A2 (en) * 2000-07-12 2002-01-17 Geneva Pharmaceuticals, Inc. α,α-DIBROMO-α-CHLORO-ACETOPHENONES AS SYNTHONS
EP1283201A1 (en) * 2001-08-10 2003-02-12 A.M.S.A. ANONIMA MATERIE SINTETICHE E AFFINI S.p.A. Process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-n-(2-piperidyl-methyl)-benzamide (flecanide)
US20050059825A1 (en) * 2003-09-17 2005-03-17 Zhi-Xian Wang Novel process for the preparation of flecainide, its pharmaceutically acceptable salts and important intermediates thereof

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Publication number Priority date Publication date Assignee Title
US4617396A (en) * 1979-03-19 1986-10-14 Riker Laboratories, Inc. Process for the preparation of derivatives of piperidine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3900481A (en) * 1974-04-01 1975-08-19 Riker Laboratories Inc Derivatives of pyrrolidine and piperidine
WO1998047853A1 (en) * 1997-04-21 1998-10-29 Finetech Ltd. Process for the preparation of trifluoroethoxyarenecarboxylic acids
WO2001090062A2 (en) * 2000-05-26 2001-11-29 Merck Patent Gmbh Method for the production of trifluoroethoxy-substituted benzoic acids
WO2002004419A2 (en) * 2000-07-12 2002-01-17 Geneva Pharmaceuticals, Inc. α,α-DIBROMO-α-CHLORO-ACETOPHENONES AS SYNTHONS
EP1283201A1 (en) * 2001-08-10 2003-02-12 A.M.S.A. ANONIMA MATERIE SINTETICHE E AFFINI S.p.A. Process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-n-(2-piperidyl-methyl)-benzamide (flecanide)
US20050059825A1 (en) * 2003-09-17 2005-03-17 Zhi-Xian Wang Novel process for the preparation of flecainide, its pharmaceutically acceptable salts and important intermediates thereof

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KR20090055638A (en) 2009-06-02
BRPI0714989A2 (en) 2013-07-30
ATE514670T1 (en) 2011-07-15
MX2009004647A (en) 2009-05-20
ZA200902184B (en) 2010-03-31
AU2007316692A1 (en) 2008-05-15
ZA200902183B (en) 2010-07-28
CA2660364A1 (en) 2008-05-15
PL2079674T3 (en) 2011-11-30
CN101516845A (en) 2009-08-26
AU2007316690A1 (en) 2008-05-15
EA200900357A1 (en) 2009-10-30
KR20090064456A (en) 2009-06-18
JP2010508330A (en) 2010-03-18
EP2079674B1 (en) 2011-06-29
MX2009004648A (en) 2009-05-21
WO2008055851A8 (en) 2009-04-09
BRPI0714991A2 (en) 2013-07-30
WO2008055851A1 (en) 2008-05-15
US20100063292A1 (en) 2010-03-11
JP2010508331A (en) 2010-03-18
EA200900356A1 (en) 2009-10-30
EP1918280A1 (en) 2008-05-07
CN101516817A (en) 2009-08-26
EP2079692A1 (en) 2009-07-22
EP2079674A1 (en) 2009-07-22
CA2660358A1 (en) 2008-05-15
US20100056794A1 (en) 2010-03-04

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