TW201139399A - New process for the preparation of dronedarone - Google Patents
New process for the preparation of dronedarone Download PDFInfo
- Publication number
- TW201139399A TW201139399A TW100100566A TW100100566A TW201139399A TW 201139399 A TW201139399 A TW 201139399A TW 100100566 A TW100100566 A TW 100100566A TW 100100566 A TW100100566 A TW 100100566A TW 201139399 A TW201139399 A TW 201139399A
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- Taiwan
- Prior art keywords
- formula
- salt
- compound
- butyl
- benzofuran
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 229960002084 dronedarone Drugs 0.000 title description 5
- ZQTNQVWKHCQYLQ-UHFFFAOYSA-N dronedarone Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 ZQTNQVWKHCQYLQ-UHFFFAOYSA-N 0.000 title description 5
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims abstract description 13
- -1 alkaline earth metal salt Chemical class 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 16
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 239000002689 soil Substances 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
- 150000001340 alkali metals Chemical class 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 229910001622 calcium bromide Inorganic materials 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- 150000002923 oximes Chemical class 0.000 claims description 2
- 125000006327 phenyl hydrazinyl group Chemical group [H]N(*)N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 229910001615 alkaline earth metal halide Inorganic materials 0.000 claims 2
- 239000012442 inert solvent Substances 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- 150000008282 halocarbons Chemical class 0.000 claims 1
- 229910003002 lithium salt Inorganic materials 0.000 claims 1
- 159000000002 lithium salts Chemical class 0.000 claims 1
- 229910000000 metal hydroxide Inorganic materials 0.000 claims 1
- 150000004692 metal hydroxides Chemical class 0.000 claims 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 abstract description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 16
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CPKOXUVSOOKUDA-UHFFFAOYSA-N 1-bromo-5-fluoro-2-iodo-4-methylbenzene Chemical compound CC1=CC(I)=C(Br)C=C1F CPKOXUVSOOKUDA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229960002919 dronedarone hydrochloride Drugs 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- XBXBZOAPPRKOHU-UHFFFAOYSA-N 1-benzofuran;sodium Chemical compound [Na].C1=CC=C2OC=CC2=C1 XBXBZOAPPRKOHU-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 2
- KPXVXTPTBDUVTL-UHFFFAOYSA-N 2-butyl-1-benzofuran-5-amine Chemical compound NC1=CC=C2OC(CCCC)=CC2=C1 KPXVXTPTBDUVTL-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000004533 benzofuran-5-yl group Chemical group O1C=CC2=C1C=CC(=C2)* 0.000 description 2
- 125000004915 dibutylamino group Chemical group C(CCC)N(CCCC)* 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 229940067157 phenylhydrazine Drugs 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- MAQKXLXQVGJOGF-UHFFFAOYSA-N (2-decylphenyl)-phenylmethanone Chemical compound CCCCCCCCCCC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAQKXLXQVGJOGF-UHFFFAOYSA-N 0.000 description 1
- KNUWYCOTCYXIBF-UHFFFAOYSA-N 1-benzofuran;1h-indole Chemical compound C1=CC=C2NC=CC2=C1.C1=CC=C2OC=CC2=C1 KNUWYCOTCYXIBF-UHFFFAOYSA-N 0.000 description 1
- PWRCBHQMTAPXQS-UHFFFAOYSA-N 1-benzofuran;potassium Chemical compound [K].C1=CC=C2OC=CC2=C1 PWRCBHQMTAPXQS-UHFFFAOYSA-N 0.000 description 1
- ZTEHOZMYMCEYRM-UHFFFAOYSA-N 1-chlorodecane Chemical compound CCCCCCCCCCCl ZTEHOZMYMCEYRM-UHFFFAOYSA-N 0.000 description 1
- OVJKFJDEVKABNF-UHFFFAOYSA-N 2-butyl-1-benzofuran Chemical compound C1=CC=C2OC(CCCC)=CC2=C1 OVJKFJDEVKABNF-UHFFFAOYSA-N 0.000 description 1
- CPCVNVLTHQVAPE-UHFFFAOYSA-N 2-propoxypropanoic acid Chemical compound CCCOC(C)C(O)=O CPCVNVLTHQVAPE-UHFFFAOYSA-N 0.000 description 1
- VZXXYILNWWRSGE-UHFFFAOYSA-N 3,5-dimethylheptan-4-one Chemical compound CCC(C)C(=O)C(C)CC VZXXYILNWWRSGE-UHFFFAOYSA-N 0.000 description 1
- OGIQUQKNJJTLSZ-UHFFFAOYSA-N 4-butylaniline Chemical compound CCCCC1=CC=C(N)C=C1 OGIQUQKNJJTLSZ-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000012679 convergent method Methods 0.000 description 1
- LPZONNUBKVPBPL-UHFFFAOYSA-N decane-1-sulfonamide Chemical compound CCCCCCCCCCS(N)(=O)=O LPZONNUBKVPBPL-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- MROCJMGDEKINLD-UHFFFAOYSA-N dichlorosilane Chemical compound Cl[SiH2]Cl MROCJMGDEKINLD-UHFFFAOYSA-N 0.000 description 1
- WINNISSSXBRWMA-UHFFFAOYSA-N dinitromethane Chemical compound [O-][N+](=O)C[N+]([O-])=O WINNISSSXBRWMA-UHFFFAOYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- LIKBJVNGSGBSGK-UHFFFAOYSA-N iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Fe+3].[Fe+3] LIKBJVNGSGBSGK-UHFFFAOYSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- QENHCSSJTJWZAL-UHFFFAOYSA-N magnesium sulfide Chemical compound [Mg+2].[S-2] QENHCSSJTJWZAL-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
201139399 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種式I之#_[2_丁基_3_{4-[(3-二丁基胺 基)丙氧基]笨甲醯基}-1-笨并呋喃_5_基]曱烷磺醯胺(決奈達 隆(Dronedarone))之新穎製備方法及其醫藥上可接受鹽和該 製備方法之新中間體。 S02
【先前技術】 式I之決奈達隆係用於治療心血管系統之特定病理變 化，特別係用於治療心絞痛、高血壓、心律不整及腦部血 液循環不足(EP 0471609 B1)。 用於製備式I之決奈達隆之已知方法有數種。公開號 WO 02/48132之專利申請案揭示下列超收斂 (super-convergent)方法： 式IV之5-胺基-2-丁基本并π夫喃係經曱確酸化，
IV 並將所得式Π之2-丁基-5-甲烧續酿胺苯并u夫喃
S 201139399
Me Η
在Friedel-Crafts條件下與式III之4-[3-(二丁基胺基）丙氧 基]-苯曱醯基氯鹽酸鹽反應，
HCI 以獲得式I之決奈達隆鹽酸鹽。 此方法就反應步驟數目而言係非常簡單且經濟的。然 而，其缺點係在最後步驟中獲得實質上經污染形式之決奈 達隆鹽酸鹽。此可藉由Friedel-Crafts反應中二丁基胺基-丙基之存在解釋。在公開實例中產率為90%，在純化步驟 期間，首先，粗製決奈達隆鹽酸鹽，然後接著於異丙醇中 以鹽酸溶液進行處理，獲得經純化之決奈達隆鹽酸鹽 (90%)。 5 201139399 °亥方法之另一項缺點為Friedel-Crafts反應中所用之反 應物及所得副產物並不溶於水，因此無法藉由水洗自系統 中去除。 'v δ玄方法之另一項缺點係在甲磺酸化5-胺基-2-丁基笨并 夫喃IV期間’經雙曱績酸化之衍生物總是以反應副產物形 式出=。純化係藉由再結晶解決其產率為。 標係設計出—種決奈達隆及其㈣上可接受鹽 、方法，該方法避免上述缺點並係經濟且可工業 吾人已發現若在該製 胺苯并呋喃II，而以其驗 條件下與式III之4^( 酸鹽反應， 你頌製程過程中，取代2-丁基-5-甲烷磺醯 以其驗金屬或鹼土金屬鹽在Friedel_Crafts • 4·[3-(二丁基胺基）丙氧基]_苯曱醯基氯鹽
然後可避免上述缺點。 【發明内容】 根據本發明，箱_ g 酸化式IV之5-胺基_2 藉由文獻已知方法(WO 02/48132)，甲磺 1-2·•丁基苯并呋喃，
S 6 IV201139399 且 將該所得式η Me 之2-丁基-5-曱烷磺醯胺苯并呋喃
合物之二::::屬或鹼土金屬鹽反應，以獲得式η化 然後將复如^/土金屬鹽， 之4-[3仁^基^所述般，在Friedel_Cra加條件下與式III 得式I之AL[2基）丙氧基]-苯曱醯基氯鹽酸鹽反應，以獲 基}-1-苯并呋喃-^^-3、4·^3-二丁基胺基）丙氧基]笨甲醯 由其鹽游離出。·_土]曱烷磺醯胺，其視情況轉換成其鹽或 根據本發明方 形成之副產物將 *點係甲4酸化式Iv化合物期間所 合物中加入會妨礙其他反應步驟，因在所得反應混 之驗金屬或队，或驗土金屬鹽溶液’該所需式11化合物 朴屬或驗土金屬鹽將溶解並留在水相中。
猎由k擇適合反應條件，可以所需純度及產率獲得式I 化合物，無形成副產物，且僅數百分比率之未反應起始物 可能留在反應混合物中’其可谷易地藉由水洗除去並可重 複使用。 根據本發明一實施例，式11化合物之鹼金屬鹽係與式 III化合物反應。術語驗金屬包括鐘、鈉或鉀。 201139399 式11化合物之鋰、鈉或鉀鹽係藉由式Π之2—丁基-5_ 甲烧續酿胺苯并呋喃與適當鹼金屬氫氧化物（氫氧化鋰、氣 氧化納、氫氧化鉀)反應而製得。 根據本發明另一實施例，式II化合物之驗土金屬鹽係 與式III化合物反應。術語鹼土金屬包括鎂或鈣。式Η之 2-丁基-5-甲烷磺醯胺苯并呋喃鋰之鎂或鈣鹽係藉由式u之 2-丁基-5-甲烷磺醯胺苯并呋喃先與鹼金屬氫氧化物（氫氧 化鋰或氫氧化鉀）反應，然後與適當鹼土金屬函化物（氯化 鈣、溴化鈣、氣化鎂、溴化鎂）反應而製得。 根據本發明較佳模式，式Η化合物之鹼金屬或鹼土金 屬鹽與式III化合物之反應係在惰性有機溶劑或惰性有機溶 劑之混合物中進行。可使用齒化烴(二氣甲烷、二氯乙烷、 氣苯)或其等之混合物作為惰性有機溶劑。 根據本發明較佳模式，式Π化合物之鹼金屬或鹼土金 屬鹽與式III化合物之反應係在Friedel_Crafts觸媒 (III)、氣化鋁)之存在下進行。 根據本發明較佳模式，式Η化合物之鹼金屬或鹼土金 屬鹽與式III化合物之反應係在1〇_1〇(rC2溫度下進行。 式II之2-丁基-5-甲燒續醮胺苯并吱喃
s
II 8 201139399 及其藉由甲磺酸化式IV之5-胺基-2-丁基苯并呋喃之製備 係由文獻(WO 02/48132)得知。
IV 該製程中所用之式ΙΠ之4_[3_(二丁基胺基）丙氧基]_ 苯甲醯基氣鹽酸鹽及其製備係由文獻(w0 02/48078)得知。
nBu
III 式π化合物之鐘鹽Ila、鈉鹽iIb、鉀鹽IIc、鎂鹽IId 及鈣鹽lie係新化合物，無法由文獻得知。 本發明其他細節係由下列實例說明，但不將申請專利 範圍限制在該等實例中。 【實施方式】 實例 實例1 基胺基）丙氧基]笨曱醯基丨_丨_笨并
#-[2-丁基-3-{4-[(3-二丁 呋喃-5-基]曱烷磺醯胺I 在由5.2克之2-丁基-5-曱烧確醮胺笨并吱喃鈉_ 及20毫升之二氣曱烷製成的懸浮液中，加入含克之 4-{3_(二丁基胺基）丙氧基卜笨甲醯基氣鹽酸鹽III之25毫升 9 201139399 之二氯曱烷溶液中。攪拌反應混合物30分鐘，在5-10°C下 於15分鐘内加入3.57克之氯化鐵(III)，並在20-25°C下攪 拌反應混合物2小時。在40°C下於10分鐘内將20毫升之 水加入混合物中並分離各相。隨攪拌以15毫升之水清洗二 氯甲烷相，然後以15毫升5%碳酸氫鈉溶液清洗之。蒸掉 二氯曱烷相。 獲得9.8克(98%)黃色油。 藉由HPLC獲得之純度：98.6% ]H NMR(DMSO) ： 0.8-0.9ppm(m, 9H); 1.2-1.5ppm(m, 10H); 1.67ppm(5,, 2H); 1.87ppm(5,, 2H); 2.38ppm(t, J=7.2Hz, 4H); 2.57ppm(m, 2H); 2.81ppm(t, J=7.5Hz, 2H); 2.91ppm(S, 3H); 9.5 lppm(t, J=6.2Hz, 2H); 7.09ppm(d, J=8.8Hz, 2H); 7.24ppm(dd，J=8.9, 2.2Hz，1H); 7.38ppm(d，J=2，lHz, 1H); 7.65ppm(d, J=8.8Hz, 1H); 7.81ppm(d, J=8.8Hz, 2H) 實例2
#-[2-丁基-3-{4-[(3-二丁基胺基）丙氧基]苯曱醯基}-1-苯并呋 喃-5-基]曱烷磺醯胺I 進行如實例1所述程序，但利用氯苯取代二氣曱烷。 產率：97.8% 藉由HPLC獲得之純度：98.4% 實例3 vV-[2-丁基-3-{4-[(3-二丁基胺基）丙氧基]苯甲醯基}-1-苯并呋 201139399
喃-5-基]曱烷磺醯胺I 進行如實例1所述程序，但差異在於利用等量之2-丁 基-5-曱烷磺醯胺苯并呋喃鉀鹽lie取代2-丁基-5-曱烷磺醯 胺苯并呋喃鈉鹽lib。所得物質與實例1之產物相同。 產率：99.1% 藉由HPLC獲得之純度：98.4% 實例4
#-[2-丁基-3-{4-[(3-二丁基胺基）丙氧基]苯曱醯基}-1-苯并 σ夫喃-5-基]曱烧橫酿胺I 進行如實例1所述程序，但差異在於利用等量之2-丁 基-5-曱烷磺醯胺苯并呋喃鋰鹽Ila取代2-丁基-5-曱烷磺醯 胺苯并呋喃鈉鹽lib。所得物質與實例1之產物相同。 產率：98.1% 藉由HPLC獲得之純度：98.7% 實例5
#-[2-丁基-3-{4-[(3-二丁基胺基）丙氧基]苯曱醯基}-1-苯并 呋喃-5-基]曱烷磺醯胺I 進行如實例1所述程序，但差異在於利用等量之2-丁 基-5-曱烷磺醯胺苯并呋喃鎂鹽lie取代2-丁基-5-曱烷磺醯 胺苯并呋喃鈉鹽lib。所得物質與實例1之產物相同。 產率：97.8% 藉由HPLC獲得之純度：99.0% 11 201139399 實例6
沁[2-丁基-3-{4-[(3-二丁基胺基）丙氧基]苯曱醯基}_κ笨并 呋喃-5-基]曱烷磺醯胺I 進行如實例1所述程序，但差異在於利用等量之2•丁 基-5-甲院續醢胺苯并呋喃鈣鹽II(i取代2-丁基_5_甲烷續酿 胺苯并呋喃鈉鹽lib。所得物質與實例1之產物相同。 產率：97.7% 藉由HPLC獲得之純度：97.6% 實例7 #-[2-丁基-3-{4-[(3-二丁基胺基）丙氧基]苯甲醯基卜u笨并 呋喃-5-基]甲烷磺醯胺j 進行如實例1所述程序，但使用2.93克之氯化鋁取代 氣化鐵(III)。 所付物質與實例1之產物相同。 產率：89.9% 藉由HPLC獲得之純度：96.1% 實例8 2-丁基-5-曱烷磺醯胺苯并呋喃鋰鹽Ila 在攪拌下將2.23克之2-丁基-5-曱烷磺醯胺笨并呋喃u 加入含0.20克氫氧化鋰之5毫升水溶液中。在室溫下授拌 反應混合物1小時，然後保持在5-10°C下8小時。收集沉
S 12 201139399 澱之白色物質，以1毫升5°C之水清洗之並在70°C下乾燥 之。 產物之質量：1.7克(74.5%)
熔點：252.1-253.7°C 元素分析：C:51.98°/〇, H:5_79%，Ν:4·61%，S:10.44%， Li:2.41% (計算值：C:57.1%，H:5.86%，Ν:5·13%，S:11.7%， Li:2.56%) 實例9 2-丁基-5-甲烷磺醯胺苯并呋喃鈉鹽lib 將2.12克之2_丁基-5-甲烷磺醯胺苯并呋喃II加入含1 克氩氧化鋰之75毫升水溶液中。將所得懸浮液溫熱至 70°C，然後令其冷卻至20°C並在5-10°C下攪拌1小時。過 濾產物，在真空中乾燥之。 產物之質量：2.04克(89.0%)
熔點：226.3-228.9°C 元素分析：C:59.9%，H:5.63%，N:5.16%，S:11.14%, Na:7.2% (計算值：C:59.98%，H:5.54%, N:4.84%, S:11.07%， Na:7.94%) 實例10 2-丁基-5-曱烷磺醯胺苯并呋喃鈉鹽lib 進行如實例9所述程序，但將40毫升之水用於反應 中。所得物質係與實例9之產物相同。 13 201139399 產率：95.0% 實例11 2-丁基-5-甲烧續醯胺苯并^夫喃鉀鹽nc 將2.12克之2-丁基甲烧續醯胺苯并咬喃u加入含！ 克85%氫氧化鐘之25毫升水溶液中。在室溫 合物！小時，_在穴下· 2小時。過物，在真空 中乾燥之。
產物之質量：2.0克(82.0〇/〇) 熔點：103.2-105.7°C Ν:4.54%，s:9.53%， N:4.58°/0j S: 10.47%, 元素分析：C:50.37%，h:5.16〇/0, Κ:12·0% (計算值：C:51.07%，H:5.24%， K:12.8°/〇) 實例12 2-丁基-5-曱烷續醯胺苯并呋喃卸鹽IIc 進行如實例11所述之程序，但將1〇毫升之水 應中。所得物質係與實例11之產物相同。 ； 產率：94.0% 實例13 2-丁基-5-甲烷磺醯胺苯并呋喃鈣鹽ne
將2.0克之2_丁基_5_曱烧伽胺笨并吹喃打加入人 85%氫氧化_之2G毫升水溶液中。㈣反應現合I扣 201139399 分鐘。在所得溶液中，於10分鐘内加入溶於5毫升水中之 0.89克氣化鈣。所得懸浮液在20-25°C下攪拌1小時，然後 在5°C下攪拌2小時。過濾產物並乾燥之。 產物之質量：1.8克(86.1%)
熔點：103.4-105.7°C 元素分析：C:51.74%, H:5.50%，N:4.55%，S:10.29%， Ca:5.8%(計算值：C:54.47%，H:5.58%，N:4.89%，S:11.17%， Ca:6.99%) 實例14 2-丁基-5-曱烷磺醯胺苯并呋喃鈣鹽lie 進行如實例13所述程序，但將15毫升之水取代20毫 升用於反應中。所得物質係與實例13之產物相同。 產率：92.0% 實例15 2-丁基-5-曱烷磺醯胺苯并呋喃鎂鹽lid 將1.6克之2-丁基-5-曱烷磺醯胺苯并呋喃II加入含 0.28克85%氫氧化鉀之16毫升水溶液中。攪拌反應混合物 30分鐘。在所得溶液中，於10分鐘内加入溶於5毫升水中 之0.76克氯化鎂。所得懸浮液在20_25°C下攪拌1小時，然 後在下攪拌2小時。過濾產物並乾燥之。 產量：1.4 克(83.8%)
熔點：高於270°C 15 201139399 元素分析：C:51.74%，H:5.50%，N:4.55%，S:10.29%, Mg:4.8% (計算值：C:56.0〇/〇, H:5.74%，N:5.03%，S:11.49%， Mg:4.36%) 實例16 2-丁基-5-甲烷磺醯、胺苯并呋喃鎂鹽lid 進行如實例15所述程序，但將10毫升之水取代16毫 升用於反應中。所得物質係與實例15之產物相同。 產率：93.7% 【圖式簡單說明】 無 【主要元件符號說明】 無
Claims (1)
- 201139399 七、申請專利範圍： 1. 一種製備式I之Λ42-丁基-3-{4-[(3-二丁基胺基）丙氧 基]苯曱醯基}-1-苯并呋喃-5-基]曱烷磺醯胺及其醫藥 上可接受鹽之方法， MeI 其特徵在於將式II化合物之鹼金屬或鹼土金屬鹽II 在觸媒的存在下與式III之4-[3-(二丁基胺基）丙氧基]-苯甲醯基氯鹽酸鹽反應， CI 〇〇一(ch2)nBu / N \ nbu *HCI III 且視情況將式I化合物轉換成其鹽或自其鹽游離出。 2. 如申請專利範圍第1項之方法，其特徵在於該鹼金屬 包括裡、鈉或钟，且驗土金屬包括鎖或J弓。 17 201139399 3. 如申請專利範圍第1-2項中任一項之方法，其特徵在 於式II化合物與式III化合物之反應係在惰性溶劑或其 等之混合物中進行。 4. 如申請專利範圍第3項之方法，其特徵在於應用鹵化 烴作為惰性溶劑。 5. 如申請專利範圍第4項之方法，其特徵在於使用二氣 曱烷、二氯乙烷、氯苯或其等之混合物作為齒化烴。 6. 如申請專利範圍第1-5項中任一項之方法，其特徵在 於使用氯化鐵(III)或氯化鋁作為觸媒。 7. 如申請專利範圍第1-6項中任一項之方法，其特徵在 於該反應係在l〇-l〇〇°C之溫度下進行。 8. —種式II之2-丁基-5-曱烷磺醯胺苯并呋喃之鹼金屬或 驗土金屬鹽9. 一種申請專利範圍第8項之式II化合物的鋰鹽Ila、鈉 201139399 鹽lib、鉀鹽lie、鎂鹽lid及鈣鹽lie。 10. —種製備申請專利範圍第8-9項中任一項之式II化合 物之鹼金屬鹽之方法，其特徵在於將式II化合物nBu 與適當驗金屬氫氧化物反應。 11.如申請專利範圍第10項之方法，其特徵在於該鹼金屬 氫氧化物包括氫氧化鋰、氫氧化鈉或氫氧化鉀。 12. —種製備申請專利範圍第8-9項中任一項之式II化合 物之鹼土金屬鹽之方法，其特徵在於將式II化合物nBu II 先與氫氧化鋰或氫氧化鉀反應，然後與適當鹼土金屬 鹵化物反應。 13.如申請專利範圍第12項之方法，其特徵在於該鹼土金 屬鹵化物包括氯化鎂、溴化鎂、氣化鈣或溴化鈣。 201139399 四、指定代表圖： (一) 本案指定代表圖為：第（無）圖。 (二) 本代表圖之元件符號簡單說明：無 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：
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| RU (1) | RU2012133967A (zh) |
| SG (1) | SG182405A1 (zh) |
| TW (1) | TW201139399A (zh) |
| UY (1) | UY33168A (zh) |
| WO (1) | WO2011083346A1 (zh) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0900759A2 (en) | 2009-12-08 | 2011-11-28 | Sanofi Aventis | Novel process for producing dronedarone |
| FR2957079B1 (fr) | 2010-03-02 | 2012-07-27 | Sanofi Aventis | Procede de synthese de derives de cetobenzofurane |
| FR2958290B1 (fr) | 2010-03-30 | 2012-10-19 | Sanofi Aventis | Procede de preparation de derives de sulfonamido-benzofurane |
| FR2958291B1 (fr) | 2010-04-01 | 2013-07-05 | Sanofi Aventis | Procede de preparation de derives d'amino-benzofurane |
| HUP1000330A2 (en) | 2010-06-18 | 2011-12-28 | Sanofi Sa | Process for the preparation of dronedarone and the novel intermediates |
| FR2962731B1 (fr) | 2010-07-19 | 2012-08-17 | Sanofi Aventis | Procede de preparation de derives d'amino-benzoyl-benzofurane |
| FR2963006B1 (fr) | 2010-07-21 | 2013-03-15 | Sanofi Aventis | Procede de preparation de derives de nitro-benzofurane |
| HUP1000386A2 (en) | 2010-07-22 | 2012-05-29 | Sanofi Sa | Novel process for producing dronedarone |
| HUP1100165A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Process for preparation of dronedarone by n-butylation |
| HUP1100167A2 (en) | 2011-03-29 | 2012-11-28 | Sanofi Sa | Process for preparation of dronedarone by mesylation |
| FR2983198B1 (fr) | 2011-11-29 | 2013-11-15 | Sanofi Sa | Procede de preparation de derives de 5-amino-benzoyl-benzofurane |
| EP2617718A1 (en) | 2012-01-20 | 2013-07-24 | Sanofi | Process for preparation of dronedarone by the use of dibutylaminopropanol reagent |
| WO2013121235A2 (en) | 2012-02-13 | 2013-08-22 | Sanofi | Process for preparation of dronedarone by removal of hydroxyl group |
| US9249119B2 (en) | 2012-02-14 | 2016-02-02 | Sanofi | Process for the preparation of dronedarone by oxidation of a sulphenyl group |
| US9382223B2 (en) | 2012-02-22 | 2016-07-05 | Sanofi | Process for preparation of dronedarone by oxidation of a hydroxyl group |
| US9238636B2 (en) | 2012-05-31 | 2016-01-19 | Sanofi | Process for preparation of dronedarone by Grignard reaction |
| EP2963869A4 (en) | 2013-02-26 | 2016-09-28 | Nec Corp | COMMUNICATION SYSTEM, SWITCH, CONTROL APPARATUS, CONTROL CHANNEL CONFIGURATION METHOD AND PROGRAM |
| CN103450124B (zh) * | 2013-08-30 | 2016-03-09 | 江苏九九久科技股份有限公司 | 决奈达隆合成方法 |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2665444B1 (fr) | 1990-08-06 | 1992-11-27 | Sanofi Sa | Derives d'amino-benzofuranne, benzothiophene ou indole, leur procede de preparation ainsi que les compositions les contenant. |
| GB9416219D0 (en) | 1994-08-11 | 1994-10-05 | Karobio Ab | Receptor ligands |
| FR2817865B1 (fr) | 2000-12-11 | 2005-02-18 | Sanofi Synthelabo | Derive aminoalkoxybenzoyle sous forme de sel, son procede de preparation et son utilisation comme intermediaire de synthese |
| FR2817864B1 (fr) * | 2000-12-11 | 2003-02-21 | Sanofi Synthelabo | Derive de methanesulfonamido-benzofurane, son procede de preparation et son utilisation comme intermediaire de synthese |
| IL146389A0 (en) | 2001-11-08 | 2002-07-25 | Isp Finetech Ltd | Process for the preparation of dronedarone |
| FR2833262A1 (fr) | 2001-12-06 | 2003-06-13 | Rhodia Chimie Sa | Procede de monosulfonylation d'un compose de type aminobenzofuranne ou aminobenzothiophene |
| DE10237819A1 (de) | 2002-08-19 | 2004-03-04 | Bayer Ag | 5-Nitrobenzofurane |
| CN101153012B (zh) * | 2006-09-29 | 2010-06-23 | 北京德众万全药物技术开发有限公司 | 一种决奈达隆关键中间体的新的制备方法 |
| UY32657A (es) | 2009-05-27 | 2010-12-31 | Sanofi Aventis | Procedimiento para la fabricación de productos intermedios de dronedarona |
| UY32656A (es) | 2009-05-27 | 2010-12-31 | Sanofi Aventis | Procedimiento para producir benzofuranos |
| FR2957079B1 (fr) | 2010-03-02 | 2012-07-27 | Sanofi Aventis | Procede de synthese de derives de cetobenzofurane |
| FR2958290B1 (fr) | 2010-03-30 | 2012-10-19 | Sanofi Aventis | Procede de preparation de derives de sulfonamido-benzofurane |
| FR2958289B1 (fr) | 2010-03-30 | 2012-06-15 | Sanofi Aventis | Procede de preparation de derives de 3-ceto-benzofurane |
| FR2958291B1 (fr) | 2010-04-01 | 2013-07-05 | Sanofi Aventis | Procede de preparation de derives d'amino-benzofurane |
| HUP1000330A2 (en) | 2010-06-18 | 2011-12-28 | Sanofi Sa | Process for the preparation of dronedarone and the novel intermediates |
| FR2962731B1 (fr) | 2010-07-19 | 2012-08-17 | Sanofi Aventis | Procede de preparation de derives d'amino-benzoyl-benzofurane |
| FR2963006B1 (fr) | 2010-07-21 | 2013-03-15 | Sanofi Aventis | Procede de preparation de derives de nitro-benzofurane |
| HUP1000386A2 (en) | 2010-07-22 | 2012-05-29 | Sanofi Sa | Novel process for producing dronedarone |
| FR2973027A1 (fr) | 2011-03-24 | 2012-09-28 | Sanofi Aventis | Procede de synthese de derives de cetobenzofurane |
| HUP1100167A2 (en) | 2011-03-29 | 2012-11-28 | Sanofi Sa | Process for preparation of dronedarone by mesylation |
| HUP1100166A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Reductive amination process for preparation of dronedarone using amine intermediary compound |
| HUP1100165A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Process for preparation of dronedarone by n-butylation |
-
2010
- 2010-01-08 HU HU1000010A patent/HUP1000010A2/hu unknown
- 2010-12-15 CN CN2010800580717A patent/CN102666522A/zh active Pending
- 2010-12-15 MX MX2012007897A patent/MX2012007897A/es not_active Application Discontinuation
- 2010-12-15 KR KR1020127020680A patent/KR20120115365A/ko not_active Application Discontinuation
- 2010-12-15 JP JP2012547552A patent/JP2013516451A/ja not_active Withdrawn
- 2010-12-15 WO PCT/HU2010/000143 patent/WO2011083346A1/en active Application Filing
- 2010-12-15 RU RU2012133967/04A patent/RU2012133967A/ru not_active Application Discontinuation
- 2010-12-15 CA CA2786218A patent/CA2786218A1/en not_active Abandoned
- 2010-12-15 BR BRBR112012016448-1A patent/BR112012016448A2/pt not_active IP Right Cessation
- 2010-12-15 EP EP10809330.3A patent/EP2521720B1/en active Active
- 2010-12-15 SG SG2012050118A patent/SG182405A1/en unknown
- 2010-12-15 AU AU2010340786A patent/AU2010340786A1/en not_active Abandoned
-
2011
- 2011-01-06 AR ARP110100030A patent/AR079843A1/es unknown
- 2011-01-07 TW TW100100566A patent/TW201139399A/zh unknown
- 2011-01-07 UY UY0001033168A patent/UY33168A/es not_active Application Discontinuation
-
2012
- 2012-06-20 IL IL220523A patent/IL220523A0/en unknown
- 2012-06-29 US US13/537,930 patent/US8658809B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| AR079843A1 (es) | 2012-02-22 |
| JP2013516451A (ja) | 2013-05-13 |
| IL220523A0 (en) | 2012-08-30 |
| BR112012016448A2 (pt) | 2015-09-01 |
| HU1000010D0 (en) | 2010-03-01 |
| MX2012007897A (es) | 2012-08-01 |
| EP2521720A1 (en) | 2012-11-14 |
| CN102666522A (zh) | 2012-09-12 |
| HUP1000010A2 (en) | 2011-11-28 |
| EP2521720B1 (en) | 2014-03-12 |
| WO2011083346A1 (en) | 2011-07-14 |
| UY33168A (es) | 2011-08-31 |
| US20120330036A1 (en) | 2012-12-27 |
| KR20120115365A (ko) | 2012-10-17 |
| CA2786218A1 (en) | 2011-07-14 |
| RU2012133967A (ru) | 2014-02-20 |
| AU2010340786A1 (en) | 2012-07-26 |
| US8658809B2 (en) | 2014-02-25 |
| SG182405A1 (en) | 2012-08-30 |
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