EP2542544A1 - Ketobenzofuran derivatives, method for synthesising same, and intermediates - Google Patents
Ketobenzofuran derivatives, method for synthesising same, and intermediatesInfo
- Publication number
- EP2542544A1 EP2542544A1 EP11712941A EP11712941A EP2542544A1 EP 2542544 A1 EP2542544 A1 EP 2542544A1 EP 11712941 A EP11712941 A EP 11712941A EP 11712941 A EP11712941 A EP 11712941A EP 2542544 A1 EP2542544 A1 EP 2542544A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- butyl
- benzofuran
- benzoyl
- butylamino
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 239000000543 intermediate Substances 0.000 title claims abstract description 61
- 238000000034 method Methods 0.000 title claims abstract description 47
- ACZGCWSMSTYWDQ-UHFFFAOYSA-N 3h-1-benzofuran-2-one Chemical class C1=CC=C2OC(=O)CC2=C1 ACZGCWSMSTYWDQ-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 32
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 30
- 238000006789 Nenitzescu synthesis reaction Methods 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 92
- -1 di-n-butylamino-2-ethoxy Chemical group 0.000 claims description 62
- 125000003118 aryl group Chemical group 0.000 claims description 52
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
- 125000005594 diketone group Chemical group 0.000 claims description 33
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 31
- 230000008569 process Effects 0.000 claims description 30
- 125000001188 haloalkyl group Chemical group 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
- 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 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 14
- 229960002084 dronedarone Drugs 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 239000012429 reaction media Substances 0.000 claims description 12
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 11
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 239000012453 solvate Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 229960000583 acetic acid Drugs 0.000 claims description 10
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 10
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 150000001336 alkenes Chemical class 0.000 claims description 6
- 150000001345 alkine derivatives Chemical class 0.000 claims description 6
- 150000004677 hydrates Chemical class 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 230000000269 nucleophilic effect Effects 0.000 claims description 5
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000005935 nucleophilic addition reaction Methods 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- NDSXSCFKIAPKJG-UHFFFAOYSA-N CC(C)O[Ti] Chemical compound CC(C)O[Ti] NDSXSCFKIAPKJG-UHFFFAOYSA-N 0.000 claims description 2
- 108010037444 diisopropylglutathione ester Proteins 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 230000007717 exclusion Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000007810 chemical reaction solvent Substances 0.000 description 7
- 125000004915 dibutylamino group Chemical group C(CCC)N(CCCC)* 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- 238000010533 azeotropic distillation Methods 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 6
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 5
- UAEPNZWRGJTJPN-UHFFFAOYSA-N Methylcyclohexane Natural products CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- MRIPEESUXRBPND-UHFFFAOYSA-N (4-hydroxyphenyl)methanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=C(O)C=C1 MRIPEESUXRBPND-UHFFFAOYSA-N 0.000 description 3
- XGAJABPTUOLUAE-UHFFFAOYSA-N 2-butyl-5-nitro-1-benzofuran Chemical compound [O-][N+](=O)C1=CC=C2OC(CCCC)=CC2=C1 XGAJABPTUOLUAE-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 3
- 150000004060 quinone imines Chemical class 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- BNGYNTKMJWWSQI-YYDJUVGSSA-N (e)-1-[4-[3-(dibutylamino)propoxy]phenyl]-3-(propan-2-ylamino)hept-2-en-1-one Chemical compound CCCCN(CCCC)CCCOC1=CC=C(C(=O)\C=C(/CCCC)NC(C)C)C=C1 BNGYNTKMJWWSQI-YYDJUVGSSA-N 0.000 description 2
- OOVQCULARLASPF-UHFFFAOYSA-N 1-phenylhept-2-en-1-one Chemical compound CCCCC=CC(=O)C1=CC=CC=C1 OOVQCULARLASPF-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- 229940073735 4-hydroxy acetophenone Drugs 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical class OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- RIXFNPNNPAKZNE-QPNALZDCSA-N FB(F)F.CCCCN(CCCC)CCCOC1=CC=C(C(=O)\C=C(\O)CCCC)C=C1 Chemical compound FB(F)F.CCCCN(CCCC)CCCOC1=CC=C(C(=O)\C=C(\O)CCCC)C=C1 RIXFNPNNPAKZNE-QPNALZDCSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N isobutyl amine Natural products CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- NDLQEBVURWOHCQ-UHFFFAOYSA-N n-(4-oxocyclohexa-2,5-dien-1-ylidene)methanesulfonamide Chemical compound CS(=O)(=O)N=C1C=CC(=O)C=C1 NDLQEBVURWOHCQ-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- LVCFZOBNRYAAME-AZPGRJICSA-N (e)-1-[4-[3-(dibutylamino)propoxy]phenyl]-3-(4-methoxyanilino)hept-2-en-1-one Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)\C=C(/CCCC)NC1=CC=C(OC)C=C1 LVCFZOBNRYAAME-AZPGRJICSA-N 0.000 description 1
- HZSLPVCWYZRQLW-KZAGWHOFSA-N (e)-1-[4-[3-(dibutylamino)propoxy]phenyl]-3-(4-methoxyanilino)hept-2-en-1-one;hydrochloride Chemical compound Cl.C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)\C=C(/CCCC)NC1=CC=C(OC)C=C1 HZSLPVCWYZRQLW-KZAGWHOFSA-N 0.000 description 1
- SEQJRHMQVKBUQY-FOXIJYENSA-N (e)-1-[4-[3-(dibutylamino)propoxy]phenyl]-3-[4-[[(e)-1-[4-[3-(dibutylamino)propoxy]phenyl]-1-oxohept-2-en-3-yl]amino]butylamino]hept-2-en-1-one Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)\C=C(/CCCC)NCCCCN\C(CCCC)=C\C(=O)C1=CC=C(OCCCN(CCCC)CCCC)C=C1 SEQJRHMQVKBUQY-FOXIJYENSA-N 0.000 description 1
- JHMNWDLJXKZXHB-UHFFFAOYSA-N 1-[4-[3-(dibutylamino)propoxy]phenyl]heptane-1,3-dione Chemical compound CCCCN(CCCC)CCCOC1=CC=C(C(=O)CC(=O)CCCC)C=C1 JHMNWDLJXKZXHB-UHFFFAOYSA-N 0.000 description 1
- ASJCNHNBHPJYRK-UHFFFAOYSA-N 1-[4-[3-(dibutylamino)propoxy]phenyl]heptane-1,3-dione;hydrochloride Chemical compound Cl.CCCCN(CCCC)CCCOC1=CC=C(C(=O)CC(=O)CCCC)C=C1 ASJCNHNBHPJYRK-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-M 4-aminobenzoate Chemical compound NC1=CC=C(C([O-])=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-M 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical class CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical class [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical class [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- VYEYJCBEXFTGBN-UHFFFAOYSA-N acetic acid;1,3-dimethyl-7h-purine-2,6-dione Chemical compound CC(O)=O.O=C1N(C)C(=O)N(C)C2=C1NC=N2 VYEYJCBEXFTGBN-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002009 alkene group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 239000011668 ascorbic acid Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- WPTMDNDUQTZHIC-UHFFFAOYSA-N but-1-yne Chemical group [CH2-]CC#[C+] WPTMDNDUQTZHIC-UHFFFAOYSA-N 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 229940018560 citraconate Drugs 0.000 description 1
- HNEGQIOMVPPMNR-IHWYPQMZSA-N citraconic acid Chemical compound OC(=O)C(/C)=C\C(O)=O HNEGQIOMVPPMNR-IHWYPQMZSA-N 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 150000002411 histidines Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- LVHBHZANLOWSRM-UHFFFAOYSA-N itaconic acid Chemical compound OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- DWKVCQXJYURSIQ-UHFFFAOYSA-N n-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]methanesulfonamide;hydron;chloride Chemical compound Cl.C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 DWKVCQXJYURSIQ-UHFFFAOYSA-N 0.000 description 1
- WIGIMTPODDMCNY-UHFFFAOYSA-N n-butyl-3-chlorobutan-1-amine Chemical compound CCCCNCCC(C)Cl WIGIMTPODDMCNY-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical class [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical class [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical class NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
Definitions
- the present invention relates to cetobenzofuran derivatives of general formula (I) shown below as well as to their synthesis process via the coupling between a quinoneimine and a synthesis mediates.
- G1 represents a linear or branched (i) alkyl group, (ii) haloalkyl, (iii) cycloalkyl, (iv) aryl, substituted or unsubstituted, (v) alkene or (vi) alkyne,
- G3 represents (i) a group -NHS0 2 c or (ii) a group -NHRc, wherein Rc is (a) alkyl, linear or branched, (b) cycloalkyl or (c) an aryl group, substituted or unsubstituted,
- G5 represents a halogen atom or a group -ORb where Rb represents a hydrogen atom, an alkyl, haloalkyl, aryl, arylalkyl, heteroaryl, cycloalkyl, heterocycloalkyl group or a -alkyleneaminoalkyl group,
- Ra is chosen from hydrogen atom, halogen atoms, alkyl, haloalkyl, alkoxy and alkoxyalkyl groups,
- na is an index equal to 0, 1, 2, 3 or 4.
- cetobenzofurans (I) is 2-n-butyl-3- [4- (3-di-n-butylaminopropoxy) benzoyl] -5-methylsulfonamido-benzofuran known as dronedarone.
- Dronedarone is particularly useful as an active ingredient in indications of cardiac arrhythmia.
- the free base form of dronedarone is synthesized according to the process described in EP0471609B1 via the key benzofuran ring intermediate, 2-butyl-5-nitro-benzofuran.
- the 2-butyl-5-nitro-benzofuran intermediate must be functionalized in position 3 and must be converted to position 5, according to scheme 1 below.
- the nitro group carried in position 5 of 2-butyl-5-nitro-benzofuran must be converted to methanesulfonamide by a reduction of - N0 2 in -NH 2 followed by sulfonylation.
- the Applicant has therefore sought new synthetic routes involving benzofurans, preferably already functionalized in the 2, 3 and 5 positions of the benzofuran ring and advantageously already suitably functionalised in positions 2 and 5, in order to achieve the synthesis of molecules. of formula (I) above, thus making it possible to circumvent the technical difficulties while at the same time best meeting the constraints of cost, toxicity, safety and respect for the environment related to the industrialization of such a synthetic process.
- Nenitzescu is controlled by the bulk of the quinonimine used: a quinonimine carrying a bulky group directs the reaction towards the A pathway whereas one would expect that a space-saving group directs the reaction as well towards the pathway. A that way B leading to obtaining a product mix.
- the invention relates to a cetobenzofuran derivative of formula (I) below:
- G 1 represents a linear or branched (i) alkyl group, advantageously a C 1 -C 8 alkyl group, even more advantageously a C 1 -C 4 alkyl group such as, for example, a methyl, ethyl, n-propyl or isopropyl group; butyl, sec-butyl or tert-butyl, (ii) haloalkyl, (iii) cycloalkyl, (iv) aryl, substituted or unsubstituted, (v) alkene or (vi) alkyne, advantageously G1 represents an alkyl group and even more advantageously G1 is n-butyl;
- G3 represents (i) a group -NHS0 2 c or (ii) a group -NHRc, wherein Rc is (a) alkyl, linear or branched, preferably an alkyl group C1-C8, even more preferably an alkyl group C1-C4, such as for example a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl group, (b) a cycloalkyl group or (c) an aryl group, substituted or unsubstituted , advantageously G 3 represents a group -NHSO 2 alkyl or a group -NHSO 2 aryl, even more advantageously G 3 represents a group -
- G5 represents a halogen atom or a group -ORb where Rb represents a hydrogen atom, an alkyl, haloalkyl, aryl or arylalkyl group, heteroaryl, cycloalkyl, heterocycloalkyl or a -alkyleneamoalkyl group, advantageously G5 represents a group -ORb with Rb chosen from -alkyleneaminoalkyl groups, advantageously Rb represents a 3- (di-n-butylamino) -propyl group;
- Ra represents a substituent chosen from hydrogen, halogen atoms, alkyl, haloalkyl, alkoxy and alkoxyalkyl groups, advantageously Ra represents a substituent chosen from the hydrogen atom, the halogen atoms and the halogen atoms; alkyl groups,
- na is an index equal to 0, 1, 2, 3 or 4,
- cetobenzofuran derivative being in the form of (i) acid, (ii) base, (iii) addition salt with an acid or a base, (iv) hydrate or (v) solvate, at least one exclusion of dronedarone, its salts, solvates and hydrates.
- the invention relates to a process for the synthesis of a cetobenzofuran derivative, in the form of (i) acid, (ii) base, (iii) acid or base addition salt, (iv) hydrate or (v) solvate, advantageously dronedarone or its hydrochloride salt, the following cetobenzo derivative I):
- G 1 represents a linear or branched (i) alkyl group, advantageously a C 1 -C 8 alkyl group, even more advantageously a C 1 -C 4 alkyl group such as, for example, a methyl, ethyl, n-propyl or isopropyl group; butyl, sec-butyl or tert-butyl, (ii) haloalkyl, (iii) cycloalkyl, (iv) aryl, substituted or unsubstituted, (v) alkene or (vi) alkyne, advantageously G1 represents an alkyl group and even more advantageously G1 is n-butyl;
- G3 represents (i) a group -NHS0 2 c or (ii) a group -NHRc, wherein Rc is (a) alkyl, linear or branched, preferably an alkyl group C1-C8, even more preferably an alkyl group C1-C4, such as for example a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl group, (b) a cycloalkyl group or (c) an aryl group, substituted or unsubstituted preferably, G 3 represents a group -NHSO 2 alkyl or a group -NHSO 2 aryl, even more advantageously G 3 represents a group - NHS0 2 CH 3 ;
- G5 represents a halogen atom or a group -ORb where Rb represents a hydrogen atom, an alkyl, haloalkyl, aryl or arylalkyl group, heteroaryl, cycloalkyl, heterocycloalkyl or a -alkyleneamoalkyl group, advantageously G5 represents a group -ORb with Rb chosen from -alkyleneaminoalkyl groups, advantageously Rb represents a 3- (di-n-butylamino) -propyl group;
- Ra represents a substituent chosen from hydrogen, halogen atoms, alkyl, haloalkyl, alkoxy and alkoxyalkyl groups, advantageously Ra represents a substituent chosen from the hydrogen atom, the halogen atoms and the halogen atoms; alkyl groups,
- na is an index equal to 0, 1, 2, 3 or 4,
- nb represents an integer of 1 to 10, advantageously nb represents an integer of
- nb is equal to 2 or 4 and where Y is of formula as defined below,
- Rd and Re are identical or different and are chosen, independently of one another, from among the hydrogen atom, the alkyl groups and the aryl groups, said aryl and alkyl groups being optionally substituted, advantageously Rd is a hydrogen atom and Re is an aryl group substituted with an alkoxyalkyl or an alkyl group, advantageously Re is a tertbutyl group or -C 6 H 4 OCH 3 , or Rd and Re form a heterocycloalkyl with the nitrogen atom to which they are attached,
- the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
- the compounds of formula (I) may exist in the form of bases or of pharmaceutically acceptable salts for addition to organic or inorganic acids. Such addition salts are part of the invention. These salts can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
- compounds of formula (I) in the form of salts mention may be made of the compounds of formula (I) in the form of salts of oxalate, hydrochloride, hydrobromide, sulfate, sulphamate, phosphate, nitrate, maleate, fumarate, methanesulphonate, benzoate, ascorbate, pamoate, succinate, hexamate, bismethylenesalicylate, ethanedisulfonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, cinnamate, mandelate, citraconate, aspartate, palmitate, stearate, itaconate, glycolate, p-aminobenzoate, glutamate, benzenesulfonate, p-toluenesulfonate, theophylline acetate and salts formed from amino acid such as lysine or hist
- the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
- the subject of the invention is, in particular, a process for synthesizing a ketosulfonamido-benzofuran derivative of formula ( ⁇ ) represented below,
- G 1 represents a linear or branched (i) alkyl group, advantageously a C 1 -C 8 alkyl group, even more advantageously a C 1 -C 4 alkyl group such as, for example, a methyl, ethyl, n-propyl or isopropyl group; butyl, sec-butyl or tert-butyl, (ii) haloalkyl, (iii) cycloalkyl, (iv) aryl, substituted or unsubstituted, (v) alkene or (vi) alkyne, advantageously G1 represents an alkyl group and even more advantageously G1 represents a methyl or n-butyl group;
- Ra is chosen from hydrogen, halogen atoms, alkyl, haloalkyl, alkoxy and alkoxyalkyl groups, advantageously Ra is chosen from a hydrogen atom, halogen atoms and alkyl groups, and even more advantageously Ra represents a hydrogen atom,
- na 0, 1, 2, 3 or 4,
- Rb represents a hydrogen atom, an alkyl, haloalkyl, aryl, arylalkyl, heteroaryl, cycloalkyl or heterocycloalkyl group or an alkyleneaminoalkyl group, advantageously Rb is chosen from a hydrogen atom, an alkyl group, a haloalkyl group and a -alkyleneaminoalkyl group; , advantageously Rb represents a group -alkyleneaminoalkyl selected from a group -alkylene-NRR 'or a group -alkylene-N + HRR' Z " with Z " the counter-anion of said salt as defined above, advantageously Z " is against -anion CI " , with R and R ', identical or different, chosen independently of one another from a hydrogen atom, aryl groups and alkyl groups, advantageously R and R' are identical and / or R and R 'are chosen from alkyls, even more advantageously R and
- the -alkylene-NRR 'group and the -alkylene-N + HRR' represents respectively a - (C 1 -C 5) alkylene-N [(C 1 -C 5) alkyl] 2 group and a - (C 1 -C 5) alkylene-N + H [(C 1 -C 5) alkyl] 2 Z "group , with Z as defined above and with - (C1-C5) alkylene-represents -CH 2 -, - (CH 2 ) 2 -, - (CH 2 ) 3 -, - (CH 2 ) 4 - or - (CH 2 ) 5 - and the - (C1-C5) alkyl, identical or different, representing independently of each other a (i) -C1 alkyl group, e.g.
- group - C2alkyle for example, the ethyl group, a (iii) -C 3 alkyl group, for example the n-propyl group or the isopropyl group, a (iv) -C 4 alkyl group, for example the n-butyl, isobutyl or tert-butyl group, or a ) -C 5 alkyl group, for example the n-pentyl or isopentyl group,
- Rb represents the group - (CH 2 ) 3N [(CH 2 ) 3 CH 3 ] 2 or the group - (CH 2 ) 3 N + H [(CH 2 ) 3 CH 3 ] 2 , Cr,
- Rc represents an alkyl group or an aryl group, advantageously Rc is a methyl or phenyl group,
- the groups G1, Ra and Rb and the index n1 are as defined above and in which the group G2 is chosen from (i) the groups -NH- (CH 2 ) nb -NHY 'with nb representing a integer from 1 to 10, advantageously an integer from 1 to 5, still more preferably nb is equal to 2 or 4 and Y 'the part of the molecule ( ⁇ ) defined above, and (ii) the groups -NRdRe with Rd and Re, identical or different, chosen independently of one another from a hydrogen atom, aryl groups and alkyl groups, one being at least one hydrogen atom, advantageously Rd is an atom of hydrogen and Re is an optionally substituted aryl group, or an alkyl group, advantageously Re is a tert-butyl group, or Rd and Re form a heterocycloalkyl with the nitrogen atom to which they are attached, and an intermediate of formula ( ⁇ )
- Rc group is as defined above, advantageously Rc is a methyl or phenyl group.
- the group G2 of the intermediate ( ⁇ ) represents a -NHtertbutylgnamen or
- the invention also relates to synthetic intermediates, in particular the enaminones of formula (II) in which G 1, G 2, G 5, Ra and n are as defined above, and the diketones of formula (V) where G1, G5, Ra and na are as defined above:
- the synthetic intermediates are chosen from the enaminones formula (II) wherein G1, G2, Ra and na are as defined in any one of claims 4 or 5, and G5 represents a halogen atom or a group -ORb where Rb represents a hydrogen atom, a haloalkyl, aryl, arylalkyl, heteroaryl, cycloalkyl, heterocycloalkyl or a -alkyleneaminoalkyl group;
- G1, Ra and na are as defined in any one of claims 4 or 5 and G5 represents a halogen atom or a group -ORb where Rb represents a haloalkyl, aryl group, arylalkyl, heteroaryl, cycloalkyl, heterocycloalkyl or a -alkyleneaminoalkyl group;
- a halogen atom a fluorine, chlorine, bromine or iodine atom
- an alkyl group a saturated, linear or branched, saturated aliphatic group which may comprise 1, 2, 3, 4 or 5 carbon atoms (abbreviated to - (C1-C5) alkyl).
- a saturated, linear or branched, saturated aliphatic group which may comprise 1, 2, 3, 4 or 5 carbon atoms (abbreviated to - (C1-C5) alkyl).
- the group -Clalkyl the methyl group, such as (ii) -C 2 alkyl group, the ethyl group, such as (iii) -C 3 alkyl group, the n-propyl group and the isopropyl group.
- a haloalkyl group an alkyl group as defined above substituted with 1, 2, 3, 4 or 5 halogen atoms, as defined previously. Mention may be made, for example, of the -halogeno (C1 -C5) alkyl groups, with (C1-C5) alkyl as defined above, for example the trifluoromethyl group (abbreviated -CF 3 ) and the -CH 2 -CF 3 group.
- an alkylene group an alkyl group as defined above, divalent saturated, linear or branched, which may comprise 1, 2, 3, 4 or 5 carbon atoms (abbreviated
- an alkoxy group an -O-alkyl radical where the alkyl group is as previously defined.
- group -O-C1 alkyl the group -Omethyl, such as ( ii) group -O-C2alkyl, -Oethyl group, such as (iii) -O-C3alkyl group, -Opropyl group and -Oisopropyl group, such as (iv) -O-C4alkyl group, -Obutyl group, - Oisobutyl and the group -Outbutyl, such as (v) -O-C5alkyl group, -pentyl group, -Oisopentyl group and -Oneopentyl group;
- an aryloxy group an -O-aryl radical in which the aryl group is as defined below;
- aryl group a cyclic aromatic group comprising 6, 7, 8, 9 or 10 carbon atoms.
- aryl groups mention may be made of the phenyl group (abbreviated
- Ph the naphthyl group
- a -C 6 H 4 -alkyl group (with the alkyl radical, as defined above, in the ortho, meta or para position of the aromatic ring). Mention may be made, as -C 6 H 4 -alkyl group, of the -C 6 H 4 -CH 3 groups with CH 3 in the ortho, meta or para position;
- an arylalkyl group an aryl group, as defined above, substituted with at least one alkyl group, as defined above.
- these are -alkyl-aryl radicals.
- benzyl that is to say the radical -CH 2 -Ph;
- an alkoxy-alkyl group a radical of formula -alkylene-O-alkyl, where the alkyl and alkylene groups, comprising the same number of carbon or not including the same number of carbon, are as defined previously.
- alkyl and alkylene groups comprising the same number of carbon or not including the same number of carbon, are as defined previously.
- a heteroaryl group a cyclic aromatic group comprising 2, 3, 4 or 5 carbon atoms and comprising 1, 2 or 3 heteroatoms, which may be chosen from the nitrogen atom, oxygen atom and the sulfur atom, independently of one another, so as to be identical or different, when they are 2 or independently of each other, so as to be identical or different when they are 3 in number.
- pyridyl, furanyl and pyrrolyl groups There may be mentioned
- a cycloalkyl group a cyclic alkyl group which can comprise 3, 4, 5 or 6 carbon atoms, abbreviated also - (C3-C6) cycloalkyl.
- C3-C6 cycloalkyl group
- a heterocycloalkyl a cyclic alkyl group, optionally bridged, comprising 5, 6 or 7 carbon atoms and comprising 1, 2 or 3 heteroatoms which can be chosen, independently of one another, from to be identical or different, when they are 2 or independently of each other, so as to be identical or different, when there are 3, among the nitrogen atom, the atom of oxygen and the sulfur atom.
- an alkyleneaminoalkyl group a group of formula -alkylene-N (alkyl) 2 in which the alkylene and alkyl groups, comprising the same number of carbon or not comprising the same number of carbon, are as defined previously.
- the two alkyl groups may comprise a different number of carbon with respect to each other.
- an alkene group a group of formula -C n H 2n where n is a natural number greater than or equal to 2, which may be linear or branched and which is characterized by the presence of at least one covalent double bond between two of its carbon atoms include the ethylenic group, but-1,3-diene group;
- an alkylene group a group of formula C n H 2n -2 where n is a natural number greater than or equal to 2, which may be linear or branched and which is characterized by the presence of at least one covalent triple bond between two of its carbon atoms.
- n is a natural number greater than or equal to 2
- acetylenic group a but-1-yne group or an acetylenic dimethyl group.
- G1 represents a C1-C8 alkyl group
- G3 represents a group -NHSO 2 Rc group chosen from -NHSO 2 alkyl groups and -NHSO 2 aryl groups; and or
- Rc is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl; and or
- G5 represents a group -ORb with Rb chosen from the groupings - alkyleneaminoalkyl, and / or
- Ra represents a substituent chosen from the hydrogen atom, the halogen atoms and the alkyl groups, and / or
- na is an index equal to 1 or 4.
- G1 represents an n-butyl group
- G3 represents a group -NHS0 2 CH 3 , and / or
- G5 represents a group -ORb with Rb representing a 3- (di-n-butylamino) -propyl group; and or
- Ra represents a substituent chosen from the hydrogen atom and na is an index equal to 4.
- the process according to the invention allows the synthesis of cetobenzofuran derivatives of formula (I) in which:
- G1 represents a linear or branched C 1 -C 8 alkyl group
- G1 represents a linear or branched C 1 -C 4 alkyl group
- G1 represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl group; or
- G1 represents an n-butyl group
- G3 represents (i) a group -NHSO 2 Rc or (ii) a group -NHRc, where Rc represents a linear or branched C 1 -C 8 alkyl group; or
- G3 represents (i) a group -NHSO 2 Rc or (ii) a group -NHRc, where Rc represents a linear or branched C 1 -C 4 alkyl group; or
- G3 represents (i) a group -NHS0 2 Rc or (ii) a group -NHRc, where Rc represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl group; or
- G3 represents a group -NHS0 2 CH 3 ;
- G5 represents a group -ORb with Rb chosen from alkyleneaminoalkyl groups; or G5 represents a group -ORb with Rb a 3- (di-n-butylamino) -propyl group;
- Ra represents a substituent chosen from the hydrogen atom, the halogen atoms and the alkyl groups; or
- na is an index equal to 1, 2, 3 or 4;
- na is an index equal to 1 or 4.
- the group G2 of said aminone intermediate Y-G2 represents a group chosen from the groups -NH- (CH 2 ) nb -NHY, where
- nb represents an integer of 1 to 5;
- ⁇ Nb is equal to 2 or 4.
- the group G 2 is chosen from
- the group G2 of said aminone intermediate Y-G2 represents a group chosen from the groups -NRdRe, where:
- Rd is a hydrogen atom and Re is an aryl group substituted with an alkoxyalkyl or an alkyl group, or Re is a tertbutyl group or -C 6 H 4 OCH 3
- Rd and Re form a heterocycloalkyl with the nitrogen atom to which they are attached.
- the Enaminone intermediate of formula (II) is a compound, where:
- G1 represents an alkyl group
- G1 represents a -C4alkyl group
- G1 represents an n-butyl group
- G5 represents a group -ORb with Rb chosen from aryl, arylalkyl, alkyleneaminoalkyl and heteroaryl groups, or
- G5 represents a group -ORb with Rb representing a phenyl or a -C 6 H 4 -alkyl group.
- the Enaminone intermediate of formula (II) is a compound of formula Y-NH- (CH 2 ) nb -NHY with:
- Nb representing an integer of 1 to 10
- Nb representing an integer of 1 to 5
- Y is selected from
- the Enaminone intermediate of formula (II) or ( ⁇ ) is a compound chosen from the compounds of formulas a), (II'b), (ll'c) and (ll'd) following :
- the compounds (II'b) and (11'd) are particularly advantageous.
- the diketone intermediate of formula (V) is a compound where:
- G1 represents an alkyl group
- G1 represents a -C4alkyl group
- G1 represents an n-butyl group
- G5 represents a halogen atom or a group -ORb where Rb represents an alkyl, arylalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group or an alkyleneaminoalkyl group, excluding the -OCH 3 and -CH 2 groups; C 6 H 5 , or
- G5 represents a group -ORb with Rb chosen from -alkyleneaminoalkyl groups, or
- G5 represents a group -O (CH 2 ) 3 -N (C 4 H 9 ) 2.
- the diketone intermediate of formula (V) is a compound (Va) of the following formula:
- G5 represents in the poses of formula (I) and / or (II) and / or (V) according to the invention:
- -ORb represents a group -O (CH 2 ) 3 -N (n-butyl) 2 .
- the ketobenzofuran of formula (I) according to the invention is characterized by:
- a group G5 chosen from the fluorine atom, a group -OH, -OCH 3 , -OC 6 H 5 , -O-CH 2 -C 6 H 5 and -O (CH 2 ) 3 -N (nBu) 2 ,
- a group G1 representing a grouping nBu, and or
- a group G3 chosen from the groups -NHS (0) 2 CH 3 and -NHS (O) 2 C 6 H 5 ;
- a group Ra being hydrogen and an index na representing 4.
- the enaminone (II) according to the invention is characterized by:
- a group G5 chosen from the fluorine atom, a group -OH, -OCH 3 , -OC 6 H 5, -O-CH 2 -C 6 H 5 and a group -O (CH 2 ) 3 -N ( nBu) 2 ,
- a group G2 chosen from (i) the groups -NH- (CH 2 ) nb -NHY with nb representing an integer of 1 to 10, advantageously an integer of 1 to 5, even more advantageously nb represents 2 or 4 and Y represents the part of the molecule (II), and (ii) the groups -NRdRe with Rd and Re as defined above, one being at least one hydrogen atom, advantageously Rd is a hydrogen atom and Re is an aryl group, advantageously an optionally substituted phenyl group or an alkyl group, still more advantageously G 2 represents a group -NHtertbutyl or
- a group Ra being hydrogen and an index n representing 4.
- the compound (V) according to the invention comprises:
- a group G5 chosen from the fluorine atom, a group -OH, -OCH 3 , -OC 6 H 5, -O-CH 2 -C 6 H 5 and a group -O (CH 2 ) 3 -N ( nBu) 2 ,
- a group G1 representing a grouping nBu, and or
- a group Ra being hydrogen and an index na representing 4.
- the diketone of formula (V) according to the invention is characterized by:
- Ra and na are as defined above;
- G 1 represents an alkyl group, advantageously G 1 represents a -C 4 alkyl group, still more advantageously G 1 the n-butyl group;
- G5 represents a halogen atom or a group -ORb where Rb represents a hydrogen atom, an alkyl, arylalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group or an alkyleneaminoalkyl group, with the exception of fluorine atom and groups -OH - OCH 3 and -CH 2 C 6 H 5, advantageously G 5 represents a group -ORb with Rb chosen from -alkyleneaminoalkyl groups, even more advantageously G5 represents a group -O (CH 2 ) 3 -N (C4H 9 ) 2.
- Schemes 2 and 3 below relate respectively to the synthesis of ketobenzofuran of formula (I) and in particular of cetobenzofuran of formula ( ⁇ ), according to the invention.
- a first step may consist in forming a complex between said diketone (V) and in particular the diketone (V) with a Lewis acid (abbreviated AL), the latter being optionally introduced into the reaction medium in a form previously complexed with a solvent .
- a complexed ketoenol (IV) or (IV) is then obtained with said Lewis acid (abbreviated as AL) as represented respectively in Schemes 2 and 3, G1, Ra, Na, nb and G5 being as defined previously for the compounds ( V) or (V).
- Lewis acids examples include BF 3 and iso-propoxytitanium (Ti (OiPr) 4 ).
- the Lewis acid BF 3 is used in the form of complex BF 3 .Et 2 0.
- This complexation of the diketone (V) or (V) with said Lewis acid generally takes place in an aprotic solvent and can be carried out at room temperature. It usually lasts about twenty hours to be complete, but the reaction can be stopped when all the diketone is gone.
- suitable aprotic solvents for this complexing step according to the invention are dichloromethane and toluene.
- a second step then consists in forming, for Scheme 2, the enaminone (II) and for Scheme 3, the enaminone ( ⁇ ), with G2, G1, Ra, Rb, Na and G5 as defined above. .
- aminone (II) or ( ⁇ ) can be done by nucleophilic addition 1, 4 respectively on the complexed ketoenol (IV) or (IV) of a nucleophilic amine G2-H followed by elimination.
- the reaction generally takes place with an excess of nucleophilic amine G 2 -H and can be carried out at room temperature. It usually lasts about twenty hours.
- Another alternative of the first and second steps may be to optionally add said diketone (V) or (V) beforehand in the presence of a suitable acid in order to form the corresponding ketoenol and to react a nucleophilic amine G2-H by addition. nucleophile 1, 4 on the diketone (V) or (V) or, where appropriate the ketoenol formed under the action of said acid, while eliminating the water formed.
- This formed water must be subtracted from the reaction medium either by eliminating it with a Dean Stark device by azeotropic distillation with an appropriate reaction solvent, or by trapping it with a desiccant in order to direct the reaction towards the formation of the respectively (II) and ( ⁇ ).
- This alternative has the advantage of being able to synthesize the intermediates (II) and ( ⁇ ) in a single step from the intermediates (V) and (V), respectively.
- Suitable acids include para-toluenesulphonic acid, camphorsulfonic acid, sulfuric acid and hydrochloric acid.
- Suitable desiccants include MgSO 4 , CaCl 2 and silica gel.
- the amine G2-H can be, for example, butylenediamine, t-butylamine, p-anisidine and ethylene diamine, but all other amines for which the group G2 is as defined above may be suitable. It can be amines G2-H, primary or secondary. Advantageously, it is t-butylamine or p-anisidine.
- reaction solvent for this second step or the alternative of the first and second stages mention may be made of toluene, dichloromethane, acetonitrile and monochlorobenzene.
- p-quinone (III) with G4 as defined above in the case of the synthesis process of (I) and (ii) p-quinone ( ⁇ ) with Rc as defined above in the case of the synthesis process of ( ⁇ ) are obtained by oxidation respectively (i ') of phenol (VI) with G3 as defined above in the case of the synthesis process of (I) and ( ⁇ ') of phenol (VI ') with Rc as defined above in the case of the synthesis process of ( ⁇ ).
- this oxidation is generally carried out in the presence of manganese oxide (MnO 2 ) in acetic acid according to operating techniques well known to those skilled in the art.
- This Nenitzescu reaction can take place, for example, in glacial acetic acid as a reactant and a reaction solvent and / or at room temperature.
- the reaction can be very fast with a transformation in minutes or seconds.
- the reaction is conducted equimolarly: at least as many moles of p-quinone (III) or ( ⁇ ) are reacted with respectively at least as many moles of enaminone (II) or ( ⁇ ).
- an enaminone (II) or ( ⁇ ) in the form of a dimer such as for example the enaminones (II 'b) and (II' c)
- the reaction can take place with at least 0.5 moles of said enaminone (II) or ( ⁇ ) for respectively at least 1 mole of p-quinone (III) or ( ⁇ ).
- the cetobenzofuran (I) or ( ⁇ ) obtained can then be purified by crystallization.
- This crystallization can be carried out in a mixture such as, for example, isopropanol / aqueous HCl in the case where it is sought to obtain said ketobenzofuran (I) or ( ⁇ ) according to the invention in the form of a hydrochloride salt.
- the crystallization can take place in ether or isopropanol or else in a mixture of diisopropyl ether / n-heptane or MTBE / n-heptane in the case where it is sought to obtain said cetobenzofuran (I) or ( ⁇ ) according to the invention in basic form.
- An alternative is to synthesize an enamine (II) or ( ⁇ ) in the form of a dimer of formula respectively (llx) or (ll'x) from respectively the diketone (V) or (V) according to scheme 4a or 4b ci below with G1, G5, Rb and nb as defined above.
- the diketone (V) or (V) is brought into the presence of acid, for example the acid paratoluene sulfonic acid, and diamine of the formula H 2 N (CH 2 ) n b NI-1 2 with nb as defined above, at reflux by eliminating the water formed in a ratio of 2 moles of diketone to 2 moles of d acid and one mole of amine. It is thus possible to obtain, for example, the dimers (II'b) and (II'c) defined above.
- acid for example the acid paratoluene sulfonic acid
- the synthesis method according to the invention allows in particular the synthesis of dronedarone (D) in base form, hydrate, solvate or a salt thereof according to scheme 5 below. All that has been described above concerning diagrams 2, 3, 4a and 4b, in particular the operating conditions, therefore applies also for scheme 5.
- the Lewis acid (LA) used in the complex synthesis reaction (IVd) from the diketone (Vd) is BF 3 or BF 3 .OEt 2, and / or
- G2-H used in the synthesis reaction of enaminone (lld) from ketoenol (IVd) is chosen from t-butylamine and p-anisidine,
- the acid used in the synthesis reaction of the enaminone (IId), such as for example the enaminones (II'b) or (II'c), from the diketone (Vd) is chosen from the acid paratoluenesulphonic acid, camphosulphonic acid, sulfuric acid and hydrochloric acid, advantageously para-toluenesulphonic acid and amine G 2 -H is chosen from primary or secondary diamines, such as, for example, ethylene diamine and butylenediamine; the water formed during said reaction being subtracted from the reaction medium either by azeotropic distillation with a suitable reaction solvent, or entrapped with a desiccant, advantageously by azeotropic distillation with a suitable reaction solvent, for example toluene,
- the amine G 2 -H in the synthesis reaction of enaminone (IId) from the diketone (Vd) is p-anisidine, the water formed during said reaction being subtracted from the reaction medium either by azeotropic distillation with a suitable reaction solvent, or preferably desiccated with a desiccant by azeotropic distillation with a suitable reaction solvent, for example toluene.
- the Nenitzescu reaction leading to the obtaining of the cetobenzofurans of formula (I), ( ⁇ ) and (D) involves, respectively, the enaminones (II), ( ⁇ ) and (lld) with respectively the quinonimines (III), ( ⁇ ) and (llld).
- this Nenitzescu reaction is advantageously carried out with glacial acetic acid and / or the reaction is advantageously carried out at room temperature.
- a step of crystallization of the ketobenzofuran (I), ( ⁇ ) or (D) obtained is carried out:
- the mass spectra are made on a quadrupole spectrometer of the Platform LCZ (WATERS) or ZQ 4000 (WATERS) type in positive electrospray ionization mode;
- NMR spectra are carried out on a Fourier transform spectrometer (BRUKER) at a temperature of 300 ° K (exchangeable protons not recorded).
- BRUKER Fourier transform spectrometer
- PIPE diisopropyl ether
- TA room temperature (between about 20 and 25 ° C)
- the 4-aminophenol (10 g, 0.091 mol, 1 eq) is suspended in methanol (100 ml) in the presence of pyridine (7.67 ml, 0.095 mol, 1.05 eq) at 20 ° C.
- Mesyl chloride (7.16 ml, 0.091 mol, 1.05 eq) is slowly poured onto the reaction medium, which then dyes orange and then pink.
- the methanol is removed by evaporation to dryness when the reaction is complete (1 h 30).
- the dry extract obtained is treated for 30 minutes with a 1N solution of dilute hydrochloric acid (85.5 ml, 1.05 eq).
- the pink solid formed is filtered and then washed with 1N HCl (30 ml) before being heat purified (45 ° C) by treatment with activated charcoal in ethyl acetate (30 ml).
- the solid obtained is washed with 1N HCl and then dried overnight in a vacuum oven at 40 ° C.
- the aqueous juices containing a lot of mesylated product, these are extracted with ethyl acetate.
- the extraction juices are treated as before. 10.4 g of sulphonamide, pale pink powder. Yield of 4-hydroxyphenylmethanesulfonamide isolated: 67% by weight.
- the sulfonamide (30 g, 0.16 mol, 1 eq) is oxidized in acetic acid (450 ml, 15 V) at 35 ° C in the presence of manganese oxide (15.76 g, 0.179 mol, 1.12 eq). After stirring for 1 h at 35 ° C., the reaction is complete and the medium is evaporated to dryness.
- the black solid obtained is taken up with dichloromethane (400 ml).
- the precipitate of manganese salts formed is filtered and washed with DCM (400 ml).
- the black organic phases are then percolated on a bed of Florisil® (190 g) to give clear orange juice. After evaporation, an orange solid is obtained (18.5 g) containing 15% benzoquinone which is removed by two slurries in 20 ml ethanol (20 ml).
- the 4-hydroxyacetophenone (47.9 g, 0.35 mol, 1 eq) is solubilized in 220 mL of MEK.
- K 2 CO 3 (53.5 g, 0.39 mmol, 1.1 eq) is added and the suspension is heated to reflux.
- 3-chloro-N, N-dibutylamine (82 g, 0.40 mol, 1.15 eq.) And then keep the reaction medium under reflux.
- distil the MEK At 25 ° C, add 200 mL of water and 200 mL of MTBE. Leave to settle and remove the two phases.
- aqueous phase is counter-extracted with MTBE and the combined organic phases are then washed with 200 ml of a 1% aqueous solution of acetic acid and then twice with 200 ml of a 5% aqueous NaCl solution.
- the organic phase is then concentrated and the MTBE replaced with 325 mL of NMP.
- Ethyl pentanoate (58.1 ml, 0.39 mol, 1.1 eq) is added and the mixture is stirred at 5 ° C.
- MeONa (57.5 g, 1.05 mol, 3 eq) is added in fractions and then the reaction medium is maintained at 20 ° C.
- the hydrolysis is carried out by casting the reaction medium on a 37% solution of HCl (104.9 g, 1.0 mmol, 3 eq) at 5 ° C.
- the hydrolysed medium is then diluted with 150 ml of water and then extracted with 3 times 200 ml of AcOEt.
- the combined organic phases are washed with twice 150 ml of water and then concentrated: the AcOEt is replaced by 300 ml of MCH.
- the suspension obtained is filtered, the cake is washed with MCH and then dried under vacuum at 40 ° C.
- the dicetone of Example 3 (23.5 g, 60 mmol, 1 eq) is dissolved at 25 ° C in dichloromethane (230 ml) and then BF 3 .Et 2 (23.5 ml, 181 mmol, 3eq) is added slowly.
- the red solution is stirred at 25 ° C until disappearance of the diketone (17h) and then dried by evaporation under vacuum.
- the diketone hydrochloride base of Example 3 (15 g, 35.2 mmol, 2 eq) was liberated in toluene (100 ml) and water (75 ml) with sodium hydrogencarbonate (3.69 g; 44 mmol, 2.5 eq).
- the aqueous phase is extracted with toluene (40 ml) and the combined organic phases are washed with water (40 ml).
- P-Toluenesulphonic acid (0.45 g, 2.6 mmol, 0.15 eq) is added to this organic solution before loading the butylenediamine (1.55 g, 17.6 mmol, 1 eq).
- the medium is then heated to reflux by removing the water formed using a Dean-Stark.
- the i-butylamine (12.9 g, 180 mmol, 5.5 eq) is cast at 25 ° C on a solution of boron complex of Example 4 (15 g, 33 mmol, 1.0 eq) in acetonitrile (100 ml) . A precipitate is formed gradually giving a red suspension which must be stirred for 20 h at 25 ° C.
- the precipitate of complexed i-butylamine is filtered and the juices are evaporated to dryness to give an opaque red syrup. After recovery with dichloromethane (100 ml) and then washing with water (5 x 50 ml), the solution is evaporated again and a red oil is obtained (13.9 g).
- Example 7 Synthesis of N- (2-butyl-3- ⁇ 4- [3- (dibutylamino) propoxy] benzoyl ⁇ -1-benzofuran-5-yl) methanesulfonamide and N- (2-butyl-3-hydrochloride) - ⁇ 4- [3- (dibutylamino) propoxy]
- Example 5 The dimer of Example 5 (4 g, 4.8 mmol, 0.5 eq) is dissolved in glacial acetic acid (28 ml).
- the quinoneimine of Example 2 (1.78 g, 9.6 mmol, 1 eq) is loaded onto the medium at 20 ° C.
- the reaction is immediate and the dronedarone base is obtained.
- the reaction medium is taken up in dichloromethane (50 ml). It is washed with a 10% w / w potassium hydrogen carbonate solution (25 ml). then with diluted HCl (3x25 ml).
- the DCM is evaporated and the crude obtained is purified by crystallization at 40 ° C. in isopropanol (15 ml).
- Dronedarone (D) in hydrochloride form is obtained in the form of a white powder (2.64 g). Isolated yield of dronedarone as hydrochloride salt: 47% by weight.
- Example 8 Synthesis of N- (2-butyl-3- ⁇ 4- [3- (dibutylamino) propoxy] benzoyl ⁇ -1-benzofuran-5-yl) methanesulfonamide and N- (2-butyl) hydrochloride - ⁇ 4- [3- (dibutylamino) propoxy]
- Example 6 The aminone of Example 6 (2.3 g, 5.2 mmol, 1 eq) is dissolved in glacial acetic acid (1 1.5 ml).
- the quinoneimine of Example 2 (0.96 g, 5.2 mmol, 1 eq) is loaded onto the medium at 20 ° C. The reaction is immediate. After evaporating the acetic acid, the reaction medium is taken up in dichloromethane (50 ml). The organic phase is washed with potassium hydrogen carbonate solution (25 ml, 10% w / w) and then washed with dilute HCl (3 x 25 ml).
- the crude product obtained is purified by crystallization from isopropanol (9.5 ml) after addition at 50 ° C. of 35% HCl. (43 mg, 4.2 mmol).
- Example 3 0.5 g of the diketone of Example 3 is charged to a reactor with 5 ml of toluene and 160 mg of p-anisidine. This mixture is heated to remove water by azeotropic distillation using a Dean-Stark.
- reaction medium is concentrated, cooled to 20 ° C. and evaporated to dryness.
- the solid obtained is taken up with ether and then filtered. After drying in a vacuum oven, 380 mg of product are recovered in the form of a cream powder.
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FR1051510A FR2957079B1 (en) | 2010-03-02 | 2010-03-02 | PROCESS FOR THE SYNTHESIS OF CETOBENZOFURAN DERIVATIVES |
PCT/FR2011/050420 WO2011107705A1 (en) | 2010-03-02 | 2011-03-01 | Ketobenzofuran derivatives, method for synthesising same, and intermediates |
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US (1) | US8796489B2 (en) |
EP (1) | EP2542544A1 (en) |
JP (1) | JP2013521264A (en) |
KR (1) | KR20130045249A (en) |
CN (1) | CN102884056A (en) |
AR (1) | AR080332A1 (en) |
AU (1) | AU2011222828A1 (en) |
BR (1) | BR112012021865A2 (en) |
CA (1) | CA2791482A1 (en) |
FR (1) | FR2957079B1 (en) |
MX (1) | MX2012010121A (en) |
RU (1) | RU2012141889A (en) |
SG (1) | SG183516A1 (en) |
TW (1) | TW201139400A (en) |
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WO (1) | WO2011107705A1 (en) |
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HUP0900759A2 (en) | 2009-12-08 | 2011-11-28 | Sanofi Aventis | Novel process for producing dronedarone |
HUP1000010A2 (en) | 2010-01-08 | 2011-11-28 | Sanofi Sa | Process for producing dronedarone |
FR2958290B1 (en) | 2010-03-30 | 2012-10-19 | Sanofi Aventis | PROCESS FOR THE PREPARATION OF SULFONAMIDO-BENZOFURAN DERIVATIVES |
FR2958291B1 (en) | 2010-04-01 | 2013-07-05 | Sanofi Aventis | PROCESS FOR PREPARING AMINO-BENZOFURAN DERIVATIVES |
HUP1000330A2 (en) | 2010-06-18 | 2011-12-28 | Sanofi Sa | Process for the preparation of dronedarone and the novel intermediates |
FR2962731B1 (en) | 2010-07-19 | 2012-08-17 | Sanofi Aventis | PROCESS FOR THE PREPARATION OF AMINO-BENZOYL-BENZOFURAN DERIVATIVES |
FR2963006B1 (en) * | 2010-07-21 | 2013-03-15 | Sanofi Aventis | PROCESS FOR THE PREPARATION OF NITRO-BENZOFURAN DERIVATIVES |
HUP1000386A2 (en) | 2010-07-22 | 2012-05-29 | Sanofi Sa | Novel process for producing dronedarone |
EP2452938A1 (en) * | 2010-11-12 | 2012-05-16 | LEK Pharmaceuticals d.d. | Process for the preparation of 3-aroyl-5-aminobenzofuran derivatives |
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 (en) | 2011-11-29 | 2013-11-15 | Sanofi Sa | PROCESS FOR THE PREPARATION OF 5-AMINO-BENZOYL-BENZOFURAN DERIVATIVES |
EP2617718A1 (en) | 2012-01-20 | 2013-07-24 | Sanofi | Process for preparation of dronedarone by the use of dibutylaminopropanol reagent |
US9221778B2 (en) | 2012-02-13 | 2015-12-29 | 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 |
WO2013124745A1 (en) | 2012-02-22 | 2013-08-29 | Sanofi | Process for preparation of dronedarone by oxidation of a hydroxyl group |
WO2013178337A1 (en) | 2012-05-31 | 2013-12-05 | Sanofi | Process for preparation of dronedarone by grignard reaction |
TW201536763A (en) * | 2013-08-27 | 2015-10-01 | Gilead Sciences Inc | Process for preparing dronedarone and salts thereof |
CN109384754B (en) * | 2017-08-14 | 2020-06-09 | 新发药业有限公司 | Preparation method of dronedarone hydrochloride |
CN107827764A (en) * | 2017-11-27 | 2018-03-23 | 上海应用技术大学 | A kind of preparation method of double β amino ketones or double β amino esters |
JP2022541739A (en) * | 2019-07-08 | 2022-09-27 | ナショナル ユニバーシティー オブ シンガポール | heart medication |
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IE45765B1 (en) * | 1976-08-19 | 1982-11-17 | Ici Ltd | Triazoles and imidazoles useful as plant fungicides and growth regulating agents |
US5066803A (en) * | 1989-12-07 | 1991-11-19 | Sterling Drug Inc. | 2- and 3-aminomethyl-6-arylcarbonyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazines |
FR2665444B1 (en) * | 1990-08-06 | 1992-11-27 | Sanofi Sa | AMINO-BENZOFURAN, BENZOTHIOPHENE OR INDOLE DERIVATIVES, THEIR PREPARATION PROCESS AND THE COMPOSITIONS CONTAINING THEM. |
FR2817865B1 (en) | 2000-12-11 | 2005-02-18 | Sanofi Synthelabo | AMINOALKOXYBENZOYLE DERIVATIVE IN SALT FORM, PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF AS SYNTHESIS INTERMEDIATE |
FR2817864B1 (en) | 2000-12-11 | 2003-02-21 | Sanofi Synthelabo | METHANESULFONAMIDO-BENZOFURANE DERIVATIVE, ITS PREPARATION METHOD AND ITS USE AS A SYNTHESIS INTERMEDIATE |
IL146389A0 (en) * | 2001-11-08 | 2002-07-25 | Isp Finetech Ltd | Process for the preparation of dronedarone |
WO2005105743A1 (en) * | 2004-04-28 | 2005-11-10 | Ono Pharmaceutical Co., Ltd. | Nitrogen-containing heterocyclic compounds and medicinal use thereof |
CA2644578A1 (en) * | 2006-03-03 | 2007-09-07 | Torrent Pharmaceuticals Ltd | Novel dual action receptors antagonists (dara) at the ati and eta receptors |
GB0719180D0 (en) * | 2007-10-02 | 2007-11-14 | Cambrex Karlskoga Ab | New process |
UY32657A (en) | 2009-05-27 | 2010-12-31 | Sanofi Aventis | PROCEDURE FOR THE MANUFACTURE OF DRONEDARONA INTERMEDIATE PRODUCTS |
UY32656A (en) | 2009-05-27 | 2010-12-31 | Sanofi Aventis | PROCEDURE TO PRODUCE BENZOFURANS |
HUP0900759A2 (en) | 2009-12-08 | 2011-11-28 | Sanofi Aventis | Novel process for producing dronedarone |
HUP1000010A2 (en) | 2010-01-08 | 2011-11-28 | Sanofi Sa | Process for producing dronedarone |
FR2958290B1 (en) | 2010-03-30 | 2012-10-19 | Sanofi Aventis | PROCESS FOR THE PREPARATION OF SULFONAMIDO-BENZOFURAN DERIVATIVES |
FR2958291B1 (en) | 2010-04-01 | 2013-07-05 | Sanofi Aventis | PROCESS FOR PREPARING AMINO-BENZOFURAN DERIVATIVES |
FR2973027A1 (en) | 2011-03-24 | 2012-09-28 | Sanofi Aventis | PROCESS FOR THE SYNTHESIS OF CETOBENZOFURAN DERIVATIVES |
HUP1100167A2 (en) | 2011-03-29 | 2012-11-28 | Sanofi Sa | Process for preparation of dronedarone by mesylation |
HUP1100165A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Process for preparation of dronedarone by n-butylation |
HUP1100166A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Reductive amination process for preparation of dronedarone using amine intermediary compound |
WO2013014478A1 (en) | 2011-07-26 | 2013-01-31 | Sanofi | Reductive amination process for preparation of dronedarone using carboxyl intermediary compound |
WO2013014479A1 (en) | 2011-07-26 | 2013-01-31 | Sanofi | Reductive animation process for preparation of dronedarone using aldehyde intermediary compound |
WO2013014480A1 (en) | 2011-07-26 | 2013-01-31 | Sanofi | Process for preparation of dronedarone using amide intermediary compound |
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2010
- 2010-03-02 FR FR1051510A patent/FR2957079B1/en not_active Expired - Fee Related
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UY33256A (en) | 2011-09-30 |
MX2012010121A (en) | 2012-09-12 |
AR080332A1 (en) | 2012-03-28 |
CN102884056A (en) | 2013-01-16 |
WO2011107705A1 (en) | 2011-09-09 |
TW201139400A (en) | 2011-11-16 |
SG183516A1 (en) | 2012-10-30 |
AU2011222828A1 (en) | 2012-09-20 |
FR2957079A1 (en) | 2011-09-09 |
BR112012021865A2 (en) | 2016-05-17 |
US20130012729A1 (en) | 2013-01-10 |
KR20130045249A (en) | 2013-05-03 |
CA2791482A1 (en) | 2011-09-09 |
US8796489B2 (en) | 2014-08-05 |
RU2012141889A (en) | 2014-04-10 |
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FR2957079B1 (en) | 2012-07-27 |
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