CN101142191B - 10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂䓬-5-甲酰胺的制备方法 - Google Patents
10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂䓬-5-甲酰胺的制备方法 Download PDFInfo
- Publication number
- CN101142191B CN101142191B CN200680008363.3A CN200680008363A CN101142191B CN 101142191 B CN101142191 B CN 101142191B CN 200680008363 A CN200680008363 A CN 200680008363A CN 101142191 B CN101142191 B CN 101142191B
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- CN
- China
- Prior art keywords
- dihydro
- dibenzo
- azepine
- methane amide
- hydroxyl
- 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.)
- Expired - Fee Related
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- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 35
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 20
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 9
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 125000006353 oxyethylene group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000005270 trialkylamine group Chemical group 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 125000002723 alicyclic group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 claims 1
- ZFXVFMBOFIEPII-UHFFFAOYSA-N 1h-azepine-4-carboxamide Chemical compound NC(=O)C1=CC=CNC=C1 ZFXVFMBOFIEPII-UHFFFAOYSA-N 0.000 abstract description 11
- 150000002118 epoxides Chemical class 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 235000019441 ethanol Nutrition 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000006735 epoxidation reaction Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 229960001816 oxcarbazepine Drugs 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000001961 anticonvulsive agent Substances 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 230000001773 anti-convulsant effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- -1 kelene hydro carbons Chemical class 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 2
- 239000004927 clay Substances 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 2
- VEUMANXWQDHAJV-UHFFFAOYSA-N 2-[2-[(2-hydroxyphenyl)methylideneamino]ethyliminomethyl]phenol Chemical compound OC1=CC=CC=C1C=NCCN=CC1=CC=CC=C1O VEUMANXWQDHAJV-UHFFFAOYSA-N 0.000 description 1
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- JQRLYSGCPHSLJI-UHFFFAOYSA-N [Fe].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 Chemical compound [Fe].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 JQRLYSGCPHSLJI-UHFFFAOYSA-N 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000004411 aluminium 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
- 238000005576 amination reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- ZLWLTDZLUVBSRJ-UHFFFAOYSA-K chembl2360149 Chemical compound [Na+].[Na+].[Na+].O=C1C(N=NC=2C=CC(=CC=2)S([O-])(=O)=O)=C(C(=O)[O-])NN1C1=CC=C(S([O-])(=O)=O)C=C1 ZLWLTDZLUVBSRJ-UHFFFAOYSA-K 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical group [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- MMIPFLVOWGHZQD-UHFFFAOYSA-N manganese(3+) Chemical group [Mn+3] MMIPFLVOWGHZQD-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Epoxy Compounds (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一种通过11a,10b-二氢-6H-二苯并/b,f/环氧乙烯并[d]氮杂-6-甲酰胺(5)的开环制备10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(1)的方法,其特征在于所述开环在高压条件下进行。
Description
本发明还涉及化合物(1)作为用于制备化合物10,11-二氢-10-氧代-5H-二苯并/b,f/氮杂-5-甲酰胺(2)的原料的用途。被称为奥卡西平的化合物(2)对于治疗癫痫具有有价值的性质,并且声称其比卡马西平(化合物3,其中R=NH2)被更好地耐受,卡马西平是一种结构相关的抗惊厥药(Grant,S.M.等人,Drugs,43,873-888(1992))。化合物(1)也是一种具有抗惊厥活性的已知化合物,并且事实上其为(2)的主要代谢产物(Schutz,H.等人,Xenobiotica,16,769-778(1986))。
除了它们的抗惊厥活性外,化合物(1)和(2)还用作制备一种更新近公开的抗惊厥药(S)-(-)-10-乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(4)的有用中间体(Benes,J.等人,J.Med.Chem.,42,2582-2587(1999),US5753646和EP0751129B)。因此,一种短时、经济、高产率且环境上可接受的用于大规模制备这两种化合物的方法是令人期望的,优选地从常用且容易获得的前体开始制备。
(1) (2) (3) (4)
先前描述的羟基化合物(1)的合成首先需要用间氯过氧苯甲酸环氧化卡马西平(即:化合物3,其中R=NH2)或其氯代类似物(即化合物3,其中R=Cl),因此,仅以中等产率(~60%)得到环氧化物(即:化合物5,其中R为NH2或Cl)(Bellucci,G.等人,J.Med.Chem.,30,768-773(1987))。然后,用氨来氨基化,得到化合物(5)。
然而,主要缺点是间氯过氧苯甲酸是有可能爆炸的,且因此其使用必须伴有严格的安全措施。另外,为了这种环氧化,需要大量过量的昂贵试剂。因此,其经不住大规模合成,且确实许多商业来源现已停止生产这种危险的试剂。化合物(3)的环氧化的其他报道包括微生物环氧化(Kittelmann,M.等人,Biosci.Biotechnol.Biochem.,57(9),1589-1590(1993);Chem.Abstr.120:75516)、铁卟啉/过氧化物催化的环氧化(Yang,S.J.等人,Inorg.Chem.,37(4),606-607(1998);(Chem.Abstr.128:140628)和使用过硫酸盐的钴介导的环氧化(Nam,W.等人,Bull.KoreanChem.Soc,17(5),414-416(1996);(Chem.Abstr.125:86408)。但是,这些方法不适合大规模生产。
在我们的WO0296881中克服了与制备化合物(5)相关的许多问题,本文将其内容引入作为参考。
环氧化物(5)为多用途的中间体。使用锂和镁的卤化物进行重排直接得到奥卡西平(2)(NL 7902811和HU 63390)。然而,这些制剂是对湿气敏感的、从商业来源获得是昂贵的或需要原位制备的,并且(2)的产率通常为低的至中等的。可选地,通过使用钯催化氢化已将环氧化物(5)转化成醇(1)(Baker,K.M.等人,J.Med.Chem.,16(6),703-705(1973))。然而,所述催化剂装载(loading)非常高,并且醇的总产率仅是中等的。
奥卡西平已经通过使用不同原料的许多方法来制备(WO9621649和WO0055138)。其通过醇(1)的直接氧化的制备被首次描述于WO02/96881中。
WO02/96881也公开了一种通过开环反应从化合物(5)制备化合物(1)的方法。在WO02/96881中,环氧化物(5)的开环通过在氢供体和金属催化剂的存在下催化转移氢化或可选地通过在金属催化剂的存在下用气态氢催化氢化进行。
在WO02/96881中描述的反应在实验室规模进行顺利,但是我们已发现当将其规模增大至工业过程时,则存在反应产率和产品纯度方面的负面影响。因此,本发明的一个目的是提供一种具有良好反应产率和产品纯度的方法。
我们现已意外地发现可通过在高压条件下,且优选地在高温条件下进行环氧化物(5)的开环来提高化合物(1)的反应产率和产品纯度。使用高压会具有这种效果是意外的,因为本领域技术人员会预测使用高压将导致化合物(1)的过度还原成完全饱和的体系。使用高压也意外地使减少在反应中需要的溶剂量成为可能。
因此,根据本发明的一个方面,提供一种通过11a,10b-二氢-6H-二苯并/b,f/环氧乙烯并[d]氮杂-6-甲酰胺(5)的开环来制备10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(1)的方法,其中所述开环在高压条件下进行。
因此,所述开环反应可表示为:
(5) (1)
有利地,环氧化物(5)的开环通过在催化剂的存在下,在高压下用气态氢催化氢化实现。如上所述,我们已经发现通过使用高压有可能在工业规模上获得良好的产率和纯度,并且我们已能降低反应中需要的溶剂水平。
可将适宜的催化剂,典型地为金属催化剂加入到在适宜的溶剂混合物中的环氧化物(5)的搅拌的溶液中,所述溶剂混合物包含任选的有机碱。
优选的催化剂为钯,优选地吸附在惰性载体比如活性炭上,且通常在载体上使用5-10wt%的钯。更优选地,在载体上有5-7wt%的钯。优选的是钯催化剂的总量为0.001至0.01mol%(基于环氧化物(5)的量。典型的催化剂装载为0.0015mol%(0.013wt%)。我们已经发现最优选择的催化剂提高反应产率。
用于所述反应的优选的溶剂包括氯化烷烃比如二氯甲烷,具有从1至6个碳原子的醇类比如甲醇、乙醇或异丙醇,以及水,或者该反应可在上述溶剂的混合物中进行。我们已用甲醇和水获得了最好的结果。水的加入通过减少副产物改善反应。优选地,甲醇以至多约20体积对一体积环氧化物的量存在,且约10体积甲醇对一体积环氧化物是优选的。优选地,水以至多约1体积对一体积环氧化物的量存在,且约0.3体积水对一体积环氧化物是优选的。
所述反应也可通过使用有机碱,尤其是三烷基胺比如三乙胺来改进。这加快反应,因此导致形成较少的副产物和更高的产率。我们已发现用少的、催化量的有机碱比如三乙胺,所述反应进行顺利。以摩尔计,优选的有机碱的量少于环氧化物的量,最优选的为基于环氧化物的量,存在不超过0.1mol%的有机碱。基于环氧化物的量,更优选的为存在0.03mol%至0.07mol%的有机碱,最优选的为存在0.05mol%的有机碱。
可将氢气鼓入通过反应混合物,并且当反应完成时(例如1-2小时后),催化剂可通过过滤回收,且可如下所述分离产物。三烷基胺优选地以少量存在——优选地仅足以用于确保反应溶液为碱性。
压力可以为从200kPa至4.0MPa。压力优选大于或等于500kPa,更优选大于或等于1.0MPa。优选地,压力为2.0MPa或更小,更优选1.5MPa或更小。在优选的实施方案中,压力在1.0MPa至2.0MPa的范围内,且压力从1.0MPa至1.5MPa是特别优选的(在本申请中所述的所有压力为绝对压力,而非计示压力(gauge))。
优选地所述反应在高温下进行,即高于25℃。更优选地,反应温度为从40℃至80℃。最优选地,反应温度为从50℃至60℃,且从50℃至55℃的温度为特别优选的。实际上,通常几乎不需要在高于约65℃下进行反应,因为在高于该温度下没有记录到改善。
在反应完成后(其典型地进行1-2小时),可通过经硅藻土或硅石过滤来回收催化剂,且可在真空下蒸发滤液。如果需要,粗制产物可从适宜的溶剂比如乙酸乙酯或低级醇比如乙醇中重结晶。
在催化氢转移和催化氢化反应两者中的产率通常为85-90%且产品纯度通常高于98%。
一个特别优选的具体方法如下:首先将环氧化物(5)在甲醇中制成浆液,并加入痕量三乙胺。将该悬浮液加料到高压釜中,加入钯催化剂和水的浆液。将该混合物在55℃和1.5MPa下氢化70分钟。用HPLC测试反应进程,当环氧化物的水平小于或等于1%a/a时,过滤除去催化剂。用甲醇洗涤滤液一次。接着,蒸发合并的产物溶液(在70kPa,65℃),蒸馏出约80%的甲醇。加入异丙醇并蒸馏出剩余的甲醇。将得到的悬浮液冷却至0-5℃,以完成化合物(1)的析出。冷却后,在该温度再搅拌混合物2小时,接着过滤。用异丙醇和去离子水的混合物(在混合物中异丙醇和水以1∶1的比例存在)洗涤滤饼。最后,在80℃真空下干燥产物几小时。
11a,10b-二氢-6H-二苯并/b,f/环氧乙烯并[d]氮杂-6-甲酰胺(5)优选地通过在WO02/96881中描述的环氧化方法形成。下述列出该方法的主要特征,其他细节可在WO02/96881中找到。
在WO02/96881中描述的反应按如下进行:
(3) (5)
通过向惰性溶剂中的卡马西平(3)和金属催化剂的搅拌的悬浮液中加入过量的过氧乙酸来满意地进行卡马西平的环氧化。该反应可在无机碱的存在下进行。过氧乙酸廉价且易于作为在乙酸中的溶液市售获得或可在原位从乙酸和过氧化氢的混合物制备(Hudlicky,M.Oxidations inOrganic Chemistry,ACS Monograph,Washington DC,1990)。优选地,使用1.5~3摩尔当量的过氧乙酸。
适宜的惰性溶剂包括氯化烃类。无机碱可为例如乙酸钠、碳酸钠或碳酸钾,所有这些都易于获得且廉价;优选地使用2.5~3.2摩尔当量的无机碱。几种适于环氧化反应的金属催化剂包括锰、钴、镍、铜、铑和铁的络合物。
优选的催化剂为锰(III)沙仑(salen)和高锰酸钾。通常,对于良好的转化,0.025-3mol%的催化剂是期望的。如果优选,可使用相转移催化剂,比如例如Adogen 464或Aliquat 336。如果需要,金属催化剂可按在反应后允许通过简单的过滤而较好回收的粉末、小球或珠粒的形式负载在惰性载体比如氧化铝、硅石或惰性粘土上,采用所述形式的一个重要因素是由于环境问题。通常,2-4%w/w的载体催化剂为优选的。
可选地且如果需要,试剂的加入顺序可以是相反的,可将卡马西平(3)加入到过氧乙酸和催化剂在优选的溶剂系统的溶液中。在任一种情况下,在温和的放热反应完成后,可通过过滤除去无机碱和载体金属催化剂,并可将滤液与亚硫酸钠水溶液一起搅拌以破坏过量的过氧化物。接着,可分离有机相,用水和碳酸氢钠洗涤。通过蒸发有机溶剂可获得粗制环氧化物(5),如果需要,可从适宜的溶剂比如乙酸乙酯或具有1至6个碳原子的醇类比如乙醇或异丙醇中纯化。产率通常高于85%,并且通过HPLC分析产物通常>97%纯。
如果需要,通过如上所述方法形成的10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(1)可转化成盐。其也可被拆分成一种或两种它的R-(+)-和S-(-)-异构体。所述盐可在拆分步骤之前或之后形成。
例如,11a,10b-二氢-6H-二苯并/b,f/环氧乙烯并[d]氮杂-6-甲酰胺(5)可被用于通过在WO02/96881中描述的方法形成奥卡西平。下述列出该过程的主要特征,其他细节可在WO02/96881中找到。
在WO02/96881中描述的反应按如下进行:
(1) (2)
通过向在适宜的溶剂中的醇(1)和金属催化剂的搅拌的悬浮液中加入过量的过氧乙酸进行醇(1)的氧化。如果需要,可使用相转移催化剂比如例如Adogen 464或Aliquat 336。通常需要3-5摩尔当量的过氧乙酸。适宜的溶剂包括氯化烷烃类,比如例如二氯甲烷或1,2-二氯乙烷。优选的金属催化剂为三氧化铬、二氧化锰、乙酸锰(III)、高锰酸钾、氯化钴(II)及重铬酸钾和重铬酸钠。如果需要,金属催化剂可按在反应后允许通过简单的过滤较好回收的粉末、小球或珠粒的形式负载在惰性载体比如氧化铝、硅石或惰性粘土上。通常,2-4%w/w的载体催化剂为优选的,且一般对于氧化反应使用0.5-5mol%的金属催化剂。
可选地且如果需要,试剂的加入顺序可以是相反的,可将固体醇(1)加入到过氧乙酸和催化剂在优选的溶剂系统的溶液中。在温和的放热反应完成后,可通过过滤除去载体金属催化剂,并可将滤液与亚硫酸钠水溶液一起搅拌以破坏过量的过氧化物。接着,可分离有机相,用水和碳酸氢钠洗涤。粗制奥卡西平(2)可通过蒸发有机溶剂获得,且如果优选,可从适宜的溶剂比如乙酸乙酯或具有1至6个碳原子的醇类比如例如乙醇或异丙醇中纯化。产率通常高于85%且产物通常>97%纯。
根据本发明的另一个方面,提供一种制备式(6)的化合物的方法:
其中R1为氢、烷基、卤代烷基、芳烷基、环烷基、环烷基烷基、烷氧基、芳基或吡啶基;术语烷基指包含1至18个碳原子的直链或支链烃链;术语卤素指氟、氯、溴或碘;术语环烷基指具有3至6个碳原子的脂环族饱和基团;且术语芳基指未取代的苯基或被烷氧基、卤素或硝基取代的苯基,所述方法包括通过如上所述的方法形成10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(1),接着处理所述10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(1)以生成式(6)的化合物。式(6)的化合物优选地通过酰化所述10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(1)来制备。
式(6)的化合物在我们的美国专利5753646中被更详细地描述,将其内容引入本文作为参考。所述方法可用于生成在US5753646中公开的任何化合物。例如,为了制备10-乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺,有可能向10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺和吡啶在二氯甲烷的悬浮液中加入在二氯甲烷中的乙酰氯,如在US5753646的实施例4中描述的。
US5753646的实施例4至17中描述的化合物可通过使用适宜的酰卤酰化来生产。实施例18至23中描述的化合物可使用适宜的羧酸来生产。
因此,使用本发明可能生产下述化合物:
1.10-乙酰氧基
9.10-(4-氯苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
13.10-丁酰氧基-10,1-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
15.10-[(2-丙基)戊酰氧基]-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
16.10-[(2-乙基)己酰氧基]-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
20.10-苯乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
28.10-溴乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
30.10-乙氧基羰基氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
如上所述,10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺可被拆分为它的(R)-(+)-和(S)-(-)-立体异构体,藉此可制备上述化合物(1)至(31)的期望的(R)-(+)或(S)-(-)立体异构体。
这些化合物或其药学可接受的衍生物(如盐)可以与药学可接受的载体组合用于制备包含化合物本身或其衍生物的药物组合物。这样的组合物具有抗惊厥性质,可用于治疗某些中枢和外周神经系统病症,比如癫痫。
本文公开的本发明会通过下述制备实施例来举例说明,其不应解释为限制公开的范围。应当理解,本发明不局限于操作的精确细节,因为明显的修饰和等效形式对本领域技术人员是显而易见的。
实施例1:11a,10b-二氢-6H-二苯并/b.f/环氧乙烯并[d]氮杂-6-甲酰胺
(5)
向卡马西平(3)(200g,847.5mmol)和碳酸钠(287.4g,2711mmol)在二氯甲烷(1000ml)的搅拌的悬浮液中加入负载在氧化铝上的高锰酸钾片(3.5%w/w,3.46g,0.77mmol)。之后,经一小时滴加过氧乙酸(在乙酸中的39%溶液,432ml,2538mmol),引起温度逐渐升高,直至溶剂温和地回流。搅拌该混合物二十分钟,接着使其保持二十分钟。然后,过滤除去碳酸钠和载体上的催化剂,并用二氯甲烷(200ml)洗涤;通过过筛筛分从碳酸钠中分离氧化铝珠。接着,将合并的滤液与亚硫酸钠(20g)和碳酸氢钠(20g)在水(250ml)中的溶液一起搅拌一小时。之后,分离各相,用二氯甲烷(50ml)萃取水相。用水(100ml)、饱和碳酸氢钠水溶液(100ml)、再次用水(100ml)和盐水洗涤合并的有机层,然后用无水硫酸钠干燥并过滤。蒸发溶剂(旋转蒸发仪,水泵压力,40℃),得到呈浅褐色固体的粗制环氧化物(5),将其从乙酸乙酯(100ml)中重结晶,得到作为类白色固体的产物,194.2g,(产率91%)。
实施例2:10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(1)
向105g水湿的(water wet)环氧化物(即,69.5g,干重)中加入600ml的甲醇和1.9ml的三乙胺。在20-30℃搅拌该浆液10分钟,接着,转移到1000ml不锈钢高压釜中,并用100ml的甲醇冲洗。加入0.89g钯炭(50%水湿的)在10ml水中的浆液。用10ml的水冲洗。在用氮气(3X)惰性化(inertisation)后,用氢气(2X)冲洗高压釜。在10-15bar H2压力和50-55℃下进行氢化(1000rpm,反应时间为大约70分钟)。氢气完全消耗后,再搅拌反应混合物30分钟以确保完全转化。通过过程中测试来检查转化(HPLC:环氧化物<=1.0%a/a)。过滤除去催化剂,并用80ml甲醇洗涤该滤液。在真空中(70-75kPa,馏出物的温度为51-61℃)将该滤液从约900ml浓缩至180-190ml。将残余物冷却至约40-45℃并加入200ml的异丙醇。重复蒸馏(100kPa,70-80℃,大约145ml的馏出物)以完全除去甲醇。将残余物冷却至0-5℃,并为结晶而在该温度搅拌至少2小时。过滤沉淀物,用80ml异丙醇/水(1∶1)洗涤。在真空中干燥湿产物(大约68g),得到58.8g外消旋的醇[产率,82%]。
会理解如上所述的本发明可以被修饰。
Claims (14)
2.根据权利要求1的方法,其中所述开环通过在催化剂的存在下在从200kPa至4.0MPa的高压下用气态氢催化氢化进行。
3.根据权利要求1或2的方法,其中所述压力为从1.0MPa至1.5MPa。
4.根据权利要求1或2的方法,其中所述反应在从40℃至65℃的温度进行。
5.根据权利要求1或2的方法,其中所述反应在从50℃至60℃的温度进行。
6.根据权利要求1或2的方法,其中所述开环反应在金属催化剂的存在下进行。
7.根据权利要求6的方法,其中基于所述11a,10b-二氢-6H-二苯并/b,f/环氧乙烯并[d]氮杂 -6-甲酰胺(5)的量,在所述开环反应中使用的所述金属催化剂为0.001-0.01mol%的钯。
8.根据权利要求1或2的方法,其中所述开环反应在有机碱的存在下进行,所述有机碱为三烷基胺。
9.根据权利要求1或2的方法,其中所述开环反应在选自氯化烃类、具有1至6个碳原子的醇类和水或其混合物的溶剂中进行。
10.根据权利要求1或2的方法,其中所述开环反应在甲醇、水和三乙胺的存在下进行。
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GB0515690D0 (en) | 2005-07-29 | 2005-09-07 | Portela & Ca Sa | Asymmetric catalytic reduction |
MX2008013675A (es) | 2006-04-26 | 2009-03-06 | Supernus Pharmaceuticals Inc | Preparaciones de liberacion controlada de oxcarbacepina que tienen perfil de liberacion sigmoidal. |
WO2008027557A2 (en) | 2006-08-31 | 2008-03-06 | Spherics, Inc. | Topiramate compositions and methods of enhancing its bioavailability |
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US8372431B2 (en) | 2007-10-26 | 2013-02-12 | Bial-Portela & C.A., S.A. | Pharmaceutical composition comprising licarbazepine acetate |
RU2012106827A (ru) | 2009-07-27 | 2013-09-10 | БИАЛ-ПОРТЕЛА энд КА., С.А. | Применение производных 5н-дибенз/в, f/азепин-5-карбоксамида для лечения фибромиалгии |
WO2011117885A1 (en) * | 2010-03-23 | 2011-09-29 | Intas Pharmaceuticals Limited | Process for preparation of enantiomers of licarbazepine |
US20150065704A1 (en) | 2011-07-13 | 2015-03-05 | Ketan Hirpara | Process for the preparation and purification of eslicarbazepine acetate and intermediates thereof |
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