ZA200301757B - New process for the production of oxabispidines. - Google Patents
New process for the production of oxabispidines. Download PDFInfo
- Publication number
- ZA200301757B ZA200301757B ZA200301757A ZA200301757A ZA200301757B ZA 200301757 B ZA200301757 B ZA 200301757B ZA 200301757 A ZA200301757 A ZA 200301757A ZA 200301757 A ZA200301757 A ZA 200301757A ZA 200301757 B ZA200301757 B ZA 200301757B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- compound
- formula
- aryl
- alkylene
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 69
- 230000008569 process Effects 0.000 title claims description 63
- 238000004519 manufacturing process Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 122
- 125000000217 alkyl group Chemical group 0.000 claims description 94
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 78
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 125000002947 alkylene group Chemical group 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 44
- 229910052799 carbon Inorganic materials 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 125000005843 halogen group Chemical group 0.000 claims description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 22
- 238000010992 reflux Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 8
- 125000001475 halogen functional group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 239000012634 fragment Substances 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003849 aromatic solvent Substances 0.000 claims description 3
- 239000006184 cosolvent Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- KZOCHEDMAHPYCK-UHFFFAOYSA-N 4-[3-[3-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonan-7-yl]propylamino]benzonitrile Chemical compound C1C(O2)CN(CC(=O)C(C)(C)C)CC2CN1CCCNC1=CC=C(C#N)C=C1 KZOCHEDMAHPYCK-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- 150000002148 esters Chemical group 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- ZEEVEFOISWRYMK-UHFFFAOYSA-N tert-butyl n-[2-[7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethyl]carbamate Chemical compound C1C(O2)CN(CCNC(=O)OC(C)(C)C)CC2CN1CCCCC1=CC=C(C#N)C=C1 ZEEVEFOISWRYMK-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 241000219498 Alnus glutinosa Species 0.000 claims 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims 1
- REQPQFUJGGOFQL-UHFFFAOYSA-N dimethylcarbamothioyl n,n-dimethylcarbamodithioate Chemical compound CN(C)C(=S)SC(=S)N(C)C REQPQFUJGGOFQL-UHFFFAOYSA-N 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- LAMDSCRMEIOKJI-UHFFFAOYSA-N tert-butyl n-[2-[7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethyl]carbamate Chemical compound C1C(O2)CN(CCNC(=O)OC(C)(C)C)CC2CN1CCCNC1=CC=C(C#N)C=C1 LAMDSCRMEIOKJI-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 32
- -1 Cys alkoxy Chemical group 0.000 description 29
- 239000000047 product Substances 0.000 description 23
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 238000007792 addition Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000005233 alkylalcohol group Chemical group 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- VZSXFJPZOCRDPW-UHFFFAOYSA-N carbanide;trioxorhenium Chemical compound [CH3-].O=[Re](=O)=O VZSXFJPZOCRDPW-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- SLFJZMKCBPIOSE-UHFFFAOYSA-N 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1C(O2)CNCC2CN1CC1=CC=CC=C1 SLFJZMKCBPIOSE-UHFFFAOYSA-N 0.000 description 3
- YGGZSXNFDOVMBH-UHFFFAOYSA-N 7-benzyl-3-(4-nitrophenyl)sulfonyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)N1CC(O2)CN(CC=3C=CC=CC=3)CC2C1 YGGZSXNFDOVMBH-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 3
- 150000002978 peroxides Chemical class 0.000 description 3
- 125000003170 phenylsulfonyl group Chemical class C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- WLDGDTPNAKWAIR-UHFFFAOYSA-N 1,4,7-trimethyl-1,4,7-triazonane Chemical compound CN1CCN(C)CCN(C)CC1 WLDGDTPNAKWAIR-UHFFFAOYSA-N 0.000 description 2
- NHDLUSFFYRBOLY-UHFFFAOYSA-N 1-(benzenesulfonyl)-5-benzyl-1,5-diazocane-3,7-diol Chemical compound C1C(O)CN(S(=O)(=O)C=2C=CC=CC=2)CC(O)CN1CC1=CC=CC=C1 NHDLUSFFYRBOLY-UHFFFAOYSA-N 0.000 description 2
- ZDOBEODZHJDKSC-UHFFFAOYSA-N 3-(benzenesulfonyl)-7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane Chemical compound C=1C=CC=CC=1S(=O)(=O)N(CC(C1)O2)CC2CN1CC1=CC=CC=C1 ZDOBEODZHJDKSC-UHFFFAOYSA-N 0.000 description 2
- QWKKYJLAUWFPDB-UHFFFAOYSA-N 4-nitrobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 QWKKYJLAUWFPDB-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000012455 biphasic mixture Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- NHAIWYADCPHYAG-UHFFFAOYSA-L dilithium 2-sulfanylacetate hydrate Chemical compound [Li+].[Li+].O.[O-]C(=O)CS.[O-]C(=O)CS NHAIWYADCPHYAG-UHFFFAOYSA-L 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- ZKTZWRUVGKLQKN-UHFFFAOYSA-N n,n-bis(oxiran-2-ylmethyl)benzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(CC1OC1)CC1CO1 ZKTZWRUVGKLQKN-UHFFFAOYSA-N 0.000 description 2
- DYUWTXWIYMHBQS-UHFFFAOYSA-N n-prop-2-enylprop-2-en-1-amine Chemical compound C=CCNCC=C DYUWTXWIYMHBQS-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- OQHPAEHSQMKXSG-UHFFFAOYSA-N (3-benzoyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan-7-yl)-phenylmethanone Chemical compound C=1C=CC=CC=1C(=O)N(CC(C1)O2)CC2CN1C(=O)C1=CC=CC=C1 OQHPAEHSQMKXSG-UHFFFAOYSA-N 0.000 description 1
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- KTSZYXNHBVWNNV-UHFFFAOYSA-N 1,2-diazabicyclo[3.3.1]nonane Chemical class C1CNN2CCCC1C2 KTSZYXNHBVWNNV-UHFFFAOYSA-N 0.000 description 1
- OUHNIVNXFPHDJI-UHFFFAOYSA-N 1,5-diazocane-3,7-diol Chemical compound OC1CNCC(O)CNC1 OUHNIVNXFPHDJI-UHFFFAOYSA-N 0.000 description 1
- LEKJAKPBCODASB-UHFFFAOYSA-N 1-hydroxy-1,5-diazocan-3-ol Chemical class OC1CNCCCN(O)C1 LEKJAKPBCODASB-UHFFFAOYSA-N 0.000 description 1
- SPXOTSHWBDUUMT-UHFFFAOYSA-N 138-42-1 Chemical compound OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HMXJZAZRNMXNIF-UHFFFAOYSA-N 6-oxa-1,3-diazatricyclo[3.3.1.13,7]decane Chemical class C1N(C2)CC3CN2CC1O3 HMXJZAZRNMXNIF-UHFFFAOYSA-N 0.000 description 1
- HWTDMFJYBAURQR-UHFFFAOYSA-N 80-82-0 Chemical compound OS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O HWTDMFJYBAURQR-UHFFFAOYSA-N 0.000 description 1
- QPZGDXHVVSBMCO-UHFFFAOYSA-N 9-oxa-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1NCC2CNCC1O2 QPZGDXHVVSBMCO-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 239000011928 denatured alcohol Substances 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- OESCMYFBOLREFE-UHFFFAOYSA-L dilithium 2-sulfanylacetate Chemical compound [Li+].[Li+].[O-]C(=O)CS.[O-]C(=O)CS OESCMYFBOLREFE-UHFFFAOYSA-L 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010943 off-gassing Methods 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- OALPPYUMFWGHEK-UHFFFAOYSA-M potassium;benzenethiolate Chemical compound [K+].[S-]C1=CC=CC=C1 OALPPYUMFWGHEK-UHFFFAOYSA-M 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PH12000002701 | 2000-10-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200301757B true ZA200301757B (en) | 2004-02-05 |
Family
ID=52573779
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| ZA200301757A ZA200301757B (en) | 2000-10-02 | 2003-03-03 | New process for the production of oxabispidines. |
| ZA200302202A ZA200302202B (en) | 2000-10-02 | 2003-03-18 | New oxabispidine compound useful in the treatment of cardiac arrhythmias. |
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| Application Number | Title | Priority Date | Filing Date |
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| ZA200302202A ZA200302202B (en) | 2000-10-02 | 2003-03-18 | New oxabispidine compound useful in the treatment of cardiac arrhythmias. |
Country Status (22)
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| US (5) | US20040039199A1 (es) |
| EP (3) | EP1330462A1 (es) |
| JP (2) | JP4248873B2 (es) |
| KR (2) | KR100812920B1 (es) |
| CN (3) | CN1468244A (es) |
| AR (1) | AR030756A1 (es) |
| AU (3) | AU9250401A (es) |
| BR (2) | BR0114366A (es) |
| CA (2) | CA2422810A1 (es) |
| CZ (1) | CZ294217B6 (es) |
| EE (1) | EE200300131A (es) |
| HU (1) | HUP0302288A3 (es) |
| IL (3) | IL154802A0 (es) |
| IS (1) | IS6744A (es) |
| MX (2) | MXPA03002759A (es) |
| NO (2) | NO20031413L (es) |
| NZ (2) | NZ524573A (es) |
| PL (1) | PL364047A1 (es) |
| RU (1) | RU2003107668A (es) |
| SK (1) | SK3862003A3 (es) |
| WO (2) | WO2002028863A1 (es) |
| ZA (2) | ZA200301757B (es) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9903759D0 (sv) * | 1999-10-18 | 1999-10-18 | Astra Ab | Pharmaceutically active compounds |
| GB0223712D0 (en) * | 2002-10-14 | 2002-11-20 | Astrazeneca Ab | Chemical intermediate |
| SE0401540D0 (sv) * | 2004-06-15 | 2004-06-15 | Astrazeneca Ab | New compounds |
| SE0401539D0 (sv) | 2004-06-15 | 2004-06-15 | Astrazeneca Ab | New compounds |
| AR057064A1 (es) | 2005-06-13 | 2007-11-14 | Astrazeneca Ab | Compuestos para el tratamiento de arritmias cardiacas, formulacion farmaceutica y preparacion del compuesto |
| WO2006137769A1 (en) * | 2005-06-20 | 2006-12-28 | Astrazeneca Ab | Process for the preparation of 3,7-dihydroxy-1,5-diazacyclooctanes |
| BRPI0611841A2 (pt) * | 2005-06-20 | 2016-08-30 | Astrazeneca Ab | processos para isolar um sal, para preparar um sal, e para a preparação de um composto |
| AR053901A1 (es) * | 2005-06-20 | 2007-05-23 | Astrazeneca Ab | Formas fisicas de oxabispidinas n,n'- disustituidas |
| EP1915380A4 (en) * | 2005-06-20 | 2010-03-17 | Astrazeneca Ab | PROCESS FOR THE SYNTHESIS OF N, N'-DISUBSTITUTED OXABISPIDINES |
| CN103319423B (zh) * | 2013-06-28 | 2015-10-28 | 江苏师范大学 | 一种3,7-双芳基-1,5-二氧-3,7-二氮杂环辛烷的合成方法 |
| KR20150082070A (ko) | 2014-01-06 | 2015-07-15 | (주)신비넷 | 위치 인식 시스템 및 그 시스템에서의 위치 인식을 위한 장치 및 방법 |
| EP3059229A1 (en) | 2015-02-17 | 2016-08-24 | Evonik Degussa GmbH | Method for the epoxidation of an olefin with hydrogen peroxide |
| CN115054728B (zh) * | 2022-07-18 | 2023-11-07 | 中国科学院大学宁波华美医院 | 一种仿生骨组织工程支架材料及其制备方法 |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3503939A (en) * | 1967-03-29 | 1970-03-31 | Du Pont | Polyamides from heterocyclic diamines |
| DE2428792A1 (de) * | 1974-06-14 | 1976-01-02 | Knoll Ag | Neue antiarrhythmika |
| DE3112055A1 (de) * | 1981-03-27 | 1982-10-07 | Basf Ag, 6700 Ludwigshafen | Bispidinderivate, ihre herstellung und diese enthaltende arzneimittel |
| DE3234697A1 (de) * | 1982-09-18 | 1984-03-22 | Kali-Chemie Pharma Gmbh, 3000 Hannover | Neue diazabicyclo-(3,3,1)-nonane |
| DE3732094A1 (de) * | 1987-09-24 | 1989-04-06 | Basf Ag | Bispidinderivate als klasse iii-antiarrhythmika |
| DE3902357A1 (de) | 1989-01-27 | 1990-08-02 | Hoechst Ag | Verwendung von rheniumorganischen verbindungen zur oxidation von c-c-mehrfachbindungen, darauf basierende oxidationsverfahren und neue rheniumorganische verbindungen |
| US5140033A (en) * | 1989-04-03 | 1992-08-18 | Bayer Aktiengesellschaft | Antibacterial 5-alkylquinolonecarboxylic acids |
| US5110933A (en) | 1989-11-13 | 1992-05-05 | Board Of Regents Of Oklahoma State University | Salts of 3-azabicyclo[3.3.1]nonanes as antiarrhythmic agents, and precursors thereof |
| US5468858A (en) * | 1993-10-28 | 1995-11-21 | The Board Of Regents Of Oklahoma State University Physical Sciences | N-alkyl and n-acyl derivatives of 3,7-diazabicyclo-[3.3.1]nonanes and selected salts thereof as multi-class antiarrhythmic agents |
| US5831099A (en) | 1995-03-10 | 1998-11-03 | The United States Of America As Represented By The Secretary Of The Army | Compounds of 1,5-disubstituted-3,7 diaza bicyclo 3.3.0! octanes and products containing the same |
| US5939568A (en) | 1997-01-31 | 1999-08-17 | The Scripps Research Institute | Accelerated catalysis of olefinic epoxidations |
| SE9704709D0 (sv) * | 1997-12-17 | 1997-12-17 | Astra Ab | Pharmaceutically active compounds |
| NZ514477A (en) * | 1999-04-09 | 2003-04-29 | Astrazeneca Ab | Adamantane derivatives |
| AUPQ274199A0 (en) | 1999-09-09 | 1999-09-30 | Ericsson Australia Pty Ltd | Information transmission rate control across a core network |
| SE9903759D0 (sv) * | 1999-10-18 | 1999-10-18 | Astra Ab | Pharmaceutically active compounds |
| GB0223712D0 (en) * | 2002-10-14 | 2002-11-20 | Astrazeneca Ab | Chemical intermediate |
-
2001
- 2001-09-18 AR ARP010104406A patent/AR030756A1/es unknown
- 2001-10-01 US US10/398,171 patent/US20040039199A1/en not_active Abandoned
- 2001-10-01 EP EP01972866A patent/EP1330462A1/en not_active Withdrawn
- 2001-10-01 EP EP01972865A patent/EP1330461A1/en not_active Withdrawn
- 2001-10-01 PL PL01364047A patent/PL364047A1/xx not_active Application Discontinuation
- 2001-10-01 CA CA002422810A patent/CA2422810A1/en not_active Abandoned
- 2001-10-01 CA CA002421776A patent/CA2421776A1/en not_active Abandoned
- 2001-10-01 JP JP2002532447A patent/JP4248873B2/ja not_active Expired - Fee Related
- 2001-10-01 MX MXPA03002759A patent/MXPA03002759A/es active IP Right Grant
- 2001-10-01 WO PCT/SE2001/002129 patent/WO2002028863A1/en not_active Application Discontinuation
- 2001-10-01 AU AU9250401A patent/AU9250401A/xx active Pending
- 2001-10-01 CN CNA018167217A patent/CN1468244A/zh active Pending
- 2001-10-01 JP JP2002532446A patent/JP2004510775A/ja active Pending
- 2001-10-01 BR BR0114366-2A patent/BR0114366A/pt not_active IP Right Cessation
- 2001-10-01 EE EEP200300131A patent/EE200300131A/xx unknown
- 2001-10-01 KR KR1020037004639A patent/KR100812920B1/ko not_active IP Right Cessation
- 2001-10-01 CN CNB018167225A patent/CN1243754C/zh not_active Expired - Fee Related
- 2001-10-01 NZ NZ524573A patent/NZ524573A/en unknown
- 2001-10-01 BR BR0114367-0A patent/BR0114367A/pt not_active IP Right Cessation
- 2001-10-01 EP EP07121849A patent/EP1900741A1/en not_active Withdrawn
- 2001-10-01 HU HU0302288A patent/HUP0302288A3/hu unknown
- 2001-10-01 IL IL15480201A patent/IL154802A0/xx unknown
- 2001-10-01 AU AU2001292503A patent/AU2001292503A1/en not_active Abandoned
- 2001-10-01 WO PCT/SE2001/002130 patent/WO2002028864A1/en active IP Right Grant
- 2001-10-01 KR KR10-2003-7004638A patent/KR20030032060A/ko not_active Application Discontinuation
- 2001-10-01 RU RU2003107668/04A patent/RU2003107668A/ru not_active Application Discontinuation
- 2001-10-01 NZ NZ524574A patent/NZ524574A/en unknown
- 2001-10-01 US US10/381,900 patent/US6936712B1/en not_active Expired - Fee Related
- 2001-10-01 MX MXPA03002679A patent/MXPA03002679A/es not_active Application Discontinuation
- 2001-10-01 CN CNA2005100035779A patent/CN1793146A/zh active Pending
- 2001-10-01 AU AU2001292504A patent/AU2001292504B2/en not_active Ceased
- 2001-10-01 IL IL15480301A patent/IL154803A0/xx active IP Right Grant
- 2001-10-01 CZ CZ2003923A patent/CZ294217B6/cs not_active IP Right Cessation
- 2001-10-01 SK SK386-2003A patent/SK3862003A3/sk not_active Application Discontinuation
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2003
- 2003-03-03 ZA ZA200301757A patent/ZA200301757B/en unknown
- 2003-03-06 IL IL154803A patent/IL154803A/en not_active IP Right Cessation
- 2003-03-13 IS IS6744A patent/IS6744A/is unknown
- 2003-03-18 ZA ZA200302202A patent/ZA200302202B/en unknown
- 2003-03-27 NO NO20031413A patent/NO20031413L/no not_active Application Discontinuation
- 2003-03-27 NO NO20031414A patent/NO20031414L/no not_active Application Discontinuation
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2005
- 2005-03-25 US US11/089,325 patent/US7439355B2/en not_active Expired - Fee Related
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2008
- 2008-09-15 US US12/232,293 patent/US20090036675A1/en not_active Abandoned
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2009
- 2009-03-06 US US12/382,068 patent/US20090240051A1/en not_active Abandoned
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