CN1230950A - 2,4’-联吡啶基衍生物的制备方法和分离方法以及苯并噁氮杂䓬衍生物及其盐的制备方法 - Google Patents
2,4’-联吡啶基衍生物的制备方法和分离方法以及苯并噁氮杂䓬衍生物及其盐的制备方法 Download PDFInfo
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- CN1230950A CN1230950A CN98800941A CN98800941A CN1230950A CN 1230950 A CN1230950 A CN 1230950A CN 98800941 A CN98800941 A CN 98800941A CN 98800941 A CN98800941 A CN 98800941A CN 1230950 A CN1230950 A CN 1230950A
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- Prior art keywords
- bipyridyl
- derivative
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- formula
- reaction
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- 238000000034 method Methods 0.000 title claims abstract description 97
- RMHQDKYZXJVCME-UHFFFAOYSA-N 2-pyridin-4-ylpyridine Chemical group N1=CC=CC=C1C1=CC=NC=C1 RMHQDKYZXJVCME-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000000926 separation method Methods 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 title claims description 25
- 238000004519 manufacturing process Methods 0.000 title abstract description 10
- ZCXLTWVZYXBHJS-UHFFFAOYSA-N 1,2-benzoxazepine Chemical class O1N=CC=CC2=CC=CC=C12 ZCXLTWVZYXBHJS-UHFFFAOYSA-N 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 73
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 47
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000003054 catalyst Substances 0.000 claims abstract description 32
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 22
- MWVTWFVJZLCBMC-UHFFFAOYSA-N 4,4'-bipyridine Chemical group C1=NC=CC(C=2C=CN=CC=2)=C1 MWVTWFVJZLCBMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 92
- 238000006243 chemical reaction Methods 0.000 claims description 82
- 238000002360 preparation method Methods 0.000 claims description 73
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 24
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical class ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 claims description 23
- 125000005843 halogen group Chemical group 0.000 claims description 22
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000011701 zinc Substances 0.000 claims description 12
- 229910052725 zinc Inorganic materials 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 235000009518 sodium iodide Nutrition 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 230000026030 halogenation Effects 0.000 claims description 5
- 238000005658 halogenation reaction Methods 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 238000005891 transamination reaction Methods 0.000 claims description 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 2
- LVIYYTJTOKJJOC-UHFFFAOYSA-N nickel phthalocyanine Chemical compound [Ni+2].C12=CC=CC=C2C(N=C2[N-]C(C3=CC=CC=C32)=N2)=NC1=NC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 LVIYYTJTOKJJOC-UHFFFAOYSA-N 0.000 claims description 2
- 150000005761 4-chloropyridine Chemical class 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 claims 1
- 229910000365 copper sulfate Inorganic materials 0.000 abstract description 16
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 abstract description 13
- 238000006880 cross-coupling reaction Methods 0.000 abstract description 4
- 150000005749 2-halopyridines Chemical class 0.000 abstract 1
- 150000005751 4-halopyridines Chemical class 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 110
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 96
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 62
- 239000012044 organic layer Substances 0.000 description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 238000000605 extraction Methods 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000010410 layer Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- 229910052801 chlorine Inorganic materials 0.000 description 20
- MJFCDPLEATUOPF-UHFFFAOYSA-L dichloronickel;triphenylphosphane Chemical compound Cl[Ni]Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MJFCDPLEATUOPF-UHFFFAOYSA-L 0.000 description 20
- XGAFCCUNHIMIRV-UHFFFAOYSA-N 4-chloropyridine;hydron;chloride Chemical compound Cl.ClC1=CC=NC=C1 XGAFCCUNHIMIRV-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 125000001309 chloro group Chemical group Cl* 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 230000035484 reaction time Effects 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 15
- 238000005406 washing Methods 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- PVMNPAUTCMBOMO-UHFFFAOYSA-N 4-chloropyridine Chemical compound ClC1=CC=NC=C1 PVMNPAUTCMBOMO-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 9
- ANCWWFAROKLXRF-UHFFFAOYSA-M tetraethylazanium;iodate Chemical compound [O-]I(=O)=O.CC[N+](CC)(CC)CC ANCWWFAROKLXRF-UHFFFAOYSA-M 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- -1 dibromo alkane Chemical class 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 150000005759 2-chloropyridine Chemical class 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
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- 230000015572 biosynthetic process Effects 0.000 description 5
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000010025 steaming Methods 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
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- IVRPDZRVHKIBBG-UHFFFAOYSA-N 2-(1,2,3,6-tetrahydropyridin-4-yl)pyridine Chemical compound C1NCCC(C=2N=CC=CC=2)=C1 IVRPDZRVHKIBBG-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
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- 125000001246 bromo group Chemical group Br* 0.000 description 3
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- 230000005494 condensation Effects 0.000 description 3
- XLOMEDHGELECDS-UHFFFAOYSA-L dibromonickel;triphenylphosphane Chemical compound Br[Ni]Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 XLOMEDHGELECDS-UHFFFAOYSA-L 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
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- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
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- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 2
- KCDNYRPDKSGQCM-UHFFFAOYSA-N 4-[4-(3-chlorophenyl)-4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1-(4-fluorophenyl)butan-1-one Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC(C=2C=C(Cl)C=CC=2)(C(=O)N2CCCC2)CC1 KCDNYRPDKSGQCM-UHFFFAOYSA-N 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- 206010034912 Phobia Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical class CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 206010007776 catatonia Diseases 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- QQAXARYEINCLLN-UHFFFAOYSA-N ethyl pyridin-1-ium-1-carboxylate Chemical class CCOC(=O)[N+]1=CC=CC=C1 QQAXARYEINCLLN-UHFFFAOYSA-N 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- QCYXGORGJYUYMT-UHFFFAOYSA-N nickel;triphenylphosphane Chemical compound [Ni].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QCYXGORGJYUYMT-UHFFFAOYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
Description
实施例1 | 实施例2 | 实施例3 | 实施例4 | ||
催化剂的制备 | |||||
镍配合物催化剂(30mol%) | NiBr2(PPh3)21.11g | NiBr2(PPh3)21.11g | NiCl2(PPh3)2981mg | NiCl2(PPh3)2981mg | |
锌(1.5当量) | 490mg | 490mg | 490mg | 490mg | |
Et4NI(1当量) | 1.28g | 1.28g | 1.28g | 1.28g | |
溶剂 | THF | THF | THF | THF | |
反应时间 | 30min. | 30min. | 30min. | 30min. | |
原料的制备 | |||||
2-氯吡啶 | 4mmol | 3mmol | 4mmol | 2.5mmol | |
盐酸4-氯吡啶 | 1mmol | 2mmol | 1mmol | 2.5mmol | |
三乙胺 | 1mmol | 2mmol | 1mmol | 2.5mmol | |
溶剂 | DMF | DMF | DMF | DMF | |
反应时间 | 1hr | 1hr | 1hr | 1hr | |
反应 | |||||
反应温度 | 50℃ | 50℃ | 50℃ | 50℃ | |
反应时间 | 16hr | 16hr | 16hr | 16hr | |
结果 | |||||
2,2’-联吡啶基收率% | 73mg(23%) | 45mg(19%) | 88mg(28%) | 72mg(18%) | |
2,4’-联吡啶基收率% | 99mg63% | 193mg61% | 132mg84% | 198mg51% | |
4,4’-联吡啶基收率% | -0% | 57mg(36%) | -0% | 57mg15% |
实施例5 | 实施例6 | 实施例7 | ||
催化剂的制备 | ||||
镍配合物催化剂(30mol%) | NiCl2(PPh3)2981mg | NiCl2(PPh3)2981g | NiCl2(PPh3)2981mg | |
锌 | 490mg | 490mg | 490mg | |
Et4NI | - | 1.28g | 1.28g | |
溶剂 | DMF | THF+DMF(10ml+5ml) | 丙酮 | |
反应时间 | 30min. | 30min. | 30min. | |
原料的制备 | ||||
2-氯吡啶 | 2.5mmol | 2.5mmol | 2.5mmol | |
盐酸4-氯吡啶 | 2.5mmol | 2.5mmol | 2.5mmol | |
三乙胺 | 2.5mmol | 2.5mmol | 2.5mmol | |
溶剂 | DMF | 直接加入 | 丙酮 | |
反应时间 | 1hr | 1hr | ||
反应 | ||||
反应温度 | 50℃ | 50℃ | 50℃ | |
反应时间 | 16hr | 16hr | 16hr | |
结果 | ||||
2,2’-联吡啶基收率% | 43mg11% | 28mg7% | 65mg17% | |
2,4’-联吡啶基收率% | 161mg41% | 163mg42% | 113mg29% | |
4,4’-联吡啶基收率% | 81mg21% | 103mg26% | 24mg6% |
实施例8 | 实施例9 | ||
催化剂的制备 | |||
镍配合物催化剂(10mol%) | NiCl2(PPh3)2327mg | NiCl2(PPh3)2327mg | |
锌 | 157mg | 490mg | |
Et4NI | - | 427mg | |
溶剂 | DMF | THF | |
反应时间 | 30min. | 30min. | |
原料的制备 | |||
2-氯吡啶 | 2.5mmol | 2.5mmol | |
盐酸4-氯吡啶 | 2.5mmol | 2.5mmol | |
三乙胺 | 2.5mmol | 2.5mmol | |
溶剂 | DMF | THF | |
反应时间 | 1hr | 1hr | |
反应 | |||
反应温度 | 50℃ | 50℃ | |
反应时间 | 16hr | 16hr | |
结果 | |||
2,2’-联吡啶基收率% | 50mg13% | 79mg*20%* | |
2,4’-联吡啶基收率% | 94mg24% | 129mg33% | |
4,4’-联吡啶基收率% | 70mg18% | 103mg26% |
实施例11 | 实施例12 | 实施例13 | ||
催化剂的制备 | ||||
镍配合物催化剂(30mol%) | NiCl2(PPh3)2981mg | NiCl2(PPh3)2981mg | NiCl2(PPh3)2981mg | |
锌 | 490mg | 490mg | 490mg | |
Et4NI | 1.28g | 1.28g | 1.28g | |
溶剂 | THF | 甲苯 | 甲苯 | |
反应时间 | 30min. | 30min. | 30min. | |
原料的制备 | ||||
2-氯吡啶 | 2.5mmol | 2.5mmol | 2.5mmol | |
盐酸4-氯吡啶 | 2.5mmol | 2.5mmol | 2.5mmol | |
三乙胺 | 2.5mmol | 2.5mmol | 2.5mmol | |
溶剂 | DMF | DMF | DMF | |
反应时间 | 1hr | 1hr | 1hr | |
反应 | ||||
反应温度 | 50℃ | 50℃ | 在0℃下加料室温下反应 | |
反应时间 | 16hr | 16hr | 16hr | |
结果 | ||||
2,2’-联吡啶基收率% | - | - | - | |
2,4’-联吡啶基收率% | 167mg40% | 90mg23% | 122mg31% | |
4,4’-联吡啶基收率% | - | - | - |
实施例14 | 实施例15 | 实施例16 | ||
催化剂的制备 | ||||
镍配合物催化剂(10或30mol%) | NiCl2(PPh3)2327mg | NiCl2(PPh3)2981g | NiCl2(PPh3)2981mg | |
锌 | 490mg | 490mg | 490mg | |
Et4NI | 1.28g | 384mg(30mol%) | 1.05g(Et4NBr) | |
溶剂 | THF | THF | THF | |
反应时间 | 30min. | 30min. | 30min. | |
原料的制备 | ||||
2-氯吡啶 | 2.5mmol | 2.5mmol | 2.5mmol | |
盐酸4-氯吡啶 | 2.5mmol | 2.5mmol | 2.5mmol | |
三乙胺 | 2.5mmol | 2.5mmol | 2.5mmol | |
溶剂 | DMF | DMF | DMF | |
反应时间 | 1hr | 1hr | 1hr | |
反应 | ||||
反应温度 | 50℃ | 50℃ | 50℃ | |
反应时间 | 16hr | 16hr | 16hr | |
结果 | ||||
2,2’-联吡啶基收率% | - | - | - | |
2,4’-联吡啶基收率% | 98mg25% | 121mg31% | 135mg35% | |
4,4’-联吡啶基收率% | - | - | - |
实施例17 | 实施例18 | ||
催化剂的制备 | |||
镍配合物催化剂(30mol%) | NiCl2(PPh3)21.96g | NiCl2(PPh3)24.9g | |
锌 | 940mg | 2.35g | |
Et4NBr | 2.1g | 5.2g | |
溶剂(浓度:两倍) | THF(10ml) | THF(25ml) | |
反应时间 | 30min. | 30min. | |
原料的制备 | |||
2-氯吡啶 | 5mmol | 12.5mmol | |
盐酸4-氯吡啶 | 5mmol | 12.5mmol | |
三乙胺 | 5mmol | 12.5mmol | |
溶剂 | DMF | THF | |
反应时间 | 1hr | 1hr | |
反应 | |||
反应温度 | 50℃ | 50℃ | |
反应时间 | 16hr | 16hr | |
分离操作 | |||
反应终止溶液 | 4NNH350ml | 10NNH350ml | |
盐酸 | 2N20ml | 2N20ml | |
氨水 | 4NNH320ml | 4NNH320ml | |
硫酸铜水溶液 | 0.2N20ml | 0.5N20ml | |
结果 | |||
2,4’-联吡啶基收率% | 231mg30% | 224mg11% |
Claims (10)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP132631/97 | 1997-05-22 | ||
JP132631/1997 | 1997-05-22 | ||
JP13263197 | 1997-05-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1230950A true CN1230950A (zh) | 1999-10-06 |
CN1107054C CN1107054C (zh) | 2003-04-30 |
Family
ID=15085850
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98800941A Expired - Fee Related CN1107054C (zh) | 1997-05-22 | 1998-05-22 | 2,4'-联吡啶基衍生物的制备方法和分离方法及其应用 |
Country Status (11)
Country | Link |
---|---|
US (2) | US6096884A (zh) |
EP (1) | EP0966440B1 (zh) |
KR (1) | KR100362958B1 (zh) |
CN (1) | CN1107054C (zh) |
AT (1) | ATE309218T1 (zh) |
AU (1) | AU727647B2 (zh) |
CA (1) | CA2260989C (zh) |
DE (1) | DE69832263T2 (zh) |
ES (1) | ES2247693T3 (zh) |
HU (1) | HUP0001300A3 (zh) |
WO (1) | WO1998052922A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103030594A (zh) * | 2012-12-11 | 2013-04-10 | 安徽国星生物化学有限公司 | 一种2,2'-联吡啶的合成方法 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2260989C (en) | 1997-05-22 | 2005-04-19 | Suntory Limited | Method of production and method of separation of 2,4'-dipyridyl derivatives and methods of production of benzoxazepine derivatives and salts thereof |
JP4603646B2 (ja) | 1999-11-15 | 2010-12-22 | 富士フイルムファインケミカルズ株式会社 | 新規なジピリジル誘導体 |
JP4603648B2 (ja) * | 1999-11-30 | 2010-12-22 | 富士フイルムファインケミカルズ株式会社 | ピリジン誘導体の製造方法 |
CN103030595A (zh) * | 2012-12-11 | 2013-04-10 | 安徽国星生物化学有限公司 | 一种2,2'-联吡啶的双碱解合成方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996024594A1 (fr) * | 1995-02-10 | 1996-08-15 | Suntory Limited | Derives de benzodiazepines, sels issus de ces derives, et medicaments a base de ces derives et sels |
CA2260989C (en) * | 1997-05-22 | 2005-04-19 | Suntory Limited | Method of production and method of separation of 2,4'-dipyridyl derivatives and methods of production of benzoxazepine derivatives and salts thereof |
-
1998
- 1998-05-22 CA CA002260989A patent/CA2260989C/en not_active Expired - Fee Related
- 1998-05-22 AT AT98921776T patent/ATE309218T1/de not_active IP Right Cessation
- 1998-05-22 KR KR1019997000461A patent/KR100362958B1/ko not_active IP Right Cessation
- 1998-05-22 ES ES98921776T patent/ES2247693T3/es not_active Expired - Lifetime
- 1998-05-22 WO PCT/JP1998/002264 patent/WO1998052922A1/en active IP Right Grant
- 1998-05-22 DE DE69832263T patent/DE69832263T2/de not_active Expired - Lifetime
- 1998-05-22 AU AU74505/98A patent/AU727647B2/en not_active Ceased
- 1998-05-22 CN CN98800941A patent/CN1107054C/zh not_active Expired - Fee Related
- 1998-05-22 EP EP98921776A patent/EP0966440B1/en not_active Expired - Lifetime
- 1998-05-22 US US09/230,168 patent/US6096884A/en not_active Expired - Lifetime
- 1998-05-22 HU HU0001300A patent/HUP0001300A3/hu unknown
-
2000
- 2000-06-09 US US09/590,678 patent/US6624308B2/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103030594A (zh) * | 2012-12-11 | 2013-04-10 | 安徽国星生物化学有限公司 | 一种2,2'-联吡啶的合成方法 |
Also Published As
Publication number | Publication date |
---|---|
DE69832263D1 (de) | 2005-12-15 |
HUP0001300A3 (en) | 2002-01-28 |
EP0966440B1 (en) | 2005-11-09 |
DE69832263T2 (de) | 2006-06-08 |
ATE309218T1 (de) | 2005-11-15 |
WO1998052922A1 (en) | 1998-11-26 |
EP0966440A1 (en) | 1999-12-29 |
AU7450598A (en) | 1998-12-11 |
CA2260989C (en) | 2005-04-19 |
US6096884A (en) | 2000-08-01 |
CN1107054C (zh) | 2003-04-30 |
US20030125547A1 (en) | 2003-07-03 |
CA2260989A1 (en) | 1998-11-26 |
KR100362958B1 (ko) | 2002-11-30 |
HUP0001300A2 (hu) | 2000-08-28 |
ES2247693T3 (es) | 2006-03-01 |
KR20000029467A (ko) | 2000-05-25 |
AU727647B2 (en) | 2000-12-21 |
US6624308B2 (en) | 2003-09-23 |
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