CN115536659B - Preparation method of benzo [4,5] imidazo [1,2-A ] pyridine - Google Patents
Preparation method of benzo [4,5] imidazo [1,2-A ] pyridine Download PDFInfo
- Publication number
- CN115536659B CN115536659B CN202211160448.0A CN202211160448A CN115536659B CN 115536659 B CN115536659 B CN 115536659B CN 202211160448 A CN202211160448 A CN 202211160448A CN 115536659 B CN115536659 B CN 115536659B
- Authority
- CN
- China
- Prior art keywords
- solvent
- reaction
- copper
- imidazo
- benzo
- 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.)
- Active
Links
- FODVQKYUAIWTKY-UHFFFAOYSA-N pyrido[1,2-a]benzimidazole Chemical compound C1=CC=CN2C3=CC=CC=C3N=C21 FODVQKYUAIWTKY-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 116
- 239000002904 solvent Substances 0.000 claims abstract description 64
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000654 additive Substances 0.000 claims abstract description 35
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 claims abstract description 33
- 230000000996 additive effect Effects 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000001301 oxygen Substances 0.000 claims abstract description 25
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 25
- 239000002994 raw material Substances 0.000 claims abstract description 16
- 150000001879 copper Chemical class 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 230000009471 action Effects 0.000 claims abstract description 8
- 238000010523 cascade reaction Methods 0.000 claims abstract description 7
- 238000005859 coupling reaction Methods 0.000 claims abstract description 5
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- 238000006317 isomerization reaction Methods 0.000 claims abstract description 4
- 230000008878 coupling Effects 0.000 claims abstract description 3
- 238000010168 coupling process Methods 0.000 claims abstract description 3
- 230000009615 deamination Effects 0.000 claims abstract description 3
- 238000006481 deamination reaction Methods 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 30
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 26
- 238000000605 extraction Methods 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 18
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 17
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 16
- 239000005711 Benzoic acid Substances 0.000 claims description 15
- 235000010233 benzoic acid Nutrition 0.000 claims description 15
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229940078552 o-xylene Drugs 0.000 claims description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 11
- 239000012046 mixed solvent Substances 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- JIDMEYQIXXJQCC-UHFFFAOYSA-L copper;2,2,2-trifluoroacetate Chemical compound [Cu+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F JIDMEYQIXXJQCC-UHFFFAOYSA-L 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 5
- ZKXWKVVCCTZOLD-UHFFFAOYSA-N copper;4-hydroxypent-3-en-2-one Chemical compound [Cu].CC(O)=CC(C)=O.CC(O)=CC(C)=O ZKXWKVVCCTZOLD-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- QMKYBPDZANOJGF-UHFFFAOYSA-N benzene-1,3,5-tricarboxylic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC(C(O)=O)=C1 QMKYBPDZANOJGF-UHFFFAOYSA-N 0.000 claims description 4
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 4
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- UMVOQQDNEYOJOK-UHFFFAOYSA-N 3,5-dimethylbenzoic acid Chemical compound CC1=CC(C)=CC(C(O)=O)=C1 UMVOQQDNEYOJOK-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims 1
- 229940045803 cuprous chloride Drugs 0.000 claims 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims 1
- 229940112669 cuprous oxide Drugs 0.000 claims 1
- 239000003513 alkali Substances 0.000 abstract description 8
- 230000007613 environmental effect Effects 0.000 abstract description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 230000007547 defect Effects 0.000 abstract description 4
- 229910052740 iodine Inorganic materials 0.000 abstract description 4
- 239000011630 iodine Substances 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 abstract description 2
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000463 material Substances 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 17
- 239000008367 deionised water Substances 0.000 description 16
- 229910021641 deionized water Inorganic materials 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 14
- 238000004321 preservation Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000001816 cooling Methods 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- 239000010949 copper Substances 0.000 description 9
- 229910052802 copper Inorganic materials 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 8
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 7
- 239000007810 chemical reaction solvent Substances 0.000 description 7
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 7
- 241000894007 species Species 0.000 description 7
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 150000001556 benzimidazoles Chemical class 0.000 description 6
- 239000007806 chemical reaction intermediate Substances 0.000 description 6
- 239000003444 phase transfer catalyst Substances 0.000 description 6
- HUDSSSKDWYXKGP-UHFFFAOYSA-N n-phenylpyridin-2-amine Chemical class C=1C=CC=NC=1NC1=CC=CC=C1 HUDSSSKDWYXKGP-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- -1 imidazole compound Chemical class 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 229940076286 cupric acetate Drugs 0.000 description 3
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- MGUDXXNWLVGZIF-UHFFFAOYSA-N (2-iodophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1I MGUDXXNWLVGZIF-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- 150000005749 2-halopyridines Chemical class 0.000 description 2
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 2
- CCZWSTFVHJPCEM-UHFFFAOYSA-N 2-iodopyridine Chemical compound IC1=CC=CC=N1 CCZWSTFVHJPCEM-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000006887 Ullmann reaction Methods 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000007614 solvation Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- 238000006964 Chan-Lam coupling reaction Methods 0.000 description 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
- 239000005751 Copper oxide Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000005669 field effect Effects 0.000 description 1
- 150000005171 halobenzenes Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- JUMCOCGEMWPRGH-UHFFFAOYSA-N n-(2-bromophenyl)pyridin-2-amine Chemical compound BrC1=CC=CC=C1NC1=CC=CC=N1 JUMCOCGEMWPRGH-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a preparation method of benzo [4,5] imidazo [1,2-A ] pyridine, belonging to the technical field of organic synthesis of benzimidazole derivatives. The method comprises the following steps: 2-pyridone and phenylhydrazine hydrochloride are used as raw materials, and benzo [4,5] imidazo [1,2-A ] pyridine is prepared through condensation isomerization deamination, C-N coupling cyclization tandem reaction under the action of a catalyst, an additive and a solvent in an oxygen atmosphere. The existing synthesis method needs to be carried out under the reaction condition of equivalent alkali, the iodine-containing compound is needed to participate in the reaction to obtain the high-yield product, and the utilization rate of iodine atoms is low, so that the method has the defects of high price, more three wastes, difficult post-treatment, outstanding environmental protection problem, high production cost and the like; compared with the existing synthesis method, the method uses the cheap copper salt to catalyze 2-hydroxypyridine and phenylhydrazine hydrochloride to synthesize benzo [4,5] imidazo [1,2-A ] pyridine, can obtain higher yield on the premise of not using an iodine-containing compound, and has the characteristics of economy, high efficiency and environmental protection.
Description
Technical Field
The invention belongs to the technical field of organic synthesis of benzimidazole derivatives, and particularly relates to a preparation method of benzo [4,5] imidazo [1,2-A ] pyridine.
Background
The benzimidazole derivative is a condensed imidazole compound, and has special electronic structure, photoelectric property and good thermal stability because of containing two nitrogen atoms in the five-membered ring, and has good fluorescence property and conductivity with a metal easily-formed complex, so that the benzimidazole derivative has wide application in the fields of high-temperature-resistant organic luminescent materials, photon absorption materials, organic dyes and the like. The benzimidazole derivative has a special molecular structure, can form a hydrogen bond with enzymes and receptors in organisms, and coordinate with metals to form pi-pi action and hydrophobic-hydrophobic action, so that the benzimidazole derivative has very wide application in the fields of biochemistry, medicinal chemistry and the like.
Wherein, the benzo [4,5] imidazo [1,2-A ] pyridine compound is a benzimidazole derivative with pyridine further condensed on a benzimidazole molecular skeleton, and the fluorescence property of the benzo [4,5] imidazo [1,2-A ] pyridine compound is obviously improved compared with benzimidazole as the molecular plane is further enlarged. Benzo [4,5] imidazo [1,2-A ] pyridine derivatives are a novel fluorescent backbone which maintains both solid and liquid fluorescent properties, and are also an important basic backbone in the pharmaceutical field, called "master keys"; therefore, the fluorescent dye has important application value in the optical fields of organic light-emitting diodes, field effect transistors, fluorescent probes and the like, and also has important pharmacological effects on the aspects of reducing blood pressure, resisting inflammation, resisting bacteria, resisting viruses, resisting tumors, resisting diabetes and the like. Therefore, research on the synthesis of benzo [4,5] imidazo [1,2-A ] pyridines is of great importance for the development of optical materials and drug molecules. According to literature reports, the main synthetic routes of the benzo [4,5] imidazo [1,2-A ] pyridine compounds are as follows.
Route one: 2-anilinopyridine compounds are used as raw materials, and benzo [4,5] imidazo [1,2-A ] pyridine derivatives are prepared by intramolecular cyclization construction of imidazole rings. For example, 2012 Kostiantyn Liubchak et al (Tetrahedron 2012,68,2993-3000) report a process for preparing benzo [4,5] imidazo [1,2-A ] pyridine starting from 2- (2-bromophenylamino) pyridine: cuprous iodide is used as a catalyst, N, N' -dimethylethylenediamine (DMEDA) is used as a ligand, potassium carbonate is used as alkali, acetonitrile is used as a solvent, and the reaction is carried out at 80 ℃ for 24 hours, wherein the reaction yield is 98%; the reaction formula is as follows:
route two: 2-aminopyridine or 2-halopyridine and 2-halophenylboric acid or 2-haloaniline compounds are used as raw materials, and two C-N bonds are formed simultaneously to construct an imidazole ring to prepare the benzo [4,5] imidazo [1,2-A ] pyridine derivatives. For example, 2015, parthasarathi Das et al (J.org.chem.2015, 80, 9321-9327) reported the preparation of benzo [4,5] imidazo [1,2-A ] pyridine derivatives starting from 2-aminopyridine and 2-iodophenylboronic acid via Ullmann coupling and Chan-Lam coupling reactions: copper acetate is used as a catalyst, cesium carbonate is used as alkali, N, N-Dimethylformamide (DMF) is used as a solvent, and the reaction is carried out at 120 ℃ for 24 hours, wherein the reaction yield is 88%; the reaction formula is as follows:
for another example, in 2011, xiangge methou et al (Eur. J. Org. Chem.2011,27, 5242-5245) reported the preparation of benzo [4,5] imidazo [1,2-A ] pyridine derivatives from 2-iodopyridine and 2-iodoaniline via two intermolecular and intramolecular Ullmann coupling reactions: cuprous iodide is used as a catalyst, 1, 10-phenanthroline (Phen) is used as a ligand, cesium carbonate is used as alkali, xylene (xylene) is used as a solvent, and the reaction is carried out at 120 ℃ for 12-24 hours, wherein the reaction yield is 90%; the reaction formula is as follows:
in the synthetic route, the reaction condition of the first route is mild, but the used raw material 2-arylaminopyridine is obtained by synthesizing 2-aminopyridine and halobenzene or aniline and 2-halopyridine through coupling reaction of Buchwald-Hartwig and Ullmann C-N under the catalysis of palladium, copper salt and the like, so the raw material has the defects of high price and difficult acquisition, high production cost and poor economical efficiency of the route. The reaction condition of the second route is relatively mild, but the first route has the defect that for example, expensive 2-iodophenylboronic acid or 2-iodopyridine and 2-iodoaniline are adopted as reaction raw materials, and expensive equivalent cesium carbonate is required to be used as alkali, so that the production cost cannot be controlled; meanwhile, the utilization rate of atoms of iodide ions is poor, more three wastes are generated, and the development rule of green chemistry is not met; in addition, if the reaction raw materials are changed into corresponding bromides, the reaction selectivity is poor, the post-purification difficulty is greatly increased, the reaction yield is obviously reduced, and the production cost is high.
In summary, the existing synthesis method generally requires ligand to promote the reaction, and the addition of the ligand not only increases the reaction cost, but also greatly increases the difficulty of separation and purification of the product; the reaction raw materials are expensive and not easy to obtain, the route economy and the atom economy are poor, and the production cost cannot be reduced; the equivalent expensive alkali is used, the atomic utilization rate is low, the recovery difficulty of the organic solvent is high, the three wastes are more, the environmental problem is outstanding, the production cost is high, and the industrial application of the equivalent expensive alkali in preparing benzo [4,5] imidazo [1,2-A ] pyridine is severely restricted. Therefore, there is a need for improvements in the art for the production of benzo [4,5] imidazo [1,2-A ] pyridines, which provides a more economical, green, efficient new synthetic route to benzo [4,5] imidazo [1,2-A ] pyridines while ensuring higher product yields.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.
Disclosure of Invention
In order to solve the technical problems of high preparation cost, general requirement of ligand participation, high purification difficulty and prominent ring-shaped problem of benzo [4,5] imidazo [1,2-A ] pyridine in the prior art, a preparation method of benzo [4,5] imidazo [1,2-A ] pyridine is provided.
The reaction principle of the invention is as follows:
under the oxygen atmosphere, the 2-pyridone and phenylhydrazine hydrochloride are subjected to dehydration condensation and isomerization under the action of copper and additives to release ammonia, so that a C-N bond is built between molecules, an N-phenylpyridine-2-amine intermediate is generated, the N-phenylpyridine-2-amine intermediate is subjected to rearrangement reaction and then subjected to electrophilic substitution reaction with copper salt, a six-membered ring copper intermediate transition state containing two N atoms is generated, the copper intermediate is dehydrated under the action of oxygen to generate a trivalent copper salt intermediate species, finally, reduction and elimination reaction is performed to build the intramolecular C-N bond to complete intramolecular cyclization to generate a target product, and meanwhile, the generated monovalent copper salt generates divalent copper salt under the action of oxygen oxidation to complete catalytic circulation.
In the method, the 2-pyridone is used as a raw material and plays a role of a ligand under the catalysis of copper salt and oxygen, and no additional ligand is needed; the 2-pyridone and phenylhydrazine hydrochloride firstly generate intermolecular C-N bond, then generate intramolecular C-N coupling reaction, and construct two C-N bonds to generate five-membered heterocyclic benzo [4,5] imidazo [1,2-A ] pyridine containing two N atoms. The method has the advantages of low and easily obtained raw material cost, simple operation, mild conditions, greener, economy and environmental protection.
The technical scheme of the invention is as follows:
the invention provides a preparation method of benzo [4,5] imidazo [1,2-A ] pyridine, which comprises the following raw materials: 2-pyridone and phenylhydrazine hydrochloride.
In some embodiments, the steps include: under the oxygen atmosphere, 2-pyridone and phenylhydrazine hydrochloride undergo condensation isomerization deamination and C-N coupling cyclization tandem reaction under the action of a catalyst, an additive and a solvent to prepare benzo [4,5] imidazo [1,2-A ] pyridine, wherein the reaction formula is as follows:
the oxygen atmosphere plays a role of an oxidant in the reaction process, avoids the use of other oxidants, and has the advantages of green, environment protection and economy. The oxygen content in the air atmosphere is low (21%), the yield and the selectivity of the reaction in the air atmosphere are poor, and the reaction effect in the air atmosphere is not ideal.
In some embodiments, the catalyst is a copper salt;
and/or, the additive comprises an additive A and an additive B; the additive A is tetrabutyl halide.
In some embodiments, the copper salt is selected from one or more of copper acetate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper acetylacetonate, copper sulfate, copper chloride, copper bromide, copper iodide, copper oxide, copper bromide, copper iodide, copper chloride, preferably copper acetate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper acetylacetonate;
and/or the additive A is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium fluoride; preferably, the additive A is tetrabutylammonium bromide;
the additive B is one or more selected from acetic acid, benzoic acid, isophthalic acid, trimesic acid, p-methylbenzoic acid, m-methylbenzoic acid, 3, 5-dimethylbenzoic acid, pivalic acid and ammonium chloride; preferably, the additive B is one of ammonium chloride, benzoic acid and pivalic acid.
The additive A plays a role of a phase transfer catalyst for catalyzing water phase-organic phase reaction in the reaction process, phenylhydrazine hydrochloride has poor solubility in an organic solvent and good solubility in water, and a reaction liquid presents a water-organic solvent two-phase system after the organic solvent and water are mixed, so that two phases are isolated from each other without adding the phase transfer catalyst, reaction substrates cannot be contacted, the reaction is very slow to carry out, and the reaction selectivity is poor; after the phase transfer catalyst is added, phenylhydrazine hydrochloride is combined with ions in the water phase, and the reaction substrate in the water phase is transferred into the organic phase by utilizing the self affinity to the organic solvent, so that the reaction is promoted, the reaction time is shortened, and the reaction selectivity and the reaction yield are improved.
The additive B and copper salt generate bivalent copper salt with larger steric hindrance such as benzene ring in the reaction process, and the additive B and the reaction intermediate N-phenylpyridine-2-amine form six-membered ring copper species, so that the stability of the reaction intermediate is improved, the forward reaction is facilitated, and the ring copper intermediate species formed when the additive B is not added are unstable and cannot be converted into a target product.
In some embodiments, the molar ratio of the 2-pyridone, the phenylhydrazine hydrochloride, the catalyst, the additive A and the additive B is 1 (1.0-2.0): 0.05-0.10): 0-0.30): 0.10-0.30.
In some embodiments, the solvent comprises solvent C, which is water, and solvent D, which is an organic solvent.
When a single organic solvent is adopted as a reaction solvent, the solvent has poor solubility and solvation effect on phenylhydrazine hydrochloride, so that the reaction speed is low and the reaction is incomplete. Meanwhile, under the condition that the organic solvent with smaller polarity is the reaction solvent, the balance between the 2-pyridone and the 2-hydroxypyridine can occur, the conversion rate of the reaction is affected, the complete conversion of the substrate can not be realized within the same reaction time, and the selectivity and the yield of the reaction are affected.
When single water is used as a reaction solvent, the solubility of reaction substrates, catalysts, additives and the like is good under the condition, the excessive water amount of the reaction substrates can not generate stable intermediates, and six-membered ring copper intermediate species can not be formed, so that no target product is generated.
In some embodiments, the volume ratio of the solvent C to the solvent D is (0-1): 2-100; further preferably, the volume ratio of the solvent C to the solvent D is (0-1): 5-20; the volume ratio of the solvent C to the organic solvent is 1 (5-20) and is the optimal mixed solvent combination.
Controlling the ratio of solvent water to solvent D in the above range facilitates the dissolution of phenylhydrazine hydrochloride in water and the transfer of the reaction substrate into the organic phase, promotes the formation of intermediates and further promotes the reaction. When the volume ratio of water to the organic solvent D in the mixed solvent is too large, the formation of the reaction intermediate and the target product is hindered.
In some embodiments, the ratio of the volume of the mixed solvent to the mass of the 2-pyridone is (4-7) mL/g; preferably, the ratio of the volume of the mixed solvent to the mass of the 2-pyridone is (5.5-6.5) mL/g.
In some embodiments, the solvent D is selected from one or more of o-xylene, toluene, o-dichlorobenzene, mesitylene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone.
In some embodiments, the temperature of the series reaction is 80 to 120 ℃ and the reaction time is 10 to 20 hours.
The preparation method of benzo [4,5] imidazo [1,2-A ] pyridine provided by the invention further comprises the following steps: post-treating benzo [4,5] imidazo [1,2-A ] pyridine prepared by the tandem reaction; preferably, the post-treatment comprises filtration, desolventization, extraction and recrystallization.
After the tandem reaction is finished, the reaction liquid is cooled to room temperature for post-treatment, which comprises the following steps: filtering, desolventizing the filtrate to recover solvent, extracting with water and extraction solvent, desolventizing the organic layer, and recrystallizing to obtain benzo [4,5] imidazo [1,2-A ] pyridine.
Wherein, the post-treatment extraction solvent is preferably one or more of butyl acetate, ethyl acetate, methylene dichloride, o-xylene, toluene and 1, 2-dichloroethane; the recrystallization solvent is preferably one or more of ethyl acetate, dichloromethane, o-xylene, methanol, ethanol, petroleum ether, n-hexane, tetrahydrofuran, and acetonitrile.
Compared with the prior art, the invention has the following technical effects:
(1) The benzo [4,5] imidazo [1,2-A ] pyridine prepared by the method adopts 2-pyridone and phenylhydrazine hydrochloride as raw materials, and the raw materials are cheap and easy to obtain, wherein the 2-pyridone not only serves as the raw materials but also plays a role of a ligand, and no additional ligand is needed, so that the cost is further reduced, the difficulty of post-treatment and purification is reduced, and the third aspect is favorable for recycling and reusing of the solvent.
(2) The existing synthesis method needs to be carried out under the reaction condition of equivalent alkali, the iodine-containing compound is needed to participate in the reaction to obtain the high-yield product, and the utilization rate of iodine atoms is low, so that the method has the defects of high price, more three wastes, difficult post-treatment, outstanding environmental protection problem, high production cost and the like; compared with the existing synthesis method, the method uses the cheap copper salt to catalyze 2-hydroxypyridine and phenylhydrazine hydrochloride to synthesize benzo [4,5] imidazo [1,2-A ] pyridine, has higher yield under the condition of not using an iodine-containing compound, and has the characteristics of economy, high efficiency and environmental protection.
(3) The method is carried out in an oxygen atmosphere, and oxygen plays a role of an oxidant in the reaction process, so that the use of other oxidants is avoided, the cost is reduced, and the method has the advantage of environmental protection.
(4) The method has mild reaction conditions, is simple and easy to operate, has the yield of more than 90 percent, and is suitable for batch production.
Detailed Description
The technical scheme of the invention is described below through specific examples. It is to be understood that the reference to one or more steps of the invention does not exclude the presence of other methods and steps before or after the combination of steps, or that other methods and steps may be interposed between the explicitly mentioned steps. It should also be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Unless otherwise indicated, the numbering of the method steps is for the purpose of identifying the method steps only and is not intended to limit the order of arrangement of the method steps or to limit the scope of the invention, which relative changes or modifications may be regarded as the scope of the invention which may be practiced without substantial technical content modification.
The raw materials and instruments used in the examples are not particularly limited in their sources, and may be purchased on the market or prepared according to conventional methods well known to those skilled in the art.
Example 1: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
The method comprises the following steps: into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 173.5g of phenylhydrazine hydrochloride (99%, 1.2 mol), 1.82g of cupric acetate (99%, 10.0 mmol), 6.45g of tetrabutylammonium bromide (99%, 20.0 mmol), 2.45g of benzoic acid (99%, 20.0 mmol), 25mL of deionized water, and 500mL of o-xylene under an oxygen atmosphere; after the material is fed, the temperature is raised to 100 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 12 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and butyl acetate for extraction, crystallizing the organic layer desolventized solvent through ethanol to obtain 152.1g of benzo [4,5] imidazo [1,2-A ] pyridine, and the yield is 90.5%.
Example 2: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
The method comprises the following steps: into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 216.9g of phenylhydrazine hydrochloride (99%, 1.5 mol), 1.45g of copper trifluoroacetate (99%, 5.0 mmol), 6.45g of tetrabutylammonium bromide (99%, 20.0 mmol), 3.0g of pivalic acid (99%, 30.0 mmol), 100mL of deionized water, and 500mL of o-dichlorobenzene under an oxygen atmosphere; after the material is fed, the temperature is raised to 100 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 16 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and methylene dichloride for extraction, removing the solvent from the organic layer, and crystallizing the organic layer by ethanol to obtain 156.5g of benzo [4,5] imidazo [1,2-A ] pyridine with the yield of 93.2%.
Example 3: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
The method comprises the following steps: into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 159.0g of phenylhydrazine hydrochloride (99%, 1.1 mol), 3.62g of copper triflate (99%, 10.0 mmol), 3.23g of tetrabutylammonium bromide (99%, 10.0 mmol), 1.60g of ammonium chloride (99%, 30.0 mmol), 50mL of deionized water, 500mL of dimethyl sulfoxide under an oxygen atmosphere; after the material is fed, the temperature is raised to 110 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 20 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and ethyl acetate for extraction, crystallizing the organic layer desolventized solvent through ethanol to obtain 153.2g of benzo [4,5] imidazo [1,2-A ] pyridine, and the yield is 91.2%.
Example 4: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
The method comprises the following steps: into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 289.0g of phenylhydrazine hydrochloride (99%, 2.0 mol), 2.62g of copper acetylacetonate (99%, 10.0 mmol), 3.23g of tetrabutylammonium bromide (99%, 10.0 mmol), 2.45g of benzoic acid (99%, 20.0 mmol), 25mL of deionized water, 500mL of N-methylpyrrolidone under an oxygen atmosphere; after the material is fed, the temperature is raised to 120 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 10 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and ethyl acetate for extraction, crystallizing the organic layer desolventized solvent by ethanol to obtain 158.0g of benzo [4,5] imidazo [1,2-A ] pyridine, with a yield of 94.0%.
Example 5: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
The method comprises the following steps: into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 144.5g of phenylhydrazine hydrochloride (99%, 1.0 mol), 1.82g of cupric acetate (99%, 10.0 mmol), 9.66g of tetrabutylammonium bromide (99%, 30.0 mmol), 1.22g of benzoic acid (99%, 10.0 mmol), 50mL of deionized water, and 500mL of toluene under an oxygen atmosphere; after the material is fed, the temperature is raised to 90 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 20 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and ethyl acetate for extraction, and crystallizing the organic layer desolventized solvent by ethanol to obtain 127.8g of benzo [4,5] imidazo [1,2-A ] pyridine with a yield of 76.1%.
Example 6: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
The method comprises the following steps: into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 159.0g of phenylhydrazine hydrochloride (99%, 1.1 mol), 1.82g of cupric acetate (99%, 10.0 mmol), 9.66g of tetrabutylammonium bromide (99%, 30.0 mmol), 3.66g of benzoic acid (99%, 30.0 mmol), 50mL of deionized water, and 500mL of o-xylene under an oxygen atmosphere; after the material is fed, the temperature is raised to 110 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 12 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and ethyl acetate for extraction, crystallizing the organic layer desolventized solvent through ethanol to obtain 140.6g of benzo [4,5] imidazo [1,2-A ] pyridine, and the yield is 83.7%.
Example 7: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
The method comprises the following steps: into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 173.5g of phenylhydrazine hydrochloride (99%, 1.2 mol), 0.91g of copper acetate (99%, 5.0 mmol), 9.66g of tetrabutylammonium bromide (99%, 30.0 mmol), 3.66g of benzoic acid (99%, 30.0 mmol), 100mL of deionized water, and 500mL of dimethyl sulfoxide under an oxygen atmosphere; after the material is fed, the temperature is raised to 80 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 12 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and ethyl acetate for extraction, crystallizing the organic layer desolventized solvent through ethanol to obtain 135.2g of benzo [4,5] imidazo [1,2-A ] pyridine, and the yield is 80.5%.
Example 8: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
This embodiment differs from embodiment 2 in that: volume of deionized water: volume of o-dichlorobenzene = 1:100.
The method comprises the following steps: into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 216.9g of phenylhydrazine hydrochloride (99%, 1.5 mol), 1.45g of copper trifluoroacetate (99%, 5.0 mmol), 6.45g of tetrabutylammonium bromide (99%, 20.0 mmol), 3.0g of pivalic acid (99%, 30.0 mmol), 5mL of deionized water, and 500mL of o-dichlorobenzene under an oxygen atmosphere; after the material is fed, the temperature is raised to 100 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 16 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and methylene dichloride for extraction, crystallizing the organic layer removed solvent through ethanol to obtain 153.4g of benzo [4,5] imidazo [1,2-A ] pyridine, and the yield is 91.2%.
Example 9: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
This embodiment differs from embodiment 2 in that: volume of deionized water: volume of o-dichlorobenzene = 1:2.
The method comprises the following steps: into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 216.9g of phenylhydrazine hydrochloride (99%, 1.5 mol), 1.45g of copper trifluoroacetate (99%, 5.0 mmol), 6.45g of tetrabutylammonium bromide (99%, 20.0 mmol), 3.0g of pivalic acid (99%, 30.0 mmol), 250mL of deionized water, and 500mL of o-dichlorobenzene under an oxygen atmosphere; after the material is fed, the temperature is raised to 100 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 16 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and methylene dichloride for extraction, removing the solvent from the organic layer, and crystallizing the organic layer by ethanol to obtain 76.7g of benzo [4,5] imidazo [1,2-A ] pyridine with the yield of 45.6%.
Example 10: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
The only difference between this example and the reaction conditions and parameters of example 1 is that additive A tetrabutylammonium bromide was not added.
Into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 173.5g of phenylhydrazine hydrochloride (99%, 1.2 mol), 1.82g of copper acetate (99%, 10.0 mmol), 2.45g of benzoic acid (99%, 20.0 mmol), 25mL of deionized water, 500mL of o-xylene under an oxygen atmosphere; after the material is fed, the temperature is raised to 100 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 12 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and butyl acetate for extraction, crystallizing the organic layer desolventized solvent through ethanol to obtain 72.6g of benzo [4,5] imidazo [1,2-A ] pyridine, and the yield is 43.2%.
In comparison with example 1, the present example gives benzo [4,5]]Imidazo [1,2-A]The yield of pyridine is obviously reduced, and the original
The following reasons:
the additive A tetrabutylammonium bromide plays a role of a phase transfer catalyst for catalyzing water phase-organic phase reaction in the reaction process, phenylhydrazine hydrochloride has poor solubility in an organic solvent and good solubility in water, and a reaction liquid presents a water-organic solvent two-phase system after the organic solvent and water are mixed, so that two phases are mutually isolated without adding the phase transfer catalyst, a reaction substrate cannot be contacted, the reaction is very slow to carry out, and the reaction selectivity is poor; after the phase transfer catalyst is added, phenylhydrazine hydrochloride is combined with ions in the water phase, and the reaction substrate in the water phase is transferred into the organic phase by utilizing the self affinity to the organic solvent, so that the reaction is promoted, the reaction time is shortened, and the reaction selectivity and the reaction yield are improved.
Example 11: preparation method of benzo [4,5] imidazo [1,2-A ] pyridine
The only difference between this example and the reaction conditions and parameters of example 1 is that this example uses o-xylene as the solvent.
Into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 173.5g of phenylhydrazine hydrochloride (99%, 1.2 mol), 1.82g of copper acetate (99%, 10.0 mmol), 6.45g of tetrabutylammonium bromide (99%, 20.0 mmol), 2.45g of benzoic acid (99%, 20.0 mmol), 550mL of o-xylene under an oxygen atmosphere; after the material is fed, the temperature is raised to 100 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 12 hours; after the reaction, cooling to room temperature, filtering, desolventizing the filtrate to recover the solvent, adding water and butyl acetate for extraction, crystallizing the organic layer desolventized solvent through ethanol to obtain 39.7g of benzo [4,5] imidazo [1,2-A ] pyridine, and the yield is 23.6%.
In comparison with example 1, the present example gives benzo [4,5]]Imidazo [1,2-A]The yield of pyridine is obviously reduced, and the original
The following reasons:
the method is characterized in that when a single organic solvent is used as a reaction solvent, the solvent has poor solubility and solvation effect on phenylhydrazine hydrochloride, so that the reaction speed is low and the reaction is incomplete. Meanwhile, under the condition that less-polar o-xylene is used as a reaction solvent, the balance between 2-pyridone and 2-hydroxypyridine can occur, the conversion rate of the reaction is affected, the complete conversion of a substrate can not be realized within the same reaction time, and the selectivity and the yield of the reaction are affected.
Comparative example 1: without addition of additive B
The only difference between this comparative example and the reaction conditions and parameters of example 1 is that comparative example 1 does not incorporate additive B benzoic acid.
Into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 173.5g of phenylhydrazine hydrochloride (99%, 1.2 mol), 1.82g of copper acetate (99%, 10.0 mmol), 6.45g of tetrabutylammonium bromide (99%, 20.0 mmol), 25mL of deionized water, 500mL of o-xylene under an oxygen atmosphere; after the material is fed, the temperature is raised to 100 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 12 hours; after the reaction is finished, cooling to room temperature, filtering, desolventizing the filtrate, recovering the solvent, adding water and butyl acetate for extraction, sampling an organic layer, and analyzing by GC-MS, wherein no benzo [4,5] imidazo [1,2-A ] pyridine is detected to be generated.
The reason why the target product was not obtained in this comparative example is as follows:
the additive B benzoic acid and copper salt generate bivalent copper salt with larger steric hindrance such as benzene ring in the reaction process, and the additive B benzoic acid and the reaction intermediate N-phenylpyridine-2-amine form six-membered ring copper species, so that the stability of the reaction intermediate is improved, the forward reaction is facilitated, and the ring copper intermediate species formed when the additive B is not added are unstable and cannot be converted into a target product.
Comparative example 2: the solvent is single solvent C (water)
The only difference between this comparative example and the reaction conditions and parameters of example 1 is that comparative example 1 uses deionized water as the solvent.
Into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 173.5g of phenylhydrazine hydrochloride (99%, 1.2 mol), 1.82g of copper acetate (99%, 10.0 mmol), 6.45g of tetrabutylammonium bromide (99%, 20.0 mmol), 2.45g of benzoic acid (99%, 20.0 mmol), 550mL of deionized water under an oxygen atmosphere; after the material is fed, the temperature is raised to 100 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 12 hours; after the reaction was completed, cooled to room temperature, butyl acetate was added for extraction, and the organic layer was sampled and analyzed by GC-MS, and no formation of benzo [4,5] imidazo [1,2-A ] pyridine was detected as a product.
The reason why the target product was not obtained in this comparative example is as follows:
when water is used as a reaction solvent, the solubility of reaction substrates, catalysts, additives and the like is good under the condition, and the excessive water quantity of the reaction substrates can not generate stable intermediates, and six-membered ring copper intermediate species can not be formed, so that no target product is generated.
Comparative example 3: solvent C (water) in the composite solvent: solvent D (organic solvent) 1:1
The only difference between this comparative example and the reaction conditions and parameters of example 1 is that the volume ratio of the mixed solvent of comparative example 1 is 1:1.
Into a 1L reaction flask were charged 95.1g of 2-pyridone (99%, 1.0 mol), 173.5g of phenylhydrazine hydrochloride (99%, 1.2 mol), 1.82g of copper acetate (99%, 10.0 mmol), 2.45g of benzoic acid (99%, 20.0 mmol), 225mL of deionized water, 225mL of o-xylene under an oxygen atmosphere; after the material is fed, the temperature is raised to 100 ℃, the stirring speed is 500rpm, and the heat preservation reaction is carried out for 12 hours; after the reaction is finished, cooling to room temperature, filtering, desolventizing the filtrate, recovering the solvent, adding water and butyl acetate for extraction, sampling an organic layer, and analyzing by GC-MS, wherein no benzo [4,5] imidazo [1,2-A ] pyridine is detected to be generated.
The reason why the target product was not obtained in this comparative example is as follows:
the mixed solvent with the volume ratio of water to the solvent D of 1:1 is adopted, and the volume ratio of the water to the organic solvent D in the mixed solvent is excessively large, similar to the condition when water is used as the only reaction solvent, so that the generation of reaction intermediates and target products is hindered.
The foregoing descriptions of specific exemplary embodiments of the present invention are presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application to thereby enable one skilled in the art to make and utilize the invention in various exemplary embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (7)
1. The preparation method of the benzo [4,5] imidazo [1,2-A ] pyridine is characterized in that the benzo [4,5] imidazo [1,2-A ] pyridine is prepared from the following raw materials: 2-pyridone and phenylhydrazine hydrochloride;
the method comprises the following steps: 2-pyridone and phenylhydrazine hydrochloride are subjected to condensation isomerization deamination and C-N coupling cyclization tandem reaction under the action of a catalyst, an additive and a solvent in an oxygen atmosphere to prepare benzo [4,5] imidazo [1,2-A ] pyridine;
the catalyst is copper salt; the copper salt is selected from copper acetate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper acetylacetonate, copper sulfate, copper chloride, copper bromide, copper iodide, cuprous oxide, cuprous bromide, cuprous iodide and cuprous chloride;
the additive comprises an additive A and an additive B;
the additive A is tetrabutyl halide; the additive A is one or more selected from tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium fluoride;
the additive B is one or more selected from acetic acid, benzoic acid, isophthalic acid, trimesic acid, p-methylbenzoic acid, m-methylbenzoic acid, 3, 5-dimethylbenzoic acid, pivalic acid and ammonium chloride;
the solvent is a mixed solvent and comprises a solvent C and a solvent D, wherein the solvent C is water, and the solvent D is an organic solvent; the volume ratio of the solvent C to the solvent D is 1 (5-20);
the solvent D is one or more selected from o-xylene, toluene, o-dichlorobenzene, mesitylene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
2. The method of claim 1, wherein the reaction formula is as follows:
3. the preparation method according to claim 1, wherein the copper salt is one or more of copper acetate, copper trifluoroacetate, copper trifluoromethane sulfonate and copper acetylacetonate.
4. The preparation method according to claim 1, wherein the molar ratio of the 2-pyridone to the phenylhydrazine hydrochloride to the catalyst to the additive A to the additive B is 1 (1.0-2.0): (0.05-0.10): (0-0.30): (0.10-0.30).
5. The preparation method according to claim 1, wherein the ratio of the volume of the mixed solvent to the mass of the 2-pyridone is (4-7) mL/g.
6. The preparation method according to claim 1, wherein the temperature of the tandem reaction is 80-120 ℃ and the reaction time is 10-20 h.
7. The method of manufacturing according to claim 1, further comprising: post-treating benzo [4,5] imidazo [1,2-A ] pyridine prepared by the tandem reaction; the post-treatment comprises filtration, desolventizing, extraction and recrystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211160448.0A CN115536659B (en) | 2022-09-22 | 2022-09-22 | Preparation method of benzo [4,5] imidazo [1,2-A ] pyridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211160448.0A CN115536659B (en) | 2022-09-22 | 2022-09-22 | Preparation method of benzo [4,5] imidazo [1,2-A ] pyridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115536659A CN115536659A (en) | 2022-12-30 |
| CN115536659B true CN115536659B (en) | 2023-12-22 |
Family
ID=84729057
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211160448.0A Active CN115536659B (en) | 2022-09-22 | 2022-09-22 | Preparation method of benzo [4,5] imidazo [1,2-A ] pyridine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115536659B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109485665A (en) * | 2017-09-13 | 2019-03-19 | 北京鼎材科技有限公司 | Compound and application thereof and organic electroluminescence device |
| CN112250685A (en) * | 2020-11-25 | 2021-01-22 | 中钢集团南京新材料研究院有限公司 | Preparation method of indolo [2,3-A ] carbazole |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10577327B2 (en) * | 2018-06-11 | 2020-03-03 | King Abdulaziz University | Pyridine based ionic fluoride for catalyzing indole and tetrazole formation |
-
2022
- 2022-09-22 CN CN202211160448.0A patent/CN115536659B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109485665A (en) * | 2017-09-13 | 2019-03-19 | 北京鼎材科技有限公司 | Compound and application thereof and organic electroluminescence device |
| CN112250685A (en) * | 2020-11-25 | 2021-01-22 | 中钢集团南京新材料研究院有限公司 | Preparation method of indolo [2,3-A ] carbazole |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115536659A (en) | 2022-12-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103274917B (en) | Method for catalyzing and synthesizing benzil derivatives from alkali type copper fluoride | |
| CN111978236B (en) | Preparation method of N-substituted-3-morpholinyl-4-phenylseleno maleimide compound | |
| CN112480050B (en) | Synthesis method of fullerene spiro-derivative | |
| CN107325037A (en) | A kind of preparation method of 1 bromine carbazole | |
| JP2004155728A (en) | Method for producing metal complex | |
| CN111978237B (en) | Preparation method of 3-morpholinyl-4-arylseleno maleimide compound | |
| CN115536659B (en) | Preparation method of benzo [4,5] imidazo [1,2-A ] pyridine | |
| CN111808023B (en) | Method for preparing 3-aryl isoquinoline derivative | |
| Chen et al. | CuI catalyzed domino coupling–cyclization of 2-iodo-phenols and 1-alkynes to the synthesis of 2-substituted benzo [b] furans/furo-pyridines | |
| CN108658841A (en) | A kind of carbazole compound and preparation method thereof | |
| CN105622625B (en) | A kind of synthetic method of benzopyrone and Imidazopyridine compound | |
| CN111116654A (en) | Phenanthroline tetradentate copper complex and preparation method and application thereof | |
| CN113912609B (en) | Preparation method of natural alkaloid tryptanthrin and derivatives thereof | |
| WO2024031753A1 (en) | Indoline compound and preparation method therefor | |
| CN111484436A (en) | Method for introducing isopentenyl group to C3 position of indole | |
| CN107162973B (en) | Method for constructing acridone derivative through C-N bonding by intramolecular decarboxylation coupling | |
| CN111004164B (en) | Preparation method of polysubstituted 2-aryl indole derivative | |
| CN110407830B (en) | Method for synthesizing N-arylphenothiazine compound | |
| CN111057080B (en) | Preparation method of boron-containing indolinone derivative | |
| CN108947900B (en) | Method for synthesizing heterocyclic compound by photoinduced metal-free catalyzed carbon arylation cascade reaction | |
| CN107935913B (en) | Carbazole compound and synthesis method and application thereof | |
| CN105859557B (en) | A kind of preparation method of esters of alpha, beta, unsaturated carboxylic acids compound | |
| CN110606839A (en) | Green synthesis method of polysubstituted quinazoline derivative | |
| CN113262816B (en) | Catalytic system and method for synthesizing benzo [1,2-b:4,5-b' ] dibenzofuran by using same | |
| CN112538087B (en) | Synthesis method of imidazopyridine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |