KR101653532B1 - Synthesis of Benzimidazoles bearing borionic acid functionality via metal-free aerobic oxidation - Google Patents
Synthesis of Benzimidazoles bearing borionic acid functionality via metal-free aerobic oxidation Download PDFInfo
- Publication number
- KR101653532B1 KR101653532B1 KR1020150038351A KR20150038351A KR101653532B1 KR 101653532 B1 KR101653532 B1 KR 101653532B1 KR 1020150038351 A KR1020150038351 A KR 1020150038351A KR 20150038351 A KR20150038351 A KR 20150038351A KR 101653532 B1 KR101653532 B1 KR 101653532B1
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- aryl
- formula
- hydrogen
- chemical formula
- Prior art date
Links
- 150000001556 benzimidazoles Chemical group 0.000 title claims description 21
- 238000007254 oxidation reaction Methods 0.000 title abstract description 9
- 230000003647 oxidation Effects 0.000 title abstract description 8
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- 239000002253 acid Substances 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 36
- 239000003054 catalyst Substances 0.000 claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 96
- 150000001875 compounds Chemical class 0.000 claims description 89
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 86
- 239000000126 substance Substances 0.000 claims description 65
- 238000006243 chemical reaction Methods 0.000 claims description 61
- 125000003118 aryl group Chemical group 0.000 claims description 59
- 239000001257 hydrogen Substances 0.000 claims description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 40
- -1 bromo, carboxy Chemical group 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 20
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 16
- 150000008045 alkali metal halides Chemical class 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
- 229910052741 iridium Inorganic materials 0.000 claims description 13
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 13
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 12
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 239000012298 atmosphere Substances 0.000 claims description 10
- 125000001246 bromo group Chemical group Br* 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 229910001615 alkaline earth metal halide Inorganic materials 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- NRJZBPNZBAJYFY-UHFFFAOYSA-N [B].N1=CNC2=C1C=CC=C2 Chemical compound [B].N1=CNC2=C1C=CC=C2 NRJZBPNZBAJYFY-UHFFFAOYSA-N 0.000 claims description 8
- 150000002503 iridium Chemical class 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 7
- 239000007800 oxidant agent Substances 0.000 abstract description 9
- 125000000524 functional group Chemical group 0.000 abstract description 7
- 230000002194 synthesizing effect Effects 0.000 abstract description 6
- 229930014626 natural product Natural products 0.000 abstract description 5
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 150000005309 metal halides Chemical class 0.000 abstract 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract 1
- 239000013067 intermediate product Substances 0.000 abstract 1
- 229910001507 metal halide Inorganic materials 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 238000012360 testing method Methods 0.000 description 30
- 239000007787 solid Substances 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 0 CCC(*)(C(*)C(*)C1(C)*)c2c1[n](*)c(C1=CC=C*1)n2 Chemical compound CCC(*)(C(*)C(*)C1(C)*)c2c1[n](*)c(C1=CC=C*1)n2 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 230000009257 reactivity Effects 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- YPSXFMHXRZAGTG-UHFFFAOYSA-N 4-methoxy-2-[2-(5-methoxy-2-nitrosophenyl)ethyl]-1-nitrosobenzene Chemical compound COC1=CC=C(N=O)C(CCC=2C(=CC=C(OC)C=2)N=O)=C1 YPSXFMHXRZAGTG-UHFFFAOYSA-N 0.000 description 3
- 241000125205 Anethum Species 0.000 description 3
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 125000005620 boronic acid group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000007243 oxidative cyclization reaction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 3
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 2
- NKCKVJVKWGWKRK-UHFFFAOYSA-N 4-(4-bromophenyl)-n,n-diphenylaniline Chemical compound C1=CC(Br)=CC=C1C1=CC=C(N(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 NKCKVJVKWGWKRK-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PCBOWMZAEDDKNH-HOTGVXAUSA-N [4-(trifluoromethoxy)phenyl]methyl (3as,6as)-2-(3-fluoro-4-sulfamoylbenzoyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C1=C(F)C(S(=O)(=O)N)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=CC(OC(F)(F)F)=CC=3)C[C@@H]2C1 PCBOWMZAEDDKNH-HOTGVXAUSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- DOAMZWOPDPPKJS-UHFFFAOYSA-N oxiran-2-ol Chemical compound OC1CO1 DOAMZWOPDPPKJS-UHFFFAOYSA-N 0.000 description 2
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- VXWBQOJISHAKKM-UHFFFAOYSA-N (4-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=O)C=C1 VXWBQOJISHAKKM-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- XWSGEVNYFYKXCP-UHFFFAOYSA-N 2-[carboxymethyl(methyl)amino]acetic acid Chemical compound OC(=O)CN(C)CC(O)=O XWSGEVNYFYKXCP-UHFFFAOYSA-N 0.000 description 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- JMFCZIVQOBUVCU-RYUDHWBXSA-N I[C@@H](CCC1)[C@H]1OCc1ccccc1 Chemical compound I[C@@H](CCC1)[C@H]1OCc1ccccc1 JMFCZIVQOBUVCU-RYUDHWBXSA-N 0.000 description 1
- 229930182559 Natural dye Natural products 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- YKOWBJJOJNGCAD-SHYZEUOFSA-N [(2r,3s,5r)-3-hydroxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl dihydrogen phosphate Chemical compound O=C1N=C(NO)C=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 YKOWBJJOJNGCAD-SHYZEUOFSA-N 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- KFIFDKLIFPYSAZ-UHFFFAOYSA-N formyloxy(phenyl)borinic acid Chemical compound O=COB(O)C1=CC=CC=C1 KFIFDKLIFPYSAZ-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- ATGAWOHQWWULNK-UHFFFAOYSA-I pentapotassium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [K+].[K+].[K+].[K+].[K+].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O ATGAWOHQWWULNK-UHFFFAOYSA-I 0.000 description 1
- XPPWLXNXHSNMKC-UHFFFAOYSA-N phenylboron Chemical group [B]C1=CC=CC=C1 XPPWLXNXHSNMKC-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical compound C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
본 발명은 벤즈이미다졸 보론 화합물 및 호기성 산화법을 이용하여 분자 내 보로닉산이 직접 포함된 벤즈이미다졸을 합성하는 방법에 관한 것으로, 보다 상세하게는 알칼리금속 할라이드 또는 알칼리토금속 할라이드 촉매하의 무수조건에서 호기성 산화법을 이용하여 분자 내에 보로닉산이 직접 포함된 벤즈이미다졸을 합성하는 신규한 방법에 관한 것이다. The present invention relates to a method for synthesizing a benzimidazole in which an intramolecular boronic acid is directly incorporated using a benzimidazole boron compound and an aerobic oxidation method, and more particularly, The present invention relates to a novel method for synthesizing benzimidazole in which a boronic acid is directly contained in a molecule by using an oxidation method.
헤테로 고리화합물은 생화학, 의약화학 뿐 아니라 재료화학을 비롯한 여러 분야에 걸쳐 매우 중요한 화합물로 간주되고 있다. 그 중에서도 벤즈이미다졸은 천연물, 의약품, 천연물, 염료 및 태양전지 재료 등 다방면에 이용되는 대표적인 헤테로고리 화합물이다. 이와 같은 특권 골격(privileged scaffold)적 특징의 중요성으로 인해 지금까지 다양한 벤즈이미다졸의 합성방법이 개발되었다.Heterocyclic compounds are regarded as very important compounds in various fields including biochemistry, pharmaceutical chemistry, and material chemistry. Among them, benzimidazole is a typical heterocyclic compound used in various fields such as natural products, medicines, natural products, dyes and solar cell materials. Due to the importance of such privileged scaffold features, a variety of methods for the synthesis of benzimidazoles have been developed so far.
종래의 대표적인 벤즈이미다졸 합성방법으로는 1,2-페닐렌디아민과 카르복시산 사이의 반응을 이용하여 아마이드를 형성한 후, 형성된 아마이드를 산 촉매하에 탈수화 반응을 시켜 고리를 형성하는 방법이 있으며, 다른 합성방법으로는 1,2-페닐렌디아민과 알데히드를 반응시켜 이민을 형성한 후, 이민을 강한 산화제 하에서 산화고리화 반응을 시켜 합성하는 방법이 있다. 그러나 상기와 같은 방법은 강한 산촉매 또는 강한 산화제가 필요하므로 기질 선택성에 제한이 따른다는 문제점이 있으며, 반응 후 많은 부산물이 형성되기 때문에 반응 용액에서 원하는 화합물을 분리하는데 많은 시간과 비용이 들며, 수율이 좋지 않다는 문제점이 있다. As a typical conventional method for synthesizing benzimidazole, there is a method of forming an amide by using a reaction between 1,2-phenylenediamine and a carboxylic acid, and then dehydrating the formed amide under an acid catalyst to form a ring. As another synthesis method, 1,2-phenylenediamine and aldehyde are reacted with each other to form an imine, and then the imine is oxidized and cyclized under a strong oxidizing agent. However, since the above method requires a strong acid catalyst or a strong oxidizing agent, there is a problem that the selectivity of the substrate is limited, and since many by-products are formed after the reaction, it takes a lot of time and money to separate the desired compound from the reaction solution, There is a problem that it is not good.
상기와 같은 문제점을 해결하고 친환경적으로 합성하기 위한 많은 연구들이 진행되고 있는데, 특히 산소를 최종산화제로 이용하는 호기성 산화법이 유기화학 분야에서 주목받고 있다. 이에 따라 호기성 산화고리화 반응을 통한 헤테로고리 화합물의 제조방법이 개발되고 있다. Cheon 그룹에서는 o-아미노페놀과 o-아미노티오페놀을 각각 촉매량의 NaCN을 첨가하에 알데히드와 반응하여 각각 벤즈옥사졸과 벤즈티아졸을 제조할 수 있으나, 같은 방법으로 o-페닐렌디아민을 출발물질로 하는 경우에는 벤즈이미다졸이 제조되지 않고 2-아미노퀴녹사졸린이 제조된다고 보고한바 있다[(a) Adv. Synth. Catal., 2012, 354, 2992; (b) Tetrahedron, 2013, 69, 6565; (c) J. Org. Chem., 2014, 79, 901]. Many researches for solving the above problems and synthesizing them in an environmentally friendly manner have been carried out. Particularly, an aerobic oxidation method using oxygen as a final oxidizing agent has been attracting attention in the field of organic chemistry. Accordingly, a process for producing a heterocyclic compound through an aerobic oxidative cyclization reaction has been developed. In the Cheon group, o-aminophenol and o-aminothiophenol can be reacted with aldehydes, respectively, in the presence of a catalytic amount of NaCN to produce benzoxazole and benzothiazole, respectively. In the same manner, o- It has been reported that benzimidazole is not prepared and 2-aminoquinazoline is prepared [(a) Adv. Synth. Catal., 2012, 354, 2992; (b) Tetrahedron, 2013, 69, 6565; (c) J. Org. Chem., 2014, 79, 901].
한편, 상기와 같은 특권 골격에 기반하여 다양한 유도체를 손쉽게 합성할 수 있는 것은 얻어진 라이브러리의 스크리닝 결과를 최대로 하는데 매우 중요한 기술이다. 특히, 다양한 치환체와 작용기로 직접 변환할 수 있는 보로닉산이 직접 도입된 벤즈이미다졸의 합성법은 이러한 관점에서 주목할 만하다.On the other hand, the ability to easily synthesize various derivatives based on the privileged framework described above is a very important technique for maximizing screening results of the library obtained. In particular, the synthesis of benzimidazoles with direct introduction of the voronic acid, which can be directly converted to various substituents and functional groups, is noteworthy in this respect.
이에, Molander 그룹에서는 보로닉산을 대체할 수 있는 안전한 작용기(surrogate)로 trifloroborate를 이용하여 산소 조건하에서 보로닉산이 도입된 벤즈이미다졸 유도체를 합성하는 방법을 개발한바 있다[Org. Lett. 2012, 14, 4242]. 상기와 같은 합성법의 경우 산소 기체를 사용하고 있어서 반응이 위험하다는 문제점이 있으며, 얇은 박막 크로마토그래피법 등의 방법으로 반응 진행 여부를 모니터링 하는 것이 불가능하다. Accordingly, Molander group has developed a method for synthesizing benzimidazole derivatives in which boronic acid is introduced under oxygen conditions using trifloroborate as a safe surrogate that can replace boronic acid (Org. Lett. 2012, 14, 4242]. In the case of the above synthesis method, there is a problem that the reaction is dangerous because oxygen gas is used, and it is impossible to monitor the progress of the reaction by thin film chromatography or the like.
또한, 강한 산화제 조건하에서 보로닉산이 양성자 탈붕소화 반응이나 알콜 산화반응이 일어날 수 있는 문제점이 있고, 상기와 같은 문제점을 피하기 위해서 약한 산화제를 사용할 경우에는 분자 내 산화-환원 반응을 통해서 1,2-위치에 두 개의 보로닉산 치환체가 도입된 벤즈이미다졸이 합성되며, 원하는 생성물과 분리가 불가능하다는 문제점이 있다. In addition, there is a problem that the proton boronation reaction or the alcohol oxidation reaction may occur under a strong oxidizing agent condition. In order to avoid the above problem, when a weak oxidizing agent is used, -Benzimidazole in which two boronic acid substituents are introduced at a position of -R < 1 > -position can not be separated from a desired product.
본 발명이 해결하고자 하는 과제는 다양한 천연물, 의약품, 유기발광 다이오드용 형광물질 등의 제조를 위한 중간체로 유용하게 이용될 수 있도록 보론 작용기를 가지는 벤즈이미다졸 보론 화합물을 제공하는 것이다. A problem to be solved by the present invention is to provide a benzimidazole boron compound having a boron functional group so as to be useful as an intermediate for the production of various natural products, pharmaceuticals, and fluorescent materials for organic light emitting diodes.
본 발명이 해결하고자 하는 다른 과제는 무수 조건하에서 알칼리 금속 할라이드를 촉매로 사용하는 호기성 산화법을 이용하여 분자 내에 보로닉 작용기를 가지는 벤즈이미다졸을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing benzimidazole having a voronic functional group in a molecule by using an aerobic oxidation method using an alkali metal halide as a catalyst under anhydrous conditions.
본 발명이 해결하고자 하는 다른 과제는 상기 벤즈이미다졸을 이용하여 유기발광다이오드용 벤즈이미다졸 유도체 배위 이리듐 착화합물을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing a benzimidazole derivative-coordinated iridium complex for an organic light emitting diode using the benzimidazole.
상술한 문제를 해결하기 위하여 본 발명은 하기 [화학식 1]로 표현되는 벤즈이미다졸 유도체를 제공한다. In order to solve the above-mentioned problems, the present invention provides a benzimidazole derivative represented by the following formula (1).
[화학식 1][Chemical Formula 1]
상기 [화학식 1]에서, In the above formula (1)
X는 CH=CH, O 및 S 중에서 선택되고,X is selected from CH = CH, O and S,
BL*는 
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1 - 6알킬, 아릴, 헤테로아릴 및 C1 - 6알킬아마이딜 중에서 선택되고,R 1, R 2, R 3 and R 4 are the same or different and each is hydrogen, fluoro independently, chloro, bromo, methyl, carboxy, trifluoromethyl, C 1 to each other - 6 alkyl, aryl, heteroaryl and C 1 - is selected from 6-alkyl probably dill,
R5는 수소, C1 - 6알킬, 아릴 및 아릴C1 - 6알킬 중에서 선택되며,R 5 is hydrogen, C 1 - 6 alkyl, aryl and aryl C 1 - 6 is selected from alkyl,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1 - 6알킬 및 C1 - 6알콕시 중에서 선택되고,R 6 is methyl, C 1 the group consisting of hydrogen, nitro, hydroxy, carboxy, trifluoromethyl-6 is selected from alkoxy, - 6 alkyl and C 1
R1 내지 R5의 상기 C1 - 8알킬, 아릴 및 아릴C1 - 6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1 - 6알킬, C1 - 6알콕시, 히드록시, COOR8 및 니트로 중에서 선택되는 치환기로 치환되며, R 1 to the above R 5 C 1 - 8 alkyl, aryl and aryl C 1 - to 6, any carbon atom one to three of the alkyl are the same or hydrogen with different and each is independently of the other, fluoro, chloro, bromo, C 1 - 6 alkyl, C 1 - 6 alkoxy, hydroxy, COOR 8, and is substituted with a substituent selected from nitro,
R7은 수소, C1 - 6알킬, 
R8은 C1 - 6알킬이다.R 8 is C 1 - 6 is alkyl.
본 발명에 있어서, 상기 아릴은 페닐, 나프틸, 안트릴 및 바이페닐 중에서 선택될 수 있다.In the present invention, the aryl may be selected from phenyl, naphthyl, anthryl, and biphenyl.
본 발명에 있어서, 상기 C1 - 6알킬은 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸 및 헥실 중에서 선택될 수 있다. In the present invention, the C 1 - 6 alkyl may be selected from methyl, pentyl and hexyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl.
본 발명에 있어서, 상기 C1 - 6알콕시는 메톡시, 에톡시, 프로폭시, 부틸옥시 및 펜틸옥시 중에서 선택될 수 있다. In the present invention, the C 1 - 6 alkoxy may be selected from methoxy, ethoxy, propoxy, butyloxy, and pentyloxy.
본 발명에 있어서, 상기 아릴C1 - 6알킬은 메틸, 에틸, 프로필, 부틸, 펜틸 또는 헥실에 연결된 아릴일 수 있다.In the present invention, the aryl C 1 - 6 alkyl may be an aryl group linked to methyl, ethyl, propyl, butyl, pentyl or hexyl.
또한, 본 발명은 하기 [화학식 2]으로 표시되는 화합물과 하기 [화학식 3]으로 표시되는 화합물을 N,N-디메틸포름아미드 및 디메틸설폭사이드 중에서 선택되는 용매 하의 무수조건에서 알칼리금속 할라이드 또는 알칼리토금속 할라이드 촉매를 첨가하여 반응시키는 단계를 포함하여 수행함으로써 상기 [화학식 1]로 표시되는 화합물을 제조하는 벤즈이미다졸 유도체의 제조방법을 제공한다.The present invention also relates to a process for producing a compound represented by the formula (2) and a compound represented by the following formula (3) in an anhydrous condition in a solvent selected from N, N-dimethylformamide and dimethylsulfoxide, And a step of adding a halide catalyst to the reaction mixture to react to form a benzimidazole derivative.
[화학식 2](2)
[화학식 3](3)
상기 [화학식 2] 또는 [화학식 3]에서, 상기 R1, R2, R3, R4, R5, R6 및 BL*의 정의는 앞에서 설명한 바와 같다. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and BL * are as defined above.
본 발명에 따른 반응은 별도의 산화제를 필요로 하지 않고, 산소 분위기 하 또는 대기 분위기 하에서 수행되는 것을 특징으로 하며, 바람직하게는 대기 중의 산소를 이용하는 것일 수 있다.The reaction according to the present invention is characterized in that the reaction is carried out in an oxygen atmosphere or an atmospheric atmosphere without requiring a separate oxidant, preferably using atmospheric oxygen.
또한, 본 발명 따른 상기 반응은 염기를 첨가하여 가수분해시키는 단계;를 더 포함하여 수행함으로써 하기 [화학식 5]로 표시되는 화합물을 제조하는 보로닉산이 직접 포함된 벤즈이미다졸 유도체의 제조방법을 제공한다. The present invention also provides a process for preparing a benzimidazole derivative, which comprises directly adding boronic acid to the compound represented by the following formula (5) by further performing a hydrolysis reaction by adding a base do.
[화학식 5][Chemical Formula 5]
또한, 본 발명은 1) 하기 [화학식 2]으로 표시되는 화합물과 하기 [화학식 3]으로 표시되는 화합물을 N,N-디메틸포름아미드 및 디메틸설폭사이드 중에서 선택되는 용매 하의 무수조건에서 알칼리금속 할라이드 또는 알칼리토금속 할라이드 촉매를 첨가하여 반응시키는 단계를 포함하여 수행함으로써 하기 [화학식 1]로 표시되는 벤즈이미다졸 보론 화합물을 제조하는 단계;The present invention also relates to a process for the preparation of a compound of formula (I), which process comprises the steps of: 1) reacting a compound represented by the following formula 2 with an alkali metal halide or an alkali metal halide in an anhydrous condition in a solvent selected from N, N-dimethylformamide and dimethylsulfoxide Adding an alkaline earth metal halide catalyst to the mixture to prepare a benzimidazole boron compound represented by Formula 1 below;
2) 하기 [화학식 1]의 화합물과 하기 [화학식 32]의 화합물을 팔라듐 촉매하에서 반응시켜 하기 [화학식 33]의 화합물을 합성하는 단계; 2) reacting a compound represented by the formula (1) and a compound represented by the following formula (32) in the presence of a palladium catalyst to synthesize a compound represented by the following formula (33);
3) 상기 [화학식 33]의 화합물과 IrCl3를 반응시켜 이리듐 1 분자에 [화학식 33]의 화합물 2 분자가 결합된 이리듐 다이머 착물을 만드는 단계; 및3) reacting the compound of Formula 33 with IrCl 3 to form an iridium dimer complex in which two molecules of the compound of Formula 33 are bonded to one molecule of iridium; And
4) 상기 이리듐 다이머 착물과 아세틸 아세톤을 반응시켜 벤즈이미다졸형 이리듐 착물을 제조하는 단계;를 포함하는 벤즈이미다졸 보론 화합물을 이용한 유기발광다이오드용 벤즈이미다졸형 이리듐 착물의 제조방법을 제공한다.4) reacting the iridium dimer complex with acetylacetone to prepare a benzimidazole-type iridium complex, and a process for preparing a benzimidazole-type iridium complex for an organic light-emitting diode using the benzimidazole boron compound.
[화학식 32](32)
[화학식 33](33)
본 발명에 따른 보로닉산이 직접 포함된 벤즈이미다졸 유도체의 제조방법은 별도의 산화제를 필요로 하지 않고, 산소분위기 하 또는 대기 중에서 수행되는 호기성 산화법을 이용하며, N,N-디메틸포름아미드 또는 디메틸설폭사이드와 같은 유기 용매하에서 알칼리금속 할라이드를 촉매로 사용하여 60 내지 120 ℃의 낮은 온도에서 원-팟(one-pot) 반응으로 벤즈이미다졸 유도체를 우수한 수율로 제조할 수 있으므로, 친환경적이며, 안전하고, 간편하여 대량공정에 용이하게 적용할 수 있다. 특히, 본 발명에 따른 벤즈이미다졸의 2번 위치에 페닐보론 치환체가 도입된 화합물은 다양한 작용기로 치환될 수 있어 천연물, 의약품의 합성 중간체로 유용하게 이용될 수 있으며, 특히, 벤즈이미다졸에 기반한 이리듐 착화합물의 합성에 이용할 수 있어, 유기발광다이오드용 형광물질의 제조를 위한 리간드로 유용하게 이용될 수 있고, 글루코스 또는 하이드로카본을 검출할 수 있는 화학센서에 이용될 수 있다. The method for preparing a benzimidazole derivative directly containing boronic acid according to the present invention uses an aerobic oxidation method performed in an oxygen atmosphere or in an atmosphere without using a separate oxidizing agent and is carried out in an organic solvent such as N, N-dimethylformamide or dimethyl The benzimidazole derivative can be produced in an excellent yield by a one-pot reaction at a low temperature of 60 to 120 캜 using an alkali metal halide as an organic solvent in an organic solvent such as sulfoxide, And can be easily applied to a mass process. In particular, the compound in which the phenylboron substituent is introduced at the 2-position of the benzimidazole according to the present invention can be substituted with various functional groups, and thus can be usefully used as a synthetic intermediate for natural products and pharmaceuticals. Particularly, Iridium complexes, can be usefully used as ligands for the production of fluorescent materials for organic light emitting diodes, and can be used in chemical sensors capable of detecting glucose or hydrocarbons.
이하, 본 발명을 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 하기 [화학식 1]로 표현되는 벤즈이미다졸 유도체를 제공한다. The present invention provides a benzimidazole derivative represented by the following formula (1).
[화학식 1][Chemical Formula 1]
상기 [화학식 1]에서, In the above formula (1)
X는 CH=CH, O 및 S 중에서 선택되고,X is selected from CH = CH, O and S,
BL*는 
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1 - 6알킬, 아릴, 헤테로아릴 및 C1 - 6알킬아마이딜 중에서 선택되고,R 1, R 2, R 3 and R 4 are the same or different and each is hydrogen, fluoro independently, chloro, bromo, methyl, carboxy, trifluoromethyl, C 1 to each other - 6 alkyl, aryl, heteroaryl and C 1 - is selected from 6-alkyl probably dill,
R5는 수소, C1 - 6알킬, 아릴 및 아릴C1 - 6알킬 중에서 선택되며,R 5 is hydrogen, C 1 - 6 alkyl, aryl and aryl C 1 - 6 is selected from alkyl,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1 - 6알킬 및 C1 - 6알콕시 중에서 선택되고,R 6 is methyl, C 1 the group consisting of hydrogen, nitro, hydroxy, carboxy, trifluoromethyl-6 is selected from alkoxy, - 6 alkyl and C 1
R1 내지 R5의 상기 C1 - 8알킬, 아릴 및 아릴C1 - 6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1 - 6알킬, C1 - 6알콕시, 히드록시, COOR8 및 니트로 중에서 선택되는 치환기로 치환되며, R 1 to the above R 5 C 1 - 8 alkyl, aryl and aryl C 1 - to 6, any carbon atom one to three of the alkyl are the same or hydrogen with different and each is independently of the other, fluoro, chloro, bromo, C 1 - 6 alkyl, C 1 - 6 alkoxy, hydroxy, COOR 8, and is substituted with a substituent selected from nitro,
R7은 수소, C1 - 6알킬, 
R8은 C1 - 6알킬이다.R 8 is C 1 - 6 is alkyl.
본 발명에 있어서, 상기 BL*는 바람직하게는 s와 p 궤도함수가 sp3을 갖는 화합물일 수 있다. In the present invention, the BL * may preferably be a compound having s and p orbital sp 3 .
본 발명에 있어서, 상기 아릴은 페닐, 나프틸, 안트릴 및 바이페닐 중에서 선택될 수 있다.In the present invention, the aryl may be selected from phenyl, naphthyl, anthryl, and biphenyl.
본 발명에 있어서, 상기 C1 - 6알킬은 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸 및 헥실 중에서 선택될 수 있다. In the present invention, the C 1 - 6 alkyl may be selected from methyl, pentyl and hexyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl.
본 발명에 있어서, 상기 C1 - 6알콕시는 메톡시, 에톡시, 프로폭시, 부틸옥시 및 펜틸옥시 중에서 선택될 수 있다. In the present invention, the C 1 - 6 alkoxy may be selected from methoxy, ethoxy, propoxy, butyloxy, and pentyloxy.
본 발명에 있어서, 상기 아릴C1 - 6알킬은 메틸, 에틸, 프로필, 부틸, 펜틸 또는 헥실에 연결된 아릴일 수 있다.In the present invention, the aryl C 1 - 6 alkyl may be an aryl group linked to methyl, ethyl, propyl, butyl, pentyl or hexyl.
본 발명에 의하면, 상기 [화학식 1]은 하기 [화학식 1a] 내지 [화학식 1g] 중에서 선택될 수 있다. According to the present invention, the above-mentioned formula (1) can be selected from the following formulas (1a) to (1g).
[화학식 1a][Formula 1a]
[화학식 1b][Chemical Formula 1b]
[화학식 1c][Chemical Formula 1c]
[화학식 1d]≪ RTI ID = 0.0 &
[화학식 1e][Formula 1e]
[화학식 1f](1f)
[화학식 1g][Formula 1g]
상기 [화학식 1a] 내지 [화학식 1g]에서, In the above formulas (1a) to (1g)
상기 R1, R2, R3, R4, R5, R6 및 BL*의 정의는 앞에서 설명한 바와 같다. The definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and BL * are as described above.
상기 [화학식 1] 로 표시되는 화합물은 하기 [화학식 6] 내지 [화학식 19]로 이루어진 군 중에서 선택되는 어느 하나일 수 있다. The compound represented by the formula (1) may be any one selected from the group consisting of the following formulas (6) to (19).
[화학식 6][Chemical Formula 6]
[화학식 7](7)
[화학식 8][Chemical Formula 8]
[화학식 9][Chemical Formula 9]
[화학식 10][Chemical formula 10]
[화학식 11](11)
[화학식 12][Chemical Formula 12]
[화학식 13][Chemical Formula 13]
[화학식 14][Chemical Formula 14]
[화학식 15][Chemical Formula 15]
[화학식 16][Chemical Formula 16]
[화학식 17][Chemical Formula 17]
[화학식 18][Chemical Formula 18]
[화학식 19][Chemical Formula 19]
한편, 본 발명은 하기 [화학식 2]으로 표시되는 화합물과 하기 [화학식 3]으로 표시되는 화합물을 N,N-디메틸포름아미드 및 디메틸설폭사이드 중에서 선택되는 용매 하의 무수조건에서 알킬할라이드 촉매를 첨가하여 반응시키는 단계를 포함하여 수행함으로써 하기 [화학식 1]로 표시되는 화합물을 제조하는 보로닉산이 직접 포함된 벤즈이미다졸 유도체의 제조방법을 제공한다.On the other hand, the present invention relates to a process for preparing a compound represented by the following formula (2) by adding an alkyl halide catalyst under anhydrous conditions in a solvent selected from N, N-dimethylformamide and dimethylsulfoxide to a compound represented by the following formula And reacting the resulting compound with a boronic acid to produce a compound represented by the following formula (1).
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3](3)
상기 [화학식 1] 내지 [화학식 3]에서, In the above Chemical Formulas 1 to 3,
X는 CH=CH, O 및 S 중에서 선택되고,X is selected from CH = CH, O and S,
BL*는 
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1 - 6알킬, 아릴, 헤테로아릴 및 C1 - 6알킬아마이딜 중에서 선택되고,R 1, R 2, R 3 and R 4 are the same or different and each is hydrogen, fluoro independently, chloro, bromo, methyl, carboxy, trifluoromethyl, C 1 to each other - 6 alkyl, aryl, heteroaryl and C 1 - is selected from 6-alkyl probably dill,
R5는 수소, C1 - 6알킬, 아릴 및 아릴C1 - 6알킬 중에서 선택되며,R 5 is hydrogen, C 1 - 6 alkyl, aryl and aryl C 1 - 6 is selected from alkyl,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1 - 6알킬 및 C1 - 6알콕시 중에서 선택되고,R 6 is methyl, C 1 the group consisting of hydrogen, nitro, hydroxy, carboxy, trifluoromethyl-6 is selected from alkoxy, - 6 alkyl and C 1
R1 내지 R5의 상기 C1 - 8알킬, 아릴 및 아릴C1 - 6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1 - 6알킬, C1 - 6알콕시, 히드록시, COOR8, 니트로 중에서 선택되는 치환기로 치환되며, R 1 to the above R 5 C 1 - 8 alkyl, aryl and aryl C 1 - to 6, any carbon atom one to three of the alkyl are the same or hydrogen with different and each is independently of the other, fluoro, chloro, bromo, C 1 - 6 alkyl, C 1 - 6 alkoxy, hydroxy, COOR 8, is substituted with a substituent selected from nitro,
R7은 수소, C1 - 6알킬, 
R8은 C1 - 6알킬이다.R 8 is C 1 - 6 is alkyl.
상기 아릴, C1 - 6알킬, C1 - 6알콕시 및 아릴C1 - 6알킬은 앞에서 정의한 바와 같다. The aryl, C 1 - 6 alkyl, C 1 - 6 alkoxy, and aryl C 1 - 6 alkyl is as defined above.
본 발명에 따른 반응은 별도의 산화제를 필요로 하지 않고, 산소 분위기 하 또는 대기 분위기 하에서 수행되는 것을 특징으로 하며, 바람직하게는 대기 중의 산소를 이용하는 것일 수 있다.The reaction according to the present invention is characterized in that the reaction is carried out in an oxygen atmosphere or an atmospheric atmosphere without requiring a separate oxidant, preferably using atmospheric oxygen.
본 발명에 따른 상기 알칼리금속 할라이드 촉매는 KI, NaI, NaCl, KCl, NaBr 및 KBr 중에서 선택되며, 상기 알칼리토금속 할라이드 촉매는 CaI2, MgI2, CaCl2, CaI2, CaBr2 및 CaBr2 중에서 선택되는 것일 수 있고, 바람직하게는 KI일 수 있다.The alkali metal halide catalyst according to the present invention is selected from KI, NaI, NaCl, KCl, NaBr and KBr, and the alkaline earth metal halide catalyst is selected from CaI 2 , MgI 2 , CaCl 2 , CaI 2 , CaBr 2 and CaBr 2 , And may preferably be KI.
상기 [화학식 2]의 화합물 1 몰에 대하여 상기 촉매는 0.01 내지 1.5 몰의 비율로 첨가될 수 있는데, 상기 범위로 첨가되는 것이 부반응이 적어 목적하는 화합물이 우수한 수율로 제조되며, 분리하기가 용이하고, 원-팟 반응으로 추가 치환반응을 수행할 수 있어 경제적이다.The catalyst may be added in a proportion of 0.01 to 1.5 moles per mole of the compound of the formula (2). When the catalyst is added in the above range, the desired compound is produced in a good yield, , One-pot reaction can be carried out, and it is economical.
본 발명에 따른 상기 반응은 무수조건하의 60 내지 120 ℃ 범위에서 수행되는 것일 수 있다. 반응 시 물이 첨가되면, 상기 [화학식 2]로 표시되는 페닐렌디아민 화합물이 [화학식 3]의 알데히드기와 반응하지 않고, 보로닉산 부분과 반응하는 부반응이 일어나 목적하는 벤즈이미다졸 화합물이 생성되지 않으므로 반응 수율이 크게 저하될 수 있다.The reaction according to the present invention may be carried out in the range of 60 to 120 캜 under anhydrous conditions. When water is added during the reaction, the phenylenediamine compound represented by the above formula (2) does not react with the aldehyde group of the formula (3), and a side reaction of reacting with the boronic acid moiety occurs to produce the desired benzimidazole compound The reaction yield may be greatly reduced.
본 발명에 따르면 상기 반응은 N,N-디메틸포름아미드 또는 디메틸설폭사이드에서 선택되는 용매 하에서 반응을 수행하는 것이 바람직하다. 상기 반응은 다이옥산에서도 수행될 수 있으나, 반응시간이 오래 걸리며, 부반응이 많이 생성되어 바람직하지 않다. According to the present invention, it is preferable that the reaction is carried out in a solvent selected from N, N-dimethylformamide or dimethylsulfoxide. The reaction can be carried out also in dioxane, but takes a long reaction time and generates a lot of side reactions, which is not preferable.
본 발명에 따르면, 상기 [화학식 1]은 하기 [화학식 1a] 내지 [화학식 1g] 중에서 선택될 수 있다.According to the present invention, the above-mentioned formula (1) can be selected from the following formulas (1a) to (1g).
[화학식 1a][Formula 1a]
[화학식 1b][Chemical Formula 1b]
[화학식 1c][Chemical Formula 1c]
[화학식 1d]≪ RTI ID = 0.0 &
[화학식 1e][Formula 1e]
[화학식 1f](1f)
[화학식 1g][Formula 1g]
상기 [화학식 1a] 내지 [화학식 1g]에서, 상기 R1, R2, R3, R4, R5, R6 및 BL*의 정의는 앞에서 설명한 바와 같다. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and BL * in the above formulas are as defined above.
본 발명에 따르면 상기 [화학식 1]로 표시되는 화합물은 구체적으로 상기 [화학식 6] 내지 [화학식 19]로 이루어진 군 중에서 선택되는 어느 하나일 수 있으나 이에 제한되는 것은 아니다. 비록 명세서상에는 구체적으로 화학식을 표기하지 않았으나, 상기 [화학식 6] 내지 [화학식 19]에서 BL*의 R7에 대응되는 작용기가 메틸기 대신에 에틸기, 
본 발명에 따르면, 상기 [화학식 3]의 화합물은 4-포르밀페닐보론산(4-formylphenylboronic acid) 1 당량부에 대하여 하기 N-치환이미노디아세트산 화합물 2 내지 5 당량부를 N,N-디메틸포름아미드 및 디메틸설폭사이드 중에서 선택되는 용매 하의 무수 조건에서 70 내지 180 ℃로 반응시킴으로써 제조될 수 있다. According to the present invention, the compound of Formula 3 is obtained by reacting 2 to 5 equivalents of the following N-substituted iminodiacetic acid compound with 1 equivalent of 4-formylphenylboronic acid in the presence of N, N-dimethylformamide Amide and dimethylsulfoxide at 70-180 < 0 > C under anhydrous conditions.
<N-치환이미노디아세트산>≪ N-substituted iminodiacetic acid >
한편, 본 발명은 1) 하기 [화학식 2]으로 표시되는 화합물과 하기 [화학식 4]로 표시되는 화합물을 N,N-디메틸포름아미드 및 디메틸설폭사이드 중에서 선택되는 용매 하의 무수조건에서 알칼리금속 할라이드 또는 알칼리토금속 할라이드 촉매를 첨가하여 반응시키는 단계; 및 2) 염기를 첨가하여 가수분해시키는 단계;를 포함하여 수행함으로써 하기 [화학식 5]로 표시되는 화합물을 제조하는 보로닉산이 직접 포함된 벤즈이미다졸 유도체의 제조방법을 제공한다. On the other hand, the present invention relates to a process for the preparation of a compound of formula (I), which comprises the steps of: 1) reacting a compound represented by the following formula 2 with an alkali metal halide or an alkali metal halide in an anhydrous condition in a solvent selected from N, N-dimethylformamide and dimethylsulfoxide Adding an alkaline earth metal halide catalyst to react; And 2) hydrolyzing the compound by adding a base to form a benzimidazole derivative directly containing boronic acid to produce a compound represented by the following formula (5).
[화학식 2](2)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
상기 [화학식 2], [화학식 4] 또는 [화학식 5]에서, X, R1, R2, R3, R4, R5, R6 및 R7는 앞에서 정의한 바와 같다. X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, in the above formulas (2), (4)
본 발명에 있어서, 상기 염기는 NaOH 또는 KOH일 수 있으나 이에 한정되는 것은 아니다. In the present invention, the base may be NaOH or KOH, but is not limited thereto.
본 발명에 따라, 상기 [화학식 2]으로 표시되는 화합물과 상기 [화학식 4]로표시되는 화합물을 반응시키면 상기 [화학식 1]의 화합물이 되며, 상기 [화학식 1]의 화합물을 가수분해하면, 상기 [화학식 5]의 화합물이 될 수 있다.According to the present invention, when the compound represented by Formula 2 is reacted with the compound represented by Formula 4, the compound of Formula 1 is hydrolyzed, and when the compound of Formula 1 is hydrolyzed, (5). ≪ / RTI >
본 발명에 따르면, 상기 [화학식 5]는 하기 [화학식 5a] 내지 [화학식 5g] 중에서 선택될 수 있다.According to the present invention, the formula (5) may be selected from the following formulas (5a) to (5g).
[화학식 5a][Chemical Formula 5a]
[화학식 5b] [Chemical Formula 5b]
[화학식 5c] [Chemical Formula 5c]
[화학식 5d] [Chemical Formula 5d]
[화학식 5e] [Chemical Formula 5e]
[화학식 5f] [Chemical Formula 5f]
[화학식 5g] [Chemical Formula 5g]
상기 [화학식 1a] 내지 [화학식 1g]에서, 상기 R1, R2, R3, R4, R5 및 R6의 정의는 앞에서 설명한 바와 같다. R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same definitions as described above in the above formulas (1a) to (1g).
본 발명에 따르면, 상기 [화학식 5]로 표시되는 화합물은 구체적으로 하기 [화학식 20] 내지 [화학식 31]로 이루어진 군 중에서 선택되는 어느 하나일 수 있다.According to the present invention, the compound represented by the formula (5) may be any one selected from the group consisting of the following formulas (20) to (31).
[화학식 20][Chemical Formula 20]
[화학식 21][Chemical Formula 21]
[화학식 22][Chemical Formula 22]
[화학식 23](23)
[화학식 24]≪ EMI ID =
[화학식 25](25)
[화학식 26](26)
[화학식 27](27)
[화학식 28](28)
[화학식 29][Chemical Formula 29]
[화학식 30](30)
[화학식 31](31)
또한, 본 발명은 1) 하기 [화학식 2]으로 표시되는 화합물과 하기 [화학식 3]으로 표시되는 화합물을 N,N-디메틸포름아미드 및 디메틸설폭사이드 중에서 선택되는 용매 하의 무수조건에서 알칼리금속 할라이드 또는 알칼리토금속 할라이드 촉매를 첨가하여 반응시키는 단계를 포함하여 수행함으로써 하기 [화학식 1]로 표시되는 벤즈이미다졸 보론 화합물을 제조하는 단계; 2) 하기 [화학식 1]의 화합물과 하기 [화학식 32]의 화합물을 팔라듐 촉매하에서 반응시켜 하기 [화학식 33]의 화합물을 합성하는 단계; 3) 상기 [화학식 33]의 화합물과 IrCl3를 반응시켜 이리듐 1 분자에 [화학식 33]의 화합물 2 분자가 결합된 이리듐 다이머 착물을 만드는 단계; 및 4) 상기 이리듐 다이머 착물과 아세틸 아세톤을 반응시켜 벤즈이미다졸형 이리듐 착물을 제조하는 단계;를 포함하는 벤즈이미다졸 보론 화합물을 이용한 유기발광다이오드용 벤즈이미다졸형 이리듐 착물의 제조방법을 제공한다.The present invention also relates to a process for the preparation of a compound of formula (I), which process comprises the steps of: 1) reacting a compound represented by the following formula 2 with an alkali metal halide or an alkali metal halide in an anhydrous condition in a solvent selected from N, N-dimethylformamide and dimethylsulfoxide Adding an alkaline earth metal halide catalyst to the mixture to prepare a benzimidazole boron compound represented by Formula 1 below; 2) reacting a compound represented by the formula (1) and a compound represented by the following formula (32) in the presence of a palladium catalyst to synthesize a compound represented by the following formula (33); 3) reacting the compound of Formula 33 with IrCl 3 to form an iridium dimer complex in which two molecules of the compound of Formula 33 are bonded to one molecule of iridium; And 4) reacting the iridium dimer complex with acetylacetone to prepare a benzimidazole-type iridium complex. The present invention further provides a process for preparing a benzimidazole-type iridium complex for organic light emitting diode using the benzimidazole boron compound .
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3](3)
[화학식 32](32)
[화학식 33](33)
상기 [화학식 1] 내지 [화학식 3] 및 [화학식 33]에서, In the above formulas (1) to (3) and (33)
X, BL*, R1, R2, R3, R4, R5 및 R6는 앞에서 정의한 바와 같다.X, BL * , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
본 발명에 있어서, 상기 2) 단계의 팔라듐 촉매는 Pd(OAc)2 및 Pd(PPh3)4 중에서 선택될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the palladium catalyst in step 2) may be selected from Pd (OAc) 2 and Pd (PPh 3 ) 4 , but is not limited thereto.
본 발명에 의하면, 상기 팔라듐 촉매의 반응성을 향상시키기 위하여 SPhos(2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)를 더 첨가할 수도 있다.According to the present invention, SPhos (2-Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl) may be further added to improve the reactivity of the palladium catalyst.
본 발명에 있어서, 상기 2) 단계의 반응은 톨루엔, Et4NOH, dioxane 및 삼인산칼륨 중에서 선택되는 1종 이상의 용매 하의 80 내지 130 ℃에서 수행될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the reaction of step 2) may be carried out at 80 to 130 ° C under at least one solvent selected from toluene, Et 4 NOH, dioxane and potassium triphosphate, but is not limited thereto.
본 발명에 있어서, 상기 3) 단계의 반응은 IrCl3 1 당량부에 대하여 상기 [화학식 33]의 화합물 2 내지 4 당량부를 첨가될 수 있는데, 상기 반응은 2-에폭시에탄올과 물의 공용매 하에서 수행함으로써 이루어질 수 있다. In the present invention, the reaction in the step 3) may be carried out by adding 2 to 4 equivalents of the compound of the formula [33] to 1 equivalent of IrCl 3 , which is carried out under a co-solvent of 2-epoxyethanol and water Lt; / RTI >
다음으로, 상기 3) 단계의 반응물 혼합물에서 용매를 제거한 뒤, IrCl3 1 당량부에 대하여 아세틸아세톤 1 내지 2 당량부를 첨가하여 약염기 조건의 에폭시에탄올 용매하에서 12 내지 36 시간 동안 반응시킴으로써 벤즈이미다졸 유도체 배위 이리듐 착화합물을 제조할 수 있다.Next, the solvent is removed from the reaction mixture in the step 3), 1 to 2 equivalents of acetylacetone is added to 1 equivalent of IrCl 3 , and the mixture is reacted for 12 to 36 hours in an epoxy-ethanol solvent under a weak base condition to obtain a benzimidazole derivative A coordination iridium complex can be prepared.
본 발명에 있어서, 상기 [화학식 33]으로 표시되는 화합물을 'TPABPBI'라 표시하고, 상기 아세틸아세톤을 'acac'라고 표시하면, 상기 벤즈이미다졸 유도체 배위 이리듐 착화합물은 Ir(TPABPBI)2(acac)로 표시될 수 있다.
In the present invention, when the compound represented by Formula 33 is represented by TPABPBI and the acetylacetone is represented by acac, the benzimidazole derivative-coordinated iridium complex may be Ir (TPABPBI) 2 (acac) . ≪ / RTI >
이하, 본 발명을 바람직한 실시예를 참고로 하여 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 상세히 설명한다. 그러나 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며, 여기에서 설명하는 실시예에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail with reference to the preferred embodiments, which will be readily apparent to those skilled in the art to which the present invention pertains. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.
실시예Example
모든 반응은 공기 분위기 하에서 오븐 건조된 유리기구를 사용하고 자기 교반기를 이용하였다. 또한 반응 조건을 별도로 명시하지 않는 한 얇은박막크로마토그래피법을 사용하여 254nm 자외선 하에서 반응 진행을 관찰하였다. 화합물의 정제는 실리카 겔 60(230-400 메쉬)로 플래쉬 컬럼크로마토그래피법을 사용하여 수행하였다. 시판되는 시약은 별다른 정제 없이 사용하였다. All the reactions were carried out using an oven-dried glass apparatus under air atmosphere and using a magnetic stirrer. Unless otherwise specified, the progress of the reaction was observed under ultraviolet light of 254 nm using thin film chromatography. Purification of the compound was performed using flash column chromatography with Silica gel 60 (230-400 mesh). Commercially available reagents were used without further purification.
제조된 화합물의 확인은 1H, 13C 핵자기공명(NMR) 스펙트럼을 이용하였으며, 각각 베리안 제미니 300(300MHz) NMR과 베리안 제미니 400(400MHz) NMR을 이용하여 측정하였다.
Identification of the prepared compounds was carried out using 1 H, 13 C nuclear magnetic resonance (NMR) spectra and measured using Verian Gemini 300 (300 MHz) NMR and Verian Gemini 400 (400 MHz) NMR, respectively.
실시예 1. Example 1.
(가). 포밀페닐 보론산(0.5 mmol), N-메틸이미노디아세트산(1.5 mmol), 4A 몰리큘라시브(200mg)을 4 mL의 N,N-디메틸포름아미드(DMF)에 용해시켰다. 반응 혼합물은 아르곤 분위기에서 130℃로 가열하며 교반하며, 반응을 확인하였다. 반응 완료 후, 실온으로 냉각시켰다. (end). Formyl phenylboronic acid (0.5 mmol), N-methyliminodiacetic acid (1.5 mmol) and 4A molycularis (200 mg) were dissolved in 4 mL of N, N-dimethylformamide (DMF). The reaction mixture was heated to 130 DEG C in an argon atmosphere and stirred to confirm the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature.
(나). 여과나 분리과정 없이 (가)의 냉각된 혼합물에 1,2-페닐렌디아민(1, 0.55mmol; 1.1당량)과 촉매량의 KI(0.1 mmol, 0.2당량)을 첨가한 후 내벽을 1 mL의 DMF로 씻어주고 80℃의 공기에 노출된 분위기로 교반하였다. (가)에서 제조한 혼합물이 모두 소모되면 반응을 종결하고 실온으로 냉각시켜 용매를 감압증류하였다. 혼합물은 고체 컬럼크로마토그래피법을 사용하여 정제함으로써 보론산이 치환된 벤즈이미다졸 유도체를 제조하였다.
(I). (1, 0.55 mmol; 1.1 eq.) And a catalytic amount of KI (0.1 mmol, 0.2 eq.) Were added to the cooled mixture of (a) without filtration or separation, and the inner wall was washed with 1 mL of DMF And the mixture was stirred in an atmosphere exposed to air at 80 ° C. When the mixture prepared in (A) was consumed, the reaction was terminated and the reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The mixture was purified using solid column chromatography to prepare a benzimidazole derivative substituted with boronic acid.
실시예 1.1. 화학식 6의 화합물 제조Example 1.1. Preparation of compound of formula 6
white solid. Yield: 162.5 mg (93%). white solid. Yield: 162.5 mg (93%).
R f = 0.3 (EtOAc:Et2O:MeOH = 3:2:1). R f = 0.3 (EtOAc: Et 2 O: MeOH = 3: 2: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.17 (d, J = 7.4 Hz, 2H), 7.61 (d, J = 7.4 Hz, 4H), 7.16 - 7.26 (m, 2H), 4.38 (d, J = 17.2 Hz, 2H), 4.17 (d, J = 17.2 Hz, 2H), 2.56 (s, 3H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.17 (d, J = 7.4 Hz, 2H), 7.61 (d, J = 7.4 Hz, 4H), 7.16 - 7.26 (m, 2H), 4.38 (d, J = 17.2 Hz, 2H), 4.17 (d, J = 17.2 Hz, 2H), 2.56 (s, 3H).
HRMS (ESI) calcd for C18H17BN3O4 ((M+H)+) 350.1312, found 350.1313.
HRMS (ESI) calcd for C 18 H 17 BN 3 O 4 ((M + H) +) 350.1312, found 350.1313.
실시예 1.2. 화학식 7의 화합물 제조Example 1.2. Preparation of Compound (7)
white solid. Yield: 127.9 mg (70%). white solid. Yield: 127.9 mg (70%).
R f = 0.3 (EtOAc:Hexanes:MeOH = 5:1:1). R f = 0.3 (EtOAc: Hexanes : MeOH = 5: 1: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.14 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 7.7 Hz, 2H), 7.43 - 7.51 (m, 1H), 7.37 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.38 (d, J = 17.3 Hz, 2H), 4.16 (d, J = 17.3 Hz, 2H), 2.55 (s, 3H), 2.43 (s, 3H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.14 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 7.7 Hz, 2H), 7.43 - 7.51 (m, 1H), 7.37 (s, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 4.38 (d, J = 17.3 Hz, 2H), 4.16 (s, 3 H).
HRMS (ESI) calcd for C19H19BN3O4 ((M+H)+) 364.1469, found 364.1468.
HRMS (ESI) calcd for C 19 H 19 BN 3 O 4 ((M + H) +) 364.1469, found 364.1468.
실시예 1.3. 화학식 8의 화합물 제조Example 1.3. Preparation of the compound of formula 8
white solid. Yield: 174.3 mg (92%). white solid. Yield: 174.3 mg (92%).
R f = 0.4 (EtOAc:MC:MeOH = 5:2:1). R f = 0.4 (EtOAc: MC : MeOH = 5: 2: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.12 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.36 (br, 2H), 4.37 (d, J = 17.1 Hz, 2H), 4.16 (d, J = 17.1 Hz, 2H), 2.55 (s, 3H), 2.32 (s, 6H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.12 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.36 (br, 2H), 4.37 (d J = 17.1 Hz, 2H), 4.16 (d, J = 17.1 Hz, 2H), 2.55 (s, 3H), 2.32 (s, 6H).
HRMS (ESI) calcd for C20H21BN3O4 ((M+H)+) 378.1625, found 378.1622.
HRMS (ESI) calcd for C 20 H 21 BN 3 O 4 ((M + H) +) 378.1625, found 378.1622.
실시예 1.4. 화학식 9의 화합물 제조Example 1.4. Preparation of Compound (9)
white solid. Yield: 139.1 mg (73 %). white solid. Yield: 139.1 mg (73%).
R f = 0.3 (EtOAc:Et2O:MeOH = 5:2:1). R f = 0.3 (EtOAc: Et 2 O: MeOH = 5: 2: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.16 (d, J = 7.98 Hz, 2H), 7.59 - 7.74 (m, 3H), 7.54 (d, J = 8.25 Hz, 1H), 7.24 (d, J = 8.25 Hz, 1H), 4.38 (d, J = 17.33 Hz, 2H), 4.17 (d, J = 17.30 Hz, 2H), 2.55 (s, 3H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.16 (d, J = 7.98 Hz, 2H), 7.59 - 7.74 (m, 3H), 7.54 (d, J = 8.25 Hz, 1H), 7.24 (d, J = 8.25 Hz, 1H), 4.38 (d, J = 17.33 Hz, 2H), 4.17 (d, J = 17.30 Hz, 2H), 2.55 (s, 3H).
13C NMR (100 MHz, DMSO-d6, ppm) δ: 169.5, 162.4, 152.8, 138.9, 134.9, 133.2, 130.1, 126.5, 125.9, 122.5, 62.0, 47.8. 13 C NMR (100 MHz, DMSO-d 6 , ppm) ?: 169.5, 162.4, 152.8, 138.9, 134.9, 133.2, 130.1, 126.5, 125.9, 122.5, 62.0, 47.8.
HRMS (ESI) calcd for C18H16BClN3O4 ((M+H)+) 384.0922, found 384.0921.
HRMS (ESI) calcd for C 18 H 16 BClN 3 O 4 ((M + H) +) 384.0922, found 384.0921.
실시예 1.5. 화학식 10의 화합물 제조Example 1.5. Preparation of compound of formula 10
white solid. Yield: 177.6 mg (85%).white solid. Yield: 177.6 mg (85%).
R f = 0.3 (EtOAc:MC:MeOH = 3:6:1). R f = 0.3 (EtOAc: MC : MeOH = 3: 6: 1).
1H NMR (400 MHz, DMSO-d6, ppm) δ: 13.29 (br. s, 1H), 8.16 (d, J = 7.8 Hz, 2H), 7.95 (s, 1H), 7.76 (s, 1H), 7.63 (d, J = 7.8 Hz, 2H), 4.38 (d, J = 17.2 Hz, 2H), 4.17 (d, J = 17.2 Hz, 2H), 2.55 (s, 3H). 1 H NMR (400 MHz, DMSO -d 6, ppm) δ: 13.29 (. Br s, 1H), 8.16 (d, J = 7.8 Hz, 2H), 7.95 (s, 1H), 7.76 (s, 1H) , 7.63 (d, J = 7.8 Hz, 2H), 4.38 (d, J = 17.2 Hz, 2H), 4.17 (d, J = 17.2 Hz, 2H), 2.55 (s, 3H).
HRMS (ESI) calcd for C18H15BCl2N3O4 ((M+H)+) 418.0533, found 418.0531.
HRMS (ESI) calcd for C 18 H 15 BCl 2 N 3 O 4 ((M + H) +) 418.0533, found 418.0531.
실시예 1.6. 화학식 11의 화합물 제조Example 1.6. Preparation of the compound of formula (11)
white solid. Yield: 99.1 mg (57%). white solid. Yield: 99.1 mg (57%).
R f = 0.3 (EtOAc:Et2O:MeOH = 5:2:1). R f = 0.3 (EtOAc: Et 2 O: MeOH = 5: 2: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.28 (s, 1H), 8.12 - 8.21 (m, 1H), 7.50 - 7.64 (m, J = 12.10 Hz, 4H), 7.16 - 7.23 (m, 2H), 4.40 (d, J = 17.30 Hz, 2H), 4.18 (d, J = 17.30 Hz, 2H), 2.56 (s, 3H). 1 H NMR (300 MHz, DMSO -d6, ppm) δ: 8.28 (s, 1H), 8.12 - 8.21 (m, 1H), 7.50 - 7.64 (m, J = 12.10 Hz, 4H), 7.16 - 7.23 (m 2H), 4.40 (d, J = 17.30 Hz, 2H), 4.18 (d, J = 17.30 Hz, 2H), 2.56 (s, 3H).
HRMS (ESI) calcd for C18H17BN3O4 ((M+H)+) 350.1312, found 350.1308.
HRMS (ESI) calcd for C 18 H 17 BN 3 O 4 ((M + H) +) 350.1312, found 350.1308.
실시예 1.7. 화학식 12의 화합물 제조Example 1.7. Preparation of the compound of formula (12)
white solid. Yield: 153.6 mg (85%). white solid. Yield: 153.6 mg (85%).
R f = 0.4 (EtOAc: MeOH = 6:1). R f = 0.4 (EtOAc: MeOH = 6: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.25 (s, 1H), 8.14 (br, 1H), 7.45 - 7.60 (m, 3H), 7.37 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.40 (d, J = 17.1 Hz, 2H), 4.18 (d, J = 17.1 Hz, 2H), 2.56 (s, 3H), 2.43 (s, 3H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.25 (s, 1H), 8.14 (br, 1H), 7.45 - 7.60 (m, 3H), 7.37 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.40 (d, J = 17.1 Hz, 2H), 4.18 (d, J = 17.1 Hz, 2H), 2.56 (s, 3H), 2.43 (s,
HRMS (ESI) calcd for C19H19BN3O4 ((M+H)+) 364.1469, found 364.1468.
HRMS (ESI) calcd for C 19 H 19 BN 3 O 4 ((M + H) +) 364.1469, found 364.1468.
실시예 1.8. 화학식 13의 화합물 제조Example 1.8. Preparation of the compound of formula (13)
white solid. Yield: 133.4 mg (71%). white solid. Yield: 133.4 mg (71%).
R f = 0.3 (EtOAc:hexanes:MeOH = 5:2:1). R f = 0.3 (EtOAc: hexanes : MeOH = 5: 2: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.23 (s, 1H), 8.09 - 8.15 (m, 1H), 7.51 (d, J = 4.40 Hz, 2H), 7.35 (s, 2H), 4.39 (d, J = 17.33 Hz, 1H), 4.18 (d, J = 17.33 Hz, 1H), 2.55 (s, 3H), 2.41 (s, 3H), 2.32 (s, 2H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.23 (s, 1H), 8.09 - 8.15 (m, 1H), 7.51 (d, J = 4.40 Hz, 2H), 7.35 (s, 2H) , 4.39 (d, J = 17.33 Hz, 1 H), 4.18 (d, J = 17.33 Hz, 1 H), 2.55 (s, 3H), 2.41 (s, 3H), 2.32 (s, 2H).
HRMS (ESI) calcd for C20H21BN3O4 ((M+H)+) 378.1625, found 378.1626.
HRMS (ESI) calcd for C 20 H 21 BN 3 O 4 ((M + H) +) 378.1625, found 378.1626.
실시예 1.9. 화학식 14의 화합물 제조Example 1.9. Preparation of compound of formula 14
white solid. Yield: 149.9 mg (78%). white solid. Yield: 149.9 mg (78%).
R f = 0.3 (EtOAc:MC:MeOH = 5:2:1). R f = 0.3 (EtOAc: MC : MeOH = 5: 2: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.27 (s, 1H), 8.16 (d, J = 6.88 Hz, 1H), 7.55 - 7.70 (m, 4H), 7.26 (d, J = 7.15 Hz, 1H), 4.40 (d, J = 17.30 Hz, 2H), 4.18 (d, J = 17.33 Hz, 2H), 2.55 (s, 3H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.27 (s, 1H), 8.16 (d, J = 6.88 Hz, 1H), 7.55 - 7.70 (m, 4H), 7.26 (d, J = 1H), 4.40 (d, J = 17.30 Hz, 2H), 4.18 (d, J = 17.33 Hz, 2H), 2.55 (s, 3H).
HRMS (ESI) calcd for C18H16BClN3O4 ((M+H)+) 384.0922, found 384.0921
HRMS (ESI) calcd for C 18 H 16 BClN 3 O 4 ((M + H) +) 384.0922, found 384.0921
실시예 1.10. 화학식 17의 화합물 제조Example 1.10. Preparation of Compound (17)
white solid. Yield: 139.7 mg (79%). white solid. Yield: 139.7 mg (79%).
R f = 0.5 (EtOAc:MeOH = 6:1). R f = 0.5 (EtOAc: MeOH = 6: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 7.85 (d, J = 3.6 Hz, 1H), 7.60 (d, J = 6.9 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.12 - 7.25 (m, 2H), 4.40 (d, J = 17.3 Hz, 2H), 4.18 (d, J = 17.3 Hz, 2H), 2.68 (s, 3H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 7.85 (d, J = 3.6 Hz, 1H), 7.60 (d, J = 6.9 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H ), 7.31 (d, J = 3.6 Hz, 1H), 7.12-7.25 (m, 2H), 4.40 (d, J = 17.3 Hz, 2H), 4.18 , 3H).
HRMS (ESI) calcd for C16H15BN3O4S ((M+H)+) 356.0876
HRMS (ESI) calcd for C 16 H 15 BN 3 O 4 S ((M + H) +) 356.0876
실시예 1.11. 화학식 18의 화합물 제조Example 1.11. Preparation of compound of formula 18
white solid. Yield: 97.6 mg (80%). white solid. Yield: 97.6 mg (80%).
R f = 0.5 (EtOAc:hexanes:MeOH = 5:1:1). R f = 0.5 (EtOAc: hexanes : MeOH = 5: 1: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 7.63 (d, J = 6.6 Hz, 1H), 7.51 (d, J = 6.9 Hz, 1H), 7.21 (m, 2H), 7.15 (d, J = 3.0 Hz, 1H), 6.84 (d, J = 3.3 Hz, 1H), 4.46 (d, J = 17.1 Hz, 2H), 4.21 (d, J = 17.1 Hz, 2H), 2.73 (s, 3H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 7.63 (d, J = 6.6 Hz, 1H), 7.51 (d, J = 6.9 Hz, 1H), 7.21 (m, 2H), 7.15 (d J = 17.1 Hz, 2H), 2.73 (s, 3H, < RTI ID = 0.0 & ).
HRMS (ESI) calcd for C16H15BN3O5 ((M+H)+) 340.1105
HRMS (ESI) calcd for C 16 H 15 BN 3 O 5 ((M + H) + ) 340.1105
실시예 1.12. 화학식 19의 화합물 제조Example 1.12. Preparation of compound of formula 19
white solid. Yield: 201.7 mg (95%). white solid. Yield: 201.7 mg (95%).
R f = 0.3 (EtOAc:MC:MeOH = 5:2:1). R f = 0.3 (EtOAc: MC : MeOH = 5: 2: 1).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 7.79 (d, J = 7.4 Hz, 1H), 7.47 - 7.60 (m, 5H), 7.38 - 7.45 (m, 3H), 7.23 - 7.35 (m, 3H), 7.18 (d, J = 7.4 Hz, 1H), 4.33 (d, J = 17.1 Hz, 2H), 4.12 (d, J = 17.1 Hz, 2H), 2.5 (s, 3H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 7.79 (d, J = 7.4 Hz, 1H), 7.47 - 7.60 (m, 5H), 7.38 - 7.45 (m, 3H), 7.23 - 7.35 ( (m, 3H), 7.18 (d, J = 7.4 Hz, 1H), 4.33 (d, J = 17.1 Hz, 2H), 4.12 (d, J = 17.1 Hz,
HRMS (ESI) calcd for C24H21BN3O4 ((M+H)+) 426.1625, found 426.1621.
HRMS (ESI) calcd for C 24 H 21 BN 3 O 4 ((M + H) + ) 426.1625, found 426.1621.
실시예 2Example 2
실시예 1에서 제조된 화합물을 NaOH 1 N을 첨가하여 상온에서 30분간 반응시켜 하기 실시예 2의 화합물들을 제조하였다.
The compound prepared in Example 1 was reacted with 1 N NaOH at room temperature for 30 minutes to prepare the compounds of Example 2 below.
실시예 2.1. 화학식 20의 화합물 제조Example 2.1. Preparation of compound of formula 20
white solid. Yield: 122.4 mg (94 %). white solid. Yield: 122.4 mg (94%).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.28 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.2 Hz, 2H), 7.84 (dd, J = 6.0, 3.0 Hz, 2H), 7.55 (dd, J = 6.0, 3.0 Hz, 2 H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.28 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.2 Hz, 2H), 7.84 (dd, J = 6.0, 3.0 Hz , 2H), 7.55 (dd, J = 6.0, 3.0 Hz, 2H).
13C NMR (100 MHz, DMSO-d6, ppm) δ: 151.3, 135.9, 134.7, 131.4, 125.4, 122.3, 115.3. 13 C NMR (100 MHz, DMSO-d 6 , ppm) ?: 151.3, 135.9, 134.7, 131.4, 125.4, 122.3, 115.3.
HRMS (ESI) calcd for C13H12BN2O2 ((M+H)+) 239.0992, found 239.0970.
HRMS (ESI) calcd for C 13 H 12 BN 2 O 2 ((M + H) +) 239.0992, found 239.0970.
실시예 2.2. 화학식 21의 화합물 제조Example 2.2. Preparation of Compound (21)
white solid. Yield: 115.0 mg (91 %) white solid. Yield: 115.0 mg (91%)
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.30 (br, 2H), 8.18 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 2.47 (s, 3H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.30 (br, 2H), 8.18 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.2 Hz, 2H), 7.60 (d J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 2.47 (s, 3H).
13C NMR (100 MHz, DMSO-d6, ppm) δ: 163.7, 150.1, 138.3, 136.2, 135.4, 134.6, 134.3, 128.5, 126.7, 126.2, 115.0, 114.5, 21.9. 13 C NMR (100 MHz, DMSO-d 6 , ppm) ?: 163.7, 150.1, 138.3, 136.2, 135.4, 134.6, 134.3, 128.5, 126.7, 126.2, 115.0, 114.5, 21.9.
HRMS (ESI) calcd for C14H14BN2O2 ((M+H)+) 253.1148, found 253.1142.
HRMS (ESI) calcd for C 14 H 14 BN 2 O 2 ((M + H) +) 253.1148, found 253.1142.
실시예 2.3. 화학식 22의 화합물 제조Example 2.3. Preparation of compound of formula 22
white solid. Yield: 125.8 mg (94 %). white solid. Yield: 125.8 mg (94%).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.28 (br, 2H), 8.24 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 7.45 (s, 2H), 2.35 (s, 6H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.28 (br, 2H), 8.24 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 7.45 (s , ≪ / RTI > 2H), 2.35 (s, 6H).
13C NMR (100 MHz, DMSO-d6, ppm) δ: 163.2, 149.5, 137.7, 135.6, 134.8, 134.1, 133.7, 128.0, 126.2, 125.6, 114.5, 113.9, 21.4. 13 C NMR (100 MHz, DMSO-d 6 , ppm) ?: 163.2, 149.5, 137.7, 135.6, 134.8, 134.1, 133.7, 128.0, 126.2, 125.6, 114.5, 113.9, 21.4.
HRMS (ESI) calcd for C15H16BN2O2 ((M+H)+) 267.1305, found 267.1307.
HRMS (ESI) calcd for C 15 H 16 BN 2 O 2 ((M + H) +) 267.1305, found 267.1307.
실시예 2.4. 화학식 23의 화합물 제조Example 2.4. Preparation of compound of formula 23
white solid. Yield: 128.3 mg (94%). white solid. Yield: 128.3 mg (94%).
1H NMR (400 MHz, DMSO-d6, ppm) δ: 8.05 (d, J = 7.0 Hz, 2 H), 7.80 (br. s., 2 H), 7.59 (br. s., 1 H), 7.56 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H). 1 H NMR (400 MHz, DMSO-d 6 , ppm) ?: 8.05 (d, J = 7.0 Hz, 2 H), 7.80 (br s, 2 H), 7.59 , 7.56 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H).
13C NMR (100 MHz, METHANOL-d4, ppm) δ: 154.7, 135.6, 131.8, 129.6, 127.0, 126.2, 124.5, 117.1, 115.9. 13 C NMR (100 MHz, METHANOL-d 4 , ppm) ?: 154.7, 135.6, 131.8, 129.6, 127.0, 126.2, 124.5, 117.1, 115.9.
HRMS (ESI) calcd for C13H11BClN2O2 ((M+H)+) 272.0602, found 273.0599.
HRMS (ESI) calcd for C 13 H 11 BClN 2 O 2 ((M + H) +) 272.0602, found 273.0599.
실시예 2.5. 화학식 24의 화합물 제조Example 2.5. Preparation of compound of formula 24
white solid. Yield: 125.6 mg (82 %). white solid. Yield: 125.6 mg (82%).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.18 (d, J = 7.8 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.92 (s, 2H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.18 (d, J = 7.8 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.92 (s, 2H).
13C NMR (100 MHz, DMSO-d6, ppm) δ: 152.6, 138.4, 135.8, 134.9, 127.6, 126.4, 116.0. 13 C NMR (100 MHz, DMSO-d 6 , ppm) ?: 152.6, 138.4, 135.8, 134.9, 127.6, 126.4, 116.0.
HRMS (ESI) calcd for C13H10BCl2N2O2 ((M+H)+) 307.0212, found 307.0211.
HRMS (ESI) calcd for C 13 H 10 BCl 2 N 2 O 2 ((M + H) +) 307.0212, found 307.0211.
실시예 2.6. 화학식 25의 화합물 제조Example 2.6. Preparation of compound of formula 25
white solid. Yield: 104.2 mg (88 %). white solid. Yield: 104.2 mg (88%).
1H NMR (400 MHz, DMSO-d6, ppm) δ: 8.62 (s, 1H), 8.26 (s, 2H), 8.19 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.59 (br, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.24 - 7.16 (m, 2H). 1 H NMR (400 MHz, DMSO -d 6, ppm) δ: 8.62 (s, 1H), 8.26 (s, 2H), 8.19 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.0 Hz , 7.59 (br, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.24-7.16 (m, 2H).
13C NMR (100 MHz, DMSO-d6, ppm) δ: 151.7, 139.3, 135.8, 132.7, 129.1, 128.2, 128.1, 122.4, 122.3, 115.1. 13 C NMR (100 MHz, DMSO-d 6 , ppm) ?: 151.7, 139.3, 135.8, 132.7, 129.1, 128.2, 128.1, 122.4, 122.3, 115.1.
HRMS (ESI) calcd for C13H12BN2O2 ((M+H)+) 239.0992, found 239.0987.
HRMS (ESI) calcd for C 13 H 12 BN 2 O 2 ((M + H) +) 239.0992, found 239.0987.
실시예 2.7. 화학식 26의 화합물 제조Example 2.7. Preparation of compound of formula 26
white solid. Yield: 71.8 mg (57 %). white solid. Yield: 71.8 mg (57%).
1H NMR (400 MHz, METHANOL-d4, ppm) δ: 8.37 (br, 1H), 8.08 (d, J = 7.8 Hz, 2H), 7.84 - 7.76 (m, 1H), 7.54 - 7.46 (m, 2H), 7.39 (s, 1H), 7.09 (d, J = 8.2 Hz, 1H), 2.46 (s, 3H). 1 H NMR (400 MHz, METHANOL -d 4, ppm) δ: 8.37 (br, 1H), 8.08 (d, J = 7.8 Hz, 2H), 7.84 - 7.76 (m, 1H), 7.54 - 7.46 (m, 2H), 7.39 (s, IH), 7.09 (d, J = 8.2 Hz, IH), 2.46 (s, 3H).
13C NMR (100 MHz, METHANOL-d4, ppm) δ: 153.3, 139.9, 138.5, 136.6, 133.9, 133.2, 130.1, 129.3, 129.2, 125.5, 115.7, 115.2, 21.8. 13 C NMR (100 MHz, METHANOL-d 4 , ppm) ?: 153.3, 139.9, 138.5, 136.6, 133.9, 133.2, 130.1, 129.3, 129.2, 125.5, 115.7, 115.2, 21.8.
HRMS (ESI) calcd for C14H14BN2O2 ((M+H)+) 253.1148, found 253.1148.
HRMS (ESI) calcd for C 14 H 14 BN 2 O 2 ((M + H) +) 253.1148, found 253.1148.
실시예 2.8. 화학식 27의 화합물 제조Example 2.8. Preparation of Compound (27)
white solid. Yield: 118.1 mg (88 %). white solid. Yield: 118.1 mg (88%).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.61 (s, 1H), 8.36 (s, 2H), 8.29 (d, J = 7.98 Hz, 1H), 8.03 (d, J = 7.15 Hz, 1H), 7.62 (t, J = 7.70 Hz, 1H), 7.50 (s, 2H), 2.37 (s, 6H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.61 (s, 1H), 8.36 (s, 2H), 8.29 (d, J = 7.98 Hz, 1H), 8.03 (d, J = 7.15 Hz 1H), 7.62 (t, J = 7.70 Hz, 1H), 7.50 (s, 2H), 2.37 (s, 6H).
13C NMR (100 MHz, DMSO-d6, ppm) δ: 148.8, 137.4, 135.6, 133.7, 133.2, 132.9, 129.0, 128.4, 124.9, 114.1, 20. 13 C NMR (100 MHz, DMSO-d 6 , ppm) ?: 148.8, 137.4, 135.6, 133.7, 133.2, 132.9, 129.0, 128.4, 124.9, 114.1,
HRMS (ESI) calcd for C15H16BN2O2 ((M+H)+) 267.1305, found 267.1303.
HRMS (ESI) calcd for C 15 H 16 BN 2 O 2 ((M + H) +) 267.1305, found 267.1303.
실시예 2.9. 화학식 28의 화합물 제조Example 2.9. Preparation of compound of formula 28
white solid. Yield: 101.7 mg (75 %). white solid. Yield: 101.7 mg (75%).
1H NMR (300 MHz, METHANOL-d4, ppm) δ: 8.36 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.80 (br. s., 1H), 7.51 - 7.62 (m, 3H), 7.25 (d, J = 8.5 Hz, 1H). 1 H NMR (300 MHz, METHANOL-d 4 , ppm) ?: 8.36 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.80 , ≪ / RTI > 3H), 7.25 (d, J = 8.5 Hz, 1H).
13C NMR (100 MHz, METHANOL-d4, ppm) δ: 155.0, 141.2, 138.8, 137.0, 133.4, 129.8, 129.4, 124.3, 116.8, 115.8. 13 C NMR (100 MHz, METHANOL-d 4 , ppm) ?: 155.0, 141.2, 138.8, 137.0, 133.4, 129.8, 129.4, 124.3, 116.8, 115.8.
HRMS (ESI) calcd for C13H11BClN2O2 ((M+H)+) 272.0602, found 273.0615.
HRMS (ESI) calcd for C 13 H 11 BClN 2 O 2 ((M + H) +) 272.0602, found 273.0615.
실시예 2.10. 화학식 29의 화합물 제조Example 2.10. Preparation of compound of formula 29
white solid. Yield: 128.9 mg (84 %). white solid. Yield: 128.9 mg (84%).
1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.59 (s, 1H), 8.20 (d, J = 7.4 Hz, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.89 (s, 2H), 7.57 (t, J = 7.6 Hz, 1H). 1 H NMR (300 MHz, DMSO -d 6, ppm) δ: 8.59 (s, 1H), 8.20 (d, J = 7.4 Hz, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.89 (s , 2H), 7.57 (t, J = 7.6 Hz, 1H).
13C NMR (100 MHz, DMSO-d6, ppm) δ: 163.3, 154.3, 138.8, 136.6, 135.4, 133.0, 130.4, 128.7, 128.3, 128.3, 124.9, 116.3. 13 C NMR (100 MHz, DMSO-d 6 , ppm) ?: 163.3, 154.3, 138.8, 136.6, 135.4, 133.0, 130.4, 128.7, 128.3, 128.3, 124.9, 116.3.
HRMS (ESI) calcd for C13H10BCl2N2O2 ((M+H)+) 307.0212, found 307.0209.
HRMS (ESI) calcd for C 13 H 10 BCl 2 N 2 O 2 ((M + H) +) 307.0212, found 307.0209.
실시예 2.11. 화학식 31의 화합물 제조Example 2.11. Preparation of compound of formula (31)
off-white solid. Yield: 138.2 mg (88 %). off-white solid. Yield: 138.2 mg (88%).
1H NMR (400 MHz, DMSO-d6, ppm) δ: 8.16 (s, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.61 - 7.52 (m, 3H), 7.48 (d, J = 7.4 Hz, 2H), 7.43 (d, J = 7.4 Hz, 2H), 7.35 - 7.25 (m, 2H), 7.20 (d, J = 7.4 Hz, 1H).
1 H NMR (400 MHz, DMSO -d 6, ppm) δ: 8.16 (s, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.61 - 7.52 (m, 3H), 7.48 (d, J = 7.4 Hz, 2H), 7.43 (d, J = 7.4 Hz, 2H), 7.35-7.25 .
실시예 3. 벤즈이미다졸 유도체 배위 이리듐 착화합물의 제조Example 3. Preparation of benzimidazole derivative-coordinated iridium complexes
(가). 실시예 1.11에서 제조한 화학식 17의 화합물(4 mmol, 1 eq), 4'-bromo-N,N-diphenyl-[1,1'-biphenyl]-4-amine(4.5 mmol, 1.12 eq), Pd(OAc)2(0.2 mmol) 및 SPhos(0.4 mmol)을 dioxane:K3PO4=5:1(부피비)인 공용매 8 ml에 용해시킨 뒤, 80 ℃에서 12시간 동안 반응시켰다. 반응 종료 후, 메틸렌클로라이드와 물을 사용하여 유기층을 추출하고, 마그네슘 설페이트로 수분을 제거한 뒤, 농축하고 실리카겔 컬럼크로마토그래피 법을 이용하여 정제하였다.(end). (4 mmol, 1 eq), 4'-bromo-N, N-diphenyl- [1,1'-biphenyl] -4-amine (4.5 mmol, 1.12 eq) prepared in Example 1.11, Pd (OAc) 2 (0.2 mmol) and SPhos (0.4 mmol) were dissolved in 8 ml of dioxane: K 3 PO 4 = 5: 1 (volume ratio) and then reacted at 80 ° C. for 12 hours. After completion of the reaction, the organic layer was extracted with methylene chloride and water, and water was removed with magnesium sulfate, followed by concentration and purification using silica gel column chromatography.
white solid. Yield : 1.29g (55%)white solid. Yield: 1.29g (55%)
1H NMR (400 MHz, CDCl3, ppm) δ: 7.92 (d, J = 8.4 Hz, 1H), 7.64 - 7.70 (m, 6H), 7.57 - 7.62 (m, 3H), 7.55 - 7.50 (m, 5H), 7.35 - 7.38 (m, 3H), 7.28 - 7.31 (m, 5H), 7.15 (d, J = 8.0 Hz, 6H), 7.04 (t, J = 7.6 Hz, 2H).
1 H NMR (400 MHz, CDCl 3, ppm) δ: 7.92 (d, J = 8.4 Hz, 1H), 7.64 - 7.70 (m, 6H), 7.57 - 7.62 (m, 3H), 7.55 - 7.50 (m, 5H), 7.15 (d, J = 8.0 Hz, 6H), 7.04 (t, J = 7.6 Hz, 2H). 7.35-7.38 (m, 3H), 7.28-7.31 (m, 5H)
(나). IrCl3·H2O(1 mmol, 1eq)과 상기 (가)에서 제조한 화합물(2.5 mmol, 2.5eq)를 2-에폭시에탄올:물=3:1(부피비)인 공용매 16 ml에 용해시킨 뒤, 질소기류하에서 24시간 동안 환류 반응시켰다. 반응 종료 후, 반응 혼합물의 온도를 상온으로 냉각시킨 뒤, 여과하여 오렌지색 침전물을 얻었다. 상기 침전물을 물, 에탄올 및 헥산으로 세척하여 불순물을 제거하였다. 이후, 건조하여 이리듐 1 분자에 (가)의 화합물이 2 분자가 결합된 다이머 착화합물을 얻었다. (I). Dissolved in 16 ml of a co-solvent of 2-epoxyethanol: water = 3: 1 (volume ratio), IrCl 3 .H 2 O (1 mmol, 1 eq) and the compound (2.5 mmol, 2.5 eq) The mixture was then subjected to a reflux reaction under a nitrogen stream for 24 hours. After completion of the reaction, the temperature of the reaction mixture was cooled to room temperature and then filtered to obtain an orange precipitate. The precipitate was washed with water, ethanol and hexane to remove impurities. Thereafter, it was dried to obtain a dimer complex compound in which two molecules of the compound (a) were bonded to one molecule of iridium.
다음으로, Na2CO3(5 mmol), acetyl acetone(1.5 mmol) 및 2-에톡시에탄올 10 ml을 혼합한 뒤, 상기 다이머 착화합물을 첨가하고, 질소 기류하에서 24 시간동안 환류반응 시켰다. 반응 종료 후, 혼합물의 농도를 상온으로 냉각시킨 뒤, 여과하고, 물, 에탄올 및 헥산으로 세척하여 오렌지색 침전물을 얻었다. 세척된 침전물을 실리카겔 컬럼크로마토그래피 법으로 정제하여 노란색의 목적하는 화합물Ir(TPABPBI)2(acac)을 얻었다.Next, Na 2 CO 3 (5 mmol), acetyl acetone (1.5 mmol) and 10 ml of 2-ethoxyethanol were mixed, the dimer complex was added, and the mixture was subjected to a reflux reaction in a nitrogen stream for 24 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered, and washed with water, ethanol and hexane to obtain an orange precipitate. The washed precipitate was purified by silica gel column chromatography to obtain the desired yellow compound Ir (TPABPBI) 2 (acac).
yellow solid: 0.35g (24%)yellow solid: 0.35 g (24%)
1H NMR(CDCl3, 400 MHz, ppm) δ: 7.89 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.68 - 7.54 (m, 16H), 7.41 - 7.33 (m, 22H), 7.18 - 7.14 (m, 6H), 7.01 - 6.98 (m, 10H), 5.17 (s, 1H), 1.76 (s, 6H).
1 H NMR (CDCl 3, 400 MHz, ppm) δ: 7.89 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 1H), 1.76 (s, 6H), 7.16 (s, 1H).
시험예Test Example 1. 용매 선택성 확인 1. Determination of solvent selectivity
용매에 따른 반응성을 확인하기 위하여, 반응온도를 80 ℃로 고정하고, open flask 및 무수조건의 다양한 용매 하에서 제조예 1의 (가)에서 제조예에서 제조한 화합물을 1,2-페닐렌디아민과 24 시간 동안 반응시켜 반응성을 확인하였으며, 이를 하기 표 1에 나타내었다. In order to confirm the reactivity according to the solvent, the reaction temperature was fixed at 80 캜, and the compound prepared in Production Example (a) of Preparation Example 1 was dissolved in 1,2-phenylene diamine The reactivity was confirmed by reacting for 24 hours, as shown in Table 1 below.
표 1에 나타낸 바와 같이, DMSO 및 DMF 하에서는 반응이 우수한 수율로 진행되었으나, Dioxane에서는 반응수율이 크게 떨어졌고, 아세토니트릴에서는 반응이 거의 진행되지 않았으며, 톨루엔, 클로로벤젠 및 아세톤에서는 반응이 진행되지 않았다.
As shown in Table 1, the reaction proceeded at an excellent yield under DMSO and DMF, but the reaction yield was greatly lowered in Dioxane, and the reaction did not progress in acetonitrile, and the reaction did not proceed in toluene, chlorobenzene and acetone I did.
시험예Test Example 2. 반응 온도에 따른 효과 2. Effect according to reaction temperature
반응 온도에 대한 효과를 확인하기 위하여 DMF 용매, KI 촉매 및 무수조건 하에서 반응을 수행하였으며, 결과를 하기 표 2에 나타내었다. The reaction was carried out under DMF solvent, KI catalyst and anhydrous conditions to confirm the effect on the reaction temperature. The results are shown in Table 2 below.
표 2에 나타낸 바와 같이, 60 ℃의 낮은 반응온도에서도 2 시간 이내에 반응이 97% 이상 진행되는 것을 확인하였으며, 반응온도를 80 ℃ 이상으로 하였을 때는 30 분 이내에 반응이 완료되는 것을 확인하였다.
As shown in Table 2, it was confirmed that the reaction proceeded by 97% or more within 2 hours even at a low reaction temperature of 60 ° C, and when the reaction temperature was 80 ° C or higher, the reaction was completed within 30 minutes.
시험예Test Example 3. 촉매 종류에 따른 반응성 확인 3. Determination of reactivity according to the type of catalyst
본 발명에 따른 제조방법에서 촉매 종류에 따른 반응성을 확인하였으며, 하기 표 1에 나타내었다. Reactivity according to the type of catalyst was confirmed in the production method according to the present invention, and it is shown in Table 1 below.
또한 본 발명에 따른 반응이 호기성 산화에 의한 산화고리화 반응인 것을 확인하기 위하여 산소가 배제된 환경의 아르곤 기류 하에서 반응을 실시하였으며, 이를 하기 표 3에 함께 나타내었다. In order to confirm that the reaction according to the present invention is an oxidative cyclization reaction by aerobic oxidation, the reaction was carried out in an argon atmosphere in an oxygen-free environment, which is shown in Table 3 below.
상기 표 3에서 확인할 수 있듯이, 알칼리금속 할라이드에서 반응이 우수하였다. 한편, 물이 첨가되는 경우에는 부반응이 30 %이상 진행되는 것을 확인하였다. 또한 산소분자가 제공되지 않는 아르곤 기류 하에서는 반응이 거의 진행되지 않아 본 발명이 호기성 산화고리화 반응에 의한 것임을 증명하였다.As shown in Table 3, the reaction was excellent in alkali metal halide. On the other hand, when water was added, it was confirmed that the side reaction proceeded by 30% or more. In addition, under the argon atmosphere in which oxygen molecules are not provided, the reaction hardly progressed, proving that the present invention is due to the aerobic oxidative cyclization reaction.
반응에 물이 함유되는 경우에는 하기 반응식에 나타낸 바와 같이, 보호기로 보호된 보로닉산을 작용기로 가지는 벤즈이미다졸이 70 % 미만으로 생성되고, 부반응이 30%이상 진행되는 것을 확인하였는데, 이는 수분 존재하에서는 보호기로 보호된 부분이 보로닉산으로 가수분해되는 현상에 의해 보로닉 산이 직접 아민과 반응 하기 때문이다. When water is contained in the reaction, as shown in the following reaction formula, it was confirmed that benzimidazole having a functional group of boronic acid protected by a protecting group was produced in less than 70% and the side reaction proceeded by 30% or more, Under the conditions that the protected portion is hydrolyzed to the boronic acid, the boronic acid reacts directly with the amine.
따라서, 본 반응은 무수 조건에서 수행하여야 함을 증명하였다.
Therefore, it is proved that this reaction should be carried out under anhydrous conditions.
시험예Test Example 4. 촉매함량에 따른 반응성 확인 4. Determination of reactivity according to catalyst content
촉매량에 따른 반응성을 확인하였으며, 이를 하기 표 4에 나타내었다.The reactivity according to the amount of catalyst was confirmed, and it is shown in Table 4 below.
알칼리금속 할라이드 촉매가 페닐렌디아민 1 몰에 대하여 0.1 몰로 첨가되는 경우에는 2시간의 반응에도 90% 이상이 목적하는 화합물로 합성되었으며, 1 몰의 비율로 첨가되는 경우에는 30분 만에 반응이 완료되었다. 한편, KI가 페닐렌디아민 1 몰에 대하여 0.01 몰로 첨가되는 경우에는 24시간의 반응에 80%이상의 수율을 나타내었으므로, 촉매가 상기 범위 미만으로 첨가되는 경우에는 반응속도가 매우 느리며, 경제성이 떨어져 바람직하지 않은 것을 확인하였다.
When the alkali metal halide catalyst is added in an amount of 0.1 mole based on 1 mole of phenylenediamine, not less than 90% of the target compound is synthesized even after 2 hours of reaction, and when it is added in a proportion of 1 mole, the reaction is completed in 30 minutes . On the other hand, when KI was added in an amount of 0.01 mol based on 1 mol of phenylenediamine, the yield was 80% or more in 24 hours of reaction. Therefore, when the catalyst was added in an amount less than the above range, the reaction rate was very slow, And it was confirmed that it was not preferable.
Claims (13)
[화학식 1]
상기 [화학식 1]에서,
X는 CH=CH, O 및 S 중에서 선택되고,
BL*는
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1-6알킬, 아릴, 헤테로아릴 및 C1-6알킬아마이딜 중에서 선택되고,
R5는 수소, C1-6알킬, 아릴 및 아릴C1-6알킬 중에서 선택되며,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1-6알킬 및 C1-6알콕시 중에서 선택되고,
R1 내지 R5의 상기 C1-6알킬, 아릴 및 아릴C1-6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1-6알킬, C1-6알콕시, 히드록시, COOR8 및 니트로 중에서 선택되는 치환기로 치환되며,
R7은 수소, C1-6알킬,
R8은 C1-6알킬이다.A benzimidazole derivative represented by the following formula 1:
[Chemical Formula 1]
In the above formula (1)
X is selected from CH = CH, O and S,
BL *
R 1 , R 2 , R 3 and R 4 are the same or different and each independently hydrogen, fluoro, chloro, bromo, carboxy, trifluoromethyl, C 1-6 alkyl, aryl, heteroaryl and C Lt; / RTI > alkylamidyl,
R 5 is selected from hydrogen, C 1-6 alkyl, aryl and aryl C 1-6 alkyl,
R 6 is selected from hydrogen, nitro, hydroxy, carboxy, trifluoromethyl, C 1-6 alkyl and C 1-6 alkoxy,
Wherein any one to three carbon atoms of said C 1-6 alkyl, aryl and aryl C 1-6 alkyl of R 1 to R 5 are the same or different and are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, COOR 8 and nitro,
R 7 is hydrogen, C 1-6 alkyl,
R 8 is C 1-6 alkyl.
상기 [화학식 1]은 하기 [화학식 1a] 내지 [화학식 1g] 중에서 선택되는 어느 하나인 것을 특징으로 하는 벤즈이미다졸 유도체.
[화학식 1a]
[화학식 1b]
[화학식 1c]
[화학식 1d]
[화학식 1e]
[화학식 1f]
[화학식 1g]
상기 [화학식 1a] 내지 [화학식 1g]에서,
BL*는
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1-6알킬, 아릴, 헤테로아릴 및 C1-6알킬아마이딜 중에서 선택되고,
R5는 수소, C1-6알킬, 아릴 및 아릴C1-6알킬 중에서 선택되며,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1-6알킬 및 C1-6알콕시 중에서 선택되고,
R1 내지 R5의 상기 C1-6알킬, 아릴 및 아릴C1-6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1-6알킬, C1-6알콕시, 히드록시, COOR8 및 니트로 중에서 선택되는 치환기로 환되며,
R7은 수소, C1-6알킬,
R8은 C1-6알킬이다.The method according to claim 1,
The benzimidazole derivative according to claim 1, wherein the compound represented by the formula (1) is any one selected from the following formulas (1a) to (1g).
[Formula 1a]
[Chemical Formula 1b]
[Chemical Formula 1c]
≪ RTI ID = 0.0 &
[Formula 1e]
(1f)
[Formula 1g]
In the above formulas (1a) to (1g)
BL *
R 1 , R 2 , R 3 and R 4 are the same or different and each independently hydrogen, fluoro, chloro, bromo, carboxy, trifluoromethyl, C 1-6 alkyl, aryl, heteroaryl and C Lt; / RTI > alkylamidyl,
R 5 is selected from hydrogen, C 1-6 alkyl, aryl and aryl C 1-6 alkyl,
R 6 is selected from hydrogen, nitro, hydroxy, carboxy, trifluoromethyl, C 1-6 alkyl and C 1-6 alkoxy,
Wherein any one to three carbon atoms of said C 1-6 alkyl, aryl and aryl C 1-6 alkyl of R 1 to R 5 are the same or different and are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, COOR 8 and nitro,
R 7 is hydrogen, C 1-6 alkyl,
R 8 is C 1-6 alkyl.
[화학식 1]
[화학식 2]
[화학식 3]
상기 [화학식 1] 내지 [화학식 3]에서,
X는 CH=CH, O 및 S 중에서 선택되고,
BL*는
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1-6알킬, 아릴, 헤테로아릴 및 C1-6알킬아마이딜 중에서 선택되고,
R5는 수소, C1-6알킬, 아릴 및 아릴C1-6알킬 중에서 선택되며,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1-6알킬 및 C1-6알콕시 중에서 선택되고,
R1 내지 R5의 상기 C1-6알킬, 아릴 및 아릴C1-6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1-6알킬, C1-6알콕시, 히드록시, COOR8 및 니트로 중에서 선택되는 치환기로 치환되며,
R7은 수소, C1-6알킬,
R8은 C1-6알킬이다.A process for the preparation of a compound represented by the formula (2) and a compound represented by the following formula (3) by adding an alkali metal halide or an alkaline earth metal halide catalyst under anhydrous condition in a solvent selected from N, N-dimethylformamide and dimethylsulfoxide And reacting the compound represented by the formula (1) with a compound represented by the following formula (1), thereby producing a benzimidazole derivative:
[Chemical Formula 1]
(2)
(3)
In the above Chemical Formulas 1 to 3,
X is selected from CH = CH, O and S,
BL *
R 1 , R 2 , R 3 and R 4 are the same or different and each independently hydrogen, fluoro, chloro, bromo, carboxy, trifluoromethyl, C 1-6 alkyl, aryl, heteroaryl and C Lt; / RTI > alkylamidyl,
R 5 is selected from hydrogen, C 1-6 alkyl, aryl and aryl C 1-6 alkyl,
R 6 is selected from hydrogen, nitro, hydroxy, carboxy, trifluoromethyl, C 1-6 alkyl and C 1-6 alkoxy,
Wherein any one to three carbon atoms of said C 1-6 alkyl, aryl and aryl C 1-6 alkyl of R 1 to R 5 are the same or different and are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, COOR 8 and nitro,
R 7 is hydrogen, C 1-6 alkyl,
R 8 is C 1-6 alkyl.
상기 [화학식 1]은 하기 [화학식 1a] 내지 [화학식 1g] 중에서 선택되는 어느 하나인 것을 특징으로 하는 벤즈이미다졸 유도체.
[화학식 1a]
[화학식 1b]
[화학식 1c]
[화학식 1d]
[화학식 1e]
[화학식 1f]
[화학식 1g]
상기 [화학식 1a] 내지 [화학식 1g]에서,
BL*는
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1-6알킬, 아릴, 헤테로아릴 및 C1-6알킬아마이딜 중에서 선택되고,
R5는 수소, C1-6알킬, 아릴 및 아릴C1-6알킬 중에서 선택되며,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1-6알킬 및 C1-6알콕시 중에서 선택되고,
R1 내지 R5의 상기 C1-6알킬, 아릴 및 아릴C1-6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1-6알킬, C1-6알콕시, 히드록시, COOR8 및 니트로 중에서 선택되는 치환기로 치환되며,
R7은 수소, C1-6알킬,
R8은 C1-6알킬이다.The method of claim 3,
The benzimidazole derivative according to claim 1, wherein the compound represented by the formula (1) is any one selected from the following formulas (1a) to (1g).
[Formula 1a]
[Chemical Formula 1b]
[Chemical Formula 1c]
≪ RTI ID = 0.0 &
[Formula 1e]
(1f)
[Formula 1g]
In the above formulas (1a) to (1g)
BL *
R 1 , R 2 , R 3 and R 4 are the same or different and each independently hydrogen, fluoro, chloro, bromo, carboxy, trifluoromethyl, C 1-6 alkyl, aryl, heteroaryl and C Lt; / RTI > alkylamidyl,
R 5 is selected from hydrogen, C 1-6 alkyl, aryl and aryl C 1-6 alkyl,
R 6 is selected from hydrogen, nitro, hydroxy, carboxy, trifluoromethyl, C 1-6 alkyl and C 1-6 alkoxy,
Wherein any one to three carbon atoms of said C 1-6 alkyl, aryl and aryl C 1-6 alkyl of R 1 to R 5 are the same or different and are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, COOR 8 and nitro,
R 7 is hydrogen, C 1-6 alkyl,
R 8 is C 1-6 alkyl.
상기 반응은 산소 분위기 또는 대기 분위기 하에서 수행되는 것을 특징으로 하는 벤즈이미다졸 유도체의 제조방법.The method of claim 3,
Wherein the reaction is carried out in an oxygen atmosphere or an air atmosphere.
상기 반응은 60 내지 120 ℃ 범위에서 수행되는 것을 특징으로 하는 벤즈이미다졸 유도체의 제조방법.The method of claim 3,
Wherein the reaction is carried out at a temperature in the range of 60 to 120 占 폚.
상기 아릴은 페닐, 나프틸, 안트릴 및 바이페닐 중에서 선택되는 것을 특징으로 하는 벤즈이미다졸 유도체의 제조방법.The method of claim 3,
Wherein said aryl is selected from phenyl, naphthyl, anthryl, and biphenyl.
상기 [화학식 1]로 표시되는 화합물은 하기 [화학식 6] 내지 [화학식 19]로 이루어진 군 중에서 선택되는 어느 하나인 것을 특징으로 하는 벤즈이미다졸 유도체의 제조방법:
[화학식 6]
[화학식 7]
[화학식 8]
[화학식 9]
[화학식 10]
[화학식 11]
[화학식 12]
[화학식 13]
[화학식 14]
[화학식 15]
[화학식 16]
[화학식 17]
[화학식 18]
[화학식 19]
Wherein the compound represented by the formula (1) is any one selected from the group consisting of the following formulas (6) to (19):
[Chemical Formula 6]
(7)
[Chemical Formula 8]
[Chemical Formula 9]
[Chemical formula 10]
(11)
[Chemical Formula 12]
[Chemical Formula 13]
[Chemical Formula 14]
[Chemical Formula 15]
[Chemical Formula 16]
[Chemical Formula 17]
[Chemical Formula 18]
[Chemical Formula 19]
상기 알칼리금속 할라이드는 KI, NaI, NaCl, KCl, NaBr 및 KBr 중에서 선택되며,
상기 알칼리토금속 할라이드는 CaI2, MgI2, CaCl2, CaI2, CaBr2 및 CaBr2 중에서 선택되는 것을 특징으로 하는 벤즈이미다졸 유도체의 제조방법.The method of claim 3,
The alkali metal halide is selected from KI, NaI, NaCl, KCl, NaBr and KBr,
The alkaline earth metal halide is CaI 2, MgI 2, CaCl 2 , CaI 2, CaBr 2 and a method of producing a benzimidazole derivative according to claim 2 selected from CaBr.
상기 알칼리금속 할라이드 또는 알칼리토금속 할라이드 촉매는 상기 [화학식 2]로 표시되는 화합물 1 몰에 대하여 0.01 내지 1.5 몰의 비율로 첨가되는 것을 특징으로 하는 벤즈이미다졸 유도체의 제조방법.The method of claim 3,
Wherein the alkali metal halide or alkaline earth metal halide catalyst is added in an amount of 0.01 to 1.5 mol based on 1 mol of the compound represented by the formula (2).
2) 염기를 첨가하여 가수분해시키는 단계;를 포함하여 수행함으로써 하기 [화학식 5]로 표시되는 화합물을 제조하는 보로닉산이 직접 포함된 벤즈이미다졸 유도체의 제조방법:
[화학식 2]
[화학식 4]
[화학식 5]
상기 [화학식 2], [화학식 4] 또는 [화학식 5]에서,
X는 CH=CH, O 및 S 중에서 선택되고,
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1-6알킬, 아릴, 헤테로아릴 및 C1-6알킬아마이딜 중에서 선택되고,
R5는 수소, C1-6알킬, 아릴 및 아릴C1-6알킬 중에서 선택되며,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1-6알킬 및 C1-6알콕시 중에서 선택되고,
R1 내지 R5의 상기 C1-6알킬, 아릴 및 아릴C1-6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1-6알킬, C1-6알콕시, 히드록시, COOR8 및 니트로 중에서 선택되는 치환기로 치환되며,
R7은 수소, C1-6알킬,
R8은 C1-6알킬이다.1) reacting a compound represented by the following formula 2 with an alkali metal halide or an alkaline earth metal halide catalyst under an anhydrous condition in a solvent selected from N, N-dimethylformamide and dimethylsulfoxide, Adding and reacting; And
2) base to form a benzimidazole derivative, wherein the step of hydrolyzing the benzimidazole derivative is carried out to prepare a compound represented by the following formula (5): < EMI ID =
(2)
[Chemical Formula 4]
[Chemical Formula 5]
In the above formulas (2), (4) or (5)
X is selected from CH = CH, O and S,
R 1 , R 2 , R 3 and R 4 are the same or different and each independently hydrogen, fluoro, chloro, bromo, carboxy, trifluoromethyl, C 1-6 alkyl, aryl, heteroaryl and C Lt; / RTI > alkylamidyl,
R 5 is selected from hydrogen, C 1-6 alkyl, aryl and aryl C 1-6 alkyl,
R 6 is selected from hydrogen, nitro, hydroxy, carboxy, trifluoromethyl, C 1-6 alkyl and C 1-6 alkoxy,
Wherein any one to three carbon atoms of said C 1-6 alkyl, aryl and aryl C 1-6 alkyl of R 1 to R 5 are the same or different and are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, COOR 8 and nitro,
R 7 is hydrogen, C 1-6 alkyl,
R 8 is C 1-6 alkyl.
상기 [화학식 5]는 하기 [화학식 5a] 내지 [화학식 5g] 중에서 선택되는 것을 특징으로 하는 보로닉산이 직접 포함된 벤즈이미다졸 유도체의 제조방법:
[화학식 5a]
[화학식 5b]
[화학식 5c]
[화학식 5d]
[화학식 5e]
[화학식 5f]
[화학식 5g]
상기 [화학식 5a] 내지 [화학식 5g]에서,
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1-6알킬, 아릴, 헤테로아릴 및 C1-6알킬아마이딜 중에서 선택되고,
R5는 수소, C1-6알킬, 아릴 및 아릴C1-6알킬 중에서 선택되며,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1-6알킬 및 C1-6알콕시 중에서 선택되고,
R1 내지 R5의 상기 C1-6알킬, 아릴 및 아릴C1-6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1-6알킬, C1-6알콕시, 히드록시, COOR8 및 니트로 중에서 선택되는 치환기로 치환되며,
R7은 수소, C1-6알킬,
R8은 C1-6알킬이다.12. The method of claim 11,
The method for producing a benzimidazole derivative which is directly incorporated with boronic acid, wherein the formula 5 is selected from the following formulas (5a) to (5g):
[Chemical Formula 5a]
[Chemical Formula 5b]
[Chemical Formula 5c]
[Chemical Formula 5d]
[Chemical Formula 5e]
[Chemical Formula 5f]
[Chemical Formula 5g]
In the above formulas (5a) to (5g)
R 1 , R 2 , R 3 and R 4 are the same or different and each independently hydrogen, fluoro, chloro, bromo, carboxy, trifluoromethyl, C 1-6 alkyl, aryl, heteroaryl and C Lt; / RTI > alkylamidyl,
R 5 is selected from hydrogen, C 1-6 alkyl, aryl and aryl C 1-6 alkyl,
R 6 is selected from hydrogen, nitro, hydroxy, carboxy, trifluoromethyl, C 1-6 alkyl and C 1-6 alkoxy,
Wherein any one to three carbon atoms of said C 1-6 alkyl, aryl and aryl C 1-6 alkyl of R 1 to R 5 are the same or different and are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, COOR 8 and nitro,
R 7 is hydrogen, C 1-6 alkyl,
R 8 is C 1-6 alkyl.
2) 하기 [화학식 1]의 화합물과 하기 [화학식 32]의 화합물을 팔라듐 촉매하에서 반응시켜 하기 [화학식 33]의 화합물을 합성하는 단계;
3) 상기 [화학식 33]의 화합물과 IrCl3를 반응시켜 이리듐 1 분자에 [화학식 33]의 화합물 2 분자가 결합된 이리듐 다이머 착물을 만드는 단계; 및
4) 상기 이리듐 다이머 착물과 아세틸 아세톤을 반응시켜 벤즈이미다졸형 이리듐 착물을 제조하는 단계;를 포함하는 벤즈이미다졸 보론 화합물을 이용한 유기발광다이오드용 벤즈이미다졸형 이리듐 착물의 제조방법:
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 32]
[화학식 33]
상기 [화학식 1] 내지 [화학식 3] 및 [화학식 33]에서,
X는 CH=CH, O 및 S 중에서 선택되고,
BL*는
R1, R2, R3 및 R4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, 카르복시, 트리플루오로메틸, C1-6알킬, 아릴, 헤테로아릴 및 C1-6알킬아마이딜 중에서 선택되고,
R5는 수소, C1-6알킬, 아릴 및 아릴C1-6알킬 중에서 선택되며,
R6는 수소, 니트로, 히드록시, 카르복시, 트리플루오로메틸, C1-6알킬 및 C1-6알콕시 중에서 선택되고,
R1 내지 R5의 상기 C1-6알킬, 아릴 및 아릴C1-6알킬의 임의의 탄소 원자 1 내지 3개는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 플루오로, 클로로, 브로모, C1-6알킬, C1-6알콕시, 히드록시, COOR8 및 니트로 중에서 선택되는 치환기로 치환되며,
R7은 수소, C1-6알킬,
R8은 C1-6알킬이다.1) reacting a compound represented by the following formula 2 with an alkali metal halide or an alkaline earth metal halide catalyst under anhydrous condition in a solvent selected from N, N-dimethylformamide and dimethylsulfoxide, To produce a benzimidazole boron compound represented by the following formula (1);
2) reacting a compound represented by the formula (1) and a compound represented by the following formula (32) in the presence of a palladium catalyst to synthesize a compound represented by the following formula (33);
3) reacting the compound of Formula 33 with IrCl 3 to form an iridium dimer complex in which two molecules of the compound of Formula 33 are bonded to one molecule of iridium; And
4) preparing a benzimidazole type iridium complex by reacting the iridium dimer complex with acetylacetone, and preparing a benzimidazole type iridium complex for an organic light emitting diode using the benzimidazole boron compound,
[Chemical Formula 1]
(2)
(3)
(32)
(33)
In the above formulas (1) to (3) and (33)
X is selected from CH = CH, O and S,
BL *
R 1 , R 2 , R 3 and R 4 are the same or different and each independently hydrogen, fluoro, chloro, bromo, carboxy, trifluoromethyl, C 1-6 alkyl, aryl, heteroaryl and C Lt; / RTI > alkylamidyl,
R 5 is selected from hydrogen, C 1-6 alkyl, aryl and aryl C 1-6 alkyl,
R 6 is selected from hydrogen, nitro, hydroxy, carboxy, trifluoromethyl, C 1-6 alkyl and C 1-6 alkoxy,
Wherein any one to three carbon atoms of said C 1-6 alkyl, aryl and aryl C 1-6 alkyl of R 1 to R 5 are the same or different and are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, COOR 8 and nitro,
R 7 is hydrogen, C 1-6 alkyl,
R 8 is C 1-6 alkyl.
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| CN115819353B (en) * | 2023-02-08 | 2023-06-30 | 长沙晶易医药科技股份有限公司 | Method for preparing 2-arylamino benzimidazole and N1-aryl-2-amino benzimidazole |
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