CN114524773A - Method for synthesizing aryl quinoxaline compound promoted by mechanical force - Google Patents
Method for synthesizing aryl quinoxaline compound promoted by mechanical force Download PDFInfo
- Publication number
- CN114524773A CN114524773A CN202210206376.2A CN202210206376A CN114524773A CN 114524773 A CN114524773 A CN 114524773A CN 202210206376 A CN202210206376 A CN 202210206376A CN 114524773 A CN114524773 A CN 114524773A
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- China
- Prior art keywords
- ball milling
- methyl
- reaction
- tank body
- quinoxaline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 aryl quinoxaline compound Chemical class 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 18
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title claims description 23
- 230000002194 synthesizing effect Effects 0.000 title claims description 12
- 238000000498 ball milling Methods 0.000 claims abstract description 116
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000000706 filtrate Substances 0.000 claims abstract description 22
- 239000011541 reaction mixture Substances 0.000 claims abstract description 22
- 239000000126 substance Substances 0.000 claims abstract description 22
- 125000001424 substituent group Chemical group 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 125000005520 diaryliodonium group Chemical group 0.000 claims abstract description 5
- 238000003801 milling Methods 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 84
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 239000002245 particle Substances 0.000 claims description 25
- 238000000227 grinding Methods 0.000 claims description 23
- 229910001220 stainless steel Inorganic materials 0.000 claims description 22
- 239000010935 stainless steel Substances 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229910002113 barium titanate Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 229910002370 SrTiO3 Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 5
- 238000009835 boiling Methods 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract 1
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 31
- 238000007789 sealing Methods 0.000 description 26
- 239000000047 product Substances 0.000 description 21
- 239000003208 petroleum Substances 0.000 description 19
- 238000001953 recrystallisation Methods 0.000 description 18
- 239000012265 solid product Substances 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 230000017525 heat dissipation Effects 0.000 description 15
- OKJJWDZXRWKKIP-UHFFFAOYSA-N 1-iodo-4-methylbenzene;trifluoromethanesulfonic acid Chemical compound CC1=CC=C(I)C=C1.OS(=O)(=O)C(F)(F)F OKJJWDZXRWKKIP-UHFFFAOYSA-N 0.000 description 9
- SBQIJPBUMNWUKN-UHFFFAOYSA-M diphenyliodanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.C=1C=CC=CC=1[I+]C1=CC=CC=C1 SBQIJPBUMNWUKN-UHFFFAOYSA-M 0.000 description 9
- CHWOJQPQAWFQEY-UHFFFAOYSA-N 2-(4-methylphenyl)quinoxaline Chemical compound C1=CC(C)=CC=C1C1=CN=C(C=CC=C2)C2=N1 CHWOJQPQAWFQEY-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ALHUXMDEZNLFTA-UHFFFAOYSA-N 2-methylquinoxaline Chemical compound C1=CC=CC2=NC(C)=CN=C21 ALHUXMDEZNLFTA-UHFFFAOYSA-N 0.000 description 2
- CQLOYHZZZCWHSG-UHFFFAOYSA-N 5-methylquinoxaline Chemical compound C1=CN=C2C(C)=CC=CC2=N1 CQLOYHZZZCWHSG-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000007769 metal material Substances 0.000 description 2
- AUJXLBOHYWTPFV-UHFFFAOYSA-N quinomycin A Natural products CN1C(=O)C(C)NC(=O)C(NC(=O)C=2N=C3C=CC=CC3=NC=2)COC(=O)C(C(C)C)N(C)C(=O)C2N(C)C(=O)C(C)NC(=O)C(NC(=O)C=3N=C4C=CC=CC4=NC=3)COC(=O)C(C(C)C)N(C)C(=O)C1CSC2SC AUJXLBOHYWTPFV-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- QFMYCPNBAGXLDL-UHFFFAOYSA-M (2-methylphenyl)-(2,4,6-trimethylphenyl)iodanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CC1=CC(C)=CC(C)=C1[I+]C1=CC=CC=C1C QFMYCPNBAGXLDL-UHFFFAOYSA-M 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- UUWUUKCTGWJRHN-UHFFFAOYSA-N 1,6,7-trimethyl-3-phenylquinoxalin-2-one Chemical compound O=C1N(C)C=2C=C(C)C(C)=CC=2N=C1C1=CC=CC=C1 UUWUUKCTGWJRHN-UHFFFAOYSA-N 0.000 description 1
- DRDHXUCEJHWQON-UHFFFAOYSA-N 1,6,7-trimethylquinoxalin-2-one Chemical compound N1=CC(=O)N(C)C2=C1C=C(C)C(C)=C2 DRDHXUCEJHWQON-UHFFFAOYSA-N 0.000 description 1
- VSOBLGMKECIRKI-UHFFFAOYSA-N 1-benzyl-3-phenylquinoxalin-2-one Chemical compound O=C1C(C=2C=CC=CC=2)=NC2=CC=CC=C2N1CC1=CC=CC=C1 VSOBLGMKECIRKI-UHFFFAOYSA-N 0.000 description 1
- XSIQIJZHBWPBDQ-UHFFFAOYSA-N 1-benzylquinoxalin-2-one Chemical compound O=C1C=NC2=CC=CC=C2N1CC1=CC=CC=C1 XSIQIJZHBWPBDQ-UHFFFAOYSA-N 0.000 description 1
- XWBFKTDOMCTTDQ-UHFFFAOYSA-N 1-methyl-3-phenylquinoxalin-2-one Chemical compound O=C1N(C)C2=CC=CC=C2N=C1C1=CC=CC=C1 XWBFKTDOMCTTDQ-UHFFFAOYSA-N 0.000 description 1
- IMEBSBZHQJUOJZ-UHFFFAOYSA-N 1-methyl-6-nitro-3-phenylquinoxalin-2-one Chemical compound [N+](=O)([O-])C=1C=C2N=C(C(N(C2=CC=1)C)=O)C1=CC=CC=C1 IMEBSBZHQJUOJZ-UHFFFAOYSA-N 0.000 description 1
- YEGRUCPCVUDQCF-UHFFFAOYSA-N 1-methyl-6-nitroquinoxalin-2-one Chemical compound C1=C([N+]([O-])=O)C=C2N=CC(=O)N(C)C2=C1 YEGRUCPCVUDQCF-UHFFFAOYSA-N 0.000 description 1
- CHPVQLYVDDOWNT-UHFFFAOYSA-N 1-methylquinoxalin-2-one Chemical compound C1=CC=C2N=CC(=O)N(C)C2=C1 CHPVQLYVDDOWNT-UHFFFAOYSA-N 0.000 description 1
- QFRFRSFOUUSHMJ-UHFFFAOYSA-N 2-(2-methylphenyl)quinoxaline Chemical compound CC1=CC=CC=C1C1=CN=C(C=CC=C2)C2=N1 QFRFRSFOUUSHMJ-UHFFFAOYSA-N 0.000 description 1
- IXHJZKFVTLPKSM-UHFFFAOYSA-N 2-bromo-3-(4-methylphenyl)quinoxaline Chemical compound CC(C=C1)=CC=C1C1=NC2=CC=CC=C2N=C1Br IXHJZKFVTLPKSM-UHFFFAOYSA-N 0.000 description 1
- XVKLMYQMVPHUPN-UHFFFAOYSA-N 2-bromoquinoxaline Chemical compound C1=CC=CC2=NC(Br)=CN=C21 XVKLMYQMVPHUPN-UHFFFAOYSA-N 0.000 description 1
- NNTKFFMFGJABBP-UHFFFAOYSA-N 2-methyl-3-(4-methylphenyl)quinoxaline Chemical compound C1=CC(C)=CC=C1C1=NC2=CC=CC=C2N=C1C NNTKFFMFGJABBP-UHFFFAOYSA-N 0.000 description 1
- WFBSEPXINAMEDR-UHFFFAOYSA-N 5-methyl-2-(4-methylphenyl)quinoxaline Chemical compound CC1=C2N=CC(=NC2=CC=C1)C1=CC=C(C=C1)C WFBSEPXINAMEDR-UHFFFAOYSA-N 0.000 description 1
- 239000001640 5-methylquinoxaline Substances 0.000 description 1
- MBCWAADSURWEBH-UHFFFAOYSA-N 6,7-difluoro-1-methylquinoxalin-2-one Chemical compound Cn1c2cc(F)c(F)cc2ncc1=O MBCWAADSURWEBH-UHFFFAOYSA-N 0.000 description 1
- QNOXYUNHIGOWNY-UHFFFAOYSA-N 6,7-dimethoxy-2-phenylquinoxaline Chemical compound N1=C2C=C(OC)C(OC)=CC2=NC=C1C1=CC=CC=C1 QNOXYUNHIGOWNY-UHFFFAOYSA-N 0.000 description 1
- SKMLAJZUMRWOOC-UHFFFAOYSA-N 6-fluoro-1-methylquinoxalin-2-one Chemical compound FC1=CC=C2N(C(C=NC2=C1)=O)C SKMLAJZUMRWOOC-UHFFFAOYSA-N 0.000 description 1
- CBQGUVKDQCRXLY-UHFFFAOYSA-N 7-chloro-1-methylquinoxalin-2-one Chemical compound ClC1=CC=C2N=CC(=O)N(C)C2=C1 CBQGUVKDQCRXLY-UHFFFAOYSA-N 0.000 description 1
- BGQMRSHGJFLOEQ-UHFFFAOYSA-N 7-methoxy-1-methylquinoxalin-2-one Chemical compound N1=CC(=O)N(C)C2=CC(OC)=CC=C21 BGQMRSHGJFLOEQ-UHFFFAOYSA-N 0.000 description 1
- GJNXZBFXJXIFNV-UHFFFAOYSA-N CC(C=CC=C1N2C)=C1N=C(C1=CC=CC=C1)C2=O Chemical compound CC(C=CC=C1N2C)=C1N=C(C1=CC=CC=C1)C2=O GJNXZBFXJXIFNV-UHFFFAOYSA-N 0.000 description 1
- PZRHMGUQAHCOAY-UHFFFAOYSA-N CN1C(C=NC2=C(C=CC=C12)C)=O Chemical compound CN1C(C=NC2=C(C=CC=C12)C)=O PZRHMGUQAHCOAY-UHFFFAOYSA-N 0.000 description 1
- UBNVYENWFXBBOK-UHFFFAOYSA-N COC=1C=C2N(C(C(=NC2=CC=1)C1=CC=CC=C1)=O)C Chemical compound COC=1C=C2N(C(C(=NC2=CC=1)C1=CC=CC=C1)=O)C UBNVYENWFXBBOK-UHFFFAOYSA-N 0.000 description 1
- AUJXLBOHYWTPFV-BLWRDSOESA-N CS[C@H]1SC[C@H]2N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C(=O)[C@@H]1N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C2=O)NC(=O)c1cnc2ccccc2n1)NC(=O)c1cnc2ccccc2n1 Chemical compound CS[C@H]1SC[C@H]2N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C(=O)[C@@H]1N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C2=O)NC(=O)c1cnc2ccccc2n1)NC(=O)c1cnc2ccccc2n1 AUJXLBOHYWTPFV-BLWRDSOESA-N 0.000 description 1
- LIVVOKVRHMNYPL-UHFFFAOYSA-N ClC1=CC=C2N=C(C(N(C2=C1)C)=O)C1=CC=CC=C1 Chemical compound ClC1=CC=C2N=C(C(N(C2=C1)C)=O)C1=CC=CC=C1 LIVVOKVRHMNYPL-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 108010009858 Echinomycin Proteins 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000000713 high-energy ball milling Methods 0.000 description 1
- 238000000875 high-speed ball milling Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010303 mechanochemical reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006561 solvent free reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C17/00—Disintegrating by tumbling mills, i.e. mills having a container charged with the material to be disintegrated with or without special disintegrating members such as pebbles or balls
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a synthesis method of aryl quinoxaline compounds promoted by mechanical force, which comprises the steps of adding quinoxaline compounds (II) and diaryl iodonium salts (III) into a ball milling tank, then adding piezoelectric materials, alkali and milling balls, carrying out ball milling reaction, transferring a reaction mixture by using an organic solvent after the reaction is finished, filtering out insoluble substances, concentrating filtrate, recrystallizing to obtain the aryl quinoxaline compounds shown in the formula (I),
wherein the substituents R1、R2And R3Each independently substituted or unsubstituted, and the substituents R1And R3When substituted, is mono-or polysubstituted, the substituent R1Selected from methyl or methoxyThe substituent R2Selected from methyl or bromine, substituents R3Selected from methyl, methoxy, fluorine, chlorine or nitro, substituents R4Selected from methyl or benzyl; ar (Ar)1And Ar2Same or different, Ar is Ar1Or Ar2. The method has mild reaction conditions, short reaction time, no use of high-boiling point solvent and environmental friendliness; simple post-treatment, high selectivity and high yield.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing an aryl quinoxaline compound promoted by mechanical force.
Background
The arylquinoxaline compound is a basic unit structure of a plurality of medicines and has biological activity, and has a plurality of activities such as antimicrobial, antibacterial, antiphlogistic, antiviral and the like. Many antibiotics, such as echinomycin, levomycin, actinomycin, contain a quinoxaline nucleus structure. The synthesis of aryl quinoxaline compounds has been paid attention by a great deal of chemists, and the condensation reaction of o-phenylenediamine and dicarbonyl compound is commonly used to synthesize aryl quinoxaline compounds (Molecules,2021,26, 4895; Synthetic Commun, 2021,51, 2510; Catal. Today,2020,345,258), but these methods generally have the disadvantages of high temperature, long reaction time, volatile solvent and expensive and unrecoverable transition metal catalyst. Although some methods for direct C-H arylation synthesis of arylquinoxaline compounds have been developed by the subject group, they still inevitably require the use of large amounts of high boiling solvents (chemistry select,2018,3, 5824; adv. synth. catal.,2019,361, 5170).
The high-energy ball milling reaction is a green, rapid, high-efficiency and solvent-free reaction mode, avoids the defects caused by using a solvent, can fully mix reactants, increases the contact surface of the reactants, improves the reaction rate and reduces the reaction temperature.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a chemical synthesis method of an arylquinoxaline compound, which has the advantages of reasonable process, safe and reliable production, high reaction yield, low cost, easy product separation and small environmental pollution.
In order to achieve the purpose, the following technical scheme is provided:
a method for synthesizing aryl quinoxaline compounds promoted by mechanical force is characterized by comprising the following steps: adding quinoxaline compound (II) and diaryl iodonium salt (III) into a ball milling pot, adding piezoelectric material, alkali and milling balls, carrying out ball milling reaction, transferring the reaction mixture by using organic solvent after the reaction is finished, filtering insoluble substances, concentrating the filtrate, recrystallizing to obtain the aryl quinoxaline compound shown in formula (I),
wherein, the substituent R1、R2And R3Each independently substituted or unsubstituted, and the substituents R1And R3When substituted, the substituent R is mono-or polysubstituted1Selected from methyl or methoxy, substituent R2Selected from methyl or bromine, substituents R3Selected from methyl, methoxy, fluorine, chlorine or nitro, substituents R4Selected from methyl or benzyl; ar (Ar)1And Ar2Same or different, Ar is Ar1Or Ar2。
Further, Ar1And Ar2Each independently selected from phenyl or substituted phenyl, the substituent of the substituted phenyl is mono-substituted or multi-substituted, and the substituent is methyl.
Further, the piezoelectric material is BaTiO3(particle size: 4 μm), BaTiO3(particle size of 100nm), ZnO or SrTiO3Preferably BaTiO3(particle size: 4 μm).
Further, the quinoxaline compound: diaryl iodonium salts: the quantity ratio of alkali feeding materials is 1: 1.5-3.0: 1 to 4.0, preferably 1: 1.5-2.0: 1.5 to 3.0.
Further, the base is sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium ethoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, DBU or triethylamine.
Furthermore, the material of the grinding ball is metal material, agate or zirconia, the metal material comprises stainless steel or copper, and the diameter of the grinding ball is 10 mm.
Further, the ball milling reaction is carried out for 1.0-2.0 hours at the ball milling rotation speed of 600-1000 r/min, and after the ball mill stops operating, air is blown to release heat until the surface of the tank body is cooled to the room temperature, and the reaction is preferably carried out for 1.5-2.0 hours at 800-1000 r/min.
Further, the organic solvent is acetonitrile, ethyl acetate, dichloromethane or C1-C6 alcohol, preferably ethyl acetate or dichloromethane.
Compared with the prior art, the invention has the beneficial effects that:
the reaction condition is mild, the operation is simple, and the reaction time is short; a high-boiling point solvent is not used, the reaction is carried out at normal temperature and normal pressure, the cost is saved, and the method is environment-friendly; simple post-treatment, high selectivity and high yield.
Detailed Description
The invention is further described below with reference to specific examples, but the scope of protection of the invention is not limited thereto.
The high speed mechanochemical reaction (HSBM) of the following examples of the present invention was carried out on a high energy planetary ball mill P-7 (German flying company) with a stainless steel milling jar volume of 20 mL.
Example 1
Quinoxaline (0.130g, 1.0mmol), bis (4-methyl) phenyliodonium trifluoromethanesulfonate (0.687g, 1.5mmol), potassium carbonate (0.207g, 1.5mmol) and BaTiO are added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, sealing the tank body, placing the tank body in the ball milling machine, enabling the ball milling rotation speed to be 1000 r/min, finishing the reaction after ball milling for 30min, enabling the temperature of the tank body to be about 50 ℃, after the ball milling machine stops operating, conducting forced air heat dissipation until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by using acetonitrile, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.013g of a yellow solid product, enabling the recrystallization yield of the product to be 5.9%, and enabling the content of the 2- (4-methylphenyl) quinoxaline to be 97.5% through HPLC detection. m.p. 90.5-91.1 ℃;1H NMR (600MHz,CDCl3)δ9.34(s,1H),8.18-8.13(m,4H),7.82-7.75(m, 2H),7.40(d,J＝8.4Hz,2H),2.48(s,3H)；13C NMR(151MHz,CDCl3) δ151.9,143.1,142.3,141.2,140.6,133.9,130.3,129.9,129.5,129.4, 129.0,127.5,21.4；MS(ESI):m/z＝221.5[M+H]+.
example 2
Quinoxaline (0.130g, 1.0mmol), bis (4-methyl) phenyliodonium trifluoromethanesulfonate (0.687g, 1.5mmol), potassium hydroxide (0.112 g, 2.0mmol), BaTiO were added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, keeping the ball milling rotation speed at 800 r/min, finishing the reaction after ball milling for 120min, after the operation of the ball milling machine is stopped, keeping the temperature of the tank body at about 50 ℃, conducting forced air heat dissipation until the surface of the tank body is cooled to room temperature, transferring the reaction mixture by using ethyl acetate, filtering out insoluble substances, concentrating the filtrate, and then recrystallizing by using petroleum ether/ethyl acetate to obtain 0.047g of a yellow solid product, wherein the recrystallization yield of the product is 21.4%, and the content of the 2- (4-methylphenyl) quinoxaline is 97.8% by HPLC (high performance liquid chromatography).
Example 3
Quinoxaline (0.130g, 1.0mmol), bis (4-methyl) phenyliodonium trifluoromethanesulfonate (0.687g, 1.5mmol), potassium tert-butoxide (0.336 g, 3.0mmol), BaTiO were added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, keeping the ball milling rotation speed at 600 rpm, finishing the reaction after ball milling for 120min, after the operation of the ball milling machine is stopped, keeping the temperature of the tank body at about 50 ℃, conducting forced air heat dissipation until the surface of the tank body is cooled to room temperature, transferring the reaction mixture by using dichloromethane, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.063g of a yellow solid product, ensuring the recrystallization yield of the product to be 28.5 percent, and detecting the content of the 2- (4-methylphenyl) quinoxaline to be 97.6 percent by HPLC.
Example 4
Quinoxaline (0.130g, 1.0mmol), bis (4-methyl) phenyliodonium trifluoromethanesulfonate (0.687g, 1.5mmol), DBU (0.608g, 4.0mmol), BaTiO were added in this order to a 20mL ball mill pot3(the particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, sealing the tank body, placing the tank body in the ball milling machine, enabling the ball milling rotation speed to be 1000 r/min, finishing the reaction after the ball milling is carried out for 60min, enabling the temperature of the tank body to be about 50 ℃, conducting forced air cooling until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by using acetonitrile, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.018g of yellow solid product, enabling the recrystallization yield of the product to be 8.4%, and detecting the content of 2- (4-methylphenyl) quinoxaline by using HPLC (high performance liquid chromatography (HPLC) to be 97.1%.
Example 5
Quinoxaline (0.130g, 1.0mmol), bis (4-methyl) phenyliodonium trifluoromethanesulfonate (0.916g, 2.0mmol), triethylamine (0.303g, 3.0mmol) and BaTiO are added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling tank, sealing the tank body, placing the tank body in the ball milling machine, enabling the ball milling rotation speed to be 800 r/min, finishing the reaction after the ball milling is carried out for 90min, enabling the temperature of the tank body to be about 50 ℃ after the ball milling machine stops operating, carrying out air blast heat dissipation until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by using ethanol, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.158g of a yellow solid product, enabling the recrystallization yield of the product to be 71.7%, and detecting the content of 2- (4-methylphenyl) quinoxaline by using HPLC (HPLC) to be 98.3%.
Example 6
Quinoxaline (0.130g, 1.0mmol), 2,4, 6-trimethylphenyl (2-methylphenyl) iodonium trifluoromethanesulfonate (0.728g, 1.5mmol), triethylamine (0.303g, 3.0mmol), BaTiO (in this order) and the like are added in a 20mL ball mill pot3(particle size of 4 μm) (1.5g), placing eight stainless steel grinding balls with diameter of 10mm, sealing the pot body of the ball milling pot, placing the pot body in the ball milling pot, performing ball milling at the ball milling rotation speed of 800 rpm for 60min, finishing the reaction, stopping the operation of the ball milling pot, performing air blast heat dissipation until the surface of the pot body is cooled to room temperature, transferring the reaction mixture by using ethyl acetate, filtering out insoluble substances, concentrating the filtrate, and recrystallizing by using petroleum ether/ethyl acetate to obtain yellow solid0.056g of product, the recrystallization yield of the product is 25.6 percent, and the content of the 2- (2-methylphenyl) quinoxaline is 97.4 percent by HPLC detection. m.p. 85.4-87.6 ℃;1H NMR(600MHz,CDCl3)δ9.04(s,1H),8.21- 8.18(m,2H),7.86-7.81(m,2H),7.59-7.57(m,1H),7.45-7.39(m, 3H),2.50(s,3H)；13C NMR(151MHz,CDCl3)δ155.0,145.8,142.0, 140.9,137.1,136.6,131.2,130.4,130.0,129.8,129.6,129.5,129.1, 126.4,20.4；MS(ESI):m/z＝220.8[M+H]+.
example 7
5-methylquinoxaline (0.144g, 1.0mmol), bis (4-methyl) phenyliodonium trifluoromethanesulfonate (0.916g, 2.0mmol), triethylamine (0.303g, 3.0mmol), BaTiO were added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, keeping the ball milling rotation speed at 1000 r/min, finishing the reaction after ball milling for 120min, after the operation of the ball milling machine is stopped, keeping the temperature of the tank body at about 50 ℃, conducting forced air heat dissipation until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by acetonitrile, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.190g of a yellow solid product, wherein the recrystallization yield of the product is 81.0%, and the content of the 2- (4-methylphenyl) -5-methylquinoxaline is 98.6% by HPLC (high performance liquid chromatography). m.p. 141.1-143.8 deg.C;1H NMR(600MHz,CDCl3)δ9.35(s,1H),8.14(d,J ＝8.4Hz,2H),8.05(d,J＝8.4Hz,1H),7.70(dd,J＝8.4,7.2Hz,1H), 7.60(d,J＝7.2Hz,1H),7.40(d,J＝7.8Hz,2H),2.86(s,3H),2.48(s, 3H)；13C NMR(151MHz,CDCl3)δ151.3,142.2,141.9,140.6,140.5, 137.3,133.9,130.1,129.9,129.5,127.5,127.3,21.4,17.3；MS(ESI): m/z＝235.4[M+H]+.
example 8
2-bromoquinoxaline (0.207g, 1.0mmol), bis (4-methyl) phenyliodonium trifluoromethanesulfonate (0.916g, 2.0mmol), triethylamine (0.202 g, 2.0mmol), BaTiO were added in this order to a 20mL ball mill pot3(particle diameter is 4 μm) (1.5g), putting eight stainless steel grinding balls with diameter of 10mm, sealing the jar body of the ball milling jar after the feeding, putting the jar body into the ball milling jar, and setting the ball milling jar in the ball milling machine at the ball milling rotating speed of 800 r/mAfter the reaction is finished after the ball milling is carried out for 100min, after the ball milling is stopped, the temperature of the tank body is about 50 ℃, air is blown for heat dissipation until the surface of the tank body is cooled to room temperature, dichloromethane is used for transferring a reaction mixture, insoluble substances are filtered out, filtrate is concentrated and then recrystallized by petroleum ether/ethyl acetate, 0.129g of yellow solid product is obtained, the recrystallization yield of the product is 43.4%, and the content of the 2-bromo-3- (4-methylphenyl) quinoxaline is 97.9% by HPLC detection. 117.2-119.6 ℃ in m.p.;1H NMR(600MHz,CDCl3)δ8.17-8.16(m,1H), 8.11-8.09(m,1H),7.84-7.79(m,2H),7.76(d,J＝8.4Hz,2H),7.37(d, J＝7.8Hz,2H),2.48(s,3H)；13C NMR(151MHz,CDCl3)δ154.6, 141.8,140.8,139.9,139.3,134.9,130.7,130.6,129.6,129.2,129.0, 128.2,21.5；HRMS-ESI:calcd for C15H11BrN2[M+H]+:299.0178；found: 299.0185.
example 9
2-methylquinoxaline (0.144g, 1.0mmol), bis (4-methyl) phenyliodonium trifluoromethanesulfonate (0.916g, 2.0mmol), triethylamine (0.404 g, 4.0mmol), BaTiO were added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), putting eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank, placing the tank body in the ball milling machine, setting the ball milling rotation speed at 1000 r/min, feeding and ball milling for 120min, finishing the reaction, stopping the operation of the ball milling machine, keeping the temperature of the tank body at about 50 ℃, conducting forced air heat dissipation until the surface of the tank body is cooled to room temperature, transferring the reaction mixture by using methanol, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.172g of a yellow solid product, wherein the recrystallization yield of the product is 73.6 percent, and the content of the 2-methyl-3- (4-methylphenyl) quinoxaline is 98.2 percent through HPLC (high performance liquid chromatography). m.p. 51.9-55.3 ℃;1H NMR(600MHz,CDCl3)δ8.14(dd,J＝7.8,1.2Hz,1H), 8.10-8.09(m,1H),7.78-7.73(m,2H),7.59(d,J＝8.4Hz,2H),7.36(d, J＝7.8Hz,2H),2.82(s,3H),2.48(s,3H)；13C NMR(151MHz,CDCl3) δ155.0,152.5,145.6,141.1,139.1,136.1,130.8,129.7,129.2,129.2, 128.9,128.1,24.4,21.4；MS(ESI):m/z＝235.0[M+H]+.
example 10
In a 20mL ball6, 7-dimethoxyquinoxaline (0.190g, 1.0mmol), diphenyliodonium trifluoromethanesulfonate (0.644g, 1.5mmol), triethylamine (0.303g, 3.0mmol) and BaTiO are added in turn to a milling pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, placing the ball milling tank in a sealing way, keeping the ball milling rotation speed at 1000 r/min, finishing the reaction after ball milling for 90min, after the operation of the ball milling machine is stopped, keeping the temperature of the tank body at about 50 ℃, conducting forced air heat dissipation until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by using ethyl acetate, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.185g of a yellow solid product, ensuring the recrystallization yield of the product to be 69.5 percent and ensuring the content of the 2-phenyl-6, 7-dimethoxy quinoxaline to be 98.3 percent by HPLC. 129.7-131.0 ℃ in m.p.;1H NMR(600MHz,CDCl3)NMR(6(s,1H),8.17- 8.16(m,2H),7.59-7.57(m,2H),7.53-7.52(m,1H),7.47(d,J＝13.8 Hz,2H),4.11(d,J＝1.8Hz,6H)；13C NMR(151MHz,CDCl3)NMR (151MHz,CDCl1(d,40.0,139.7,138.2,137.0,129.8,129.1,127.2, 107.0,106.2,56.5；MS(ESI):m/z＝266.4[M+H]+.
example 11
1-methylquinoxalinone (0.160g, 1.0mmol), diphenyliodonium trifluoromethanesulfonate (1.287g, 3.0mmol), triethylamine (0.303g, 3.0mmol), BaTiO were added in this order to a 20mL ball mill pot3(the particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling tank, sealing the tank body, placing the tank body in the ball milling machine, enabling the ball milling rotation speed to be 1000 r/min, finishing the reaction after the ball milling is carried out for 60min, enabling the temperature of the tank body to be about 50 ℃ after the ball milling machine stops operating, carrying out air blast heat dissipation until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by acetonitrile, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.175g of a yellow solid product, wherein the recrystallization yield of the product is 74.3%, and the content of the 1-methyl-3-phenylquinoxalinone is 98.5% by HPLC (high performance liquid chromatography). m.p. 130.6-133.3 ℃;1H NMR(600MHz,CDCl3)δ8.35-8.32(m,2H),7.97(dd,J＝8.4,1.2 Hz,1H),7.59-7.57(m,1H),7.51-7.50(m,3H),7.40-7.37(m,1H), 7.34(d,J＝8.4Hz,1H),3.78(s,3H)；13C NMR(151MHz,CDCl3)δ 154.7,154.1,136.1,133.4,133.1,130.4,130.3,130.3,129.6,128.1, 123.7,113.6,29.3；MS(ESI):m/z＝237.3[M+H]+.
example 12
1, 5-dimethylquinoxalinone (0.174g, 1.0mmol), diphenyliodonium trifluoromethanesulfonate (0.644g, 1.5mmol), triethylamine (0.404 g, 4.0mmol) and BaTiO were added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, keeping the ball milling rotation speed at 800 r/min, finishing the reaction after ball milling for 120min, after the operation of the ball milling machine is stopped, keeping the temperature of the tank body at about 50 ℃, conducting forced air heat dissipation until the surface of the tank body is cooled to room temperature, transferring the reaction mixture by using ethanol, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.176g of a yellow solid product, wherein the recrystallization yield of the product is 70.5%, and the content of 1, 5-dimethyl-3-phenylquinoxalinone is 98.4% by HPLC (high performance liquid chromatography). 157.4-159.3 ℃ in m.p.;1H NMR(600MHz,CDCl3)δ8.46-8.44(m,2H),7.51- 7.50(m,3H),7.48-7.45(m,1H),7.24(d,J＝7.8Hz,1H),7.19(d,J＝ 8.4Hz,1H),3.78(s,3H),2.78(s,3H)；13C NMR(151MHz,CDCl3)δ 154.6,151.7,139.3,136.5,133.5,131.6,130.2,130.1,129.7,128.0, 124.9,111.5,29.4,17.6；MS(ESI):m/z＝250.7[M+H]+.
example 13
1,6, 7-trimethylquinoxalinone (0.188g, 1.0mmol), diphenyliodonium trifluoromethanesulfonate (0.858g, 2.0mmol), triethylamine (0.152 g, 1.5mmol) and BaTiO are added in sequence in a 20mL ball mill pot3(particle size of 4 μm) (1.5g), placing eight stainless steel grinding balls with diameter of 10mm, sealing the pot body of the ball milling pot, placing the pot body in the ball milling pot, performing ball milling at the ball milling rotation speed of 800 r/min, finishing the reaction after ball milling for 90min, after the operation of the ball milling pot is stopped, keeping the temperature of the pot body at about 50 ℃, performing air blast heat dissipation until the surface of the pot body is cooled to room temperature, transferring the reaction mixture by using dichloromethane, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.193g of yellow solid product, and re-crystallizing the product to obtain 0.193g of yellow solid productThe crystallization yield is 73.2 percent, and the content of the 1,6, 7-trimethyl-3-phenylquinoxalinone is 98.5 percent by HPLC detection. 173.5-175.3 ℃ in m.p.;1H NMR(600MHz,CDCl3)δ8.32-8.30(m,2H), 7.73(s,1H),7.51-7.48(m,3H),7.12(s,1H),3.77(s,3H),2.46(s,3H), 2.39(s,3H)；13C NMR(151MHz,CDCl3)δ154.8,153.0,140.3,136.3, 132.7,131.6,131.4,130.5,130.0,129.4,128.0,114.1,29.2,20.6,19.2； MS(ESI):m/z＝264.3[M+H]+.
example 14
1-methyl-7-methoxyquinoxalinone (0.190g, 1.0mmol), diphenyliodonium trifluoromethanesulfonate (0.644g, 1.5mmol), triethylamine (0.303g, 3.0mmol) and BaTiO were added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, placing the ball milling tank in a sealing way, transferring the ball milling rotation speed to the ball milling machine at 1000 r/min, finishing the reaction after ball milling for 120min, after the operation of the ball milling machine is stopped, blowing air to dissipate heat until the surface of the tank body is cooled to room temperature, transferring the reaction mixture by using ethyl acetate, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.182g of yellow solid product, wherein the recrystallization yield of the product is 68.5 percent, and the content of the 1-methyl-3-phenyl-7-methoxy quinoxalinone is 98.7 percent by HPLC (high performance liquid chromatography). m.p. 97.5-99.7 ℃;1H NMR(600MHz,CDCl3)δ8.34-8.31 (m,2H),7.52-7.49(m,3H),7.45(d,J＝3.0Hz,1H),7.29(d,J＝3.0Hz, 1H),7.22(dd,J＝9.0,2.4Hz,1H),3.93(s,3H),3.78(s,3H)；13C NMR (151MHz,CDCl3)δ156.1,154.6,154.4,136.1,133.8,130.3,129.6, 128.1,127.7,119.8,114.5,111.6,55.8,29.5；MS(ESI):m/z＝267.4 [M+H]+.
example 15
1-methyl-6-fluoroquinoxalinone (0.178g, 1.0mmol), diphenyliodonium trifluoromethanesulfonate (0.644g, 1.5mmol), triethylamine (0.303g, 3.0mmol) and BaTiO are added in sequence to a 20mL ball mill pot3(particle diameter is 4 μm) (1.5g), putting eight stainless steel grinding balls with diameter of 10mm, sealing the jar body of the ball milling jar after feeding, putting the jar body into the ball milling jar, performing ball milling at the ball milling rotation speed of 1000 rpm for 12 r/minAfter 0min, the reaction is finished, after the ball mill stops operating, the temperature of the tank body is about 50 ℃, air is blown to dissipate heat until the surface of the tank body is cooled to room temperature, dichloromethane is used for transferring the reaction mixture, insoluble substances are filtered out, the filtrate is concentrated and then recrystallized by petroleum ether/ethyl acetate to obtain 0.171g of yellow solid product, the recrystallization yield of the product is 67.5%, and the content of the 1-methyl-3-phenyl-6-fluoroquinoxalinone is 98.6% by HPLC detection. 119.5-121.3 ℃ in m.p.;1H NMR(600MHz,CDCl3)δ8.35-8.32(m, 2H),7.66(dd,J＝9.0,3.0Hz,1H),7.54-7.49(m,3H),7.36-7.30(m, 2H),3.79(s,3H)；13C NMR(151MHz,CDCl3)δ158.8(d,J＝243.1 Hz),155.4,154.4,135.7,133.6(d,J＝12.1Hz),130.7,130.1(d,J＝1.5 Hz),129.6,128.1,118.0(d,J＝24.2Hz),115.7(d,J＝21.1Hz),114.6(d, J＝9.1Hz),29.6；MS(ESI):m/z＝255.5[M+H]+.
example 16
1-methyl-6, 7-difluoroquinoxalinone (0.196g, 1.0mmol), bis (4-methyl) phenyliodonium trifluoromethanesulfonate (0.687g, 1.5mmol), triethylamine (0.303g, 3.0mmol), BaTiO were added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, keeping the ball milling rotation speed at 1000 r/min, finishing the reaction after the ball milling is carried out for 90min, after the operation of the ball milling machine is stopped, keeping the temperature of the tank body at about 50 ℃, conducting forced air cooling until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by acetonitrile, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.208g of a yellow solid product, wherein the recrystallization yield of the product is 72.6 percent, and the content of 1-methyl-3- (4-methylphenyl) -6, 7-difluoroquinoxalinone is 98.6 percent by HPLC (high performance liquid chromatography). m.p. 160.1-161.4 ℃;1H NMR(600MHz,CDCl3) δ8.24(d,J＝8.4Hz,2H),7.76-7.73(m,1H),7.30(d,J＝8.4Hz,2H), 7.13(dd,J＝10.8,6.6Hz,1H),3.73(s,3H),2.44(s,3H)；13C NMR(151 MHz,CDCl3)δ154.3,154.2(d,J＝3.0Hz),152.2(d,J＝15.1Hz), 150.5(d,J＝15.1Hz),147.6(d,J＝15.1Hz),146.0(d,J＝13.6Hz), 141.1,132.8,129.2(d,J＝96.6Hz),117.7(d,J＝1.5Hz),117.6(d,J＝ 3.0Hz),102.1(d,J＝22.6Hz),29.8,21.5；MS(ESI):m/z＝287.6 [M+H]+.
example 17
1-methyl-7-chloroquinoxalinone (0.194g, 1.0mmol), diphenyliodonium trifluoromethanesulfonate (0.644g, 1.5mmol), triethylamine (0.303g, 3.0mmol) and BaTiO are added in sequence in a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, placing the ball milling tank in a closed state, keeping the ball milling rotation speed at 800 r/min, finishing the reaction after the ball milling is carried out for 60min, after the operation of the ball milling machine is stopped, carrying out air blast heat dissipation until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by using ethanol, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.178g of a yellow solid product, wherein the recrystallization yield of the product is 66.1%, and the content of the 1-methyl-3-phenyl-7-chloroquinoxalinone is 98.4% by HPLC (high performance liquid chromatography). m.p. 158.1-160.5 ℃;1H NMR(600MHz,CDCl3)δ8.33(dd,J＝7.8,1.8 Hz,2H),7.93(d,J＝2.4Hz,1H),7.53-7.50(m,4H),7.27(d,J＝19.2 Hz,1H),3.75(s,3H)；13C NMR(151MHz,CDCl3)δ155.1,154.3, 135.6,133.6,132.0,130.7,130.2,129.6,129.6,129.0,128.1,114.7,29.5；MS(ESI):m/z＝270.8[M+H]+.
example 18
1-benzyl quinoxalinone (0.236g, 1.0mmol), diphenyliodonium trifluoromethanesulfonate (0.644g, 1.5mmol), triethylamine (0.303g, 3.0mmol) and BaTiO were added in this order to a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, sealing the tank body, placing the tank body in the ball milling machine, enabling the ball milling rotation speed to be 1000 r/min, finishing the reaction after the ball milling is carried out for 90min, enabling the temperature of the tank body to be about 50 ℃ after the ball milling machine stops operating, carrying out air blast heat dissipation until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by using ethyl acetate, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.252g of a yellow solid product, wherein the recrystallization yield of the product is 80.7%, and the content of the 1-benzyl-3-phenylquinoxalinone is 98.8% by HPLC (HPLC). 147.9-149.5 ℃ in m.p.;1H NMR(600MHz,CDCl3)δ8.44-8.41(m,2H),8.00(dd,J＝7.8,1.2 Hz,1H),7.55-7.52(m,3H),7.48-7.46(m,1H),7.37-7.28(m,7H), 5.60(s,2H)；13C NMR(151MHz,CDCl3)δ154.8,154.2,136.0,135.4, 133.4,132.8,130.6,130.5,130.4,129.7,129.0,128.2,127.7,127.0, 123.8,114.4,46.2；MS(ESI):m/z＝312.4[M+H]+.
example 19
1-methyl-6-nitroquinoxalinone (0.205g, 1.0mmol), diphenyliodonium trifluoromethanesulfonate (0.644g, 1.5mmol), triethylamine (0.303g, 3.0mmol) and BaTiO are added in sequence in a 20mL ball mill pot3(particle size is 4 mu m) (1.5g), placing eight stainless steel grinding balls with the diameter of 10mm, sealing a tank body of a ball milling tank after the charging is finished, placing the tank body in the ball milling machine, keeping the ball milling rotating speed at 600 rpm, finishing the reaction after ball milling for 120min, after the operation of the ball milling machine is stopped, keeping the temperature of the tank body at about 50 ℃, conducting forced air heat dissipation until the surface of the tank body is cooled to the room temperature, transferring the reaction mixture by using dichloromethane, filtering out insoluble substances, concentrating the filtrate, recrystallizing by using petroleum ether/ethyl acetate to obtain 0.080g of a yellow solid product, wherein the recrystallization yield of the product is 28.5 percent, and the content of the 1-methyl-3-phenyl-6-nitroquinoxalinone is 97.2 percent through HPLC (high performance liquid chromatography). m.p. 180.4-182.1 deg.C;1H NMR(600MHz,CDCl3)δ8.81(d,J＝2.4 Hz,1H),8.41(dd,J＝9.0,2.4Hz,1H),8.36(d,J＝7.8Hz,2H),7.57- 7.51(m,3H),7.44(d,J＝9.6Hz,1H),3.82(s,3H)；13C NMR(151MHz, CDCl3)δ156.0,154.2,143.4,137.8,135.0,132.1,131.3,129.7,128.2, 126.0,124.6,114.2,29.9；MS(ESI):m/z＝281.6[M+H]+。
Claims (8)
1. a method for synthesizing aryl quinoxaline compounds promoted by mechanical force is characterized by comprising the following steps: adding quinoxaline compound (II) and diaryl iodonium salt (III) into a ball milling pot, adding piezoelectric material, alkali and milling balls, carrying out ball milling reaction, transferring the reaction mixture by using organic solvent after the reaction is finished, filtering insoluble substances, concentrating the filtrate, recrystallizing to obtain the aryl quinoxaline compound shown in formula (I),
wherein, the substituent R1、R2And R3Each independently substituted or unsubstituted, and the substituents R1And R3When substituted, the substituent R is mono-or polysubstituted1Selected from methyl or methoxy, substituent R2Selected from methyl or bromine, substituents R3Selected from methyl, methoxy, fluorine, chlorine or nitro, substituents R4Selected from methyl or benzyl; ar (Ar)1And Ar2Same or different, Ar is Ar1Or Ar2。
2. The method for synthesizing a mechanically accelerated arylquinoxaline compound according to claim 1, wherein Ar is Ar1And Ar2Each independently selected from phenyl or substituted phenyl, the substituent of the substituted phenyl is mono-substituted or multi-substituted, and the substituent is methyl.
3. The method for synthesizing aryl quinoxaline compound promoted by mechanical force as claimed in claim 1, wherein the piezoelectric material is BaTiO3(particle size: 4 μm), BaTiO3(particle size of 100nm), ZnO or SrTiO3Preferably BaTiO3(particle size: 4 μm).
4. The method for synthesizing a mechanically accelerated arylquinoxaline compound according to claim 1, wherein the quinoxaline compound: diaryl iodonium salts: the quantity ratio of alkali feeding materials is 1: 1.5-3.0: 1 to 4.0, preferably 1: 1.5-2.0: 1.5 to 3.0.
5. The method for synthesizing a mechanically accelerated arylquinoxaline compound according to claim 1 or 3, wherein the base is sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium ethoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, DBU or triethylamine.
6. The method for synthesizing aryl quinoxaline compounds promoted by mechanical force according to claim 1, wherein the grinding ball is made of metal, agate or zirconia, the metal comprises stainless steel or copper, and the diameter of the grinding ball is 10 mm.
7. The method for synthesizing arylquinoxaline compounds according to claim 1, wherein the ball milling reaction is performed at a ball milling rotation speed of 600 to 1000 rpm for 1.0 to 2.0 hours, and after the ball milling is stopped, air is blown to release heat until the surface of the can body is cooled to room temperature, preferably at 800 to 1000 rpm for 1.5 to 2.0 hours.
8. The method for synthesizing aryl quinoxaline compounds promoted by mechanical force according to claim 1, wherein the organic solvent is acetonitrile, ethyl acetate, dichloromethane or alcohol of C1-C6, preferably ethyl acetate or dichloromethane.
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