CN104447539B - A kind of two grades, the synthetic method of three-level aromatic amides - Google Patents
A kind of two grades, the synthetic method of three-level aromatic amides Download PDFInfo
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- CN104447539B CN104447539B CN201410634539.2A CN201410634539A CN104447539B CN 104447539 B CN104447539 B CN 104447539B CN 201410634539 A CN201410634539 A CN 201410634539A CN 104447539 B CN104447539 B CN 104447539B
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- methyl
- ring
- quinoline
- reaction
- acid
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- 150000008430 aromatic amides Chemical class 0.000 title claims abstract description 20
- 238000010189 synthetic method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000010949 copper Substances 0.000 claims abstract description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 14
- 239000001301 oxygen Substances 0.000 claims abstract description 14
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 229910052802 copper Inorganic materials 0.000 claims abstract description 13
- 150000001412 amines Chemical class 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- 239000007848 Bronsted acid Substances 0.000 claims abstract description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- -1 amino, trimethyl-acetyl Chemical group 0.000 claims description 15
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical class C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 238000007789 sealing Methods 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 238000005292 vacuum distillation Methods 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical group C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- ALHUXMDEZNLFTA-UHFFFAOYSA-N 2-methylquinoxaline Chemical compound C1=CC=CC2=NC(C)=CN=C21 ALHUXMDEZNLFTA-UHFFFAOYSA-N 0.000 claims description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- VZWOXDYRBDIHMA-UHFFFAOYSA-N 2-methyl-1,3-thiazole Chemical class CC1=NC=CS1 VZWOXDYRBDIHMA-UHFFFAOYSA-N 0.000 claims description 2
- DXDPHHQJZWWAEH-UHFFFAOYSA-N 2-methyl-6-nitroquinoline Chemical class C1=C([N+]([O-])=O)C=CC2=NC(C)=CC=C21 DXDPHHQJZWWAEH-UHFFFAOYSA-N 0.000 claims description 2
- DXYYSGDWQCSKKO-UHFFFAOYSA-N 2-methylbenzothiazole Chemical class C1=CC=C2SC(C)=NC2=C1 DXYYSGDWQCSKKO-UHFFFAOYSA-N 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- COCFIBRMFPWUDW-UHFFFAOYSA-N 2-methylquinolin-4-amine Chemical class C1=CC=CC2=NC(C)=CC(N)=C21 COCFIBRMFPWUDW-UHFFFAOYSA-N 0.000 claims description 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- OCCIBGIEIBQGAJ-UHFFFAOYSA-N 6-chloro-2-methylquinoline Chemical class C1=C(Cl)C=CC2=NC(C)=CC=C21 OCCIBGIEIBQGAJ-UHFFFAOYSA-N 0.000 claims description 2
- NAGJQQFMJKMXJQ-UHFFFAOYSA-N 6-methoxy-2-methylquinoline Chemical class N1=C(C)C=CC2=CC(OC)=CC=C21 NAGJQQFMJKMXJQ-UHFFFAOYSA-N 0.000 claims description 2
- OQXVXPBDSJQYRR-UHFFFAOYSA-N 8-methoxy-2-methylquinoline Chemical class C1=C(C)N=C2C(OC)=CC=CC2=C1 OQXVXPBDSJQYRR-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 229960004365 benzoic acid Drugs 0.000 claims description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 150000003983 crown ethers Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical class CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 claims description 2
- 229950002366 nafoxidine Drugs 0.000 claims description 2
- FUTDPDUVTNANNA-UHFFFAOYSA-N nitromethyl formate Chemical compound [O-][N+](=O)COC=O FUTDPDUVTNANNA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 claims 1
- SQRYQSKJZVQJAY-UHFFFAOYSA-N 6-bromo-2-methylquinoline Chemical class C1=C(Br)C=CC2=NC(C)=CC=C21 SQRYQSKJZVQJAY-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 5
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract description 4
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 230000004913 activation Effects 0.000 abstract description 2
- 239000000654 additive Substances 0.000 abstract description 2
- 230000000996 additive effect Effects 0.000 abstract description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 abstract 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 abstract 2
- 229960003966 nicotinamide Drugs 0.000 abstract 1
- 235000005152 nicotinamide Nutrition 0.000 abstract 1
- 239000011570 nicotinamide Substances 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 230000005311 nuclear magnetism Effects 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- ZEXKKIXCRDTKBF-UHFFFAOYSA-N quinoline-2-carboxamide Chemical compound C1=CC=CC2=NC(C(=O)N)=CC=C21 ZEXKKIXCRDTKBF-UHFFFAOYSA-N 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 4
- 238000007306 functionalization reaction Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 150000008422 chlorobenzenes Chemical class 0.000 description 2
- 125000000068 chlorophenyl group Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- KUDPGZONDFORKU-UHFFFAOYSA-N n-chloroaniline Chemical compound ClNC1=CC=CC=C1 KUDPGZONDFORKU-UHFFFAOYSA-N 0.000 description 2
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical group COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 1
- 0 C*1CC/C(/C(N(C)*)=O)=N\CCC1 Chemical compound C*1CC/C(/C(N(C)*)=O)=N\CCC1 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000165940 Houjia Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001124569 Lycaenidae Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000014987 copper Nutrition 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 229960004643 cupric oxide Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- QZRJWCCFONJIMC-UHFFFAOYSA-N n-phenylquinoline-2-carboxamide Chemical class C=1C=C2C=CC=CC2=NC=1C(=O)NC1=CC=CC=C1 QZRJWCCFONJIMC-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical class CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Quinoline Compounds (AREA)
- Catalysts (AREA)
Abstract
Two grades, the synthetic methods of three-level aromatic amides formed by the direct function dough of methyl the invention provides a kind of.This method is using 2 methyl N heterocyclic aromatic compounds and amine source as raw material, using metallic copper as catalyst, and bronsted acid is additive, with molecule O2(oxygen) is oxidant, passes through the sp of 2 methyl N heterocyclic aromatic compounds of activation under oxygen atmosphere3C H keys generate corresponding aldehyde, aldehyde and the reaction of different amine sources generation two grades or three-level aromatic amides.The method is characterized in that with cheap metallic copper as catalyst, 2 methyl N heterocyclic aromatic compounds of commercialization are substrate, molecule O2(oxygen) is that oxidant carries out oxidized nicotinamide reaction.This method reaction condition is gentle, and simple to operate, applicability is good, with good prospects for commercial application.
Description
【Technical field】
The present invention relates to organic synthesis field, and in particular to a kind of to form two grades, three-level virtue by the direct function dough of methyl
The synthetic method of fragrant acid amides.
【Background technology】
Amido link is one of most common functional group in pharmaceutical synthesis, fine chemistry industry and high polymer material, according to statistics result
Being showed more than 25% fragrant medicine has amide functional group.Therefore, the synthesis of aromatic amides is always not only biology
Learn the emphasis paid close attention to pharmaceutical field, even more one of heat subject of organic synthesis and the research of other industrial circles.
For the synthesis of two grades or three-level aromatic amides, most traditional synthetic method be no more than by carboxylic acid or
Not only there is the not high defect of Atom economy but also produce the accessory substance shadow of equivalent in the reaction of carboxylic acid derivates and amine, this method
Ring the speed of reaction.Because two grades or three-level amide compound have very high value, for many years for build two grades or
The work of three-level amide compound never stopped.In recent years, research worker updates from raw material and catalyst, successively
Report is on two grades or three-level aromatic amides synthetic method:(1) C.Ramalingan and Y.Park utilizes improved
Conventional method Beckmann rearrangement reaction synthesizing secondary aromatic amides, although overcome traditional harsh conditions, such as avoid making
With substantial amounts of strong acid and very high reaction temperature, but need the larger HgCl of toxicity2Make catalyst；(2) Y.J.Wu et al.
Probe into the amidation process of aldehyde and amine, undeniably have high conversion advantage, yet with aldehyde characteristic, long Kubo
Deposit and using being enough to allow people worried；(3) B.Roberts and D.Liptrot et al. have found that amino can be carried out using halogenated aryl hydrocarbon
Carboxylation reaction obtains two grades of aromatic amides, but this method not only need transition metal make catalyst and also need substantial amounts of alkali with
And the participation of part；(4) A.J.A.Watson and A.C.Maxwell carries out two grades of oxidation generation or three-level fragrance using alkohol and amine
Amide compound, accessory substance only hydrogen generation still needs noble metal to make catalyst (such as at present：Ruthenium).The above method is not
Defect is only individually present, and they have a common conversion or activation being disadvantageous in that dependent on feature functional group
Functional group.It is well known that c h bond is the chemical bond of most generally existing in the boundless universe.
Thus, develop under a kind of temperate condition and two grades or three-level aromatic amides are efficiently directly prepared by c h bond functionalization
The method of compound, is most direct and optimal synthetic method, is also one of technical barrier of organic synthesis solution too impatient to wait.
(bibliography：a)Y.Y.Lai,L.J.Huang,K.H.Lee,Z.Y.Xiao,K.F.Bastow,T.Yamoric,S.C.Kuo,
Bioorg.Med.Chem.2005,13 265；b)N.A.Owston,A.J.Parker,J.M.Williams,
Org.Lett.2007,9,3599；c)Y.J.Wu,S.W.Wang,L.J.Zhang,G.S.Yang,X.C.Zhu,Z.H.Zhou,
H.Zhu,S.H.Wu,Eur.J.Org.Chem.2010,326；d)B.Roberts,D.Liptrot,L.Alcaraz,T.Luker,
M.J.Stocks,Org.Chem.2010,75,8410；e)A.J.A.Watson,A.C.Maxwell,J.M.J.Williams,
Org.Lett,2009,11,2667.)
The present invention provides one kind by the direct functionalization of methyl, and metal copper catalysis, mild condition, simple to operate, raw material are easy to get
And high applicability prepares the synthetic method of two grades or three-level aromatic amides.
【The content of the invention】
The purpose of the present invention is that development is a kind of by the direct functionalization of methyl, and catalyst, bronsted acid are made of metallic copper and is done
Additive, 2- methyl-N- heterocyclic aromatic compounds cheap and easy to get and source of ammonium are raw material, and oxidant, high applicability are done from oxygen
The method for preparing two grades or three-level aromatic amides.
The goal of the invention of the present invention is realized by following technical method：
A kind of two grades as shown in structure formula (I) or the synthetic method of three-level aromatic amides,
Include following operating procedure：
It will be equipped with metal copper catalyst, bronsted acid, amine source, 2- methyl-N- heterocyclic aromatic compoundsReaction vessel vacuumize, fill oxygen, then add organic solvent sealing；It is heated to 100~150
DEG C reaction 8~24h, reaction terminate after be cooled to room temperature, washed with saturated sodium bicarbonate, then with chloroform extraction, dry,
Vacuum distillation concentration removes solvent, and crude product produces target product through pillar layer separation.
Wherein described N- heterocycles are pyridine ring, thiazole ring, pyrazine ring, benzothiazole ring, quinoxaline ring, quinoline ring or luxuriant and rich with fragrance hello
Quinoline ring；
The R1For amino, trimethyl-acetyl, methyl, fluorine, chlorine, bromine, nitro, methyl formate base or methoxyl group；
When structure formula (I) is two grades of aromatic amides, corresponding R2For hydrogen, R3For phenyl, 2- methoxyphenyls, 2- chlorobenzenes
Base, 4- aminomethyl phenyls, 4- chlorphenyls, 4- nitrobenzophenones, isopropyl or normal-butyl；
When structure formula (I) is three-level aromatic amides, R2It is not hydrogen, R2、R3Piperidine ring, morpholine are formed together with connected N
Ring or nafoxidine ring.
Further, described metal copper catalyst, bronsted acid, 2- methyl-N- heterocyclic aromatic compounds and amine source
Mol ratio be [0.05~0.2]:[0.5~1.0]：1：[1.0~2.0].
The organic solvent is to be selected from 1,4- dioxane, N,N-dimethylformamide, chlorobenzene, methyl phenyl ethers anisole, toluene or four
The one or more of hydrogen furans.
Further, described metal copper catalyst is to be selected from Cu, CuBr, CuCl, CuI, Cu (OAc)2、CuBr2、CuI2、
CuO or Cu (OTf)2One or more.
Further, described bronsted acid is to be selected from acetic acid, benzoic acid, phenylacetic acid, benzene sulfonic acid or diphenylphosphoric acid
One or more.
Further, described amine source is selected from aniline, paranitroanilinum, parachloroanilinum, open-chain crown ether, adjacent chlorobenzene
Amine, o-aminoanisole, isopropylamine, n-butylamine, piperidines, morpholine or nafoxidine.
Further, the 2- methyl-N- heterocyclic aromatic compounds (II) be selected from 2- picolines, 2- methylthiazols,
2- methylpyrazines, 2- methylbenzothiazoles, 2- methyl-quinoxalines, 2- methylquinolines, 2- methyl -4- aminoquinolines, 2- methyl -4-
Pivaloyl amido quinoline, 2,6- dimethyl quinolines, 2- methyl -6- fluorine quinoline, 2- methyl -6- chloroquinolines, 2- methyl -6- bromines
Quinoline, 2- methyl -6- nitroquinolines, 2- methyl -6- methyl formate bases quinoline, 2- methyl -6- methoxy quinolines, 2- methyl -8-
Methoxy quinoline or 2,9- dimethyl -1,10- ferrosins.
The present invention provides a kind of directly by methyl functionalization, and metal copper catalysis, mild condition, simple to operate, raw material are easy to get
And high applicability prepares the synthetic method of two grades or three-level aromatic amides, with good prospects for commercial application.
【Brief Description Of Drawings】
Fig. 1 is two grades provided of the invention or the synthesis path figure of three-level aromatic amides class compound.
【Embodiment】
Synthetic method of the present invention is described further with reference to the synthesis example of the present invention, it is necessary to illustrate
It is that embodiment does not constitute the limitation to the claimed scope of the invention：
Synthesis example 1
The synthesis of N- phenylchinoline -2- formamides
10mol% cuprous iodide is added in reaction vessel, is vacuumized, oxygen is backfilled, 0.2mmol vinegar is then added
Acid, 0.2mmol 2- methylquinolines, 0.4mmol aniline and 1mL methyl phenyl ethers anisoles, sealing；Reaction 24h. at 100 DEG C is heated to treat instead
Answer liquid to be cooled to room temperature, washed with saturated sodium bicarbonate solution, then with chloroform extraction, dried, vacuum distillation concentration is removed
Solvent is removed, crude product produces target product through pillar layer separation, and yield is 69%.Examined through nuclear-magnetism without other impurities residual.1H
NMR(400MHz,CDCl3) δ 10.24 (s, 1H), 8.35-8.42 (m, 2H), 8.19 (d, J=8.4Hz, 1H), 7.79-7.92
(m,4H),7.65(dd,J1=J2=8.0Hz, 1H), 7.42 (dd, J1=J2=8.0Hz, 2H), 7.17 (t, J=7.6Hz,
1H)；13C NMR(100MHz,CDCl3)δ162.18,149.68,146.31,137.87,137.80,130.33,129.68,
129.44,129.12,128.17,127.83,124.36,119.79,118.77.
Synthesis example 2
The synthesis of N- (4- methylphenyls) quinoline-2-formamide
The protobromide of 0.4mmol 4- methylanilines, 0.2mmol diphenylphosphoric acids and 10mol% is added in reaction vessel
Copper and 10mol% copper powders, are vacuumized, and backfill oxygen, then add 0.2mmol 2- methylquinolines and 0.5mL Isosorbide-5-Nitraes-dioxy six
Ring and 0.5mL methyl phenyl ethers anisoles, sealing；It is heated to reaction 8h. question response liquid at 130 DEG C and is cooled to room temperature, it is molten with saturated sodium bicarbonate
Liquid is washed, then with chloroform extraction, is dried, and vacuum distillation concentration removes solvent, and crude product produces mesh through pillar layer separation
Product is marked, yield is 60%.Examined through nuclear-magnetism without other impurities residual.1H NMR(400MHz,CDCl3)δ10.18(s,1H),
8.35-8.41 (m, 2H), 8.18 (d, J=8.4Hz, 1H), 7.91 (d, J=8.0Hz, 1H), 7.80 (dd, J1=J2=8.0Hz,
1H), 7.74 (d, J=8.4Hz, 2H), 7.65 (dd, J1=J2=8.0Hz, 1H), 7.22 (d, J=8.4Hz, 2H), 2.36 (s,
3H)；13C NMR(100MHz,CDCl3)δ162.04,149.83,146.33,137.83,135.29,133.98,130.30,
129.68,129.63,129.41,128.10,127.83,119.77,119.68,118.78,20.97.
Synthesis example 3
The synthesis of N- (2- methoxyl groups-phenyl) quinoline-2-formamide
0.1mmol benzoic acid and 20mol% stannous chloride are added in reaction vessel, is vacuumized, oxygen is backfilled, then
Add 0.2mmol 2- methylquinolines, 0.2mmol 2- aminoanisoles and 1mL chlorobenzenes, sealing；It is heated to react at 100 DEG C
24h. question response liquid is cooled to room temperature, is washed with saturated sodium bicarbonate solution, then with chloroform extraction, dries, and decompression is steamed
Evaporate concentration and remove solvent, crude product produces target product through pillar layer separation, and yield is 34%.Examined through nuclear-magnetism without other impurities
Residual.1H NMR(400MHz,CDCl3)δ10.82(s,1H),8.65(dd,J1=1.6Hz, J2=8.0Hz, 1H), 8.34-
8.41 (m, 2H), 8.21 (d, J=8.4Hz, 1H), 7.90 (d, J=8.4Hz, 1H), 7.79 (dd, J1=J2=8.0Hz, 1H),
7.64(dd,J1=J2=7.6Hz, 1H), 7.03-7.13 (m, 2H), 6.96-6.98 (dd, J1=1.2Hz, J2=8.0Hz,
1H),4.02(s,3H)；13C NMR(100MHz,CDCl3)δ162.19,150.19,148.92,146.43,137.68,
130.12,130.01,129.36,128.04,127.76,127.65,124.02,121.14,119.80,118.80,110.20
Synthesis example 4
The synthesis of N- (the chloro- phenyl of 2-) quinoline-2-formamide
0.2mmol benzene sulfonic acids and 10mol% copper acetate are added in reaction vessel, is vacuumized, oxygen, Ran Houjia is backfilled
Enter the chloro- aniline of 0.4mmol 2-, 0.2mmol 2- methylquinolines and 1mL toluene, seal；Reaction 12h. at 140 DEG C is heated to treat
Reaction solution is cooled to room temperature, is washed with saturated sodium bicarbonate solution, then with chloroform extraction, dries, vacuum distillation concentration
Solvent is removed, crude product produces target product through pillar layer separation, and yield is 67%.Examined through nuclear-magnetism without other impurities residual.1H NMR(400MHz,CDCl3) δ 10.98 (s, 1H), 8.70 (d, J=8.4Hz, 1H), 8.38 (b, 2H), 8.21 (d, J=
8.4Hz, 1H), 7.91 (d, J=8.0Hz, 1H), 7.81 (dd, J1=J2=8.0Hz, 1H), 7.66 (dd, J1=J2=7.6Hz,
1H), 7.46 (d, J=8.0Hz, 1H), 7.36 (dd, J1=J2=8.0Hz, 1H), 7.09 (ddd, J1=1.2Hz, J2=
7.6Hz,J2=7.6Hz, 1H)；13C NMR(100MHz,CDCl3)δ162.35,149.47,146.35,137.89,134.84,
130.35,130.08,129.51,129.27,128.33,127.79,127.73,124.62,123.58,121.02,118.65.
Synthesis example 5
The synthesis of N- (the chloro- phenyl of 4-) quinoline-2-formamide
Add the chloro- aniline of 0.4mmol 4- in reaction vessel, 0.1mmol phenylacetic acids and 0.1mmol diphenylphosphoric acids and
10mol% copper bromide and 10mol% cupric iodides, is vacuumized, backfill oxygen, then add 0.2mmol 2- methylquinolines and
1mL N, N- dimethyl formyls are pressed, sealing；It is heated to reaction 19h. question response liquid at 130 DEG C and is cooled to room temperature, uses ammonia saturated carbon
Sour hydrogen sodium solution washing, then with chloroform extraction, is dried, and vacuum distillation concentration removes solvent, and crude product is through column chromatography point
From target product is produced, yield is 66%.Examined through nuclear-magnetism without other impurities residual.1H NMR(400MHz,CDCl3)δ10.25
(s, 1H), 8.38 (b, 2H), 8.18 (d, J=8.4Hz, 1H), 7.92 (d, J=7.6Hz, 1H), 7.80-7.84 (m, 3H),
7.67(dd,J1=J2=8.0Hz, 1H), 7.38 (d, J=8.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ162.21,
149.37,146.30,137.99,136.41,130.45,129.65,129.51,129.30,129.15,128.30,127.87,
120.98,118.72.
Synthesis example 6
The synthesis of N- (4- nitro-phenyls) quinoline-2-formamide
0.4mmol 4- nitro-analines, 0.2mmol diphenylphosphoric acids and 20mol% iodate are added in reaction vessel
It is cuprous, vacuumize, backfill oxygen, then add 0.2mmol 2- methylquinolines and 1mL methyl phenyl ethers anisoles, sealing；It is heated at 150 DEG C
Reaction 24h. question response liquid is cooled to room temperature, is washed with saturated sodium bicarbonate solution, then with chloroform extraction, dries, subtracts
Distillation and concentration is pressed to remove solvent, crude product produces target product through pillar layer separation, and yield is 39%.Examined through nuclear-magnetism without other
Impurity is remained.1H NMR(400MHz,CDCl3) δ 10.59 (s, 1H), 8.38-8.43 (m, 2H), 8.31 (d, J=9.2Hz, 2H),
8.21 (d, J=8.4Hz, 1H), 8.04 (d, J=9.2Hz, 2H), 7.95 (d, J=8.4Hz, 1H), 7.85 (dd, J1=J2=
8.0Hz,1H),7.70(dd,J1=J2=8.0Hz, 1H)；13C NMR(100MHz,CDCl3)δ162.60,148.65,146.26,
143.65,143.53,138.28,130.72,129.71,129.65,128.68,127.94,125.25,119.25,118.71.
Synthesis example 7
The synthesis of N- isopropyls-quinoline-2-formamide
0.2mmol diphenylphosphoric acids and 10mol% cuprous iodide and 5mol% cupric oxide are added in reaction vessel, is taken out
Vacuum, backfills oxygen, then adds 0.4mmol isopropylamines, 0.2mmol 2- methylquinolines and 1mL chlorobenzenes and 1mL tetrahydrofurans,
Sealing；It is heated to reaction 15h. question response liquid at 100 DEG C and is cooled to room temperature, is washed with saturated sodium bicarbonate solution, then with three
Chloromethanes is extracted, and is dried, and vacuum distillation concentration removes solvent, and crude product produces target product through pillar layer separation, and yield is
29%.Examined through nuclear-magnetism without other impurities residual.1H NMR(400MHz,CDCl3)δ8.29-8.33(m,2H),8.11-8.13
(m, 2H), 7.88 (d, J=8.4Hz, 1H), 7.74-7.79 (m, 1H), 7.59-7.63 (m, 1H), 4.30-4.39 (m, 1H),
1.35 (d, J=6.4Hz)；13C NMR(100MHz,CDCl3)δ163.58,150.06,146.48,137.44,130.02,
129.65,129.28,127.79,127.77,118.86,41.56,22.85.
Synthesis example 8
The synthesis of (piperidines -1)-(quinoline -2)-ketone
0.2mmol benzoic acid and 15mol% trifluoracetic acid coppers are added in reaction vessel, is vacuumized, oxygen is backfilled, then
Add 0.4mmol piperidines, 0.2mmol 2- methylquinolines and 1mL methyl phenyl ethers anisoles, sealing；Reaction 12h. at 130 DEG C is heated to treat instead
Answer liquid to be cooled to room temperature, washed with saturated sodium bicarbonate solution, then with chloroform extraction, dried, vacuum distillation concentration is removed
Solvent is removed, crude product produces target product through pillar layer separation, and yield is 41%.Examined through nuclear-magnetism without other impurities residual.1H
NMR(400MHz,CDCl3) δ 8.25 (d, J=8.4Hz, 1H), 8.11 (d, J=8.4Hz, 1H), 7.85 (d, J=8.0Hz,
1H), 7.74-7.78 (m, 1H), 7.66 (d, J=8.0Hz, 1H), 7.58-7.62 (m, 1H), 3.81 (t, J=5.2Hz, 2H),
3.52 (t, J=5.2Hz, 2H), 1.73 (b, 6H)；13C NMR(100MHz,CDCl3)δ167.60,154.42,146.79,
137.12,130.00,129.74,127.94,127.65,127.38,120.41,48.35,43.36,26.52,25.60,
24.60.
Claims (3)
1. the synthetic method of two grade or three-level aromatic amides of the one kind with following structural formula (I),
Include following reactions steps：
Metal copper catalyst, bronsted acid, amine source, the reaction vessel of 2- methyl-N- heterocyclic aromatic compounds is will be equipped with to take out very
Sky, fills oxygen, then adds organic solvent sealing；100~150 DEG C of 8~24h of reaction are heated to, reaction is cooled to after terminating
Room temperature, is washed with saturated sodium bicarbonate, then with chloroform extraction, is dried, and vacuum distillation concentration removes solvent, crude product warp
Pillar layer separation, produces target product；
The equation of the synthetic method is：
The N- heterocycles are to be selected from pyridine ring, thiazole ring, pyrazine ring, benzothiazole ring, quinoxaline ring, quinoline ring or ferrosin
Ring；
The R1It is to be selected from amino, trimethyl-acetyl, methyl, fluorine, chlorine, bromine, nitro, methyl formate base or methoxyl group；
Work as R2When being hydrogen, R3Be phenyl, 2- methoxyphenyls, 2- chlorphenyls, 4- aminomethyl phenyls, 4- chlorphenyls, 4- nitrobenzophenones or
Isopropyl or normal-butyl；
Work as R2When being not hydrogen, R2、R3Piperidine ring, morpholine ring or nafoxidine ring are formed together with connected N；
The organic solvent is to be selected from 1,4- dioxane, N,N-dimethylformamide, chlorobenzene, methyl phenyl ethers anisole, toluene or tetrahydrochysene furan
The one or more muttered；
Described metal copper catalyst is to be selected from Cu, CuBr, CuCl, CuI, Cu (OAc)2、CuBr2、CuI2, CuO or Cu (OTf)2
One or more；
Described bronsted acid be selected from acetic acid, benzoic acid, phenylacetic acid, benzene sulfonic acid or diphenylphosphoric acid it is one or two kinds of with
On；
Described amine source is to be selected from aniline, paranitroanilinum, parachloroanilinum, open-chain crown ether, o-chloraniline, O-methoxy benzene
Amine, isopropylamine, n-butylamine, piperidines, morpholine or nafoxidine.
2. two grades according to claim 1 or the synthetic method of three-level aromatic amides, it is characterised in that described
Metal copper catalyst, bronsted acid, 2- methyl-N- heterocyclic aromatic compounds and the mol ratio in amine source are [0.05~0.2]:
[0.5~1.0]：1：[1.0~2.0].
3. two grades according to claim 1 or the synthetic method of three-level aromatic amides, it is characterised in that described
2- methyl-N- heterocyclic aromatic compounds are selected from 2- picolines, 2- methylthiazols, 2- methylpyrazines, 2- methylbenzothiazoles, 2-
Methyl-quinoxaline, 2- methylquinolines, 2- methyl -4- aminoquinolines, 2- methyl -4- pivaloyl amidos quinoline, 2,6- diformazans
Base quinoline, 2- methyl -6- fluorine quinoline, 2- methyl -6- chloroquinolines, 2- methyl -6- bromoquinolines, 2- methyl -6- nitroquinolines, 2- first
Base -6- methyl formate bases quinoline, 2- methyl -6- methoxy quinolines, 2- methyl -8- methoxy quinolines or 2,9- dimethyl -1,10-
Ferrosin.
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