CN104447539B - 一种二级、三级芳香酰胺化合物的合成方法 - Google Patents
一种二级、三级芳香酰胺化合物的合成方法 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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- Prior art keywords
- methyl
- ring
- acid
- quinoline
- synthetic method
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- 150000008430 aromatic amides Chemical class 0.000 title claims description 9
- 238000010189 synthetic method Methods 0.000 title claims description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- -1 aromatic amide compounds Chemical group 0.000 claims abstract description 20
- 239000010949 copper Substances 0.000 claims abstract description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000001301 oxygen Substances 0.000 claims abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001412 amines Chemical class 0.000 claims abstract description 11
- 229910052802 copper Inorganic materials 0.000 claims abstract description 11
- 229910052751 metal Inorganic materials 0.000 claims abstract description 11
- 239000002184 metal Substances 0.000 claims abstract description 11
- 239000007848 Bronsted acid Substances 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical class C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 claims description 19
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 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
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910021595 Copper(I) iodide Inorganic materials 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
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-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
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- ALHUXMDEZNLFTA-UHFFFAOYSA-N 2-methylquinoxaline Chemical compound C1=CC=CC2=NC(C)=CN=C21 ALHUXMDEZNLFTA-UHFFFAOYSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 claims description 3
- DXYYSGDWQCSKKO-UHFFFAOYSA-N 2-methylbenzothiazole Chemical class C1=CC=C2SC(C)=NC2=C1 DXYYSGDWQCSKKO-UHFFFAOYSA-N 0.000 claims description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical class CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 claims description 3
- 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
- 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
- SQRYQSKJZVQJAY-UHFFFAOYSA-N 6-bromo-2-methylquinoline Chemical class C1=C(Br)C=CC2=NC(C)=CC=C21 SQRYQSKJZVQJAY-UHFFFAOYSA-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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-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
- 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
- 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
- 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 6
- 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 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims 2
- 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 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims 1
- 150000003983 crown ethers Chemical class 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 229950002366 nafoxidine Drugs 0.000 claims 1
- 150000003053 piperidines Chemical class 0.000 claims 1
- 238000007789 sealing Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 238000005292 vacuum distillation Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- 238000007306 functionalization reaction Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 150000001299 aldehydes Chemical class 0.000 abstract description 3
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 239000000654 additive Substances 0.000 abstract description 2
- 230000000996 additive effect Effects 0.000 abstract description 2
- 238000007112 amidation reaction Methods 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract 3
- 239000000758 substrate Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000004440 column chromatography Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 238000007689 inspection Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- JJPSZKIOGBRMHK-UHFFFAOYSA-N 2,6-dimethylquinoline Chemical compound N1=C(C)C=CC2=CC(C)=CC=C21 JJPSZKIOGBRMHK-UHFFFAOYSA-N 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 150000003334 secondary amides Chemical class 0.000 description 2
- HCAIPPMINDHAHV-UHFFFAOYSA-N 2,6-dimethylquinoline-3-carboxylic acid Chemical compound N1=C(C)C(C(O)=O)=CC2=CC(C)=CC=C21 HCAIPPMINDHAHV-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- GPIARMSVZOEZCV-UHFFFAOYSA-N 6-fluoro-2-methylquinoline Chemical compound C1=C(F)C=CC2=NC(C)=CC=C21 GPIARMSVZOEZCV-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
- 239000005751 Copper oxide Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical group C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical group 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
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000021523 carboxylation Effects 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
- 239000012141 concentrate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 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
- JIDMEYQIXXJQCC-UHFFFAOYSA-L copper;2,2,2-trifluoroacetate Chemical compound [Cu+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F JIDMEYQIXXJQCC-UHFFFAOYSA-L 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- PHAVLZCLRNUYKA-UHFFFAOYSA-N n-(2-chlorophenyl)quinoline-2-carboxamide Chemical compound ClC1=CC=CC=C1NC(=O)C1=CC=C(C=CC=C2)C2=N1 PHAVLZCLRNUYKA-UHFFFAOYSA-N 0.000 description 1
- LYKNLZIPXGRGDI-UHFFFAOYSA-N n-(2-methoxyphenyl)quinoline-2-carboxamide Chemical compound COC1=CC=CC=C1NC(=O)C1=CC=C(C=CC=C2)C2=N1 LYKNLZIPXGRGDI-UHFFFAOYSA-N 0.000 description 1
- GGVUUHOQVQLSMP-UHFFFAOYSA-N n-(4-chlorophenyl)quinoline-2-carboxamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1=CC=C(C=CC=C2)C2=N1 GGVUUHOQVQLSMP-UHFFFAOYSA-N 0.000 description 1
- CHAMDSHHLSPFOW-UHFFFAOYSA-N n-(4-methylphenyl)quinoline-2-carboxamide Chemical compound C1=CC(C)=CC=C1NC(=O)C1=CC=C(C=CC=C2)C2=N1 CHAMDSHHLSPFOW-UHFFFAOYSA-N 0.000 description 1
- KDMFKOCHLDSHAO-UHFFFAOYSA-N n-(4-nitrophenyl)quinoline-2-carboxamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1NC(=O)C1=CC=C(C=CC=C2)C2=N1 KDMFKOCHLDSHAO-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QZRJWCCFONJIMC-UHFFFAOYSA-N n-phenylquinoline-2-carboxamide Chemical compound C=1C=C2C=CC=CC2=NC=1C(=O)NC1=CC=CC=C1 QZRJWCCFONJIMC-UHFFFAOYSA-N 0.000 description 1
- MWZFFJAEAZQGLX-UHFFFAOYSA-N n-propan-2-ylquinoline-2-carboxamide Chemical compound C1=CC=CC2=NC(C(=O)NC(C)C)=CC=C21 MWZFFJAEAZQGLX-UHFFFAOYSA-N 0.000 description 1
- IYRGXJIJGHOCFS-UHFFFAOYSA-N neocuproine Chemical compound C1=C(C)N=C2C3=NC(C)=CC=C3C=CC2=C1 IYRGXJIJGHOCFS-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 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
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000002360 preparation method Methods 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
- 239000000126 substance Substances 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- 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)
- Catalysts (AREA)
- Quinoline Compounds (AREA)
Abstract
本发明提供了一种由甲基直接官能团化形成二级、三级芳香酰胺化合物的合成方法。该方法以2‑甲基‑N‑杂环芳香化合物与胺源为原料，以金属铜为催化剂，布朗斯特酸为添加剂，以分子O2(氧气)为氧化剂，在氧气氛围下通过活化2‑甲基‑N‑杂环芳香化合物的sp3C‑H键生成相应的醛，醛与不同胺源反应生成二级或三级芳香酰胺化合物。该方法的特征在于用价格低廉的金属铜作为催化剂，商业化2‑甲基‑N‑杂环芳香化合物为底物，分子O2(氧气)为氧化剂进行氧化酰胺化反应。该方法反应条件温和，操作简单，适用性好，具有良好的工业应用前景。
Description
【技术领域】
本发明涉及有机合成领域，具体涉及一种由甲基直接官能团化形成二级、三级芳香酰胺的合成方法。
【背景技术】
酰胺键在药物合成、精细化工和高分子材料是最常见的官能团之一，据统计结果显示超过25％的芳香药物具有酰胺官能团。因此，芳香酰胺化合物的合成不仅一直是生物学和药学领域关注的重点，更是有机合成及其他工业领域研究的热门课题之一。
对于二级或三级芳香酰胺化合物的合成而言，最传统的合成方法莫过于由羧酸或羧酸衍生物与胺的反应，该方法不但存在原子经济性不高的缺陷而且产生当量的副产物影响反应的速率。由于二级或三级酰胺化合物有很高的利用价值，许多年来对于构建二级或三级酰胺化合物的工作从未停止过。近年来，研究工作者从原料和催化剂上不断改进，陆续报道关于二级或三级芳香酰胺化合物合成方法:(1)C.Ramalingan和Y.Park利用改良过的传统方法Beckmann重排反应合成二级芳香酰胺，虽然克服了传统的苛刻条件，比如避免使用大量的强酸以及很高的反应温度，但是需要毒性较大的HgCl2做催化剂；(2)Y.J.Wu等人探究醛和胺的酰胺化反应，不可否认具有高转化率的优势，然而由于醛内在的特性，长久保存和使用足以让人苦恼；(3)B.Roberts和D.Liptrot等人发现可以利用卤代芳烃进行氨基羧基化反应得到二级芳香酰胺，但该方法不仅需要过渡金属做催化剂而且需要大量的碱以及配体的参与；(4)A.J.A.Watson和A.C.Maxwell利用醇和胺进行氧化生成二级或三级芳香酰胺化合物，副产物只有氢气生成但是目前需要贵金属做催化剂(如：钌)。以上这些方法不仅各自存在缺陷，而且他们有一个共同的不足之处在于依赖于功能性官能团的转化或活化的官能团。众所周知，C-H键是大千世界中最普遍存在的化学键。
因而，开发一种温和条件下直接由C-H键官能化高效制备二级或三级芳香酰胺化合物的方法，是最直接和最理想的合成方法，也是有机合成迫不及待解决的技术难题之一。(参考文献：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.)
本发明提供一种由甲基直接官能化，金属铜催化，条件温和、操作简单、原料易得以及高适用性制备二级或三级芳香酰胺化合物的合成方法。
【发明内容】
本发明的目的是发展一种由甲基直接官能化，用金属铜做催化剂、布朗斯特酸做添加剂，廉价易得2-甲基-N-杂环芳香化合物和铵源为原料，选用氧气做氧化剂，高适用性制备二级或三级芳香酰胺化合物的方法。
本发明的发明目的是通过如下技术方法实现的：
一种如结构式(I)所示的二级或三级芳香酰胺化合物的合成方法，
包含如下操作步骤：
将装有金属铜催化剂、布朗斯特酸、胺源、2-甲基-N-杂环芳香化合物的反应容器抽真空，填充氧气，然后加入有机溶剂密封；加热到100～150℃反应8～24h，反应结束后冷却至室温，用饱和碳酸氢钠洗涤，然后用三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离，即得目标产物。
其中所述N-杂环为吡啶环、噻唑环、吡嗪环、苯并噻唑环、喹喔啉环、喹啉环或菲啰啉环；
所述R1为氨基、三甲基乙酰氨基、甲基、氟、氯、溴、硝基、甲酸甲酯基或甲氧基；
当结构式(I)是二级芳香酰胺时，对应的R2为氢，R3为苯基、2-甲氧基苯基、2-氯苯基、4-甲基苯基、4-氯苯基、4-硝基苯基、异丙基或正丁基；
当结构式(I)是三级芳香酰胺时，R2不是氢，R2、R3与所连的N一起形成哌啶环、吗啉环或四氢吡咯环。
进一步地，所述的金属铜催化剂、布朗斯特酸、2-甲基-N-杂环芳香化合物和胺源的摩尔比为[0.05～0.2]:[0.5～1.0]：1：[1.0～2.0]。
所述有机溶剂是选自1,4-二氧六环、N,N-二甲基甲酰胺、氯苯、苯甲醚、甲苯或四氢呋喃的一种或两种以上。
进一步地，所述的金属铜催化剂是选自Cu、CuBr、CuCl、CuI、Cu(OAc)2、CuBr2、CuI2、CuO或Cu(OTf)2的一种或两种以上。
进一步地，所述的布朗斯特酸是选自醋酸、苯甲酸、苯乙酸、苯磺酸或二苯基磷酸的一种或两种以上。
进一步地，所述的胺源是选自苯胺、对硝基苯胺、对氯苯胺、对甲基苯胺、邻氯苯胺、邻甲氧基苯胺、异丙胺、正丁胺、哌啶、吗啉或四氢吡咯。
进一步地，所述2-甲基-N-杂环芳香化合物(II)是选自2-甲基吡啶、2-甲基噻唑、2-甲基吡嗪、2-甲基苯并噻唑、2-甲基喹喔啉、2-甲基喹啉、2-甲基-4-氨基喹啉、2-甲基-4-三甲基乙酰胺基喹啉、2,6-二甲基喹啉、2-甲基-6-氟喹啉、2-甲基-6-氯喹啉、2-甲基-6-溴喹啉、2-甲基-6-硝基喹啉、2-甲基-6-甲酸甲酯基喹啉、2-甲基-6-甲氧基喹啉、2-甲基-8-甲氧基喹啉或2,9-二甲基-1,10-菲啰啉。
本发明提供一种直接由甲基官能化，金属铜催化，条件温和、操作简单、原料易得以及高适用性制备二级或三级芳香酰胺化合物的合成方法,具有良好工业应用前景。
【附图简要说明】
图1为本发明提供的二级或三级芳香酰胺类化合物的合成路径图。
【具体实施方式】
下面结合本发明的合成例对本发明所述的合成方法作进一步说明，需要说明的是，实施例并不构成对本发明要求保护范围的限制：
合成例1
N-苯基喹啉-2-甲酰胺的合成
在反应容器中加入10mol％的碘化亚铜，抽真空，回填氧气，然后加入0.2mmol醋酸、0.2mmol 2-甲基喹啉，0.4mmol苯胺以及1mL苯甲醚，密封；加热到100℃下反应24h.待反应液冷却至室温，用饱和碳酸氢钠溶液洗涤，然后以三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离即得目标产物，产率为69％。经核磁检验无其他杂质残留。1HNMR(400MHz,CDCl3)δ10.24(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.
合成例2
N-(4-甲基-苯基)喹啉-2-甲酰胺的合成
在反应容器中加入0.4mmol 4-甲基苯胺，0.2mmol二苯基磷酸和10mol％的溴化亚铜和10mol％铜粉，抽真空，回填氧气，然后加入0.2mmol 2-甲基喹啉和0.5mL 1,4-二氧六环和0.5mL苯甲醚，密封；加热到130℃下反应8h.待反应液冷却至室温，用饱和碳酸氢钠溶液洗涤，然后以三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离即得目标产物，产率为60％。经核磁检验无其他杂质残留。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.
合成例3
N-(2-甲氧基-苯基)喹啉-2-甲酰胺的合成
在反应容器中加入0.1mmol苯甲酸和20mol％的氯化亚铜，抽真空，回填氧气，然后加入0.2mmol 2-甲基喹啉，0.2mmol 2-甲氧基苯胺和1mL氯苯，密封；加热到100℃下反应24h.待反应液冷却至室温，用饱和碳酸氢钠溶液洗涤，然后以三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离即得目标产物，产率为34％。经核磁检验无其他杂质残留。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
合成例4
N-(2-氯-苯基)喹啉-2-甲酰胺的合成
在反应容器中加入0.2mmol苯磺酸和10mol％的醋酸铜，抽真空，回填氧气，然后加入0.4mmol 2-氯-苯胺，0.2mmol 2-甲基喹啉和1mL甲苯，密封；加热到140℃下反应12h.待反应液冷却至室温，用饱和碳酸氢钠溶液洗涤，然后以三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离即得目标产物，产率为67％。经核磁检验无其他杂质残留。1H NMR(400MHz,CDCl3)δ10.98(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.
合成例5
N-(4-氯-苯基)喹啉-2-甲酰胺的合成
在反应容器中加入0.4mmol 4-氯-苯胺，0.1mmol苯乙酸和0.1mmol二苯基磷酸和10mol％的溴化铜和10mol％碘化铜，抽真空，回填氧气，然后加入0.2mmol 2-甲基喹啉和1mL N,N-二甲基甲酰按，密封；加热到130℃下反应19h.待反应液冷却至室温，用氨饱和碳酸氢钠溶液洗涤，然后以三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离即得目标产物，产率为66％。经核磁检验无其他杂质残留。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.
合成例6
N-(4-硝基-苯基)喹啉-2-甲酰胺的合成
在反应容器中加入0.4mmol 4-硝基-苯胺，0.2mmol二苯基磷酸和20mol％的碘化亚铜，抽真空，回填氧气，然后加入0.2mmol 2-甲基喹啉和1mL苯甲醚，密封；加热到150℃下反应24h.待反应液冷却至室温，用饱和碳酸氢钠溶液洗涤，然后以三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离即得目标产物，产率为39％。经核磁检验无其他杂质残留。1H NMR(400MHz,CDCl3)δ10.59(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.
合成例7
N-异丙基-喹啉-2-甲酰胺的合成
在反应容器中加入0.2mmol二苯基磷酸和10mol％的碘化亚铜和5mol％氧化铜，抽真空，回填氧气，然后加入0.4mmol异丙胺，0.2mmol 2-甲基喹啉和1mL氯苯和1mL四氢呋喃，密封；加热到100℃下反应15h.待反应液冷却至室温，用饱和碳酸氢钠溶液洗涤，然后以三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离即得目标产物，产率为29％。经核磁检验无其他杂质残留。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.
合成例8
(哌啶-1)-(喹啉-2)-甲酮的合成
在反应容器中加入0.2mmol苯甲酸和15mol％三氟醋酸铜，抽真空，回填氧气，然后加入0.4mmol哌啶，0.2mmol 2-甲基喹啉和1mL苯甲醚，密封；加热到130℃下反应12h.待反应液冷却至室温，用饱和碳酸氢钠溶液洗涤，然后以三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离即得目标产物，产率为41％。经核磁检验无其他杂质残留。1HNMR(400MHz,CDCl3)δ8.25(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)
1.一种具有下述结构式(I)的二级或三级芳香酰胺化合物的合成方法，
包含如下反应步骤：
将装有金属铜催化剂、布朗斯特酸、胺源、2-甲基-N-杂环芳香化合物的反应容器抽真空，填充氧气，然后加入有机溶剂密封；加热到100～150℃反应8～24h，反应结束后冷却至室温，用饱和碳酸氢钠洗涤，然后用三氯甲烷萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离，即得目标产物；
所述合成方法的方程式为：
所述N-杂环是选自吡啶环、噻唑环、吡嗪环、苯并噻唑环、喹喔啉环、喹啉环或菲啰啉环；
所述R1是选自氨基、三甲基乙酰氨基、甲基、氟、氯、溴、硝基、甲酸甲酯基或甲氧基；
当R2是氢时，R3是苯基、2-甲氧基苯基、2-氯苯基、4-甲基苯基、4-氯苯基、4-硝基苯基或异丙基或正丁基；
当R2不是氢时，R2、R3与所连的N一起形成哌啶环、吗啉环或四氢吡咯环；
所述有机溶剂是选自1,4-二氧六环、N,N-二甲基甲酰胺、氯苯、苯甲醚、甲苯或四氢呋喃的一种或两种以上；
所述的金属铜催化剂是选自Cu、CuBr、CuCl、CuI、Cu(OAc)2、CuBr2、CuI2、CuO或Cu(OTf)2的一种或两种以上；
所述的布朗斯特酸是选自醋酸、苯甲酸、苯乙酸、苯磺酸或二苯基磷酸的一种或两种以上；
所述的胺源是选自苯胺、对硝基苯胺、对氯苯胺、对甲基苯胺、邻氯苯胺、邻甲氧基苯胺、异丙胺、正丁胺、哌啶、吗啉或四氢吡咯。
2.根据权利要求1所述的二级或三级芳香酰胺化合物的合成方法，其特征在于，所述的金属铜催化剂、布朗斯特酸、2-甲基-N-杂环芳香化合物和胺源的摩尔比为[0.05～0.2]:[0.5～1.0]：1：[1.0～2.0]。
3.根据权利要求1所述的二级或三级芳香酰胺化合物的合成方法，其特征在于，所述的2-甲基-N-杂环芳香化合物选自2-甲基吡啶、2-甲基噻唑、2-甲基吡嗪、2-甲基苯并噻唑、2-甲基喹喔啉、2-甲基喹啉、2-甲基-4-氨基喹啉、2-甲基-4-三甲基乙酰胺基喹啉、2,6-二甲基喹啉、2-甲基-6-氟喹啉、2-甲基-6-氯喹啉、2-甲基-6-溴喹啉、2-甲基-6-硝基喹啉、2-甲基-6-甲酸甲酯基喹啉、2-甲基-6-甲氧基喹啉、2-甲基-8-甲氧基喹啉或2,9-二甲基-1,10-菲啰啉。
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