CN106632075B - 一种2,4,6-三苯基嘧啶类衍生物的合成方法 - Google Patents
一种2,4,6-三苯基嘧啶类衍生物的合成方法 Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 12
- 150000003222 pyridines Chemical class 0.000 title description 3
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 16
- LZCZIHQBSCVGRD-UHFFFAOYSA-N benzenecarboximidamide;hydron;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=C1 LZCZIHQBSCVGRD-UHFFFAOYSA-N 0.000 claims abstract description 16
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- FRZHWQQBYDFNTH-UHFFFAOYSA-N 2,4,6-triphenylpyridine Chemical class C1=CC=CC=C1C1=CC(C=2C=CC=CC=2)=NC(C=2C=CC=CC=2)=C1 FRZHWQQBYDFNTH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000005751 Copper oxide Substances 0.000 claims abstract description 6
- 229910000431 copper oxide Inorganic materials 0.000 claims abstract description 6
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 claims 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 claims 1
- 229910001948 sodium oxide Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- 229910000510 noble metal Inorganic materials 0.000 abstract description 2
- 239000007800 oxidant agent Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 28
- 239000012043 crude product Substances 0.000 description 18
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- 230000015572 biosynthetic process Effects 0.000 description 16
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical class C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 8
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 8
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- 150000003230 pyrimidines Chemical class 0.000 description 7
- 230000005311 nuclear magnetism Effects 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000003935 benzaldehydes Chemical class 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- DZWYOFOTUIZLTL-UHFFFAOYSA-N 2-(4-methylphenyl)-4,6-diphenylpyrimidine Chemical compound C1=CC(C)=CC=C1C1=NC(C=2C=CC=CC=2)=CC(C=2C=CC=CC=2)=N1 DZWYOFOTUIZLTL-UHFFFAOYSA-N 0.000 description 2
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical class ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical class ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- YHBDIEWMOMLKOO-UHFFFAOYSA-I pentachloroniobium Chemical compound Cl[Nb](Cl)(Cl)(Cl)Cl YHBDIEWMOMLKOO-UHFFFAOYSA-I 0.000 description 2
- 239000010970 precious metal Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- MYUPFXPCYUISAG-UHFFFAOYSA-N (2,4-dichlorophenyl)(phenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC(Cl)=CC=1)Cl)(O)C1=CC=CC=C1 MYUPFXPCYUISAG-UHFFFAOYSA-N 0.000 description 1
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- CXNPLSGKWMLZPZ-GIFSMMMISA-N (2r,3r,6s)-3-[[(3s)-3-amino-5-[carbamimidoyl(methyl)amino]pentanoyl]amino]-6-(4-amino-2-oxopyrimidin-1-yl)-3,6-dihydro-2h-pyran-2-carboxylic acid Chemical compound O1[C@@H](C(O)=O)[C@H](NC(=O)C[C@@H](N)CCN(C)C(N)=N)C=C[C@H]1N1C(=O)N=C(N)C=C1 CXNPLSGKWMLZPZ-GIFSMMMISA-N 0.000 description 1
- CQRUIYKYVFQBRT-UHFFFAOYSA-N (6-methyl-2-propylpyrimidin-4-yl) n,n-dimethylcarbamate Chemical compound CCCC1=NC(C)=CC(OC(=O)N(C)C)=N1 CQRUIYKYVFQBRT-UHFFFAOYSA-N 0.000 description 1
- SZKWMQWGJPCXOF-UHFFFAOYSA-N 2,4,6-triphenylpyrimidine Chemical class C1=CC=CC=C1C1=CC(C=2C=CC=CC=2)=NC(C=2C=CC=CC=2)=N1 SZKWMQWGJPCXOF-UHFFFAOYSA-N 0.000 description 1
- XGVJIKBARHCQHE-UHFFFAOYSA-N 2-(trifluoromethyl)benzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=CC=C1C(F)(F)F XGVJIKBARHCQHE-UHFFFAOYSA-N 0.000 description 1
- USHZYUPZIKQYMI-UHFFFAOYSA-N 2-methylbenzenecarboximidamide;hydrochloride Chemical compound Cl.CC1=CC=CC=C1C(N)=N USHZYUPZIKQYMI-UHFFFAOYSA-N 0.000 description 1
- OXPDQFOKSZYEMJ-UHFFFAOYSA-N 2-phenylpyrimidine Chemical class C1=CC=CC=C1C1=NC=CC=N1 OXPDQFOKSZYEMJ-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- MLDVVJZNWASRQL-UHFFFAOYSA-N 4-diethoxyphosphinothioyloxy-n,n,6-trimethylpyrimidin-2-amine Chemical group CCOP(=S)(OCC)OC1=CC(C)=NC(N(C)C)=N1 MLDVVJZNWASRQL-UHFFFAOYSA-N 0.000 description 1
- CTSLUCNDVMMDHG-UHFFFAOYSA-N 5-bromo-3-(butan-2-yl)-6-methylpyrimidine-2,4(1H,3H)-dione Chemical compound CCC(C)N1C(=O)NC(C)=C(Br)C1=O CTSLUCNDVMMDHG-UHFFFAOYSA-N 0.000 description 1
- 150000000644 6-membered heterocyclic compounds Chemical class 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229910019804 NbCl5 Inorganic materials 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- TZBPRYIIJAJUOY-UHFFFAOYSA-N Pirimiphos-ethyl Chemical group CCOP(=S)(OCC)OC1=CC(C)=NC(N(CC)CC)=N1 TZBPRYIIJAJUOY-UHFFFAOYSA-N 0.000 description 1
- 229930182764 Polyoxin Natural products 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- HUTDUHSNJYTCAR-UHFFFAOYSA-N ancymidol Chemical compound C1=CC(OC)=CC=C1C(O)(C=1C=NC=NC=1)C1CC1 HUTDUHSNJYTCAR-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- CXNPLSGKWMLZPZ-UHFFFAOYSA-N blasticidin-S Natural products O1C(C(O)=O)C(NC(=O)CC(N)CCN(C)C(N)=N)C=CC1N1C(=O)N=C(N)C=C1 CXNPLSGKWMLZPZ-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- YFGYUFNIOHWBOB-UHFFFAOYSA-N pirimicarb Chemical compound CN(C)C(=O)OC1=NC(N(C)C)=NC(C)=C1C YFGYUFNIOHWBOB-UHFFFAOYSA-N 0.000 description 1
- QHOQHJPRIBSPCY-UHFFFAOYSA-N pirimiphos-methyl Chemical compound CCN(CC)C1=NC(C)=CC(OP(=S)(OC)OC)=N1 QHOQHJPRIBSPCY-UHFFFAOYSA-N 0.000 description 1
- YEBIHIICWDDQOL-YBHNRIQQSA-N polyoxin Polymers O[C@@H]1[C@H](O)[C@@H](C(C=O)N)O[C@H]1N1C(=O)NC(=O)C(C(O)=O)=C1 YEBIHIICWDDQOL-YBHNRIQQSA-N 0.000 description 1
- GHUURDQYRGVEHX-UHFFFAOYSA-N prop-1-ynylbenzene Chemical group CC#CC1=CC=CC=C1 GHUURDQYRGVEHX-UHFFFAOYSA-N 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- ZZORFUFYDOWNEF-UHFFFAOYSA-N sulfadimethoxine Chemical compound COC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ZZORFUFYDOWNEF-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明提供了一种2,4,6‑三苯基嘧啶类衍生物的合成方法,在空气条件下利用氧化铜催化苄脒盐酸盐、醛、炔三组分一锅法反应,与现有技术相比,本发明具有以下优点:(1)没有使用贵金属,有机氧化剂,而是利用商品化氧化铜作催化剂,节约成本;(2)利用苄脒盐酸盐、醛、炔为反应原料,原料易得;(3)该合成方法效率高,使用范围广,底物适用性广。
Description
技术领域
本发明属于有机合成方法领域,具体涉及一种2,4,6-三苯基嘧啶类衍生物的合成方法。
技术背景
嘧啶类化合物是指分子结构中含有两个氮原子的六元杂环化合物,与哒嗪、吡嗪互为同分异构体。嘧啶类化合物因具有不同的生物活性,如杀虫、杀菌、除草、抗病毒等。从而引起人们对这类化合物的广泛兴趣并进行了深入研究。例如维生素B、磺胺嘧啶、磺胺异二甲嘧啶、磺胺间二甲氧嘧啶;农药原料,如二嗪农、嘧啶醇、灭瘟素、除草定、环菌灵、甲菌定、乙菌定、磺嘧菌灵、比嗪农、抗蚜威、乙基虫螨磷、虫螨磷、多氧霉素、嘧啶威、嘧啶磷、氧嘧啶磷、嘧菌醇、异嘧菌醇、尿嘧啶等由于嘧啶化合物具有高效、对人类低毒等优点,因此其分子设计、合成与生物活性研究仍然是当今绿色农药创制的一个热点。
2,4,6-三苯基嘧啶是嘧啶环上的三个氢原子被其他原子或基团所取代,由于结构特点,在生物活性和药理性质方面有着广泛的应用,因此探索发展2,4,6-三苯基嘧啶的合成方法与技术任然是有机化学领域重要的研究课题之一。
目前文献中介绍的合成2,4,6-三苯基嘧啶的方法主要有以下几种:
(一)使用复杂的催化剂A催化苄脒盐酸盐和两组分的醇一锅法反应合成2,4,6-三苯基嘧啶衍生物。
该反应做到了三组分一锅法反应,且运用两种醇反应,符合绿色化学理念,但催化剂合成复杂,制约了其工业发展。
(二)使用五氯化铌(NbCl5)催化腈和炔反应合成2,4,6-三苯基嘧啶衍生物。
此法反应条件温和,但两组分腈制约嘧啶的取代基相同,且产率较低。
(三)2012年Jean-Marc Campagne课题组利用β-enaminones作为中间体和酰胺进行反应得到2,4,6-三取代嘧啶衍生物。
该合成方法需要对中间体进行保护基团保护,且反应分步进行,合成效率不高。
(四)以苄脒盐酸盐和丙炔醇类化合物在微波条件反应合成2,4,6-三取代嘧啶衍生物。
这种方法利用微波条件,条件简单但不利于工业扩大生产且反应过程使用MnO2重金属,污染环境。
(五)使用醋酸钯和碘化亚铜催化苄脒盐酸盐、碘苯、炔合成路线合成目标产物
但该合成方法使用了贵金属Pd做催化剂,三叔丁基磷做配体,且反应产率一般。
综上所述,现代合成2,4,6-三取代嘧啶化合物的方法很多,但有些合成方法4,6位取代基相同,不能做到不同取代基产物;有些使用贵金属钯作为催化剂,成本较高;有些合成步骤较为复杂或产率较低;因此提供一种合成高效,底物适用性广的新型合成方法十分必要。
发明内容
针对现有技术上的不足,本发明旨在提供一种2,4,6-三苯基嘧啶类衍生物的合成方法,在空气条件下利用氧化铜催化苄脒盐酸盐、醛、炔三组分一锅法反应,合成方法成本低,原料易得,底物普适性高。
本发明提供的一种2,4,6-三苯基嘧啶类衍生物的合成方法,包括以下步骤:
A、在空气条件下,混合苄脒盐酸盐、醛和炔,然后加入催化剂、碱和溶剂,加热反应;
B、反应结束后,将产物分离、干燥、纯化后得到2,4,6-三苯基嘧啶类衍生物。
步骤A中所述苄脒盐酸盐、醛、炔、催化剂、碱的物质的量比为1:1.1-1.3:1.2-1.5:0.1:2-3。
步骤A中所述苄脒盐酸盐结构为:
式中R1为4-H、4-CH3、4-Cl、4-Br或4-CF3中的一种。
步骤A中所述醛结构为:
式中R2选自4-H、4-CH3、4-OCH3、4-Cl、3-Cl、2-Cl、4-Br、4-F或4-CF3中的一种。
步骤A中所述炔结构为:
式中R3选自4-H、4-CH3、4-OCH3、4-Cl、4-Br或4-F中的一种。
步骤A中所述加热反应是指:在120℃-140℃条件下反应20-24小时;
步骤A中所述催化剂为氧化铜;所述碱为氢氧化钾、氢氧化钠、碳酸铯或碳酸钾中的一种;所述溶剂为N,N-二甲基甲酰胺、二甲基亚砜或N,N-二甲基乙酰胺。苄脒盐酸盐在溶剂中的浓度为0.1-0.5mol/L。
步骤B具体为:将所得产物用乙酸乙酯萃取,然后无水硫酸镁干燥,减压浓缩后,得粗产物,以体积比纯石油醚:乙酸乙酯=50:1为展开剂,通过柱层析分离得到2,4,6-三苯基嘧啶类衍生物。
步骤B所得2,4,6-三苯基嘧啶类衍生物结构式为式中,R1R1为4-H、4-CH3、4-Cl、4-Br或4-CF3;R2选自4-H、4-CH3、4-OCH3、4-Cl、3-Cl、2-Cl、4-Br、4-F或4-CF3;R3选自4-H、4-CH3、4-OCH3、4-Cl、4-Br或4-F。
本发明中,首先醛与离去盐酸的脒进行了缩合反应生成亚胺,紧接着炔通过质子的转移与亚胺结合形成嘧啶中间体,最后在氧气的作用下脱H质子得到六元环2,4,6-嘧啶。本发明控制原料用量比,保证产率,以苄脒盐酸盐为反应基准,所以醛和炔是过量的,首先苄脒盐酸盐和醛进行缩合,所以1.2-1.3equiv的量可以使苄脒盐酸盐较为充分的转化,炔的量加到1.3-1.5equiv,是因为炔易挥发,也是确保最大程度的进行反应,保证最大化的产物收率。
与现有技术相比,本发明具有以下优点:(1)没有使用贵金属,有机氧化剂,而是利用商品化氧化铜作催化剂,节约成本;(2)利用苄脒盐酸盐、醛、炔为反应原料,原料易得;(3)该合成方法效率高,使用范围广,底物适用性广。
附图说明
图1为反应方程式;
式中,R1为4-H、4-CH3、4-Cl、3-Br或4-CF3;R2选自4-H、4-CH3、4-OCH3、4-Cl、3-Cl、2-Cl、4-Br、4-F或4-CF3;R3选自4-H、4-CH3、4-OCH3、4-Cl、4-Br、或4-F;
图2为实施例1核磁共振氢谱;
图3为实施例1核磁共振碳谱;
图4为实施例2核磁共振氢谱;
图5为实施例2核磁共振碳谱;
图6为实施例3核磁共振氢谱;
图7为实施例3核磁共振碳谱;
图8为实施例4核磁共振氢谱;
图9为实施例4核磁共振碳谱;
图10为实施例5核磁共振氢谱;
图11为实施例5核磁共振碳谱;
图12为实施例6核磁共振氢谱;
图13为实施例6核磁共振碳谱;
图14为实施例7核磁共振氢谱;
图15为实施例7核磁共振碳谱;
图16为实施例8核磁共振氢谱;
图17为实施例9核磁共振氢谱;
图18为实施例9核磁共振碳谱。
具体实施方式
实施例1
2,4,6-三苯基嘧啶的合成,包括以下步骤:
A、取0.3mmol苄脒盐酸盐和0.39mmol苯甲醛、0.45mmol苯乙炔混合,再往其加入0.03mmol CuO,0.9mmol KOH和2-3ml DMF,在140℃下搅拌反应24小时;
B、所得产物用乙酸乙酯萃取,然后无水硫酸镁干燥,减压浓缩后,得粗产物,用硅胶柱层析(溶剂体积比为石油醚:乙酸乙酯=50:1)纯化得白色固体即2,4,6-三苯基嘧啶,产率85%,熔点为182℃。
核磁表征数据:
1H NMR(300MHz,CDCl3):δ7.48-7.50(m,9H);7.97(s,1H),8.24–8.25(m,4H),8.67–8.69(m,2H);
13C NMR(75MHz,CDCl3):δ110.35,127.33,128.47,128.51,128.65,128.94,130.68,130.82,137.51,138.10,164.50,164.78。
实施例2
4-(4-氯苯基)-2,6-二苯基嘧啶的合成,包括以下步骤:
A、0.3mmol对苄脒盐酸盐和0.36mmol对氯苯甲醛、0.45mmol苯乙炔,再往其加入0.03mmol CuO,0.9mmol KOH以及2-3ml DMF,在140℃下搅拌反应24小时后,得产物;
B、将产物用乙酸乙酯进行萃取,干燥得到粗产物,将粗产物用硅胶柱层析(溶剂体积比为石油醚:乙酸乙酯=50:1)纯化得白色固体4-(4-氯苯基)-2,6-二苯基嘧啶。产率81%,165-167℃。
核磁表征数据:
1H NMR(300MHz,CDCl3):δ7.47-7.50(t,8H),7.79(s,1H),8.18-8.24(m,4H),8.66(t,J=3Hz,2H).
13C NMR(75MHz,CDCl3):δ109.91,127.29,128.49,128.95,129.13,135.89,136.97,137.31,137.95,163.42,164.51,164.89.
实施例3
2-(4-氯苯基)-4-苯基-6-(对甲苯基)嘧啶的合成,包括以下步骤:
A、取0.3mmol苄脒盐酸盐和0.39mmol对氯苯甲醛、0.40mmol对甲基苯乙炔,再往其加入0.03mmol CuO,0.9mmol KOH以及2-3ml DMF,在140℃下搅拌反应24小时;
B、将产物用乙酸乙酯进行萃取,干燥得到粗产物,将粗产物用硅胶柱层析(溶剂体积比为石油醚:乙酸乙酯=50:1)纯化得白色固体即2-(4-氯苯基)-4-苯基-6-(对甲苯基)嘧啶,产率76%,熔点为164℃。
核磁表征数据:
1H NMR(300MHz,CDCl3):δ2.41(s,3H),7.30-7.33(d,J=9.0Hz,2H),7.48-7.49(d,J=3Hz,2H),7.90(s,1H),8.12-8.20(m,4H),8.64-8.65(d,J=3Hz,2H);
13C NMR(75MHz,CDCl3):δ109.63,127.20,128.48,128.57,129.13,129.69,130.71,134.51,136.04,136.89,138.04,141.34,163.35,164.48,164.88。
实施例4
4-(2-氯苯基)-2,6-二苯基嘧啶的合成,包括以下步骤:
A、取1.5mmol苄脒盐酸盐和1.9mmol邻氯苯甲醛、2.25mmol苯乙炔,再往其加入0.15mmol CuO,4.5mmol KOH以及3-4ml DMF,在140℃下搅拌反应24小时得到产物;
B、将产物用乙酸乙酯进行萃取,干燥得到粗产物,将粗产物用硅胶柱层析(溶剂体积比为石油醚:乙酸乙酯=50:1)纯化得白色固体即4-(2-氯苯基)-2,6-二苯基嘧啶。产率70%,熔点为124-125℃。
核磁表征数据:
1H NMR(300MHz,CDCl3):δ7.38-7.51(m,9H),7.79-7.81(t,1H),7.97(s,1H),8.23(d,J=3.9Hz,2H),8.62(d,J=3.6Hz,2H);
13C NMR(75MHz,CDCl3):δ115.19,127.26,127.40,128.08,128.50,128.97,130.52,130.73,130.93,131.72,132.45,137.26,137.56,137.93,163.90,164.69。
实施例5
4-(3-氯苯基)-2,6-二苯基嘧啶的合成,包括以下步骤:
A、取2mmol苄脒盐酸盐和2.6mmol间氯苯甲醛、3mmol苯乙炔,再往其加入0.2mmolCuO,6mmol KOH以及6-8ml DMF,在140℃下搅拌反应24小时后,得产物;
B、将产物用乙酸乙酯进行萃取,干燥得到粗产物,将粗产物用硅胶柱层析(溶剂体积比为石油醚:乙酸乙酯=50:1)纯化得白色固体即4-(3-Cl苯基)-2,6-二苯基嘧啶,产率52%,熔点为147-148℃.
核磁表征数据:
1H NMR(300MHz,CDCl3):δ7.46-7.50(m,8H)7.94(s,1H),8.11(d,J=5.7Hz,1H,)8.24,(s,3H),8.67(d,J=4.8Hz,2H)
13C NMR(75MHz,CDCl3):δ110.218,125.34,127.31,127.42,128.51,128.66,128.96,130.16,130.71,130.83,130.98,135.08,137.23,137.87,139.33,163.24,164.57,164.98.
实施例6
4-(对甲苯基)-2,6-二苯基嘧啶的合成,包括以下步骤:
A、取3mmol苄脒盐酸盐和3.9mmol对甲基苯甲醛、4.5mmol苯乙炔,再往其加入0.3mmol CuO,9mmol KOH以及6-8ml DMF,在140℃下搅拌反应24小时,得到产物;
B、将产物用乙酸乙酯进行萃取,干燥得到粗产物,将粗产物用硅胶柱层析(溶剂体积比为石油醚:乙酸乙酯=50:1)纯化得白色固体即4-(对甲苯基)-2,6-二苯基嘧啶,产率83.1%,熔点为152-154℃.
核磁表征数据:
1H NMR(300MHz,CDCl3):δ2.41(s,3H),7.32(d,J=7.5Hz),7.48-7.50(m,6H),7.50(s,1H),8.15(d,J=7.8Hz,2H),8.24(d,J=5Hz),8.67(d,J=6Hz).
13C NMR(75MHz,CDCl3):δ21.51,109.99,127.23,127.32,128.44,128.50,128.91,129.67,130.60,130.72,134.70,137.64,138.23,141.18,164.42,164.62,164.69.
实施例7
2,4-二苯基-6-(2-噻吩基)嘧啶的合成,包括以下步骤:
A、取0.15mmol苄脒盐酸盐和0.18mmol 2-噻吩甲醛、0.225mmol苯乙炔,再往其加入0.015mmol CuO,0.45mmol KOH以及1-2ml DMF,在120℃下搅拌反应24小时得到产物;
B、将产物用乙酸乙酯进行萃取,干燥得到粗产物,将粗产物用硅胶柱层析(溶剂体积比为石油醚:乙酸乙酯=50:1)纯化得白色固体,2,4-二苯基-6-(2-噻吩基),嘧啶产率86.3%,熔点为169-172℃
1H NMR(300MHz,CDCl3):δ7.17(d,J=3.6Hz,2H),7.48-7.50(m,6H),7.81(s,1H),7.89(s,1H),8.21(d,J=3.9Hz,2H),8.63(d,J=4.5Hz 2H).
13C NMR(75MHz,CDCl3):δ108.44,127.09,127.26,128.33,128.47,128.63,128.92,129.82,130.76,130.85,137.34,137.77,143.39,159.70,164.45,164.56.
实施例8
4,6-二苯基-2-(对甲苯基)嘧啶的合成,包括以下步骤:
A、0.3mmol对甲基苄脒盐酸盐和0.39mmol苯甲醛、0.45mmol苯乙炔,再往其加入0.03mmol CuO,0.9mmol KOH以及2-3ml DMF,在140℃下搅拌反应24小时,得到产物;
B、将产物用乙酸乙酯进行萃取,干燥得到粗产物,将粗产物用硅胶柱层析(溶剂体积比为石油醚:乙酸乙酯=50:1)纯化得白色固体即4,6-二苯基-2-(对甲苯基)嘧啶。产率为88%,熔点为182-185℃
1H NMR(300MHz,CDCl3):δ2.41(s,3H),7.30(d,J=7.8Hz),7.50-7.52(d,6H),7.94(s,1H),8.24(t,J=5.4Hz,4H),8.58(d,J=7.8Hz,2H);
13C NMR(75MHz,CDCl3):δ21.60,110.06,127.31,128.48,128.91,129.94,130.72,135.51,137.67,140.85,164.67.
实施例9
4,6-二苯基-2-(对三氟甲基)嘧啶的合成,包括以下步骤:
A、0.3mmol对三氟甲基苄脒盐酸盐和0.39mmol苯甲醛、0.45mmol苯乙炔,再往其加入0.03mmol CuO,0.9mmol KOH以及2-3ml DMF,在140℃下搅拌反应24小时,得到产物;
B、将产物用乙酸乙酯进行萃取,干燥得到粗产物,将粗产物用硅胶柱层析(溶剂体积比为石油醚:乙酸乙酯=50:1)纯化得白色固体4,6-二苯基-2-(对三氟甲基)嘧啶。产率为84.5%,熔点197-199℃
1H NMR(500MHz,CDCl3):δ7.58-7.61(m,6H),7.79(d,2H,8.5Hz),8.08(s,1H),8.29(t,4H),8.84(d,2H,8Hz).
13C NMR(75MHz,CDCl3):δ110.94,125.34,125.39,127.29,128.74,129.01,131.03,132.37,137.16,141.41,163.17,164.95.
以上详细描述了本发明的优选实施方式。但是,本发明并不限于上述实施方式中的具体细节。只要在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型的均属于本发明的保护范围。
Claims (1)
1.一种2,4,6-三苯基嘧啶类衍生物的合成方法,其特征在于,所述合成方法包括以下步骤:
A、在空气条件下,混合苄脒盐酸盐、醛和炔,然后加入催化剂、碱和溶剂,加热反应;
B、反应结束后,将产物分离、干燥、纯化后得到2,4,6-三苯基嘧啶类衍生物;
步骤A中所述苄脒盐酸盐、醛、炔、催化剂、碱的物质的量比为1:1.1-1.3:1.2-1.5:0.1:2-3;所述苄脒盐酸盐结构为:
式中R1为4-H、4-CH3、4-Cl、4-Br或4-CF3中的一种;所述醛结构为:
式中R2选自4-H、4-CH3、4-OCH3、4-Cl、3-Cl、2-Cl、4-Br、4-F或4-CF3中的一种;所述炔结构为:
式中R3选自4-H、4-CH3、4-OCH3、4-Cl、4-Br或4-F中的一种;所述加热反应是指:在120℃-140℃条件下反应20-24小时;所述催化剂为氧化铜;所述碱为氢氧化钾、氢氧化钠、碳酸铯或碳酸钾中的一种;所述溶剂为N,N-二甲基甲酰胺、二甲基亚砜或N,N-二甲基乙酰胺;
步骤B所得2,4,6-三苯基嘧啶类衍生物结构式为式中,R1为4-H、4-CH3、4-Cl、4-Br或4-CF3;R2选自4-H、4-CH3、4-OCH3、4-Cl、3-Cl、2-Cl、4-Br、4-F或4-CF3;R3选自4-H、4-CH3、4-OCH3、4-Cl、4-Br或4-F。
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