CN108003156B - 一种咪唑并吡啶基1,2-乙二酮衍生物的合成方法 - Google Patents
一种咪唑并吡啶基1,2-乙二酮衍生物的合成方法 Download PDFInfo
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- CN108003156B CN108003156B CN201810081226.7A CN201810081226A CN108003156B CN 108003156 B CN108003156 B CN 108003156B CN 201810081226 A CN201810081226 A CN 201810081226A CN 108003156 B CN108003156 B CN 108003156B
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- ethanedione
- imidazopyridyl
- imidazo
- pyridine
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- CNPNBMVJCTYDDE-UHFFFAOYSA-N 2-(1H-imidazo[4,5-b]pyridin-2-yl)-2-oxoacetaldehyde Chemical class O=CC(=O)c1nc2ncccc2[nH]1 CNPNBMVJCTYDDE-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title abstract description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- -1 2-substituted imidazo [1,2-a]Pyridine Chemical class 0.000 claims abstract description 15
- 238000005810 carbonylation reaction Methods 0.000 claims abstract description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- 150000007524 organic acids Chemical class 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 239000000047 product Substances 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical class C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 239000003480 eluent Substances 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 3
- 238000010189 synthetic method Methods 0.000 claims 3
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 claims 1
- 239000008346 aqueous phase Substances 0.000 claims 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000003446 ligand Substances 0.000 abstract description 5
- 125000001424 substituent group Chemical group 0.000 abstract description 4
- YQBLQKZERMAVDO-UHFFFAOYSA-N 2-oxo-2-phenylacetaldehyde;hydrate Chemical class O.O=CC(=O)C1=CC=CC=C1 YQBLQKZERMAVDO-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000654 additive Substances 0.000 abstract description 3
- 230000000996 additive effect Effects 0.000 abstract description 3
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 125000004076 pyridyl group Chemical group 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 84
- 239000011734 sodium Substances 0.000 description 26
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000012512 characterization method Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Inorganic materials [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003699 antiulcer agent Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000006315 carbonylation Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- IOONPDHKLYFDML-UHFFFAOYSA-N 2-(4-bromophenyl)-2-oxoacetaldehyde;hydrate Chemical compound O.BrC1=CC=C(C(=O)C=O)C=C1 IOONPDHKLYFDML-UHFFFAOYSA-N 0.000 description 1
- KDHWCFCNNGUJCP-UHFFFAOYSA-N 2-phenylimidazo[1,2-a]pyridine Chemical compound N1=C2C=CC=CN2C=C1C1=CC=CC=C1 KDHWCFCNNGUJCP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SYKZTEDULDXVHY-UHFFFAOYSA-N benzaldehyde hydrate Chemical class O.O=CC1=CC=CC=C1.O=CC1=CC=CC=C1 SYKZTEDULDXVHY-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-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
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- CKFGINPQOCXMAZ-UHFFFAOYSA-N formaldehyde hydrate Natural products OCO CKFGINPQOCXMAZ-UHFFFAOYSA-N 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- JPAWFIIYTJQOKW-UHFFFAOYSA-N olprinone Chemical compound N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C JPAWFIIYTJQOKW-UHFFFAOYSA-N 0.000 description 1
- 229950005421 olprinone Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 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
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940100595 phenylacetaldehyde Drugs 0.000 description 1
- OJUGVDODNPJEEC-UHFFFAOYSA-N phenylglyoxal Chemical class O=CC(=O)C1=CC=CC=C1 OJUGVDODNPJEEC-UHFFFAOYSA-N 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- VSLIUWLPFRVCDL-UHFFFAOYSA-N zolimidine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CN(C=CC=C2)C2=N1 VSLIUWLPFRVCDL-UHFFFAOYSA-N 0.000 description 1
- 229960003118 zolimidine Drugs 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明的目的是为了解决现有技术中咪唑并吡啶基1，2‑乙二酮的合成方法存在反应条件和方法复杂的问题，提供了一种咪唑并吡啶基1，2‑乙二酮衍生物的合成方法，特别是对于咪唑并[1，2‑a]吡啶的2，3位均无取代基的反应物的合成方法，属于有机化合物合成技术领域。本方法以R1，R2‑取代咪唑并[1，2‑a]吡啶与R3‑取代苯甲酰甲醛水合物为原料，在60‑130℃条件下，进行双羰基化反应6‑10小时，得到产物1‑(3‑咪唑并[1，2‑a]吡啶基)‑2‑芳基‑1，2‑乙二酮衍生物。本发明采用了廉价易得的有机酸促进剂，直接进行双羰基化反应，体系不需要加入配体和额外添加剂等，反应条件温和，收率高。
Description
技术领域
本发明属于有机化合物合成技术领域，特别涉及一种咪唑并吡啶基1，2-乙二酮衍生物的合成方法。
背景技术
杂环化合物中的氮杂环广泛存在于多种生物碱中，其中咪唑和吡啶作为含氮杂环中最典型的五元和六元杂环，在多种天然产物中被发现并表现出广泛的药理学活性。由咪唑和吡啶稠合而成的氮杂双环化合物咪唑并[1,2-a]吡啶除了具有它们各自的特性外，还广泛应用于材料化学(J.S.Bae et al.,PCT Int.Appl Wo2007011163A1,2007)和医药化学(G.C.Moraski et al.,Bioorg.Med.Chem.Lett., 2003,13,347)中，其中不少已成为上市的药物，如安眠药Zolpidem(T.S.Harrison et al.,CNS Drugs,2005,19,65)、血管扩张药Olprinone(C.Enquehard-Gueiffier et al., Mini-Rev.Med.Chem.,2007,7,888)、抗溃疡药Soraprazan和Zolimidine(A.R. Katritzky et al.,J.Org.Chem.,2003,68,4935)和抗焦虑药Alpidem(S.Z.Langer et al., Adv.Biochem.Psychopharmacol.,1990,46,61)和Saripidem(N.Hsu et al.,Behav. Brain Res.,2009,201,233)。因此，咪唑并[1,2-a]吡啶化合物的合成和功能化受到了有机化学家和药物学家的广泛关注。
另外，1，2-二羰基化合物不但在光敏试剂(Matsuschita Electric IndustrialCo.Ltd. JP Pat.，56098203，1981)、腐蚀抑制剂(B.I.Ita et al.，Mater.Chem.Phys.，2001，70， 330)以及光激发剂(B.Husár et al.J.Phys.Chem.B，2006，110，5315)等方面具有重要应用，而且也广泛存在于天然产物和药物中(G.W.Gordonet et al.，J.Org.Chem.，1992，57，3636；W.Yan et al，PNAS，2014，111，18138；K.C.Nicolaou et al.，J.Am.Chem.Soc.，2004，126，613；B.M.Young et al.，J.Med.Chem.，2010，53，8709；)，其还可作为多种化学转化的重要骨架(S.E.Wolkenberg et al.，Org.Lett.，2004，6， 1453；H.Liet al.，Org.Lett.，2011，13，46；G.H.Spikes et al.，Angew.Chem.，Int.Ed.， 2008，47，2973；A.J.Herrera et al.，J.Org.Chem.，2008，73，3384；Y.Takada et al.，Org. Lett.，2010，12，5204)。
因此，合成咪唑并吡啶基1，2-乙二酮衍生物对于随后构筑生物活性和功能性化合物具有重要意义。
目前咪唑并吡啶基1，2-乙二酮类化合物合成方法包括，一是采用铜催化2-苯基咪唑并[1，2-a]吡啶与苯乙醛经氧化脱氢偶联合成咪唑并吡啶基1，2-乙二酮(S.M.A.Shakoor et al.，Tetrahedron，2016，72，645)，反应方程式如下所示：
二是采用甲基酮为羰基化试剂，经I2/DMSO/PTSA(对甲苯磺酸)促进的2-芳基咪唑并[1，2-a]吡啶的C-H键直接双羰基化反应合成咪唑并吡啶基1，2-乙二酮(M. Chennapuramet al.，RSC Adv.，2015，5，19418)，反应仅适用于咪唑并[1，2-a]吡啶的2 位被苯基取代的底物，具体方程式如下所示。
之三是采用铜催化咪唑并[1，2-a]吡啶与甲基酮的双羰基化反应合成咪唑并吡啶基1，2-乙二酮，反应需要在140℃下氧气作为氧化剂且密闭条件下才可顺利进行，且发生在咪唑并[1，2-a]吡啶的3位，底物的适用性考查发现，当芳基甲酮上含有敏感基团如OH和NH2时，反应不顺利(S.Lei et al.，Adv.Synth.Catal.，2016，358， 67)，方程式如下所示。
对于咪唑并吡啶基1，2-乙二酮的合成方法来说，其合成方法仍有限，且存在难处理试剂如I2的使用、配体的加入、密闭体系、反应时间长等不足。因此，开发更为廉价高效的咪唑并吡啶基1，2-乙二酮化合物的合成方法显得尤为重要。
发明内容
本发明的目的是为了解决现有技术中咪唑并吡啶基1，2-乙二酮的合成方法存在反应条件和方法复杂的问题，提供了一种咪唑并吡啶基1，2-乙二酮衍生物的合成方法，特别是对于咪唑并[1，2-a]吡啶的2，3位均无取代基的反应物的合成方法。本方法采用了廉价易得的有机酸促进剂，双羰基化试剂直接与R1，R2-取代咪唑并 [1，2-a]吡啶进行双羰基化反应，体系不需要加入配体和额外添加剂等，反应条件温和，收率高。
一种咪唑并吡啶基1，2-乙二酮衍生物的合成方法，包括以下步骤：
a.以R1，R2-取代咪唑并[1，2-a]吡啶(II)与R3-取代苯甲酰甲醛水合物(III) 为原料，在60-130℃条件下，进行双羰基化反应6-10小时，得到产物1-(3-咪唑并 [1，2-a]吡啶基)-2-芳基-1，2-乙二酮(I)衍生物反应液；反应式(1)为：
进一步的，在双羰基化反应之前还加入有机酸促进剂；
反应式中，R1表示氢、烷基中的任意一种，并且R1为单位点取代或多位点取代；其中，所述烷基为甲基、乙基、丙基、异丙基等；
R2表示苯基和含有取代基的苯基中的任意一种；其中，所述含有取代基的苯基为4位取代；进一步的，所述含有取代基的苯基为4-氟苯基、4-溴苯基、4-氯苯基或4-硝基苯基；
R3表示氢、三氟甲基、硝基、酯基、甲基、甲氧基、羟基和卤素中的任意一种，并且R3为单位点取代或多位点取代；其中，卤素为氟、氯、溴和碘的任意一种；
所述的R1，R2-取代咪唑并[1，2-a]吡啶与R3-取代苯甲酰甲醛水合物投料摩尔比为1∶1.0-1.5；
所述的有机溶剂为甲苯或苯；
所述的有机溶剂与R1，R2-取代咪唑并[1，2-a]吡啶的比例为7-15∶1L/mol；
所述的促进剂与R1，R2-取代咪唑并[1，2-a]吡啶的比例为0.6-4∶1L/mol；
所述的促进剂为冰醋酸；
b.将1-(3-咪唑并[1，2-a]吡啶基)-2-芳基-1，2-乙二酮衍生物反应液经过纯化得到目标产物；
其中，所述目标产物的纯化方法包括如下步骤：
1)将所述反应液冷却至室温，向其中加入乙酸乙酯和水，水相用乙酸乙酯萃取，收集有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，收集滤液，加入硅胶，旋转蒸发，得到粗产品；
2)粗产品经硅胶柱色谱法分离提纯，洗脱剂为石油醚和乙酸乙酯，得到目标产物。
本发明与现有同类技术相比，其显著的有益效果体现在：
本发明提供的咪唑并吡啶基1，2-乙二酮衍生物的合成方法，是一种新的合成方法，采用了廉价易得的有机酸促进剂，R2-取代苯甲酰甲醛水合物为双羰基化试剂，直接与R1，R2-取代咪唑并[1，2-a]吡啶进行双羰基化反应，体系不需要加入配体和额外添加剂等，反应条件温和，收率高，为该类化合物的合成提供了新的方法指导。
具体实施方式
下面通过实施例来进一步说明本发明，但不以任何方式限制本发明。
实施例1-23：咪唑并吡啶基1，2-乙二酮的合成
将咪唑并[1，2-a]吡啶0.5mmol、59.1mg，4-溴苯甲酰甲醛水合物0.5mmol、115.5mg，以及促进剂加入到装有磁力搅拌子的25mL两口瓶中，加热至目标温度反应，6～10h，并通过薄层色谱跟踪反应，待原料消耗完毕，将反应液冷却至室温，向其中加入乙酸乙酯和水，水相用乙酸乙酯萃取。收集有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，收集滤液，加入硅胶，旋转蒸发，粗产品经硅胶柱色谱法分离提纯，洗脱剂为石油醚和乙酸乙酯，得到目标产物，真空干燥，称重，计算分离收率，具体内容如下表1所示：
表1、不同条件下咪唑并吡啶基1，2-乙二酮的合成结果
注：表中PdCl2、Pd(OAc)2、Cu(OAc)2·H2O、CuBr、CuI的中文名称分别为氯化钯、醋酸钯、一水合醋酸铜、溴化亚铜、碘化亚铜；Toluene、Benzene、Dioxane、 HOAc、MeCN、DMSO、EtOH、TFA、HCOOH、CH3CH2COOH的中文名称分别为甲苯、苯、二氧六环、冰醋酸、乙腈、二甲基亚砜、乙醇、三氟乙酸、甲酸、丙酸。
实施例24-44：
将R1，R2-取代咪唑并[1，2-a]吡啶0.5mmol、R2-取代苯甲酰甲醛水合物0.5mmol、冰醋酸0.5mL、甲苯4mL，加入到装有磁力搅拌子的25mL两口瓶中，反应温度为100℃，经6-12小时双羰基化反应。其它操作方法与步骤同实施例1-23，具体内容如表2所示：
表2、不同产物的结构及收率
实施例1所得产物的结构表征数据为：
Yellow solid,m.p.:215.8-217.2℃.1H NMR(500MHz,DMSO-d6):δ9.62(d, J＝6.5Hz,1H),8.48(d,J＝1.5Hz,1H),7.99(dd,J＝9.0,2.0Hz,3H),7.85-7.83(m,3H), 7.48(dd,J＝7.0,6.5Hz,1H)；13C NMR(125MHz,DMSO-d6)δ190.58,180.12, 149.33,147.33,132.05,131.86,131.57,131.50,129.18,128.85,120.86,117.55,116.62. HRMS(ESI)forC15H9N2O2NaBr([M+Na]+):calcd 350.9745,352.9725,found 350.9738,352.9710.
实施例24所得产物的结构表征数据为：
Yellow solid,m.p.:182.8-183.6℃.1H NMR(500MHz,DMSO-d6):δ9.62(dd, J＝5.5,1.0Hz,1H),8.48(d,J＝2.0Hz,1H),8.09-8.07(m,2H),7.99(d,J＝8.5Hz,1H), 7.84(dd,J＝8.5,7.0Hz,1H),7.71-7.69(m,2H),7.49-7.47(m,1H)；13C NMR(125 MHz,DMSO-d6)δ190.36,180.15,149.33,147.32,139.82,131.85,131.56,131.18, 129.09,128.85,120.86,117.55,116.61.HRMS(ESI)for C15H9N2O2NaCl([M+Na]+): calcd 307.0250,309.0221,found 307.0241,309.0214.
实施例25所得产物的结构表征数据为：
Yellow solid,m.p.:167.3-167.6℃.1H NMR(500MHz,DMSO-d6):δ9.62(d, J＝6.5Hz,1H),8.46(s,1H),8.17-8.14(m,2H),7.97(d,J＝9.0Hz,1H),7.85-7.82(m, 1H),7.49-7.44(m,3H)；13C NMR(125MHz,DMSO-d6)δ190.06,180.49,165.83(d, J＝252.5Hz),149.30,147.21,133.22(d,J＝8.75Hz),131.51,129.22(d,J＝2.5Hz), 128.84,120.89,117.54,116.57,116.17(d,J＝22.5Hz).HRMS(ESI)for C15H9N2O2NaF ([M+Na]+):calcd291.0546,found 291.0523.
实施例26所得产物的结构表征数据为：
Yellow solid,m.p.:138.4-138.8℃.1H NMR(500MHz,DMSO-d6):δ9.61(d, J＝7.0Hz,1H),8.46(s,1H),8.02(d,J＝8.0Hz,3H),7.80(d,J＝7.5Hz,2H),7.70(d, J＝8.0Hz,1H),7.47(d,J＝7.0,7.0Hz,1H)；13C NMR(125MHz,DMSO-d6)δ191.00, 180.23,149.31,147.28,131.74,131.56,131.41,130.73,128.84,120.85,117.55,116.62,104.22.HRMS(ESI)for C15H9N2O2NaI([M+Na]+):calcd 398.9606,found 398.9615.
实施例27所得产物的结构表征数据为：
Yellow solid,m.p.:142.7-144.1℃.1H NMR(500MHz,DMSO-d6):δ9.63(d, J＝6.5Hz,1H),8.55(s,1H),8.26(d,J＝7.5Hz,2H),8.01-7.98(m,3H),7.85(d,J＝8.5,8.0Hz,1H),7.49(d,J＝7.0,6.5Hz,1H)；13C NMR(125MHz,DMSO-d6)δ190.36, 179.40,149.38,147.58,135.80,133.58(d,J＝3.25Hz),131.67,130.84,130.00,129.92, 128.89,125.77(q,J＝3.75Hz),120.84,117.34(d,J＝111.25Hz).HRMS(ESI)for C16H9N2O2NaF3([M+Na]+):calcd 341.0514,found 341.0528.
实施例28所得产物的结构表征数据为：
Yellow solid,m.p.:219.4-212.0℃.1H NMR(500MHz,DMSO-d6):δ9.62(d, J＝7.0Hz,1H),8.48(d,J＝2.5Hz,1H),7.99(dd,J＝8.0,2.5Hz,3H),7.86-7.82(m,3H), 7.48(d,J＝7.0,6.5Hz,1H)；13C NMR(125MHz,DMSO-d6)δ190.58,180.11,149.33, 147.33,132.05,131.86,131.57,131.50,129.18,128.85,120.85,117.55,116.62.HRMS (ESI)forC15H9N3O4Na([M+Na]+):calcd 318.0491,found 318.0498.
实施例29所得产物的结构表征数据为：
Yellow solid,m.p.:168.8-167.9℃.1H NMR(500MHz,DMSO-d6):δ9.63(dd, J＝7.0,1.5Hz,1H),8.52(d,J＝1.5Hz,1H),8.18(d,J＝7.5Hz,2H),8.15(d,J＝8.5Hz, 2H),7.80(d,J＝8.5Hz,1H),7.85(dd,J＝8.5,7.0Hz,1H),7.48(dd,J＝7.0,6.5Hz,1H), 3.89(s,3H)；13C NMR(125MHz,DMSO-d6)δ190.83,179.84,165.44,149.38,147.48, 135.89,132.98,130.29,129.40,129.15,128.87,120.83,117.58,116.68,52.27.HRMS (ESI)forC17H12N2O4Na([M+Na]+):calcd 331.0695,found 331.0687.
实施例30所得产物的结构表征数据为：
Yellow solid,m.p.:154.9-156.7℃.1H NMR(500MHz,DMSO-d6):δ9.63(d, J＝7.0Hz,1H),8.44(s,1H),8.05(d,J＝7.0Hz,2H),7.98(d,J＝9.0Hz,1H),7.85-7.82 (m,1H),7.78(dd,J＝7.5,7.0Hz,1H),7.62(dd,J＝7.5,7.5Hz,2H),7.47(dd,J＝6.5,6.5 Hz,1H)；13C NMR(125MHz,DMSO-d6)δ191.65,181.00,149.28,147.10,134.85, 132.42,131.46,129.96,128.93,128.81,120.89,117.54,116.57.HRMS(ESI)for C15H10N2O2Na([M+Na]+):calcd 273.0640,found 273.0658.
实施例31所得产物的结构表征数据为：
Yellow solid,m.p.:110.5-112.3℃.1H NMR(500MHz,DMSO-d6):δ9.59(d, J＝6.5Hz,1H),8.41(s,1H),7.97(d,J＝9.0Hz,1H),7.81(dd,J＝7.5,7.5Hz,1H),7.68 (d,J＝7.5Hz,1H),7.44(dd,J＝7.0,6.0Hz,1H),7.27(s,1H),7.16(d,J＝8.0Hz,1H), 2.59(s,3H),2.36(s,3H)；13C NMR(125MHz,DMSO-d6)δ193.60,182.03,149.11, 146.79,144.31,140.45,132.79,131.25,128.67,126.50,120.89,117.51,116.48,20.99. HRMS(ESI)forC17H14N2O2Na([M+Na]+):calcd 301.0953,found 301.0967.
实施例32所得产物的结构表征数据为：
Yellow solid,m.p.:110.6-111.9℃.1H NMR(500MHz,DMSO-d6):δ9.62(d, J＝7.0Hz,1H),8.37(s,1H),8.02(dd,J＝9.0,2.0Hz,2H),7.97(d,J＝8.5Hz,1H), 7.83-7.80(m,1H),7.47-7.44(m,1H),7.13(dd,J＝9.0,2.0Hz,2H),3.89(s,3H)；13C NMR(125MHz,DMSO-d6)δ190.22,181.68,164.48,146.80,132.49,131.28,128.74, 125.20,120.97,117.51,116.48,114.37,55.66.HRMS(ESI)for C16H12N2O3Na ([M+Na]+):calcd 303.0746,found 303.0758.
实施例34所得产物的结构表征数据为：
Yellow solid,m.p.:139.4-140.7℃.1H NMR(500MHz,DMSO-d6):δ9.72(d, J＝7.0Hz,1H),7.98(d,J＝9.0Hz,1H),7.87(dd,J＝8.0,8.0Hz,1H),7.70(d,J＝8.0Hz, 2H),7.66(d,J＝8.0Hz,2H),7.47(dd,J＝7.0,7.0Hz,1H),7.33-7.29(m,3H),7.14(dd, J＝7.5,7.5Hz,2H)；13C NMR(125MHz,DMSO-d6)δ190.07,183.04,157.76,147.80, 132.74,131.87,131.84,131.68,131.03,129.74,129.26,128.82,128.70,127.57,118.08, 117.23,116.50.HRMS(ESI)for C21H13N2O2NaBr([M+Na]+):calcd 427.0058, 429.0038,found427.0036,429.0023.
实施例35所得产物的结构表征数据为：
Yellow solid,m.p.:134.2-135.4℃.1H NMR(500MHz,DMSO-d6):δ9.72(d, J＝7.0Hz,1H),8.00(d,J＝9.0Hz,1H),7.89(dd,J＝8.5,8.0Hz,1H),7.73(d,J＝8.5Hz, 2H),7.68(d,J＝8.0Hz,2H),7.50(dd,J＝7.5,7.0Hz,1H),7.36(d,J＝8.0Hz,2H),7.24 (d,J＝8.0Hz,2H)；13C NMR(125MHz,DMSO-d6)δ190.30,182.80,156.37,147.79, 132.03,131.99,131.90,131.69,131.53,131.06,130.58,128.97,128.89,123.01,118.15, 117.30,116.69.HRMS(ESI)for C21H12N2O2NaBr2([M+Na]+):calcd 504.9163, 506.9143,508.9122,found 504.9147,506.9134,508.9113.
实施例36所得产物的结构表征数据为：
Yellow solid,m.p.:148.2-149.5℃.1H NMR(500MHz,DMSO-d6):δ9.72(d, J＝7.0Hz,1H),7.98(d,J＝9.0Hz,1H),7.88(dd,J＝8.5,8.0Hz,1H),7.72(d,J＝8.0Hz, 2H),7.67(d,J＝8.5Hz,2H),7.49(dd,J＝7.0,7.0Hz,1H),7.33(dd,J＝7.0,6.0Hz,2H), 7.00(dd,J＝8.5,8.5Hz,2H)；13C NMR(125MHz,DMSO-d6)δ190.30,182.90,162.57 (d,J＝246.25Hz),156.68,147.75,132.01,131.95(d,J＝2.5Hz),131.90,131.53,131.00,129.21(d,J＝2.5Hz),128.91,128.85,118.24,117.23,116.59,114.61(d,J＝22.5Hz).HRMS(ESI)for C21H12N2O2NaBrF([M+Na]+):calcd 444.9964,446.9943,found 444.9946,446.9935.
实施例37所得产物的结构表征数据为：
Yellow solid,m.p.:136.7-138.4℃.1H NMR(500MHz,DMSO-d6):δ9.72(d, J＝7.0Hz,1H),8.00(d,J＝9.5Hz,1H),7.89(dd,J＝8.0,8.0Hz,1H),7.73(d,J＝7.5Hz, 2H),7.68(d,J＝7.5Hz,2H),7.50(dd,J＝7.0,7.0Hz,1H),7.31(d,J＝7.5Hz,2H),7.22 (d,J＝7.5Hz,2H)；13C NMR(125MHz,DMSO-d6)δ190.29,182.80,156.33,147.77, 134.27,132.03,131.91,131.64,131.52,131.46,131.07,128.98,128.88,127.66,118.19, 117.29,116.69.HRMS(ESI)for C21H12N2O2NaBrCl([M+Na]+):calcd 460.9668, 462.9648,found460.9643,462.9632.
实施例38所得产物的结构表征数据为：
Yellow solid,m.p.:154.4-155.8℃.1H NMR(500MHz,DMSO-d6):δ9.56(s,1H),7.91(d,J＝9.0Hz,1H),7.76(d,J＝9.5Hz,1H),7.72(d,J＝8.0Hz,2H),7.66(d,J＝8.5 Hz,2H),7.34(d,J＝8.0Hz,2H),7.21(d,J＝7.5Hz,2H),2.50(s,3H)；13C NMR(125 MHz,DMSO-d6)δ190.33,182.64,156.19,146.73,134.54,132.07,131.89,131.67, 131.57,131.01,130.54,128.92,126.59,126.46,122.91,117.92,116.61,17.75.HRMS (ESI)forC22H14N2O2NaBr2([M+Na]+):calcd 518.9320,520.9299,522.9279,found 518.9309,520.9276,522.9263.
实施例39所得产物的结构表征数据为：
Yellow solid,m.p.:173.8-175.4℃.1H NMR(500MHz,DMSO-d6):δ9.56(s,1H),7.91(d,J＝9.0Hz,1H),7.76(d,J＝9.0Hz,1H),7.72(d,J＝8.5Hz,2H),7.65(d,J＝8.5 Hz,2H),7.31(dd,J＝5.5,3.0Hz,2H),7.00(dd,J＝8.5,8.5Hz,2H),2.50(s,3H)；13C NMR(125MHz,DMSO-d6)δ190.35,182.75,162.52(d,J＝246.25Hz),156.51,146.70, 134.50,131.98,131.91,131.57,130.95,129.29(d,J＝2.5Hz),128.87,126.58,126.37, 118.03,116.57,114.57(d,J＝22.5Hz),17.75.HRMS(ESI)for C22H14N2O2NaBrF ([M+Na]+):calcd459.0120,461.0100,found 459.0134,461.0109.
实施例40所得产物的结构表征数据为：
Yellow solid,m.p.:157.2-159.8℃.1H NMR(500MHz,DMSO-d6):δ9.56(s,1H),7.91(d,J＝9.0Hz,1H),7.76(d,J＝9.0Hz,1H),7.73(d,J＝8.5Hz,2H),7.67(d,J＝8.5 Hz,2H),7.29(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,2H),2.50(s,3H)；13C NMR(125 MHz,DMSO-d6)δ190.31,182.64,156.16,146.72,134.53,134.18,131.91,131.73, 131.56,131.44,131.02,128.93,127.62,126.58,126.46,117.96,116.61,17.75.HRMS (ESI)forC22H14N2O2NaBrCl([M+Na]+):calcd 474.9825,476.9804,found 474.9847, 476.9835.
实施例41所得产物的结构表征数据为：
Brown solid,m.p.:134.4-135.7℃.1H NMR(500MHz,DMSO-d6):δ9.55(s,1H),7.91(d,J＝9.0Hz,1H),7.76(d,J＝8.5Hz,1H),7.73(d,J＝8.5Hz,2H),7.66(d,J＝8.0 Hz,2H),7.34(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,2H),2.49(s,3H)；13C NMR(125 MHz,DMSO-d6)δ190.33,182.64,156.19,146.73,134.53,132.07,131.89,131.67, 131.57,131.01,130.54,128.92,126.59,126.45,122.91,117.92,116.61,17.75.HRMS (ESI)forC22H14N3O4NaBr([M+Na]+):calcd 486.0065,488.0045,found 486.0072, 488.0055.
实施例42所得产物的结构表征数据为：
Yellow solid,m.p.:152.2-152.9℃.1H NMR(500MHz,DMSO-d6):δ9.59(d, J＝7.0Hz,1H),7.80(s,1H),7.71(dd,J＝8.5,2.0Hz,2H),7.64(dd,J＝8.5,2.0Hz,2H), 7.35-7.30(m,2H),7.28(d,J＝7.5Hz,2H),2.54(s,3H)；13C NMR(125MHz,DMSO-d6) δ190.20,182.57,158.07,148.22,143.40,132.81,131.83,131.76,131.00,129.69, 129.22,128.63,127.99,127.55,118.64,117.83,115.93,20.93.HRMS(ESI)for C22H15N2O2NaBr([M+Na]+):calcd 441.0215,443.0194,found 441.0236,443.0185.
实施例43所得产物的结构表征数据为：
Yellow solid,m.p.:144.4-145.2℃.1H NMR(500MHz,DMSO-d6):δ9.58(dd, J＝7.0,2.5Hz,1H),7.81(s,1H),7.73(dd,J＝8.5,2.0Hz,2H),7.67(dd,J＝8.5,2.0Hz, 2H),7.35(dd,J＝8.0,2.5Hz,3H),7.22(dd,J＝8.0,2.5Hz,2H),2.54(s,3H)；13C NMR (125MHz,DMSO-d6)δ190.41,182.33,156.66,148.20,143.56,132.06,131.89, 131.64,131.03,130.55,128.90,128.03,127.15,122.95,118.80,117.89,115.97,20.93. HRMS(ESI)forC22H14N2O2NaBr2([M+Na]+):calcd 518.9320,520.9299,522.9279, found 518.9309,520.9276,522.9263.
实施例44所得产物的结构表征数据为：
Yellow solid,m.p.:120.1-120.9℃.1H NMR(500MHz,DMSO-d6):δ9.59(d, J＝7.0Hz,1H),7.80(s,1H),7.72(d,J＝8.0Hz,2H),7.66(d,J＝8.0Hz,2H),7.35(d, J＝7.0Hz,1H),7.31(dd,J＝7.0,6.5Hz,2H),6.99(d,J＝9.0,8.5Hz,2H),2.54(s,3H)；13C NMR(125MHz,DMSO-d6)δ190.43,182.44,156.99,148.17,143.52,131.96, 131.90,131.53,131.11,130.97,128.84,128.48,128.01,118.72,115.93,114.67,114.50, 20.93.HRMS(ESI)for C22H14N3O4NaBr([M+Na]+):calcd 486.0065,488.0045,found 486.0072,488.0055.
Claims (5)
1.一种咪唑并吡啶基1,2-乙二酮衍生物的合成方法，其特征在于，包括以下步骤：
a.以R1，R2-取代咪唑并[1,2-a]吡啶与R3-取代苯甲酰甲醛水合物为原料，在100℃条件下，进行双羰基化反应6-10小时，得到产物1-(3-咪唑并[1,2-a]吡啶基)-2-芳基-1,2-乙二酮衍生物反应液；反应式为：
b.将1-(3-咪唑并[1,2-a]吡啶基)-2-芳基-1,2-乙二酮衍生物反应液经过纯化得到目标产物；
反应式中，R1表示氢、甲基中的任意一种，并且R1为单位点取代；
R2表示4-氟苯基、4-溴苯基、4-氯苯基；
R3表示溴，并且R3为单位点取代；
所述步骤a中在双羰基化反应之前还加入冰醋酸作为有机酸促进剂，加入甲苯作为有机溶剂。
2.根据权利要求1所述的一种咪唑并吡啶基1,2-乙二酮衍生物的合成方法，其特征在于，所述的R1，R2-取代咪唑并[1,2-a]吡啶与R3-取代苯甲酰甲醛水合物投料摩尔比为1：1.0-1.5。
3.根据权利要求1所述的一种咪唑并吡啶基1,2-乙二酮衍生物的合成方法，其特征在于，所述甲苯与R1，R2-取代咪唑并[1,2-a]吡啶的比例为7-15:1L/mol。
4.根据权利要求1所述的一种咪唑并吡啶基1,2-乙二酮衍生物的合成方法，其特征在于，所述的冰醋酸与R1，R2-取代咪唑并[1,2-a]吡啶的比例为0.6-4:1L/mol。
5.根据权利要求1至4任一所述的一种咪唑并吡啶基1,2-乙二酮衍生物的合成方法，其特征在于，步骤b中，所述目标产物的纯化方法包括如下步骤：
1)将所述反应液冷却至室温，向其中加入乙酸乙酯和水，水相用乙酸乙酯萃取，收集有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，收集滤液，加入硅胶，旋转蒸发，得到粗产品；
2)粗产品经硅胶柱色谱法分离提纯，洗脱剂为石油醚和乙酸乙酯，得到目标产物。
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