CN113861192A - Preparation method of C-3 halogenated imidazo [1,2-a ] pyridine derivative - Google Patents
Preparation method of C-3 halogenated imidazo [1,2-a ] pyridine derivative Download PDFInfo
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- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 238000004440 column chromatography Methods 0.000 claims abstract description 8
- 150000004820 halides Chemical class 0.000 claims abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- -1 imidazo [1,2-a ] pyridine compound Chemical class 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000004071 biological effect Effects 0.000 abstract description 7
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 150000002367 halogens Chemical class 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 208000012902 Nervous system disease Diseases 0.000 abstract description 2
- 208000025966 Neurological disease Diseases 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 241000894006 Bacteria Species 0.000 abstract 1
- 206010061218 Inflammation Diseases 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 206010037660 Pyrexia Diseases 0.000 abstract 1
- 208000025865 Ulcer Diseases 0.000 abstract 1
- 241000700605 Viruses Species 0.000 abstract 1
- 230000004054 inflammatory process Effects 0.000 abstract 1
- 229940002612 prodrug Drugs 0.000 abstract 1
- 239000000651 prodrug Substances 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 231100000397 ulcer Toxicity 0.000 abstract 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 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 3
- 229960001475 zolpidem Drugs 0.000 description 3
- HVPPJXIGEZYEGQ-UHFFFAOYSA-N 3-bromo-2-phenylimidazo[1,2-a]pyridine Chemical compound N1=C2C=CC=CN2C(Br)=C1C1=CC=CC=C1 HVPPJXIGEZYEGQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- YRMLUAGKHYADKJ-UHFFFAOYSA-N necopidem Chemical compound C1=CC(CC)=CC=C1C1=C(CN(C)C(=O)CC(C)C)N2C=C(C)C=CC2=N1 YRMLUAGKHYADKJ-UHFFFAOYSA-N 0.000 description 2
- 229950002306 necopidem Drugs 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- PAJUGVYKHDMQCN-UHFFFAOYSA-N 2-(4-chlorophenyl)-3-iodoimidazo[1,2-a]pyridine Chemical compound Clc1ccc(cc1)-c1nc2ccccn2c1I PAJUGVYKHDMQCN-UHFFFAOYSA-N 0.000 description 1
- WVQAVPXMFNTXDN-UHFFFAOYSA-N 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbonitrile Chemical compound C1=CC(Cl)=CC=C1C1=C(C#N)N2C=CC=CC2=N1 WVQAVPXMFNTXDN-UHFFFAOYSA-N 0.000 description 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- KXOFIOXIXKPCIS-UHFFFAOYSA-N 3-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine Chemical compound BrC1=C(N=C2N1C=CC=C2)C1=CC=C(C=C1)Cl KXOFIOXIXKPCIS-UHFFFAOYSA-N 0.000 description 1
- 102000004300 GABA-A Receptors Human genes 0.000 description 1
- 108090000839 GABA-A Receptors Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229940127590 IRAK4 inhibitor Drugs 0.000 description 1
- 102000001419 Melatonin receptor Human genes 0.000 description 1
- 108050009605 Melatonin receptor Proteins 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- QUDMHFVRKBVGBY-FQEVSTJZSA-N [5-(4-methylpiperazin-1-yl)-2-[[methyl-[(8s)-5,6,7,8-tetrahydroquinolin-8-yl]amino]methyl]imidazo[1,2-a]pyridin-3-yl]methanol Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC(=C(N12)CO)N=C1C=CC=C2N1CCN(C)CC1 QUDMHFVRKBVGBY-FQEVSTJZSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000005518 electrochemistry Effects 0.000 description 1
- 238000006056 electrooxidation reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- MBVAHHOKMIRXLP-UHFFFAOYSA-N imidazo[1,2-a]pyrazine Chemical compound C1=CN=CC2=NC=CN21 MBVAHHOKMIRXLP-UHFFFAOYSA-N 0.000 description 1
- JMANUKZDKDKBJP-UHFFFAOYSA-N imidazo[1,5-a]pyridine Chemical compound C1=CC=CC2=CN=CN21 JMANUKZDKDKBJP-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 description 1
- 229950011129 minodronic acid Drugs 0.000 description 1
- OJGQFYYLKNCIJD-UHFFFAOYSA-N miroprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CN(C=CC=C2)C2=N1 OJGQFYYLKNCIJD-UHFFFAOYSA-N 0.000 description 1
- 229950006616 miroprofen Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940000041 nervous system drug Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical compound C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- LIFDPEORUVTOCP-UHFFFAOYSA-N saripidem Chemical compound N1=C2C=CC=CN2C(CN(C)C(=O)CCC)=C1C1=CC=C(Cl)C=C1 LIFDPEORUVTOCP-UHFFFAOYSA-N 0.000 description 1
- 229950007359 saripidem Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
Abstract
The invention discloses a preparation method of a C-3 halogenated imidazo [1,2-a ] pyridine derivative, belonging to the field of organic synthesis. The method takes imidazo [1,2-a ] pyridine as a starting material, cuprous halide as a halogen source and oxygen as a catalyst, and the C-3 halogenated imidazo [1,2-a ] pyridine derivative is obtained by column chromatography separation after reaction. Compared with the prior art, the method has the advantages of high reaction yield, simple post-treatment and suitability for industrial production. The prepared C-3 halogenated imidazo [1,2-a ] pyridine derivative can be used as a prodrug and has various biological activities and pharmacological effects of resisting bacteria, viruses, ulcers and tumors, resisting inflammation, relieving pain, relieving fever, treating neurological diseases and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a synthesis method of imidazo [1,2-a ] pyridine derivatives, in particular to a preparation method of C-3 halogenated imidazo [1,2-a ] pyridine derivatives.
Background
Nitrogen-containing heterocycles are a class of ubiquitous motifs, have a heterocyclic skeleton formed by fusing simple heterocycles or benzene rings, and are widely used in the fields of medicinal chemistry, material science, and the like because of their wide biological, medical, and optical activities, such as imidazo [1,2-a ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyrazine, indomethamine, and pyrazolo [1,5-a ] pyridine, and the like. Among them, imidazo [1,2-a ] pyridine skeleton is found in a large number of natural products, and many exhibit remarkable biological activities, and thus has been receiving attention from scientists.
The compound containing imidazo [1,2-a ] pyridine nucleus has various biological activities and pharmacological actions such as antibiosis, antivirus, antiulcer, antitumor, anti-inflammatory, analgesic, antipyretic and treatment of neurological diseases, and particularly, different substituents on C-3 position of imidazo [1,2-a ] pyridine can directly influence the biological activity. For example, C-3 alkylated imidazo [1,2-a ] pyridines are useful as GABA, potent IRAK-4 inhibitors, benzodiazepine receptor agonists, GnRH antagonists and cardiotonic agents. The imidazo [1,2-a ] pyridine skeleton is also present in many commercially available drugs such as thalipidem (anxiolytic), zolpidem (hypnotic), minodronic acid (anti-osteoporosis, anxiety and heart failure), zolpidem (for peptic ulcers), zolpidem, azolopyridine, apintan, nopide, miroprofen, Olprione, opropiolinone and GSK812397 (anti-HIV) molecules.
N-heterocyclic compounds are important molecules, not only have unique biological activity, but also have interesting chemical properties, and are also researched in the field of material science. Besides the synthesis research of imidazo [1,2-a ] pyridine compounds in medicinal chemistry, the scaffold is also successfully applied to the field of material science. In fact, they exhibit interesting optical properties with high fluorescence quantum yields.
At present, the strategies for synthesizing C-3 halogenated imidazo [1,2-a ] pyridine compounds mainly comprise methods of electrochemical oxidation, photochemical oxidation, alkali metal salt oxidation catalysis and the like by taking NXS and NaX as halogen sources. Although there are many methods for synthesizing C-3 haloimidazo [1,2-a ] pyridines, these methods suffer from disadvantages such as the need for expensive reagents, the need for more toxic starting materials or substrates, and the need for multi-step preparation. C-3 substituted imidazo [1,2-a ] pyridines are important block and multifunctional complexes and can be further substituted by cross-coupling reactions to produce a range of biologically active 3-substituted imidazo [1,2-a ] pyridine derivatives, with different substitutions at the 3-position of the imidazo [1,2-a ] pyridine leading to different drug properties. Therefore, it is highly desirable to exploit the structural diversity of imidazo [1,2-a ] pyridine derivatives and integrate functions at the C-3 position, which facilitates further functionalization.
Disclosure of Invention
The invention aims to provide a novel preparation method which has high yield and simple post-treatment and is suitable for industrial production of 3-halogenated imidazo [1,2-a ] pyridine derivatives.
To achieve the purpose of the invention, the reaction route of the invention is as follows:
preferably:
the reaction steps of the invention are as follows:
under the action of oxygen, adding an imidazo [1,2-a ] pyridine compound, cuprous halide and a solvent into a reaction bottle, then reacting under the condition of heating (120 ℃), after the reaction is finished, washing the reaction liquid with water and saturated saline water respectively, extracting with ethyl acetate, and separating an organic layer by column chromatography to obtain a corresponding C-3 halogenated imidazo [1,2-a ] pyridine compound;
the molar ratio of the imidazo [1,2-a ] pyridine compound to cuprous halide is 1: 1-3.
The solvent is selected from N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or glacial acetic acid, and preferably N, N-dimethylformamide.
The possible mechanism of the present invention is presumed to be as follows:
the biological activity application of the C-3 halogenated imidazo [1,2-a ] pyridine derivative provided by the invention is as follows:
1) as an intermediate for synthesizing a selective melatonin receptor ligand, the intermediate can be synthesized from 2-phenyl-3-bromoimidazo [1,2-a ] pyridine by the following operation steps.
2) The thalipidem (Saripidem) is used as a central nervous system drug for treating mental disorder and anxiety, and the Necopidem (Necopidem) is used as an anesthetic and an auxiliary drug thereof and is applied to medicines. 2-p-chlorophenyl-3-iodoimidazo [1,2-a ] pyridine is used as a raw material, and is firstly converted into 2-p-chlorophenyl-3-cyanoimidazo [1,2-a ] pyridine, and then the two kinds of medicinal active molecules can be synthesized through operations such as reductive amination and the like. The reaction process is shown as the following formula:
the invention has the beneficial effects that: imidazo [1,2-a ] pyridine compounds are used as initial raw materials, cuprous halide is used as a halogen source, oxygen is used as a catalyst to react to generate C-3 halogenated imidazo [1,2-a ] pyridine compounds, the use of alkali metal catalysts, electrochemistry and photochemistry in the traditional process is changed, and the use of expensive raw materials for providing halogen sources is avoided. The reaction is simple to operate, mild in condition, free of other impurities, capable of generating the 3-halogenated imidazo [1,2-a ] pyridine compound with the yield of more than 69%, wide in functional group tolerance, wide in substrate range for products and more suitable for industrial production. The prepared 3-halogenated imidazo [1,2-a ] pyridine compound can be effectively applied to the fields of organic drug synthesis, organic photoelectric materials, medicines, biological probes, fluorescent dyes and the like.
Detailed Description
To better illustrate the invention, the following examples are given:
EXAMPLE 12 Synthesis of phenyl-3-bromoimidazo [1,2-a ] pyridine
Adding 2-phenylimidazo [1,2-a ] into a round-bottom flask under the action of oxygen]Pyridine (1.5mmol,300 mg), cuprous bromide (1.8mmol,266mg) and 8ml N, N-dimethylformamide, then reacted in an oil bath at 120 ℃ for 6 h. The reaction solution was washed with water and saturated brineWashing, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, and separating by column chromatography to obtain 2-phenyl-3-bromoimidazo [1,2-a ]]Pyridine 405mg, yield 96.2%;1H NMR(400MHz,CDCl3)δ8.16(dd,J＝7.8,5.8Hz,3H),7.65 (d,J＝9.0Hz,1H),7.50(t,J＝7.4Hz,2H),7.41(t,J＝7.4Hz,1H), 7.28-7.23(m,1H),6.92(td,J＝6.8Hz,1.0Hz,1H)。
example Synthesis of 22-phenyl-3, 6-dibromoimidazo [1,2-a ] pyridine
Adding 2-phenyl-6-bromoimidazo [1,2-a ] into a round-bottom flask under the action of oxygen]Pyridine (1.1 mmol,300mg), cuprous bromide (1.3mmol,189mg) and 8ml N, N-dimethylformamide, then reacted in an oil bath at 120 ℃ for 6 h. Washing the reaction solution with water and saturated saline solution respectively, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, and separating by column chromatography to obtain 2-phenyl-3, 6-dibromo-imidazo [1,2-a ]]Pyridine 305mg, yield 78.9%;1H NMR(400MHz,CDCl3)δ8.34(s,1H),8.12(d, J＝7.7Hz,2H),7.56-7.48(m,3H),7.42(t,J＝7.4Hz,1H),7.34(dd, J＝9.5Hz,1.8Hz,1H)。
EXAMPLE synthesis of 32-phenyl-6-chloro-3-bromoimidazo [1,2-a ] pyridine
Adding 2-phenyl-6-chloroimidazo [1,2-a ] into a round-bottom flask under the action of oxygen]Pyridine (1.3mmol, 300mg), cuprous bromide (1.6mmol,226mg) and 8ml N, N-dimethylformamide, then reacted in an oil bath at 120 ℃ for 6 h. Washing the reaction solution with water and saturated saline solution respectively, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, and separating by column chromatography to obtain 2-phenyl-6-chloro-3-bromoimidazo [1,2-a ]]279mg of pyridine, yield 69.8%;1H NMR(400MHz,CDCl3)δ8.25(s,1H),8.12(d, J＝7.7Hz,2H),7.61(d,J＝9.5Hz,1H),7.51(t,J＝7.3Hz,2H),7.42 (t,J＝7.4Hz,1H),7.26-7.23(m,1H)。
EXAMPLE 42 Synthesis of (4-chloro) phenyl-3-bromoimidazo [1,2-a ] pyridine
Adding 2- (4-chloro) phenylimidazo [1,2-a ] into a round-bottom flask under the action of oxygen]Pyridine (1.3mmol, 300mg), cuprous bromide (1.6mmol,226mg) and 8ml N, N-dimethylformamide, then reacted in an oil bath at 120 ℃ for 6 h. The reaction mixture was washed with water and saturated brine, and ethyl acetateExtracting the ester, drying the organic layer with anhydrous sodium sulfate, and separating by column chromatography to obtain 2- (4-chloro) phenyl-3-bromoimidazo [1,2-a ]]Pyridine 343mg, yield 85.8%;1H NMR(400MHz,CDCl3)δ8.16-8.10(m,1H),8.09– 8.05(m,2H),7.61(d,J＝9.1Hz,1H),7.46–7.40(m,2H),7.28–7.21 (m,1H),6.94–6.87(m,1H)。
example Synthesis of 52- (4-bromo) phenyl-3-bromoimidazo [1,2-a ] pyridine
Adding 2- (4-bromine) phenylimidazo [1,2-a ] into a round-bottom flask under the action of oxygen]Pyridine (1.1 mmol,300mg), cuprous bromide (1.3mmol,189mg) and 8ml N, N-dimethylformamide, then reacted in an oil bath at 120 ℃ for 6 h. Washing the reaction solution with water and saturated saline solution respectively, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, and separating by column chromatography to obtain 2- (4-bromo) phenyl-3-bromoimidazo [1,2-a ]]Pyridine 370mg, yield 95.6%;1H NMR(400MHz,CDCl3)δ8.08(dd,J＝6.9,1.3 Hz,1H),8.03-7.95(m,2H),7.70–7.48(m,3H),7.27-7.15(m,1H),6.95– 6.80(m,1H)。
Claims (3)
1. a method for preparing imidazo [1,2-a ] pyridine derivatives, characterized in that it is carried out by the following steps: under the action of oxygen, adding an imidazo [1,2-a ] pyridine compound of a formula 1, an N, N-dimethylformamide solvent and cuprous halide of a formula 2 into a reaction bottle, then reacting under a heating condition, and stopping the reaction after the reaction is finished; washing the reaction solution with water and saturated saline solution respectively, extracting with ethyl acetate, and separating the organic phase by column chromatography to obtain C-3 halogenated imidazo [1,2-a ] pyridine compounds of formula 3;
2. a process for the preparation of imidazo [1,2-a ] pyridine derivatives according to claim 1, characterized by the following substituents:
3. the process for producing an imidazo [1,2-a ] pyridine derivative according to claim 1 or 2, wherein the molar ratio of the imidazo [1,2-a ] pyridine compound to cuprous halide is 1:1 to 3.
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| CN107118210A (en) * | 2017-04-28 | 2017-09-01 | 贵州大学 | A kind of 3 iodine 6（Trifluoromethyl）The preparation technology of imidazo [1,2 a] pyridine |
| CN111004234A (en) * | 2019-11-28 | 2020-04-14 | 湖南农业大学 | C3-site halogenation method of 2-phenylimidazo [1,2- α ] pyridine compound |
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| CN107118210A (en) * | 2017-04-28 | 2017-09-01 | 贵州大学 | A kind of 3 iodine 6（Trifluoromethyl）The preparation technology of imidazo [1,2 a] pyridine |
| CN111004234A (en) * | 2019-11-28 | 2020-04-14 | 湖南农业大学 | C3-site halogenation method of 2-phenylimidazo [1,2- α ] pyridine compound |
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| QIAODONG WEN等: "Copper-mediated three-component synthesis of 3-cyanoimidazo[1,2-a]pyridines" * |
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