CN105837579A - Method for preparing multi-substituted benzo-[4,5]imidazo-[1,2-b] pyrazole derivative - Google Patents
Method for preparing multi-substituted benzo-[4,5]imidazo-[1,2-b] pyrazole derivative Download PDFInfo
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- SCAVIRZESCFSPE-UHFFFAOYSA-N 1h-pyrazolo[1,5-a]benzimidazole Chemical class C1=CC=C2N(NC=C3)C3=NC2=C1 SCAVIRZESCFSPE-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000000758 substrate Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- -1 substituted-phenyl Chemical group 0.000 claims description 6
- MFGQIJCMHXZHHP-UHFFFAOYSA-N 5h-imidazo[1,2-b]pyrazole Chemical class N1C=CC2=NC=CN21 MFGQIJCMHXZHHP-UHFFFAOYSA-N 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 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
- 238000012545 processing Methods 0.000 claims description 2
- 150000003217 pyrazoles Chemical class 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims 1
- 125000005594 diketone group Chemical group 0.000 claims 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims 1
- 239000002243 precursor Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 12
- 238000010189 synthetic method Methods 0.000 abstract description 7
- 239000000047 product Substances 0.000 abstract description 5
- 239000012043 crude product Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 abstract description 3
- 239000000706 filtrate Substances 0.000 abstract description 3
- 239000012074 organic phase Substances 0.000 abstract description 3
- 238000010898 silica gel chromatography Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 238000001914 filtration Methods 0.000 abstract description 2
- 239000012141 concentrate Substances 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000000605 extraction Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- NJOHZFQUJCXUPR-UHFFFAOYSA-N 1h-benzimidazole;1h-pyrazole Chemical class C=1C=NNC=1.C1=CC=C2NC=NC2=C1 NJOHZFQUJCXUPR-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- KSCRVOKQPYZBHZ-IXPOFIJOSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(C)C)C(=O)OCC1=CC=CC=C1 KSCRVOKQPYZBHZ-IXPOFIJOSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000813090 Rhizoctonia solani Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241000589636 Xanthomonas campestris Species 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 125000005251 aryl acyl group Chemical group 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- 238000006480 benzoylation reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- PTFYQSWHBLOXRZ-UHFFFAOYSA-N imidazo[4,5-e]indazole Chemical class C1=CC2=NC=NC2=C2C=NN=C21 PTFYQSWHBLOXRZ-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 208000004124 rheumatic heart disease Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of organic synthesis and discloses a method for preparing a multi-substituted benzo-[4,5]imidazo-[1,2-b] pyrazole derivative. The method comprises the steps of adding N-(2-bromoaryl)-5-aryl-1H-pyrazole-3-amine compounds, caesium carbonate, catalyst cuprous iodide and ligand 3-(imidazolidine-2-subunit)pentane-2,4-diketone and solvent dimethylsulfoxide (DMSO) into a reactor, performing heating until the reaction is over, cooling a system to room temperature, adding water, using ethyl acetate to perform extraction three times, combining organic phases, adding anhydrous magnesium sulfate to perform drying and filtration, using a rotary evaporator to concentrate filtrate to obtain a crude product, and performing separation through silica gel column chromatography to obtain a product. The method for preparing the multi-substituted benzo-[4,5]imidazo-[1,2-b] pyrazole derivative has the advantages that the method is scientific and reasonable, the reaction is quick, a synthetic method is simple, the yield is high, and the product is easy to purify. The reaction equation is as follows: .
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to the preparation method of a kind of polysubstituted benzo [4,5] imidazo [1,2-b] pyrazole derivatives.
Background technology
Benzimidazole pyrazole derivatives are the heterocyclic compounds that a class is important.A lot of benzimidazoles pyrazoles and derivative thereof have physiologically active and pharmacologically active widely, such as anti-inflammatory, antibacterial and be used for treating angiocardiopathy, rheumatic heart disease etc..
Research finds, benzimidazole pyrazole derivatives have inhibitory action well to the growth of bacterium (such as: Escherichia coli, Xanthomonas campestris etc.) and fungi (such as: aspergillus fumigatus, Rhizoctonia solani Kuhn etc.).It is expected to become treatment bacteriosis, mycotic a kind of active drug, causes extensive concern and the research (Phosphorus, Sulfur and Silicon and the Related Elements 2006,181,2,051 2061) of people.
Benzimidazole pyrazole derivatives have extensive use in various fields, and therefore the synthesis of these compounds has the meaning of particular importance.
The preparation method of benzimidazole pyrazole derivatives has:
1) Junjappa synthetic method: with DMF for solvent in the presence of CuI, L-PROLINE, highly basic NaH, add thermal response and make N-(bromo aryl)-1H-pyrazoles-5-aminated compounds generation intramolecular N-aromatisation, obtain 4H-benzo [4,5] imidazo [1,2-b] pyrazole derivatives.
2) V.V.Kuz'menko synthetic method: in the presence of potassium carbonate, 1-amino-2-methyl-3R-benzoglioxaline salt and acetic anhydride occur to be acylated and cyclization, obtain 4H-benzo [4,5] imidazo [1,2-b] pyrazole derivatives.
3) T.A.Kuz ' menko synthetic method: in the presence of triethylamine; aryl formyl chloride and 1-benzyl imines-2-tolimidazole first carry out benzoylation reaction on methyl; then under concentrated hydrochloric acid effect, remove a part benzaldehyde and then cyclization occurs; finally give 4H-benzo [4; 5] imidazo [1,2-b] pyrazole derivatives.
4) Ali Deeb synthetic method: 5-azido-3-methyl-4-nitro-1-phenyl-1H-pyrazoles and methanesulfonic acid are heated slowly to 102 DEG C in 10 minutes under nitrogen atmosphere, then continues reaction 10 minutes at 125 DEG C.React through a nitrence intermediate, then nitrence intermediate generation cyclization, finally give 2-methyl-3-nitro-4H-benzo [4,5] imidazo [1,2-b] pyrazoles.
Utilizing said method to prepare polysubstituted benzo imidazolopyrazole derivatives in the lab, there is obvious shortcoming: 1) synthesis step is many, and operation is complicated and the reaction time is longer.2) agents useful for same sodium hydride has strong basicity, and aryl-acyl chlorides, triethylamine, concentrated hydrochloric acid have excitant and environment is unfriendly.
Summary of the invention
In order to overcome above-mentioned the deficiencies in the prior art, the invention provides the preparation method of a kind of polysubstituted benzo [4,5] imidazo [1,2-b] pyrazole derivatives.
A kind of preparation method of polysubstituted benzo [4,5] imidazo [1,2-b] pyrazole derivatives, described polysubstituted benzo [4,5] imidazo [1,2-b] pyrazole derivatives has a structure shown in formula I:
In formula I, wherein R1Selected from hydrogen atom, fluorine atom, methyl；R2Selected from phenyl and substituted-phenyl, replacing atom is fluorine atom, chlorine atom, bromine atoms, methyl；In reactor, add N-(2-bromine aryl)-5-aryl-1H-pyrazoles-3-aminated compounds, cesium carbonate, catalyst cuprous iodide, part 3-(imidazolidine-2-subunit) pentane-2,4-diketone, solvent is DMSO, is heated to reacting complete, and system is cooled to room temperature, add water, extract in three times with ethyl acetate, merge organic phase, add anhydrous magnesium sulfate to be dried, filtering, Rotary Evaporators concentrated filtrate obtains crude product, separates to obtain product with silica gel column chromatography；Its chemical process is shown in reaction Formula II:
Described reaction substrate is N-(2-bromine aryl)-5-aryl-1H-pyrazoles-3-aminated compounds, add relative to the cesium carbonate that reaction substrate mol ratio is 2 and be relative to reaction substrate mol ratio 0.2 catalyst CuI, part 3-(imidazolidine-2-subunit) pentane-2,4-diketone, solvent is selected from DMSO, and needs not move through Non-aqueous processing before use.Reaction time is 10min, and reaction temperature is 120 DEG C, and eluant, eluent used by column chromatography is petroleum ether: ethyl acetate=4:1.
The invention have the benefit that the polysubstituted benzo [4 that the present invention provides, 5] synthetic method of imidazo [1,2-b] pyrazole derivatives is scientific and reasonable, can synthesize the polysubstituted benzo [4 obtaining having multiple substituent, 5] imidazo [1,2-b] pyrazole derivatives；And be swift in response, synthetic method is simple, and productivity is higher, product is prone to the features such as purifying.
Accompanying drawing explanation
Fig. 1 is the compound 2a of embodiment 1 preparation1H NMR spectra；
Fig. 2 is the compound 2a of embodiment 1 preparation13C NMR spectra；
Fig. 3 is the compound 2c of embodiment 3 preparation1H NMR spectra；
Fig. 4 is the compound 2c of embodiment 3 preparation13C NMR spectra；
Fig. 5 is the compound 2i of embodiment 9 preparation1H NMR spectra；
Fig. 6 is the compound 2i of embodiment 9 preparation13C NMR spectra.
Detailed description of the invention
The present invention is described in more detail with specific embodiment below in conjunction with the accompanying drawings:
Test method described in following embodiment, if no special instructions, is conventional method；Described reagent and material, if no special instructions, the most commercially obtain.
Embodiment 1
1) benzimidazole the preparation of pyrazole derivatives 2a
N-(2-bromophenyl)-5-phenyl-1H-pyrazoles-3-amine 1a (94.25mg is added in 50mL round-bottomed flask, 0.3mmol), catalyst cuprous iodide (11.43mg, 0.06mmol), part 3-(imidazolidine-2-subunit) pentane-2,4-diketone (10.11mg, 0.06mmol), cesium carbonate (195.5mg, 0.6mmol) with DMSO (1mL), it is placed in 120 DEG C of oil baths stirring.TLC detection reaction substrate disappears, and reaction terminates.After reaction system is cooled to room temperature, adds 5mL water, then extract in three times with 30mL ethyl acetate, merge organic phase, and use anhydrous MgSO4Being dried 30 minutes, filter, filtrate is concentrated to give crude product with Rotary Evaporators.Crude product is separated by silica gel column chromatography (eluant, eluent PE:EA=4:1), utilizes Rotary Evaporators to be concentrated to give pure products, turns out to be benzimidazole pyrazole derivatives 2a through NMR, HRMS, and its yield is 92%.
Spectrum elucidation data 2a:
1H NMR(CDCl3, 500MHz): δ 7.93 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.88 7.89 (m, 1H), 7.43 (t, J=7.6Hz, 2H), 7.32 7.35 (m, 2H), 7.27 7.28 (m, 1H), 7.23 7.25 (m, 1H), 6.11 (s, 1H, NH)；13C NMR(CDCl3,125MHz):δ110.7,111.4,121.3,123.4,126.1,128.0,128.7,134.2,134.9,156.6；HRMS(ESI-TOF,[M+H]+):calcd for C15H12N3 234.1031,found 234.1039.
Embodiment 2
Replacing the 1a in example 1 with 1b, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 2b:
1H NMR(DMSO-d6, 500MHz): δ 11.52 (s, 1H), 7.94 7.97 (m, 2H), 7.76 (d, J=7.9Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 7.23 7.29 (m, 3H), 7.17 7.20 (m, 1H), 6.32 (s, 1H)；13C NMR(DMSO-d6,125MHz):δ80.3,112.7,114.9,118.5(2JC – F=21.2Hz), 123.2,126.3,128.4,130.4 (3JC – F=8.5Hz), 133.8,138.3,148.0,157.1,164.8 (1JC – F=241.9Hz)；HRMS(ESI-TOF,[M+H]+):calcd for C15H11FN3 252.0937,found 252.0939.
Embodiment 3
Replacing the 1a in example 1 with 1c, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 2c:
1H NMR(DMSO-d6, 500MHz): δ 11.57 (s, 1H), 7.78 7.98 (m, 2H), 7.79 (d, J=10.8Hz, 1H), 7.47 7.51 (m, 2H), 7.45 (d, J=8.4Hz, 1H), 7.27 7.32 (m, 1H), 7.19 7.23 (m, 1H), 6.38 (s, 1H)；13C NMR(DMSO-d6,125MHz):δ77.9,110.2,112.4,120.6,123.9,125.8,127.6,129.0,132.6,133.6,135.8,145.4,154.2；HRMS(ESI-TOF,[M+H]+):calcd for C15H11ClN3 268.0642,found 268.0652.
Embodiment 4
Replacing the 1a in example 1 with 1d, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 2d:
1H NMR(DMSO-d6, 500MHz): δ 11.55 (s, 1H), 7.87 7.89 (m, 1H), 7.77 (d, J=7.85Hz, 1H), 7.60 7.62 (m, 2H), 7.43 (d, J=7.95Hz, 1H), 7.25 7.30 (m, 1H), 7.18 7.21 (m, 2H), 6.36 (s, 1H)；13C NMR(DMSO-d6,125MHz):δ78.0,110.2,112.4,120.7,121.1,123.9,125.8,127.9,131.9,134.0,135.8,145.4,154.2；HRMS(ESI-TOF,[M+H]+):calcd for C15H11BrN3 312.0136,found 312.0142.
Embodiment 5
Replacing the 1a in example 1 with 1e, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 2e:
1H NMR(DMSO-d6, 500MHz): δ 11.49 (s, 1H), 7.80 (d, J=7.8Hz, 2H), 7.75 (d, J=7.8Hz, 1H), 7.41 (d, J=7.9Hz, 1H), 7.17 7.25 (m, 4H), 6.27 (s, 1H), 2.31 (s, 3H)；13C NMR(DMSO-d6,125MHz):δ21.4,77.6,110.2,112.3,120.6,123.7,125.9,129.7,135.7,137,5,145.4,155.6；HRMS(ESI-TOF,[M+H]+):calcd for C16H14N3248.1188,found 248.1192.
Embodiment 6
Replacing the 1a in example 1 with 1f, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 2f:
1H NMR(DMSO-d6, 500MHz): δ 11.56 (s, 1H), 7.93 7.95 (m, 2H), 7.77 (d, J=7.7Hz, 1H), 7.46 7.48 (m, 2H), 7.43 (d, J=8.7Hz, 1H), 7.27 7.30 (m, 1H), 7.18 7.21 (m, 1H), 6.36 (s, 1H)；13C NMR(DMSO-d6,125MHz):δ78.1,110.3,112.5,120.8,124.0,125.8,127.6,129.1,132.7,133.6,135.8,145.4,154.2；HRMS(ESI-TOF,[M+H]+):calcd for C15H11ClN3 268.0642,found 268.0652.
Embodiment 7
Replacing the 1a in example 1 with 1g, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 2g:
1H NMR(DMSO-d6, 500MHz): δ 11.54 (s, 1H), 7.88 (d, J=7.3Hz, 1H), 7.79 (d, J=7.9Hz, 1H), 7.54 (d, J=7.7Hz, 1H), 7.46 (d, J=7.9Hz, 1H), 7.37 7.43 (m, 2H), 7.30 (t, J=7.7Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 6.28 (s, 1H)；13C NMR(DMSO-d6,125MHz):δ81.8,110.5,112.6,120.7,124.1,125.7,127.7,129.8,130.8,131.5,125.7,144.6,152.8；HRMS(ESI-TOF,[M+H]+):calcd for C15H11ClN3 268.0642,found 268.0653.
Embodiment 8
Replacing other conditions of 1a in example 1 with example 1 with 1h, experimental result is shown in Table 1.
Spectrum elucidation data 2h:
1H NMR(DMSO-d6, 500MHz): δ 11.59 (s, 1H), 7.92 (d, J=8.5Hz, 1H), 7.80 (d, J=7.9Hz, 1H), 7.70 7.72 (m, 1H), 7.50 (dd, J=8.5,2.0Hz, 1H), 7.47 (d, J=8Hz, 1H), 7.31 (t, J=7.5Hz, 1H), 7.21 (t, J=7.6Hz, 1H), 6.33 (s, 1H)；13C NMR(DMSO-d6,125MHz):δ81.7,110.4,112.6,120.7,124.2,125.7,127.9,130.1,132.2,133.3,135.7,144.7,151.6；HRMS(ESI-TOF,[M+H]+):calcd for C15H10Cl2N3302.0252,found 302.0249.
Embodiment 9
Replacing other conditions of 1a in example 1 with example 1 with 1i, experimental result is shown in Table 1.
Spectrum elucidation data 2i:
1H NMR(DMSO-d6, 500MHz): δ 11.61 (s, 1H), 7.96 7.97 (m, 1H), 7.94 7.95 (m, 1H), 7.69 (dd, J=8.5,2.0Hz, 1H), 7.48 7.51 (m, 2H), 7.44 (dd, J=8.9,4.4Hz, 1H), 7.13 7.17 (m, 1H), 6.38 (s, 1H)；13C NMR(DMSO-d6,125MHz):δ82.9,102.7(2JC – F=28.5Hz), 115.7 (2JC – F=24.8Hz), 117.9 (3JC – F=9.5Hz), 130.5 (3JC – F=7.8Hz), 132.5,133.9,137.1,137.7,138.1,151.5,159.6,162.2 (1JC – F=248.5Hz)；HRMS(ESI-TOF,[M+H]+):calcd for C15H10BrFN3 330.0042,found 330.0051.
Embodiment 10
Replacing the 1a in example 1 with 1j, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 2j:
1H NMR(DMSO-d6, 500MHz): δ 11.51 (s, 1H), 7.80 (d, J=7.8Hz, 2H), 7.60 7.70 (m, 1H), 7.40 (dd, J=8.6,4.3Hz, 1H), 7.22 (d, J=7.7Hz, 2H), 7.09 7.11 (m, 1H), 6.27 (s, 1H), 2.32 (s, 3H, CH3)；13C NMR(DMSO-d6,125MHz):δ21.3,77.6,97.8(2JC – F=28.4Hz), 110.6 (2JC – F=24.9Hz), 112.9 (3JC – F=11.4Hz), 125.9,129.6,131.8,132.2,137.7,146.7,156.2,157.3 (1JC – F=236.7Hz)；HRMS(ESI-TOF, [M+H]+):calcd for C16H13FN3 266.1094,found 266.1086.
Table 1
Claims (3)
1. the preparation method of polysubstituted benzo [4,5] imidazo [1, a 2-b] pyrazole derivatives, described polysubstituted
Benzo [4,5] imidazo [1,2-b] pyrazole derivatives has a structure shown in formula I:
In formula I, wherein R1Selected from hydrogen atom, fluorine atom, methyl；R2Selected from phenyl and substituted-phenyl, take
It is fluorine atom, chlorine atom, bromine atoms, methyl for atom；It is characterized in that, with N-(2-bromine aryl)-5-aryl
-1H-pyrazoles-3-aminated compounds is precursor, at cesium carbonate, cuprous iodide and part 3-(imidazolidine-2-subunit)
Pentane-2, under the effect of 4-diketone, heat the complete polysubstituted benzo obtained shown in formula I of fast reaction in solvent
[4,5] imidazo [1,2-b] pyrazole derivatives；This preparation method below equation represents:
Preparation method the most according to claim 1, it is characterised in that reaction substrate is N-(2-bromine virtue
Base)-5-aryl-1H-pyrazoles-3-aminated compounds, add relative to the cesium carbonate that reaction substrate mol ratio is 2 and
Catalyst CuI, part 3-(imidazolidine-2-subunit) pentane-2,4-of 0.2 it is relative to reaction substrate mol ratio
Diketone, solvent is DMSO and needs not move through Non-aqueous processing before use, 120 DEG C of stirring reactions.
Preparation method the most according to claim 1, it is characterised in that the reaction time is 10 minutes, reaction
Temperature is 120 DEG C.
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