CN108383795B - 1-benzimidazole-N-amide derivative and preparation method thereof - Google Patents
1-benzimidazole-N-amide derivative and preparation method thereof Download PDFInfo
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- CN108383795B CN108383795B CN201810430827.4A CN201810430827A CN108383795B CN 108383795 B CN108383795 B CN 108383795B CN 201810430827 A CN201810430827 A CN 201810430827A CN 108383795 B CN108383795 B CN 108383795B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 substituted aryl aldehyde Chemical class 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 27
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000005457 ice water Substances 0.000 claims description 17
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 11
- 235000019439 ethyl acetate Nutrition 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 2
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 11
- 238000011161 development Methods 0.000 abstract description 7
- 239000000575 pesticide Substances 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000003899 bactericide agent Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 150000001556 benzimidazoles Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- WEEMDRWIKYCTQM-UHFFFAOYSA-N 2,6-dimethoxybenzenecarbothioamide Chemical compound COC1=CC=CC(OC)=C1C(N)=S WEEMDRWIKYCTQM-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241000589615 Pseudomonas syringae Species 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- TWFZGCMQGLPBSX-UHFFFAOYSA-N carbendazim Chemical compound C1=CC=C2NC(NC(=O)OC)=NC2=C1 TWFZGCMQGLPBSX-UHFFFAOYSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960002385 streptomycin sulfate Drugs 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- HGINADPHJQTSKN-UHFFFAOYSA-M 3-ethoxy-3-oxopropanoate Chemical compound CCOC(=O)CC([O-])=O HGINADPHJQTSKN-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229940122236 Histamine receptor antagonist Drugs 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RIOXQFHNBCKOKP-UHFFFAOYSA-N benomyl Chemical compound C1=CC=C2N(C(=O)NCCCC)C(NC(=O)OC)=NC2=C1 RIOXQFHNBCKOKP-UHFFFAOYSA-N 0.000 description 1
- MITFXPHMIHQXPI-UHFFFAOYSA-N benzoxaprofen Natural products N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000006013 carbendazim Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical compound FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- YFNCATAIYKQPOO-UHFFFAOYSA-N thiophanate Chemical compound CCOC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OCC YFNCATAIYKQPOO-UHFFFAOYSA-N 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a 1-benzimidazole-N-amide derivative and a preparation method thereof. Firstly synthesizing 1-benzimidazole-N-ethyl formylacetate, and then reacting with substituted aryl aldehyde to generate the 1-benzimidazole-N-amide derivative. The preparation method disclosed by the invention is simple in operation process and high in yield, and the prepared 1-benzimidazole-N-amide derivative has good antibacterial activity, can be well applied to the fields of medicines and agricultural medicines, provides a new thought for creating new pesticides, and has a good development prospect.
Description
Technical Field
The invention relates to a 1-benzimidazole-N-amide derivative and a preparation method thereof, belonging to the technical field of chemical synthesis.
Background
The benzimidazole compound has wide biological activity, a plurality of drugs containing benzimidazole structural fragments are clinically used, and the benzimidazole compound has application in the fields of histamine receptor antagonists, proton pump inhibitors, hypertension resistance, parasite resistance, bacteria resistance, fungi resistance, virus resistance, cancer resistance and the like, and the research and development of the benzimidazole compound are active. The discovery of new drugs cannot be separated from the development of new compounds based on lead compounds, and the competitiveness of drugs depends on the synthesis design thought and preparation process of raw material drugs to a great extent, so that the design and synthesis of novel benzimidazole compounds have important significance in the screening, activity research and supply of medical intermediates of new clinical drugs.
In addition, in the field of agricultural chemicals, benzimidazole compounds are also widely used as bactericides, and representative compounds include benomyl, carbendazim, thiophanate and the like. However, in recent years, due to the long-term use of such fungicides, the resistance of pathogenic microorganisms has been increased, and the bactericidal effect has been reduced, so the development and development of novel, highly effective and alternative benzimidazoles fungicides is an important research topic.
Disclosure of Invention
In order to solve the problem that the existing bactericide has increasingly serious drug resistance and urgently needs to carry out iterative updating on products, the invention aims to provide a benzimidazole compound which has a novel structure, is simple to prepare, has better bactericidal activity and has potential development value and a preparation method thereof.
In order to achieve the object of the present invention, the present invention provides, in one aspect, a 1-benzimidazole-N-amide derivative represented by formula (I),
wherein Ar is aryl or heteroaryl, the aryl or heteroaryl is optionally substituted by 0-3 substituents selected from one or more of methyl, methoxy, alkylamino, dialkylamino, hydroxy, fluorine, chlorine, bromine, nitro, nitroso, cyano, trifluoromethyl and ester groups,
R1is C1-4An alkyl group.
Wherein aryl groups of the present invention comprise phenyl.
Alternatively,
ar is C6-14Aryl or C2-12Heteroaryl of said C6-14Aryl or C2-12Heteroaryl having 0 to 3 substituentsThe group is selected from one or more of methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-ethyl methylamino, hydroxyl, fluorine, chlorine, bromine, nitro, nitroso, cyano, trifluoromethyl, carbomethoxy and carbethoxy;
the R is1Is methyl, ethyl, isopropyl or tert-butyl.
Alternatively,
said C is6-14Aryl includes phenyl, naphthyl;
said C is2-12Heteroaryl includes furyl, pyridyl, pyridazinyl, pyrazinyl, thienyl or indolyl;
the phenyl, naphthyl, furyl, pyridyl, pyridazinyl, pyrazinyl, thienyl or indolyl contains 0-2 substituents, and the substituents are selected from at least one or more of methyl, methoxy, methylamino, dimethylamino, hydroxyl, fluorine, chlorine, bromine, nitro, cyano and trifluoromethyl.
Optionally, Ar is p-methoxyphenyl, p-hydroxyphenyl, 3, 4-dihydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 3-methoxy-4-hydroxyphenyl, and R is1Is methyl or ethyl.
In order to achieve the object of the present invention, according to another aspect of the present invention, there is provided a method for preparing the aforementioned 1-benzimidazole-N-amide derivative, comprising the steps of:
in an organic solvent, a 1-benzimidazole-N-formyl acetic ester compound shown in a formula (II) and aromatic aldehyde shown in a formula (IV) are heated to react under the catalysis of an amine compound and acid, and the compound shown in the formula (I) is obtained through post-treatment. .
Optionally, the organic solvent is DMF or an alcohol; DMF is preferred.
Alternatively, the amine compound is piperidine, triethylamine, diisopropylethylamine, cyclohexanediamine or DBU, preferably piperidine. The molar fraction of the amine compound relative to the compound of the formula (II) is 0.2-10%.
Optionally, the acid is acetic acid, hydrochloric acid; the molar fraction of the acid relative to the compound of formula (II) is between 0.2% and 10%, preferably between 1% and 5%.
Optionally, the temperature of the heating reaction is 60-120 ℃, preferably 80 ℃.
Optionally, the molar ratio of aryl aldehyde to compound of formula (II) is 1:1 to 2: 1.
Optionally, the post-processing step includes: adding ice water to quench the reaction, extracting with dichloromethane, chloroform or ethyl acetate, washing with saturated NaCl solution, and adding anhydrous Na2SO4Drying, filtering, removing the extraction solvent under reduced pressure, and performing column chromatography with dichloromethane and methanol or petroleum ether and ethyl acetate at a ratio of 40: 1-10: 1 or 5: 1-3: 1 to obtain the purified 1-benzimidazole-N-amide derivative.
Alternatively, the method for preparing the 1-benzimidazole-N-amide derivative comprises the following steps: adding 1-benzimidazole-N-formyl acetic ester compound shown in formula (II), aryl formaldehyde, catalytic amount of piperidine and acetic acid into DMF solvent, heating to 80 deg.C for reaction until the raw materials completely disappear, adding ice water solution for quenching reaction, extracting with dichloromethane, washing with saturated NaCl solution, and adding anhydrous Na2SO4Drying, filtering, removing dichloromethane under reduced pressure, and performing column chromatography with dichloromethane/methanol or petroleum ether/ethyl acetate as eluent to obtain purified 1-benzimidazole-N-amide derivative.
Alternatively, the method for synthesizing the 1-benzimidazole-N-formylacetate compound shown in the formula (II) comprises the following steps: in an anhydrous solvent, benzimidazole reacts with malonic acid monoester acyl chloride compound shown as the formula (III) to obtain the compound shown as the formula (II).
Optionally, the reaction temperature is-20-35 ℃.
Optionally, the anhydrous solvent comprises: anhydrous pyridine, anhydrous chloroform, anhydrous dichloromethane or anhydrous tetrahydrofuran, and preferably anhydrous pyridine.
Alternatively, the reacting benzimidazole with the malonic acid monoester acyl chloride compound represented by formula (III) in an anhydrous solvent comprises: dissolving benzimidazole in an anhydrous solvent, cooling to 20-10 ℃, slowly dripping the compound of the formula (III) into the obtained benzimidazole solution, gradually returning to room temperature, and reacting benzimidazole with the compound of the formula (III), wherein the room temperature is 15-35 ℃.
Optionally, the method for synthesizing the 1-benzimidazole-N-formylacetate compound shown in the formula (II) further comprises the following steps: adding a base selected from the group consisting of triethylamine, pyridine, diisopropylethylamine, piperidine, DBU and DMAP to the anhydrous solvent or the resulting benzimidazole solution.
Alternatively, the molar ratio of the benzimidazole to the compound of formula (III) is 1:1.2 to 1:2.5, preferably 1: 5.
Optionally, the method further comprises a post-treatment step after the reaction of the benzimidazole and the malonic acid monoester acyl chloride compound shown as the formula (III) is finished.
Optionally, when said anhydrous solvent is miscible with water, said post-treatment step comprises: and (3) after the benzimidazole reaction is finished, adding ice water with the volume more than three times that of the reaction mixture to separate out a white solid, performing suction filtration, washing with the ice water, and drying to obtain the 1-benzimidazole-N-formyl acetic ester compound shown in the formula (II).
Optionally, when the anhydrous solvent is immiscible with water, the post-treatment step comprises: and after the benzimidazole is reacted, pouring the reaction mixture into ice water with the volume which is 0.5-3 times that of the reaction mixture, standing for layering, separating an organic phase, extracting, combining the organic phase, drying, concentrating, and performing silica gel column chromatography to obtain the 1-benzimidazole-N-formyl acetate compound shown in the formula (II).
Alternatively, the compound shown in the formula (II) generated after the benzimidazole and the malonic acid monoester acyl chloride compound shown in the formula (III) are reacted can be subjected to heating reaction with aryl formaldehyde under the catalysis of an amine compound and an acid by a one-pot method without separation and purification.
In order to achieve the object of the present invention, the third aspect of the present invention provides an intermediate compound (II) for synthesizing the aforementioned 1-benzimidazole-N-amide derivative,
wherein R is1Is C1-4An alkyl group.
Alternatively, R1Methyl, ethyl isopropyl and tert-butyl.
The invention has the beneficial effects that:
the 1-benzimidazole-N-amide derivative shown in the formula (I) is a compound with simple preparation method, high yield and brand new structure, and has different degrees of bactericidal activity after screening, wherein the activity of part of the compound is equivalent to that of a commercial bactericide.
In addition, the method for synthesizing the 1-benzimidazole-N-amide derivative shown in the formula (I) is simple in operation process, and the synthesized 1-benzimidazole-N-amide derivative is novel in structure and has good antibacterial activity, can be well applied to the fields of medicines and agricultural medicines, provides a new thought for creating new pesticides and medicines, and has good development prospect.
Detailed Description
The main solution of the embodiment of the invention is as follows:
in order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
For the purpose of facilitating understanding of the present invention, a method for synthesizing a 1-benzimidazole-N-amide derivative represented by the formula (I):
the compound represented by the formula (II) (0.1mmol) and an arylcarboxaldehyde (0.11mmol) were weighed out in a 25mL round-bottomed flask, 10mL of N, N-Dimethylformamide (DMF) was added as a solvent, 100. mu.L of piperidine and 100. mu.L of glacial acetic acid were further added, and the reaction was monitored until the compound represented by the formula (II) was reacted. Adding ice water to quench the reaction, extracting with dichloromethane, washing with saturated NaCl solution, and adding anhydrous Na2SO4Drying, filtering, removing dichloromethane under reduced pressure, and performing column chromatography with DCM (methanol to ethanol) and MeOH (40: 1-10: 1) or PE (EA) and EA (5: 1-1: 1) to obtain the 1-benzimidazole-N-amide derivative shown in the formula (I).
Example 1
The compound 1-benzimidazole-N-formyl acetic acid ethyl ester 1(0.1mmol) and p-methoxybenzaldehyde 2a (0.11mmol) were weighed into a 25mL round-bottom flask, 10mL of N, N-Dimethylformamide (DMF) was added as a solvent, 100. mu.L of piperidine and 100. mu.L of glacial acetic acid were added, the reaction was carried out at 80 ℃ for about 18 hours, and the reaction was monitored until the reaction of 1-benzimidazole-N-formyl acetic acid ethyl ester was completed. Adding ice water to quench the reaction, extracting with dichloromethane, washing with saturated NaCl solution, and adding anhydrous Na2SO4Drying, filtering, removing dichloromethane under reduced pressure, and performing column chromatography with DCM: MeOH 40:1 to 10:1 or PE: EA 5:1 to 1:1 to obtain 1-benzimidazole-N-amide derivative 3 a.
3a, yellow oily liquid with yield of 78%;1H-NMR(300MHz,CDCl3),δ(ppm):8.12(1H,s)，7.72(1H,s)，7.62～7.58(2H,m)，7.42(1H,d,J＝8.5Hz)，7.24～7.21(2H,m),6.84(1H,d,J＝8.5Hz)，4.28(2H,q,J＝7.0Hz)，3.83(3H,s),1.23(3H,t,J＝7.0Hz)；13C-NMR(75MHz,CDCl3),δ(ppm):168.5,164.8,158.4，151.9,151.2,147.7,133.7,131.4,129.1,123.8,123.3,116.4，115.4,62.8,52.0,14.7.
example 2
The compound 1-benzimidazole-N-formyl acetic acid ethyl ester 1(0.1mmol) and p-methoxybenzaldehyde 2b (0.11mmol) were weighed into a 25mL round-bottom flask, 10mL of N, N-Dimethylformamide (DMF) was added as a solvent, 100. mu.L of piperidine and 100. mu.L of glacial acetic acid were added, the reaction was carried out at 80 ℃ for about 18 hours, and the reaction was monitored until the reaction of 1-benzimidazole-N-formyl acetic acid ethyl ester was completed. Adding ice water to quench the reaction, extracting with dichloromethane, washing with saturated NaCl solution, and adding anhydrous Na2SO4Drying, filtering, removing dichloromethane under reduced pressure, and performing column chromatography with DCM: MeOH 40:1 to 10:1 or PE: EA 5:1 to 1:1 to obtain 1-benzimidazole-N-amide derivative 3 b.
3b, light yellow solid, yield 65%;1H-NMR(300MHz,DMSO),δ(ppm):8.11(1H,s)，7.68(1H,s)，7.62～7.58(2H,m)，7.32(1H,d,J＝8.5Hz)，7.24～7.19(2H,m),6.82(1H,d,J＝8.5Hz)，4.29(2H,q,J＝7.0Hz)，1.24(3H,t,J＝7.0Hz)；13C-NMR(75MHz,DMSO),δ(ppm):168.5,166.8,164.3,158.5，151.9,151.2,147.7,133.7,130.4,129.1,122.8,122.3,115.4，114.4,62.8,15.7.
example 3
The compound 1-benzimidazole-N-formyl acetic acid ethyl ester 1(0.1mmol) and p-methoxybenzaldehyde 2c (0.11mmol) were weighed into a 25mL round-bottomed flask, 10mL of N, N-Dimethylformamide (DMF) was added as a solvent, 100. mu.L of piperidine and 100. mu.L of glacial acetic acid were added, and the reaction was monitored until the reaction of 1-benzimidazole-N-formyl acetic acid ethyl ester was completed at 80 ℃ for about 18 hours. Adding ice water to quench the reaction, extracting with dichloromethane, washing with saturated NaCl solution, and adding anhydrous Na2SO4Drying, filtering, removing dichloromethane under reduced pressure, and performing column chromatography with DCM: MeOH 40:1 to 10:1 or PE: EA 5:1 to 1:1 to obtain 1-benzimidazole-N-amide derivative 3 c.
3c, yellow solid, yield 58%,1H-NMR(300MHz,DMSO),δ(ppm):1H-NMR(300MHz,DMSO),δ(ppm):8.15(1H,s)，7.82(1H,s)，7.60～7.54(2H,m)，7.24～7.19(2H,m),6.86(1H,d,J＝2.5Hz)，6.80(1H,dd,J＝2.5，8.5Hz)，6.76(1H,d,J＝8.5Hz)，4.29(2H,q,J＝7.0Hz)，1.24(3H,t,J＝7.0Hz)；13C-NMR(75MHz,DMSO),δ(ppm):167.5,165.8,163.3,158.5，151.9,151.2,147.7,143.7,130.4,129.1,122.8,122.3,115.4，114.4,62.8,16.7.
example 4
The compound 1-benzimidazole-N-formyl acetic acid ethyl ester 1(0.1mmol) and p-methoxybenzaldehyde 2d (0.11mmol) were weighed into a 25mL round-bottom flask, 10mL of N, N-Dimethylformamide (DMF) was added as a solvent, 100. mu.L of piperidine and 100. mu.L of glacial acetic acid were added, the reaction was carried out at 80 ℃ for about 18 hours, and the reaction was monitored until the reaction of 1-benzimidazole-N-formyl acetic acid ethyl ester was completed. Adding ice water to quench the reaction, extracting with dichloromethane, washing with saturated NaCl solution, and adding anhydrous Na2SO4Drying, filtering, removing dichloromethane under reduced pressure, and performing column chromatography with DCM: MeOH 40:1 to 10:1 or PE: EA 5:1 to 1:1 to obtain 1-benzimidazole-N-amide derivative 3 d.
3d, yellow solid, yield 60%,1H-NMR(300MHz,DMSO),δ(ppm):1H-NMR(300MHz,CDCl3),δ(ppm):7.99(1H,s)，7.72(1H,s)，7.60～7.50(2H,m)，7.24～7.15(2H,m),6.66(1H,d,J＝2.5Hz)，6.70(1H,dd,J＝2.5，8.5Hz)，6.46(1H,d,J＝8.5Hz)，4.19(2H,q,J＝7.0Hz)，3.99(3H,s)，1.84(3H,t,J＝7.0Hz)；13C-NMR(75MHz,DMSO),δ(ppm):167.5,165.8,163.3,158.5，151.9,151.2,147.7,143.7,130.4,129.1,122.8,122.3,115.4，114.4,62.8,56.2，15.7.
example 5
The compound 1-benzimidazole-N-formyl acetic acid ethyl ester 1(0.1mmol) and p-methoxybenzaldehyde 2e (0.11mmol) were weighed into a 25mL round-bottom flask, 10mL of N, N-Dimethylformamide (DMF) was added as a solvent, 100. mu.L of piperidine and 100. mu.L of glacial acetic acid were added, the reaction was carried out at 80 ℃ for about 18 hours, and the reaction was monitored until the reaction of 1-benzimidazole-N-formyl acetic acid ethyl ester was completed. Adding ice water to quench the reaction, extracting with dichloromethane, washing with saturated NaCl solution, and adding anhydrous Na2SO4Drying, filtering, removing dichloromethane under reduced pressure, and performing column chromatography with DCM: MeOH: 40: 1-10: 1 or PE: EA: 5: 1-1: 1 to obtain 1-benzimidazole-N-amide derivative 3 e.
3e, light yellow solid, yield 56%,1H-NMR(300MHz,DMSO),δ(ppm):1H-NMR(300MHz,CDCl3),δ(ppm):8.15(1H,s)，7.58(1H,s)，7.72～7.58(2H,m)，7.22(1H,d,J＝8.5Hz)，7.22～7.19(2H,m),6.72(1H,d,J＝8.5Hz)，4.29(2H,q,J＝7.0Hz)，3.86(3H,s)，1.24(3H,t,J＝7.0Hz)；13C-NMR(75MHz,DMSO),δ(ppm):167.5,166.8,162.3,158.5，151.9,151.2,147.7,133.7,131.4,129.1,122.8,122.3,115.4，114.4,62.8,58.1,16.7.
example 6
The first synthesis method of the 1-benzimidazole-N-formyl acetic ester 1 comprises the following steps:
weighing benzimidazole 5(0.1mol, 11.8g), placing the benzimidazole in a 500mL round-bottom flask, adding 150mL of anhydrous pyridine, stirring to dissolve the pyridine, cooling to 0 ℃, dropwise adding malonic acid monoethyl ester acyl 4(0.1mol, 22.5g), returning to room temperature after the addition is finished, pouring the mixture into 1000mL of ice water after the benzimidazole is reacted, precipitating a large amount of white solid, performing suction filtration, washing with ice water for 2-3 times, and drying to obtain a compound 1-benzimidazole-N-formyl acetic acid ethyl ester 1, wherein the yield is 87%.
The compound 1 is a compound of formula (I),1H-NMR(300MHz,CDCl3),δ(ppm):8.08(1H,s)，7.57～7.54(2H,m)，7.24～7.21(2H,m)，4.28(2H,q,J＝7.0Hz)，3.53(3H,s),1.23(3H,t,J＝7.0Hz)；13C-NMR(75MHz,CDCl3),δ(ppm):δ169.9,163.2,142.6,137.2,137.6,123.6,123.1 120.2,114.1,62.0,41.8,14.1
example 7
The second synthesis method of the 1-benzimidazole-N-formyl acetate 1 comprises the following steps:
weighing benzimidazole 5(0.1mol, 11.8g) into a 500mL round-bottom flask, adding 300mL of anhydrous dichloromethane and 30mL of triethylamine, stirring to dissolve, cooling to 0 ℃, dropwise adding 4(0.1mol, 22.5g) of monoethyl malonate, returning to room temperature after the addition is finished until the raw materials are completely reacted, pouring into 500mL of ice water, separating organic phases by layers, extracting twice by using 200mL of dichloromethane, combining the organic phases, drying and concentrating, and performing gradient column chromatography by using petroleum ether-ethyl acetate to obtain the compound 1-benzimidazole-N-ethyl formylacetate 1, namely the white solid with the yield of 73%.
The method for synthesizing the 1-benzimidazole-N-amide derivative shown in the formula (I) is simple in operation process, and the synthesized 1-benzimidazole-N-amide derivative is novel in structure and has good antibacterial activity, can be well applied to the fields of medicines and agricultural medicines, provides a new thought for creating new pesticides and medicines, and has good development prospect.
Example 8
Bacteriostatic activity determination experiment
(1) Preparation of LB Medium
5g of sodium chloride, 10 g of peptone and 5g of yeast extract were weighed, respectively dissolved in hot water, heated and boiled (agar was boiled and dissolved in LB solid medium) to a constant volume of 1L. And (3) subpackaging the prepared culture medium into triangular flasks or test tubes, and placing in a sterilization pot for high-temperature sterilization for 20 minutes.
(2) Sample configuration
Streptomycin sulfate was dissolved in distilled water to prepare 500ppm of streptomycin sulfate solution a as a positive control sample.
1-benzimidazole-N-amide derivatives 3a to 3e were independently dissolved in a mixed solution of acetone and water at a ratio of 10:1(V/V), and 1-benzimidazole-N-amide derivative solutions 3a, 3b, 3c, 3d, and 3e were prepared at 500ppm as test samples.
(3) Experimental procedure
Pseudomonas syringae was inoculated in LB liquid medium and cultured in an incubator at 25 ℃ for 24 hours. Taking about 0.3ml of bacterial liquid to evenly coat the bacterial liquid on an LB plate dish, airing, adsorbing sample solution by using a filter paper sheet aiming at each sample, putting the sample solution on the plate, placing the plate in an incubator at 25 ℃ for culturing for 24-36 hours, observing the size of a sterile ring around the filter paper sheet, and paralleling for three times.
The results of the experiment are shown in the following table:
as can be seen, the 1-benzimidazole-N-amide derivative has obvious inhibition effect on the growth of pseudomonas syringae.
The 1-benzimidazole-N-amide derivative shown in the formula (I) is a compound with simple preparation method, high yield and brand new structure, and has different degrees of bactericidal activity after screening, wherein the activity of part of the compound is equivalent to that of a commercial bactericide.
Claims (10)
1. A1-benzimidazole-N-amide derivative is characterized in that the structure of the 1-benzimidazole-N-amide derivative is shown as a formula (I),
wherein Ar is phenyl, and the phenyl contains 0-2A substituent, R is methoxy and/or hydroxyl1Is C1-4An alkyl group.
2. The 1-benzimidazole-N-amide derivative according to claim 1,
the R is1Is methyl, ethyl, isopropyl or tert-butyl.
3. The 1-benzimidazole-N-amide derivative of claim 1, wherein Ar is p-methoxyphenyl, p-hydroxyphenyl, 3, 4-dihydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 3-methoxy-4-hydroxyphenyl, and R is1Is ethyl.
4. A process for the preparation of a 1-benzimidazole-N-amide derivative according to any one of claims 1 to 3, comprising:
in an organic solvent, a 1-benzimidazole-N-formyl acetic ester compound shown in a formula (II) and aromatic aldehyde shown in a formula (IV) are heated and reacted under the catalysis of an amine compound and acid, and a compound shown in a formula (I) is obtained after post-treatment,
5. the process for producing 1-benzimidazole-N-amide derivatives according to claim 4,
the organic solvent is DMF or alcohol;
the amine compound is piperidine, triethylamine, diisopropylethylamine, cyclohexanediamine or DBU;
the acid is acetic acid or hydrochloric acid;
the mole fraction of the amine compound relative to the compound of the formula (II) is 0.2-10 percent respectively;
the mole fraction of the acid relative to the compound of the formula (II) is 0.2-10 percent respectively;
the temperature of the heating reaction is 60-120 ℃.
6. The method for producing a 1-benzimidazole-N-carboxamide derivative according to claim 4, wherein the method for synthesizing the 1-benzimidazole-N-formylacetate compound represented by formula (II) comprises:
in an anhydrous solvent, benzimidazole reacts with malonic acid monoester acyl chloride compound shown as a formula (III) to obtain a compound shown as a formula (II),
the reaction temperature is-20 to 35 ℃,
the anhydrous solvent is one of anhydrous pyridine, anhydrous chloroform, anhydrous dichloromethane or anhydrous tetrahydrofuran.
7. The method for preparing 1-benzimidazole-N-amide derivatives according to claim 6, wherein the reaction of benzimidazole with malonic acid monoester acid chloride compound of formula (III) in anhydrous solvent comprises: dissolving benzimidazole in an anhydrous solvent, cooling to-20-10 ℃, slowly dropwise adding the compound of the formula (III) into the obtained benzimidazole solution, and gradually returning to room temperature to enable benzimidazole to react with the compound of the formula (III).
8. The process for producing 1-benzimidazole-N-amide derivatives according to claim 7,
the method for synthesizing the 1-benzimidazole-N-formylacetate compound shown in the formula (II) further comprises the following steps: adding a base to an anhydrous solvent or a benzimidazole solution obtained by dissolving benzimidazole in the anhydrous solvent, wherein the base is selected from triethylamine, pyridine, diisopropylethylamine, piperidine, DBU and DMAP.
9. The method for producing a 1-benzimidazole-N-amide derivative according to any one of claims 6 to 8, wherein the method further comprises a post-treatment step after the reaction of the benzimidazole with the malonic acid monoester acid chloride compound of formula (III) is completed, the method comprising:
when the anhydrous solvent is miscible with water, the post-treatment step comprises: after the benzimidazole reaction is finished, adding ice water with the volume more than three times that of the reaction mixture to separate out white solid, performing suction filtration, washing with the ice water, and drying to obtain the 1-benzimidazole-N-formyl acetic ester compound shown in the formula (II);
when the anhydrous solvent is immiscible with water, the post-treatment step comprises: and after the benzimidazole is reacted, pouring the reaction mixture into ice water with the volume which is 0.5-3 times that of the reaction mixture, standing for layering, separating an organic phase, extracting, combining the organic phase, drying, concentrating, and performing silica gel column chromatography to obtain the 1-benzimidazole-N-formyl acetate compound shown in the formula (II).
10. The method for producing a 1-benzimidazole-N-amide derivative according to any one of claims 6 to 8, wherein the compound of formula (II) produced after the reaction of benzimidazole with the malonic acid monoester acid chloride compound of formula (III) is reacted with an aryl formaldehyde by a one-pot method without isolation and purification, under the catalysis of an amine compound and an acid.
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| Synthesis，Characterization and Biological Activities of Novel Acrylamide Compounds;XU Liang．Zhong等;《CHEM．RES．CHINESE UNlVERSITIES》;20081231;第24卷(第5期);第576-578页 * |
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