CN115466212B - 2-trifluoromethyl quinoline compound and synthetic method and application thereof - Google Patents

2-trifluoromethyl quinoline compound and synthetic method and application thereof Download PDF

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CN115466212B
CN115466212B CN202211320692.9A CN202211320692A CN115466212B CN 115466212 B CN115466212 B CN 115466212B CN 202211320692 A CN202211320692 A CN 202211320692A CN 115466212 B CN115466212 B CN 115466212B
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trifluoromethyl
quinoline
ethyl
nmr
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CN115466212A (en
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樊良鑫
何方雨
史书豪
徐翠莲
朱鑫鑫
刘兴源
杨国玉
吴璐璐
潘振良
王彩霞
史力军
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Henan Agricultural University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • 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
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Abstract

The invention provides a 2-trifluoromethyl quinoline compound, a synthesis method and application thereof, belongs to the technical field of organic fluorine chemical synthesis, and aims to solve the technical problems that the operation difficulty of the synthesis reaction of the existing 2-trifluoromethyl quinoline skeleton is increased and the environment is not friendly. A2-trifluoromethyl quinoline compound has a structural formula shown as follows:the preparation method comprises the following steps: adding reactants of the o-aminobenzaldehyde compound 1, the ethyl trifluoroacetoacetate compound 2 and the catalyst into a solvent to obtain a mixed solution, and fully reacting to obtain the 2-trifluoromethyl quinoline compound. The preparation method disclosed by the invention is simple in reaction operation, mild in condition and strong in functional group tolerance, does not need to add a metal catalyst, has higher step economy and atom economy, and is a typical case of green synthesis because only water is used as a reaction byproduct.

Description

2-trifluoromethyl quinoline compound and synthetic method and application thereof
Technical Field
The invention belongs to the technical field of organic fluorine chemical synthesis, and particularly relates to a 2-trifluoromethyl quinoline compound, a synthesis method and application thereof.
Background
Fluorine exhibits special chemical properties due to its small atomic radius, low orbital energy and the strongest electronegativity. Studies have shown that the physical and chemical properties of organic molecules are significantly altered by the introduction of fluorine atoms or fluorine-containing groups at specific positions in the organic molecules, such as acid-base changes, conformational inversions, increased lipid solubility, increased oxidation resistance, etc. (ChemMedChem, 2015, 10, 715-726). At present, fluorine-containing compounds have been widely used in various fields such as medicines, pesticides, liquid crystals, organic devices, high-energy materials and the like due to their unique physiological activities, wherein compounds containing trifluoromethyl groups in molecules are focused by synthetic chemists, and particularly by fluorochemical chemists, the application of the compounds is also most widespread.
Among the fluorine-containing molecules, the 2-trifluoromethyl quinoline skeleton has attracted more and more attention in recent years as an important nitrogen heterocycle, and the medicine molecules containing the molecular skeleton generally have pharmacological activities such as anti-inflammation, sterilization, anti-tumor, antihypertensive, antimalarial agents and the like. Meanwhile, clinical researches show that the 2-trifluoromethyl quinoline can also be used for treating HIV and mental diseases. For example, compound I (mefloquine) shows a high antimalarial activity as a novel antimalarial agent drug already on the market (j. Med. Chem., 1971, 14, 926-928), and is used in a small amount with few side effects compared to conventional chloroquine. Compound II, which is one of the major neurotransmitters in the human central and peripheral nervous systems, as serotonin 5-HT5A receptor, contributes to the regulation of appetite, memory, cognition and emotion through serotonin receptors. The compound III is a target inhibitor of phosphodiesterase 4, can effectively inhibit the activity of the phosphodiesterase 4, increases the intracellular cAMP level and exerts better anti-inflammatory effect. Compound V showed better activity against tuberculosis. Compound VI acts as an AChE inhibitor, crossing the blood brain barrier, increasing acetylcholine levels in the cortex. Furthermore, this type of scaffold also exhibits remarkable effects in fluorescent probes, such as compound IV,
。
the synthesis of most common organic compounds is not suitable for preparing 2-trifluoromethyl quinoline skeleton, and the synthesis of 2-trifluoromethyl quinoline skeleton is still limited. In view of the wide biological activity and the great application value of the 2-trifluoromethyl quinoline structure, the simple structure and the high-efficiency synthesis are realized, and the aim of the fluorochemical cumin is fulfilled. The simplest method of synthesizing 2-trifluoromethyl quinolines from the product structure is to introduce trifluoromethyl directly into the C-2 position of the quinoline (org. Lett., 2018, 20, 1593-1596; nat. Commun., 2014, 5, 3387; j. Org. Chem., 2013, 78, 11126-11146; chem. Commun., 2009, 1909-1911). However, such methods, although in a simple form, are complex and difficult to control under severe conditions. The fluorinating agent is expensive, larger groups are often required to be removed in the reaction process, and the atom economy is poor. Especially when the molecular structure is complex or contains sensitive groups, the target compounds are often not obtained with such methods and even result in molecular decomposition. The fluorine-containing compound prepared by the fluorine-containing building blocks can well solve the problem that complex molecules are difficult to fluorinate, and can be synthesized in large dosage. The fluorine-containing building block is essentially a series of small molecular compounds containing fluorine atoms or fluorine groups, and can realize the synthesis of complex fluorine-containing compounds and the accurate positioning of the fluorine-containing groups by taking the fluorine-containing building block as a reaction substrate through one or more steps of common chemical reactions. No involvement of C-R in the reaction f Has the advantages of mild conditions, high yield and good reaction selectivity (org. Chem. Front., 2022, 9, 413-419; org. Lett. 2019, 21, 1984-1988; org. Chem. Front., 2020, 7, 3368-3373; org. Lett., 2019, 21, 1681-1685; chem. Eur. J., 2013, 19, 16928-16933; org. Lett., 2001, 3, 1109-1112). Among them, ethyl trifluoroacetoacetate is a building block with wider application.
However, the construction of 2-trifluoromethyl quinoline skeleton by using ethyl trifluoroacetoacetate compounds has been less studied, and the existing method for synthesizing 2-trifluoromethyl quinoline blocks by using ethyl trifluoroacetoacetate compounds mainly promotes the reaction by means of Lewis acid catalysis such as indium, rubidium and the like and reagents such as triphenylphosphine and the like. On the one hand, the existing means require the participation of metal salt or organic phosphine reagent, the operation difficulty of the reaction is increased, and the method is not friendly to the environment and does not meet the concept requirements of developing sustainable chemistry and green chemistry at present. Therefore, it is very valuable to further develop efficient construction of novel, green 2-trifluoromethyl quinoline backbones from the viewpoint of development of sustainable and environment-friendly chemistry.
Disclosure of Invention
Aiming at the technical problems, the invention provides a 2-trifluoromethyl quinoline compound, a synthesis method and application thereof, and the reaction is simple in operation, mild in condition and strong in functional group tolerance, does not need to add a metal catalyst, and has higher step economy and atom economy.
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
according to the invention, commercially available o-aminobenzaldehyde compounds 1 and ethyl trifluoroacetoacetate compounds 2 are used as raw materials, and added into a catalyst and a solvent, so that the synthesis of novel 2-trifluoromethyl quinoline compounds is realized in one step, and 26 2-trifluoromethyl quinoline compounds with novel structures are synthesized. The reaction equation is:
ar is Me, OMe, NH 2 、F、Cl、Br、CF 3 Or NO 2 Any one of the substituted benzene rings or pyridine rings; r is R 2 Is CF (CF) 3 Or CHF 2 ；R 3 Is Me, OEt, O i Pr or Ph.
The method comprises the following specific steps: under the air atmosphere, adding reactants of o-aminobenzaldehyde compound 1 and trifluoro acetoacetate ester compound 2 into a 150 mL reaction bottle provided with a magnetic stirring rod, then adding an analytically pure catalyst and a solvent into the reaction bottle to form a mixed solution, fully reacting at 50-110 ℃, reacting for 1-10 hours, separating and purifying by column chromatography to obtain a corresponding 2-trifluoro methylquinoline compound 3, wherein the eluent is prepared from petroleum ether and ethyl acetate according to a certain volume ratio, and the common proportion is 30:1-2:1.
The molar ratio of the compound 1 to the compound 2 is 1 (1-2). Preferably, the molar ratio of compound 1 to compound 2 is 1:1.5.
The concentration of the compound 1 in the mixed solution is 0.05-0.2. 0.2M. Preferably, the concentration is 0.1M.
The catalyst is secondary amine such as tetrahydropyrroline, piperidine, morpholine, piperazine and the like which can be used as the catalyst to promote the reaction. In addition, amino acids such as proline can also be used as catalysts for such reactions. Preferably, the catalyst is tetrahydropyrroline.
The catalyst is used in an amount of 10 to 100 mol% of the reactants.
Preferably, the catalyst tetrahydropyrroline is used in an amount of 50 mole% of the reactants.
The solvent is any one of water, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone (acetone), ethyl acetate (EtOAc), dichloroethane (DCE), methanol (MeOH) or Tetrahydrofuran (THF). Preferably, the solvent is ethanol (EtOH).
Preferably, the molar ratio of compound 1 to compound 2 is 1:1.5, the solvent is EtOH, the concentration is 0.1M, the reaction temperature is 90 degrees, and the reaction time is 5 h.
The application of the 2-trifluoromethyl quinoline compound in the field of antibiosis and sterilization.
The invention has the beneficial effects that: the invention creatively selects commercially available o-aminobenzaldehyde compounds and trifluoro acetoacetic acid ethyl ester compounds as reactants, realizes the construction of a novel 2-trifluoromethyl quinoline skeleton through one-step reaction, provides a simple and effective synthesis method for the construction of the skeleton, and has mild reaction condition, simple operation and atom economyThe method has the characteristics of economical steps, strong functional group tolerance, good yield (96%) and the like. In addition, the solvent used in the reaction can be environment-friendly EtOH, and the by-product of the reaction is only green H 2 O. The product obtained by the reaction has wide medical application prospect, and provides a new thought and a new method for the fields of industry, natural product synthesis, luminescent materials and the like.
The invention carries out activity measurement on 5 common pathogenic bacteria in agricultural production, namely fusarium graminearum (from wheat), fusarium graminearum (from corn), rhizoctonia solani, fusarium moniliforme and fusarium oxysporum. The result shows that the synthesized 26 novel 2-trifluoromethyl quinoline compounds 3a-3z have certain inhibition forces on 5 different pathogenic bacteria, wherein the compound 3w has good bactericidal activity on four of five pathogenic bacteria, and the inhibition rate of the rhizoctonia solani can reach 83%.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a nuclear magnetism of Compound 3a 1 H spectrogram; FIG. 2 is a nuclear magnetism of Compound 3a 13 C, spectrogram;
FIG. 3 is a nuclear magnetism of Compound 3a 19 F spectrogram.
FIG. 4 is a nuclear magnetism of Compound 3b 1 H spectrogram; FIG. 5 is a nuclear magnetism of Compound 3b 13 C, spectrogram;
FIG. 6 is a nuclear magnetism of Compound 3b 19 F spectrogram.
FIG. 7 is a nuclear magnetism of Compound 3c 1 H spectrogram; FIG. 8 is a nuclear magnetism of Compound 3c 13 C, spectrogram;
FIG. 9 is a nuclear magnetism of Compound 3c 19 F spectrogram.
FIG. 10 is a nuclear magnetism of Compound 3d 1 H spectrogram; FIG. 11 is a nuclear magnetism of Compound 3d 13 C, spectrogram;
FIG. 12 is a nuclear magnetism of Compound 3d 19 F spectrogram.
FIG. 13 is a nuclear magnetism of Compound 3e 1 H spectrogram; FIG. 14 is a nuclear magnetism of Compound 3e 13 C, spectrogram;
FIG. 15 is a nuclear magnetism of Compound 3e 19 F spectrogram.
FIG. 16 is a nuclear magnetism of Compound 3f 1 H spectrogram; FIG. 17 is a nuclear magnetism of Compound 3f 13 C, spectrogram;
FIG. 18 is a nuclear magnetism of Compound 3f 19 F spectrogram.
FIG. 19 is a nuclear magnetism of Compound 3g 1 H spectrogram; FIG. 20 is a nuclear magnetism of 3g of Compound 13 C, spectrogram;
FIG. 21 is a nuclear magnetism of Compound 3g 19 F spectrogram.
FIG. 22 is a nuclear magnetism of Compound 3h 1 H spectrogram; FIG. 23 is a nuclear magnetism of Compound 3h 13 C, spectrogram;
FIG. 24 is a nuclear magnetism of Compound 3h 19 F spectrogram.
FIG. 25 is a nuclear magnetism of Compound 3i 1 H spectrogram; FIG. 26 is a nuclear magnetism of Compound 3i 13 C, spectrogram;
FIG. 27 is a nuclear magnetism of Compound 3i 19 F spectrogram.
FIG. 28 is a nuclear magnetism of Compound 3j 1 H spectrogram; FIG. 29 is a nuclear magnetism of Compound 3j 13 C, spectrogram;
FIG. 30 is a nuclear magnetism of Compound 3j 19 F spectrogram.
FIG. 31 is a nuclear magnetism of Compound 3k 1 H spectrogram; FIG. 32 is a nuclear magnetism of Compound 3k 13 C, spectrogram;
FIG. 33 is a nuclear magnetism of Compound 3k 19 F spectrogram.
FIG. 34 is a nuclear magnetism of Compound 3l 1 H spectrogram; FIG. 35 is a nuclear magnetism of Compound 3l 13 C, spectrogram;
FIG. 36 is a nuclear magnetism of Compound 3l 19 F spectrogram.
FIG. 37 is a nuclear magnetism of Compound 3m 1 H spectrogram; FIG. 38 is a schematic view of a chemical processNuclear magnetism of compound 3m 13 C, spectrogram;
FIG. 39 is a nuclear magnetism of Compound 3m 19 F spectrogram.
FIG. 40 is a nuclear magnetism of Compound 3n 1 H spectrogram; FIG. 41 is a nuclear magnetism of Compound 3n 13 C, spectrogram;
FIG. 42 is a nuclear magnetism of Compound 3n 19 F spectrogram.
FIG. 43 is a nuclear magnetism of Compound 3o 1 H spectrogram; FIG. 44 is a nuclear magnetism of Compound 3o 13 C, spectrogram;
FIG. 45 is a nuclear magnetism of Compound 3o 19 F spectrogram.
FIG. 46 is a nuclear magnetism of Compound 3p 1 H spectrogram; FIG. 47 is a nuclear magnetism of Compound 3p 13 C, spectrogram;
FIG. 48 is a nuclear magnetism of Compound 3p 19 F spectrogram.
FIG. 49 is a nuclear magnetism of Compound 3q 1 H spectrogram; FIG. 50 is a nuclear magnetism of Compound 3q 13 C, spectrogram;
FIG. 51 is a nuclear magnetism of Compound 3q 19 F spectrogram.
FIG. 52 is a nuclear magnetism of Compound 3r 1 H spectrogram; FIG. 53 is a nuclear magnetism of Compound 3r 13 C, spectrogram;
FIG. 54 is a nuclear magnetism of Compound 3r 19 F spectrogram.
FIG. 55 is a nuclear magnetism of Compound 3s 1 H spectrogram; FIG. 56 is a nuclear magnetism of Compound 3s 13 C, spectrogram;
FIG. 57 is a nuclear magnetism of Compound 3s 19 F spectrogram.
FIG. 58 is a nuclear magnetism of Compound 3t 1 H spectrogram; FIG. 59 is a nuclear magnetism of Compound 3t 13 C, spectrogram;
FIG. 60 is a nuclear magnetism of Compound 3t 19 F spectrogram.
FIG. 61 is a nuclear magnetism of Compound 3u 1 H spectrogram; FIG. 62 is a nuclear magnetic resonance of Compound 3u 13 C, spectrogram;
FIG. 63 is a nuclear magnetism of Compound 3u 19 F spectrogram.
FIG. 64 is a nuclear magnetism of Compound 3v 1 H spectrogram; FIG. 65 is a nuclear magnetism of Compound 3v 13 C spectrumA figure;
FIG. 66 is a nuclear magnetism of Compound 3v 19 F spectrogram.
FIG. 67 is a nuclear magnetism of Compound 3w 1 H spectrogram; FIG. 68 is a nuclear magnetism of Compound 3w 13 C, spectrogram;
FIG. 69 is a nuclear magnetism of Compound 3w 19 F spectrogram.
FIG. 70 is a nuclear magnetism of Compound 3x 1 H spectrogram; FIG. 71 is a nuclear magnetism of Compound 3x 13 C, spectrogram;
FIG. 72 is a nuclear magnetism of Compound 3x 19 F spectrogram.
FIG. 73 is a nuclear magnetism of Compound 3y 1 H spectrogram; FIG. 74 is a nuclear magnetism of Compound 3y 13 C, spectrogram;
FIG. 75 is a nuclear magnetism of Compound 3y 19 F spectrogram.
FIG. 76 is a nuclear magnetism of Compound 3z 1 H spectrogram; FIG. 77 is a nuclear magnetism of Compound 3z 13 C, spectrogram;
FIG. 78 is a nuclear magnetic resonance of Compound 3z 19 F spectrogram.
Fig. 79 shows the inhibition of fusarium graminearum (from wheat) by 26 compounds.
Fig. 80 shows the inhibition of fusarium graminearum (from corn) by 26 compounds.
FIG. 81 shows the inhibition of rhizoctonia solani by 26 compounds.
FIG. 82 shows the inhibition of Fusarium moniliforme by 26 compounds.
FIG. 83 shows the inhibition of F.oxysporum by 26 compounds.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without any inventive effort, are intended to be within the scope of the invention.
Example 1
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, o-aminobenzaldehyde 1a (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, the mixture is reacted in a 90-DEG reaction module to obtain 5 h, after the reaction is finished, the mixture is filtered by a sand core funnel with a diatomite pad, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product 2- (trifluoromethyl) quinoline-3-ethyl formate (3 a), and all eluents are petroleum ether and ethyl acetate according to the proportion of 10:1. Characterization of product data: (PE: ea=10:1, R f =0.29, white solid, 89% yield). The nuclear magnetic test results are shown in figures 1-3, 1 H NMR (400 MHz, CDCl 3 ): δ 8.69 (s, 1H), 8.26 (d,J= 8.5 Hz, 1H), 8.00 – 7.87 (m, 2H), 7.78 – 7.70 (m, 1H), 4.48 (q,J= 7.2 Hz, 2H), 1.44 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.7, 147.1, 144.9 (q,J= 35.2 Hz), 140.3, 132.5, 130.3, 129.7, 128.3, 127.6, 124.2, 121.3 (q,J= 275.8 Hz), 62.6, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -63.87.
example 2
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under air atmosphere, 5-methyl-anthranilaldehyde 1b (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round bottom flask, the mixture is reacted in a 100 ℃ reaction module to 4 h, after the reaction is finished, the mixture is filtered by a sand core funnel with a diatomite pad, the solvent is removed under reduced pressure, and the residue is separated by a silica gel column to obtain the target product 6-methyl-2- (trifluoromethyl) quinoline-3-carboxylic acidEthyl ester (3 b), all the eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 10:1. Characterization of product data: (PE: ea=10:1, R f =0.48, white solid, 65% yield). The nuclear magnetic test results are shown in figures 4-6, 1 H NMR (400 MHz, CDCl 3 ): δ 8.56 (s, 1H), 8.11 (d,J= 8.5 Hz, 1H), 7.73 – 7.67 (m, 2H), 4.46 (q,J= 7.2 Hz, 2H), 2.58 (s, 3H), 1.43 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 166.2, 146.0, 144.2 (q,J= 35.1 Hz), 140.5, 139.7, 135.2, 130.1, 128.0, 127.3, 121.7 (q,J= 275.5 Hz), 62.9, 22.2, 14.4 19 F NMR (376 MHz, CDCl 3 ): δ -63.72.
example 3
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, o-aminobenzaldehyde 1c (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (30 mol%) and solvent EtOH (50 mL) are added into a 150 mL round bottom flask, 3h is reacted in a 70-DEG reaction module, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 6-bromo-2- (trifluoromethyl) quinoline-3-ethyl formate (3 c), and all eluents are petroleum ether and ethyl acetate according to the proportion of 9:1. Characterization of product data: (PE: ea=9:1, R f =0.29, white solid, 84% yield). The nuclear magnetic test results are shown in figures 7-9, 1 H NMR (400 MHz, Acetone): δ 8.80 (s, 1H), 8.37 (d,J= 1.8 Hz, 1H), 8.06 – 7.97 (m, 2H), 4.33 (q,J= 7.1 Hz, 2H), 1.28 (t,J= 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 145.2 (q,J= 29.8 Hz), 139.1, 136.1, 131.8, 130.3, 128.7, 125.2, 124.1, 121.1 (q,J= 275.9 Hz), 62.9, 14.1. 19 F NMR (376 MHz, Acetone): δ -64.55.
example 4
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, o-aminobenzaldehyde 1d (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round bottom flask, 7 h is reacted in a 90-DEG reaction module, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product 2- (trifluoromethyl) -1, 8-naphthyridine-3-ethyl formate (3 d), and all eluents are petroleum ether and ethyl acetate according to the proportion of 2:1. Characterization of product data: (PE: ea=2:1, R f =0.39, white solid, 78% yield). The nuclear magnetic test results are shown in figures 10-12, 1 H NMR (400 MHz, CDCl 3 ): δ 9.29 (dd,J= 4.1, 1.9 Hz, 1H), 8.75 (s, 1H), 8.37 (dd,J= 8.2, 1.9 Hz, 1H), 7.69 (dd,J= 8.2, 4.2 Hz, 1H), 4.47 (q,J= 7.1 Hz, 2H), 1.43 (t,J= 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 164.9, 156.7, 154.6, 147.9 (q,J= 35.7 Hz), 141.7, 137.5, 125.5, 124.9, 122.6, 120.8 (d,J= 276.3 Hz), 63.0, 14.0. 19 F NMR (376 MHz, CDCl 3 ): δ -64.17.
example 5
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under air atmosphere, 4, 5-dimethoxy-anthranilaldehyde 1e (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL round bottom flask, reacted in a 90℃reaction block at 5 h, filtered through a sand core funnel with a celite pad after completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified using siliconThe target product of 6, 7-dimethoxy-3- (trifluoromethyl) -2-ethyl naphthoate (3 e) is obtained by separation of a rubber column, and all eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 5:1. Characterization of product data: (PE: ea=5:1, R f =0.34, mp=148-149 ℃, white solid, 68% yield). The nuclear magnetic test results are shown in figures 13-15, 1 H NMR (400 MHz, CDCl 3 ): δ 8.51 (s, 1H), 7.52 (s, 1H), 7.14 (s, 1H), 4.45 (q,J= 7.1 Hz, 2H), 4.05 (d,J= 6.4 Hz, 6H), 1.42 (t,J= 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 166.0, 155.0, 152.3, 144.6, 142.8 (q,J= 35.0 Hz), 137.9, 125.7, 123.9, 122.4, 121.6 (q,J= 275.0 Hz), 108.4, 105.0, 62.4, 56.7, 56.5, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -63.43. HRMS (ESI) m/z calculated for C 15 H 16 F 3 NO 4 [M+H] + 330.0953, found 330.0955.
example 6
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 4, 5-dimethoxy anthranilaldehyde 1f (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round bottom flask, 4 h is reacted in a 90-DEG reaction module, a sand core funnel with a diatomite pad is used for suction filtration after the reaction is finished, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 6-chloro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 f), and all eluent is petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.38, white solid, 76% yield). Nuclear magnetic test results are shown in figures 16-18, 1 H NMR (400 MHz, CDCl 3 ): δ 8.59 (s, 1H), 8.19 (d,J= 9.0 Hz, 1H), 7.95 (d,J= 2.1 Hz, 1H), 7.84 (dd,J= 9.0, 2.2 Hz, 1H), 4.48 (q,J= 7.1 Hz, 2H), 1.44 (t,J= 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 145.1 (q,J= 35.6 Hz), 139.2, 135.9, 133.6, 131.8, 128.3, 126.9, 125.2, 121.1 (q,J= 275.6 Hz), 62.6, 14.0. 19 F NMR (376 MHz, CDCl 3 ): δ -63.98.
example 7
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under air atmosphere, 1g (5.0 mmol) of 6-fluoro-o-aminobenzaldehyde, 2a (7.5 mmol) of ethyl trifluoroacetoacetate, piperidine (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round bottom flask, the mixture is reacted in a 90-DEG reaction module to obtain 5 h, after the reaction is finished, the mixture is filtered by a sand core funnel with a diatomite pad, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 5-fluoro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 g), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.50, mp=68-69 ℃, white solid, 83% yield). The nuclear magnetic test results are shown in figures 19-21, 1 H NMR (400 MHz, CDCl 3 ): δ 8.91 (s, 1H), 8.04 (d,J= 8.6 Hz, 1H), 7.83 (td,J= 8.2, 6.0 Hz, 1H), 7.39 (t,J= 8.5 Hz, 1H), 4.48 (q,J= 7.2 Hz, 2H), 1.44 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 157.8 (d,J= 258.9 Hz), 147.4, 145.8 (q,J= 35.5 Hz), 134.0 (d,J= 4.0 Hz), 132.3 (d,J= 8.9 Hz), 126.1 (d,J= 4.4 Hz), 124.5 (d,J= 2.4 Hz), 121.1 (q,J= 276.0 Hz), 118.6 (d,J= 16.3 Hz), 113.2 (d,J= 18.9 Hz), 62.8, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -64.13, -119.93. HRMS (ESI) m/z calculated for C 13 H 10 F 4 NO 2 [M+H] + 288.0648, found 288.0652.
example 8
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 4-chloro-o-aminobenzaldehyde is added into a 150 mL round-bottomed flask through adding ethyl trifluoroacetoacetate 2a (7.5 mmol) and a solvent EtOH (50 mol%), reacting 7 h in a reaction module with 80 degrees, filtering the reaction module with a sand core funnel with a diatomite pad after the reaction is finished, decompressing and removing the solvent, separating residues through a silica gel column to obtain a target product 7-chloro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 h), and preparing all eluents by petroleum ether and ethyl acetate according to a ratio of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.29, mp=81-83 ℃, pale yellow solid, 60% yield). The nuclear magnetic test results are shown in figures 22-24, 1 H NMR (400 MHz, CDCl 3 ): δ 8.65 (s, 1H), 8.21 (d,J= 1.7 Hz, 1H), 7.88 (d,J= 8.8 Hz, 1H), 7.66 (dd,J= 8.7, 2.0 Hz, 1H), 4.46 (q,J= 7.2 Hz, 2H), 1.43 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 147.3, 145.9 (q,J= 35.5 Hz), 140.1, 138.8, 130.9, 129.4, 129.2, 125.9, 124.4, 121.0 (q,J= 275.9 Hz), 62.8, 14.0. 19 F NMR (376 MHz, CDCl 3 ): δ -64.06. HRMS (ESI) m/z calculated for C 13 H 10 ClF 3 NO 2 [M+H] + 304.0352, found 304.0357.
example 9
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under air, 4-Bromoanthranilaldehyde 1i (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL round bottom flask at 6And (3) reacting 5 h in a reaction module at 0 ℃, filtering by using a sand core funnel with a diatomite pad after the reaction is finished, removing the solvent under reduced pressure, separating residues by using a silica gel column to obtain a target product of 7-bromo-2- (trifluoromethyl) quinoline-3-ethyl formate (3 i), and preparing all eluents of petroleum ether and ethyl acetate according to a ratio of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.23, mp=82-85 ℃, pale yellow solid, 85% yield). The nuclear magnetic test results are shown in figures 25-27, 1 H NMR (400 MHz, CDCl 3 ): δ 8.64 (d,J= 3.7 Hz, 1H), 8.41 (d,J= 7.8 Hz, 1H), 7.79 (t,J= 6.9 Hz, 2H), 4.46 (q,J= 7.1 Hz, 2H), 1.42 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 147.3, 145.8 (d,J= 35.7 Hz), 140.2, 133.3, 132.5, 129.4, 127.1, 126.2, 124.5, 121.0 (d,J= 276.0 Hz), 62.8, 14.0. 19 F NMR (376 MHz, CDCl 3 ): δ -64.05. HRMS (ESI) m/z calculated for C 13 H 10 BrF 3 NO 2 [M+H] + 347.9847, found 347.9850.
example 10
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 5-nitro-o-aminobenzaldehyde 1j (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, 4 h is reacted in a 90-DEG reaction module, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 6-nitro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 j), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.19, mp=128-130 ℃, white solid, 48% yield). The nuclear magnetic test results are shown in figures 28-30, 1 H NMR (400 MHz, CDCl 3 ): δ 8.95 – 8.84 (m, 2H), 8.64 (dd,J= 9.3, 2.5 Hz, 1H), 8.41 (d,J= 9.3 Hz, 1H), 4.50 (q,J= 7.2 Hz, 2H), 1.45 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 164.6, 148.7, 148.0 (d,J= 36.0 Hz), 147.6, 141.9, 132.3, 126.8, 126.1, 125.7, 124.7, 120.7 (d,J= 276.3 Hz), 63.2, 14.0. 19 F NMR (376 MHz, CDCl 3 ): δ -64.34. HRMS (ESI) m/z calculated for C 13 H 10 F 3 N 2 O 4 [M+H] + 315.0593 , found 315.0600.
example 11
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 3-methyl o-aminobenzaldehyde 1k (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round bottom flask, the mixture is reacted in a 90-DEG reaction module to obtain 5 h, after the reaction is finished, the mixture is filtered by a sand core funnel with a diatomite pad in a suction mode, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product 8-methyl-2- (trifluoromethyl) quinoline-3-ethyl formate (3 k), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.33, white solid, 50% yield). The nuclear magnetic test results are shown in figures 31-33, 1 H NMR (400 MHz, CDCl 3 ): δ 10.05 (s, 1H), 8.41 (d,J= 7.5 Hz, 1H), 7.77 – 7.71 (m, 2H), 7.58 – 7.48 (m, 2H), 7.16 (t,J= 8.6 Hz, 2H), 7.04 (t,J= 7.6 Hz, 1H), 4.22 (q,J= 7.1 Hz, 2H), 1.31 (t,J= 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.9, 146.1, 143.5 (q,J= 35.0 Hz), 140.3, 138.8, 132.4, 129.4, 127.6, 126.1, 123.7, 121.4 (q,J= 275.5 Hz), 62.5, 17.6, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -63.80.
example 12
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 1l (5.0 mmol) of 3, 5-dibromo-o-aminobenzaldehyde, 2a (7.5 mmol) of ethyl trifluoroacetoacetate, tetrahydropyrroline (20 mol%) and a solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, 2 h is reacted in a 50-DEG reaction module, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 6, 8-dibromo-2- (trifluoromethyl) quinoline-3-ethyl formate (3 l), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.43, mp=115-116 ℃, white solid, 96% yield). The nuclear magnetic test results are shown in figures 34-36, 1 H NMR (400 MHz, CDCl 3 ): δ 8.57 (s, 1H), 8.26 (d,J= 2.0 Hz, 1H), 8.05 (d,J= 2.0 Hz, 1H), 4.47 (q,J= 7.1 Hz, 2H), 1.43 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 164.7, 145.6 (q,J= 36.0 Hz), 143.0, 139.8, 138.8, 129.8, 129.4, 126.9, 125.9, 123.5, 120.8 (q,J= 275.9 Hz), 63.0, 14.0. 19 F NMR (376 MHz, CDCl 3 ): δ -63.97. HRMS (ESI) m/z calculated for C 13 H 9 Br 2 F 3 NO 2 [M+H] + 425.8952, found 425.8955.
example 13
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under air atmosphere, 6-methyl-anthranilaldehyde 1m (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL round bottom burnIn a bottle, reacting 5 h in a 90-degree reaction module, after the reaction is finished, carrying out suction filtration by using a sand core funnel with a diatomite pad, decompressing and removing a solvent, separating residues by using a silica gel column to obtain a target product of 5-methyl-2- (trifluoromethyl) quinoline-3-ethyl formate (3 m), wherein all eluents are petroleum ether and ethyl acetate according to a proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.43, mp=79-81 ℃, yellow solid, 88% yield). The nuclear magnetic test results are shown in figures 37-39, 1 H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H),8.07 (d,J= 8.5 Hz, 1H), 7.80 – 7.72 (m, 1H), 7.52 (d,J= 7.1 Hz, 1H), 4.48 (q,J= 7.1 Hz, 2H), 2.74 (s, 3H), 1.44 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 166.1, 147.5, 144.3 (q,J= 35.1 Hz), 136.8, 135.8, 132.2, 130.0, 128.3, 127.1, 123.6, 121.3 (q,J= 275.5 Hz), 62.6, 18.7, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -63.84 (s, 1H). HRMS (ESI) m/z calculated for C 14 H 13 F 3 NO 2 [M+H] + 284.0898, found 284.0906.
example 14
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 6-chloro-o-aminobenzaldehyde 1n (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, reaction is carried out in a 90-DEG reaction module for 5 h, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 5-chloro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 n), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.50, mp=83-85 ℃, white solid, 76% yield). Nuclear magnetic test results are shown in figures 40-42, 1 H NMR (400 MHz, CDCl 3 ): δ 9.00 (s, 1H), 8.13 (d,J= 7.6 Hz, 1H), 7.85 – 7.67 (m, 2H), 4.49 (q,J= 7.2 Hz, 2H), 1.44 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 147.6, 145.5 (q,J= 35.6 Hz), 137.2, 132.1, 129.5, 129.3, 126.0, 125.1, 121.1 (q,J= 276.0 Hz), 62.8, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -64.02. HRMS (ESI) m/z calculated for C 13 H 10 ClF 3 NO 2 [M+H] + 304.0352, found 304.0358.
example 15
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 3-fluoro-o-aminobenzaldehyde 1o (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, reaction is carried out in a 90-DEG reaction module for 5 h, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 8-fluoro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 o), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.23, mp=71-73 ℃, pale yellow solid, 66% yield). The nuclear magnetic test results are shown in figures 43-45, 1 H NMR (400 MHz, CDCl 3 ): δ 8.69 (s, 1H), 7.69 (ddd,J= 14.9, 12.6, 6.5 Hz, 2H), 7.56 (td,J= 8.9, 1.2 Hz, 1H), 4.46 (q,J= 7.1 Hz, 2H), 1.42 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.1, 158.0 (d,J= 261.9 Hz), 144.8 (q,J= 36.3 Hz), 139.9 (d,J= 2.7 Hz), 137.1 (d,J= 12.1 Hz), 129.8 (d,J= 7.9 Hz), 129.0, 125.1, 123.9 (d,J= 5.0 Hz), 120.9 (q,J= 275.7 Hz), 116.5 (d,J= 18.5 Hz), 62.7, 13.9. 19 F NMR (376 MHz, CDCl 3 ): δ -63.88, -122.05. HRMS (ESI) m/z calculated for C 13 H 10 F 4 NO 2 [M+H] + 288.0648, found 288.0650.
example 16
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 5-trifluoromethyl o-aminobenzaldehyde 1p (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, 5 h is reacted in a 90-DEG reaction module, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 6-trifluoromethyl-2- (trifluoromethyl) quinoline-3-ethyl formate (3 p), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.43, mp=93-94 ℃, white solid, 65% yield). Nuclear magnetic test results are shown in figures 46-48, 1 H NMR (400 MHz, CDCl 3 ): δ 8.78 (s, 1H), 8.36 (d,J= 8.9 Hz, 1H), 8.28 (s, 1H), 8.06 (dd,J= 8.9, 1.5 Hz, 1H), 4.49 (q,J= 7.1 Hz, 2H), 1.44 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.0, 147.9, 146.9 (q,J= 35.6 Hz), 141.1, 131.6, 131.5 (q,J= 33.2 Hz), 128.1 (q,J= 2.9 Hz), 126.8, 126.2 (q,J= 4.4 Hz), 125.5, 120.9 (q,J= 260.0 Hz), 63.0, 14.0. 19 F NMR (376 MHz, CDCl 3 ): δ -62.90, -64.21. HRMS (ESI) m/z calculated for C 14 H 10 F 6 NO 2 [M+H] + 338.0616, found 338.0619.
example 17
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 4, 5-difluoro-o-aminobenzaldehyde 1q (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, 5 h is reacted in a 90-DEG reaction module, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product 6, 7-difluoro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 q), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.30, mp=75-76 ℃, yellow solid, 55% yield). The nuclear magnetic test results are shown in figures 49-51, 1 H NMR (400 MHz, CDCl 3 ): δ 8.62 (s, 1H), 8.00 (dd,J= 10.5, 7.5 Hz, 1H), 7.70 (dd,J= 9.3, 8.4 Hz, 1H), 4.47 (q,J= 7.2 Hz, 2H), 1.43 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.2, 154.3 (dd,J= 260.2, 16.1 Hz), 152.2 (dd,J= 258.7, 16.0 Hz), 145.3 (dd,J= 35.5, 3.2 Hz), 144.5 (d,J= 11.8 Hz), 139.4 (dd,J= 5.4, 1.5 Hz), 125.0 (d,J= 8.6 Hz), 124.6 (d,J= 2.0 Hz), 121.0 (q,J= 275.7 Hz), 116.7 (dd,J= 16.9, 1.3 Hz), 113.6 (dd,J= 18.1, 1.7 Hz), 62.9, 14.0. 19 F NMR (376 MHz, CDCl 3 ): δ -64.04, -125.46, -129.27. HRMS (ESI) m/z calculated for C 13 H 9 F 5 NO 2 [M+H] + 306.0553, found 306.0559.
example 18
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under an air atmosphere, 4-fluoroanthranilaldehyde 1r (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (5)0 mL) is added into a 150 mL round bottom flask, 5 h is reacted in a 90-DEG reaction module, a sand core funnel with a diatomite pad is used for suction filtration after the reaction is finished, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 7-fluoro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 r), and all eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 10:1. Characterization of product data: (PE: ea=10:1, R f =0.29, mp=43-44 ℃, yellow solid, 66% yield). Nuclear magnetic test results are shown in figures 52-54, 1 H NMR (400 MHz, CDCl 3 ): δ 8.70 (s, 1H), 7.99 (dd,J= 9.0, 5.8 Hz, 1H), 7.88 (dd,J= 9.5, 2.4 Hz, 1H), 7.54 (td,J= 8.7, 2.5 Hz, 1H), 4.47 (q,J= 7.2 Hz, 2H), 1.43 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.4, 164.8 (d,J= 255.6 Hz), 148.3 (d,J= 13.4 Hz), 146.0 (q,J= 35.5 Hz), 140.2, 130.6 (d,J= 10.2 Hz), 124.7, 123.7 (d,J= 2.7 Hz), 121.1 (q,J= 275.9 Hz), 120.6 (d,J= 25.7 Hz), 114.1 (d,J= 21.0 Hz), 62.7, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -64.02, -103.68. HRMS (ESI) m/z calculated for C 13 H 10 F 4 NO 2 [M+H] + 288.0648, found 288.0657.
example 19
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 4-amino-o-aminobenzaldehyde 1s (5.0 mmol), ethyl trifluoroacetoacetate 2a (10 mmol), proline (50 mol%) and solvent DMF (100 mL) are added into a 150 mL round bottom flask, 1h is reacted in a 110-DEG reaction module, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 7-amino-2- (trifluoromethyl) quinoline-3-ethyl formate (3 s), and all eluents are petroleum ether and ethyl acetate according to the proportion of 3:1.Characterization of product data: (PE: ea=3:1, R f =0.38, mp=126-128 ℃, yellow solid, yield 24%). The nuclear magnetic test results are shown in figures 55-57, 1 H NMR (400 MHz, CDCl 3 ): δ 8.52 (s, 1H), 7.73 (d,J= 8.7 Hz, 1H), 7.11 (d,J= 8.5 Hz, 1H), 4.42 (dt,J= 19.8, 9.9 Hz, 4H), 1.42 (t,J= 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 166.0, 150.6, 149.2, 145.5 (q,J= 69.4, 34.8 Hz), 140.1, 129.7, 121.5 (q,J= 280.2 Hz), 121.4, 121.2, 119.9, 109.0, 62.2, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -63.91. HRMS (ESI) m/z calculated for C 13 H 12 F 3 N 2 O 2 [M+H] + 285.0851, found 285.0855.
example 20
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 3-chloro-o-aminobenzaldehyde 1t (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, reaction is carried out in a 90-DEG reaction module for 5 h, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 8-chloro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 t), and all eluents are petroleum ether and ethyl acetate according to the proportion of 10:1. Characterization of product data: (PE: ea=10:1, R f =0.29, mp=79-81 ℃, yellow solid, 57% yield). Nuclear magnetic test results are shown in figures 58-60, 1 H NMR (400 MHz, CDCl 3 ): δ 8.70 (s, 1H), 7.99 (d,J= 7.5 Hz, 1H), 7.88 (d,J= 8.2 Hz, 1H), 7.65 (t,J= 7.9 Hz, 1H), 4.48 (q,J= 7.1 Hz, 2H), 1.44 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 145.3 (d,J= 35.8 Hz), 143.4, 140.8, 135.0, 132.5, 129.7, 129.0, 127.2 125.1, 121.1 (d,J= 275.8 Hz), 62.8, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -63.88. HRMS (ESI) m/z calculated for C 13 H 10 ClF 3 NO 2 [M+H] + 304.0352, found 304.0358.
example 21
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 1u (5.0 mmol) of 6-bromo-o-aminobenzaldehyde, 2a (7.5 mmol) of ethyl trifluoroacetoacetate, tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, the mixture is reacted in a 90-DEG reaction module to obtain 5 h, after the reaction is finished, the mixture is filtered by a sand core funnel with a diatomite pad, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of 5-bromo-2- (trifluoromethyl) quinoline-3-ethyl formate (3 u), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.49, mp=91-92 ℃, white solid, 92% yield). The nuclear magnetic test results are shown in figures 61-63, 1 H NMR (400 MHz, CDCl 3 ): δ 9.09 – 8.89 (m, 1H), 8.18 (dd,J= 9.8, 4.1 Hz, 1H), 8.02 – 7.90 (m, 1H), 7.79-7.66 (m, 1H), 4.50(q,J= 7.1 Hz, 2H), 1.45 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 147.6, 145.5 (q,J= 35.6 Hz), 139.8, 133.3, 132.6, 130.0, 127.3, 125.4, 122.4, 119.6, 62.9, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -63.97. HRMS (ESI) m/z calculated for C 13 H 10 BrF 3 NO 2 [M+H] + 347.9847, found 347.9853.
example 22
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, 3-bromo-o-aminobenzaldehyde 1v (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round-bottomed flask, the mixture is reacted in a 90-DEG reaction module to obtain 5 h, after the reaction is finished, the mixture is filtered by a sand core funnel with a diatomite pad, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain the target product 8-bromo-2- (trifluoromethyl) quinoline-3-ethyl formate (3 v), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.29, mp=86-87 ℃, white solid, 83% yield). Nuclear magnetic test results are shown in figures 64-66, 1 H NMR (400 MHz, CDCl 3 ): δ 8.69 (s, 1H), 8.20 (dd,J= 7.5, 1.0 Hz, 1H), 7.92 (d,J= 8.2 Hz, 1H), 7.58 (t,J= 7.8 Hz, 1H), 4.48 (q,J= 7.2 Hz, 2H), 1.44 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.2, 145.4 (q,J= 35.8 Hz), 144.3, 140.9, 136.1, 130.1, 128.9, 128.0, 126.0, 125.1, 121.0 (q,J= 275.8 Hz), 62.8, 14.1. 19 F NMR (376 MHz, CDCl 3 ): δ -63.88. HRMS (ESI) m/z calculated for C 13 H 10 BrF 3 NO 2 [M+H] + 347.9847, found 347.9850.
example 23
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under air atmosphere, anthranilaldehyde 1a (5.0 mmol), trifluoroacetylacetone 2b (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round bottom flask, reacted in a 90 DEG reaction module to 5 h, after the reaction is finished, filtered through a sand core funnel with a diatomite pad, the solvent is removed under reduced pressure, and the residue is separated by a silica gel column to obtain the target product 3-acetyl-2-trifluoromethylquinoline (3 w), all of which areThe eluent is prepared from petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=5:1, R f =0.29, yellow solid, 71% yield). Nuclear magnetic test results are shown in figures 67-69, 1 H NMR (400 MHz, CDCl 3 ): δ 8.35 (s, 1H), 8.23 (d,J= 8.5 Hz, 1H), 7.96 – 7.84 (m, 2H), 7.76 – 7.70 (m, 1H), 2.70 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 199.6, 146.8, 136.9, 132.7, 132.3, 130.2, 129.8, 128.2, 127.6, 121.3 (q,J= 275.7 Hz), 30.6. 19 F NMR (376 MHz, CDCl 3 ): δ -62.95.
example 24
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, o-aminobenzaldehyde 1a (5.0 mmol), difluoroacetoacetic acid ethyl ester 2c (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150 mL round bottom flask, the mixture is reacted in a 90-DEG reaction module to obtain 5 h, after the reaction is finished, the mixture is filtered by a sand core funnel with a diatomite pad, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product 2- (difluoromethyl) quinoline-3-ethyl formate (3 x), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.30, yellow liquid, 42% yield). Nuclear magnetic test results are shown in figures 70-72, 1 H NMR (400 MHz, CDCl 3 ): δ 8.86 (s, 1H), 8.26 (d,J= 8.5 Hz, 1H), 7.96 (d,J= 8.2 Hz, 1H), 7.92 – 7.82 (m, 1H), 7.72 – 7.66 (m, 1H), 4.48 (q,J= 7.1 Hz, 2H), 1.46 (t,J= 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.2, 150.6 (t,J= 22.0 Hz), 148.1, 141.0, 132.6, 130.2, 129.0, 128.7, 127.3, 122.7 (t,J= 1.9 Hz), 111.4 (t,J= 241.3 Hz), 62.3, 14.3. 19 F NMR (376 MHz, CDCl 3 ): δ -118.28.
example 25
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under the air atmosphere, o-aminobenzaldehyde 1a (5.0 mmol), difluoroacetyl phenyl ketone 2d (5 mmol), morpholine (100 mol%) and solvent THF (25 mL) are added into a 150 mL round bottom flask, 10 h is reacted in a 70-DEG reaction module, after the reaction is finished, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product 3-benzoyl-2-trifluoromethyl quinoline (3 y), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.17, yellow liquid, 15% yield). Nuclear magnetic test results are shown in figures 73-75, 1 H NMR (400 MHz, CDCl 3 ): δ 8.35 – 8.25 (m, 2H), 7.98 – 7.89 (m, 2H), 7.84 (d,J= 7.3 Hz, 2H), 7.76 (t,J= 7.6 Hz, 1H), 7.66 (t,J= 7.4 Hz, 1H), 7.50 (t,J= 7.8 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ 193.6, 146.8, 144.8 (q,J= 34.9 Hz), 137.4, 136.4, 134.2, 132.0, 130.7, 130.3, 130.2, 129.7, 128.8, 127.9, 127.3, 121.2 (q,J= 276.2 Hz). 19 F NMR (376 MHz, CDCl 3 ): δ -62.76. HRMS (ESI) m/z calculated for C 17 H 11 F 3 NO [M+H] + 302.0793, found 302.0799.
example 26
The preparation method of the 2-trifluoromethyl quinoline compound comprises the following steps:
under air atmosphere, o-aminobenzaldehyde 1a (5.0 mmol), isopropyl trifluoroacetoacetate 2e (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL round bottom flask in a 90℃reaction blockAfter the reaction is finished, 5 h, a sand core funnel with a diatomite pad is used for suction filtration, the solvent is removed under reduced pressure, the residue is separated by a silica gel column to obtain a target product of isopropyl 2- (trifluoromethyl) quinoline-3-carboxylate (3 z), and all eluents are petroleum ether and ethyl acetate according to the proportion of 5:1. Characterization of product data: (PE: ea=10:1, R f =0.51, mp=51-52 ℃, yellow solid, 58% yield). Nuclear magnetic test results are shown in figures 76-78, 1 H NMR (400 MHz, CDCl 3 ): δ 8.66 (s, 1H), 8.24 (d,J= 8.5 Hz, 1H), 7.96 (d,J= 8.2 Hz, 1H), 7.92 – 7.85 (m, 1H),7.73 (t,J= 7.5 Hz, 1H), 5.33 (dt,J= 12.5, 6.3 Hz, 1H), 1.42(d,J= 6.3 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 146.9, 144.7 (q,J= 35.3 Hz), 140.1, 132.4, 130.2, 129.6, 128.3, 127.6, 124.7, 121.3 (q,J= 275.6 Hz), 70.6, 21.7. 19 F NMR (376 MHz, CDCl 3 ): δ -63.60. HRMS (ESI) m/z calculated for C 14 H 13 F 3 NO 2 [M+H] + 284.0898, found 284.0906.
application example
And (3) bactericidal activity test: 16.6. 16.6 mg of the synthesized medicine is taken and dissolved in 0.66 mL of DMSO, and then an aqueous solution containing 1% Tween 80 is added to prepare a raw medicine of 5 mg/mL. The test reagents are respectively sucked into conical flasks with proper amount under the aseptic condition, are fully and evenly shaken, and are poured into three culture dishes with the diameter of 9 cm in equal amount to prepare a 500 ug/mL medicine-containing flat plate. The above experiment was run with no drug treatment as a blank, and each treatment was repeated three times. Cutting bacterial cakes along the edges of bacterial colonies by using a puncher with the diameter of 6.5 mm under the aseptic condition, inoculating the bacterial cakes to the center of a medicine-containing flat plate by using an inoculator, covering a dish cover with the mycelium surface upwards, placing a culture dish in a constant-temperature incubator at 25 ℃ for culture, measuring the bacterial colony diameter by using a crisscross method when the diameter of a control bacterial colony is expanded to be more than 6 cm, and taking the average value; and (5) calculating the bacteriostasis rate after the cultivation is finished.
The calculation formula is as follows: antibacterial ratio i= (D) 0 -D t )/D 0 ×100％
D 0 For comparison of discsAverage hypha diameter, dt is the average hypha diameter of the sample tray.
The present invention carried out activity assays on 5 pathogens common in agricultural production, namely fusarium graminearum (from wheat) (fig. 79), fusarium graminearum (from corn) (fig. 80), rhizoctonia solani (fig. 81), fusarium moniliforme (fig. 82) and fusarium oxysporum (fig. 83), respectively. The result shows that the synthesized 26 novel 2-trifluoromethyl quinoline compounds 3a-3z have certain inhibition forces on 5 different pathogenic bacteria, wherein the compound 3w has good bactericidal activity on four of five pathogenic bacteria, and the inhibition rate of the rhizoctonia solani can reach 83%.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (1)

1. The application of the 2-trifluoromethyl quinoline compound in the field of agricultural antibacterial sterilization is characterized in that the 2-trifluoromethyl quinoline compound is as follows: ethyl 2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 6-methyl-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 6-bromo-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 6, 7-dimethoxy-3- (trifluoromethyl) -2-naphthoate, ethyl 6-chloro-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 5-fluoro-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 7-chloro-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 7-bromo-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 6-nitro-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 8-methyl-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 6, 8-dibromo-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 5-methyl-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 5-chloro-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 8-fluoro-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 6-trifluoromethyl) quinoline-3-carboxylate, ethyl 8-methyl-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 6-trifluoromethyl-3-carboxylate, any one of ethyl 6, 7-difluoro-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 7-fluoro-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 7-amino-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 8-chloro-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 5-bromo-2- (trifluoromethyl) quinoline-3-carboxylate, ethyl 8-bromo-2- (trifluoromethyl) quinoline-3-carboxylate, 3-acetyl-2-trifluoromethyl quinoline, ethyl 2- (difluoromethyl) quinoline-3-carboxylate, 3-benzoyl-2-trifluoromethyl quinoline, or isopropyl 2- (trifluoromethyl) quinoline-3-carboxylate.
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