CN115466212A - 2-trifluoromethyl quinoline compound and synthetic method and application thereof - Google Patents
2-trifluoromethyl quinoline compound and synthetic method and application thereof Download PDFInfo
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Abstract
The invention provides a 2-trifluoromethyl quinoline compound and 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 existing synthesis reaction of 2-trifluoromethyl quinoline skeleton is increased and the environment is not friendly. A2-trifluoromethyl quinoline compound has a structural formula as follows:
the preparation method comprises the following steps: adding reactants of anthranilaldehyde compounds 1, ethyl trifluoroacetoacetate compounds 2 and a catalyst into a solvent to obtain a mixed solution, and fully reacting to obtain the 2-trifluoromethyl quinoline compounds. The preparation method disclosed by the invention is simple in reaction operation, mild in condition, strong in functional group tolerance, high in step economy and atom economy, and water is the only by-product of the reaction, and the preparation method is a typical case of green synthesis, and does not need to add a metal catalyst.
Description
Technical Field
The invention belongs to the technical field of organic fluorine chemical synthesis, and particularly relates to a 2-trifluoromethyl quinoline compound and a synthesis method and application thereof.
Background
Fluorine elements exhibit particular chemical properties due to their small atomic radius, low orbital energy, and strongest electronegativity. Research shows that when fluorine atoms or fluorine-containing groups are introduced to specific positions of organic molecules, the physicochemical properties of the organic molecules are remarkably changed, such as acid-base change, conformation inversion, fat solubility improvement, oxidation resistance enhancement and the like (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 in their molecules are most concerned by synthetic chemists, and particularly, fluorine chemists have also been most widely used.
Among many fluorine-containing molecules, 2-trifluoromethyl quinoline skeleton has attracted more and more attention in recent years as an important nitrogen heterocycle, and drug molecules containing the molecular skeleton generally have pharmacological activities such as anti-inflammation, sterilization, anti-tumor, anti-hypertension, anti-malarial agents and the like. Meanwhile, clinical researches find that the 2-trifluoromethyl quinoline can also be used for treating HIV and mental diseases. For example, compound I (mefloquine), as a novel antimalarial drug (j.med.chem., 1971,14,926-928) that has been marketed, shows a high antimalarial activity compared to conventional chloroquine, and is small in dosage and less in side effects. Compound II is one of the major neurotransmitters in the central and peripheral nervous systems of humans as serotonin 5-HT5A receptors, which contributes to the regulation of appetite, memory, cognition and mood through serotonin receptors. The compound III is a target inhibitor of phosphodiesterase 4, can effectively inhibit the activity of the phosphodiesterase 4 and increase the cAMP level in cells to play a better anti-inflammatory effect. The compound V shows better activity in resisting tuberculosis. Compound VI acts as an AChE inhibitor, crossing the blood-brain barrier, increasing acetylcholine levels in the cortex. In addition, the skeleton also shows remarkable effect on fluorescent probes, such as compound IV,
as for most common synthetic methods of organic compounds, it is not appropriate to apply these methods to the preparation of 2-trifluoromethylquinoline skeleton, and the current synthetic methods regarding 2-trifluoromethylquinoline skeleton are still limited. In view of the wide biological activity and the larger application value of the structure of the 2-trifluoromethyl quinoline, the aim of synthesizing the cumin in the fluorine chemistry is to realize simple and convenient structure and high efficiency. From the product structure point of view, the simplest method for synthesizing 2-trifluoromethylquinoline compounds is to introduce trifluoromethyl directly into the C-2 position of 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, although this method is simple in form, the system is complicated and the conditions are severe, and it is difficult to control. The fluorinating reagent is expensive, and a larger group is often required to be removed in the reaction process, so that the atom economy is poor. Especially when the molecular structure is complex or contains sensitive groups, the target compound is often not obtained or even the molecule is decomposed by such methods. The fluorine-containing compound is prepared by the fluorine-containing building block, so that the problem that complex molecules are difficult to fluorinate can be well solved, and the fluorine-containing compound can be synthesized in a large amount. The fluorine-containing building block is essentially a series of micromolecular compounds containing fluorine atoms or fluorine-containing groups, and the synthesis of complex fluorine-containing compounds and the accurate positioning of the fluorine-containing groups can be realized by using the micromolecular compounds as reaction substrates through one-step or several-step common chemical reaction. C-R is not involved in the reaction process f The method has the advantages of mild conditions, high yield and good reaction selectivity (org. Chem. Front.,2022,9,413-419, org. Chet.2019, 21,1984-1988, org. Chem. Front.,2020,7,3368-3373, org.lett.,2019,21,1681-1685, chem. -eur.j.,2013,19,16928-933 16. Among them, ethyl trifluoroacetoacetate is a building block with wide application.
However, the research on constructing the 2-trifluoromethyl quinoline skeleton by using the ethyl trifluoroacetoacetate compound is less, and the existing method for synthesizing the 2-trifluoromethyl quinoline block by using the ethyl trifluoroacetoacetate compound mainly uses Lewis acid catalysis such as indium and rubidium and reagents such as triphenylphosphine to promote the reaction. On one hand, the existing means needs the participation of metal salt or organic phosphine reagent, the operation difficulty of the reaction is increased, and meanwhile, the method is not environment-friendly and does not meet the requirement of the concept of developing sustainable chemistry and green chemistry. Therefore, it is very valuable to develop a novel, green, efficient structure of 2-trifluoromethylquinoline skeleton from the viewpoint of sustainable and environmentally friendly chemistry.
Disclosure of Invention
Aiming at the technical problems, the invention provides a 2-trifluoromethyl quinoline compound and a synthesis method and application thereof, and the reaction has the advantages of simple operation, mild conditions, strong functional group tolerance, no need of adding a metal catalyst, and higher step economy and atom economy.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
the invention takes the commercially available anthranilic aldehyde compound 1 and the ethyl trifluoroacetoacetate compound 2 as raw materials, and adds the raw materials into a catalyst and a solvent to synthesize 26 novel 2-trifluoromethyl quinoline compounds by one step. The reaction equation is:
ar is Me, OMe, NH 2 、F、Cl、Br、CF 3 Or NO 2 Any one of a substituted benzene ring or pyridine ring; r 2 Is CF 3 Or CHF 2 ；R 3 Is Me, OEt, O i Pr or Ph.
The specific steps are as follows: under the air atmosphere, adding reactants of an anthranilic aldehyde compound 1 and an ethyl trifluoroacetoacetate compound 2 into a 150mL reaction bottle with a magnetic stirring bar, then adding an analytically pure catalyst and a solvent into the reaction bottle to form a mixed solution, fully reacting the mixed solution at the reaction temperature of 50-110 ℃ for 1-10 hours, separating and purifying by column chromatography after the reaction is finished to obtain a corresponding 2-trifluoromethylquinoline compound 3, wherein an eluant is prepared from petroleum ether and ethyl acetate according to a certain volume ratio and is prepared according to the general proportion of 30-2:1.
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.
The concentration of compound 1 in the mixed solution is 0.05-0.2M. 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 a catalyst to promote the reaction. In addition, amino acids such as proline may also be used as catalysts for such reactions. Preferably, the catalyst is tetrahydropyrroline.
The dosage of the catalyst is 10-100mol% of reactants.
Preferably, the amount of the catalyst tetrahydropyrroline is 50mol% of 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 the compound 1 to the compound 2 is 1.5, the solvent is EtOH, the concentration is 0.1M, the reaction temperature is 90 ℃, and the reaction time is 5h.
The 2-trifluoromethyl quinoline compound is applied to the field of antibiosis and sterilization.
The invention has the beneficial effects that: the invention creatively selects commercially available anthranilic aldehyde compounds and ethyl trifluoroacetoacetate compounds as reactants, realizes the construction of a novel 2-trifluoromethyl quinoline framework through one-step reaction, provides a simple and effective synthesis method for the construction of the framework, and has the characteristics of mild reaction conditions, simple operation, atom economy, economic steps, strong functional group tolerance, good yield (96%), and the like. In addition, the solvent used in the reaction can be environmentally friendly EtOH, and the by-product of the reaction is only green H 2 And O. The product obtained by the reaction has wide medical application prospect, and provides a new idea 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 power on 5 different pathogenic bacteria, wherein the compound 3w has better bactericidal activity on four of five pathogenic bacteria, and the inhibition rate on rhizoctonia solani can reach 83%.
Drawings
In order to more clearly illustrate the embodiments or prior art solutions of the present invention, the drawings that are needed in the description of the embodiments or prior art will be briefly described below, and it is apparent that, the drawings in the following description are only some embodiments of the invention and other drawings may be derived from those drawings by a person skilled in the art without inventive effort.
FIG. 1 is nuclear magnetism of Compound 3a 1 H, spectrogram; FIG. 2 is nuclear magnetism of Compound 3a 13 C, spectrum;
FIG. 3 is nuclear magnetism of Compound 3a 19 And F, spectrum.
FIG. 4 nuclear magnetism of Compound 3b 1 H, spectrogram; FIG. 5 nuclear magnetism of Compound 3b 13 C, spectrum;
FIG. 6 nuclear magnetism of Compound 3b 19 And F, spectrum.
FIG. 7 nuclear magnetism of Compound 3c 1 H, spectrogram; FIG. 8 is nuclear magnetism of Compound 3c 13 C, spectrum;
FIG. 9 nuclear magnetism of Compound 3c 19 And F, spectrum.
FIG. 10 nuclear magnetism of Compound 3d 1 H, spectrogram; FIG. 11 is nuclear magnetism of Compound 3d 13 C, spectrum;
FIG. 12 Nuclear magnetism of Compound 3d 19 And F, spectrum.
FIG. 13 Nuclear magnetism of Compound 3e 1 H, spectrogram; FIG. 14 nuclear magnetism of Compound 3e 13 C, spectrum;
FIG. 15 nuclear magnetism of Compound 3e 19 And F, spectrum.
FIG. 16 is nuclear magnetism of compound 3f 1 H, spectrogram; FIG. 17 is nuclear magnetism of compound 3f 13 C, spectrum;
FIG. 18 is nuclear magnetism of compound 3f 19 And F, spectrum.
FIG. 19 nuclear magnetism of compound 3g 1 H, spectrogram; FIG. 20 nuclear magnetism of compound 3g 13 C, spectrum;
FIG. 21 nuclear magnetism of compound 3g 19 And F, spectrum.
FIG. 22 nuclear magnetism of compound 3h 1 H, spectrogram; FIG. 23 NMR of Compound 3h 13 C, spectrum;
FIG. 24 nuclear magnetism of compound 3h 19 And F, spectrum.
FIG. 25 nuclear magnetism of Compound 3i 1 H, spectrogram; FIG. 26 nuclear magnetism of Compound 3i 13 C, spectrum;
FIG. 27 nuclear magnetism of Compound 3i 19 And F, spectrum.
FIG. 28 is nuclear magnetism of Compound 3j 1 H, spectrogram; FIG. 29 nuclear magnetism of Compound 3j 13 C, spectrum;
FIG. 30 nuclear magnetism of Compound 3j 19 And F, spectrum.
FIG. 31 nuclear magnetism of Compound 3k 1 H, spectrogram; FIG. 32 NMR of Compound 3k 13 C, spectrum;
FIG. 33 nuclear magnetism of Compound 3k 19 And F, spectrum.
FIG. 34 NMR of Compound 3l 1 H, spectrogram; FIG. 35 nuclear magnetism of Compound 3l 13 C, spectrum;
FIG. 36 NMR of Compound 3l 19 And F, spectrum.
FIG. 37 nuclear magnetism of compound 3m 1 H, spectrogram; FIG. 38 nuclear magnetism of compound 3m 13 C, spectrum;
FIG. 39 nuclear magnetism of compound 3m 19 And F, spectrum.
FIG. 40 is nuclear magnetism of Compound 3n 1 H, spectrogram; FIG. 41 is nuclear magnetism of Compound 3n 13 C, spectrum;
FIG. 42 is nuclear magnetism of Compound 3n 19 And F, spectrum.
FIG. 43 NMR of Compound 3O 1 H, spectrogram; FIG. 44 Nuclear magnetism of Compound 3o 13 C, spectrum;
FIG. 45 nuclear magnetism of compound 3o 19 And F, spectrum.
FIG. 46 nuclear magnetism of Compound 3p 1 H, spectrogram; FIG. 47 is nuclear magnetism of Compound 3p 13 C, spectrum;
FIG. 48 is nuclear magnetism of Compound 3p 19 And F, spectrum.
FIG. 49 nuclear magnetism of compound 3q 1 H, spectrogram; FIG. 50 is Compound 3Nuclear magnetism of q 13 C, spectrum;
FIG. 51 is nuclear magnetism of Compound 3q 19 And F, spectrum.
FIG. 52 NMR of Compound 3r 1 H, spectrogram; FIG. 53 nuclear magnetism of Compound 3r 13 C, spectrum;
FIG. 54 nuclear magnetism of Compound 3r 19 And F, spectrum.
FIG. 55 is nuclear magnetism of Compound 3s 1 H, spectrogram; FIG. 56 Nuclear magnetism of Compound 3s 13 C, spectrum;
FIG. 57 shows nuclear magnetism of Compound 3s 19 And F, spectrum.
FIG. 58 NMR of Compound 3t 1 H, spectrogram; FIG. 59 is nuclear magnetism of compound 3t 13 C, spectrum;
FIG. 60 nuclear magnetism of Compound 3t 19 And F, spectrum.
FIG. 61 nuclear magnetism of Compound 3u 1 H, spectrogram; FIG. 62 nuclear magnetism of Compound 3u 13 C, spectrum;
FIG. 63 is nuclear magnetism of compound 3u 19 And F, spectrum.
FIG. 64 is nuclear magnetism of Compound 3v 1 H, spectrogram; FIG. 65 nuclear magnetism of Compound 3v 13 C, spectrum;
FIG. 66 NMR of Compound 3v 19 And F, spectrum.
FIG. 67 nuclear magnetism of Compound 3w 1 H, spectrogram; FIG. 68 is nuclear magnetism of Compound 3w 13 C, spectrum;
FIG. 69 nuclear magnetism of Compound 3w 19 And F, spectrum.
FIG. 70 is nuclear magnetism of compound 3x 1 H, spectrogram; FIG. 71 is nuclear magnetism of compound 3x 13 C, spectrum;
FIG. 72 is nuclear magnetism of compound 3x 19 And F, spectrum.
FIG. 73 NMR for Compound 3y 1 H, spectrogram; FIG. 74 is nuclear magnetism of Compound 3y 13 C, spectrum;
FIG. 75 nuclear magnetism of Compound 3y 19 And F, spectrum.
FIG. 76 is nuclear magnetism of compound 3z 1 H, spectrogram; FIG. 77 is nuclear magnetism of Compound 3z 13 C, spectrum;
FIG. 78 NMR of Compound 3z 19 And F, spectrum.
FIG. 79 shows the inhibition rate of 26 compounds against Fusarium graminearum (from wheat).
FIG. 80 shows the inhibition rate of 26 compounds against Fusarium graminearum (from maize).
FIG. 81 shows the inhibition rates of 26 compounds against Rhizoctonia solani.
FIG. 82 shows the inhibition rate of the 26 compounds against Fusarium moniliforme.
FIG. 83 shows the inhibition rate of 26 compounds against Fusarium oxysporum.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.
Example 1
A preparation method of 2-trifluoromethyl quinoline compounds 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 150mL round-bottom flask, the mixture is reacted for 5 hours in a reaction module of 90 degrees, 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, namely ethyl 2- (trifluoromethyl) quinoline-3-carboxylate (3 a), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 10. And (3) product data characterization: (PE: EA =10 f =0.29, white solid, 89% yield). The results of the nuclear magnetic tests are shown in figures 1-3, 1 H NMR(400MHz,CDCl 3 ):δ8.69(s,1H),8.26(d,J＝8.5Hz,1H),8.00–7.87(m,2H),7.78–7.70(m,1H),4.48(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.7,147.1,144.9(q,J＝35.2Hz),140.3,132.5,130.3,129.7,128.3,127.6,124.2,121.3(q,J＝275.8Hz),62.6,14.1. 19 F NMR(376MHz,CDCl 3 ):δ-63.87.
example 2
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the air atmosphere, 5-methyl o-aminobenzaldehyde 1b (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150mL round bottom flask, the mixture is reacted for 4h in a reaction module with 100 ℃, 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-methyl-2- (trifluoromethyl) quinoline-3-ethyl formate (3 b), and all eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 10. And (3) product data characterization: (PE: EA =10 f =0.48, white solid, 65% yield). The results of the nuclear magnetic tests are shown in figures 4-6, 1 HNMR(400MHz,CDCl 3 ):δ8.56(s,1H),8.11(d,J＝8.5Hz,1H),7.73–7.67(m,2H),4.46(q,J＝7.2Hz,2H),2.58(s,3H),1.43(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ166.2,146.0,144.2(q,J＝35.1Hz),140.5,139.7,135.2,130.1,128.0,127.3,121.7(q,J＝275.5Hz),62.9,22.2,14.4 19 F NMR(376MHz,CDCl 3 ):δ-63.72.
example 3
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
o-aminobenzaldehyde 1 in air atmospherec (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrrole (30 mol%) and solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture reacts for 3h 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, namely 6-bromo-2- (trifluoromethyl) quinoline-3-ethyl formate (3 c), and all eluents are prepared from petroleum ether and ethyl acetate according to the proportion of 9:1. And (3) product data characterization: (PE: EA =9 f =0.29, white solid, 84% yield). The results of the nuclear magnetic tests are shown in figures 7-9, 1 H NMR(400MHz,Acetone):δ8.80(s,1H),8.37(d,J＝1.8Hz,1H),8.06–7.97(m,2H),4.33(q,J＝7.1Hz,2H),1.28(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.3,145.2(q,J＝29.8Hz),139.1,136.1,131.8,130.3,128.7,125.2,124.1,121.1(q,J＝275.9Hz),62.9,14.1. 19 F NMR(376MHz,Acetone):δ-64.55.
example 4
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the air atmosphere, o-aminobenzaldehyde 1d (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and a solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 7 hours in a reaction module of 90 ℃, 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, namely 2- (trifluoromethyl) -1,8-naphthyridine-3-ethyl formate (3 d), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 2:1. And (3) product data characterization: (PE: EA =2 f =0.39, white solid, 78% yield). The results of the nuclear magnetic tests are shown in figures 10-12, 1 H NMR(400MHz,CDCl 3 ):δ9.29(dd,J＝4.1,1.9Hz,1H),8.75(s,1H),8.37(dd,J＝8.2,1.9Hz,1H),7.69(dd,J＝8.2,4.2Hz,1H),4.47(q,J＝7.1Hz,2H),1.43(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ164.9,156.7,154.6,147.9(q,J＝35.7Hz),141.7,137.5,125.5,124.9,122.6,120.8(d,J＝276.3Hz),63.0,14.0. 19 F NMR(376MHz,CDCl 3 ):δ-64.17.
example 5
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
in the air atmosphere, 4,5-dimethoxy-anthranaldehyde 1e (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours in a 90-degree 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-dimethoxy-3- (trifluoromethyl) -2-ethyl naphthoate (3 e), and all eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 5:1. And (3) product data characterization: (PE: EA =5 f =0.34, mp =148-149 ℃, white solid, 68% yield). The results of the nuclear magnetic testing are shown in figures 13-15, 1 H NMR(400MHz,CDCl 3 ):δ8.51(s,1H),7.52(s,1H),7.14(s,1H),4.45(q,J＝7.1Hz,2H),4.05(d,J＝6.4Hz,6H),1.42(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ166.0,155.0,152.3,144.6,142.8(q,J＝35.0Hz),137.9,125.7,123.9,122.4,121.6(q,J＝275.0Hz),108.4,105.0,62.4,56.7,56.5,14.1. 19 F NMR(376MHz,CDCl 3 ):δ-63.43.HRMS(ESI)m/z calculated for C 15 H 16 F 3 NO 4 [M+H] + 330.0953,found330.0955.
example 6
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
4,5-dimethoxy anthranilic acid under air atmosphereAldehyde 1f (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 4 hours in a 90-degree 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, namely 6-chloro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 f), and all eluents are prepared from petroleum ether and ethyl acetate according to the proportion of 5:1. Product data characterization: (PE: EA =10 f =0.38, white solid, 76% yield). The results of the nuclear magnetic testing are shown in figures 16-18, 1 H NMR(400MHz,CDCl 3 ):δ8.59(s,1H),8.19(d,J＝9.0Hz,1H),7.95(d,J＝2.1Hz,1H),7.84(dd,J＝9.0,2.2Hz,1H),4.48(q,J＝7.1Hz,2H),1.44(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.3,145.1(q,J＝35.6Hz),139.2,135.9,133.6,131.8,128.3,126.9,125.2,121.1(q,J＝275.6Hz),62.6,14.0. 19 F NMR(376MHz,CDCl 3 ):δ-63.98.
example 7
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the air atmosphere, 1g (5.0 mmol) of 6-fluoro-o-aminobenzaldehyde, ethyl trifluoroacetoacetate 2a (7.5 mmol), piperidine (50 mol%) and a solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours in a reaction module of 90 degrees, 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, namely 6-fluoro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 g), and all eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.50, mp =68-69 ℃, white solid, 83% yield). The results of the nuclear magnetic tests are shown in figures 19-21, 1 H NMR(400MHz,CDCl 3 ):δ8.91(s,1H),8.04(d,J＝8.6Hz,1H),7.83(td,J＝8.2,6.0Hz,1H),7.39(t,J＝8.5Hz,1H),4.48(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.3,157.8(d,J＝258.9Hz),147.4,145.8(q,J＝35.5Hz),134.0(d,J＝4.0Hz),132.3(d,J＝8.9Hz),126.1(d,J＝4.4Hz),124.5(d,J＝2.4Hz),121.1(q,J＝276.0Hz),118.6(d,J＝16.3Hz),113.2(d,J＝18.9Hz),62.8,14.1. 19 F NMR(376MHz,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,found288.0652.
example 8
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the atmosphere of air, 4-chloro-o-aminobenzaldehyde 1h (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 7h in an 80-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, namely 4-chloro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 h), and all eluents are prepared from petroleum ether and ethyl acetate according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.29, mp =81-83 ℃, light yellow solid, 60% yield). The results of the nuclear magnetic testing are shown in figures 22-24, 1 H NMR(400MHz,CDCl 3 ):δ8.65(s,1H),8.21(d,J＝1.7Hz,1H),7.88(d,J＝8.8Hz,1H),7.66(dd,J＝8.7,2.0Hz,1H),4.46(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.3,147.3,145.9(q,J＝35.5Hz),140.1,138.8,130.9,129.4,129.2,125.9,124.4,121.0(q,J＝275.9Hz),62.8,14.0. 19 F NMR(376MHz,CDCl 3 ):δ-64.06.HRMS(ESI)m/z calculated for C 13 H 10 ClF 3 NO 2 [M+H] + 304.0352,found304.0357.
example 9
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the atmosphere of air, 4-bromo-o-aminobenzaldehyde 1i (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours in a 60-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, namely 4-bromo-2- (trifluoromethyl) quinoline-3-ethyl formate (3 i), and all eluents are prepared from petroleum ether and ethyl acetate according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.23, mp =82-85 ℃, light yellow solid, 85% yield). The results of the nuclear magnetic tests are shown in figures 25-27, 1 HNMR(400MHz,CDCl 3 ):δ8.64(d,J＝3.7Hz,1H),8.41(d,J＝7.8Hz,1H),7.79(t,J＝6.9Hz,2H),4.46(q,J＝7.1Hz,2H),1.42(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.3,147.3,145.8(d,J＝35.7Hz),140.2,133.3,132.5,129.4,127.1,126.2,124.5,121.0(d,J＝276.0Hz),62.8,14.0. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
adding 5-nitro o-aminobenzaldehyde 1j (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) into a 150mL round-bottom flask under an air atmosphere, reacting for 4h in a 90-degree reaction module, performing suction filtration by using a sand core funnel with a kieselguhr pad after the reaction is finished, removing the solvent under reduced pressure, and separating the residue by using a silica gel column to obtain the target product 5-nitro-2- (trifluoro-2)Methyl) quinoline-3-carboxylic acid ethyl ester (3 j), all eluents were petroleum ether and ethyl acetate formulated in a ratio of 5:1. And (3) product data characterization: (PE: EA =10 f =0.19, mp =128-130 ℃, white solid, 48% yield). The results of the nuclear magnetic testing are shown in figures 28-30, 1 H NMR(400MHz,CDCl 3 ):δ8.95–8.84(m,2H),8.64(dd,J＝9.3,2.5Hz,1H),8.41(d,J＝9.3Hz,1H),4.50(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ164.6,148.7,148.0(d,J＝36.0Hz),147.6,141.9,132.3,126.8,126.1,125.7,124.7,120.7(d,J＝276.3Hz),63.2,14.0. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds 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 a solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours in a reaction module of 90 degrees, 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, namely 3-methyl-2- (trifluoromethyl) quinoline-3-ethyl formate (3 k), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.33, white solid, 50% yield). The results of the nuclear magnetic testing are shown in figures 31-33, 1 H NMR(400MHz,CDCl 3 ):δ10.05(s,1H),8.41(d,J＝7.5Hz,1H),7.77–7.71(m,2H),7.58–7.48(m,2H),7.16(t,J＝8.6Hz,2H),7.04(t,J＝7.6Hz,1H),4.22(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.9,146.1,143.5(q,J＝35.0Hz),140.3,138.8,132.4,129.4,127.6,126.1,123.7,121.4(q,J＝275.5Hz),62.5,17.6,14.1. 19 F NMR(376MHz,CDCl 3 ):δ-63.80.
example 12
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the atmosphere of air, 3,5-dibromo-o-aminobenzaldehyde 1l (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (20 mol%) and a solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 2 hours 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 3,5-dibromo-2- (trifluoromethyl) quinoline-3-ethyl formate (3 l), and all eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 5:1. Product data characterization: (PE: EA =10 f =0.43, mp =115-116 ℃, white solid, 96% yield). The results of the nuclear magnetic testing are shown in figures 34-36, 1 H NMR(400MHz,CDCl 3 ):δ8.57(s,1H),8.26(d,J＝2.0Hz,1H),8.05(d,J＝2.0Hz,1H),4.47(q,J＝7.1Hz,2H),1.43(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ164.7,145.6(q,J＝36.0Hz),143.0,139.8,138.8,129.8,129.4,126.9,125.9,123.5,120.8(q,J＝275.9Hz),63.0,14.0. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
6-Methyloaminobenzaldehyde 1m (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), and tetrahydropyrroline (50 mol%) And a solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours in a reaction module with the temperature of 90 ℃, a sand core funnel with a diatomite pad is used for suction filtration after the reaction is finished, the solvent is removed by decompression, the residue is separated by a silica gel column to obtain a target product 6-methyl-2- (trifluoromethyl) quinoline-3-ethyl formate (3 m), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.43, mp =79-81 ℃, yellow solid, 88% yield). The results of the nuclear magnetic tests are shown in figures 37-39, 1 H NMR(400MHz,CDCl3)δ8.81(s,1H),8.07(d,J＝8.5Hz,1H),7.80–7.72(m,1H),7.52(d,J＝7.1Hz,1H),4.48(q,J＝7.1Hz,2H),2.74(s,3H),1.44(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ166.1,147.5,144.3(q,J＝35.1Hz),136.8,135.8,132.2,130.0,128.3,127.1,123.6,121.3(q,J＝275.5Hz),62.6,18.7,14.1. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the atmosphere of air, 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 150mL round-bottom flask, the mixture is reacted for 5 hours 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 the target product 6-chloro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 n), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 5:1. Product data characterization: (PE: EA =10 f =0.50, mp =83-85 ℃, white solid, 76% yield). The results of the nuclear magnetic testing are shown in figures 40-42, 1 H NMR(400MHz,CDCl 3 ):δ9.00(s,1H),8.13(d,J＝7.6Hz,1H),7.85–7.67(m,2H),4.49(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.3,147.6,145.5(q,J＝35.6Hz),137.2,132.1,129.5,129.3,126.0,125.1,121.1(q,J＝276.0Hz),62.8,14.1. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds 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 150mL round-bottom flask, the mixture is reacted for 5 hours in a reaction module of 90 degrees, 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 the target product, namely 3-fluoro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 o), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.23, mp =71-73 ℃, light yellow solid, 66% yield). The results of the nuclear magnetic testing are shown in figures 43-45, 1 H NMR(400MHz,CDCl 3 ):δ8.69(s,1H),7.69(ddd,J＝14.9,12.6,6.5Hz,2H),7.56(td,J＝8.9,1.2Hz,1H),4.46(q,J＝7.1Hz,2H),1.42(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.1,158.0(d,J＝261.9Hz),144.8(q,J＝36.3Hz),139.9(d,J＝2.7Hz),137.1(d,J＝12.1Hz),129.8(d,J＝7.9Hz),129.0,125.1,123.9(d,J＝5.0Hz),120.9(q,J＝275.7Hz),116.5(d,J＝18.5Hz),62.7,13.9. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds 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 a solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours 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, namely 5-trifluoromethyl-2- (trifluoromethyl) quinoline-3-ethyl formate (3 p), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.43, mp =93-94 ℃, white solid, 65% yield). The results of the nuclear magnetic testing are shown in figures 46-48, 1 H NMR(400MHz,CDCl 3 ):δ8.78(s,1H),8.36(d,J＝8.9Hz,1H),8.28(s,1H),8.06(dd,J＝8.9,1.5Hz,1H),4.49(q,J＝7.1Hz,2H),1.44(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.0,147.9,146.9(q,J＝35.6Hz),141.1,131.6,131.5(q,J＝33.2Hz),128.1(q,J＝2.9Hz),126.8,126.2(q,J＝4.4Hz),125.5,120.9(q,J＝260.0Hz),63.0,14.0. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
4,5-Difluoro-aminobenzaldehyde 1q (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150mL round bottom flask under air atmosphere, reacted in a 90 degree reaction block for 5h, after the reaction was completed using a sand core funnel with a celite padSuction filtering, decompression to eliminate solvent, silica gel column separation of the residue to obtain 4,5-difluoro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 q), and eluting with petroleum ether and ethyl acetate in 5:1 proportion. And (3) product data characterization: (PE: EA =10 f =0.30, mp =75-76 ℃, yellow solid, 55% yield). The results of the nuclear magnetic tests are shown in figures 49-51, 1 H NMR(400MHz,CDCl 3 ):δ8.62(s,1H),8.00(dd,J＝10.5,7.5Hz,1H),7.70(dd,J＝9.3,8.4Hz,1H),4.47(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.2,154.3(dd,J＝260.2,16.1Hz),152.2(dd,J＝258.7,16.0Hz),145.3(dd,J＝35.5,3.2Hz),144.5(d,J＝11.8Hz),139.4(dd,J＝5.4,1.5Hz),125.0(d,J＝8.6Hz),124.6(d,J＝2.0Hz),121.0(q,J＝275.7Hz),116.7(dd,J＝16.9,1.3Hz),113.6(dd,J＝18.1,1.7Hz),62.9,14.0. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the air atmosphere, 4-fluoro-o-aminobenzaldehyde 1r (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours in a reaction module of 90 degrees, 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, namely 4-fluoro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 r), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 10. And (3) product data characterization: (PE: EA =10 f =0.29, mp =43-44 ℃, yellow solid, 66% yield). The results of the nuclear magnetic testing are shown in figures 52-54, 1 HNMR(400MHz,CDCl 3 ):δ8.70(s,1H),7.99(dd,J＝9.0,5.8Hz,1H),7.88(dd,J＝9.5,2.4Hz,1H),7.54(td,J＝8.7,2.5Hz,1H),4.47(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.4,164.8(d,J＝255.6Hz),148.3(d,J＝13.4Hz),146.0(q,J＝35.5Hz),140.2,130.6(d,J＝10.2Hz),124.7,123.7(d,J＝2.7Hz),121.1(q,J＝275.9Hz),120.6(d,J＝25.7Hz),114.1(d,J＝21.0Hz),62.7,14.1. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the atmosphere of air, 4-aminoo-aminobenzaldehyde 1s (5.0 mmol), ethyl trifluoroacetoacetate 2a (10 mmol), proline (50 mol%) and a solvent DMF (100 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 1h in a reaction module at 110 ℃, 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, namely 4-amino-2- (trifluoromethyl) quinoline-3-ethyl formate (3 s), and all eluents are prepared from petroleum ether and ethyl acetate according to the proportion of 3:1. And (3) product data characterization: (PE: EA =3 f =0.38, mp =126-128 ℃, yellow solid, 24% yield). The results of the nuclear magnetic testing are shown in figures 55-57, 1 H NMR(400MHz,CDCl 3 ):δ8.52(s,1H),7.73(d,J＝8.7Hz,1H),7.11(d,J＝8.5Hz,1H),4.42(dt,J＝19.8,9.9Hz,4H),1.42(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ166.0,150.6,149.2,145.5(q,J＝69.4,34.8Hz),140.1,129.7,121.5(q,J＝280.2Hz),121.4,121.2,119.9,109.0,62.2,14.1. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds 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 150mL round-bottom flask, the mixture is reacted for 5 hours in a reaction module of 90 degrees, 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, namely 3-chloro-2- (trifluoromethyl) quinoline-3-ethyl formate (3 t), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 10. And (3) product data characterization: (PE: EA =10 f =0.29, mp =79-81 ℃, yellow solid, 57% yield). The results of the nuclear magnetic tests are shown in figures 58-60, 1 H NMR(400MHz,CDCl 3 ):δ8.70(s,1H),7.99(d,J＝7.5Hz,1H),7.88(d,J＝8.2Hz,1H),7.65(t,J＝7.9Hz,1H),4.48(q,J＝7.1Hz,2H),1.44(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.3,145.3(d,J＝35.8Hz),143.4,140.8,135.0,132.5,129.7,129.0,127.2125.1,121.1(d,J＝275.8Hz),62.8,14.1. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
6-bromoanthranaldehyde 1u (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and the solvent EtOH (50 mL) were added to a 150mL round bottom flask under an air atmosphere, reacted in a 90 ℃ reaction block for 5h, after the reaction was completed, filtered with suction through a sand-core funnel with a celite pad,the solvent was removed under reduced pressure and the residue was separated on silica gel column to give the desired product ethyl 6-bromo-2- (trifluoromethyl) quinoline-3-carboxylate (3 u), all eluents were petroleum ether and ethyl acetate formulated at a ratio of 5:1. And (3) product data characterization: (PE: EA =10 f =0.49, mp =91-92 ℃, white solid, 92% yield). The results of the nuclear magnetic tests are shown in figures 61-63, 1 HNMR(400MHz,CDCl 3 ):δ9.09–8.89(m,1H),8.18(dd,J＝9.8,4.1Hz,1H),8.02–7.90(m,1H),7.79-7.66(m,1H),4.50(q,J＝7.1Hz,2H),1.45(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.3,147.6,145.5(q,J＝35.6Hz),139.8,133.3,132.6,130.0,127.3,125.4,122.4,119.6,62.9,14.1. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds 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 a solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours in a 90-degree 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, namely 3-bromo-2- (trifluoromethyl) quinoline-3-ethyl formate (3 v), and all eluents are prepared from petroleum ether and ethyl acetate according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.29, mp =86-87 ℃, white solid, 83% yield). The results of the nuclear magnetic testing are shown in figures 64-66, 1 H NMR(400MHz,CDCl 3 ):δ8.69(s,1H),8.20(dd,J＝7.5,1.0Hz,1H),7.92(d,J＝8.2Hz,1H),7.58(t,J＝7.8Hz,1H),4.48(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.2,145.4(q,J＝35.8Hz),144.3,140.9,136.1,130.1,128.9,128.0,126.0,125.1,121.0(q,J＝275.8Hz),62.8,14.1. 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the air atmosphere, o-aminobenzaldehyde 1a (5.0 mmol), trifluoroacetylacetone 2b (7.5 mmol), tetrahydropyrroline (50 mol%) and a solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours in a reaction module of 90 ℃, 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 1- (2- (trifluoromethyl) quinolin-3-yl) ethane-1-ketone (3 w), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 5:1. And (3) product data characterization: (PE: EA =5 f =0.29, yellow solid, 71% yield). The results of the nuclear magnetic tests are shown in figures 67-69, 1 H NMR(400MHz,CDCl 3 ):δ8.35(s,1H),8.23(d,J＝8.5Hz,1H),7.96–7.84(m,2H),7.76–7.70(m,1H),2.70(s,3H). 13 C NMR(100MHz,CDCl 3 ):δ199.6,146.8,136.9,132.7,132.3,130.2,129.8,128.2,127.6,121.3(q,J＝275.7Hz),30.6. 19 F NMR(376MHz,CDCl 3 ):δ-62.95.
example 24
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
o-aminobenzaldehyde 1a (5.0 mmol), ethyl difluoroacetoacetate 2c (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150mL round bottom flask under an air atmosphere at 90 deg.CThe reaction module is used for reaction for 5 hours, a sand core funnel with a diatomite cushion is used for suction filtration after the reaction is finished, the solvent is removed by decompression, 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 prepared by petroleum ether and ethyl acetate according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.30, yellow liquid, 42% yield). The results of the nuclear magnetic testing are shown in figures 70-72, 1 HNMR(400MHz,CDCl 3 ):δ8.86(s,1H),8.26(d,J＝8.5Hz,1H),7.96(d,J＝8.2Hz,1H),7.92–7.82(m,1H),7.72–7.66(m,1H),4.48(q,J＝7.1Hz,2H),1.46(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 ):δ165.2,150.6(t,J＝22.0Hz),148.1,141.0,132.6,130.2,129.0,128.7,127.3,122.7(t,J＝1.9Hz),111.4(t,J＝241.3Hz),62.3,14.3. 19 F NMR(376MHz,CDCl 3 ):δ-118.28.
example 25
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the atmosphere of air, o-aminobenzaldehyde 1a (5.0 mmol), difluoroacetophenone 2d (5 mmol), morpholine (100 mol%) and solvent THF (25 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 10h 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 the target product phenyl (2- (trifluoromethyl) quinolin-3-yl) methanone (3 y), and all eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 5:1. And (3) product data characterization: (PE: EA =10 f =0.17, yellow liquid, 15% yield). The results of the nuclear magnetic tests are shown in figures 73-75, 1 HNMR(400MHz,CDCl 3 ):δ8.35–8.25(m,2H),7.98–7.89(m,2H),7.84(d,J＝7.3Hz,2H),7.76(t,J＝7.6Hz,1H),7.66(t,J＝7.4Hz,1H),7.50(t,J＝7.8Hz,2H). 13 C NMR(100MHz,CDCl 3 ):δ193.6,146.8,144.8(q,J＝34.9Hz),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＝276.2Hz). 19 F NMR(376MHz,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
A preparation method of 2-trifluoromethyl quinoline compounds comprises the following steps:
under the air atmosphere, o-aminobenzaldehyde 1a (5.0 mmol), isopropyl trifluoroacetoacetate 2e (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) are added into a 150mL round-bottom flask, the mixture is reacted for 5 hours in a reaction module of 90 degrees, 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 the target product 2- (trifluoromethyl) quinoline-3-carboxylic acid isopropyl ester (3 z), and all eluents are prepared by petroleum ether and ethyl acetate according to the proportion of 5:1. Product data characterization: (PE: EA =10 f =0.51, mp =51-52 ℃, yellow solid, 58% yield). The results of the nuclear magnetic testing are shown in figures 76-78, 1 H NMR(400MHz,CDCl 3 ):δ8.66(s,1H),8.24(d,J＝8.5Hz,1H),7.96(d,J＝8.2Hz,1H),7.92–7.85(m,1H),7.73(t,J＝7.5Hz,1H),5.33(dt,J＝12.5,6.3Hz,1H),1.42(d,J＝6.3Hz,6H). 13 C NMR(100MHz,CDCl 3 ):δ165.3,146.9,144.7(q,J＝35.3Hz),140.1,132.4,130.2,129.6,128.3,127.6,124.7,121.3(q,J＝275.6Hz),70.6,21.7. 19 F NMR(376MHz,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: 16.6mg of the above synthesized drug was dissolved in 0.66mL of ldmso, and then aqueous solution containing 1% tween 80 was added to make 5mg/mL of the original drug. The test reagents are respectively absorbed into a conical flask in proper amount under the aseptic condition, fully and uniformly shaken, and then poured into three culture dishes with the diameter of 9cm in equal amount to prepare a 500ug/mL drug-containing flat plate. The above experiment was blanked with treatments without agent, each treatment being repeated three times. Cutting a bacterial cake along the edge of a bacterial colony by using a puncher with the diameter of 6.5 mm under aseptic conditions, inoculating the bacterial cake to the center of a drug-containing flat plate by using an inoculator, enabling the hypha surface to face upwards, covering a dish cover, placing a culture dish in a constant-temperature incubator at 25 ℃ for culture, measuring the diameter of the bacterial colony by using a cross method when the diameter of a contrast bacterial colony is expanded to be more than 6cm, and taking the average value; and (5) calculating the bacteriostasis rate after the culture is finished.
The calculation formula is as follows: bacteriostatic rate I = (D) 0 -D t )/D 0 ×100％
D 0 The average diameter of the control disc hyphae and Dt the average diameter of the sample disc hyphae.
The activity of 5 common pathogenic bacteria in agricultural production is measured, namely fusarium graminearum (from wheat) (figure 79), fusarium graminearum (from corn) (figure 80), rhizoctonia solani (figure 81), fusarium moniliforme (figure 82) and fusarium oxysporum (figure 83). The result shows that the synthesized 26 novel 2-trifluoromethyl quinoline compounds 3a-3z have certain inhibitory power on 5 different pathogenic bacteria, wherein the compound 3w has good bactericidal activity on four of five pathogenic bacteria, and the inhibition rate of rhizoctonia solani can reach 83%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The 2-trifluoromethyl quinoline compound is characterized in that the structural formula is as follows:
ar is Me, OMe, NH 2 、F、Cl、Br、CF 3 Or NO 2 Any one of a substituted benzene ring or pyridine ring; r 2 Is CF 3 Or CHF 2 ；R 3 Is Me, OEt, O i Pr or Ph.
2. The method for synthesizing 2-trifluoromethylquinoline compound according to claim 1, wherein the method comprises the following steps: adding reactants of an anthranilic aldehyde compound 1, a trifluoroacetylacetic acid ethyl ester compound 2 and a catalyst into a solvent to obtain a mixed solution, and fully reacting to obtain a 2-trifluoromethyl quinoline compound; the reaction equation is:
ar is Me, OMe, NH 2 、F、Cl、Br、CF 3 Or NO 2 Any one of a substituted benzene ring or pyridine ring; r 2 Is CF 3 Or CHF 2 ；R 3 Is Me, OEt, O i Pr or Ph.
3. The method for synthesizing 2-trifluoromethylquinoline compound according to claim 2, wherein the molar ratio of the anthranilaldehyde compound 1 to the ethyl trifluoroacetoacetate compound 2 is 1 (1-2).
4. The method for synthesizing 2-trifluoromethylquinoline compound according to claim 3, wherein the concentration of the anthranilaldehyde compound 1 in the mixed solution is 0.05 to 0.2M.
5. The method for synthesizing 2-trifluoromethylquinoline compound according to claim 4, wherein the solvent is any one of water, ethanol, N-dimethylformamide, dimethyl sulfoxide, acetone, ethyl acetate, dichloroethane, methanol, and tetrahydrofuran.
6. The method for synthesizing 2-trifluoromethylquinoline according to any of the claims 2 to 5, wherein the amount of the catalyst is 10 to 100mol% of the reactants.
7. The method for synthesizing 2-trifluoromethylquinoline according to claim 6, wherein the catalyst is a secondary amine or an amino acid.
8. The method for synthesizing the 2-trifluoromethyl quinoline compound according to claim 7, wherein the secondary amine is any one of tetrahydropyrroline, piperidine, morpholine or piperazine; the amino acid is proline.
9. The method for synthesizing 2-trifluoromethylquinoline compound according to claim 7 or 8, wherein the reaction temperature is 50-110 ℃ and the reaction time is 1-10h.
10. The use of 2-trifluoromethylquinolines as claimed in claim 1 in the antibacterial and fungicidal field.
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