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

Abstract

The present invention proposes a 2-trifluoromethylquinoline compound and its synthesis method and application, which belongs to the technical field of organic fluorine chemical synthesis and is used to solve the problem of the synthesis of existing 2-trifluoromethylquinoline skeletons. It reflects technical issues that make operations more difficult and are unfriendly to the environment. A 2-trifluoromethylquinoline compound with the following structural formula: The preparation method includes the following steps: adding the reactants anthranilic aldehyde compound 1, ethyl trifluoroacetoacetate compound 2, and a catalyst into a solvent to obtain a mixed solution, and after sufficient reaction, a 2-trifluoromethylquinoline compound is obtained . The preparation method of the present invention has simple reaction operations, mild conditions, strong functional group tolerance, does not require the addition of metal catalysts, has high step economy and atom economy, and the by-product of the reaction is only water, making it a typical case of green synthesis.

Description

A kind of 2-trifluoromethylquinoline compound and its synthesis method and application

Technical field

The invention belongs to the technical field of organic fluorine chemical synthesis, and particularly relates to a 2-trifluoromethylquinoline compound and its synthesis method and application.

Background technique

Fluorine shows special chemical properties due to its smaller atomic radius, lower orbital energy and strongest electronegativity. Studies have shown that when fluorine atoms or fluorine-containing groups are introduced into specific positions of organic molecules, the physical and chemical properties of organic molecules will be significantly changed, such as acid-base changes, conformational inversion, increased fat solubility, enhanced antioxidant properties, etc. (ChemMedChem ,2015, 10, 715-726). At present, fluorine-containing compounds have been widely used in many fields such as medicine, pesticides, liquid crystals, organic devices, high-energy materials, etc. due to their unique physiological activities. Among them, compounds containing trifluoromethyl groups in the molecules are the most concerned by synthetic chemists, especially It is fluorine chemists who have the most extensive applications.

Among many fluorine-containing molecules, the 2-trifluoromethylquinoline skeleton, as an important type of nitrogen heterocycle, has attracted more and more attention in recent years. Drug molecules containing this type of molecular skeleton usually have anti-inflammatory and sterilizing properties. , anti-tumor, anti-hypertensive, anti-malarial and other pharmacological activities. At the same time, clinical studies have found that 2-trifluoromethylquinoline can also be used in the treatment of HIV and mental diseases. For example, Compound I (mefloquine), a new antimalarial drug that has been marketed (J. Med. Chem., 1971, 14,926-928), shows a high degree of antimalarial activity compared to traditional chloroquine, and its dosage is small and Few side effects. Compound II acts as a serotonin 5-HT5A receptor, one of the major neurotransmitters in the human central nervous system and peripheral nervous system, and it helps regulate appetite, memory, cognition, and mood through serotonin receptors. Compound III is a target inhibitor of phosphodiesterase 4, which can effectively inhibit the activity of phosphodiesterase 4, increase intracellular cAMP levels and exert better anti-inflammatory effects. Compound V has shown good activity against tuberculosis. Compound VI, as an AChE inhibitor, can cross the blood-brain barrier and increase acetylcholine levels in the cortex. In addition, this type of framework has also shown extraordinary results in fluorescent probes, such as compound IV,

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As far as the synthesis methods of most common organic compounds are concerned, these methods are not suitable for preparing 2-trifluoromethylquinoline skeleton. Currently, the synthesis methods of 2-trifluoromethylquinoline skeleton are still limited. In view of the wide biological activity and great application value of the 2-trifluoromethylquinoline structure, achieving a simple and efficient synthesis is a goal that fluorine chemists strive for. From the perspective of product structure, the simplest method to synthesize 2-trifluoromethylquinoline compounds is to directly introduce the trifluoromethyl group 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 type of method is simple in form, the system is complex and the conditions are harsh, making it difficult to control. Fluorination reagents are expensive, and larger groups often need to be removed during the reaction process, resulting in poor atom economy. Especially when the molecular structure is complex or contains sensitive groups, such methods often fail to obtain the target compound or even cause the molecule to decompose. Preparing fluorine-containing compounds with the help of fluorine-containing building blocks can well solve the problem of difficult fluorination of complex molecules, and can synthesize fluorine-containing compounds in large doses. Fluorine-containing building blocks are essentially a series of small molecule compounds containing fluorine atoms or fluorine-containing groups. Using them as reaction substrates can achieve the synthesis of complex fluorine-containing compounds and the synthesis of fluorine-containing groups through one or several ordinary chemical reactions. Precise positioning. The reaction process does not involve the fragmentation and generation of CR _f , so it 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 widely used building block.

However, there are few studies on using ethyl trifluoroacetoacetate compounds to construct 2-trifluoromethylquinoline skeleton. The existing ethyl trifluoroacetoacetate compounds are used as building blocks for the synthesis of 2-trifluoromethylquinoline. The method mainly relies on Lewis acid catalysis such as indium and rubidium and reagents such as triphenylphosphine to promote the reaction. On the one hand, the currently used methods require the participation of metal salts or organophosphine reagents, making the reaction more difficult to operate. At the same time, they are not friendly to the environment and do not meet the current conceptual requirements for the development of sustainable chemistry and green chemistry. Therefore, it is of great research value to further develop efficient construction of novel, green 2-trifluoromethylquinoline skeletons from the perspective of developing sustainable and environmentally friendly chemistry.

Contents of the invention

In view of the above technical problems, the present invention proposes a 2-trifluoromethylquinoline compound and its synthesis method and application. The reaction is simple to operate, has mild conditions, has strong functional group tolerance, does not require the addition of a metal catalyst, and is relatively high. step economy and atom economy.

In order to achieve the above objects, the technical solution of the present invention is implemented as follows:

The present invention uses commercially available anthranilic aldehyde compounds 1 and ethyl trifluoroacetoacetate compounds 2 as raw materials, adds them to catalysts and solvents, and realizes the synthesis of new 2-trifluoromethylquinoline compounds in one step. Twenty-six structurally novel 2-trifluoromethylquinolines were synthesized. The reaction equation is:

Ar is a benzene ring or pyridine ring substituted by any one of Me, OMe, NH ₂ , F, Cl, Br, CF ₃ or NO ₂ ; R ² is CF ₃ or CHF ₂ ; R ³ is Me, OEt, O ⁱ Either Pr or Ph.

The specific steps are as follows: under air atmosphere, add the reactants anthranilic aldehyde compound 1 and ethyl trifluoroacetoacetate compound 2 into a 150 mL reaction bottle equipped with a magnetic stirrer, and then add analytically pure catalyst and solvent to A mixed solution is formed in the reaction bottle to fully react. The reaction temperature is 50-110 degrees and the reaction time is 1 to 10 hours. After the reaction is completed, the corresponding 2-trifluoromethylquinoline compound 3 is obtained by column chromatography separation and purification. , the eluent used is petroleum ether and ethyl acetate prepared in a certain volume ratio, the common ratio is 30:1-2:1.

The molar ratio of compound 1 and compound 2 is 1:(1-2). Preferably, the molar ratio of Compound 1 and Compound 2 is 1:1.5.

The concentration of compound 1 in the mixed solution is 0.05-0.2 M. Preferably, the concentration is 0.1 M.

The catalyst is tetrahydropyrroline, piperidine, morpholine, piperazine and other secondary amines which can be used as catalysts to promote the reaction. In addition, amino acids such as proline can also serve as catalysts for this type of reaction. Preferably, the catalyst is tetrahydropyrroline.

The dosage of the catalyst is 10-100 mol% of the reactants.

Preferably, the dosage of the catalyst tetrahydropyrroline is 50 mol% of the reactants.

The solvents are water, N,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 and compound 2 is 1:1.5, the solvent is EtOH, the concentration is 0.1 M, the reaction temperature is 90 degrees, and the reaction time is 5 h.

Application of the above-mentioned 2-trifluoromethylquinoline compounds in the field of antibacterial and sterilization.

Beneficial effects of the present invention: The present invention innovatively selects commercially available anthranilic aldehyde compounds and ethyl trifluoroacetoacetate compounds as reactants, and realizes a new 2-trifluoromethylquinoline skeleton through a one-step reaction. The construction provides a simple and effective synthetic method for the construction of this type of framework, and this method has mild reaction conditions, simple operation, atom economy, step economy, strong functional group tolerance and good yield (96%). Features. In addition, the solvent used in this reaction can be environmentally friendly EtOH, and the by-product of the reaction is only green H ₂ O. The product obtained by the reaction has broad medical application prospects, and at the same time provides a new idea and method for industry, natural product synthesis, luminescent materials and other fields.

The present invention conducts activity measurements on five common pathogenic bacteria in agricultural production, namely Fusarium graminearum (from wheat), Fusarium graminearum (from corn), Rhizoctonia solani, Fusarium moniliforme and Fusarium oxysporum. bacteria. The results show that the 26 new 2-trifluoromethylquinoline compounds 3a-3z synthesized have certain inhibitory effects on 5 different pathogenic bacteria. Among them, compound 3w showed good performance against four of the five pathogenic bacteria. The bactericidal activity can reach 83% against Rhizoctonia solani.

Description of the drawings

In order to explain the embodiments of the present invention or the technical solutions in the prior art more clearly, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings in the following description are only These are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without exerting creative efforts.

Figure 1 is the NMR ¹ H spectrum of compound 3a; Figure 2 is the NMR ¹³ C spectrum of compound 3a;

Figure 3 is the NMR ¹⁹ F spectrum of compound 3a.

Figure 4 is the NMR ¹ H spectrum of compound 3b; Figure 5 is the NMR ¹³ C spectrum of compound 3b;

Figure 6 is the NMR ¹⁹ F spectrum of compound 3b.

Figure 7 is the NMR ¹ H spectrum of compound 3c; Figure 8 is the NMR ¹³ C spectrum of compound 3c;

Figure 9 is the NMR ¹⁹ F spectrum of compound 3c.

Figure 10 is the NMR ¹ H spectrum of compound 3d; Figure 11 is the NMR ¹³ C spectrum of compound 3d;

Figure 12 is the NMR ¹⁹ F spectrum of compound 3d.

Figure 13 is the NMR ¹ H spectrum of compound 3e; Figure 14 is the NMR ¹³ C spectrum of compound 3e;

Figure 15 is the NMR ¹⁹ F spectrum of compound 3e.

Figure 16 is the NMR ¹ H spectrum of compound 3f; Figure 17 is the NMR ¹³ C spectrum of compound 3f;

Figure 18 is the NMR ¹⁹ F spectrum of compound 3f.

Figure 19 is the NMR ¹ H spectrum of compound 3g; Figure 20 is the NMR ¹³ C spectrum of compound 3g;

Figure 21 is the NMR ¹⁹ F spectrum of compound 3g.

Figure 22 is the NMR ¹ H spectrum of compound 3h; Figure 23 is the NMR ¹³ C spectrum of compound 3h;

Figure 24 is the NMR ¹⁹ F spectrum of compound 3h.

Figure 25 is the NMR ¹ H spectrum of compound 3i; Figure 26 is the NMR ¹³ C spectrum of compound 3i;

Figure 27 is the NMR ¹⁹ F spectrum of compound 3i.

Figure 28 is the NMR ¹ H spectrum of compound 3j; Figure 29 is the NMR ¹³ C spectrum of compound 3j;

Figure 30 is the NMR ¹⁹ F spectrum of compound 3j.

Figure 31 is the NMR ¹ H spectrum of compound 3k; Figure 32 is the NMR ¹³ C spectrum of compound 3k;

Figure 33 is the NMR ¹⁹ F spectrum of compound 3k.

Figure 34 is the NMR ¹ H spectrum of compound 3l; Figure 35 is the NMR ¹³ C spectrum of compound 3l;

Figure 36 is the NMR ¹⁹ F spectrum of compound 3l.

Figure 37 is the NMR ¹ H spectrum of compound 3m; Figure 38 is the NMR ¹³ C spectrum of compound 3m;

Figure 39 is the NMR ¹⁹ F spectrum of compound 3m.

Figure 40 is the NMR ¹ H spectrum of compound 3n; Figure 41 is the NMR ¹³ C spectrum of compound 3n;

Figure 42 is the NMR ¹⁹ F spectrum of compound 3n.

Figure 43 is the NMR ¹ H spectrum of compound 3o; Figure 44 is the NMR ¹³ C spectrum of compound 3o;

Figure 45 is the NMR ¹⁹ F spectrum of compound 3o.

Figure 46 is the NMR ¹ H spectrum of compound 3p; Figure 47 is the NMR ¹³ C spectrum of compound 3p;

Figure 48 is the NMR ¹⁹ F spectrum of compound 3p.

Figure 49 is the NMR ¹ H spectrum of compound 3q; Figure 50 is the NMR ¹³ C spectrum of compound 3q;

Figure 51 is the NMR ¹⁹ F spectrum of compound 3q.

Figure 52 is the NMR ¹ H spectrum of compound 3r; Figure 53 is the NMR ¹³ C spectrum of compound 3r;

Figure 54 is the NMR ¹⁹ F spectrum of compound 3r.

Figure 55 is the NMR ¹ H spectrum of compound 3s; Figure 56 is the NMR ¹³ C spectrum of compound 3s;

Figure 57 is the NMR ¹⁹ F spectrum of compound 3s.

Figure 58 is the NMR ¹ H spectrum of compound 3t; Figure 59 is the NMR ¹³ C spectrum of compound 3t;

Figure 60 is the NMR ¹⁹ F spectrum of compound 3t.

Figure 61 is the NMR ¹ H spectrum of compound 3u; Figure 62 is the NMR ¹³ C spectrum of compound 3u;

Figure 63 is the NMR ¹⁹ F spectrum of compound 3u.

Figure 64 is the NMR ¹ H spectrum of compound 3v; Figure 65 is the NMR ¹³ C spectrum of compound 3v;

Figure 66 is the NMR ¹⁹ F spectrum of compound 3v.

Figure 67 is the NMR ¹ H spectrum of compound 3w; Figure 68 is the NMR ¹³ C spectrum of compound 3w;

Figure 69 is the NMR ¹⁹ F spectrum of compound 3w.

Figure 70 is the NMR ¹ H spectrum of compound 3x; Figure 71 is the NMR ¹³ C spectrum of compound 3x;

Figure 72 is the NMR ¹⁹ F spectrum of compound 3x.

Figure 73 is the NMR ¹ H spectrum of compound 3y; Figure 74 is the NMR ¹³ C spectrum of compound 3y;

Figure 75 is the NMR ¹⁹ F spectrum of compound 3y.

Figure 76 is the NMR ¹ H spectrum of compound 3z; Figure 77 is the NMR ¹³ C spectrum of compound 3z;

Figure 78 is the NMR ¹⁹ F spectrum of compound 3z.

Figure 79 shows the inhibitory rates of 26 compounds against Fusarium graminearum (from wheat).

Figure 80 shows the inhibitory rates of 26 compounds against Fusarium graminearum (from corn).

Figure 81 shows the inhibitory rates of 26 compounds against Rhizoctonia solani.

Figure 82 shows the antibacterial rates of 26 compounds against Fusarium moniliforme.

Figure 83 shows the inhibitory rates of 26 compounds against Fusarium oxysporum.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without exerting creative efforts fall within the scope of protection of the present invention.

Example 1

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, anthranilic aldehyde 1a (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. , react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 2-(trifluoromethyl ) Quinoline-3-carboxylic acid ethyl ester (3a), all eluents are prepared from petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: (PE:EA = 10:1, R _f = 0.29, white solid, 89% yield). The nuclear magnetic test results are shown in Figure 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, 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 5-methyl anthranilic aldehyde 1b (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to 150 mL In a round-bottomed flask, react in a 100-degree reaction module for 4 hours. After the reaction is completed, use a sand core funnel with a diatomite pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 6-methyl. Ethyl-2-(trifluoromethyl)quinoline-3-carboxylate (3b), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: (PE:EA = 10:1, R _f = 0.48, white solid, 65% yield). The NMR test results are shown in Figure 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, anthranilic aldehyde 1c (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (30 mol%) and solvent EtOH (50 mL) were added to a 150 mL round-bottomed flask. , react in a reaction module at 70 degrees for 3 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 6-bromo-2-( Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3c), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 9:1. Product data characterization: (PE:EA = 9:1, R _f = 0.29, white solid, 84% yield). The NMR test results are shown in Figure 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, anthranilic aldehyde 1d (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL round-bottomed flask. , react in a reaction module at 90 degrees for 7 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 2-(trifluoromethyl )-1,8-Naphthyridine-3-carboxylic acid ethyl ester (3d), all eluents are petroleum ether and ethyl acetate in a ratio of 2:1. Product data characterization: (PE:EA = 2:1, R _f = 0.39, white solid, 78% yield). The NMR test results are shown in Figure 10-12, ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.29 (dd, J = 4.1, 1.9Hz, 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. ^19F NMR (376 MHz, CDCl ₃ ): δ -64.17.

Example 5

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 4,5-dimethoxy anthranilic aldehyde 1e (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) Add it to a 150 mL round-bottomed flask and react in a 90-degree reaction module for 5 hours. After the reaction, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target The product is 6,7-dimethoxy-3-(trifluoromethyl)-2-naphthoic acid ethyl ester (3e). All eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 5:1, R _f =0.34, mp = 148-149 ℃, white solid, 68% yield). The NMR test results are shown in Figure 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 = 7.1Hz, 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 FNMR (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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 4,5-dimethoxy anthranilic aldehyde 1f (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) Add it to a 150 mL round-bottomed flask, and react in a reaction module at 90 degrees for 4 hours. After the reaction, use a sand core funnel with a diatomaceous earth pad to suction filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target The product is ethyl 6-chloro-2-(trifluoromethyl)quinoline-3-carboxylate (3f). All eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.38, white solid, 76% yield). The nuclear magnetic test results are shown in Figure 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, 2.2Hz, 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 (3 76MHz , CDCl ₃ ): δ -63.98.

Example 7

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 1g (5.0 mmol) of 6-fluoroanthraniline, ethyl trifluoroacetoacetate 2a (7.5 mmol), piperidine (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL round-bottomed flask. , react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 5-fluoro-2- (Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3g), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.50, mp = 68-69 ℃, white solid, 83% yield). The NMR test results are shown in Figure 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 = 4.0Hz), 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 4-chloroanthranilic aldehyde 1h (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL round In the bottom flask, react in a reaction module at 80 degrees for 7 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 7-chloro- 2-(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3h), all eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.29, mp = 81-83°C, light yellow solid, 60% yield). The NMR test results are shown in Figure 22-24, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.65 (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 (100MHz, 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 ( 376MHz, 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 4-bromoanthranilic aldehyde 1i (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL circle. In the bottom flask, react in a reaction module at 60 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 7-bromo- 2-(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3i), all eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.23, mp = 82-85°C, light yellow solid, 85% yield). The nuclear magnetic test results are shown in Figure 25-27, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.64 (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, 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 5-nitro anthranilic aldehyde 1j (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to 150 mL In a round-bottomed flask, react in a 90-degree reaction module for 4 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 6-nitrate. Ethyl-2-(trifluoromethyl)quinoline-3-carboxylate (3j), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.19, mp =128-130 ℃, white solid, 48% yield). The NMR test results are shown in Figure 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 = 9.3Hz, 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 3-methyl anthranilic aldehyde 1k (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to 150 mL In a round-bottomed flask, react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 8-methyl. Ethyl-2-(trifluoromethyl)quinoline-3-carboxylate (3k), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA= 10:1, R _f = 0.33, white solid, 50% yield). The NMR test results are shown in Figure 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 1l of 3,5-dibromoanthranilic aldehyde (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5mmol), tetrahydropyrroline (20 mol%) and solvent EtOH (50 mL) were added to In a 150 mL round-bottomed flask, react for 2 hours in a reaction module at 50 degrees Celsius. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 6. , 8-dibromo-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3l), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.43, mp= 115-116 ℃, white solid, 96% yield). The nuclear magnetic test results are shown in Figure 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(ES I ) m/z calculated for C ₁₃ H ₉ Br ₂ F ₃ NO ₂ [M+H] ⁺ 425.8952, found 425.8955.

Example 13

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 6-methyl anthranilic aldehyde 1m (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to 150 mL In a round-bottomed flask, react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 5-methyl. Ethyl-2-(trifluoromethyl)quinoline-3-carboxylate (3m), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.43, mp =79-81 ℃, yellow solid, 88% yield). The NMR test results are shown in Figure 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 CNMR (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 FNMR ( 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 6-chloroanthrinobenzaldehyde 1n (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL circle. In the bottom flask, react in a reaction module at 90 degrees for 5 h. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 5-chloro- 2-(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3n), all eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.50, mp = 83-85°C, white solid, 76% yield). The NMR test results are shown in Figure 40-42, ¹ H NMR (400 MHz, CDCl ₃ ): δ9.00 (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 = 276.0Hz), 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 3-fluoro anthranilic aldehyde 1o (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL circle. In the bottom flask, react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 8-fluoro- 2-(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3o), all eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.23, mp = 71-73°C, light yellow solid, 66% yield). The NMR test results are shown in Figure 43-45, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.69 (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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 5-trifluoromethyl anthranilic aldehyde 1p (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to In a 150 mL round-bottomed flask, react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 6. -Trifluoromethyl-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3p), all eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.43, mp = 93-94 ℃, white solid, 65% yield). The nuclear magnetic test results are shown in Figure 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 (100MHz, 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 4,5-difluoroanthranilic aldehyde 1q (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to In a 150 mL round-bottomed flask, react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 6. , 7-Difluoro-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3q), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.30, mp= 75-76 ℃, yellow solid, 55% yield). The NMR test results are shown in Figure 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, 8.4Hz, 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 4-fluoroanthrinobenzaldehyde 1r (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL circle. In the bottom flask, react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 7-fluoro- 2-(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3r), all eluents are petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: (PE:EA = 10:1, R _f = 0.29, mp = 43-44°C, yellow solid, 66% yield). The nuclear magnetic test results are shown in Figure 52-54, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.70 (s, 1H), 7.99 (dd, J = 9.0, 5.8 Hz, 1H), 7.88 (dd, J 13 C NMR ^_ (100 MHz, CDCl ₃ ): δ 165.4, 164.8 (d, J = 255.6 Hz), 148.3 (d, J = 13.4Hz), 146.0 (q, J = 35.5 Hz), 140.2, 130.6 (d, J = 10.2 19 _ _ _ ^_ F NMR (376 MHz, CDCl ₃ ): δ -64.02, -103.68. HRMS (ESI) m/zcalculated for C ₁₃ H ₁₀ F ₄ NO ₂ [M+H] ⁺ 288.0648, found 288.0657.

Example 19

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 4-aminoanthranilinaldehyde 1s (5.0 mmol), ethyl trifluoroacetoacetate 2a (10mmol), proline (50 mol%) and solvent DMF (100 mL) were added to a 150 mL round-bottomed flask. , react in a reaction module at 110 degrees for 1 h. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 7-amino-2- (Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3s), all eluents are petroleum ether and ethyl acetate in a ratio of 3:1. Product data characterization: (PE:EA = 3:1, R _f = 0.38, mp =126-128 ℃, yellow solid, 24% yield). The nuclear magnetic test results are shown in Figure 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 ): δ166.0, 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, found285.0855.

Example 20

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 3-chloroanthrinobenzaldehyde 1t (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL circle. In the bottom flask, react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 8-chloro- 2-(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3t), all eluents are petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: (PE:EA = 10:1, R _f = 0.29, mp = 79-81°C, yellow solid, 57% yield). The nuclear magnetic test results are shown in Figure 58-60, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.70 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.65 (t, J = 7.9Hz, 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 6-bromoanthranilic aldehyde 1u (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL circle. In the bottom flask, react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 5-bromo- 2-(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3u), all eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.49, mp = 91-92°C, white solid, 92% yield). The NMR test results are shown in Figure 61-63, ¹ H NMR (400 MHz, CDCl ₃ ): δ9.09 – 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, 3-bromoanthranilic aldehyde 1v (5.0 mmol), ethyl trifluoroacetoacetate 2a (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL circle. In the bottom flask, react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 8-bromo- 2-(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (3v), all eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.29, mp = 86-87°C, white solid, 83% yield). The nuclear magnetic test results are shown in Figure 64-66, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.69 (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 (100MHz, 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 ( 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 kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, anthranilic aldehyde 1a (5.0 mmol), trifluoroacetylacetone 2b (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL round-bottom flask. React in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 3-acetyl-2-trifluoromethyl. Quinoline (3w), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 5:1, R _f = 0.29, yellow solid, 71% yield). The nuclear magnetic test results are shown in Figure 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, anthranilic aldehyde 1a (5.0 mmol), ethyl difluoroacetoacetate 2c (7.5 mmol), tetrahydropyrroline (50 mol%) and solvent EtOH (50 mL) were added to a 150 mL round-bottom flask. , react in a 90 degree reaction module for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 2-(difluoromethyl ) Quinoline-3-carboxylic acid ethyl ester (3x), all eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.30, yellow liquid, 42% yield). The nuclear magnetic test results are shown in Figure 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 (376MHz, CDCl ₃ ): δ -118.28.

Example 25

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, anthranilic aldehyde 1a (5.0 mmol), difluoroacetylphenyl ketone 2d (5 mmol), morpholine (100 mol%) and solvent THF (25 mL) were added to a 150 mL round-bottomed flask. React in a reaction module at 70 degrees for 10 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 3-benzoyl-2-trifluoro Methylquinoline (3y), all eluents are petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.17, yellow liquid, 15% yield). The nuclear magnetic test results are shown in Figure 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

A kind of 2-trifluoromethylquinoline compound, the preparation method includes the following steps:

Under air atmosphere, anthranilic aldehyde 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-bottomed flask. , react in a reaction module at 90 degrees for 5 hours. After the reaction is completed, use a sand core funnel with a diatomaceous earth pad to filter, remove the solvent under reduced pressure, and separate the residue with a silica gel column to obtain the target product 2-(trifluoromethyl base)quinoline-3-carboxylic acid isopropyl ester (3z), all eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: (PE:EA = 10:1, R _f = 0.51, mp = 51-52 ℃, yellow solid, 58% yield). The nuclear magnetic test results are shown in Figure 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 CNMR (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 examples

Bactericidal activity test: Dissolve 16.6 mg of the above synthesized drug in 0.66 mL DMSO, and then add an aqueous solution containing 1% Tween 80 to prepare a 5 mg/mL original drug. Pour an appropriate amount of each test agent into an Erlenmeyer flask under sterile conditions, shake it thoroughly, and then pour equal amounts into three 9 cm diameter petri dishes to make a 500 ug/mL drug-containing plate. The above experiment set up a treatment without chemicals as a blank control, and each treatment was repeated three times. Use a 6.5 mm diameter hole punch to cut the cultured pathogenic bacteria along the edge of the colony under sterile conditions. Use an inoculator to inoculate the bacteria cake into the center of the medicine-containing plate with the mycelial side facing up. Cover the dish with a lid. Place the petri dish in a constant temperature incubator at 25 degrees Celsius for cultivation. When the diameter of the control colony expands to more than 6 cm, use the cross method to measure the diameter of the colony and take the average value; after the culture is completed, the antibacterial rate is calculated.

The calculation formula is: antibacterial rate I = (D ₀ -D _t )/D ₀ ×100%

_D0 is the average diameter of mycelium in the control disk, and Dt is the average diameter of mycelium in the sample disk.

The present invention conducts activity measurements on five common pathogenic bacteria in agricultural production, namely Fusarium graminearum (from wheat) (Figure 79), Fusarium graminearum (from corn) (Figure 80), Rhizoctonia solani (Fig. 81), Fusarium moniliforme (Fig. 82), and Fusarium oxysporum (Fig. 83). The results show that the 26 new 2-trifluoromethylquinoline compounds 3a-3z synthesized have certain inhibitory effects on 5 different pathogenic bacteria. Among them, compound 3w showed good inhibitory effect on four of the five pathogenic bacteria. Bactericidal activity, the inhibition rate against Rhizoctonia solani can reach 83%.

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the present invention. within the scope of protection.

Claims (1)

1. The application of a 2-trifluoromethylquinoline compound in the field of agricultural antibacterial sterilization, characterized in that the 2-trifluoromethylquinoline compound is: 2-(trifluoromethyl)quinoline Phenoline-3-carboxylic acid ethyl ester, 6-methyl-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 6-bromo-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester , 6,7-dimethoxy-3-(trifluoromethyl)-2-naphthoic acid ethyl ester, 6-chloro-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 5-fluoro -2-(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 7-chloro-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 7-bromo-2-(trifluoromethyl) )quinoline-3-carboxylic acid ethyl ester, 6-nitro-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 8-methyl-2-(trifluoromethyl)quinoline-3- Ethyl formate, ethyl 6,8-dibromo-2-(trifluoromethyl)quinoline-3-carboxylate, ethyl 5-methyl-2-(trifluoromethyl)quinoline-3-carboxylate, 5-Chloro-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 8-fluoro-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 6-trifluoromethyl-2 -(Trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 6,7-difluoro-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 7-fluoro-2-(trifluoromethyl ethyl)quinoline-3-carboxylate, 7-amino-2-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester, 8-chloro-2-(trifluoromethyl)quinoline-3-carboxylic acid Ethyl ester, ethyl 5-bromo-2-(trifluoromethyl)quinoline-3-carboxylate, ethyl 8-bromo-2-(trifluoromethyl)quinoline-3-carboxylate, 3-acetyl- 2-Trifluoromethylquinoline, 2-(difluoromethyl)quinoline-3-carboxylic acid ethyl ester, 3-benzoyl-2-trifluoromethylquinoline or 2-(trifluoromethyl)quinoline Any one of pholine-3-carboxylic acid isopropyl ester.