A 3-amidoquinoline structural compound and a synthesis method thereof

Abstract

The application belongs to the technical field of compound preparation, and discloses a kind of 3-amido quinoline structure containing compound, its chemical structural formula is as follows: wherein, R1 is halogen;R2 is N-substituted five or six-membered nitrogen heterocyclic primary amine group or 3-substituted six-membered nitrogen heterocyclic primary amine group;R3 is 4-methylphenyl or 4-benzyl morpholinyl.The 4-methylphenyl or 4-benzyl morpholinyl substituted terminal alkyne ketone, 2-amino-5-halogen benzaldehyde is used as raw material to synthesize intermediate product, and the intermediate product is reacted with N-substituted five or six-membered nitrogen heterocyclic primary amine or 3-substituted six-membered nitrogen heterocyclic primary amine, to obtain a variety of 3-amido quinoline structure containing compounds, the raw material is widely sourced, low in price, green and environmentally friendly, and easy to operate, simple in condition, fast in reaction time, convenient in post-treatment, high in product yield, suitable for large-scale preparation, and has wide application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of compound preparation and relates to a 3-amido quinoline structure-containing compound and a synthesis method thereof. BACKGROUND

[0002] Quinoline and its derivatives are important nitrogen-containing heterocyclic compounds, have biological activities and pharmacological activities such as bactericidal, antibacterial, antihypertensive, antiallergic, antitumor and the like, are structural backbones of many natural products, and have an increasingly important position in the chemical field. Ian.H.Gilbert reported that halogen atoms are inserted on the basis of a 2,6-disubstituted quinoline-4-carboxamide support, which can effectively reduce the mass and lipophilicity of the molecule, ethyl pyrrolidinyl groups are replaced on the corresponding groups, 3-pyridyl amino groups are replaced, and a methylene morpholine group is added, so that an anti-malaria drug DDD107498 (CAS No. 1469439-69-7) is obtained. However, in the reaction of directly synthesizing a quinoline skeleton with biological activity from a simple and readily available substrate, there are still problems such as harsh reaction conditions and a long synthesis path. SUMMARY

[0003] The application provides a 3-amido quinoline structure-containing compound and a synthesis method thereof, which are green and environmentally friendly, simple to operate, simple in conditions, fast in reaction time, convenient in post-processing, and high in product yield.

[0004] To achieve the above object, the application adopts the following technical solutions.

[0005] In a first aspect, the application provides a 3-amido quinoline structure-containing compound, which has the following chemical structural formula:

[0006]

[0007] wherein R1 is halogen; R2 is a five-membered or six-membered nitrogen heterocyclic primary amine group substituted with N or a six-membered nitrogen heterocyclic primary amine group substituted with 3; and R3 is a 4-methylphenyl group or a 4-benzyl morpholinyl group.

[0008] In a preferred technical solution, the five-membered or six-membered nitrogen heterocyclic primary amine group substituted with N in the 3-amido quinoline structure-containing compound is an N-(2-aminoethyl) pyrrolidinyl group or a 1-(2-aminoethyl) piperidinyl group; and the six-membered nitrogen heterocyclic primary amine group substituted with 3 is a 3-aminopyridyl group.

[0009] In a second aspect, the present application provides a synthesis method of a compound containing a 3-amidoquinoline structure, comprising the following steps: adding a compound shown in formula I and magnesium chloride into a reactor, then adding a compound shown in formula II, stirring and reacting at 105℃ for 18h, after the reaction is completed, cooling to room temperature, purifying to obtain a compound shown in formula III containing a 3-amidoquinoline structure; then adding the compound shown in formula III and N-substituted five-membered or six-membered primary amine under the action of sodium hydroxide solid in an inert gas atmosphere, heating and stirring at 110℃ for 3h, cooling to room temperature, removing the solvent under reduced pressure, purifying to obtain a compound shown in formula V containing a 3-amidoquinoline structure; the above reaction route is shown as follows:

[0010]

[0011] In one technical solution, the molar ratio of the compound shown in formula I to the compound shown in formula II is 1:2.

[0012] In one technical solution, the molar ratio of the compound shown in formula III to N-substituted five-membered or six-membered primary amine is 1:2.

[0013] In one technical solution, the amount of magnesium chloride added is 10% of the molar amount of the compound shown in formula I; the molar ratio of the sodium hydroxide solution to the compound shown in formula III is 1.5:1.

[0014] In a third aspect, the present application provides another synthesis method of a compound containing a 3-amidoquinoline structure, comprising the following steps: adding a compound shown in formula I and magnesium chloride into a reactor, then adding a compound shown in formula II, stirring and reacting at 105℃ for 18h, after the reaction is completed, cooling to room temperature, purifying to obtain a compound shown in formula III containing a 3-amidoquinoline structure; then adding the compound shown in formula III under the action of sodium hydroxide solid in an inert gas atmosphere, heating and stirring at 120℃ for 4h, cooling to room temperature, removing the solvent under reduced pressure to obtain a compound shown in formula IV containing a 3-amidoquinoline structure; finally dissolving the compound shown in formula IV in thionyl chloride, stirring and reacting at 80℃ for 4h, after the reaction is completed, cooling to room temperature, removing the solvent under reduced pressure to obtain a crude product; dissolving the crude product in dichloromethane, then adding 3-substituted six-membered primary amine and triethylamine in an inert gas atmosphere, stirring and reacting at room temperature for 12h, after the reaction is completed, removing the solvent under reduced pressure, purifying to obtain a compound shown in formula V containing a 3-amidoquinoline structure; the above reaction route is shown as follows:

[0015]

[0016] In one technical solution, the molar ratio of the compound shown in formula I to the compound shown in formula II is 1:2.

[0017] In one technical solution, the molar ratio of the compound shown in formula III and the 3-substituted six-membered nitrogen heterocyclic primary amine is 1:1.

[0018] In one technical solution, the amount of the added magnesium chloride is 10% of the molar amount of the compound shown in formula I; the molar ratio of the sodium hydroxide solution and the compound shown in formula III is 1.5:1; the added ratio of the thionyl chloride and the compound shown in formula III is 5 mL:2 mmol; the molar ratio of the triethylamine and the compound shown in formula IV is 3:2; and the added ratio of the dichloromethane and the compound shown in formula IV is 2 mL:0.2 mmol.

[0019] Compared with the prior art, the present application has the following beneficial effects:

[0020] The present application uses 4-methylphenyl or 4-benzyl morpholinyl substituted terminal alkyne ketone and 2-amino-5-halogen benzaldehyde as raw materials to synthesize an intermediate product (a compound shown in formula III), and the intermediate product is reacted with N-substituted five-membered or six-membered nitrogen heterocyclic primary amine or 3-substituted six-membered nitrogen heterocyclic primary amine to obtain various 3-amide quinoline structure containing compounds, the amide group of which is at the meta position of the N element, and the compounds have a good inhibitory effect on cancer cells.

[0021] The synthesis method of the present application has the advantages of wide raw material source, low price, green environmental protection, simple operation, simple conditions, fast reaction time, convenient post-treatment, high product yield, suitability for large-scale preparation, and wide application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 It is the nuclear magnetic resonance hydrogen spectrum of 2,2,2-trifluoro-1-(6-fluoro-2-(4-morpholinylmethylphenyl) quinolin-3-yl) ethanone in Example 1 of the present application.

[0023] Figure 2 It is the nuclear magnetic resonance fluorine spectrum of 2,2,2-trifluoro-1-(6-fluoro-2-(4-morpholinylmethylphenyl) quinolin-3-yl) ethanone in Example 1 of the present application.

[0024] Figure 3 It is the nuclear magnetic resonance carbon spectrum of 2,2,2-trifluoro-1-(6-fluoro-2-(4-morpholinylmethylphenyl) quinolin-3-yl) ethanone in Example 1 of the present application.

[0025] Figure 4 It is the nuclear magnetic resonance hydrogen spectrum of 6-fluoro-2-(4-morpholinylmethyl) phenyl-N-(2-(pyrrolidin-1-yl) ethyl) quinoline-3-carboxamide in Example 2 of the present application.

[0026] Figure 5NMR spectrum of the fluorine of 6-fluoro-2-(4-morpholinylmethyl)phenyl-N-(2- (pyrrolidin-1-yl)ethyl)quinoline-3-carboxamide in Example 2 of the present invention.

[0027] Figure 6 NMR spectrum of the carbon of 6-fluoro-2-(4-morpholinylmethyl)phenyl-N-(2- (pyrrolidin-1-yl)ethyl)quinoline-3-carboxamide in Example 2 of the present invention.

[0028] Figure 7 NMR spectrum of the hydrogen of 6-fluoro-2-(4-morpholinylmethyl)phenyl-N-(2- (piperidin-1-ethyl)ethyl)quinoline-3-carboxamide in Example 3 of the present invention.

[0029] Figure 8 NMR spectrum of the fluorine of 6-fluoro-2-(4-morpholinylmethyl)phenyl-N-(2- (piperidin-1-ethyl)ethyl)quinoline-3-carboxamide in Example 3 of the present invention.

[0030] Figure 9 NMR spectrum of the carbon of 6-fluoro-2-(4-morpholinylmethyl)phenyl-N-(2- (piperidin-1-ethyl)ethyl)quinoline-3-carboxamide in Example 3 of the present invention.

[0031] Figure 10 NMR spectrum of the hydrogen of 2,2,2-trifluoro-1-(6-fluoro-2-(p-tolyl)quinolin-3- yl)ethan-1-one in Example 4 of the present invention.

[0032] Figure 11 NMR spectrum of the fluorine of 2,2,2-trifluoro-1-(6-fluoro-2-(p-tolyl)quinolin-3- yl)ethan-1-one in Example 4 of the present invention.

[0033] Figure 12 NMR spectrum of the carbon of 2,2,2-trifluoro-1-(6-fluoro-2-(p-tolyl)quinolin-3- yl)ethan-1-one in Example 4 of the present invention.

[0034] Figure 13 NMR spectrum of the hydrogen of 6-fluoro-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3- carboxamide in Example 5 of the present invention.

[0035] Figure 14 NMR spectrum of the fluorine of 6-fluoro-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3- carboxamide in Example 5 of the present invention.

[0036] Figure 15NMR spectrum of the carbon of 6-fluoro-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3- carboxamide in Example 5 of the present invention.

[0037] Figure 16 NMR spectrum of the hydrogen of 2,2,2-trifluoro-l-(6-bromo-2-p-tolyl)quinolin-3- yl)ethan-l-one in Example 6 of the present invention.

[0038] Figure 17 NMR spectrum of the fluorine of 2,2,2-trifluoro-l-(6-bromo-2-p-tolyl)quinolin-3- yl)ethan-l-one in Example 6 of the present invention.

[0039] Figure 18 NMR spectrum of the carbon of 2,2,2-trifluoro-l-(6-bromo-2-p-tolyl)quinolin-3- yl)ethan-l-one in Example 6 of the present invention.

[0040] Figure 19 NMR spectrum of the hydrogen of 6-bromo-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3- carboxamide in Example 7 of the present invention.

[0041] Figure 20 NMR spectrum of the carbon of 6-bromo-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3- carboxamide in Example 7 of the present invention. DETAILED DESCRIPTION

[0042] The following examples are intended to illustrate the present invention but not to limit the scope of protection of the present invention. If not specifically mentioned, the technical means used in the examples are the conventional means known to those skilled in the art. The test methods used in the following examples are the conventional methods unless otherwise specified.

[0043] Example 1 Preparation of 2,2,2-trifluoro-l-(6-fluoro-2-(4-morpholinomethylphenyl)quinolin-3- yl)ethan-l-one

[0044] Into a 25 mL Schlenk tube equipped with a magnetic bar, 2-amino-5-fluorobenzaldehyde (139.1 mg, 1.0 mmol), MgCl2(9.9 mg, 0.1 mmol), 1,1,1-trifluoro-4-(4- (morpholinomethyl)phenyl)but-3-yn-2-one (594.6 mg, 2.0 mmol) were sequentially added. The mixture was stirred at 105 °C for 18 h under argon atmosphere. After cooling to room temperature, the residue was purified by column chromatography to give the product 2,2,2-trifluoro-l-(6-fluoro-2-(4-morpholinomethylphenyl)quinolin-3-yl)ethan-l-one as a white solid with a yield of 74%.

[0045] The above reaction equation is as follows:

[0046]

[0047] 2,2,2-trifluoro-1-(6-fluoro-2-(4-morpholinomethylphenyl)quinolin-3-yl)ethanone was characterized by nuclear magnetic resonance hydrogen spectrum (spectrum see Figure 2) as follows: Figure 1 1 H NMR (300 MHz, CDC13) δ 8.51 (s, 1H), 8.27-8.16 (m, 1H), 7.73-7.43 (m, 6H), 3.73 (s, 4H), 3.57 (s, 2H), 2.47 (s, 4H).

[0048] 2,2,2-trifluoro-1-(6-fluoro-2-(4-morpholinomethylphenyl)quinolin-3-yl)ethanone was characterized by nuclear magnetic resonance fluorine spectrum (spectrum see Figure 3) as follows: Figure 2 19 F NMR (376 MHz, CDC13) δ -73.3 (s), -111.1 (s).

[0049] 2,2,2-trifluoro-1-(6-fluoro-2-(4-morpholinomethylphenyl)quinolin-3-yl)ethanone was characterized by nuclear magnetic resonance carbon spectrum (spectrum see Figure 4) as follows: Figure 3 13 C NMR (75 MHz, CDC13) δ 184.8 (q, J = 36.0 Hz), 162.6, 159.3, 156.7, 145.8, 139.5, 137.8, 132.3 (d, J = 9.0 Hz), 129.5, 128.8, 126.8, 125.6 (d, J = 9.8 Hz), 123.1 (d, J = 30.8 Hz), 115.4 (q, J = 290.3 Hz), 111.6 (d, J = 21.8 Hz), 67.0, 63.0, 53.6.

[0050] Preparation of 6-fluoro-2-(4-morpholinomethyl)phenyl-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-3-carboxamide

[0051] ​​​In a dry 25 mL Schlenk tube equipped with a magnetic bar, 2,2,2-trifluoro-1-(6-fluoro-2-(4- morpholinomethylphenyl)quinolin-3-yl)ethanone (41.8 mg, 0.1 mmol) synthesized in Example one, NaOH (6.0 mg, 0.15 mmol), N-(2-aminoethyl)pyrrolidine (22.8 mg, 0.2 mmol) were added. The mixture was stirred at 110 °C for 3 h under argon atmosphere. Cooled to room temperature, then the residue was purified by column chromatography to give the product 6-fluoro-2-(4-morpholinomethyl)phenyl-N-(2-(pyrrolidin-1- yl)ethyl)quinoline-3-carboxamide as a white solid with a yield of 71%.

[0052] The above reaction equation is as follows:

[0053]

[0054] The nuclear magnetic resonance hydrogen spectrum characterization of 6-fluoro-2-(4-morpholinomethyl)phenyl-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-3-carboxamide (the spectrum is shown in Figure 4 ) as follows: 1 H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 8.18-8.07 (m, 1H), 7.76-7.60 (m, 4H), 7.48 (d, J = 8.0 Hz, 2H), 3.75-3.66 (m, 4H), 3.60 (s, 2H), 3.42 (t, J = 6.8 Hz, 2H), 2.68-2.38 (m, 10H), 1.90-1.70 (m, 4H), NH signal was overlapped.

[0055] The nuclear magnetic resonance fluorine spectrum characterization of 6-fluoro-2-(4-morpholinomethyl)phenyl-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-3-carboxamide (the spectrum is shown in Figure 5 ) as follows: 19 F NMR (376 MHz, CD3OD) δ -112.3 (s).

[0056] The nuclear magnetic resonance carbon spectrum characterization of 6-fluoro-2-(4-morpholinomethyl)phenyl-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-3-carboxamide (the spectrum is shown in Figure 6 ) as follows: 13C NMR (75 MHz, CD3OD) δ 171.0, 162.2 (d, J = 246.8 Hz), 157.2 (d, J = 3.0 Hz), 146.0, 139.7, 137.4 (d, J = 5.3 Hz), 132.4 (d, J = 9.0 Hz), 130.5, 130.0, 128.4 (d, J = 10.5 Hz), 122.3 (d, J = 26.3 Hz), 112.2 (d, J = 22.5 Hz), 67.8, 63.9, 55.6, 55.0, 54.6, 39.6, 24.2, two carbon signals were overlapped.

[0057] Example Three Preparation of 6-fluoro-2-(4-morpholinylmethyl)phenyl-N-(2-(piperidin-1- ylethyl)ethyl)quinoline-3-carboxamide

[0058] In a 25 mL Schlenk tube equipped with a magnetic bar, 2,2,2-trifluoro-l-(6-fluoro-2-(4- morpholinylmethylphenyl)quinolin-3-yl)ethanone (41.8 mg, 0.1 mmol) synthesized in Example One, NaOH (6.0 mg, 0.15 mmol), l-(2-aminoethyl)piperidine (0.2 mmol) were added. The mixture was stirred at 110 °C under argon atmosphere for 3 h. After cooling to room temperature, the residue was purified by column chromatography to give the product 6-fluoro-2-(4-morpholinylmethyl)phenyl-N-(2-(piperidin-l-ylethyl)ethyl)quinoline-3-carboxamide as a white solid in 73% yield.

[0059] The above reaction scheme is as follows:

[0060]

[0061] The nuclear magnetic resonance hydrogen spectrum of 6-fluoro-2-(4-morpholinylmethyl)phenyl-N-(2-(piperidin-l-ylethyl)ethyl)quinoline-3-carboxamide is characterized (the spectrum is shown in Figure Figure 7 ) as follows: 1 H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.15 (dd, J = 8.8, 5.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.57-7.43 (m, 4H), 6.33 (s, 1H), 3.70 (t, J = 4.8 Hz, 4H), 3.53 (s, 2H), 3.33 (dd, J = 11.2, 5.6 Hz, 2H), 2.46 (s, 4H), 2.27-2.06 (m, 6H), 1.36 (s, 6H).

[0062] 6-Fluoro-2-(4-morpholinylmethyl)phenyl-N-(2-(piperidin-1-yl- ethyl)ethyl)quinoline-3-carboxamide was characterized by nuclear magnetic resonance fluorine spectrum (spectrum see Figure 6) as follows: Figure 8 ) as follows: 19 F NMR (376 MHz, CD3OD) δ -112.6 (s).

[0063] 6-Fluoro-2-(4-morpholinylmethyl)phenyl-N-(2-(piperidin-1-yl- ethyl)ethyl)quinoline-3-carboxamide was characterized by nuclear magnetic resonance fluorine spectrum (spectrum see Figure 6) as follows: Figure 9 ) as follows: 13 C NMR (75 MHz, CDCl3) δ 168.1, 160.7 (d, J = 248.3 Hz), 155.3, 145.2, 139.0, 138.3, 136.7 (d, J = 5.3 Hz), 131.9 (d, J = 9.0 Hz), 130.6, 129.3, 128.8, 126.8 (d, J = 9.8 Hz), 121.2 (d, J = 25.5 Hz), 110.9 (d, J = 17.3 Hz), 66.9, 63.0, 56.3, 53.9, 53.6, 36.3, 25.6, 24.0.

[0064] Example Four Preparation of 2,2,2-trifluoro-1-(6-fluoro-2-(p-tolyl)quinolin-3-yl)ethan-1-one

[0065] Into a 25 mL Schlenk tube equipped with a magnetic stir bar, 2-amino-5- fluorobenzaldehyde (1.0 mmol), MgCl2(9.9 mg, 0.1 mmol), 1,1,1-trifluoro-4-(p- tolyl)but-3-yn-2-one (2.0 mmol) were added successively. The mixture was stirred at 105 °C for 18 h under argon atmosphere. It was cooled to room temperature. The residue was purified by column chromatography to give the product 2,2,2-trifluoro-1-(6-fluoro-2-(p-tolyl)quinolin-3-yl)ethan-1-one as a white solid in 63% yield.

[0066] The above reaction equation is as follows:

[0067]

[0068] 2,2,2-trifluoro-1-(6-fluoro-2-(p-tolyl)quinolin-3-yl)ethan-1-one was characterized by nuclear magnetic resonance hydrogen spectrum (spectrum see Figure 7) as follows: Figure 10 ) as follows: 1H NMR (400 MHz, CDC13) δ 8.47 (s, 1H), 8.24-8.16 (m, 1H), 7.66-7.61 (m, 1H), 7.59-7.53 (m, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H).

[0069] NMR Fluorine Spectrum of 2,2,2-trifluoro-l-(6-fluoro-2-(p-tolyl)quinolin-3-yl)ethan-l-one (spectrum seen in Figure 6) is as follows: Figure 11 19 F NMR (376 MHz, CDC13) δ -73.3 (s), -111.4 (s).

[0070] NMR Carbon Spectrum of 2,2,2-trifluoro-l-(6-fluoro-2-(p-tolyl)quinolin-3-yl)ethan-l-one (spectrum seen in Figure 7) is as follows: Figure 12 13 C NMR (75 MHz, CDC13) δ 184.8 (q, J = 36.0 Hz), 160.9 (d, J = 249.0 Hz), 156.8 (d, J = 3.0 Hz), 145.9, 139.6, 137.8 (q, J = 3.0 Hz), 136.1, 132.2 (d, J = 9.0 Hz), 129.5, 128.8, 126.9, 125.5 (d, J = 10.5 Hz), 122.9 (d, J = 25.5 Hz), 137.8 (q, J = 291.0 Hz), 111.5 (d, J = 21.8 Hz), 21.3.

[0071] Example Five Preparation of 6-fluoro-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3- carboxamide

[0072] ​​In a 25 mL Schlenk tube equipped with a magnetic bar was placed 2,2,2-trifluoro-1-(6-fluoro-2-p-tolyl)quinolin-3-yl)ethan-1-one (2.0 mmol) synthesized in Example four, NaOH (212.0 mg, 5.3 mmol). The mixture was heated at 120 °C under argon atmosphere for 4 h. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was purified by column chromatography to give 6-fluoro-2-p-tolylquinoline-3-carboxylic acid as a white solid. 6-Fluoro-2-p-tolylquinoline-3-carboxylic acid (0.2 mmol), sulphuric acid chloride (0.5 mL) were heated at 80 °C under stirring for 4 h. After completion of the reaction, the mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2 mL) and 3-aminopyridine (18.8 mg, 0.2 mmol) and triethylamine (41.7 μL, 0.3 mmol) were added. The reaction mixture was stirred at room temperature under argon atmosphere for 12 h. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography to give 6-fluoro-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3-carboxamide as a white solid with a yield of 64%.

[0073] The above reaction scheme is as follows:

[0074]

[0075] The nuclear magnetic resonance hydrogen spectrum characterization of 6-fluoro-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3-carboxamide (the spectrum is shown in Figure 13 ) is as follows: 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.68 (s, 1H), 8.32 (d, J = 4.8 Hz, 1H), 8.22 - 8.16 (m, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.96 - 7.91 (m, 1H), 7.82 - 7.76 (m, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.42 - 7.37 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H).

[0076] The nuclear magnetic resonance fluorine spectrum characterization of 6-fluoro-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3-carboxamide (the spectrum is shown in Figure 14 ) is as follows: 19 F NMR (376 MHz, DMSO-d6) δ -112.0 (s).

[0077] The nuclear magnetic resonance carbon hydrogen spectrum characterization of 6-fluoro-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3-carboxamide (the spectrum is shown in Figure 15 ) is as follows:13 C NMR (75 MHz, DMSO-d6) δ 167.0, 160.0 (d, J = 245.3 Hz), 155.1 (d, J = 2.2 Hz), 144.8, 144.5, 141.2, 138.4, 136.3, 135.8 (d, J = 5.3 Hz), 135.4, 131.7 (d, J = 9.0 Hz), 130.7, 128.8, 128.4, 126.6, 126.2 (d, J = 11.3 Hz), 123.7, 121.1 (d, J = 25.5 Hz), 111.1 (d, J = 21.8 Hz), 20.7.

[0078] Example Six Preparation of 2,2,2-trifluoro-1-(6-bromo-2-p-tolyl)quinolin-3-yl)ethan-1-one

[0079] In a 25 mL Schlenk tube equipped with a magnetic bar, 2-amino-5-bromobenzaldehyde (1.0 mmol), 1,1,1-trifluoro-4-(p-tolyl)but-3-yn-2-one (2.0 mmol), MgCl2(9.9 mg, 0.1 mmol) were added. The mixture was stirred at 105 °C for 18 h under argon atmosphere. The residue was purified by column chromatography to give the product 2,2,2-trifluoro-1-(6-bromo-2-p-tolyl)quinolin-3-yl)ethan-1-one as a white solid with a yield of 68%.

[0080] The above reaction equation is as follows:

[0081]

[0082] The nuclear magnetic resonance hydrogen spectrum characterization of 2,2,2-trifluoro-1-(6-bromo-2-p-tolyl)quinolin-3-yl)ethan-1-one (spectrum see Figure 16 ) is as follows: 1 H NMR (300 MHz, CDC13) δ 8.43 (s, 1H), 8.12-8.03 (m, 2H), 7.96-7.89 (m, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 2.42 (s, 3H).

[0083] The nuclear magnetic resonance fluorine spectrum characterization of 2,2,2-trifluoro-1-(6-bromo-2-p-tolyl)quinolin-3-yl)ethan-1-one (spectrum see Figure 17 ) is as follows: 19 F NMR (376 MHz, CDC13) δ -73.3 (s).

[0084] 2,2,2-trifluoro-1-(6-bromo-2-p-tolyl)quinolin-3-yl)ethan-1-one. The NMR carbon spectrum of the compound is shown in Figure 1. Figure 18 ) as follows: 13 C NMR (75 MHz, CDC13) δ 184.8 (q, J = 36.0 Hz), 157.8, 147.3, 139.8, 137.5 (q, J = 1.5 Hz), 136.1, 136.0, 131.2, 130.4, 129.6, 128.8, 126.8, 125.9, 121.6, 115.7 (q, J = 290.3 Hz), 21.3.

[0085] Example Seven Preparation of 6-bromo-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3- carboxamide

[0086] In a 25 mL Schlenk tube equipped with a magnetic stir bar was placed 2,2,2-trifluoro-1-(6-bromo-2-p-tolyl)quinolin-3-yl)ethan-1-one (2.0 mmol) synthesized in Example Four, NaOH (212.0 mg, 5.3 mmol). The mixture was heated with stirring at 120 °C under argon atmosphere for 4 h. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the product 6-bromo-2-p-tolylquinoline-3-carboxylic acid as a white solid. The 6-bromo-2-p-tolylquinoline-3-carboxylic acid (0.2 mmol), thionyl chloride (0.5 mL) were heated with stirring at 80 °C for 4 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2 mL), and 3-aminopyridine (18.8 mg, 0.2 mmol) and triethylamine (41.7 μL, 0.3 mmol) were added. The mixture was stirred at room temperature for 12 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give the product 6-bromo-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3-carboxamide as a white solid in 61% yield.

[0087] The above reaction scheme is as follows:

[0088]

[0089] The NMR hydrogen spectrum of the compound is shown in Figure 1. Figure 19 ) as follows: 1H NMR (300 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.32 (d, J = 4.2 Hz, 1H), 8.09 - 7.93 (m, 3H), 7.70 (d, J = 7.8 Hz, 2H), 7.44 - 7.34 (m, 1H), 7.27 (d, J = 7.8 Hz, 2H), 2.33 (s, 3H).

[0090] 6-Bromo-N-(pyridin-3-yl)-2-(p-tolyl)quinoline-3-carboxamide was characterized by nuclear magnetic resonance spectroscopy (the spectrum is shown in Figure 1) as follows: Figure 20 13 C NMR (75 MHz, DMSO-d6) δ 166.9, 156.0, 145.9, 144.8, 141.2, 138.7, 136.2, 135.5, 135.4, 134.0, 131.0, 130.8, 130.0, 128.8, 128.5, 126.8, 126.6, 123.7, 120.0, 20.7.

[0091] The above-described embodiments are only preferred embodiments of the present application and are used to explain the present application, but not to limit the scope of the present application. For those skilled in the art, other embodiments can be easily obtained by substitution or change based on the technical content disclosed in the present specification, and therefore, any changes and improvements made on the principles of the present application shall be included in the scope of the patent application of the present application.​

Claims

1. A method for synthesizing compounds containing a 3-amide-quinoline structure, characterized in that, Includes the following steps: The compound shown in Formula I and magnesium chloride were added to a reactor, followed by the compound shown in Formula II. The mixture was stirred at 105 °C for 18 h. After the reaction was complete, the mixture was cooled to room temperature and purified to obtain the compound shown in Formula III, which contains a 3-amidoquinoline structure. Subsequently, the compound shown in Formula III and an N-substituted five- or six-membered nitrogen-containing primary amine were reacted with sodium hydroxide solid at 110 °C under an inert gas atmosphere for 3 h. The mixture was then cooled to room temperature, the solvent was removed under reduced pressure, and the mixture was purified to obtain the compound shown in Formula V, which contains a 3-amidoquinoline structure. The N-substituted five- or six-membered nitrogen-containing primary amine was N-(2-aminoethyl)pyrrolidine or 1-(2-aminoethyl)piperidine. The above reaction route is shown below: Where R1 is a halogen; R2 is R3 is 2. The method for synthesizing a compound containing a 3-amide-quinoline structure according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to the compound shown in Formula II is 1:

2.

3. The method for synthesizing a compound containing a 3-amide-quinoline structure according to claim 1, characterized in that, The molar ratio of the compound represented by Formula III to the N-substituted five- or six-membered nitrogen-containing primary amine is 1:

2.

4. The method for synthesizing a compound containing a 3-amide-quinoline structure according to claim 1, characterized in that, The amount of magnesium chloride added is 10% of the molar amount of the compound shown in I; the molar ratio of the sodium hydroxide solid to the compound shown in III is 1.5:

1.

5. A method for synthesizing compounds containing a 3-amide-quinoline structure, characterized in that, Includes the following steps: The compound shown in Formula I and magnesium chloride were added to a reactor, followed by the compound shown in Formula II. The mixture was stirred at 105°C for 18 h. After the reaction was complete, the mixture was cooled to room temperature and purified to obtain the compound shown in Formula III, which contains a 3-amide-quinoline structure. Subsequently, the compound shown in Formula III was heated and stirred at 120°C for 4 h in an inert gas atmosphere with the aid of solid sodium hydroxide. After cooling to room temperature, the solvent was removed under reduced pressure to obtain the compound shown in Formula IV, which contains a 3-amide-quinoline structure. Finally, the compound shown in Formula IV was dissolved in thionyl chloride and stirred at 80°C for 4 h. After the reaction was complete, the mixture was cooled to room temperature and the solvent was removed under reduced pressure to obtain a crude product. The crude product was dissolved in dichloromethane, and a 3-substituted hexacyclic amine and triethylamine were added. The mixture was stirred at room temperature in an inert gas atmosphere for 12 h. After the reaction was complete, the solvent was removed under reduced pressure and the mixture was purified to obtain the compound shown in Formula V, which contains a 3-amide-quinoline structure. The 3-substituted hexacyclic amine is 3-aminopyridine. The above reaction route is shown below: Where R1 is a halogen; R2 is R3 is 6. The method for synthesizing a compound containing a 3-amide-quinoline structure according to claim 5, characterized in that, The molar ratio of the compound shown in Formula I to the compound shown in Formula II is 1:

2.

7. The method for synthesizing a compound containing a 3-amide-quinoline structure according to claim 5, characterized in that, The molar ratio of the compound represented by Formula III to the 3-substituted six-membered nitrogen-containing heterocyclic primary amine is 1:

1.

8. The method for synthesizing a compound containing a 3-amide-quinoline structure according to claim 5, characterized in that, The amount of magnesium chloride added is 10% of the molar amount of the compound shown in I; the molar ratio of sodium hydroxide to the compound shown in III is 1.5:1; the addition ratio of thionyl chloride to the compound shown in III is 5 mL: 2 mmol; the molar ratio of triethylamine to the compound shown in IV is 3:2; and the addition ratio of dichloromethane to the compound shown in IV is 2 mL: 0.2 mmol.

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