A quinoline derivative and a preparation method thereof

Abstract

The present invention discloses a quinoline derivative and a preparation method thereof, belonging to the technical field of organic synthesis; the preparation method of a quinoline derivative provided by the present invention uses the compound shown in Formula I as a raw material, and under the action of an inert gas and an organic acid, a dehydrogenation ring-closure reaction occurs in an organic solvent to obtain the quinoline derivative shown in Formula II; in the preparation method provided by the present invention, there is no need for a carbon-carbon double bond at the 1,2 positions of the raw material, and dehydrogenation and then ring-closure can be directly carried out under the action of the organic acid provided by the present invention, so that the applicable substrate range is wider and the practical utilization value is higher. In addition, the preparation method provided by the present invention is simple in operation, low in equipment requirements, and high in yield, which is beneficial to practical application. Specifically, the yield of the obtained product can reach 90%;

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a quinoline derivative and a preparation method thereof. Background Art

[0002] The structure of quinoline (Formula A) is a class of molecules composed of a benzene ring and a pyrrole ring, and most of its derivatives (Formula B and Formula C) have biological activities. Quinoline compounds are widely used in medicine, dyes, photosensitive materials, rubber, solvents, chemical reagents, etc. Quinoline is mainly used in medicine to manufacture three major categories of drugs: nicotinic acid series, 8-hydroxyquinoline series, and quinine series. Drugs in the nicotinic acid series include nicotinamide, cardiac stimulants, stimulants, and drugs for treating tapeworm diseases; 8-hydroxyquinoline series can be used to manufacture drugs for treating amoebiasis and wound disinfectants, as well as mildew inhibitors and textile auxiliaries, etc.; primaquine, chloroquine, and hydroxychloroquine are synthetic specific drugs for treating malaria. Methylquinoline can be used to manufacture color film sensitizers and dyes, and can also be used as solvents, impregnants, corrosion inhibitors, quinine series drugs, and insecticides, etc.

[0003] According to existing literature reports, currently, for the synthesis of quinoline and quinoline derivatives, the widely used approaches are all starting from aniline or derivatives of aniline to form a pyridine ring through the following 4 methods to obtain quinoline or quinoline derivatives: (1) pericyclic reaction (Aza D-A Reaction); (2) Aldol Reaction ring closure reaction, such as Camps quinoline Synthesis, Reaction, Pfitinger Reaction, Niementowski quinoline Synthesis; (3) constructing an electrophilic center at the γ-position of the N of aniline and closing the ring through SEAr reaction, such as Combes Reaction, Skraup Reaction, Gould-Jacobs Reaction, Doebner-Miller Reaction, Doebner Reaction, Knorr Reaction, Conrad-Limpach Reaction; (4) utilizing the affinity of N to construct quinoline compounds through SNAr reaction, such as constructing the core of floxacin drugs (quinolone).

[0004] Among these strategies, the methods for synthesizing quinoline and quinoline derivatives either use expensive reagents or require relatively large amounts of catalysts, etc. Some reactions need to use expensive ligands and metal oxidants, etc., which do not conform to the development of green chemistry. Most of the past syntheses of quinoline and quinoline derivatives have been accomplished by intermolecular reactions of aniline or aniline derivatives to construct the quinoline skeleton, and there are few intramolecular reactions to construct the quinoline skeleton. In addition, the currently synthesized quinoline derivatives are all derivatized at the 1, 2, 3, and 4 positions of quinoline, and there is still no quinoline derivative that can construct quinoline and derivatize on the benzene ring in one step. Due to the orientation effect caused by electron-withdrawing and electron-donating substituents, therefore, having groups on the benzene ring of quinoline is often not conducive to the subsequent reactions. So far, no reports have been found on direct derivatization, especially at the 6-position carbon on the benzene ring. The past methods all had the groups directly on the raw materials;

[0005] Summary of the Invention

[0006] The object of the present invention is to overcome the deficiencies of the above-mentioned prior art and provide a quinoline derivative capable of efficiently constructing a quinoline skeleton in one step intramolecularly and derivatizing on the benzene ring carbon of quinoline, and a preparation method thereof.

[0007] To achieve the above object, the technical solution adopted by the present invention is: a preparation method of a quinoline derivative, the preparation method comprising the following steps: using the compound shown in formula I as a raw material, under the action of an inert gas and an organic acid, carrying out a dehydrogenation cyclization reaction in an organic solvent to obtain the quinoline derivative shown in formula II,

[0008]

[0009] wherein, R1 is selected from any one of hydrogen, alkyl, acyl, alkoxy, ester group, and carbonyl group;

[0010] R2 is selected from any one of hydrogen, alkyl, acyl, alkoxy, ester group, and carbonyl group;

[0011] R3 is selected from any one of alkyl, alkoxy, and ester group;

[0012] R’ is selected from any one of -OMs, -OTf, and -NTf2.

[0013] In the preparation method of a quinoline derivative provided by the present invention, a compound shown in Formula I (phenyl azide ketone derivative) is used as a substrate, and an intramolecular dehydrogenation cyclization reaction is carried out under the action of an organic acid to form a quinoline ring structure compound; at the same time, in the intramolecular dehydrogenation cyclization reaction provided by the present invention, there is no need for a carbon-carbon double bond at the 1,2 positions of the raw material, and dehydrogenation and then cyclization can be directly carried out under the action of the organic acid provided by the present invention, so that the applicable substrate range is wider and the practical utilization value is higher.

[0014] As a preferred embodiment of the preparation method of the present invention, R1 is selected from any one of hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester group, and C1-C6 carbonyl group; R2 is selected from any one of hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester group, and C1-C6 carbonyl group; R3 is selected from any one of C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 ester group.

[0015] Preferably, R1 is selected from any one of hydrogen, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate, ethyl acetate, methyl ketone, and cyclopentanone; R2 is selected from any one of hydrogen, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate, ethyl acetate, methyl ketone, and cyclopentanone; R3 is selected from any one of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate, and ethyl acetate.

[0016] As a preferred embodiment of the preparation method of the present invention, the organic acid is any one of trifluoromethanesulfonic acid, methanesulfonic acid, and bis(trifluoromethanesulfonyl)imide.

[0017] Preferably, the organic acid is any one of trifluoromethanesulfonic acid and methanesulfonic acid; more preferably, the organic acid is trifluoromethanesulfonic acid.

[0018] The inventors have found through research that trifluoromethanesulfonic acid, methanesulfonic acid, and bis(trifluoromethanesulfonyl)imide are strong proton acids. By adding a strong proton acid, the dehydrogenation reaction can occur efficiently, which is beneficial to the subsequent cyclization to form a quinoline ring; further preferably trifluoromethanesulfonic acid and methanesulfonic acid, because considering that the synthesized quinoline derivatives are intermediates and need to be further reacted to synthesize the corresponding active substances, and trifluoromethanesulfonate and methanesulfonate are very active reaction groups and are easy to leave, and then substitution, hydrolysis and other chemical reactions occur to form quinoline active substances.

[0019] As a preferred embodiment of the preparation method of the present invention, the molar ratio of the organic acid to the compound shown in Formula I is organic acid: compound shown in Formula I = (1 - 8): 1.

[0020] Preferably, when the selected organic acid is trifluoromethanesulfonic acid, the molar ratio of the organic acid to the compound shown in Formula I is organic acid: compound shown in Formula I = 3: 1; when the selected organic acid is methanesulfonic acid, the molar ratio of the organic acid to the compound shown in Formula I is organic acid: compound shown in Formula I = (5 - 8): 1.

[0021] The inventors have found through research that when further controlling the molar ratio of the organic acid to the compound shown in Formula I at the above point value or small range value according to the selection of the organic acid, the yield of the obtained product is better, above 60%, and can even reach 90%.

[0022] As a preferred embodiment of the preparation method of the present invention, the organic solvent is at least one of toluene, acetonitrile, chloroform, dichloromethane, and dichloroethane.

[0023] As a preferred embodiment of the preparation method of the present invention, the mass-volume ratio of the compound shown in Formula I to the organic solvent is (0.01 - 0.1) g: 1 mL.

[0024] As a preferred embodiment of the preparation method of the present invention, the temperature of the dehydrogenation ring closure reaction is (-40) - 25 °C.

[0025] Preferably, the temperature of the dehydrogenation ring closure reaction is (-20) - 25 °C.

[0026] The inventors have found through research that when further preferably the temperature is (-20) - 25 °C, the yield of the obtained product is higher and the reaction conditions are relatively simple, with low requirements for equipment.

[0027] As a preferred embodiment of the preparation method of the present invention, the time of the dehydrogenation ring closure reaction is 6 - 18 h; in actual experiments, TLC spotting is used to determine the end point of the reaction.

[0028] As a preferred embodiment of the preparation method of the present invention, the inert gas is any one of nitrogen or noble gases.

[0029] As a preferred embodiment of the preparation method of the present invention, a post-treatment step is further included after the reaction. The post-treatment step includes quenching with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, washing, collecting the organic phase, and then concentrating the organic phase and performing column chromatography.

[0030] Preferably, the washing is sequentially performed with water and saturated brine.

[0031] Preferably, the silica gel used in the column chromatography has a mesh number of 200-300, the eluent is petroleum ether and ethyl acetate, and 2 mL of triethylamine is added to every 100 mL of the eluent.

[0032] In addition, the present invention also provides a quinoline derivative prepared by the preparation method described in the present invention.

[0033] The quinoline derivative provided by the present invention can be used to synthesize a variety of quinoline active compounds or natural products containing the quinoline derivative of the present invention, such as Topotecan (Formula C), RORgt modulator (Formula B), etc.;

[0034]

[0035] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0036] In the preparation method of the quinoline derivative provided by the present invention, by using the compound shown in Formula I (phenyl azide ketone derivative) as a substrate, an intramolecular dehydrogenation ring-closure reaction is carried out under the action of an organic acid to form a quinoline ring structure compound; at the same time, in the intramolecular dehydrogenation ring-closure reaction provided by the present invention, there is no need for the carbon-carbon double bond at the 1,2 positions of the raw material, and dehydrogenation and ring closure can be directly carried out under the action of the organic acid provided by the present invention, so that the range of applicable substrates is wider and the practical utilization value is higher. In addition, the preparation method provided by the present invention is simple in operation, low in equipment requirements, and high in yield, which is conducive to practical application. Specifically, the yield of the obtained product can reach 90%, and the purity is also above 95%. Specific Embodiments

[0037] To better illustrate the purpose, technical solution and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0038] The reagents, methods and equipment used in the present invention are all conventional reagents, methods and equipment in the art unless otherwise specified.

[0039] Example 1

[0040] The present invention provides a quinoline derivative T-1 in an embodiment, and its structure is as shown in Formula T-1.

[0041]

[0042] The preparation method of the quinoline derivative T-1 includes the following steps:

[0043] The synthesis route is as follows:

[0044]

[0045] Specifically,

[0046] (1) Synthesis of S-2

[0047] Add S-1 (3.278 g, 21.98 mmol) into a 100 mL dry round-bottom flask. Under a nitrogen atmosphere, add 65 mL of dichloromethane and stir to dissolve. Slowly drop thionyl chloride (2.4 mL, 32.97 mmol) into the solution under an ice bath and stir for reaction for 6 h. Monitor the reaction by TLC until the raw materials are completely reacted. Remove the excess thionyl chloride and solvent by distillation under reduced pressure to obtain a yellow oily liquid. Dissolve it with 60 mL of acetone, then add sodium iodide (6.600 g, 44.00 mmol) and stir for reaction for 10 h. Add 60 mL of water and stir. A large amount of solid precipitates. Filter out the solid to obtain the product S-2 (3.80 g, 14.67 mmol). The total yield of the two-step reaction is 67%;

[0048] Characterization of S-2: 1H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 8.0, 1.3 Hz, 1H), 7.46 (dd, J = 7.6, 1.7 Hz, 1H), 7.28 (td, J = 7.5, 1.2 Hz, 1H), 7.14 (td, J = 7.7, 1.7 Hz, 1H), 4.57 (s, 2H);

[0049] 13C NMR (126 MHz, Chloroform-d) δ 138.2, 130.7, 130.3, 129.5, 125.1, 118.7, 0.3.

[0050] (2) Synthesis of S-6

[0051] Add S-5 (1.261 g, 10.00 mmol), S-2 (2.590 g, 10.00 mmol), potassium carbonate (2.764 g, 20.00 mmol) and 50 mL of tetrahydrofuran into a 100 mL dry round-bottom flask in sequence and stir for reaction for 8 h. Monitor the reaction by TLC until it is completely reacted. Quench the reaction with 50 mL of water. Extract the mixed system with ethyl acetate. Wash the organic phase with water twice and with saturated brine once. Combine the organic phases and dry them over anhydrous sodium sulfate. Concentrate by distillation under reduced pressure and purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain the compound S-6, a yellow oily liquid, 2.187 g, with a yield of 85%.

[0052] Characterization of S-5: 1H NMR (500 MHz, Chloroform-d) δ 7.33 - 7.25 (m, 1H), 7.14 (ddd, J = 8.0, 2.5, 1.2 Hz, 1H), 7.10 - 7.00 (m, 2H), 3.26 (dd, J = 14.1, 2.1 Hz, 1H), 3.12 (dd, J = 14.1, 2.5 Hz, 1H), 2.53 (ddt, J = 11.7, 5.7, 1.8 Hz, 1H), 2.37 - 2.26 (m, 4H), 2.15 - 2.04 (m, 1H), 1.83 - 1.64 (m, 3H);

[0053] 13C NMR (126 MHz, Chloroform-d) δ 216.11, 204.12, 138.90, 131.37, 128.47, 128.23, 124.88, 118.15, 77.05, 69.47, 38.57, 33.91, 30.12, 26.39, 19.42.

[0054] (3) Synthesis of T-1

[0055] Compound S-6 (0.257 g, 1.00 mmol) was added to a 15 mL dry reaction tube. 5 mL of DCM (dichloromethane) was added under a N2 atmosphere. The reaction system was cooled to 0 °C, and methanesulfonic acid (0.577 g, 6.00 mmol) was slowly added dropwise. Stirring was continued at 0 °C for 30 minutes. After reacting for 6 h, TLC monitored that the raw materials had completely reacted. 5 mL of saturated sodium bicarbonate aqueous solution was added at 0 °C and stirred for 10 minutes to quench the reaction. The mixed system was extracted with ethyl acetate, and the organic phase was washed with water twice and with saturated brine once. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by vacuum distillation and column chromatography (the stationary phase was 200 - 300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. And 2 mL of triethylamine was added to every 100 mL of eluent) to obtain compound T-1 with a yield of 68%. The color of the compound in air was purple-black.

[0056] Characterization of T-1: 1H NMR (500 MHz, Chloroform-d) δ 7.35 (d, J = 8.4 Hz, 1H), 7.16 (ddd, J = 8.5, 2.7, 1.0 Hz, 1H), 7.09 (dd, J = 2.9, 1.2 Hz, 1H), 3.16 (s, 3H), 2.98 (dd, J = 16.1, 1.2 Hz, 1H), 2.59 (d, J = 16.1 Hz, 1H), 2.53 - 2.41 (m, 2H), 2.12 (s, 3H), 2.08 - 2.05 (m, 1H), 2.01 - 1.89 (m, 2H), 1.90 - 1.77 (m, 1H);

[0057] 13C NMR (126 MHz, Chloroform-d) δ 171.20, 170.20, 147.23, 141.96, 127.43, 126.75, 121.71, 121.07, 53.22, 39.19, 37.45, 32.51, 30.99, 23.65, 19.18, 19.31.

[0058] Example 2

[0059] An embodiment of the present invention provides a quinoline derivative T-2,

[0060]

[0061] The only difference between it and Example 1 lies in the synthesis of step (3). The synthesis step (3) of T-2 in this example is as follows: Add compound S-6 (0.257 g, 1.00 mmol) into a 15 mL dry reaction tube. Add 5 mL of DCM (dichloromethane) under a N2 atmosphere. Cool the reaction system to 0 °C, and slowly drop in trifluoromethanesulfonic acid (0.300 g, 2.00 mmol). Continue to stir at 0 °C for 30 minutes. After reacting for 8 h, monitor by TLC that the raw materials have completely reacted. Add 5 mL of saturated sodium bicarbonate aqueous solution at 0 °C and stir for 10 minutes to quench the reaction. Extract the mixed system with ethyl acetate, wash the organic phase with water twice and with saturated brine once. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, and purify by vacuum distillation and column chromatography (the stationary phase is 200 - 300 mesh silica gel pretreated with triethylamine, and the eluent is petroleum ether and ethyl acetate. And add 2 mL of triethylamine to every 100 mL of eluent) to obtain compound T-1 with a yield of 70%.

[0062] Example 3

[0063] Based on Examples 1 - 2, an embodiment of the present invention explores the effects of the molar ratio of raw materials, reaction temperature, and selection of organic solvents during the reaction on the synthesis of quinoline derivatives using S-6 as the raw material;

[0064] 1. On the basis of Example 1, exploration was carried out. Except for the differences in the conditions given in Table 1, the rest was exactly the same as step (3) in Example 1;

[0065] Table 1

[0066]

[0067]

[0068] 2. On the basis of Example 2, exploration was carried out. Except for the differences in the conditions given in Table 2, the rest was exactly the same as step (3) in Example 2;

[0069] Table 2

[0070]

[0071] It can be seen from No. 5 and No. 18, No. 8 and No. 21, No. 9 and No. 22 in Table 1 - 2 that even when the reaction temperature, organic solvent and reactant molar ratio during the reaction process are the same, the difference in organic acids will also have a significant impact on the yield of the product; in addition, it can be seen from Table 1 and Table 2 respectively that when the organic acid is fixed, the reaction temperature, organic solvent and reactant molar ratio during the reaction process will also have a significant impact on the yield; when methanesulfonic acid is used as the organic acid, as the molar ratio of methanesulfonic acid to S - 6 gradually increases, the yield first increases and then almost remains unchanged. When the molar ratio of the two is (2 - 8):1, the obtained yield is between 44 - 69%; when trifluoromethanesulfonic acid is used as the organic acid, as the molar ratio of trifluoromethanesulfonic acid to S - 6 gradually increases, the yield first increases and then decreases significantly. When the preferred molar ratio of the two is (2 - 3):1, the obtained yield is between 70 - 86%. In addition, as the reaction temperature gradually increases, the yield also shows a trend of increasing first and then decreasing. Further preferably, when the reaction temperature is (-20) - 25°C, the obtained yield is between 75 - 90%.

[0072] Example 4

[0073] The embodiment of the present invention provides a quinoline derivative T - 3, and its structure is shown as formula T - 3,

[0074]

[0075] The preparation method of the quinoline derivative T - 3 includes the following steps:

[0076] The synthetic route is as follows:

[0077]

[0078] Specifically,

[0079] (1) The synthesis of S-2 was the same as that in Example 1.

[0080] (2) Synthesis of S-4

[0081] Into a 100 mL dry round-bottom flask, S-2 (3.80 g, 14.67 mmol), S3 (2.06 g, 14.67 mmol), potassium carbonate (4.055 g, 29.34 mmol) and 50 mL of tetrahydrofuran were added successively, and the mixture was stirred and reacted for 8 hours. The reaction was detected to be complete by TLC, and the reaction was quenched with 50 mL of water. The mixed system was extracted with ethyl acetate, the organic phase was washed with water twice and with saturated brine once, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. The mixture was concentrated by distillation under reduced pressure and purified by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 2.963 g of compound S-4.

[0082] Characterization of S-4: 1H NMR (500 MHz, Chloroform-d) δ 7.40–7.25 (m, 1H), 7.16 (dd, J = 8.1, 1.2 Hz, 1H), 7.13 (dd, J = 7.6, 1.6 Hz, 1H), 7.04 (td, J = 7.5, 1.2 Hz, 1H), 3.08 (s, 2H), 2.88 (p, J = 6.5 Hz, 1H), 2.37 (ddd, J = 18.8, 8.7, 6.3 Hz, 2H), 2.16 (ddd, J = 18.8, 9.3, 7.0 Hz, 2H), 2.05 (ddt, J = 13.5, 9.3, 6.7 Hz, 2H), 1.85–1.57 (m, 2H);

[0083] 13C NMR (126 MHz, Chloroform-d) δ 211.9, 138.7, 131.9, 128.6, 128.2, 125.1, 118.0, 70.8, 42.6, 37.3, 33.2, 24.6.

[0084] (3) Synthesis of T-3

[0085] In a 15 mL dry reaction tube, add compound S-4 (0.085 g, 1.00 mmol). Under a N2 atmosphere, add 2 mL of DCM (dichloromethane). Cool the reaction system to 0 °C, and slowly drip in methanesulfonic acid (0.577 g, 6.00 mmol). Continue to stir at 0 °C for 15 minutes. After reacting for 6 h, monitor by TLC until the raw materials are completely reacted. Add 5 mL of saturated sodium bicarbonate aqueous solution at 0 °C and stir for 10 minutes to quench the reaction. Extract the mixed system with ethyl acetate, wash the organic phase twice with water and once with saturated brine. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, and purify by reduced pressure distillation and column chromatography (the stationary phase is 200 - 300 mesh silica gel pretreated with triethylamine, and the eluent is petroleum ether and ethyl acetate. And add 2 mL of triethylamine to every 100 mL of eluent) to obtain compound T-3 with a yield of 55%. The color of the compound in air is purple-black.

[0086] Characterization of T-3: 1H NMR (500 MHz, Chloroform-d) δ 7.38 (d, J = 8.4 Hz, 1H), 7.15 (dd, J = 2.7, 0.9 Hz, 0H), 7.04 (d, 1H), 3.14 (s, 3H), 2.94 (t, 2H), 2.78 - 2.60 (m, 3H), 2.60 - 2.51 (m, 1H), 2.49 - 2.37 (m, 1H), 2.04 - 1.95 (m, 1H), 1.71 - 1.53 (m, 1H).

[0087] Example 5

[0088] An embodiment of the present invention provides a quinoline derivative T-4, whose structure is shown in formula T-4,

[0089]

[0090] The preparation method of the quinoline derivative T-4 includes the following steps:

[0091] The synthesis route is as follows:

[0092]

[0093] Specifically,

[0094] (1) The synthesis of S-2 is the same as in Example 1

[0095] (2) The synthesis of S-8

[0096] In a 100 mL dry round-bottom flask, S-7 (1.141 g, 10 mmol), S-2 (2.590 g, 10 mmol), potassium carbonate (2.764 g, 15 mmol) and 50 mL of tetrahydrofuran were added successively and stirred for 8 hours. The reaction was monitored by TLC and was found to be complete. The reaction was quenched with 50 mL of water. The mixture was extracted with ethyl acetate, and the organic phase was washed twice with water and once with saturated brine. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography to obtain 1.594 g of compound S-8 with a yield of 65%.

[0097] Characterization of S-8: 1H NMR (500 MHz, Chloroform-d) δ 7.28 (ddd, J = 9.4, 4.9, 2.1 Hz, 1H), 7.13 (dt, J = 8.0, 1.7 Hz, 1H), 7.06 (dtt, J = 16.6, 7.4, 1.9 Hz, 2H), 3.34 - 3.12 (m, 2H), 2.18 (p, J = 3.9, 3.0 Hz, 6H), 1.34 - 1.18 (m, 3H);

[0098] 13C NMR (126 MHz, Chloroform-d) δ 207.02, 207.00, 138.91, 132.12, 128.37, 128.27, 124.68, 118.17, 67.19, 67.17, 33.70, 27.11, 17.70.

[0099] (3) Synthesis of T-4

[0100] Compound S-8 (0.245 g, 1.00 mmol) was added to a 15 mL dry reaction tube. Under a nitrogen atmosphere, 5 mL of DCM (dichloromethane) was added, and the reaction system was cooled to 0 °C. Methanesulfonic acid (0.577 g, 6.00 mmol) was slowly added dropwise, and the mixture was stirred at 0 °C for an additional 15 minutes. After reacting for 8 h, the reaction was monitored by TLC and found that the raw materials had completely reacted. At 0 °C, 5 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed twice with water and once with saturated brine. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (the stationary phase was silica gel of 200 - 300 mesh pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. And 2 mL of triethylamine was added to every 100 mL of the eluent) to obtain compound T-4 with a yield of 23%. The compound was purple-black in air.

[0101] Characterization of T-4: 1H NMR (500 MHz, Chloroform-d) δ 6.83 (d, J = 8.0 Hz, 1H), 6.15 (dd, J = 8.1, 2.4 Hz, 1H), 6.01 (d, J = 2.5 Hz, 1H), 3.11 (d, J = 7.5 Hz, 2H), 2.19 (s, 2H), 1.17 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H).

[0102] Example 6

[0103] An embodiment of the present invention provides a quinoline derivative T-5, whose structure is shown in Formula T-5,

[0104]

[0105] The preparation method of the quinoline derivative T-5 includes the following steps:

[0106] The synthetic route is as follows:

[0107]

[0108] Specifically,

[0109] (1) The synthesis of S-2 is the same as in Example 1

[0110] (2) Synthesis of S-10

[0111] Add S-2 (3.80 g, 14.67 mmol), S9 (2.06 g, 14.67 mmol), potassium carbonate (4.055 g, 29.34 mmol) and 50 mL of tetrahydrofuran to a 100 mL dry round-bottom flask in sequence and stir for reaction for 8 hours. TLC detects that the reaction is complete, and 50 mL of water is used to quench the reaction. The mixed system is extracted with ethyl acetate, the organic phase is washed with water twice and with saturated brine once, the organic phases are combined, and the organic phase is dried over anhydrous sodium sulfate. Concentrate by reduced pressure distillation and purify by column chromatography to obtain 12.625 g of compound S-10, with a yield of 69%.

[0112] Characterization of S-10: 1H NMR (500 MHz, Chloroform-d) δ 7.32 - 7.23 (m, 1H), 7.12 (ddd, J = 8.3, 7.3, 1.5 Hz, 2H), 7.03 (tt, J = 7.5, 1.2 Hz, 1H), 4.09 (t, J = 7.3 Hz, 1H), 3.08 (dd, J = 7.4, 1.3 Hz, 2H), 2.64 - 2.42 (m, 2H), 2.43 - 2.27 (m, 2H), 0.98 (td, J = 7.2, 1.2 Hz, 5H);

[0113] 13C NMR (126 MHz, Chloroform-d) δ 206.2, 138.0, 131.5, 129.5, 128.3, 118.1, 65.9, 36.2, 30.2, 7.5。

[0114] (3) Synthesis of T-5

[0115] Add S-10 (0.259 g, 1.00 mmol) to a 15 mL dry reaction tube. Under N2 atmosphere, add 5 mL of DCM, cool down to 0 °C, and slowly drip TfOH (0.450 g, 3.00 mmol). Continue stirring at 0 °C for 15 min. After reacting for 10 h, monitor the reaction by TLC until it is complete, then add 5 mL of saturated sodium bicarbonate to quench the reaction. Extract the mixed system with ethyl acetate, wash the organic phase twice with water and once with saturated brine. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, and purify it by vacuum distillation and column chromatography (the stationary phase is silica gel of 200 - 300 mesh pretreated with triethylamine, and the eluent is petroleum ether and ethyl acetate. And add 2 mL of triethylamine to every 100 mL of eluent) to obtain 0.184 g of compound T-5 with a yield of 51%.

[0116] Characterization of T-5: 1H NMR (500 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 7.67 (dd, J = 9.2, 2.8 Hz, 1H), 3.19 (q, J = 7.5 Hz, 2H), 3.06 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.5 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H);

[0117] 13C NMR (126 MHz, Chloroform-d) δ 203.7, 163.3, 147.0, 146.8, 135.9, 133.5, 131.7, 125.6, 124.6, 120.0, 119.5, 117.5, 35.5, 30.5, 21.6, 13.7, 8.3;

[0118] 19F NMR (471 MHz, Chloroform-d) δ -72.61.

[0119] Example 7

[0120] The embodiment of the present invention provides a quinoline derivative T-6, whose structure is shown in formula T-6,

[0121]

[0122] The only difference between the preparation method of the quinoline derivative T-6 and Example 6 lies in step (3). Step (3) of the example of the present invention is the synthesis of T-6:

[0123] Add compound S-10 (0.259 g, 1.00 mmol) to a 15 mL dry reaction tube. Add 5 mL of DCM under a nitrogen atmosphere, cool down to 0 °C, slowly dropwise add MsOH (0.577 g, 6.00 mmol), and continue stirring at 0 °C for 15 min. After reacting for 10 h, monitor the reaction by TLC until it is complete, and add 5 mL of saturated sodium bicarbonate to quench the reaction. Extract the mixed system with ethyl acetate, wash the organic phase twice with water and once with saturated brine. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, and purify by reduced pressure distillation and column chromatography (the stationary phase is 200 - 300 mesh silica gel pretreated with triethylamine, and the eluent is petroleum ether and ethyl acetate. And add 2 mL of triethylamine to every 100 mL of eluent) to obtain 0.080 g of compound T-6 with a yield of 26%.

[0124] Characterization of T-6: 1H NMR (500 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.15 (d, J = 9.1 Hz, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 9.1, 2.6 Hz, 1H), 3.25 (s, 3H), 3.19 (q, J = 7.5 Hz, 3H), 3.06 (q, J = 7.2 Hz, 3H), 1.37 (t, J = 7.5 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H).

[0125] Example 8

[0126] The example of the present invention provides a quinoline derivative T-7, whose structure is as shown in formula T-7,

[0127]

[0128] The preparation method of the quinoline derivative T-7 includes the following steps:

[0129] The synthesis route is as follows:

[0130]

[0131] Specifically,

[0132] (1) The synthesis of S-2 is the same as in Example 1

[0133] (2) The synthesis of S-12

[0134] In a 100 mL dry round-bottom flask, S-2 (3.80 g, 14.67 mmol), S-11 (2.06 g, 14.67 mmol), potassium carbonate (4.055 g, 29.34 mmol) and 50 mL of tetrahydrofuran were added successively and stirred for 8 hours. The reaction was monitored by TLC and was complete. The reaction was quenched with 50 mL of water. The mixture was extracted with ethyl acetate, and the organic phase was washed with water twice and with saturated brine once. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography to obtain 2.951 g of compound S-12 with a yield of 77%.

[0135] (3) Synthesis of T-7

[0136] Compound S-12 (0.261 g, 1.00 mmol) was added to a 15 mL dry reaction tube. Under a nitrogen atmosphere, 5.0 mL of DCM was added, and the temperature was cooled to 0 °C. TfOH (0.450 g, 3.00 mmol) was slowly added dropwise, and the mixture was stirred at 0 °C for 15 min. After reacting for 12 h, the reaction was monitored by TLC and was complete. The reaction was quenched by adding 5 mL of saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic phase was washed with water twice and with saturated brine once. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (the stationary phase was silica gel of 200 - 300 mesh pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. And 2 mL of triethylamine was added to every 100 mL of the eluent) to obtain 0.185 g of compound T-7 with a yield of 51%.

[0137] Characterization of T-7: 1H NMR (500 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.29 - 8.11 (m, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.69 (dd, J = 9.3, 2.7 Hz, 1H), 4.49 (d, J = 7.1 Hz, 2H), 3.05 (s, 3H), 1.49 (s, 1H);

[0138] 19F NMR (471 MHz, Chloroform-d) δ -72.80.

[0139] Example 9

[0140] The present invention provides a quinoline derivative T-8, and its structure is as shown in formula T-8,

[0141]

[0142] The only difference between the preparation method of the quinoline derivative T-8 and Example 8 lies in step (3). Step (3) of the present invention is the synthesis of T-8:

[0143] In a 15 mL dry reaction tube, add compound S-12 (0.261 g, 1.00 mmol). Under a N2 atmosphere, add 5 mL of DCM, cool down to 0 °C, and slowly dropwise add MsOH (0.577 g, 6.00 mmol). Stir at 0 °C for an additional 15 min. After reacting for 14 h, monitor the reaction by TLC until it is complete, then add 1 mL of saturated sodium bicarbonate to quench the reaction. Extract the mixed system with ethyl acetate, wash the organic phase twice with water and once with saturated brine. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, and purify it by distillation under reduced pressure and column chromatography (the stationary phase is silica gel of 200 - 300 mesh pretreated with triethylamine, and the eluent is petroleum ether and ethyl acetate. And add 2 mL of triethylamine to every 100 mL of eluent) to obtain 0.109 g of compound T-8 with a yield of 35%.

[0144] Characterization of T-8: 1H NMR (500 MHz, Chloroform-d) δ 8.78 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.70 (dd, J = 9.1, 2.7 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.26 (s, 3H), 3.03 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H).

[0145] Example 10

[0146] The present invention provides an application transformation of quinoline derivative T-2. The transformation route from T-2 to compound 2 is as follows:

[0147]

[0148] Specifically,

[0149] Weigh quinoline derivative T-2 (0.181 g, 0.5 mmol, 1.0 eq.) and add it to a dry 25 mL round-bottom flask, then add 3 mL of ultra-dry tetrahydrofuran to dissolve the system. Slowly dropwise add tetrabutylammonium fluoride solution (1.5 mL, 1.5 mmol, 3.0 eq., 1 M in THF) under an ice bath, then warm up to 40 °C and stir the reaction at 40 °C for 3 hours. Monitor the reaction by TLC until the raw materials are completely reacted (petroleum ether:ethyl acetate = 1:1, Rf = 0.35), then add 5 mL of saturated ammonium chloride solution to quench the reaction. Extract the reaction system with ethyl acetate, wash the organic phase with water and saturated brine, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, and purify it by column chromatography to obtain 0.084 g of a yellow oily liquid with a yield of 73%.

[0150] Characterization of Compound 2: 1H NMR (500 MHz, Chloroform-d) δ 7.15 (d, J = 9.1 Hz, 1H), 6.71 - 6.59 (m, 2H), 2.95 (d, J = 15.8 Hz, 1H), 2.53 (d, J = 15.9 Hz, 1H), 2.49 - 2.36 (m, 2H), 2.12 (s, 3H), 2.09 - 2.01 (m, 3H), 2.00 - 1.89 (m, 1H), 1.90 - 1.77 (m, 1H);

[0151] 13C NMR (126 MHz, Chloroform-d) δ 167.0, 156.5, 134.7, 126.6, 126.3, 115.7, 114.4, 54.0, 39.2, 32.6, 30.8, 22.5, 19.1.

[0152] As can be seen from Example 10, the preparation method of the present invention can not only efficiently construct the quinoline skeleton in one step within the molecule, but also the obtained product can be easily converted into other reactive substrates, thereby forming quinoline-based active substances.

[0153] Finally, it should be noted that the above embodiments are used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a quinoline derivative, characterized in that, The preparation method comprises the following steps: using the compound shown in Formula I as a raw material, under the action of an inert gas and an organic acid, a dehydrogenative ring-closure reaction occurs in an organic solvent to obtain a quinoline derivative shown in Formula II, wherein, R1 is selected from any one of hydrogen, C1-C6 acyl group, and C1-C6 ester group; R2 is selected from any one of hydrogen, C1-C6 acyl group, and C1-C6 ester group; R3 is selected from C1-C6 alkyl group; R’ is selected from any one of -OMs and -OTf; the organic acid is any one of trifluoromethanesulfonic acid, methanesulfonic acid, and bis(trifluoromethanesulfonyl)imide; the molar ratio of the organic acid to the compound shown in Formula I is organic acid:compound shown in Formula I = 1-8:1; the organic solvent is at least one of toluene, acetonitrile, chloroform, dichloromethane, and dichloroethane; the temperature of the dehydrogenative ring-closure reaction is -40 to 25 °C.

2. The preparation method according to claim 1, characterized in that, the mass-volume ratio of the compound shown in Formula I to the organic solvent is 0.01-0.1 g:1 mL.

3. The preparation method according to claim 1, characterized in that, the time of the dehydrogenative ring-closure reaction is 6-18 h.

4. The preparation method according to claim 1, wherein the inert gas is any one of nitrogen or noble gas.

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