Method for promoting titanocene dichloride to catalytically synthesize quinoline derivative by taking p-toluenesulfonic acid as ligand

Abstract

The invention discloses a method for promoting titanocene dichloride to catalytically synthesize a quinoline derivative by using p-toluenesulfonic acid as a ligand, which is characterized in that an o-aminoacetophenone compound and a carbonyl compound are used as raw materials, titanocene dichloride is used as a Lewis acid catalyst, p-toluenesulfonic acid is used as the ligand, and the quinoline derivative is prepared at high efficiency and high yield under mild conditions. According to the method, the used catalyst is small in dosage, low in price, non-toxic and stable to air, the synthesis method is easy to operate, the quinoline derivative can be obtained only by conducting simple column chromatography separation on the product after the reaction is finished, a green, efficient and low-cost way is opened up for preparation of the quinoline derivative, and the method has wide application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of quinoline derivatives, and particularly relates to a method for synthesizing quinoline derivatives by using p-toluenesulfonic acid as a ligand to promote the catalysis of dichlorotantalum. Background Art

[0002] Quinoline derivatives are widely present in nature in various forms. They have biological activities such as anticancer, antibacterial, antiviral, anticonvulsant, and anti-inflammatory. For example, chloroquine is widely used as an antimalarial and anti-inflammatory agent for the treatment of malaria and rheumatoid arthritis. At the same time, quinoline derivatives are also widely used in agriculture, dyes and other fields.

[0003] Currently, the most direct method to obtain polysubstituted quinolines is the Friedlander Quinoline Synthesis. This transformation is usually completed by dehydration condensation between 2-amino-substituted aromatic carbonyl compounds and carbonyl derivatives. A considerable number of reported synthetic methods for quinoline derivatives have certain limitations, such as low yield, long reaction time, and relatively harsh catalytic conditions. For example: In 2022, the Subhrajyoti Ghosh team reported a method for synthesizing quinoline derivatives using a metal skeleton organic material with hafnium as the metal center and 2,5-diethylamino terephthalic acid as the organic ligand. The yield was only 3% to 35% when alicyclic ketones were used as reaction substrates; in 2023, the Rumpa Sarkar team reported a method for synthesizing quinoline derivatives by catalysis of nickel boride, which needed to be carried out at 0°C; in 2017, the Benyapa Kaewmee team reported a method for synthesizing quinoline derivatives by metal copper catalysis. The reaction of 0.5 mmol of substrate with 50 mmol of copper iodide also exposed the disadvantage of excessive catalyst dosage. Therefore, the development of a green, efficient, mild and low-cost catalytic method is of great significance for the preparation of quinoline derivatives. Summary of the invention

[0004] The purpose of the present invention is to provide a method for efficiently synthesizing quinoline derivatives which is green, environmentally friendly, simple to operate, short in reaction time, has a single reaction product and good substrate applicability.

[0005] In view of the above purpose, the technical scheme adopted by the present invention is: adding an o-aminoacetophenone compound represented by formula I and a carbonyl compound represented by formula II or formula II′ to a solvent, and adding dichlorotantalum and p-toluenesulfonic acid, reacting at 80-120° C., separating and purifying the product after the reaction, and obtaining a quinoline derivative represented by formula III or formula III′; the reaction equation is as follows:

[0006]

[0007] In the formula, R1 represents any one of H, F, Cl, Br, and methoxy; R2 represents any one of methyl, ethyl, phenyl, and phenyl with a substituent, and the substituent is selected from any one of Cl and Br; R3 represents any one of H, F, Cl, Br, and methoxy; R4 represents any one of H, hydroxyl, and methoxy; R5 represents any one of methyl and C1~C4 alkoxy; n represents an integer of 1 to 3.

[0008] In the above method, when the o-aminoacetophenone compound represented by formula I and the carbonyl compound represented by formula II react to synthesize the quinoline derivative represented by formula III, the reaction is preferably carried out at 90-100° C. for 5-10 hours.

[0009] In the above method, when the o-aminoacetophenone compound represented by formula I and the carbonyl compound represented by formula II' react to synthesize the quinoline derivative represented by formula III', the reaction is preferably carried out at 100-110°C for 20-24 hours.

[0010] In the above method, the molar ratio of the o-aminoacetophenone compound to the carbonyl compound is preferably 1:1.1-1.3.

[0011] In the above method, preferably, the added amount of the dichlorotitanocene is 8% to 12% of the molar amount of the o-aminoacetophenone compound.

[0012] In the above method, the added amount of p-toluenesulfonic acid is preferably 8% to 12% of the molar amount of the o-aminoacetophenone compound.

[0013] In the above method, preferably the solvent is any one of ethanol, methanol and dichloromethane.

[0014] The beneficial effects of the present invention are as follows:

[0015] The present invention uses o-aminoacetophenone compounds and carbonyl compounds as reaction substrates, uses dichlorotantalum as a catalyst, uses p-toluenesulfonic acid as a ligand, reacts under mild conditions, and separates by column chromatography to obtain quinoline derivatives. The present invention uses a small amount of catalyst, is low in price, has the advantages of being green, safe, and easy to operate, and has high atom economy, high yield of target products, good substrate universality, and broad application prospects. DETAILED DESCRIPTION

[0016] The present invention is further described in detail below with reference to the embodiments, but the scope of the present invention is not limited to these embodiments.

[0017] Example 1

[0018] Synthesize 1-(2,4-dimethyl-3-quinolinyl)ethanone with the following structural formula

[0019]

[0020] In a 15 mL thick-walled pressure bottle equipped with a magnet, 0.0248 g (0.1 mmol) of dichlorotantalum, 0.0172 g (0.1 mmol) of p-toluenesulfonic acid, 125 μL (1 mmol) of o-aminoacetophenone, 123 μL (1.2 mmol) of acetylacetone and 2 mL of ethanol were added, and the mixture was stirred at 100 ° C for 6 h. After the reaction, it was separated by a silica gel column (the eluent was a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:6) to obtain 1-(2,4-dimethyl-3-quinolinol)ethanone with a yield of 81%.

[0021] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR (400MHz, Chloroform-d) δ7.97(dd,J=18.4,8.4Hz,2H),7.68(t,J=6.9Hz,1H),7.52(t,J=7.6Hz,1H),2.61(s,3H),2.56(d,J=4.4Hz,6H); 13 C NMR (101MHz, Chloroform-d) δ206.75,152.69,147.03,138.69,135.81,129.92,129.36,126.48,126.05,123.76,32.76,23.65,15.34.

[0022] Example 2

[0023] Synthesize 1-(6-fluoro-2,4-dimethyl-3-quinolinyl)ethanone with the following structural formula

[0024]

[0025] In this example, an equal molar amount of 2-amino-5-fluoroacetophenone was used to replace the o-aminoacetophenone in Example 1, and the other steps were the same as in Example 1 to obtain 1-(6-fluoro-2,4-dimethyl-3-quinolinol)ethanone with a yield of 82%.

[0026] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR (400MHz, Chloroform-d) δ7.99 (dd, J=9.2, 5.5Hz, 1H), 7.55 (dd, J=9.9, 2.8Hz, 1H), 7.49-7.42 (m, 1H), 2.61 (s, 3H), 2.59 (s, 3H), 2.52 (s, 3H); 13C NMR(101MHz,Chloroform-d)δ206.52,161.85,159.39,152.13,152.10,144.18,138.14,138.08, 136.34,131.92,131.82,127.00,126.91,120.07,119.82,107.69,107.46,32.72,23.54,15.47.

[0027] Example 3

[0028] Synthesize 1-(6-chloro-2,4-dimethyl-3-quinolinyl)ethanone with the following structural formula

[0029]

[0030] In this example, an equal molar amount of 2-amino-5-chloroacetophenone was used to replace the o-aminoacetophenone in Example 1, and the other steps were the same as in Example 1 to obtain 1-(6-chloro-2,4-dimethyl-3-quinolinol)ethanone with a yield of 80%.

[0031] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR (400MHz, Chloroform-d) δ7.94 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 9.0 Hz, 1H), 2.61 (s, 3H), 2.58 (s, 3H), 2.53 (s, 3H); 13 C NMR (101MHz, Chloroform-d) δ206.35,153.20,145.49,137.94,136.49,132.42,131.04,130.78,126.93,122.97,32.73,23.67,15.38.

[0032] Example 4

[0033] Synthesize 1-(6-bromo-2,4-dimethyl-3-quinolinyl)ethanone with the following structural formula

[0034]

[0035] In this example, an equal molar amount of 2-amino-5-bromoacetophenone was used to replace the o-aminoacetophenone in Example 1, and the other steps were the same as in Example 1 to obtain 1-(6-bromo-2,4-dimethyl-3-quinolinol)ethanone with a yield of 80%.

[0036] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR (400MHz, Chloroform-d) δ8.11(s,1H),7.87(d,J=8.7Hz,1H),7.77(d,J=10.5Hz,1H),2.60(s,3H),2.59(s,3H),2.54(s,3H); 13 C NMR (101MHz, Chloroform-d) δ206.30,153.37,145.71,137.87,136.47,133.36,131.16,127.45,126.31,120.62,32.73,23.71,15.39.

[0037] Example 5

[0038] Synthesize 1-(5-bromo-2,4-dimethyl-3-quinolinyl)ethanone with the following structural formula

[0039]

[0040] In this example, an equal molar amount of 2-amino-4-bromoacetophenone was used to replace the o-aminoacetophenone in Example 1, and the other steps were the same as in Example 1 to obtain 1-(5-bromo-2,4-dimethyl-3-quinolinol)ethanone with a yield of 71%.

[0041] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR (400MHz, Chloroform-d) δ8.19(s,1H),7.83(d,J=8.9Hz,1H),7.62(d,J=8.9Hz,1H),2.61(s,3H),2.58(s,3H),2.56(s,3H); 13 C NMR (101MHz, Chloroform-d) δ206.35,154.14,147.85,138.89,136.13,131.80,129.99,125.26,124.88,124.15,32.73,23.75,15.36.

[0042] Example 6

[0043] Synthesize 2,4-dimethylquinoline-3-carboxylic acid ethyl ester with the following structural formula

[0044]

[0045] In this example, ethyl acetoacetate was used to replace acetylacetone in Example 1 in an equal molar amount, and the other steps were the same as those in Example 1 to obtain ethyl 2,4-dimethylquinoline-3-carboxylate with a yield of 70%.

[0046] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.98(dd,J=13.1,8.4Hz,2H),7.69(t,J=7.6Hz,1H),7.51( t,J=7.6Hz,1H),4.47(q,J=7.1Hz,2H),2.69(s,3H),2.63(s,3H),1.42(t,J=7.1Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ169.30,154.41,147.19,141.51,130.13,129.34,128.07,126.39,125.85,124.08,61.76,23.89,15.78,14.33.

[0047] Example 7

[0048] Synthesize 2,4-dimethylquinoline-3-carboxylic acid methyl ester with the following structural formula

[0049]

[0050] In this example, methyl acetoacetate was used to replace acetylacetone in Example 1 in an equal molar amount, and the other steps were the same as those in Example 1 to obtain methyl 2,4-dimethylquinoline-3-carboxylate with a yield of 52%.

[0051] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR (400MHz, Chloroform-d) δ7.94(q,J=16.1,11.6Hz,2H),7.69(s,1H),7.52(s,1H),3.95(d,J=24.0Hz,3H),2.59(d,J=23.6Hz,6H); 13 C NMR (101MHz, Chloroform-d) δ169.80,154.46,147.22,141.77,130.23,129.35,127.80,126.44,125.79,124.11,52.62,23.94,15.92.

[0052] Example 8

[0053] Synthesize 6-fluoro-2,4-dimethylquinoline-3-carboxylic acid ethyl ester with the following structural formula

[0054]

[0055] In this example, an equal molar amount of 2-amino-5-fluoroacetophenone was used to replace the o-aminoacetophenone in Example 1, and an equal molar amount of ethyl acetoacetate was used to replace the acetylacetone in Example 1. The other steps were the same as those in Example 1 to obtain ethyl 6-fluoro-2,4-dimethylquinoline-3-carboxylate with a yield of 89%.

[0056] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.01(dd,J=9.2,5.5Hz,1H),7.59(dd,J=9.9,2.8Hz,1H),7.47( td,J=8.6,2.8Hz,1H),4.49(q,J=7.1Hz,2H),2.68(s,3H),2.60(s,3H),1.44(t,J=7.1Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ169.14,161.82,159.37,153.87,153.84,144.38,140.92,140.87,131 .95,131.86,128.72,126.82,126.73,120.28,120.03,108.00,107.77,61.94,23.78,15.95,14.38.

[0057] Example 9

[0058] Synthesize 6-chloro-2,4-dimethylquinoline-3-carboxylic acid ethyl ester with the following structural formula

[0059]

[0060] In this example, an equal molar amount of 2-amino-5-chloroacetophenone was used to replace the o-aminoacetophenone in Example 1, and an equal molar amount of ethyl acetoacetate was used to replace the acetylacetone in Example 1. The other steps were the same as those in Example 1 to obtain ethyl 6-chloro-2,4-dimethylquinoline-3-carboxylate with a yield of 83%.

[0061] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR (400MHz, Chloroform-d) δ7.94(d,J=9.2Hz,2H),7.64(dd,J=8.9,2.3Hz,1H),4.49(q,J=7.1Hz,2H),2.68(s,3H),2.61(s,3H),1.44(t,J=7.1Hz,3H);13 C NMR (101MHz, Chloroform-d) δ169.00,154.93,145.70,140.72,132.34,131.08,131.00,128.88,126.76,123.29,61.98,23.90,15.84,14.38.

[0062] Example 10

[0063] Synthesize 6-bromo-2,4-dimethylquinoline-3-carboxylic acid ethyl ester with the following structural formula

[0064]

[0065] In this example, an equal molar amount of 2-amino-5-bromoacetophenone was used to replace the o-aminoacetophenone in Example 1, and an equal molar amount of ethyl acetoacetate was used to replace the acetylacetone in Example 1. The other steps were the same as those in Example 1 to obtain ethyl 6-bromo-2,4-dimethylquinoline-3-carboxylate with a yield of 82%.

[0066] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.14(d,J=2.1Hz,1H),7.87(d,J=8.9Hz,1H),7.77(dd,J= 8.9,2.1Hz,1H),4.51(d,J=7.1Hz,2H),2.68(s,3H),2.61(s,3H),1.44(t,J=7.1Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ168.83,155.00,145.77,140.60,133.49,131.09,128.77,127.18,126.54,120.45,61.92,23.87,15.77,14.33.

[0067] Embodiment 11

[0068] Synthesize 9-methyl-2,3-dihydro-1H-cyclohexanedano[B]quinoline having the following structural formula

[0069]

[0070] In this example, acetylacetone in Example 1 was replaced by an equal molar amount of cyclohexanone, the reaction time was extended to 24 h, and the other steps were the same as in Example 1 to obtain 9-methyl-2,3-dihydro-1H-cyclohexane[B]quinoline with a yield of 63%.

[0071] The obtained product was characterized by 400MHz nuclear magnetic resonance spectrometer, characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.96(d,J=8.7Hz,2H),7.60(t,J=7.7Hz,1H),7.45(t,J=7.7Hz,1H),3.12(s,2H),2.90(s,2H),2.55(s,3H),1.93(s,4H); 13 C NMR (101MHz, Chloroform-d) δ158.72,146.06,141.36,129.11,128.81,128.22,127.06,125.36,123.43,34.65,27.23,23.35,22.91,13.66.

[0072] Example 12

[0073] Synthesize 9-methyl-2,3-dihydro-1H-cyclopenta[B]quinoline having the following structural formula

[0074]

[0075] In this example, acetylacetone in Example 1 was replaced by an equal molar amount of cyclopentanone, the reaction time was extended to 24 h, and the other steps were the same as in Example 1 to obtain 9-methyl-2,3-dihydro-1H-cyclopenta[B]quinoline with a yield of 74%.

[0076] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.00(d,J=8.4Hz,1H),7.93(d,J=9.9Hz,1H),7.60(t,J=8.3Hz,1H),7. 47(t,J=7.6Hz,1H),3.16(t,J=7.7Hz,2H),3.04(t,J=7.4Hz,2H),2.57(s,3H),2.19(p,J=7.6Hz,2H); 13 C NMR (101MHz, Chloroform-d) δ167.09,147.50,138.23,134.14,129.24,128.12,127.16,125.35,123.46,35.23,29.76,23.10,15.03.

[0077] Embodiment 13

[0078] Synthesis of 7-fluoro-9-methyl-2,3-dihydro-1H-cyclopenta[B]quinoline having the following structural formula

[0079]

[0080] In this example, an equal molar amount of 2-amino-5-fluoroacetophenone was used to replace the o-aminoacetophenone in Example 1, and an equal molar amount of cyclopentanone was used to replace the acetylacetone in Example 1. The reaction time was extended to 24 h, and the other steps were the same as in Example 1 to obtain 7-fluoro-9-methyl-2,3-dihydro-1H-cyclopenta[B]quinoline with a yield of 81%.

[0081] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.99(dd,J=9.2,5.6Hz,1H),7.53(dd,J=10.3,2.8Hz,1H),7.40- 7.34(m,1H),3.16(t,J=7.7Hz,2H),3.06(t,J=7.4Hz,2H),2.54(s,3H),2.21(p,J=7.6Hz,2H); 13 CNMR(101MHz,Chloroform-d)δ166.56,161.42,158.98,144.46,135.04,131.39,13 1.30,128.06,127.97,118.01,117.76,107.43,107.20,35.05,29.84,23.14,15.18.

[0082] Embodiment 14

[0083] Synthesis of 7-chloro-9-methyl-2,3-dihydro-1H-cyclopenta[B]quinoline having the following structural formula

[0084]

[0085] In this example, an equal molar amount of 2-amino-5-chloroacetophenone was used to replace the o-aminoacetophenone in Example 1, and an equal molar amount of cyclopentanone was used to replace the acetylacetone in Example 1, and the reaction time was extended to 24 h to obtain 7-chloro-9-methyl-2,3-dihydro-1H-cyclopenta[B]quinoline with a yield of 73%.

[0086] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.94(d,J=8.9Hz,1H),7.90(d,J=2.3Hz,1H),7.54(dd,J=8.9, 2.3Hz, 1H), 3.16 (t, J = 7.7Hz, 2H), 3.06 (t, J = 7.4Hz, 2H), 2.55 (s, 3H), 2.21 (p, J = 7.6Hz, 2H); 13 CNMR(101MHz,Chloroform-d)δ167.53,145.95,137.39,135.12,131.10,130.77,128.79,128.00,122.67,35.15,29.79,23.00,14.99.

[0087] Embodiment 15

[0088] Synthesis of 7-bromo-9-methyl-2,3-dihydro-1H-cyclopenta[B]quinoline having the following structural formula

[0089]

[0090] In this example, an equal molar amount of 2-amino-5-bromoacetophenone was used to replace the o-aminoacetophenone in Example 1, and an equal molar amount of cyclopentanone was used to replace the acetylacetone in Example 1, and the reaction time was extended to 24 h to obtain 7-bromo-9-methyl-2,3-dihydro-1H-cyclopenta[B]quinoline with a yield of 74%.

[0091] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.07(d,J=2.2Hz,1H),7.86(d,J=8.9Hz,1H),7.67(dd,J=8.9, 2.2Hz,1H),3.15(t,J=7.8Hz,2H),3.06(t,J=7.4Hz,2H),2.54(s,3H),2.20(p,J=7.6Hz,2H); 13 CNMR(101MHz,Chloroform-d)δ167.70,146.16,137.46,135.18,131.47,130.95,128.60,126.05,119.37,35.21,29.84,23.04,15.06.

[0092] Example 16

[0093] Synthesize 1-(2-methyl-4-phenyl-3-quinoline)ethanone with the following structural formula

[0094]

[0095] In this example, an equal molar amount of benzophenone was used to replace the o-aminoacetophenone in Example 1, and the other steps were the same as in Example 1 to obtain 1-(2-methyl-4-phenyl-3-quinolinyl)ethanone with a yield of 88%.

[0096] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J=8.4Hz,1H),7.75-7.69(m,1H),7.62(d,J=8.9Hz,1H) ,7.51(dd,J=4.4,1.7Hz,3H),7.47-7.42(m,1H),7.37-7.34(m,2H),2.70(s,3H),2.00(s,3H); 13 CNMR(101MHz,Chloroform-d)δ205.80,153.69,147.59,144.16,135.32,134.98, 130.30,130.18,129.07,128.96,128.86,126.70,126.31,125.19,32.09,23.99.

[0097] Embodiment 17

[0098] Synthesize 1-(4-(4-chlorophenyl)-2-methyl-3-quinolinyl)ethanone with the following structural formula

[0099]

[0100] In this example, an equal molar amount of 2-amino-4-chlorobenzophenone was used to replace the o-aminobenzophenone in Example 1, and the other steps were the same as in Example 1 to obtain 1-(4-(4-chlorophenyl)-2-methyl-3-quinoline)ethanone with a yield of 91%.

[0101] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.11(d,J=8.5Hz,1H),7.74(t,J=6.9Hz,1H),7.57(d,J=8.4Hz,1 H),7.52-7.48(m,2H),7.46(d,J=7.1Hz,1H),7.31(d,J=8.4Hz,2H),2.71(s,3H),2.06(s,3H); 13C NMR(101MHz,Chloroform-d)δ205.48,153.56,147.62,142.61,135.38,135.04, 133.67,131.50,130.37,129.17,129.13,126.88,125.88,124.91,32.25,23.94.

[0102] Embodiment 18

[0103] Synthesize 1-(4-(4-bromophenyl)-2-methyl-3-quinolinyl)ethanone with the following structural formula

[0104]

[0105] In this example, an equal molar amount of 2-amino-4-bromobenzophenone was used to replace the o-aminoacetophenone in Example 1, and the other steps were the same as in Example 1 to obtain 1-(4-(4-bromophenyl)-2-methyl-3-quinolinol)ethanone with a yield of 98%.

[0106] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J=8.5Hz,1H),7.76-7.70(m,1H),7.66(dd,J=8.3,1.5Hz,2H),7.56(d,J=8.5H z,1H),7.48-7.43(m,1H),7.25(d,J=1.5Hz,1H),7.23(d,J=1.6Hz,1H),2.70(d,J=1.4Hz,3H),2.06(d,J=1.4Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ205.44,153.59,147.55,142.73,135.01,134.16, 132.16,131.78,130.47,129.09,126.96,125.92,124.87,123.62,32.31,23.92.

[0107] Embodiment 19

[0108] Synthesize 1-(6-chloro-4-(2-chlorophenyl)-2-methyl-3-quinolinyl)ethanone with the following structural formula

[0109]

[0110] In this example, an equal molar amount of 2-amino-2,5-dichlorobenzophenone was used to replace the o-aminoacetophenone in Example 1, and the other steps were the same as in Example 1 to obtain 1-(6-chloro-4-(2-chlorophenyl)-2-methyl-3-quinolinol)ethanone with a yield of 68%.

[0111] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR (400MHz, Chloroform-d) δ8.05 (d, J=9.1Hz, 1H), 7.67 (dd, J=8.9, 2.3Hz, 1H), 7.59 (dd, J=8.0, 1.3Hz, 1H), 7.50 (td, J= 7.7,1.7Hz,1H),7.42(td,J=7.5,1.3Hz,1H),7.27(d,J=2.3Hz,1H),7.23(dd,J=7.5,1.7Hz,1H),2.72(s,3H),2.15(s,3H); 13 C NMR(101MHz,Chloroform-d)δ204.39,154.07,145.62,140.51,135.70,133.40, 133.35,132.81,132.04,131.20,130.87,130.61,130.05,127.42,31.28,23.82.

[0112] Embodiment 20

[0113] Synthesize 2-methyl-4-phenylquinoline-3-carboxylic acid ethyl ester with the following structural formula

[0114]

[0115] In this example, an equal molar amount of 2-aminobenzophenone was used to replace the o-aminoacetophenone in Example 1, and an equal molar amount of ethyl acetoacetate was used to replace the acetylacetone in Example 1. The other steps were the same as in Example 1 to obtain ethyl 2-methyl-4-phenylquinoline-3-carboxylate with a yield of 90%.

[0116] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR (400MHz, Chloroform-d) δ8.10 (d, J=8.5Hz, 1H), 7.73 (ddd, J=8.4, 6.8, 1.5Hz, 1H), 7.58 (dd, J=8.8, 1.3Hz, 1H), 7.48 (dd, J= 5.0,1.9Hz,3H),7.43(ddd,J=8.3,6.8,1.2Hz,1H),7.38-7.35(m,2H),4.06(q,J=7.1Hz,2H),2.80(s,3H),0.95(t,J=7.1Hz,3H); 13 CNMR(101MHz,Chloroform-d)δ168.50,154.67,147.77,146.31,135.82,130.30,129 .45,128.92,128.51,128.29,127.48,126.55,126.47,125.21,61.37,23.88,13.70.

[0117] Embodiment 21

[0118] Synthesize 4-(4-chlorophenyl)-2-methylquinoline-3-carboxylic acid ethyl ester with the following structural formula

[0119]

[0120] In this example, an equal molar amount of 2-amino-4-chlorobenzophenone was used to replace the o-aminoacetophenone in Example 1, and an equal molar amount of ethyl acetoacetate was used to replace the acetylacetone in Example 1. The other steps were the same as in Example 1 to obtain ethyl 4-(4-chlorophenyl)-2-methylquinoline-3-carboxylate with a yield of 98%.

[0121] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.08(d,J=8.5Hz,1H),7.76-7.70(m,1H),7.52(d,J=8.6Hz,1H),7.47(dd,J=8.5,2.0H z,2H),7.43(d,J=8.2Hz,1H),7.31(dd,J=8.4,2.0Hz,2H),4.11(q,J=7.1Hz,2H),2.79(s,3H),1.03(t,J=7.1Hz,3H); 13C NMR(101MHz,Chloroform-d)δ168.33,154.77,147.78,145.09,134.88,134.28,130 .93,130.58,129.11,128.69,127.57,126.81,126.27,125.06,61.63,23.92,13.88.

[0122] Embodiment 22

[0123] Synthesize 4-(4-bromophenyl)-2-methylquinoline-3-carboxylic acid ethyl ester with the following structural formula

[0124]

[0125] In this example, an equal molar amount of 2-amino-4-bromobenzophenone was used to replace the o-aminoacetophenone in Example 1, and an equal molar amount of ethyl acetoacetate was used to replace the acetylacetone in Example 1. The other steps were the same as in Example 1 to obtain ethyl 4-(4-bromophenyl)-2-methylquinoline-3-carboxylate with a yield of 88%.

[0126] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J=8.5Hz,1H),7.73(dd,J=8.5,6.8Hz,1H),7.63(dd,J=8.4,1.7Hz,2H),7.52 (d,J=8.4Hz,1H),7.47-7.42(m,1H),7.26-7.23(m,2H),4.11(q,J=7.2Hz,2H),2.79(s,3H),1.03(t,J=7.1Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ168.20,154.67,147.72,144.92,134.69,131.54,131 .12,130.45,129.05,127.36,126.70,126.14,124.84,122.92,61.52,23.87,13.80.

Claims

1. A method for synthesizing quinoline derivatives by using p-toluenesulfonic acid as a ligand to promote the catalysis of dichlorotantalum, characterized in that: The o-aminoacetophenone compound represented by formula I and the carbonyl compound represented by formula II or formula II′ are added to a solvent, and dichlorotantalum and p-toluenesulfonic acid are added, and the reaction is carried out at 80-120° C. After the reaction is completed, the product is separated and purified to obtain a quinoline derivative represented by formula III or formula III′; In the formula, R1 represents any one of H, F, Cl, Br, and methoxy; R2 represents any one of methyl, ethyl, phenyl, and phenyl with a substituent, and the substituent is selected from any one of Cl and Br; R3 represents any one of H, F, Cl, Br, and methoxy; R4 represents any one of H, hydroxyl, and methoxy; R5 represents any one of methyl and C1~C4 alkoxy; n represents an integer of 1 to 3.

2. The method for synthesizing quinoline derivatives by using p-toluenesulfonic acid as a ligand to promote dichlorotitanocene catalysis according to claim 1, characterized in that: The o-aminoacetophenone compound represented by formula I and the carbonyl compound represented by formula II are added to a solvent, and dichlorotantalum and p-toluenesulfonic acid are added, and the reaction is carried out at 90-100° C. for 5-10 hours. After the reaction is completed, the product is separated and purified to obtain a quinoline derivative represented by formula III.

3. The method for synthesizing quinoline derivatives by using p-toluenesulfonic acid as a ligand to promote dichlorotitanocene catalysis according to claim 1, characterized in that: The o-aminoacetophenone compound represented by formula I and the carbonyl compound represented by formula II′ are added to a solvent, and dichlorotantalum and p-toluenesulfonic acid are added, and the reaction is carried out at 100-110° C. for 20-24 hours. After the reaction is completed, the product is separated and purified to obtain a quinoline derivative represented by formula III or formula III′.

4. The method for synthesizing quinoline derivatives by using p-toluenesulfonic acid as a ligand to promote dichlorotantalum catalysis according to any one of claims 1 to 3, characterized in that: The molar ratio of the o-aminoacetophenone compound to the carbonyl compound is 1:1.1-1.

3.

5. The method for synthesizing quinoline derivatives by using p-toluenesulfonic acid as a ligand to promote dichlorotantalum catalysis according to any one of claims 1 to 3, characterized in that: The added amount of the dichlorotitanocene is 8% to 12% of the molar amount of the o-aminoacetophenone compound.

6. The method for synthesizing quinoline derivatives by using p-toluenesulfonic acid as a ligand to promote dichlorotitanocene catalysis according to any one of claims 1 to 3, characterized in that: The added amount of the p-toluenesulfonic acid is 8% to 12% of the molar amount of the o-aminoacetophenone compound.

7. The method for synthesizing quinoline derivatives by using p-toluenesulfonic acid as a ligand to promote dichlorotantalum catalysis according to any one of claims 1 to 3, characterized in that: The solvent is any one of ethanol, methanol and dichloromethane.

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