A 4-chloroquinoline compound and a synthesis method thereof

Abstract

The present invention discloses a method for synthesizing 4-chloroquinoline compounds, belonging to the technical field of organic synthesis. At room temperature, triphosgene and triphenylphosphine oxide are mixed and dissolved in an organic solvent. After stirring for 10 to 30 minutes, an N-aryl enamine compound is added. The reaction system is heated to 50 to 100 °C and stirring reaction is continued for 1 to 4 hours. The obtained reaction solution is post-treated to obtain 4-chloroquinoline compounds. By using the method of the present invention to synthesize 4-chloroquinoline compounds, the steps are few, the yield is high, and it is safer and more convenient than the traditional method using phosphorus chloride compounds.

Description

Technical Field

[0001] The present invention relates to a 4-chloroquinoline compound and a synthesis method thereof, belonging to the technical field of organic synthesis. Background Art

[0002] 4-chloroquinoline compounds belong to a class of quinoline derivatives and are widely used as raw materials or intermediates for synthesizing quinoline drug active molecules (ACS Omega 2021, 6, 12984 - 12994), catalysts (Angew.Chem.Int.Ed. 2020, 59, 2735–2739), organic light-emitting materials (Chem.Commun. 2015, 51, 15241 - 15244), etc.

[0003] Currently, the commonly used method for synthesizing 4-chloroquinoline compounds is to pre-construct a 4-hydroxyquinoline intermediate through a condensation reaction, and then convert it into a 4-chloroquinoline compound under the action of chlorinating reagents such as POCl3, PCl3 or PCl5 (①J.Med.Chem. 2020, 63, 11756 - 11785②Bioorg.Med.Chem.Lett. 2013, 23, 1974 - 1977). Although this method is classical and reliable, it has obvious disadvantages. For example, the chlorinating reagents such as POCl3, PCl3 or PCl5 used are highly corrosive liquid hazardous chemicals, which are inconvenient for transportation, storage and handling; the synthesis of 4-hydroxyquinoline usually requires the use of high-boiling-point and difficult-to-recover organic solvents (>200 °C); from commercial raw materials to products, at least three independent chemical reactions are required, the reaction time and steps are relatively long, and the total yield of the product is about 50%, or even lower; a large amount of difficult-to-treat waste acid is generated after the reaction. These disadvantages greatly limit the industrial application of the above method. In recent years, there have also been literature reports on the method of one-step synthesizing 4-chloroquinoline compounds using various functionalized aromatic amines as raw materials (①Synthesis 2015, 47, 3139–3146②Org.Lett. 2018, 10, 2657–2659③Mendeleev Commun. 2008, 18, 109–111④Tetrahedron2001, 57, 3465–3469⑤J.Org.Chem. 2013, 78, 10319–10328), but due to the limitations of overly special and difficult-to-prepare raw materials or the need to use noble metal palladium catalysts, etc., these methods have not been widely used. Summary of the Invention

[0004] Aiming at the deficiencies of the existing technology, the present invention provides a method for one-step synthesis of 4-chloroquinoline compounds from N-aryl enamine. This method has the advantages of simple and easily available raw materials, few steps, mild reaction conditions, safe and convenient operation, low production cost, high yield, wide application range, etc.

[0005] The technical solution adopted by the present invention is as follows: A method for synthesizing 4-chloroquinoline compounds, the method is as follows: At room temperature, trichloromethyl chloroformate and triphenylphosphine oxide are mixed and dissolved in an organic solvent, and after stirring for 10 - 30 min, an N-aryl enamine compound is added, and the reaction system is heated to 50 - 100 °C, and stirring is continued for reaction for 1 - 4 h. The obtained reaction solution is post-treated to obtain 4-chloroquinoline compounds.

[0006] Further, the N-aryl enamine compound in the above synthesis method has a structural formula as shown in formula (Ⅰ):

[0007]

[0008] Among them, R 1 , R 2 , R 3 and R 4 each independently selected from hydrogen, C1 - C4 alkyl, C1 - C4 alkoxy, C1 - C4 alkoxycarbonyl, C1 - C4 alkylthio, C1 - C4 alkylamino, phenyl, vinyl, allyl, halogen, nitro or trifluoromethyl; R 5 is selected from C1 - C4 alkyl, C1 - C4 alkoxycarbonyl, benzyl, allyl, phenyl, 4-halophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-furyl, 2-thienyl; R 6 is selected from C1 - C4 alkoxycarbonyl, benzoyl.

[0009] Further, in the above synthesis method, in terms of the molar ratio, trichloromethyl chloroformate: triphenylphosphine oxide = (1 - 4): 1.

[0010] Further, in the above synthesis method, the organic solvent is selected from (including but not limited to) one or more of benzene, toluene, xylene, acetonitrile, tetrahydrofuran, chlorobenzene or 1,2-dichloroethane.

[0011] Further, in the above synthesis method, the amount of the organic solvent used is 2 - 10 mL of the organic solvent added per 1 mmol of the N-aryl enamine compound.

[0012] Further, in the above synthesis method, in terms of the molar ratio, N-aryl enamine compound: trichloromethyl chloroformate = 1: (1 - 3).

[0013] Further, for the above synthesis method, the post-treatment method is as follows: The obtained reaction solution is concentrated under reduced pressure, and the obtained concentrate is separated by silica gel column chromatography. A mixed solution of petroleum ether and ethyl acetate is used as the eluent, and the eluent containing the target product is collected, the solvent is evaporated and dried to obtain the 4-chloroquinoline compound.

[0014] Further, for the above synthesis method, for the eluent, by volume ratio, petroleum ether:ethyl acetate = (10 - 40):1.

[0015] The 4-chloroquinoline compound synthesized according to the above method has the structural formula of general formula (Ⅱ):

[0016]

[0017] Among them, R 1 , R 2 , R 3 and R 4 each independently selected from hydrogen, C1 - C4 alkyl, C1 - C4 alkoxy, C1 - C4 alkoxycarbonyl, C1 - C4 alkylthio, C1 - C4 alkylamino, phenyl, vinyl, allyl, halogen, nitro or trifluoromethyl; R 5 is selected from C1 - C4 alkyl, C1 - C4 alkoxycarbonyl, benzyl, allyl, phenyl, 4-halophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-furyl, 2-thienyl; R 6 is selected from C1 - C4 alkoxycarbonyl, benzoyl.

[0018] The reaction formula of the present invention is as follows:

[0019]

[0020] The beneficial effects of the present invention are as follows:

[0021] (1) The present invention shortens the synthesis reaction time and steps of the 4-chloroquinoline compound.

[0022] (2) The raw material N-aryl enamine compound (Ⅰ) used in the present invention is easy to prepare and has low cost.

[0023] (3) Both the triphosgene and triphenylphosphine oxide used in the present invention are solids, which are safer and more convenient to operate. Moreover, they are bulk chemical products with low prices. Triphenylphosphine oxide can also be recycled, thereby reducing the emission of phosphorus-containing waste, and is suitable for industrial production. Specific Embodiments

[0024] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0025] Example 1 Synthesis of Ethyl 2-Methyl-4-chloroquinoline-3-carboxylate

[0026] At room temperature, 8 mL of chlorobenzene, 0.444 g of triphosgene (1.5 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 25 minutes. Then, 0.205 g of ethyl 3-anilinocrotonate (1a, 1.0 mmol) was added thereto, and the reaction system was heated to 60 °C and stirred for another 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluent containing the target product was collected, the solvent was evaporated and dried to obtain 0.212 g of a pale yellow liquid product, ethyl 2-methyl-4-chloroquinoline-3-carboxylate (2a), with a yield of 85%.

[0027] The above reaction formula is as follows:

[0028]

[0029] For the product ethyl 2-methyl-4-chloroquinoline-3-carboxylate (2a), 1 the 13 1H NMR and

[0030] 1 1H NMR (300 MHz, CDCl3): δ 8.27–8.17 (m, 1H), 8.09–7.99 (m, 1H), 7.79 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.67–7.59 (m, 1H), 4.53 (q, J = 7.1 Hz, 2H), 2.74 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13 13C NMR (75 MHz, CDCl3): δ 166.17, 154.63, 147.67, 139.27, 130.94, 128.80, 127.25, 127.23, 124.08, 123.80, 62.08, 23.44, 13.99.

[0031] Example 2 Synthesis of Ethyl 2,6-Dimethyl-4-chloroquinoline-3-carboxylate

[0032] At room temperature, 10 mL of toluene, 0.296 g of triphosgene (1.0 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 30 minutes. Then, 0.219 g of ethyl 3-(p-toluidino)-2-butenoate (1b, 1.0 mmol) was added thereto, and the reaction system was heated to 55 °C and stirred for an additional 2.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 25:1 as the eluent. The eluate containing the target product was collected, the solvent was evaporated and dried to obtain 0.184 g of a pale yellow solid product, ethyl 2,6-dimethyl-4-chloroquinoline-3-carboxylate (2b), with a yield of 70%.

[0033] The above reaction formula is as follows:

[0034]

[0035] For the product ethyl 2,6-dimethyl-4-chloroquinoline-3-carboxylate 2b 1 H NMR and 13 C NMR data are as follows:

[0036] 1 H NMR (300 MHz, CDCl3): δ 7.99–7.90 (m, 2H), 7.61 (dt, J = 8.6, 1.5 Hz, 1H), 4.52 (qd, J = 7.1, 1.0 Hz, 2H), 2.71 (d, J = 1.0 Hz, 3H), 2.57 (s, 3H), 1.46 (td, J = 7.1, 1.0 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 166.32, 153.50, 146.24, 138.55, 137.41, 133.19, 128.47, 127.15, 123.67, 122.87, 62.03, 23.28, 21.57, 13.99.

[0037] Example 3 Synthesis of ethyl 2-methyl-6-methoxy-4-chloroquinoline-3-carboxylate

[0038] At room temperature, 10 mL of 1,2-dichloroethane, 0.592 g of triphosgene (2.0 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 20 minutes. Then, 0.235 g of ethyl 3-(p-methoxyanilino)-2-butenoate (1c, 1.0 mmol) was added thereto, and the reaction system was heated to 70 °C and stirred for another 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluent containing the target product was collected, the solvent was evaporated and dried to obtain 0.201 g of yellow solid product ethyl 2-methyl-6-methoxy-4-chloroquinoline-3-carboxylate (2c) with a yield of 72%.

[0039] The above reaction formula is as follows:

[0040]

[0041] For the product ethyl 2-methyl-6-methoxy-4-chloroquinoline-3-carboxylate 2c 1 H NMR and 13 C NMR data are as follows:

[0042] 1 H NMR (300 MHz, CDCl3): δ 7.98–7.88 (m, 1H), 7.41 (tt, J = 4.9, 2.3 Hz, 2H), 4.52 (qd, J = 7.1, 1.1 Hz, 2H), 3.96 (d, J = 1.0 Hz, 3H), 2.69 (d, J = 1.1 Hz, 3H), 1.45 (td, J = 7.1, 1.0 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 166.42, 158.42, 151.76, 143.76, 137.62, 130.36, 127.37, 124.85, 123.71, 101.68, 62.04, 55.49, 23.08, 14.01.

[0043] Example 4 Synthesis of ethyl 2-methyl-4-chloro-6-iodoquinoline-3-carboxylate

[0044] At room temperature, 8 mL of chlorobenzene, 0.592 g of triphosgene (2.0 mmol) and 0.139 g of triphenylphosphine oxide (0.5 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 20 minutes. Then, 0.331 g of ethyl 3-(p-iodoanilino)-2-butenoate (1d, 1.0 mmol) was added thereto, and the reaction system was heated to 70 °C and stirred for an additional 3.0 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 as the eluent. The eluent containing the target product was collected, the solvent was evaporated and dried to obtain 0.188 g of white solid product ethyl 2-methyl-4-chloro-6-iodoquinoline-3-carboxylate (2d) with a yield of 50%.

[0045] The above reaction formula is as follows:

[0046]

[0047] For the product ethyl 2-methyl-4-chloro-6-iodoquinoline-3-carboxylate 2d 1 H NMR and 13 C NMR data are as follows:

[0048] 1 H NMR (300 MHz, CDCl3): δ 8.58 (d, J = 1.9 Hz, 1H), 8.01 (dd, J = 8.9, 1.9 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 165.76, 155.42, 146.60, 139.73, 137.85, 132.91, 130.40, 127.76, 125.39, 93.10, 62.28, 23.57, 14.05.

[0049] Example 5 Synthesis of ethyl 2-methyl-8-methoxy-4-chloroquinoline-3-carboxylate

[0050] At room temperature, 10 mL of chlorobenzene, 0.296 g of triphosgene (1.0 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 30 minutes. Then, 0.235 g of ethyl 3-(o-methoxyanilino)-2-butenoate (1e, 1.0 mmol) was added thereto, and the reaction system was heated to 65 °C and stirred for 2.0 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 15:1 as the eluent. The eluent containing the target product was collected, the solvent was evaporated and dried to obtain 0.153 g of yellow liquid product ethyl 2-methyl-8-methoxy-4-chloroquinoline-3-carboxylate (2e), and the yield was 55%.

[0051] The above reaction formula is as follows:

[0052]

[0053] For the product ethyl 2-methyl-8-methoxy-4-chloroquinoline-3-carboxylate 2e 1 H NMR and 13 C NMR data are as follows:

[0054] 1 H NMR (300 MHz, CDCl3): δ 7.79 (dd, J = 8.5, 1.1 Hz, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.13 (dd, J = 7.9, 1.1 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.09 (s, 3H), 2.78 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 166.29, 154.67, 153.59, 139.60, 139.29, 127.97, 127.42, 125.05, 115.79, 109.17, 62.15, 56.18, 23.78, 14.01.

[0055] Example 6 Synthesis of ethyl 2,8-dimethyl-4-chloroquinoline-3-carboxylate

[0056] At room temperature, 10 mL of acetonitrile, 0.296 g of triphosgene (1.0 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 30 minutes. Then, 0.219 g of ethyl 3-(o-toluidino)-2-butenoate (1f, 1.0 mmol) was added thereto, and the reaction system was heated to 60 °C and stirred for 4.0 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluent containing the target product was collected, the solvent was evaporated and dried to obtain 0.158 g of white solid product ethyl 2,8-dimethyl-4-chloroquinoline-3-carboxylate (2f), and the yield was 60%.

[0057] The above reaction formula is as follows:

[0058]

[0059] For the product ethyl 2,8-dimethyl-4-chloroquinoline-3-carboxylate 2f 1 H NMR and 13 C NMR data are as follows:

[0060] 1 H NMR (300 MHz, CDCl3): δ 8.12–7.97 (m, 1H), 7.61 (ddd, J = 7.1, 1.6, 0.9 Hz, 1H), 7.53–7.43 (m, 1H), 4.52 (d, J = 7.1 Hz, 2H), 2.78 (d, J = 0.8 Hz, 3H), 2.74 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 166.64, 153.25, 146.88, 139.26, 137.08, 131.06, 126.96, 126.84, 123.76, 122.03, 62.05, 23.76, 18.02, 14.09.

[0061] Example 7 Synthesis of ethyl 2-methyl-6-trifluoromethyl-4-chloroquinoline-3-carboxylate

[0062] At room temperature, 10 mL of chlorobenzene, 0.592 g of triphosgene (2.0 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 20 minutes. Then, 0.273 g of ethyl 3-(p-trifluoromethylanilino)-2-butenoate (1 g, 1.0 mmol) was added thereto, and the reaction system was heated to 70 °C and stirred for an additional 2.0 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting concentrate was separated by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluent containing the target product was collected, the solvent was evaporated and dried to obtain 0.111 g of white solid product ethyl 2-methyl-6-trifluoromethyl-4-chloroquinoline-3-carboxylate (2 g), and the yield was 35%.

[0063] The above reaction formula is as follows:

[0064]

[0065] For the product ethyl 2-methyl-6-trifluoromethyl-4-chloroquinoline-3-carboxylate 2 g 1 H NMR and 13 C NMR data are as follows:

[0066] 1 H NMR (300 MHz, CDCl3): δ 8.53 (dq, J = 1.9, 0.9 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.96 (dd, J = 8.9, 2.0 Hz, 1H), 4.54 (qd, J = 7.1, 0.9 Hz, 2H), 2.77 (d, J = 0.8 Hz, 3H), 1.47 (td, J = 7.1, 0.9 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 165.66, 157.49, 148.71, 140.11, 130.32, 129.52–128.24 (m), 126.72, 125.43, 123.30, 122.40, 62.46, 23.72, 14.03.

[0067] Example 8 Synthesis of methyl 2-methyl-4-chloroquinoline-3-carboxylate

[0068] At room temperature, 10 mL of chlorobenzene, 0.444 g of triphosgene (1.5 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 25 minutes. Then, 0.191 g of methyl 3-anilino-2-butenoate (1h, 1.0 mmol) was added thereto, and the reaction system was heated to 60 °C and stirred for an additional 2.0 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluate containing the target product was collected, the solvent was evaporated and dried to obtain 0.150 g of a pale yellow solid product, methyl 2-methyl-4-chloroquinoline-3-carboxylate (2h), with a yield of 65%.

[0069] The above reaction formula is as follows:

[0070]

[0071] For the product methyl 2-methyl-4-chloroquinoline-3-carboxylate 2h 1 1H NMR and 13 13C NMR data are as follows:

[0072] 1 1H NMR (300 MHz, CDCl3): δ 8.26–8.16 (m, 1H), 8.09–7.99 (m, 1H), 7.78 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.62 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 4.03 (s, 3H), 2.72 (s, 3H). 13 13C NMR (75 MHz, CDCl3): δ 166.75, 154.72, 147.77, 139.51, 131.10, 128.86, 127.33, 127.06, 124.19, 123.81, 52.86, 23.54.

[0073] Example 9 Synthesis of 2-methyl-3-benzoyl-4-chloroquinoline

[0074] At room temperature, 10 mL of chlorobenzene, 0.592 g of triphosgene (2.0 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 20 minutes. Then, 0.237 g of 1-phenyl-3-anilino-but-2-en-1-one (1i, 1.0 mmol) was added thereto, and the reaction system was heated to 60 °C and stirred for another 2.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluent containing the target product was collected, the solvent was evaporated and dried to obtain 0.087 g of a light gray solid product, 2-methyl-3-benzoyl-4-chloroquinoline (2i), with a yield of 31%.

[0075] The above reaction formula is as follows:

[0076]

[0077] For the product 2-methyl-3-benzoyl-4-chloroquinoline 2i 1 H NMR and 13 C NMR data are as follows:

[0078] 1 H NMR (300 MHz, CDCl3): δ 8.28–8.19 (m, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.92–7.74 (m, 3H), 7.73–7.60 (m, 2H), 7.57–7.45 (m, 2H), 2.59 (s, 3H). 13 C NMR (75 MHz, CDCl3): δ 194.54, 155.12, 147.93, 138.94, 135.68, 134.43, 131.88, 131.03, 129.48, 129.04, 128.98, 127.47, 124.13, 123.95, 23.70.

[0079] Example 10 Synthesis of Ethyl 2-propyl-4-chloroquinoline-3-carboxylate

[0080] At room temperature, 10 mL of chlorobenzene, 0.592 g of triphosgene (2.0 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 20 minutes, and 0.233 g of ethyl 3-anilino-2-hexenoate (1j, 1.0 mmol) was added thereto. The reaction system was heated to 50 °C and stirred for an additional 2.0 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting concentrate was separated by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluate containing the target product was collected, the solvent was evaporated and dried to obtain 0.241 g of colorless liquid product ethyl 2-propyl-4-chloroquinoline-3-carboxylate (2j) with a yield of 87%.

[0081] The above reaction formula is as follows:

[0082]

[0083] For the product ethyl 2-propyl-4-chloroquinoline-3-carboxylate 2j 1 H NMR and 13 C NMR data are as follows:

[0084] 1 H NMR (300 MHz, CDCl3): δ 8.22 (ddd, J = 8.4, 1.5, 0.6 Hz, 1H), 8.06 (ddd, J = 8.5, 1.2, 0.6 Hz, 1H), 7.78 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.62 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 2.98–2.87 (m, 2H), 1.96–1.77 (m, 2H), 1.46 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 166.31, 158.32, 147.85, 139.27, 130.83, 129.01, 127.28, 127.20, 124.05, 123.79, 62.03, 38.94, 22.60, 13.99, 13.96.

[0085] Example 11 Synthesis of ethyl 2-cyclopropyl-4-chloroquinoline-3-carboxylate

[0086] At room temperature, 10 mL of chlorobenzene, 0.444 g of triphosgene (1.5 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 25 minutes. Then, 0.231 g of ethyl 3-anilino-3-cyclopropylacrylate (1k, 1.0 mmol) was added thereto, and the reaction system was heated to 60 °C and stirred for an additional 2.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluate containing the target product was collected, the solvent was evaporated, and the residue was dried to obtain 0.182 g of a pale yellow liquid product, ethyl 2-propyl-4-chloroquinoline-3-carboxylate (2k), with a yield of 66%.

[0087] The above reaction formula is as follows:

[0088]

[0089] For the product ethyl 2-cyclopropyl-4-chloroquinoline-3-carboxylate 2k 1 H NMR and 13 C NMR data are as follows:

[0090] 1 H NMR (300 MHz, CDCl3): δ 8.17 (ddt, J = 8.4, 1.3, 0.7 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.72 (dddd, J = 8.4, 6.9, 1.5, 0.8 Hz, 1H), 7.65–7.50 (m, 1H), 4.54 (q, J = 7.1 Hz, 2H), 2.11 (tt, J = 8.1, 4.8 Hz, 1H), 1.46 (t, J = 7.1 Hz, 3H), 1.42–1.22 (m, 2H), 1.18–0.90 (m, 2H). 13 C NMR (75 MHz, CDCl3): δ 166.55, 158.74, 148.02, 138.62, 130.72, 129.00, 127.45, 126.70, 124.05, 123.64, 62.13, 15.57, 14.10, 10.59.

[0091] Example 12 Synthesis of ethyl 2-phenyl-4-chloroquinoline-3-carboxylate

[0092] At room temperature, 10 mL of chlorobenzene, 0.596 g of triphosgene (2.0 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 20 minutes. Then, 0.267 g of ethyl 3-anilino-3-phenylacrylate (1l, 1.0 mmol) was added thereto, and the reaction system was heated to 80 °C and stirred for 2.0 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluent containing the target product was collected, the solvent was evaporated and dried to obtain 0.233 g of a pale yellow liquid product, ethyl 2-phenyl-4-chloroquinoline-3-carboxylate (2l), with a yield of 75%.

[0093] The above reaction formula is as follows:

[0094]

[0095] For the product ethyl 2-phenyl-4-chloroquinoline-3-carboxylate 2l 1 H NMR and 13 C NMR data are as follows:

[0096] 1 H NMR (300 MHz, CDCl3): δ 8.30 (ddd, J = 8.4, 1.5, 0.6 Hz, 1H), 8.19 (ddd, J = 8.5, 1.3, 0.7 Hz, 1H), 7.83 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.79–7.59 (m, 3H), 7.57–7.40 (m, 3H), 4.26 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.1 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 166.11, 156.03, 147.78, 140.20, 139.13, 131.22, 129.69, 129.07, 128.33, 128.26, 127.89, 126.84, 124.16, 124.02, 61.96, 13.53. Example 14 Synthesis of diethyl 4-chloroquinoline-2,3-dicarboxylate

[0097] At room temperature, 10 mL of chlorobenzene, 0.894 g of triphosgene (3.0 mmol) and 0.278 g of triphenylphosphine oxide (1.0 mmol) were added to a 38 mL pressure-resistant tube equipped with a magnetic stir bar. The mixture was magnetically stirred at room temperature for 15 minutes. Then, 0.263 g of diethyl 2-anilinomaleate (1m, 1.0 mmol) was added thereto, and the reaction system was heated to 90 °C and stirred for another 2.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting concentrate was separated by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 15:1 as the eluent. The eluent containing the target product was collected, the solvent was evaporated and dried to obtain 0.120 g of a yellow liquid product, diethyl 4-chloroquinoline-2,3-dicarboxylate (2m), with a yield of 39%.

[0098] The above reaction formula is as follows:

[0099]

[0100] For the product diethyl 4-chloroquinoline-2,3-dicarboxylate 2m 1 H NMR and 13 C NMR data are as follows:

[0101] 1 H NMR (300 MHz, CDCl3): δ 8.32 (dddd, J = 8.5, 4.9, 1.4, 0.7 Hz, 2H), 7.85 (dddd, J = 27.6, 8.2, 6.9, 1.4 Hz, 2H), 4.54 (qd, J = 7.1, 1.6 Hz, 4H), 1.46 (dt, J = 7.7, 7.1 Hz, 6H). 13 C NMR (75 MHz, CDCl3): δ 165.14, 163.96, 146.97, 145.22, 141.22, 131.70, 130.71, 130.13, 127.21, 126.18, 124.26, 62.74, 62.32, 14.05, 13.87.

Claims

1. A method for synthesizing a 4-chloroquinoline compound, characterized in that, The method is as follows: At room temperature, triphosgene and triphenylphosphine oxide are mixed and dissolved in an organic solvent, stirred, and an N-aryl enamine compound is added. The reaction system is heated to 50 - 100 °C and stirred for 1 - 4 h. The obtained reaction solution is post-treated to obtain a 4-chloroquinoline compound; The N-aryl enamine compound has the structural formula shown in (I): Among them, R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylthio, C1-C4 alkylamino, phenyl, vinyl, allyl, halogen, nitro or trifluoromethyl; R 5 is selected from C1-C4 alkyl, C1-C4 alkoxycarbonyl, benzyl, allyl, phenyl, 4-halophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-furyl, 2-thienyl; R 6 is selected from C1-C4 alkoxycarbonyl, benzoyl.

2. The synthesis method according to claim 1, characterized in that, In terms of the molar ratio, triphosgene:triphenylphosphine oxide = (1 - 4):

1.

3. The synthesis method according to claim 1, characterized in that, The organic solvent is selected from one or more of benzene, toluene, xylene, acetonitrile, tetrahydrofuran, chlorobenzene, or 1,2-dichloroethane.

4. The synthesis method according to claim 1, wherein The amount of the organic solvent used is 2 - 10 mL of the organic solvent added per 1 mmol of the N-aryl enamine compound.

5. The synthesis method according to claim 1, characterized in that, In terms of the molar ratio, N-aryl enamine compound:triphosgene = 1:(1 - 3).

6. The synthesis method according to claim 1, wherein The post-treatment method is: The obtained reaction solution is concentrated under reduced pressure, and the obtained concentrate is separated by silica gel column chromatography. Using a mixed solution of petroleum ether and ethyl acetate as the eluent, the eluent containing the target product is collected, the solvent is evaporated and dried to obtain a 4-chloroquinoline compound.

7. The synthesis method according to claim 6, wherein, In terms of the volume ratio, petroleum ether:ethyl acetate = (10 - 40):

1.

8. The 4-chloroquinoline compound synthesized by the method according to any one of claims 1-7, characterized in that, The 4-chloroquinoline compound has the structural formula of general formula (II): Among them, R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylthio, C1-C4 alkylamino, phenyl, vinyl, allyl, halogen, nitro or trifluoromethyl; R 5 is selected from C1-C4 alkyl, C1-C4 alkoxycarbonyl, benzyl, allyl, phenyl, 4-halophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-furyl, 2-thienyl; R 6 is selected from C1-C4 alkoxycarbonyl, benzoyl.

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