A preparation method of quinoline fused ring derivative

Abstract

The present patent application provides a preparation method of quinoline fused ring derivatives: in a reaction flask, a copper-containing catalyst is added, a part and an alkali are used as a promoter, an inert gas is introduced, a solvent is added, an anthranilic anhydride (Formula III), a terminal alkynol or a terminal alkynamine (Formula II) are added sequentially, under the conditions of less than 100 DEG C, the stirring reaction is 8-18 hours, the reaction is cooled to room temperature after terminating, the reaction solution is washed with water, then extracted with ethyl acetate to remove the solvent, and dried over anhydrous magnesium sulfate, and purified to obtain the quinoline fused ring derivatives (Formula I) described in the series. The synthetic method of the quinoline fused ring derivatives of the present patent application is cheap, easy to obtain, safe and simple to operate, has good adaptability to functional groups, is widely adaptable to substrates, and is environmentally friendly and conducive to industrial production, and has a large application potential in pesticides, medicines and natural product synthesis.

Description

Technical Field

[0001] This patent application relates to the field of pharmaceutical chemical synthesis technology, and more specifically, to a method for preparing a quinoline fused-ring derivative. Background Art

[0002] Quinoline fused ring structures are widely found in natural products, pharmaceuticals, and functional materials. For example, the four furanoquinoline alkaloids from the Rutaceae family—kokusaginine, tecleaverdoornine, maculine, and montrifoline—and (+)-Myrtopsine all contain quinoline-furan fragments. Bioactive molecules containing 8-hydroxyfuroquinoline fused ring fragments can protect DNA from AAPH-induced oxidation (Med Chem Res., 2013, 22, 1563-1569). Furthermore, azanaphthobenzofurans have important applications in materials for organic electroluminescent devices. Due to their widespread applications, synthetic methods for quinoline-fused rings have garnered significant attention from both academia and industry.

[0003] In 2007, Professor Liu Qun of Northeast Normal University developed a tandem ring-opening and recyclization reaction of a doubly activated cyclopropane precursor, 1-acetyl-N-phenylcyclopropane-1-carboxamide, to synthesize furanoquinoline fused rings (Angew. Chem. Int. Ed. 2007, 46, 1726–1729). This reaction, using SnCl₄·5H₂O as a Lewis acid and xylene as a solvent, was carried out at 120°C for 6 h to yield the desired furanoquinoline fused ring. However, the complex and difficult-to-obtain starting materials hindered industrial production.

[0004] In 2016, Professor Shi Min of the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, converted the amino group of 2-(1-cyclopropylideneethyl)aniline into an isocyanate or thioisocyanate, which then triggered an intramolecular [3+2] cyclization reaction under heating to synthesize a furanoquinoline product (Chem. Commun., 2016, 52, 2701-2704). This reaction requires no catalyst, but the isocyanate intermediate must be treated with the highly toxic triphosgene, posing a significant safety hazard, especially in large-scale production.

[0005] In 2019, Professor Ruixiong Liu of National Tsing Hua University in Taiwan developed a gold-catalyzed reaction of anthranilic anhydride with prop-2-yn-1-yloxybenzene, which then aromatized to 5H-isochromo[3,4-b]quinoline via an α-iminogold carbene and a Friedel-Crafts reaction (Org. Biomol. Chem., 2019, 17, 4452–4455). This reaction required the use of an expensive gold catalyst, took up to 35 hours, and was performed in two steps, making it uneconomical.

[0006] While the aforementioned methods can, to a certain extent, address the synthesis of quinoline fused-ring products, they suffer from numerous limitations, including the limited product structure and limited applicability to the synthesis of furanoquinoline, pyranoquinoline, pyrroloquinoline, and similar structures; the complex starting materials, requiring multi-step synthesis; and the harsh reaction conditions or the use of hazardous chemicals. Therefore, developing a green and efficient method for the synthesis of quinoline fused-ring derivatives is of great significance.

[0007] Patent application content

[0008] To overcome at least one problem existing in the prior art, this patent application provides a method for preparing quinoline fused-ring derivatives. This method utilizes readily available, inexpensive raw materials, is safe and simple to operate, features a moderate reaction temperature and short reaction time, exhibits good adaptability to functional groups, and is broadly adaptable to substrates. It is applicable to the synthesis of furanoquinoline, pyranoquinoline, pyrroloquinoline, and similar structures. The method utilizes simple starting materials, allows for a one-step synthesis of quinoline fused-ring derivatives, and is environmentally friendly and beneficial for industrial production. The method has significant potential for application in the synthesis of pesticides, pharmaceuticals, and natural products, and thus possesses potential practical value.

[0009] The preparation principle of the quinoline fused ring derivatives in this patent application is that a terminal alkyne with a heteroatom and anthranilic anhydride are aminated via a spC-H bond to obtain an alkynylamine active intermediate; next, the alcohol or amine on the alkyne acts as a nucleophile to attack the alkyne and alkynylamine to initiate an intramolecular tandem cyclization to obtain a quinoline fused ring derivative.

[0010] In the preparation method of this patent application, the possible reaction mechanism flow chart is as follows:

[0011] The reaction conditions are as follows: adding 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, followed by introduction of 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of 3-butyn-1-ol 2a, stirring and reacting at 100° C. for 12 hours, stopping heating and stirring, cooling to room temperature, adding 20 ml of water to the reaction solution for washing, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, and removing the solvent by rotary evaporation under reduced pressure. The reaction solution is then separated and purified by column chromatography, wherein the column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain a white solid product, 2,3-dihydrofuro[2,3-b]quinoline 1a. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, the anthranilic anhydride 3a of Formula III, and the quinoline fused-ring derivative 1a of Formula I are shown below:

[0012]

[0013] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-fluorobenzo[c]isoxazole 3b, 1.2 mmol of 3-butyn-1-ol 2a, stirring at 100 ° C for 12 hours, stopping heating and stirring, cooling to room temperature, and adding 20 ml of water to the reaction solution. The product was washed with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain a white solid product 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline 1b. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, the anthranilic anhydride 3b of Formula III, and the quinoline fused ring derivative 1b of Formula I are shown below:

[0014]

[0015] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-bromobenzisoxazole 3c, 1.2 mmol of 3-butyn-1-ol 2a, stirring at 100 ° C for 12 hours, stopping heating and stirring, cooling to room temperature, and adding 20 ml of water to the reaction solution for 2 hours. The product was washed with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain a silvery white solid product 6-bromo-2,3-dihydrofuro[2,3-b]quinoline 1c. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, the anthranilic anhydride 3c of Formula III, and the quinoline fused ring derivative 1c of Formula I are shown below:

[0016]

[0017] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 3-methylbenzo[c]isoxazole 3d, 1.2 mmol of 3-butyn-1-ol 2a are added, and the reaction is stirred at 100° C. for 12 hours, and then heating and stirring are stopped, the reaction solution is cooled to room temperature, and 20 ml of The mixture was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as the eluent to obtain 4-methyl-2,3-dihydrofuro[2,3-b]quinoline 1d as a white solid. The structures of the terminal alkynol or terminal alkynamine 2a of Formula II, anthranilic anhydride 3d of Formula III, and the quinoline fused-ring derivative 1d of Formula I are shown below:

[0018]

[0019] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-chloro-3-phenylbenzisoxazole 3e, 1.2 mmol of 3-butyn-1-ol 2a, stirring at 100 ° C for 12 hours, stopping heating and stirring, cooling to room temperature, adding 20 ml of water to the reaction solution, The residue was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was then separated and purified by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 as the eluent to obtain an off-white solid product, 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline 1e. The structures of the terminal alkynol or terminal alkynamine 2a of Formula II, anthranilic anhydride 3e of Formula III, and the quinoline fused-ring derivative 1e of Formula I are shown below:

[0020]

[0021] Alternatively, the reaction conditions are as follows: adding 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, followed by introduction of 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of 4-pentyn-1-ol 2b, stirring and reacting at 100° C. for 12 hours, stopping heating and stirring, cooling to room temperature, adding 20 ml of water to the reaction solution, extracting with ethyl acetate, drying over anhydrous magnesium sulfate, removing the solvent by rotary evaporation under reduced pressure, and then separating and purifying by column chromatography, wherein the column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain a green solid product 3,4-dihydropyrano[2,3-b]quinoline 1f. The structural formulas of the terminal alkynol or terminal alkynamine 2b of Formula II, the anthranilic anhydride 3a of Formula III, and the quinoline fused-ring derivative 1f of Formula I are shown below:

[0022]

[0023] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate are added, followed by the introduction of 1 atmosphere of argon gas, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of (2-ethynylphenyl)methanol 2c. After stirring and reacting at 100° C. for 12 hours, heating and stirring are stopped, and the mixture is cooled to room temperature. 20 ml of water is added to the reaction solution, and the mixture is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent is removed by rotary evaporation under reduced pressure. The mixture is then separated and purified by column chromatography, wherein the column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1. 1 g of a light yellow solid product, 5H-isochromatic [3,4-b]quinoline, can be obtained. The structural formulas of the terminal alkynol or terminal alkynamine 2c of Formula II, the anthranilic anhydride 3a of Formula III, and the quinoline fused-ring derivative 1 g of Formula I are shown below:

[0024]

[0025] Alternatively, the reaction conditions are as follows: adding 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, followed by introduction of 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of 2-((trimethylsilyl)ethynyl)phenol 2d, stirring and reacting at 100° C. for 12 hours, stopping heating and stirring, cooling to room temperature, adding 20 ml of water to the reaction solution, extracting with ethyl acetate, drying over anhydrous magnesium sulfate, removing the solvent by rotary evaporation under reduced pressure, and then separating and purifying by column chromatography, wherein the column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1, to obtain a white solid benzofurano[2,3-b]quinoline 1h. The structural formulas of the terminal alkynol or terminal alkynamine 2d of Formula II, the anthranilic anhydride 3a of Formula III, and the quinoline fused-ring derivative 1h of Formula I are shown below:

[0026]

[0027] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate are added, the mixture is filled with 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of N-(4-chlorobenzyl)but-3-yn-1-amine 2e, and the mixture is stirred at 100° C. for 12 hours, then heating and stirring are stopped, the mixture is cooled to room temperature, and 20 ml of water is added to the reaction solution. The residue was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was then separated and purified by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1 as the column chromatography eluent to obtain light yellow solid 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline 1i. The structures of the terminal alkynol or terminal alkynamine 2e of Formula II, anthranilic anhydride 3a of Formula III, and the quinoline fused ring derivative 1i of Formula I are shown below:

[0028] In order to solve the above technical problems, the technical solution adopted in this patent application is:

[0029] A method for preparing quinoline fused-ring derivatives comprises: adding a copper-containing catalyst, a ligand and a base as a promoter to a reaction flask, introducing an inert gas, adding a solvent, and sequentially adding anthranilic anhydride (Formula III) and a terminal alkynol or terminal alkynamine (II). The mixture is stirred and reacted at a temperature below 100° C. for 8-18 hours. After the reaction is completed, the mixture is cooled to room temperature, washed with water, extracted with ethyl acetate to remove the solvent, dried over anhydrous magnesium sulfate, and purified to obtain the series of quinoline fused-ring derivatives (I). The reaction is shown in the following formula:

[0030] The reaction conditions are as follows: adding 0.015 mmol of copper tetraethylcyanide hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, charging with 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of 3-butyn-1-ol 2a, stirring and reacting at 100° C. for 12 hours, stopping heating and stirring, cooling to room temperature, adding 20 ml of water to wash the reaction solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent by vacuum rotary evaporation, and then separating and purifying by column chromatography, wherein the column chromatography eluent used is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain a white solid product 2,3-dihydrofuro[2,3-b]quinoline 1a. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, the anthranilic anhydride 3a of Formula III, and the quinoline fused ring derivative 1a of Formula I are shown below:

[0031]

[0032] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-fluorobenzo[c]isoxazole 3b, 1.2 mmol of 3-butyn-1-ol 2a, stirring at 100 ° C for 12 hours, stopping heating and stirring, cooling to room temperature, and adding 20 ml of water to the reaction solution. The product was washed with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain a white solid product 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline 1b. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, the anthranilic anhydride 3b of Formula III, and the quinoline fused ring derivative 1b of Formula I are shown below:

[0033]

[0034] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-bromobenzisoxazole 3c, 1.2 mmol of 3-butyn-1-ol 2a, stirring at 100 ° C for 12 hours, stopping heating and stirring, cooling to room temperature, and adding 20 ml of water to the reaction solution for 2 hours. The product was washed with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain a silvery white solid product 6-bromo-2,3-dihydrofuro[2,3-b]quinoline 1c. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, the anthranilic anhydride 3c of Formula III, and the quinoline fused ring derivative 1c of Formula I are shown below:

[0035]

[0036] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 3-methylbenzo[c]isoxazole 3d, 1.2 mmol of 3-butyn-1-ol 2a are added, and the reaction is stirred at 100° C. for 12 hours, and then heating and stirring are stopped, the reaction solution is cooled to room temperature, and 20 ml of The mixture was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as the eluent to obtain 4-methyl-2,3-dihydrofuro[2,3-b]quinoline 1d as a white solid. The structures of the terminal alkynol or terminal alkynamine 2a of Formula II, anthranilic anhydride 3d of Formula III, and the quinoline fused-ring derivative 1d of Formula I are shown below:

[0037]

[0038] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-chloro-3-phenylbenzisoxazole 3e, 1.2 mmol of 3-butyn-1-ol 2a, stirring at 100 ° C for 12 hours, stopping heating and stirring, cooling to room temperature, adding 20 ml of water to the reaction solution, The residue was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was then separated and purified by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 as the eluent to obtain an off-white solid product, 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline 1e. The structures of the terminal alkynol or terminal alkynamine 2a of Formula II, anthranilic anhydride 3e of Formula III, and the quinoline fused-ring derivative 1e of Formula I are shown below:

[0039]

[0040] Alternatively, the reaction conditions are as follows: adding 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, followed by introduction of 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of 4-pentyn-1-ol 2b, stirring and reacting at 100° C. for 12 hours, stopping heating and stirring, cooling to room temperature, adding 20 ml of water to the reaction solution, extracting with ethyl acetate, drying over anhydrous magnesium sulfate, removing the solvent by rotary evaporation under reduced pressure, and then separating and purifying by column chromatography, wherein the column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain a green solid product 3,4-dihydropyrano[2,3-b]quinoline 1f. The structural formulas of the terminal alkynol or terminal alkynamine 2b of Formula II, the anthranilic anhydride 3a of Formula III, and the quinoline fused-ring derivative 1f of Formula I are shown below:

[0041]

[0042] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate are added, followed by the introduction of 1 atmosphere of argon gas, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of (2-ethynylphenyl)methanol 2c. After stirring and reacting at 100° C. for 12 hours, heating and stirring are stopped, and the mixture is cooled to room temperature. 20 ml of water is added to the reaction solution, and the mixture is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent is removed by rotary evaporation under reduced pressure. The mixture is then separated and purified by column chromatography, wherein the column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1. 1 g of a light yellow solid product, 5H-isochromatic [3,4-b]quinoline, can be obtained. The structural formulas of the terminal alkynol or terminal alkynamine 2c of Formula II, the anthranilic anhydride 3a of Formula III, and the quinoline fused-ring derivative 1 g of Formula I are shown below:

[0043]

[0044] Alternatively, the reaction conditions are as follows: adding 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, followed by introduction of 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of 2-((trimethylsilyl)ethynyl)phenol 2d, stirring and reacting at 100° C. for 12 hours, stopping heating and stirring, cooling to room temperature, adding 20 ml of water to the reaction solution, extracting with ethyl acetate, drying over anhydrous magnesium sulfate, removing the solvent by rotary evaporation under reduced pressure, and then separating and purifying by column chromatography, wherein the column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1, to obtain a white solid benzofurano[2,3-b]quinoline 1h. The structural formulas of the terminal alkynol or terminal alkynamine 2d of Formula II, the anthranilic anhydride 3a of Formula III, and the quinoline fused-ring derivative 1h of Formula I are shown below:

[0045]

[0046] Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate are added, the mixture is filled with 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of N-(4-chlorobenzyl)but-3-yn-1-amine 2e, and the mixture is stirred at 100° C. for 12 hours, then heating and stirring are stopped, the mixture is cooled to room temperature, and 20 ml of water is added to the reaction solution. The residue was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was then separated and purified by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1 as the column chromatography eluent to obtain light yellow solid 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline 1i. The structures of the terminal alkynol or terminal alkynamine 2e of Formula II, anthranilic anhydride 3a of Formula III, and the quinoline fused ring derivative 1i of Formula I are shown below:

[0047]

[0048] Compared with the prior art, the beneficial effects of this patent application are:

[0049] The preparation method of quinoline fused ring derivatives provided in this patent application is safe and simple to operate, with low-cost and easily available raw materials, wide adaptability to substrates, moderate temperature, high safety performance and high yield; this method can construct furanoquinoline, pyranoquinoline and pyrroloquinoline derivatives in one step, and has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 This is the H NMR spectrum of 2,3-dihydrofuro[2,3-b]quinoline (1a) prepared in Example 1 of this patent application;

[0051] Figure 2 This is the carbon NMR spectrum of 2,3-dihydrofuro[2,3-b]quinoline (1a) prepared in Example 1 of this patent application;

[0052] Figure 3 This is the H NMR spectrum of 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b) prepared in Example 2 of this patent application;

[0053] Figure 4 This is the carbon NMR spectrum of 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b) prepared in Example 2 of this patent application;

[0054] Figure 5 This is the NMR fluorine spectrum of 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b) prepared in Example 2 of this patent application;

[0055] Figure 6 This is the H NMR spectrum of 6-bromo-2,3-dihydrofuro[2,3-b]quinoline (1c) prepared in Example 3 of this patent application;

[0056] Figure 7 This is the carbon NMR spectrum of 6-bromo-2,3-dihydrofuro[2,3-b]quinoline (1c) prepared in Example 3 of this patent application;

[0057] Figure 8 This is the H NMR spectrum of 4-methyl-2,3-dihydrofuro[2,3-b]quinoline (1d) prepared in Example 4 of this patent application;

[0058] Figure 9 This is the carbon NMR spectrum of 4-methyl-2,3-dihydrofuro[2,3-b]quinoline (1d) prepared in Example 4 of this patent application;

[0059] Figure 10 This is the H NMR spectrum of 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline (1e) prepared in Example 5 of this patent application;

[0060] Figure 11 This is the carbon NMR spectrum of 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline (1e) prepared in Example 5 of this patent application;

[0061] Figure 12 This is the H NMR spectrum of 3,4-dihydropyrano[2,3-b]quinoline (1f) prepared in Example 6 of this patent application;

[0062] Figure 13 This is the carbon NMR spectrum of 3,4-dihydropyrano[2,3-b]quinoline (1f) prepared in Example 6 of this patent application;

[0063] Figure 14 This is the H NMR spectrum of 5H-isochromo[3,4-b]quinoline (1 g) prepared in Example 7 of this patent application;

[0064] Figure 15 This is the carbon NMR spectrum of 5H-isochromo[3,4-b]quinoline (1 g) prepared in Example 7 of this patent application;

[0065] Figure 16 This is the H NMR spectrum of benzofuro[2,3-b]quinoline (1h) prepared in Example 8 of this patent application;

[0066] Figure 17This is the carbon NMR spectrum of benzofurano[2,3-b]quinoline (1h) prepared in Example 8 of this patent application;

[0067] Figure 18 This is the H NMR spectrum of 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline (1i) prepared in Example 9 of this patent application;

[0068] Figure 19 The carbon NMR spectrum of 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline (1i) prepared in Example 9 of this patent application is shown in FIG. DETAILED DESCRIPTION

[0069] The embodiments of the present application will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are only used to illustrate the present application and should not be considered as limiting the scope of the present application. Where specific conditions are not specified in the examples, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0070] It should be noted that:

[0071] In this patent application, unless otherwise specified, all the embodiments and preferred implementation methods mentioned herein can be combined with each other to form a new technical solution.

[0072] In this patent application, unless otherwise stated, each reaction or operation step can be carried out sequentially or in accordance with the sequence. Preferably, the reaction method herein is carried out sequentially.

[0073] Unless otherwise indicated, the professional and scientific terms used herein are the same as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the described content may also be applied to this patent application.

[0074] To address the technical challenges of the prior art, the applicants of this patent envisioned utilizing readily available terminal alkynes bearing heteroatoms and anthranilic anhydride as starting materials to efficiently prepare a variety of quinoline fused-ring products under mild reaction conditions. Through exploration, they achieved this tandem cyclization reaction: first, the terminal alkyne and anthranilic anhydride undergo a spC-H amination reaction to yield an alkynylamine reactive intermediate. Next, the alcohol or amine attached to the alkyne acts as a nucleophile to attack the alkynylamine, initiating an intramolecular tandem cyclization to yield quinoline fused-ring derivatives. This synthetic strategy utilizes readily available starting materials, employs mild reaction conditions, and can synthesize a wide variety of quinoline fused-ring products by regulating the type and position of the nucleophile, demonstrating its promising application.

[0075] The present patent application provides a method for preparing quinoline fused ring derivatives, which comprises the following steps: adding a copper-containing catalyst, a ligand and a base as a promoter into a reaction flask, introducing an inert gas, adding a solvent, and sequentially adding anthranilic anhydride (Formula III), a terminal alkynol or a terminal alkynamine (II), stirring and reacting at a temperature below 100° C. for 8-18 hours. After the reaction is completed, the reaction solution is cooled to room temperature, washed with water, extracted with ethyl acetate to remove the solvent, dried over anhydrous magnesium sulfate, and purified to obtain a series of quinoline fused ring derivatives (I). The reaction is shown in the following formula:

[0076]

[0077] Among them, R 1 R is selected from hydrogen, phenyl, phenyl with halogen as a substituent, etc. 2 It is selected from hydrogen, halogen, methyl, phenyl with halogen, etc. When X=O, n can be 0 or 1; when X=N, n can be 0.

[0078] The preparation method disclosed in this patent application uses a copper-containing catalyst to catalyze the amination of a terminal alkyne with a heteroatom and anthranilic anhydride through an spC-H bond to obtain an alkynamine active intermediate; then, the alcohol or amine on the alkyne acts as a nucleophile to attack the alkyne and alkynamine, triggering an intramolecular tandem cyclization to obtain a quinoline fused-ring derivative.

[0079] In some embodiments, the copper-containing catalyst is selected from one or more of cupric chloride, cuprous chloride, cuprous iodide, cuprous sulfide, anhydrous cuprous acetate, anhydrous cupric acetate, copper trifluoromethanesulfonate, cuprous oxide, tetrakis-p-methoxyporphyrin copper, and tetraacetic cyanide copper hexafluorophosphate. The catalyst disclosed in this patent application is much cheaper than the expensive transition metal catalysts used in the prior art, such as palladium catalysts.

[0080] In some more preferred embodiments, the copper-containing catalyst is copper tetraethyl cyanide hexafluorophosphate, and the molar ratio of anthranilic anhydride to copper tetraethyl cyanide hexafluorophosphate is 1:0.05. By achieving a molar ratio of anthranilic anhydride to copper tetraethyl cyanide hexafluorophosphate of 1:0.05, the catalytic cycle effect is optimized, the reaction rate of the raw materials is maximized, and the best reaction effect is achieved.

[0081] In some embodiments, the base is selected from one or more of cesium carbonate, anhydrous sodium carbonate, anhydrous potassium carbonate, potassium phosphate, anhydrous potassium acetate, and anhydrous sodium acetate.

[0082] In some more preferred embodiments, the base is potassium phosphate, and the molar ratio of anthranilic anhydride to potassium phosphate is 1: 1. This configuration can maximize the reaction rate of the raw materials and the yield in the preparation method.

[0083] In some preferred embodiments, the solvent is selected from one or more of dimethyl sulfoxide, ultra-dry dimethyl sulfoxide, N,N-dimethylaniline, N-methylpyrrolidone, ultra-dry tetrahydrofuran, ultra-dry 1,4-dioxane, N,N-dimethylformamide, and toluene.

[0084] In some more preferred embodiments, the solvent is ultra-dry dimethyl sulfoxide, and 1 mL of the ultra-dry dimethyl sulfoxide is required to be added to 0.2 mmol of the anthranilic anhydride.

[0085] In some preferred embodiments, the molar ratio of the anthranilic anhydride to the terminal alkynol or terminal alkynamine (II) is 1:(1-4).

[0086] In some more preferred embodiments, the terminal alkynol or terminal alkynamine (II) is a terminal alkyne of an alcohol or amine with a heteroatom, and the molar ratio of anthranilic anhydride to the terminal alkyne of the heteroatom-containing alcohol or amine is 1:4. With this arrangement, while ensuring the reaction yield, the reaction system allows substantially all of the anthranilic anhydride to participate in the reaction, and the reaction effect is optimal. This ratio is the minimum value required to achieve optimal consumption of the two raw materials.

[0087] In some embodiments, the inert gas is selected from argon, nitrogen, and carbon dioxide.

[0088] In some more preferred embodiments, argon is preferred.

[0089] In some embodiments, the reaction temperature is 30-100°C.

[0090] In some more preferred embodiments, 100°C is preferred.

[0091] In some embodiments, the reaction time is 8-16 hours.

[0092] In some more preferred embodiments, 12 hours is preferred.

[0093] In some embodiments, after the reaction is completed, the product is separated and purified by column chromatography, wherein the column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate.

[0094] Next, the preparation method of the quinoline fused ring derivatives of the present patent application is described in detail with reference to specific examples.

[0095] Example 1 Preparation of 2,3-dihydrofuro[2,3-b]quinoline (1a)

[0096] In a reaction flask, 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate were added, and the mixture was filled with 1 atmosphere of argon. 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of 3-butyn-1-ol 2a were stirred and reacted at 100°C for 12 hours. Heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with 20 ml of water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The reaction solution was then separated and purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1 as the eluent. 33.4 mg of 2,3-dihydrofuro[2,3-b]quinoline (1a) was obtained as a white solid product with a yield of 65% and an m.p. of 117.8-119.1°C. The reaction equation is as follows:

[0097]

[0098] The H-NMR spectrum and C-NMR spectrum of the derivative 1a prepared in Example 1 are as follows: Figure 1 、 Figure 2 shown. 1 H NMR (400MHz, CDCl3) δ7.81(d,J=8.4Hz,1H),7.77(s,1H),7.62(d,J=6.7Hz,1H),7.57- 7.51(m,1H),7.34-7.29(m,1H),4.65(t,J=8.2Hz,2H),3.31(td,J=8.3,1.4Hz,2H)ppm; 13 C NMR (100 MHz, CDCl3) δ 167.7, 146.9, 132.8, 129.1, 127.4, 127.3, 125.4, 124.0, 121.6, 69.1, 27.7 ppm. The molecular hydrogen and carbon spectrum peaks can correspond one to one with the target product. At the same time, the applicant of the present invention also performed high performance liquid chromatography mass spectrometry analysis on the product obtained in Example 1. The test results are as follows: HRMS ESI (m / z): calculated for C 11 H 10 NO + (M+H) + :172.07569; found:172.07544. Combining the results of the above H NMR spectrum, C NMR spectrum and mass spectrometry analysis, it can be seen that the product prepared in Example 1 is 2,3-dihydrofuro[2,3-b]quinoline (1a).

[0099] In this example, 3-butyn-1-ol 2a and anthranilic anhydride 3a were used as raw materials. In the presence of inexpensive catalysts including copper tetraethylcyanide hexafluorophosphate, 4,7-diphenyl-1,10-phenanthroline, and potassium phosphate, a two-component tandem cyclization reaction was performed to synthesize the quinoline fused-ring derivative 2,3-dihydrofuro[2,3-b]quinoline (1a). The reaction in this example merely required stirring at 100° C. for 12 hours in an inert argon atmosphere, followed by cooling and a series of subsequent treatments to obtain the final target product, 2,3-dihydrofuro[2,3-b]quinoline (1a), in a very high yield (65%).

[0100] Therefore, the method for preparing quinoline fused ring derivatives in this embodiment is a green and efficient synthesis method. The method uses cheap and readily available chemicals as starting materials, undergoes a green, safe, and efficient reaction process, and efficiently synthesizes 2,3-dihydrofuro[2,3-b]quinoline (1a) under mild reaction conditions. All raw materials in the reaction are cheap and readily available, the method is simple and easy to operate, and the operation is safe, thus having potential practical value.

[0101] The product 2,3-dihydrofuro[2,3-b]quinoline (1a) obtained in this example can be used as a precursor of furo[2,3-b]quinoline (2,3-dihydrofuro[2,3-b]quinoline (1a) is prepared by adding bromine atoms in NBS and CCl4 solutions and then reducing and eliminating in NaH and DMF solvents to obtain furo[2,3-b]quinoline).

[0102] Example 2 Preparation of 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b)

[0103] To a reaction flask were added 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, followed by the addition of 1 atm of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-fluorobenzo[c]isoxazole 3b, and 1.2 mmol of 3-butyn-1-ol 2a. The reaction was stirred at 100°C for 12 hours. Heating and stirring were then stopped, and the mixture was cooled to room temperature. The reaction solution was washed with 20 ml of water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography using a 3:1 by volume mixture of petroleum ether and ethyl acetate as the eluent to obtain 40.9 mg of 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b) as a white solid product with a yield of 72% and an mp of 147.2-149.1°C. The reaction equation is as follows:

[0104]

[0105] The H-NMR spectrum, C-NMR spectrum and F-NMR spectrum of the derivative prepared in Example 2 are as follows: Figure 3 、 Figure 4 、 Figure 5 shown. 1 H NMR (400MHz, CDCl3) δ7.79(dd,J=9.1,5.3Hz,1H),7.76(s,1H),7.33(d,J=8.7Hz,1H),7.30–7.25(m,1H),4.69(t,J=8.2Hz,2H),3.37(t,J=7.7Hz,2H)ppm; 13 C NMR (100MHz, CDCl3) δ167.2 (d, J = 2.2 Hz), δ 159.0 (d, J = 243.5 Hz), 143.5, δ 131.7 (d, J = 4.6 Hz), 129. 1(d,J=8.8Hz),125.6(d,J=9.5Hz),125.6(d,J=9.5Hz),122.7,110.8(d,J=22.1Hz),69.0,27.6ppm; 19 F NMR (365MHz,CDCl3)δ-118.0ppm; the molecular hydrogen, carbon, and fluorine spectrum peaks can correspond one-to-one with the target product. Combining the above NMR hydrogen spectrum, carbon spectrum, and fluorine spectrum results, it can be seen that the product obtained in Example 2 is 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b).

[0106] In this example, readily available 5-fluorobenzo[c]isoxazole 3b and 3-butyn-1-ol 2a were used as raw materials. In the presence of inexpensive catalysts including copper tetraethylcyanide hexafluorophosphate, 4,7-diphenyl-1,10-phenanthroline, and potassium phosphate, a two-component tandem reaction was performed to synthesize the quinoline fused-ring derivative 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b). The reaction in this example only required stirring at a relatively mild temperature of 100° C. in an inert argon atmosphere for 12 hours, followed by cooling and a series of subsequent treatments to obtain the final target product, 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b), in a very high yield (72%).

[0107] Therefore, the method for preparing quinoline fused ring derivatives in this embodiment is a green, efficient synthesis method. This method uses inexpensive and readily available chemicals as starting materials, undergoes a green, safe, and efficient reaction process, and efficiently synthesizes 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b) under mild reaction conditions. All raw materials in the reaction are inexpensive and readily available, the method is simple and easy to operate, and the operation is safe, thus having potential practical value.

[0108] The product 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline (1b) obtained in this example contains a halogen fluorine atom and can be used for further modification of the product.

[0109] Example 3 Preparation of 6-bromo-2,3-dihydrofuro[2,3-b]quinoline (1c)

[0110] To a reaction flask were added 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate. The mixture was then filled with 1 atm of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-bromobenzisoxazole 3c, and 1.2 mmol of 3-butyn-1-ol 2a. The reaction was stirred at 100°C for 12 hours. Heating and stirring were then stopped, and the mixture was cooled to room temperature. The reaction solution was washed with 20 ml of water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated and purified by column chromatography using a 3:1 by volume mixture of petroleum ether and ethyl acetate as the eluent to obtain 52.3 mg of 6-bromo-2,3-dihydrofuro[2,3-b]quinoline (1c) as a silvery white solid in a 70% yield with an mp of 174.5-176.2°C. The reaction equation is as follows:

[0111]

[0112] The H-NMR spectrum and C-NMR spectrum of the derivative prepared in Example 3 are as follows: Figure 6 、 Figure 7 shown. 1 H NMR (400MHz, CDCl3) δ7.77(d,J=2.0Hz,1H),7.72(s,1H),7.68(d,J=8.9Hz,1H),7.62(s,1H),4.70(t,J=8.2Hz,2H),3.37(t,J=8.2Hz,2H)ppm; 13 C NMR (100 MHz, CDCl3) δ 167.9, 145.6, 132.2, 131.7, 129.1, 129.0, 126.6, 122.8, 117.2, 69.2, 27.6 ppm. The molecular hydrogen and carbon spectral peaks correspond one-to-one with the target product, and the quantity is reasonable. Combined with the results of the above H-NMR and C-NMR spectra analysis, it can be seen that the product obtained in Example 3 is 6-bromo-2,3-dihydrofuro[2,3-b]quinoline (1c).

[0113] In this example, readily available 5-bromobenzisoxazole 3c and 3-butyn-1-ol 2a were used as raw materials. In the presence of inexpensive catalysts (tetraethylcyanocopper hexafluorophosphate, 4,7-diphenyl-1,10-phenanthroline, and potassium phosphate), a two-component tandem reaction was performed to synthesize the quinoline fused-ring derivative 6-bromo-2,3-dihydrofuro[2,3-b]quinoline (1c). The reaction in this example simply required stirring at a relatively mild temperature of 100° C. for 12 hours in an inert argon atmosphere, followed by cooling and a series of subsequent treatments to obtain the final target product, 6-bromo-2,3-dihydrofuro[2,3-b]quinoline (1c), in a very high yield (70%).

[0114] Therefore, the method for preparing quinoline fused ring derivatives in this embodiment is a green and efficient synthesis method. This method uses inexpensive and readily available chemicals as starting materials, undergoes a green, safe, and efficient reaction process, and efficiently synthesizes 6-bromo-2,3-dihydrofuro[2,3-b]quinoline (1c) under mild reaction conditions. All raw materials in the reaction are inexpensive and readily available, the method is simple and easy to operate, and it is safe to operate, thus having potential practical value.

[0115] The product obtained in this embodiment contains bromine atoms, which can be further used for later modification of the product, such as coupling reaction with boric acid containing a large number of conjugated structures, and further developed into material molecules, which has good application prospects.

[0116] Example 4 Preparation of 4-methyl-2,3-dihydrofuro[2,3-b]quinoline (1d)

[0117] To a reaction flask were added 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, followed by the addition of 1 atm of argon. 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 3-methylbenzo[c]isoxazole 3d, and 1.2 mmol of 3-butyn-1-ol 2a were stirred and reacted at 100° C. for 12 hours. Heating and stirring were then stopped, and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated and purified by column chromatography using a 1:1 v / v mixture of petroleum ether and ethyl acetate as the eluent. 4-methyl-2,3-dihydrofuro[2,3-b]quinoline (1d) was obtained as a white solid (34.4 mg, yield 62%), mp 117.2-121.9° C. The reaction equation is as follows:

[0118]

[0119] The H-NMR spectrum and C-NMR spectrum of the derivative prepared in Example 4 are as follows: Figure 8 、 Figure 9 As shown, 1 H NMR (400MHz, CDCl3) δ7.80 (dd, J=12.9, 8.3Hz, 2H), 7.54 (t, J=7.6Hz, 1H), 7.35 (t,J=7.6Hz,1H),4.65(t,J=8.2Hz,2H),3.26(t,J=8.2Hz,2H),2.47(s,3H)ppm; 13 C NMR (100 MHz, CDCl3) δ 166.9, 146.8, 140.6, 128.7, 127.9, 125.2, 123.6, 123.1, 119.8, 68.8, 27.0, 15.2 ppm; the molecular hydrogen and carbon spectrum peaks correspond one-to-one to the target product, and the quantity is reasonable. Combined with the results of the above H-NMR and C-NMR analysis, it can be seen that the product obtained in Example 4 is a white solid 4-methyl-2,3-dihydrofuro[2,3-b]quinoline (1d).

[0120] In this example, readily available 3-methylbenzo[c]isoxazole 3d and 3-butyn-1-ol 2a were used as raw materials. In the presence of inexpensive catalysts (tetraethylcyanocopper hexafluorophosphate, 4,7-diphenyl-1,10-phenanthroline, and potassium phosphate), a two-component tandem reaction was performed to synthesize the quinoline fused-ring derivative 4-methyl-2,3-dihydrofuro[2,3-b]quinoline (1d). The reaction in this example simply required stirring at a relatively mild temperature of 100°C for 12 hours in an inert argon atmosphere, followed by cooling and a series of subsequent treatments to obtain the final target product, 4-methyl-2,3-dihydrofuro[2,3-b]quinoline (1d), in a high yield (62%).

[0121] Therefore, all raw materials in the reaction of the method for preparing quinoline fused ring derivatives in this embodiment are cheap and easily available, the method is simple and easy to perform, the operation is safe, and the yield is good, so it has potential practical value.

[0122] The product 4-methyl-2,3-dihydrofuro[2,3-b]quinoline (1d) obtained in this example contains an alkyl group, further enriching the diversity of the product.

[0123] Example 5 Preparation of 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline (1e)

[0124] 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate were added to a reaction flask, and the mixture was filled with 1 atmosphere of argon. 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-chloro-3-phenylbenzisoxazole 3e, and 1.2 mmol of 3-butyn-1-ol 2a were stirred at 100° C. for 12 hours. Heating and stirring were stopped, and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1. 54.8 mg of 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline (1e) was obtained as an off-white solid product with a yield of 65%. The reaction equation is as follows:

[0125]

[0126] The H-NMR and C-NMR spectra of the derivatives prepared in Example 5 are as follows: Figure 10 、 Figure 11 As shown, 1 H NMR (400MHz, CDCl3) δ7.81-7.74(m,1H),7.52(q,J=6.1,5.5Hz,3H),7.47(d,J=5. 9Hz, 2H), 7.34 (d, J = 6.6Hz, 2H), 4.66 (t, J = 8.2Hz, 2H), 3.19 (t, J = 8.2Hz, 2H) ppm.; 13 C NMR (100 MHz, CDCl3) δ 167.2, 145.8, 144.4, 135.2, 129.5, 129.5, 129.0, 128.9, 128.7, 128.6, 125.3, 124.4, 120.8, 69.2, 27.5 ppm; the molecular hydrogen and carbon spectrum peaks correspond one to one with the target product, and the quantity is reasonable. At the same time, combined with the results of the above H NMR spectrum, C spectrum and mass spectrometry analysis, it can be seen that the product obtained in Example 5 is 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline (1e).

[0127] The preparation method in this embodiment uses readily available 5-chloro-3-phenylbenzisoxazole 3e and 3-butyn-1-ol 2a as raw materials. In the presence of inexpensive catalysts including copper tetraethylcyanide hexafluorophosphate, 4,7-diphenyl-1,10-phenanthroline, and potassium phosphate, a two-component tandem reaction is performed to synthesize the quinoline fused-ring derivative 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline (1e). The reaction in this embodiment requires only stirring at a relatively mild temperature of 100° C. for 12 hours in an inert argon atmosphere, followed by cooling and a series of subsequent treatments to obtain the final target product, 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline (1e), in a high yield (65%).

[0128] Therefore, the method for preparing a quinoline fused ring derivative in this embodiment has readily available raw materials, low cost, safe and simple operation, moderate reaction temperature, short reaction time, and good atom economy. Under mild reaction conditions, the quinoline fused ring derivative 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline (1e) can be efficiently synthesized. All raw materials in this reaction are readily available and inexpensive, the method is simple and easy to perform, and the operation is safe, thus having potential practical value.

[0129] The product 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline (1e) obtained in this example is an analog of 6-chloro-4-(2-chlorophenyl)-2,3-dihydrofuro[2,3-b]quinoline with anti-hepatitis B virus in vitro, enriching the product's potential in medicine.

[0130] Example 6 Preparation of 3,4-dihydropyrano[2,3-b]quinoline (1f)

[0131] 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate were added to a reaction flask, and the mixture was filled with 1 atmosphere of argon gas, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of 4-pentyn-1-ol 2b. After stirring at 100° C. for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum rotary evaporation, and the mixture was separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 3:1. 41.6 mg of a green solid product, 3,4-dihydropyrano[2,3-b]quinoline (1f), was obtained in a yield of 75%. The reaction equation is as follows:

[0132]

[0133] The H-NMR and C-NMR spectra of the derivatives prepared in Example 6 are as follows: Figure 12 、 Figure 13 As shown, 1 HNMR (400MHz, CDCl3) δ7.82(d,J=8.5Hz,1H),7.79(s,1H),7.64(d,J=8.1Hz,1H),7.58–7.53(m,1 H),7.36–7.31(m,1H),4.46–4.43(m,2H),2.99(t,J=6.3Hz,2H),2.07(tt,J=9.1,4.6Hz,2H)ppm; 13 C NMR (100MHz, CDCl3) δ160.0, 146.2, 137.8, 129.1, 127.2, 126.6, 125.4, 124.0, 119.0, 67.7, 25.7, 22.0ppm; molecular hydrogen and carbon spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. At the same time, the applicant of the present invention also performed high-performance liquid chromatography-mass spectrometry analysis on the product obtained in Example 6, and the test results are as follows: HRMS ESI (m / z): calcd. for C 12 H 12 NO[M+H] + 186.09134; found 186.09108. Combining the results of the above H-NMR spectrum, C-NMR spectrum and mass spectrometry analysis, it can be seen that the product obtained in Example 6 is 3,4-dihydropyrano[2,3-b]quinoline (1f).

[0134] The preparation method in this embodiment uses readily available anthranilic anhydride 3a and 4-pentyn-1-ol 2b as raw materials. In the presence of inexpensive catalysts including copper tetraethylcyanide hexafluorophosphate, 4,7-diphenyl-1,10-phenanthroline, and potassium phosphate, a two-component tandem reaction is performed to synthesize the quinoline fused-ring derivative 3,4-dihydropyrano[2,3-b]quinoline (1f). The reaction in this embodiment requires only stirring at a relatively mild temperature of 100° C. for 12 hours in an inert argon atmosphere, followed by cooling and a series of subsequent treatments to obtain the final target product, compound 3,4-dihydropyrano[2,3-b]quinoline (1f), in a very high yield (75%).

[0135] Therefore, the method for preparing the quinoline fused ring derivative in this embodiment is safe and simple to operate, has readily available and inexpensive raw materials, has wide adaptability to substrates, operates at a moderate temperature, has high safety performance, and has a high yield, and can efficiently synthesize the quinoline fused ring derivative 3,4-dihydropyrano[2,3-b]quinoline (1f). All raw materials in the reaction are inexpensive and readily available, the method is simple and easy to operate, and the operation is safe, thus having potential practical value.

[0136] The product 3,4-dihydropyrano[2,3-b]quinoline (1f) obtained in this example can provide a new strategy for the synthesis of 2H-pyrano[2,3-b]quinoline: that is, 3,4-dihydropyrano[2,3-b]quinoline (1f) can be reduced and eliminated to obtain 2H-pyrano[2,3-b]quinoline by adding bromine atoms in NBS and CCl4 solutions and then in NaH and DMF solvents.

[0137] Example 7 Preparation of 5H-isochromo[3,4-b]quinoline (1 g)

[0138] To a reaction flask were added 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, followed by the addition of 1 atm of argon. 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of (2-ethynylphenyl)methanol 2c were stirred at 100° C. for 12 hours. Heating and stirring were then stopped, and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated and purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 as the eluent. 48.2 mg of the pale yellow solid product 5H-isochromatic [3,4-b]quinoline (1 g) was obtained in a yield of 69% with an m.p. of 147.5-149.1° C. The reaction equation is as follows:

[0139]

[0140] The H-NMR and C-NMR spectra of the derivatives prepared in Example 7 are as follows: Figure 14 、 Figure 15 As shown, 1 HNMR(400MHz, CDCl3) δ8.43(s,1H),7.87(dd,J=7.8,5.5Hz,2H),7.79(dd,J=8.1,1.3Hz,1H),7. 64-7.60(m,1H),7.46-7.38(m,2H),7.38-7.32(m,1H),7.19(d,J=0.6Hz,1H),5.43(s,2H)ppm.; 13CNMR (100MHz, CDCl3) δ159.7,146.8,131.7,131.2,130.0,128.9,128.7,127.6,127.6,126.2,125.0,124.8,122.8,117.7,68.9ppm; molecular hydrogen and carbon spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. At the same time, the applicant of the present invention also performed high liquid chromatography mass spectrometry analysis on the product obtained in Example 7, and the test results are as follows HRMS ESI (m / z): calcd.for C 16 H 12 NO[M+H] + 234.09134; found 234.09097. Combining the results of the above H NMR spectrum, C NMR spectrum and mass spectrum analysis, it can be seen that the product prepared in Example 7 is 5H-isochromo[3,4-b]quinoline (1 g).

[0141] The preparation method in this embodiment uses readily available anthranilic anhydride 3a and (2-ethynylphenyl)methanol 2c as raw materials. In the presence of inexpensive catalysts including copper tetraethylcyanide hexafluorophosphate, 4,7-diphenyl-1,10-phenanthroline, and potassium phosphate, a two-component cascade reaction is performed to synthesize the quinoline fused-ring derivative 5H-isochromo[3,4-b]quinoline (1 g). The reaction in this embodiment requires only stirring at a relatively mild temperature of 100° C. for 12 hours in an inert argon atmosphere, followed by cooling and a series of subsequent treatments to obtain the final target product, 5H-isochromo[3,4-b]quinoline (1 g), in a very high yield (69%), achieving good atom economy.

[0142] Therefore, all raw materials in the reaction of the method for preparing quinoline fused ring derivatives in this embodiment are cheap and easily available, the method is simple and easy to perform, the operation is safe, and the yield is good, so it has potential practical value.

[0143] The product 5H-isochromo[3,4-b]quinoline (1 g) obtained in this example enriches the strategy for the one-step synthesis of benzo structures in material molecules.

[0144] Example 8 Preparation of benzofuro[2,3-b]quinoline (1h)

[0145] To a reaction flask were added 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate, followed by 1 atm of argon gas, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of 2-((trimethylsilyl)ethynyl)phenol 2d. The reaction was stirred at 100° C. for 12 hours, then heating and stirring were stopped and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated and purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 as the eluent. 39.4 mg of benzofurano[2,3-b]quinoline (1h) as a white solid was obtained in a yield of 60%. The reaction equation is as follows:

[0146]

[0147] The H-NMR spectrum, C-NMR spectrum and F-NMR spectrum of the derivative prepared in Example 8 are as follows: Figure 16 、 Figure 17 As shown, 1 H NMR (400MHz, CDCl3) δ8.53(s,1H),8.12(d,J=8.5Hz,1H),7.92(dd,J=7.4,4.2Hz,2H),7.7 1(t,J=7.7Hz,1H),7.56(d,J=8.2Hz,1H),7.50(t,J=7.5Hz,2H),7.34(t,J=7.5Hz,1H)ppm; 13 C NMR (100 MHz, CDCl3) δ 162.2, 155.5, 145.7, 129.3, 129.0, 128.7, 128.1, 127.9, 125.7, 124.8, 123.2, 121.9, 121.4, 117.3, 111.7 ppm; Combined with the results of the above H-NMR and C-NMR analyses, it can be seen that the product obtained in Example 8 is benzofurano[2,3-b]quinoline (1h).

[0148] In this example, inexpensive and readily available 2-((trimethylsilyl)ethynyl)phenol 2e (2-ethynylphenol is expensive on the market, reaching over a thousand yuan) and anthranilic anhydride 3a were used as raw materials. In the presence of the inexpensive catalysts of copper tetraethylcyanide hexafluorophosphate and potassium phosphate, a two-component tandem cyclization reaction was performed to synthesize the quinoline fused-ring derivative, benzofuro[2,3-b]quinoline (1h). The reaction in this example requires only stirring at a relatively mild temperature of 100°C for 12 hours in an inert argon atmosphere, followed by cooling and a series of subsequent treatments to obtain the target compound, benzofuro[2,3-b]quinoline (1h), in a high yield (65%).

[0149] The product obtained in this example has a benzofuro[2,3-b]quinoline (1h) structure, which emits blue fluorescence under 365nm ultraviolet flashlight irradiation and has the potential to be used as an organic light-emitting material.

[0150] Example 9 Preparation of 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline (1i)

[0151] 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, and 0.3 mmol of potassium phosphate were added to a reaction flask, and the mixture was filled with 1 atmosphere of argon. 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, and 1.2 mmol of N-(4-chlorobenzyl)but-3-yn-1-amine 2e were added. After stirring at 100° C. for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1. 52.9 mg of 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline (1i) as a light yellow solid was obtained with a yield of 60% and an mp of 1. 117.2-119.6℃, the reaction equation is as follows:

[0152]

[0153] The H-NMR and C-NMR spectra of the derivative prepared in Example 9 are as follows: Figure 18 、 Figure 19 As shown, 1 H NMR (400MHz, CDCl3) δ7.71(d,J=8.3Hz,1H),7.52(d,J=8.0Hz,1H),7.47(d,J=11.4Hz,2H),7.34–7 .27(m,4H),7.19(t,J=7.4Hz,1H),4.72(s,2H),3.45(t,J=7.8Hz,2H),3.05(t,J=7.8Hz,2H)ppm.; 3 C NMR (100MHz, CDCl3) δ161.2,147.7,136.2,132.9,129.7,129.5,128.5,128.3,127.1,125.8,125.7,124.2,121.7,47.9,25.0ppm; molecular hydrogen and carbon spectra can correspond to the target product one by one, and the quantity is reasonable. At the same time, the applicant of the present invention also performed high performance liquid chromatography mass spectrometry analysis on the product obtained in Example 9, and the test results are as follows: HRMS ESI (m / z): calcd.for C18 H 16 ClN2[M+H] + 295.09965; found 295.09930; Based on the above H-NMR, C-NMR and MS analysis results, it can be seen that the product obtained in Example 9 is 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline (1i).

[0154] In this example, inexpensive and readily available N-(4-chlorobenzyl)but-3-yn-1-amine 2e and anthranilic anhydride 3a were used as raw materials. In the presence of inexpensive catalysts, copper tetraethylcyanide hexafluorophosphate and potassium phosphate, a two-component tandem reaction was performed to synthesize the quinoline fused-ring derivative 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline (1i). The reaction in this example simply required stirring at a relatively mild temperature of 100°C for 12 hours in an inert argon atmosphere, followed by cooling and a series of subsequent treatments to obtain the target product, 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline (1i), in a high yield (60%).

[0155] Therefore, the method for preparing quinoline fused-ring derivatives in this embodiment is a green, efficient synthesis method. This method uses inexpensive and readily available chemicals as starting materials, undergoes a green, safe, and efficient reaction process, and efficiently synthesizes quinoline fused-ring derivatives under mild reaction conditions. All raw materials used in this reaction are inexpensive and readily available, and the method is simple, easy to operate, and safe, thus having potential practical value.

[0156] This example can obtain derivatives of molecules compatible with pharmaceutical activity. 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline (1i) can be converted into a 1-(2,3-dihydropyrrolo[2,3-b]quinolin-1-yl)ethane-1-one molecular fragment that is effective against androgen-independent prostate cancer cells in vitro by removing the benzyl group with a chlorine substituent under Pd-C catalyst and hydrogen reduction, and then under acetyl chloride, 4-dimethylaminopyridine, and pyridine conditions, further demonstrating the diversity of the products.

[0157] In summary, the present patent application provides a method for preparing quinoline fused ring derivatives, which comprises the following steps: adding a copper-containing catalyst, a ligand and a base as a promoter to a reaction flask, introducing an inert gas, adding a solvent, and sequentially adding anthranilic anhydride (Formula III), a terminal alkynol or a terminal alkynamine (II), stirring and reacting at a temperature below 100° C. for 8-18 hours. After the reaction is completed, the reaction solution is cooled to room temperature, washed with water, extracted with ethyl acetate to remove the solvent, dried over anhydrous magnesium sulfate, and purified to obtain the series of quinoline fused ring derivatives (I). The reaction is shown in the following formula:

[0158]

[0159] Among them, R 1 R is selected from hydrogen, phenyl, phenyl with halogen as a substituent, etc. 2 It is selected from hydrogen, halogen, methyl, phenyl with halogen, etc. When X=O, n can be 0 or 1; when X=N, n can be 0.

[0160] The preparation principle of quinoline fused ring derivatives in this patent application is that a terminal alkyne with a heteroatom and anthranilic anhydride are aminated via a spC-H bond to obtain an alkynylamine active intermediate; next, the alcohol or amine on the alkyne acts as a nucleophile to attack the alkyne and alkynylamine to initiate an intramolecular tandem cyclization to obtain a quinoline fused ring derivative.

[0161] The preparation method provided in this patent application is safe and simple to operate, uses cheap and readily available raw materials, has wide adaptability to substrates, operates at a moderate temperature, has high safety performance, and has a high yield. This method can be used to construct furanoquinoline, pyranoquinoline, and pyrroloquinoline derivatives in one step, and has good application prospects.

[0162] In the description of this specification, reference to the terms "one embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples" means that the specific features, structures, materials, or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of this patent application. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any appropriate manner in any one or more embodiments or examples.

[0163] Although several embodiments of the present patent application have been shown and described, those skilled in the art will appreciate that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the present patent application, and the scope of the present patent application is defined by the claims and their equivalents.

Claims

1. A method for preparing a quinoline fused-ring derivative, characterized in that: In the reaction flask, the following reaction occurs under certain reaction conditions, and a series of quinoline fused ring derivatives (I) are obtained by purification, as shown in the following reaction formula: ； The reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, 1.2 mmol of 3-butyn-1-ol 2a, at 100 o C. After stirring and reacting for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with 20 ml of water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain a white solid product, 2,3-dihydrofuro[2,3-b]quinoline 1a. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, anthranilic anhydride 3a of Formula III, and the quinoline fused-ring derivative 1a of Formula I are shown below: , and ; Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-fluorobenzo[c]isoxazole 3b, 1.2 mmol of 3-butyn-1-ol 2a, at 100 o C and stirred for 12 hours, then heating and stirring were stopped and the mixture was cooled to room temperature. The reaction solution was washed with 20 ml of water and extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain a white solid product, 6-fluoro-2,3-dihydrofuro[2,3-b]quinoline 1b. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, anthranilic anhydride 3b of Formula III and the quinoline fused ring derivative 1b of Formula I are shown below: , and ; Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-bromobenzisoxazole 3c, 1.2 mmol of 3-butyn-1-ol 2a, at 100 o C. After stirring and reacting for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with 20 ml of water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain a silvery white solid product 6-bromo-2,3-dihydrofuro[2,3-b]quinoline 1c. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, anthranilic anhydride 3c of Formula III, and the quinoline fused ring derivative 1c of Formula I are shown below, respectively: , and ; Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 3-methylbenzo[c]isoxazole 3d, 1.2 mmol of 3-butyn-1-ol 2a, at 100 o C and stirred for 12 hours, then heating and stirring were stopped and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 4-methyl-2,3-dihydrofuro[2,3-b]quinoline 1d as a white solid. The structures of the terminal alkynol or terminal alkynamine 2a of Formula II, anthranilic anhydride 3d of Formula III, and quinoline fused-ring derivative 1d of Formula I are shown below: , and ; Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of 5-chloro-3-phenylbenzisoxazole 3e, 1.2 mmol of 3-butyn-1-ol 2a, at 100 o C. After stirring for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1, to obtain an off-white solid product, 6-chloro-4-phenyl-2,3-dihydrofuro[2,3-b]quinoline 1e. The structural formulas of the terminal alkynol or terminal alkynamine 2a of Formula II, anthranilic anhydride 3e of Formula III, and the quinoline fused-ring derivative 1e of Formula I are shown below, respectively: , and ; Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, 1.2 mmol of 4-pentyn-1-ol 2b, at 100 o After stirring at C for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain a green solid product 3,4-dihydropyrano[2,3-b]quinoline 1f. The structural formulas of the terminal alkynol or terminal alkynamine 2b of Formula II, the anthranilic anhydride 3a of Formula III, and the quinoline fused ring derivative 1f of Formula I are shown below: , and ; Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, 1.2 mmol of (2-ethynylphenyl)methanol 2c, at 100 o After stirring at C for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1, to obtain 1 g of a light yellow solid product, 5H-isochromatico[3,4-b]quinoline. The structural formulas of the terminal alkynol or terminal alkynamine 2c of Formula II, anthranilic anhydride 3a of Formula III, and 1 g of the quinoline fused ring derivative of Formula I are shown below: , and ; Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, 1.2 mmol of 2-((trimethylsilyl)ethynyl)phenol 2d, at 100 o C and stirred for 12 hours, then heating and stirring were stopped and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 to obtain a white solid benzofurano[2,3-b]quinoline 1h. The structures of the terminal alkynol or terminal alkynamine 2d of Formula II, anthranilic anhydride 3a of Formula III, and the quinoline fused-ring derivative 1h of Formula I are shown below: , and ; Alternatively, the reaction conditions are as follows: 0.015 mmol of tetraethylcyanocopper hexafluorophosphate, 0.225 mmol of 4,7-diphenyl-1,10-phenanthroline, 0.3 mmol of potassium phosphate, 1 atmosphere of argon, 1.5 ml of ultra-dry dimethyl sulfoxide, 0.3 mmol of anthranilic anhydride 3a, 1.2 mmol of N-(4-chlorobenzyl)but-3-yn-1-amine 2e, at 100 o After stirring at C for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1, to obtain a light yellow solid 1-(4-chlorobenzyl)-2,3-dihydropyrrolo[2,3-b]quinoline 1i. The structures of the terminal alkynol or terminal alkynamine 2e of Formula II, anthranilic anhydride 3a of Formula III, and the quinoline fused ring derivative 1i of Formula I are shown below, respectively: , and .

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