A preparation method of 2,3-disubstituted quinoline derivatives

Abstract

This patent application relates to a new method for synthesizing 2,3-disubstituted quinoline derivatives: Add a nickel catalyst, a phosphorus ligand, an arylboronic acid (Formula IV), and an inorganic base into a reaction flask, introduce an inert gas, add a solvent, and successively add a terminal alkyne (Formula II) and phthalic anhydride imide (Formula III). Stir and react at a temperature between room temperature and 100 °C for 12-24 hours. After the reaction is completed, cool to room temperature, wash with water, extract with ethyl acetate, dry with anhydrous magnesium sulfate, and remove the solvent by distillation under reduced pressure to obtain a crude product, which is then purified by column chromatography to obtain the series of 2,3-disubstituted arylquinoline derivatives (I). The synthesis method of the 2,3-disubstituted quinoline derivatives provided by this patent is safe and simple to operate, the raw materials are cheap and easily available, the functional group adaptability is good, the substrate adaptability is wide, it is environmentally friendly, and is conducive to industrial production, and is widely used in the synthesis of pesticides, pharmaceuticals and natural products.

Description

Technical Field

[0001] This patent application relates to the technical field of organic compound synthesis, and more specifically, to a method for preparing 2,3-disubstituted quinoline derivatives. Background Art

[0002] Quinoline is an important class of nitrogen-containing heterocycles and is widely used in fine chemicals such as pharmaceuticals, materials, and dyes. Although chemists have developed various methods for synthesizing quinoline, the synthesis of 2,3-disubstituted quinoline has certain limitations. When the substituents at the C2 and C3 positions are different, most common synthesis methods have regioselectivity problems and result in mixtures that are difficult to separate. Therefore, it is of great significance to develop new green synthesis methods for the efficient synthesis of quinoline with asymmetric substituents at the C2 and C3 positions.

[0003] In 2018, Professor Maddi Sridhar Redd reported the addition cyclization reaction of 2-azidophenyl propargyl alcohol with arylboronic acid catalyzed by nickel diacetylacetonate to synthesize 2,3-disubstituted quinoline (Chem. Commun., 2018, 54, 759-762). This reaction first generates an arylnickel species through the transmetalation of a nickel catalyst and arylboronic acid, and then undergoes a regioselective migratory insertion reaction with an alkyne to obtain a key alkenylnickel intermediate. Finally, 2,3-disubstituted quinoline is obtained through an intramolecular C-N coupling and aromatization process. Although this reaction can avoid the regioselectivity problem in the synthesis of 2,3-disubstituted quinoline, the starting materials are relatively complex, requiring multiple steps of synthesis, and the use of azides poses certain safety hazards, which is not conducive to large-scale production.

[0004] In 2020, the research group of Jetze J. Tepe, Ph.D. at Michigan State University reported the tandem cyclization reaction of electron-rich aniline and propylene oxide catalyzed by scandium trifluoromethanesulfonate to synthesize 2,3-disubstituted quinoline (J. Org. Chem. 2020, 85, 6741-6746). Although the raw materials of this reaction are simple and readily available, and the reaction conditions are relatively mild, the scope of application of this method has obvious limitations and cannot be compatible with anilines substituted with electron-withdrawing groups. In addition, the scandium catalyst is expensive (scandium(III) trifluoromethanesulfonate, which costs 740.15 yuan per gram (Merck Drug Network)). Therefore, the practicality of this method is greatly affected.

[0005] In 2021, Professor Huang Huawen of Xiangtan University used ketoxime acetate and o-fluorobenzaldehyde as raw materials, under the action of copper catalyst, sodium sulfite as reducing agent, and a two-component tandem reaction occurred to produce 2,3-diphenylquinoline derivatives (Organic Letters. 2021, 23, (3), 936-942). The reaction firstly obtains imino copper through the reaction of copper salt and oxime ester, and obtains enamine intermediate through tautomerism, and then condenses with aromatic aldehyde and undergoes intramolecular nucleophilic substitution to obtain the target product. However, the substrate of this reaction is relatively special and its application range is limited; and the reaction temperature requires 130°C, and the reaction conditions are relatively harsh, which is not conducive to industrial production.

[0006] In summary, the existing methods for synthesizing 2,3-disubstituted quinolines all have certain limitations; therefore, it is necessary to develop new green and efficient synthesis methods to synthesize 2,3-disubstituted quinoline products with high regioselectivity using cheap and readily available starting materials under mild reaction conditions.

[0007] Patent application content

[0008] In order to overcome at least one problem of the prior art, the present patent application provides a method for preparing 2,3-disubstituted quinoline derivatives. The raw materials required for the method are readily available, cheap, safe and simple to operate, the reaction temperature and time are moderate, and the yield is good.

[0009] In order to solve the above technical problems, the technical solution adopted by this patent application is:

[0010] A method for preparing a 2,3-disubstituted quinoline derivative: a nickel-containing catalyst, a monodentate phosphine ligand, and an aryl boronic acid (Formula IV) are added to a reaction flask, an inert gas is introduced, and a solvent, a terminal alkyne (Formula II), and anthracene anhydride (Formula III) are added in sequence, and the mixture is stirred for reaction for 12 hours. After the reaction is completed, the mixture is cooled to room temperature, extracted with ethyl acetate, and then dried with anhydrous magnesium sulfate. The solvent is removed under reduced pressure to obtain a crude product, and finally purified by column chromatography to obtain the 2,3-disubstituted quinoline compound (Formula I). The reaction is shown in the following formula:

[0011]

[0012] Wherein, R is an aryl, a heteroaryl and an alkyl group, wherein the aryl group is a phenyl group and a phenyl group with a halogen substitution, an ester group, an acyl group or a nitrile functional group; the heteroaryl group is furan, thiophene, pyridine, etc.; the alkyl group is a C1-C10 straight-chain alkyl group, a cyclopropyl group and an alkyl group with N, O heteroatoms, etc.; R 1 is selected from halogen, methyl, methoxy, ester group, etc.; R 2 Select ester, methoxy, fluorine, chlorine, bromine, etc.

[0013] Compared with the prior art, the beneficial effects of this patent application are as follows:

[0014] The method for preparing 2,3-disubstituted quinoline derivatives provided by this patent application is safe and simple to operate, with easily available raw materials, good adaptability to functional groups, wide adaptability to substrates, environmental friendliness, moderate reaction temperature, relatively short reaction time, and high yield. Through this synthetic method, a variety of bioactive molecules can be efficiently constructed, and the obtained products are relatively specific, having good industrial application prospects. Description of the Drawings

[0015] Figure 1 1H NMR spectrum of 2,3-diphenylquinoline (1a) prepared in Example 1 of this patent application;

[0016] Figure 2 13C NMR spectrum of 2,3-diphenylquinoline (1a) prepared in Example 1 of this patent application;

[0017] Figure 3 1H NMR spectrum of 3-(4-methoxyphenyl)-quinolin-2-ylphenyl (1b) prepared in Example 2 of this patent application;

[0018] Figure 4 13C NMR spectrum of 3-(4-methoxyphenyl)-quinolin-2-ylphenyl (1b) prepared in Example 2 of this patent application;

[0019] Figure 5 1H NMR spectrum of 3-(4-esterylphenyl)-quinolin-2-ylphenyl (1c) prepared in Example 3 of this patent application;

[0020] Figure 6 13C NMR spectrum of 3-(4-esterylphenyl)-quinolin-2-ylphenyl (1c) prepared in Example 3 of this patent application;

[0021] Figure 7 1H NMR spectrum of 3-(4-chlorophenyl)-quinolin-2-ylphenyl (1d) prepared in Example 4 of this patent application;

[0022] Figure 8 13C NMR spectrum of 3-(4-chlorophenyl)-quinolin-2-ylphenyl (1d) prepared in Example 4 of this patent application;

[0023] Figure 9 1H NMR spectrum of 3-(4-methylphenyl)quinolin-2-ylphenyl (1e) prepared in Example 5 of this patent application;

[0024] Figure 10 13C NMR spectrum of 3-(4-methylphenyl)quinolin-2-ylphenyl (1e) prepared in Example 5 of this patent application;

[0025] Figure 11 1H NMR spectrum of 3-(4-bromophenyl)quinoline-2-phenyl (1f) prepared in Example 6 of this patent application;

[0026] Figure 12 13C NMR spectrum of 3-(4-bromophenyl)quinoline-2-phenyl (1f) prepared in Example 6 of this patent application;

[0027] Figure 13 1H NMR spectrum of 3-(4-thienylphenyl)quinoline-2-phenyl (1g) prepared in Example 7 of this patent application;

[0028] Figure 14 13C NMR spectrum of 3-(4-thienylphenyl)quinoline-2-phenyl (1g) prepared in Example 7 of this patent application;

[0029] Figure 15 1H NMR spectrum of 7-chloro-3-phenylquinoline-2-phenyl (1h) prepared in Example 8 of this patent application;

[0030] Figure 16 13C NMR spectrum of 7-chloro-3-phenylquinoline-2-phenyl (1h) prepared in Example 8 of this patent application;

[0031] Figure 17 1H NMR spectrum of 2-ethyl alcohol-quinoline-3-phenyl (1i) prepared in Example 9 of this patent application;

[0032] Figure 18 13C NMR spectrum of 2-ethyl alcohol-quinoline-3-phenyl (1i) prepared in Example 9 of this patent application;

[0033] Figure 19 1H NMR spectrum of 2-nonyl-3-phenylquinoline (1j) prepared in Example 10 of this patent application;

[0034] Figure 20 13C NMR spectrum of 2-nonyl-3-phenylquinoline (1j) prepared in Example 10 of this patent application. Detailed implementation manners

[0035] The following will describe the implementation plans of this patent application in detail in combination with examples. However, those skilled in the art will understand that the following examples are only used to illustrate this patent application and should not be regarded as limiting the scope of this patent application. For those not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0036] It should be noted that:

[0037] 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.

[0038] In this patent application, unless otherwise stated, each reaction or operation step can be carried out sequentially or in a sequential manner. Preferably, the reaction methods herein are carried out sequentially.

[0039] Unless otherwise specified, the professional and scientific terms used herein have the same meaning as those familiar to persons skilled in the art. In addition, any method or material similar or equivalent to the described content can also be applied to this patent application.

[0040] A method for preparing a 2,3-disubstituted quinoline derivative: In a reaction flask, a nickel catalyst, a monodentate phosphine ligand, and an arylboronic acid (Formula IV) are added. After introducing an inert gas, a solvent, a terminal alkyne (Formula II), and phthalic anhydride (Formula III) are added in sequence, and the mixture is stirred and reacted. After the reaction is completed, it is cooled to room temperature, the reaction solution is washed with water, then extracted with ethyl acetate, immediately dried with anhydrous magnesium sulfate, and then the solvent is removed under reduced pressure to obtain a crude product, and finally the 2,3-disubstituted quinoline compound (Formula I) is purified by column chromatography. The reaction is shown in the following formula:

[0041]

[0042] Wherein, R is an aryl group, a heteroaryl group, or an alkyl group. The aryl group is a phenyl group and a phenyl group with halogen substitution, an ester group, an acyl group, or a nitrile functional group; the heteroaryl group is furan, thiophene, pyridine, etc.; the alkyl group is a straight-chain alkyl group with 1 to 10 carbon atoms, a cyclopropyl group, and an alkyl group with N or O heteroatoms, etc.; R 1 is selected from halogen, methyl, methoxy, ester group, etc.; R 2 is selected from an ester group, methoxy, fluorine, chlorine, bromine, etc.

[0043] The principle of this patent application is to use arylboronic acid, phthalic anhydride, and terminal alkyne as starting materials, and under the action of a metal nickel catalyst and a ligand, a three-component tandem cyclization reaction occurs to synthesize 2,3-disubstituted quinoline.

[0044] The principle of the preparation method of this patent application is to use arylboronic acid, phthalic anhydride, and terminal alkyne as starting materials, and under the action of a metal nickel catalyst and a ligand, a three-component tandem cyclization reaction occurs to synthesize 2,3-disubstituted quinoline. First, a divalent nickel catalyst (such as nickel acetylacetonate Ni(acac)2) generates an intermediate V-1 under the action of the ligand triphenylphosphine and the base cesium carbonate, and then it undergoes transmetalation with arylboronic acid (Formula IV) to generate an aryl nickel species V-2; next, the terminal alkyne (Formula II) inserts into this aryl nickel species V-2 to generate a key alkenyl nickel intermediate V-3, and this intermediate V-3 further undergoes an intermolecular C-N coupling with phthalic anhydride (Formula III), followed by reductive elimination and migratory insertion to provide the key intermediate V-4. The generated intermediate V-4 is rapidly protonated under the action of cesium carbonate and water to generate intermediate V-5, and the nickel catalyst is regenerated for the next cycle. Finally, intermediate V-5 undergoes an intramolecular condensation to generate the target product 2,3-disubstituted quinoline (Formula I). This three-component tandem cyclization reaction can have a specific regioselectivity, better reaction substrate applicability, and the target product with more functional groups can be obtained through the coupling of three molecules; it has the advantages of cheap and easily available raw materials, simple and easy operation, and safe operation. Therefore, it has high industrial application value.

[0045] In the preparation method of this patent application, the possible reaction mechanism process is as follows:

[0046]

[0047] In some embodiments, the nickel-containing catalyst is selected from one or more of nickel acetylacetonate, nickel bromide, nickel iodide, nickel acetate, and nickel trifluoromethanesulfonate. The nickel-containing catalyst in this patent application is much lower in price compared to the expensive transition metal catalysts, such as palladium catalysts, used in the prior art.

[0048] In some more preferred embodiments, the nickel-containing catalyst is nickel acetylacetonate, and the molar ratio of phthalic anhydride to nickel acetylacetonate is 1:0.1. By screening phthalic anhydride with different molar amounts of the catalyst, when the molar ratio of phthalic anhydride to nickel acetylacetonate is 1:0.1, the catalytic cycle effect is the best and the catalyst dosage is relatively small, achieving the best reaction effect.

[0049] In some preferred embodiments, the monodentate phosphine ligand is one or a combination of tricyclohexylphosphine, triphenylphosphine, tris(4-methoxyphenyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, and tris(2-methylphenyl)phosphine.

[0050] In some more preferred embodiments, the monodentate nitrogen ligand is triphenylphosphine, and the molar ratio of phthalic anhydride to triphenylphosphine is 1:0.1. With such a setting, the consumption of the reaction raw materials can be maximized, and thus the yield is the highest.

[0051] In some embodiments, an alkali is further added, and the alkali is selected from one or more of triethylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, and potassium acetate.

[0052] In some embodiments, the solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylaniline, N,N-dimethylpropyleneurea, acetonitrile, N-methylpyrrolidone, tetrahydrofuran, triethylamine, methanol, toluene, and cyclohexane.

[0053] In some more preferred embodiments, the solvent is toluene, and 1 mL of the solvent needs to be added to 0.1 mmol of the phthalic anhydride.

[0054] In some more preferred embodiments, the molar ratio of phthalic anhydride: the terminal alkyne: the arylboronic acid is 1:1.5:1.2. Such a setting can enable the reaction system to basically participate in the reaction of phthalic anhydride and achieve the best effect during the reaction. This ratio is the minimum value for the optimal consumption of the three raw materials in total.

[0055] In some embodiments, the inert gas is selected from argon, nitrogen, and carbon dioxide.

[0056] In some embodiments, the reaction temperature is 60 - 100 °C.

[0057] In some embodiments, the reaction time is 12 - 24 hours.

[0058] In some embodiments, after the reaction, the product is separated and purified by column chromatography, and the eluent for column chromatography is a mixed solvent of petroleum ether and ethyl acetate.

[0059] Next, the preparation method of the 2,3-disubstituted quinoline derivative of this patent application will be described in detail with specific examples.

[0060] In the following examples, various raw materials are readily available and inexpensive. For example, phenylboronic acid (5 g, 22 yuan, Bidepharm), cesium carbonate (25 g, 30.8 yuan, Bidepharm), triphenylphosphine (100 g, 139 yuan, Bidepharm), toluene (500 mL, 25 yuan, Titan Chemical), phthalic anhydride (1 g, 88 yuan, Bidepharm) is synthesized from o-nitrobenzaldehyde (100 g, 46 yuan, Bidepharm) with a yield of 80% (synthesizing 1 g saves about 40 yuan in cost), and phenylacetylene (25 mL, 523.66 yuan, Merck).

[0061] Example 1 Preparation of 2,3-diphenylquinoline (1a)

[0062]

[0063] 0.03 mmol of nickel diacetylacetonate and 0.06 mmol of cesium carbonate were added to a reaction flask, followed by 0.36 mmol of phenylboronic acid 4a. Argon was charged at 0.5 Mpa, along with 3 mL of ultradry toluene, 0.3 mmol of anthranilic anhydride 3a, and 0.45 mmol of phenylacetylene 2a. After stirring the reaction at 80 °C for 12 hours, heating and stirring were stopped, and the reaction mixture was cooled to room temperature. 3 mL of water was added to the reaction solution, and it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. Then, it was separated and purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 15:1. A pale yellow solid, 2,3-diphenylquinoline (1a), 78.4 mg was obtained with a yield of 93%.

[0064] The 1H NMR and 13C NMR spectra of the compound prepared in Example 1 are shown respectively as Figure 1 and Figure 2 shown. From Figure 1 it can be seen that: 1 H NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 8.6, 1.1 Hz, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.84 (dd, J = 8.3, 1.5 Hz, 1H), 7.71 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.54 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.29 - 7.25 (m, 6H), 7.24 - 7.21 (m, 2H) ppm. The peaks in the 1H NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. From Figure 2 it can be seen 13 C NMR (100 MHz, CDCl3) δ 158.4, 147.3, 140.4, 139.9, 137.5, 134.5, 130.0, 129.7, 129.6, 129.4, 128.2, 127.9 (d, J = 7.7 Hz), 127.4, 127.2 (d, J = 5.2 Hz), 126.7 ppm. The peaks in the 13C NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. Combining the above analysis results of the 1H NMR and 13C NMR spectra, the product obtained in Example 1 is 2,3-diphenylquinoline (1a).

[0065] In this example, using readily available and inexpensive phenylboronic acid 4a, phthalic anhydride 3a and phenylacetylene 2a as raw materials, under the action of inexpensive catalyst nickel(II) acetylacetonate and ligand triphenylphosphine, a three-component tandem reaction occurs to synthesize 2,3-diphenylquinoline (1a). The reaction in this example only needs to be stirred for 12 hours at a relatively mild temperature of 80 °C in an inert gas argon atmosphere, then cooled, and then subjected to a series of subsequent treatments to obtain the final target product 2,3-diphenylquinoline (1a) in a relatively high yield (93%).

[0066] Therefore, the method for preparing 2,3-disubstituted quinoline derivatives in this example is a green and efficient synthesis method. This method uses readily available and inexpensive chemicals as starting materials, undergoes a green, safe and efficient reaction process, and efficiently synthesizes 2,3-diphenylquinoline (1a) under mild reaction conditions. All raw materials in this reaction are inexpensive and readily available, the synthesis method is simple and easy to operate, and the operation is safe.

[0067] Example 2 Preparation of 3-(4-methoxyphenyl)-quinolin-2-ylphenyl (1b)

[0068]

[0069] Add 0.03 mmol of nickel(II) acetylacetonate and 0.06 mmol of cesium carbonate to the reaction flask, then add 0.36 mmol of 4-methoxyphenylboronic acid 4b, charge 0.5 Mpa of argon, 3 mL of toluene, 0.3 mmol of phthalic anhydride 3a, 0.45 mmol of phenylacetylene 2a, stir and react at 80 °C for 12 hours, then stop heating and stirring, cool to room temperature, add 3 mL of water to the reaction solution, extract with ethyl acetate, dry with anhydrous magnesium sulfate, remove the solvent by rotary evaporation under reduced pressure, and then separate and purify by column chromatography. The eluent used for column chromatography is a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 15:1. 74.65 mg of pale yellow solid 3-(4-methoxyphenyl)-quinolin-2-ylphenyl (1b) can be obtained, with a yield of 90%.

[0070] The 1H NMR spectrum and 13C NMR spectrum of the compound prepared in Example 2 are respectively as Figure 3 and Figure 4 shown. From Figure 3 it can be seen that: 11H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 8.5, 1.0 Hz, 1H), 8.14 (d, J = 0.8 Hz, 1H), 7.86 (dd, J = 8.1, 1.4 Hz, 1H), 7.72 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.55 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.30 (tt, J = 3.7, 2.4 Hz, 3H), 7.18 - 7.14 (m, 2H), 6.85 - 6.81 (m, 2H), 3.81 (s, 3H) ppm. The peaks in the 1H NMR spectrum can correspond one by one to the target product, and the quantity is reasonable. From Figure 4 it can be seen that: 13 13C NMR (100 MHz, CDCl3) δ 158.9, 158.5, 147.1, 140.6, 137.2, 134.2, 132.3, 130.8, 130.0, 129.4, 127.9 (d, J = 3.6 Hz), 127.4, 127.3, 126.7, 113.7, 55.2 ppm. The peaks in the 13C NMR spectrum can correspond one by one to the target product, and the quantity is reasonable. It can be obtained that the product prepared in Example 2 is 3-(4-methoxyphenyl)-quinolin-2-ylbenzene (1b).

[0071] In this example, using the cheap and easily available p-methoxyphenylboronic acid 4b, phthalic anhydride 3a and phenylacetylene 2a as raw materials, under the action of the inexpensive catalyst nickel acetylacetonate and the ligand triphenylphosphine, a three-component tandem reaction occurs to synthesize the compound 3-(4-methoxyphenyl)-quinolin-2-ylbenzene (1b). The reaction in this example only needs to be stirred for 12 hours at a relatively mild temperature of 80 °C in an inert gas argon atmosphere, then cooled to room temperature, and then a series of subsequent treatments are carried out to obtain the final target product 3-(4-methoxyphenyl)-quinolin-2-ylbenzene (1b) with a very high yield (90%).

[0072] Therefore, the preparation method of 2,3-disubstituted quinoline derivatives in this example is a green and efficient synthesis method. This method uses cheap and easily available chemicals as the initial raw materials, and through a green, safe and efficient reaction process, under mild reaction conditions, efficiently synthesizes the compound 3-(4-methoxyphenyl)-quinolin-2-ylbenzene (1b).

[0073] The 3-(4-methoxyphenyl)-quinolin-2-ylbenzene (1b) obtained in this example can undergo hydrolysis reaction due to the presence of an ester group, increasing the reaction types of the product and expanding the application range.

[0074] Example 3 Preparation of 3-(4-esterylphenyl)-quinolin-2-ylbenzene (1c)

[0075]

[0076] 0.03 mmol of nickel diacetylacetonate and 0.06 mmol of cesium carbonate were added to a reaction flask, followed by 0.36 mmol of 4-carbomethoxyphenylboronic acid 4c. Argon was charged at 0.5 Mpa, along with 3 mL of toluene, 0.3 mmol of phthalic anhydride 3a, and 0.45 mmol of phenylacetylene 2a. After stirring the reaction at 80 °C for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. 3 mL of water was added to the reaction solution, and it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. Then, it was separated and purified by column chromatography. The eluent for column chromatography used was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 15:1, and 86.45 mg of the target product 3-(4-carbomethoxyphenyl)-2-phenylquinoline (1c) was obtained with a yield of 85%.

[0077] The 1H NMR spectrum and 13C NMR spectrum of the compound prepared in Example 3 are shown respectively as Figure 5 and Figure 6 shown. It can be seen from Figure 5 that: 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.6 Hz, 1H), 8.20 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.1 Hz, 1H), 7.76 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.43 (dd, J = 7.5, 2.0 Hz, 2H), 7.30 (dd, J = 18.2, 7.7 Hz, 5H), 3.92 (s, 3H) ppm. The peaks in the 1H NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. It can be seen from Figure 6 that: 13 13C NMR (100 MHz, CDCl3) δ 166.9, 158.1, 147.5, 144.8, 140.0, 137.8, 133.5, 132.2, 130.1, 130.0, 129.8, 129.6, 129.4, 128.9, 128.3, 128.1, 127.6, 127.0 (d, J = 2.9 Hz), 117.4, 52.2 ppm. The peaks in the 13C NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. The product obtained in Example 3 is 3-(4-carbomethoxyphenyl)-2-phenylquinoline (1c).

[0078] In this example, using readily available and inexpensive 4-(4-esterphenyl)benzeneboronic acid 4c, phthalic anhydride 3a, and phenylacetylene 2a as raw materials, under the action of inexpensive catalyst nickel(II) acetylacetonate and ligand triphenylphosphine, a three-component tandem reaction occurs to synthesize compound 3-(4-esterphenyl)quinolin-2-yl)phenyl (1c). The reaction in this example only requires stirring for 12 hours at a relatively mild temperature of 80 °C in an inert gas argon atmosphere, then cooling, and then performing a series of subsequent treatments to obtain the final target product 3-(4-esterphenyl)quinolin-2-yl)phenyl (1c) with a high yield (85%).

[0079] Therefore, the method for preparing 2,3-disubstituted quinoline derivatives in this example is a green and efficient synthesis method. This method uses readily available and inexpensive chemicals as starting materials, undergoes a green, safe, and efficient reaction process, and efficiently synthesizes compound 3-(4-esterphenyl)quinolin-2-yl)phenyl (1c) under mild reaction conditions. All raw materials in this reaction are readily available and inexpensive, the method is simple and easy to implement, and the operation is safe.

[0080] In 3-(4-esterphenyl)quinolin-2-yl)phenyl (1c) obtained in this example, due to the presence of an ester group, it can undergo hydrolysis reaction, increasing the reaction types of the product and expanding the application range.

[0081] Example 4 Preparation of 3-(4-chlorophenyl)quinolin-2-yl)phenyl (1d)

[0082]

[0083] Add 0.03 mmol of nickel(II) acetylacetonate and 0.06 mmol of cesium carbonate to a reaction flask, then add 0.36 mmol of 4-(4-chlorophenyl)benzeneboronic acid 4d, fill with 0.5 Mpa of argon, 3 mL of toluene, 0.3 mmol of phthalic anhydride 3a, and 0.45 mmol of phenylacetylene 2a. Stir the reaction at 80 °C for 12 hours, then stop heating and stirring, cool to room temperature, add 3 mL of water to the reaction solution, extract with ethyl acetate, dry with anhydrous magnesium sulfate, remove the solvent by rotary evaporation under reduced pressure, and then separate and purify by column chromatography. The eluent used for column chromatography is a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 15:1, and 80.03 mg of pale yellow solid 3-(4-chlorophenyl)quinolin-2-yl)phenyl (1d) can be obtained with a yield of 83%.

[0084] The 1H NMR spectrum and 13C NMR spectrum of the compound prepared in Example 4 are respectively as Figure 7 and Figure 8 shown. As can be seen from Figure 7 : 11H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.5 Hz, 1H), 8.11 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.72 (t, 1H), 7.54 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.43 (t, J = 6.6, 3.0 Hz, 2H), 7.31 - 7.22 (m, 5H), 7.15 (d, J = 8.5 Hz, 2H) ppm. The peaks in the 1H NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. From Figure 8 it can be seen that: 13 13C NMR (100 MHz, CDCl3) δ 158.1, 147.3, 140.1, 138.4, 137.5, 133.3, 133.2, 130.9, 129.9 (d, J = 13.2 Hz), 129.4, 128.4, 128.1 (d, J = 7.8 Hz), 127.4, 127.0, 126.8 ppm. The peaks in the 13C NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. From the above evidence, the product prepared in Example 2 is 3-(4-chlorophenyl)-quinoline-2-phenyl (1d).

[0085] In this example, using cheap and readily available 4-chlorophenylboronic acid 4d, phthalic anhydride 3a and phenylacetylene 2a as raw materials, under the action of the inexpensive catalyst nickel acetylacetonate and the ligand triphenylphosphine, a three-component tandem reaction occurs to synthesize the compound 3-(4-chlorophenyl)quinoline-2-phenyl (1d). The reaction in this example only needs to be stirred for 12 hours at a relatively mild temperature of 80 °C in an inert gas argon atmosphere, then cooled to room temperature, and then a series of subsequent treatments are carried out to obtain the final target product 3-(4-chlorophenyl)-quinoline-2-phenyl (1d) with a very high yield (83%).

[0086] Therefore, the preparation method of 2,3-disubstituted quinoline derivatives in this example is a green and efficient synthesis method. This method uses cheap and readily available chemicals as the initial raw materials, undergoes a green, safe and efficient reaction process, and efficiently synthesizes the compound 3-(4-chlorophenyl)-quinoline-2-phenyl (1d) under mild reaction conditions. All raw materials in this reaction are cheap and readily available, the method is simple and easy to operate, and the operation is safe.

[0087] The 3-(4-chlorophenyl)-quinoline-2-phenyl (1d) obtained in this example enriches the types of substrates and expands the application scope.

[0088] Example 5 Preparation of 3-(4-methylphenyl)-quinoline-2-phenyl (1e)

[0089]

[0090] 0.03 mmol of nickel diacetylacetonate and 0.06 mmol of cesium carbonate were added to a reaction flask, followed by 0.36 mmol of phenylboronic acid 4a, 0.5 Mpa of argon was charged, 3 mL of toluene, 0.3 mmol of phthalic anhydride 3a, and 0.45 mmol of p-methylphenylacetylene 2e. After stirring at 80 °C for 14 h, heating and stirring were stopped, and the reaction mixture was cooled to room temperature. 3 mL of water was added to the reaction solution, and it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and then purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, and the target product, pale yellowish green solid 3-(4-methylphenyl)-quinoline-2-phenyl (1e), 72.45 mg, with a yield of 83% was obtained.

[0091] The 1H NMR spectrum and 13C NMR spectrum of the compound prepared in Example 5 are shown respectively as Figure 9 and Figure 10 shown. From Figure 9 it can be seen that: 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H), 7.79 (dd, J = 8.1, 1.4 Hz, 1H), 7.67 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.49 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.24 (qd, J = 7.8, 6.5, 3.0 Hz, 5H), 7.04 (d, J = 7.9 Hz, 2H), 2.29 (s, 3H). ppm, and the peaks in the 1H spectrum can correspond to the target product one by one, and the quantity is reasonable. From Figure 8 it can be seen 13 C NMR (100 MHz, CDCl3) δ 159.5, 147.0, 140.3, 139.3, 136.8, 135.8, 135.3, 130.2, 130.1, 129.6, 129.5, 129.4, 128.1, 128.0, 127.6, 127.4, 127.2, 126.8, 125.5, 19.8 ppm. The peaks in the 13C spectrum of the molecular spectrum can correspond to the target product one by one, and the quantity is reasonable. The product obtained in Example 5 is 3-(4-methylphenyl)-quinoline-2-phenyl (1e).

[0092] In this example, using inexpensive and readily available phenylboronic acid 4a, phthalic anhydride 3a, and p-methylphenylacetylene 2e as raw materials, under the action of inexpensive catalyst nickel(II) acetylacetonate and ligand triphenylphosphine, a three-component tandem reaction occurs to synthesize compound 3-(4-methylphenyl)-quinolin-2-ylphenyl (1e). The reaction in this example only requires stirring for 12 hours at a relatively mild temperature of 80 °C in an inert gas argon atmosphere, then cooling, and then performing a series of subsequent treatments to obtain the final target product 3-(4-methylphenyl)-quinolin-2-ylphenyl (1e) with a very high yield (83%).

[0093] Therefore, the preparation method of 2,3-diquinoline derivatives in this example is a green and efficient synthesis method. This method uses inexpensive and readily available chemicals as the initial raw materials, undergoes a green, safe, and efficient reaction process, and efficiently synthesizes compound 3-(4-methylphenyl)-quinolin-2-ylphenyl (1e) under mild reaction conditions. All raw materials in this reaction are inexpensive and readily available, the method is simple and easy to implement, and the operation is safe.

[0094] The 3-(4-methylphenyl)-quinolin-2-ylphenyl (1e) obtained in this example has biological activity and is a good reaction precursor.

[0095] Example 6 Preparation of 3-(4-bromophenyl)-quinolin-2-ylphenyl (1f)

[0096]

[0097] Add 0.03 mmol of nickel(II) acetylacetonate and 0.06 mmol of cesium carbonate to the reaction flask, add 0.36 mmol of p-bromophenylboronic acid 4f, charge 0.5 Mpa of argon, 3 mL of toluene, 0.3 mmol of phthalic anhydride 3a, and 0.45 mmol of phenylacetylene 2a. After stirring and reacting at 80 °C for 12 hours, stop heating and stirring, cool to room temperature, add 3 mL of water to the reaction solution, extract with ethyl acetate, dry with anhydrous magnesium sulfate, remove the solvent by rotary evaporation under reduced pressure, and then separate and purify by column chromatography. The eluent used for column chromatography is a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 15:1, and a pale yellow solid 3-(4-bromophenyl)-quinolin-2-ylphenyl (1f), 84.2 mg, with a yield of 78% can be obtained.

[0098] The 1H NMR spectrum and 13C NMR spectrum of the compound prepared in Example 6 are respectively as Figure 11 and Figure 12 shown. It can be seen from Figure 11 that 11H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 8.6, 1.2 Hz, 1H), 8.14 (s, 1H), 7.87 (dd, J = 8.1, 1.4 Hz, 1H), 7.75 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.57 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.47 - 7.39 (m, 4H), 7.31 (dd, J = 5.0, 1.9 Hz, 3H), 7.14 - 7.10 (m, 2H) ppm. The peaks of the 1H NMR spectrum can correspond one by one to the target product, and the quantity is reasonable. It can be seen from Figure 12 it can be seen that: 13 13C NMR (100 MHz, CDCl3) δ 158.0, 147.3, 140.0, 138.9, 137.5, 133.2, 131.4, 131.3, 129.9 (d, J = 9.5 Hz), 129.4, 128.1 (d, J = 8.6 Hz), 127.4, 127.1, 126.9, 121.6 ppm. The peaks of the 13C NMR spectrum of the molecular spectrum can correspond one by one to the target product, and the quantity is reasonable. The product obtained in Example 5 is 3-(4-bromophenyl)-quinoline-2-phenyl (1f).

[0099] In this example, using the cheap and easily available 4-bromophenylboronic acid 4f, phthalic anhydride 3a and phenylacetylene 2a as raw materials, under the action of the inexpensive catalyst nickel(II) acetylacetonate and the ligand triphenylphosphine, a three-component tandem reaction occurs to synthesize the compound 3-(4-bromophenyl)quinoline-2-phenyl (1f). The reaction in this example only needs to be stirred at a relatively mild temperature of 80 °C for 12 hours in an inert gas argon atmosphere, then cooled, and then a series of subsequent treatments are carried out to obtain the final target product 3-(4-bromophenyl)-quinoline-2-phenyl (1f) with a relatively high yield (78%).

[0100] Therefore, the preparation method of 2,3-disubstituted quinoline derivatives in this example is a green and efficient synthesis method. This method uses cheap and easily available chemicals as the initial raw materials, and through a green, safe and efficient reaction process, under mild reaction conditions, efficiently synthesizes the compound 3-(4-bromophenyl)-quinoline-2-phenyl (1f). All raw materials in this reaction are cheap and easily available, the method is simple and easy to operate, and the operation is safe.

[0101] The 3-(4-bromophenyl)-quinoline-2-phenyl (1f) obtained in this example contains halogen atoms, further expanding the types of products.

[0102] Example 7 Preparation of 3-(4-thienylphenyl)-quinoline-2-phenyl (1g)

[0103]

[0104] 0.03 mmol of nickel diacetylacetonate and 0.06 mmol of cesium carbonate were added to a reaction flask, followed by 0.36 mmol of 3-thienylphenylboronic acid (4 g), 0.5 Mpa of argon was charged, 3 mL of toluene, 0.3 mmol of phthalic anhydride (3a), and 0.45 mmol of phenylacetylene (2a). After stirring at 80 °C for 12 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. 3 mL of water was added to the reaction solution, and it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography. The target product was obtained. The eluent used for column chromatography was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 15:1, and a yellowish-brown solid 3-(4-thienylphenyl)-quinolin-2-ylphenyl (1g), 73.2 mg, with a yield of 85% was obtained.

[0105] The 1H NMR spectrum and 13C NMR spectrum of the compound prepared in Example 7 are respectively as Figure 13 、 Figure 14 shown. It can be seen from Figure 13 that: 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 1H), 8.24 (s, 1H), 7.85 (dd, J = 8.2, 1.4 Hz, 1H), 7.73 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.56 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.35 (dd, J = 5.2, 1.9 Hz, 3H), 7.21 (dd, J = 4.9, 2.9 Hz, 1H), 7.16 (dd, J = 3.0, 1.3 Hz, 1H), 6.81 (dd, J = 4.9, 1.3 Hz, 1H) ppm. The peaks in the 1H NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. It can be seen from Figure 14 that: 13 C NMR (100 MHz, CDCl3) δ 158.3, 146.8, 140.1, 137.3, 129.9, 129.7, 129.5, 129.2, 128.9, 128.4, 128.1, 127.4, 127.3, 127.0, 125.4, 123.8 ppm. The peaks in the 13C NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. The product obtained in Example 7 is 3-(4-thienylphenyl)-quinolin-2-ylphenyl (1g).

[0106] In this example, 4 g of inexpensive and readily available 3-thiopheneboronic acid, phthalic anhydride 3a, and phenylacetylene 2a were used as raw materials. Under the action of inexpensive catalysts nickel acetylacetonate and ligand triphenylphosphine, a three-component tandem reaction occurred to synthesize compound 3-(4-thienylphenyl)-quinoline-2-phenyl (1g). The reaction in this example only needed to be stirred at a relatively mild temperature of 80 °C for 12 hours in an inert gas argon atmosphere, then cooled, and then a series of subsequent treatments were carried out to obtain the target product 3-(4-thienylphenyl)-quinoline-2-phenyl (1g) with a very high yield (85%).

[0107] Therefore, the method for preparing 2,3-disubstituted quinoline derivatives in this example 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 compound 3-(4-thienylphenyl)-quinoline-2-phenyl (1g) under mild reaction conditions. All raw materials in this reaction are inexpensive and readily available, the method is simple and easy to operate, and the operation is safe.

[0108] The 3-(4-thienylphenyl)-quinoline-2-phenyl (1g) obtained in this example can be used for further post-modification of the product heterocycle.

[0109] Example 8 Preparation of 7-chloro-3-phenylquinoline-2-phenyl (1h)

[0110]

[0111] 0.03 mmol of nickel acetylacetonate and 0.06 mmol of cesium carbonate were added to the reaction flask, 0.36 mmol of phenylboronic acid 4a, 0.3 mmol of 5-chlorophthalic anhydride 3h were added, 0.5 Mpa of argon was charged, 3 mL of toluene, 0.45 mmol of phenylacetylene 2a were added. After stirring at 80 °C for 12 hours, heating and stirring were stopped, and it was cooled to room temperature. 3 mL of water was added to the reaction solution, and it was extracted with ethyl acetate, dried with anhydrous magnesium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 15:1, and the yellow solid 7-chloro-3-phenyl-quinoline-2-phenyl (1h), 78.44 mg, with a yield of 83% could be obtained.

[0112] The 1H NMR spectrum and 13C NMR spectrum of the compound prepared in Example 8 are respectively as Figure 15 and Figure 16 shown. It can be seen from Figure 15 : 11H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.0 Hz, 1H), 8.06 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 9.0, 2.4 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.29 (tt, J = 3.7, 2.3 Hz, 5H), 7.26 - 7.19 (m, 3H). ppm. The peaks of the molecular hydrogen spectrum can correspond one by one to the target product, and the quantity is reasonable. From Figure 16 It can be seen that: 13 13C NMR (100 MHz, CDCl3) δ 158.6, 145.6, 140.0, 139.5, 136.5, 135.4, 132.3, 131.0, 130.5, 129.9, 129.6, 128.2 (d, J = 9.8 Hz), 127.9 (d, J = 17.4 Hz), 127.4, 126.0 ppm. The peaks of the molecular spectrum can correspond one by one to the target product, and the quantity is reasonable. The product obtained in Example 8 is 7-chloro-3-phenylquinoline-2-phenyl(1H).

[0113] In this example, inexpensive and readily available phenylboronic acid 4a, 5-chloroanthranilic anhydride 3h and phenylacetylene 2a were used as raw materials, and under the action of inexpensive catalyst nickel acetylacetonate and ligand triphenylphosphine, a three-component tandem reaction occurred to synthesize compound 7-chloro-3-phenylquinoline-2-phenyl(1H).

[0114] The reaction in this example only needs to be stirred for 12 hours at a relatively mild temperature of 80 °C in an inert gas argon atmosphere, then cooled, and then a series of subsequent treatments are carried out to obtain the target product 7-chloro-3-phenylquinoline-2-phenyl(1H) with a very high yield (83%).

[0115] Therefore, the preparation method of 2,3-disubstituted quinoline derivatives in this example 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 compound 7-chloro-3-phenylquinoline-2-phenyl(1H) under mild reaction conditions. All raw materials in this reaction are inexpensive and readily available, the method is simple and easy to operate, and the operation is safe.

[0116] The 7-chloro-3-phenylquinoline-2-phenyl(1H) obtained in this example increases the substrate range, making its application value higher.

[0117] Example 9 Preparation of 2-ethyl alcohol-quinoline-3-phenyl(1i)

[0118]

[0119] 0.03 mmol of nickel diacetylacetonate and 0.06 mmol of cesium carbonate were added to a reaction flask, followed by 0.36 mmol of phenylboronic acid 4a, 0.3 mmol of anthranilic anhydride 3a. 0.5 Mpa of argon gas was charged, along with 3 mL of toluene and 0.45 mmol of 3-butyn-1-ol 2i. After stirring the reaction at 80 °C for 12 hours, heating and stirring were stopped, and the reaction mixture was cooled to room temperature. 3 mL of water was added to the reaction solution, and it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. Then, it was separated and purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 5:1, and the target product, deep yellow solid 2-ethylol-quinoline-3-phenyl (1i), 60.51 mg, with a yield of 81% was obtained.

[0120] The 1H NMR spectrum and 13C NMR spectrum of the compound prepared in Example 9 are shown in Figure 17 and Figure 18 respectively. It can be seen from Figure 17 that: 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.5 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J = 8.1, 1.4 Hz, 1H), 7.72 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.55 (ddd, J = 8.0, 6.8, 0.9 Hz, 1H), 7.51 - 7.43 (m, 3H), 7.41 - 7.35 (m, 2H), 4.07 (t, J = 5.3 Hz, 2H), 3.11 (t, J = 5.3 Hz, 2H) ppm. The peaks in the 1H NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. It can be seen from Figure 18 that: 13 C NMR (100 MHz, CDCl3) δ δ 159.9, 146.1, 139.0, 136.8, 135.7, 129.8, 129.3, 128.6, 128.3, 127.9, 127.6, 126.7, 126.6, 61.2, 36.9 ppm. The peaks in the 13C NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. The product obtained in Example 9 is 2-ethylol-quinoline-3-phenyl (1i).

[0121] In this example, using readily available and inexpensive phenylboronic acid 4a, anthranilic anhydride 3a and 3-butyn-1-ol 2i as raw materials, under the action of the inexpensive catalyst nickel diacetylacetonate and the ligand triphenylphosphine, a three-component tandem reaction occurs to synthesize the compound 2-ethylol-quinoline-3-phenyl (1i).

[0122] The reaction in this example only requires stirring and reacting for 12 hours at a relatively mild temperature of 80 °C in an inert gas argon atmosphere, then cooling, and then performing a series of subsequent treatments to obtain the final target product 2-ethylol-quinoline-3-phenyl (1i) with a very high yield (81%).

[0123] Therefore, the preparation method of 2,3-disubstituted quinoline derivatives in this example is a green and efficient synthesis method. This method uses cheap and readily available chemicals as the initial raw materials, and through a green, safe, and efficient reaction process, under mild reaction conditions, efficiently synthesizes the compound 2-ethylol-quinoline-3-phenyl (1i). All raw materials in this reaction are cheap and readily available, the method is simple and easy to implement, and the operation is safe.

[0124] The 2-ethylol-quinoline-3-phenyl (1i) obtained in this example contains a hydroxyl group and can undergo various types of reactions, making the scope of application of the product wider.

[0125] Example 10 2-nonyl-3-phenyl-quinoline (1j)

[0126]

[0127] Add 0.03 mmol of nickel acetylacetonate and 0.06 mmol of cesium carbonate to the reaction flask, add 0.36 mmol of phenylboronic acid 4a, 0.3 mmol of anthranilic anhydride 3a, fill with 0.5 Mpa of argon, 3 ml of toluene, 0.45 mmol of 1-decyne 2j, stir and react at 80 °C for 12 hours, then stop heating and stirring, cool to room temperature, add 3 ml of water to the reaction solution, extract with ethyl acetate, dry with anhydrous magnesium sulfate, remove the solvent by rotary evaporation under reduced pressure, and then separate and purify by column chromatography. The column chromatography eluent used is a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 15:1, and a pale yellow solid 2-nonyl-3-phenyl-quinoline (1j), 83.4 mg, with a yield of 84% can be obtained.

[0128] The 1H NMR spectrum and 13C NMR spectrum of the compound prepared in Example 10 are respectively as Figure 19 and Figure 20 shown. From Figure 19 it can be seen that: 11H NMR (400 MHz, CDCl3) δ 8.13 - 8.06 (m, 1H), 7.94 (s, 1H), 7.78 (dd, J = 8.1, 1.4 Hz, 1H), 7.69 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.55 - 7.35 (m, 6H), 2.99 - 2.90 (m, 2H), 1.71 - 1.59 (m, 2H), 1.28 - 1.14 (m, 10H), 0.85 (t, J = 7.0 Hz, 3H) ppm. The peaks in the 1H NMR spectrum can correspond to the target product one by one, and the quantity is reasonable. From Figure 20 it can be seen that 13 13C NMR (100 MHz, CDCl3) δ 161.3, 147.2, 140.0, 136.4, 135.6, 129.3, 129.2, 128.6, 128.3, 127.4 (d, J = 6.3 Hz), 126.6 ppm. The peaks in the molecular spectrum can correspond to the target product one by one, and the quantity is reasonable. The product obtained in Example 10 is 2-nonyl-3-phenyl-quinoline (1j).

[0129] In this example, using inexpensive and readily available phenylboronic acid 4a, phthalic anhydride 3a and 1-decyne 2j as raw materials, under the action of inexpensive catalyst nickel acetylacetonate and ligand triphenylphosphine, a three-component tandem reaction occurs to synthesize compound 2-nonyl-3-phenyl-quinoline (1j).

[0130] The reaction in this example only needs to be stirred for 12 hours at a relatively mild temperature of 80 °C in an inert gas argon atmosphere, then cooled, and then a series of subsequent treatments are carried out to obtain the final target product 2-nonyl-3-phenyl-quinoline (1j) with a high yield (84%).

[0131] Therefore, the preparation method of 2,3-disubstituted quinoline derivatives in this example 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 compound 2-nonyl-3-phenyl-quinoline (1j) under mild reaction conditions. All raw materials in this reaction are inexpensive and readily available, the method is simple and easy to operate, and the operation is safe.

[0132] The 2-nonyl-3-phenyl-quinoline (1j) obtained in this example contains an alkyl group, further enriching the product types.

[0133] In summary, this patent application provides a method for preparing 2,3-disubstituted quinoline derivatives, which is characterized in that: in a reaction flask, a catalyst, a monodentate phosphine ligand, and an arylboronic acid (Formula IV) are added. After introducing an inert gas, a solvent, a terminal alkyne (Formula II), and phthalic anhydride imide (Formula III) are successively added, and the reaction is stirred; after the reaction is completed, it is cooled to room temperature, the reaction solution is washed with water, extracted with ethyl acetate, immediately dried with anhydrous magnesium sulfate, and then the solvent is removed under reduced pressure to obtain a crude product, and finally the 2,3-disubstituted quinoline compound (Formula I) is purified by column chromatography. The reaction is as follows:

[0134]

[0135] Among them, R is an aryl group, a heteroaryl group, or an alkyl group. The aryl group is a phenyl group and a phenyl group with halogen substitution, an ester group, an acyl group, or a nitrile functional group; the heteroaryl group is furan, thiophene, pyridine, etc.; the alkyl group is a straight-chain alkyl group with 1 to 10 carbon atoms, cyclopropyl, and an alkyl group with N or O heteroatoms, etc.; R 1 is selected from halogen, methyl, methoxy, ester group, etc.; R 2 is selected from ester group, methoxy, fluorine, chlorine, bromine, etc.

[0136] The method for preparing 2,3-disubstituted quinoline derivatives provided by this patent application is safe and simple to operate, the raw materials are easily available, it has good adaptability to functional groups and a wide range of substrate adaptability (it can adapt to various different reaction substrates, such as phenylacetylene 2a, p-methylphenylacetylene 2e, 3-butyn-1-ol 2i, and 1-decyne 2j, etc.), is environmentally friendly, and the reaction temperature required is moderate, the reaction time is relatively short, and the yield is high. Through this synthesis method, a variety of bioactive molecules can be efficiently constructed, and the obtained products are relatively specific, having good industrial application prospects.

Claims

1. A method for preparing a 2,3-disubstituted quinoline derivative, characterized in that: In a reaction flask, nickel catalyst bis(acetylacetonato)nickel, monodentate phosphine ligand triphenylphosphine, cesium carbonate, and arylboronic acid (Formula IV) are added. After introducing an inert gas, a solvent, terminal alkyne (Formula II), and phthalic anhydride imide (Formula III) are added in sequence, and the mixture is stirred for reaction; after the reaction is completed, it is cooled to room temperature, the reaction solution is washed with water, extracted with ethyl acetate, then dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure to obtain a crude product, and finally the 2,3-disubstituted quinoline compound (Formula I) is obtained by column chromatography purification. The reaction is as follows: Among them, R is aryl, heteroaryl or alkyl, the aryl is phenyl and phenyl with halogen substitution, ester group, acyl group or nitrile group functional groups; the heteroaryl is furan, thiophene or pyridine; the alkyl is straight-chain alkyl with C1-C10, cyclopropyl or alkyl with N or O heteroatom; R 1 is selected from halogen, methyl, methoxy or ester group; R 2 selects ester group, methoxy, fluorine, chlorine or bromine.

2. The preparation method of the 2,3-disubstituted quinoline derivative according to claim 1, characterized in that: The molar ratio of the phthalic anhydride imide to the bis(acetylacetonato)nickel is 1:0.

1.

3. The preparation method of the 2,3-disubstituted quinoline derivative according to claim 1, characterized in that: The molar ratio of the phthalic anhydride imide to the triphenylphosphine is 1:0.

1.

4. The preparation method of the 2,3-disubstituted quinoline derivative according to claim 1, characterized in that: The molar ratio of the phthalic anhydride imide to the cesium carbonate is 1:0.

2.

5. The preparation method of the 2,3-disubstituted quinoline derivative according to claim 1, wherein: The solvent is selected from one or more of 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylaniline, acetonitrile, tetrahydrofuran, methanol, toluene, and cyclohexane.

6. The preparation method of the 2,3-disubstituted quinoline derivative according to claim 5, characterized in that, The solvent is toluene, and 1 mL of toluene needs to be added for 0.1 mmol of the phthalic anhydride imide.

7. The preparation method of the 2,3-disubstituted quinoline derivative according to claim 1, characterized in that: The molar ratio of the phthalic anhydride imide, the terminal alkyne, and the arylboronic acid is 1:1.5:1.2.

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