An Evodiaein Analog, Its Preparation Method and Application

Abstract

The present application relates to a kind of evodia rutaecarpine analog and its preparation method and application, belong to the field of synthetic chemistry of medicine. With 4 (3H) -quinazolinone derivative as substrate, phthalocyanine iron as catalyst, evodia rutaecarpine analog is synthesized by intramolecular hydrogen transfer reaction, high yield, low production cost. When concentration is 25 μM, LPS concentration 1 μg / mL, compound 1c, 1t, 1u, 1v inhibit NO release ability is superior to anti-inflammatory drug indometacin, and 1a, 1b, 1i is equivalent to indometacin;Inhibit NO release ability stronger compound 1c, 1t, 1u and 1v are weak to RAW264.7 cell cytotoxicity;Anti-inflammatory effect is obvious, and toxicity is very small, has very high medical value and broad market prospect.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to an erythropoietin analogue, its preparation method, and its application. Background Technology

[0002] Quinazolinones are important nitrogen-containing heterocycles in organic synthesis. They are ubiquitous in natural products and bioactive compounds, and play a crucial role as pharmacophores in drug development. Evodia alkaloids and their derivatives are an important class of alkaloids containing quinazolinone and indole groups. Numerous studies have shown that evodia alkaloid analogs and other quinazolinone-containing compounds exhibit significant anti-obesity, anti-platelet aggregation, anti-inflammatory, antibacterial, antidiabetic, and anticancer activities. Therefore, structural modification of evodia alkaloid analogs can yield new compounds with broad biological activities. Currently, the synthesis methods of evodia alkaloids and their derivatives are mainly based on tryptamines and their derivatives, leading to insufficient structural diversity of evodia alkaloid analogs. Therefore, developing a new method for constructing the evodia alkaloid skeleton is urgent and has promising applications. Hydrogenation reactions are a highly anticipated class of reactions in organic synthesis. This reaction typically uses alcohols as alkylating agents, with water as the only byproduct, making it a green and sustainable synthetic method. In recent years, with in-depth research on hydrogen-borrowing reactions, significant progress has been made in transition metal-catalyzed alkylation of indoles at the C3 or N1 position. This invention utilizes intramolecular hydrogen-borrowing reactions to synthesize a series of evodiamine analogs and their derivatives.

[0003] We recently synthesized a novel eugenol alkaloid analogue, which has not been reported in any literature. Summary of the Invention

[0004] The main content of this invention is to provide a method for synthesizing evodiamine analogues, using indomethacin anhydride and its derivatives, 1H-indole-2-carboxaldehyde and its derivatives, ethanolamine, etc. as raw materials, and phthalocyanine iron as a catalyst, to synthesize evodiamine analogues via an intramolecular hydrogen-dependent reaction. The synthetic route is attached. Figure 1 The method involves synthesizing an anthracitic anhydride and its derivatives as raw materials, followed by a condensation and oxidation reaction with 1H-indole-2-carboxaldehyde and its derivatives under acidic conditions to generate a 4(3H)-quinazolinone derivative (II). Finally, a cyclization reaction catalyzed by iron phthalocyanine is performed to generate the target compound (III). R1 ​​and R2 are substituents such as F, Cl, Br, methyl, and methoxy; R3 is substituents such as H and hydroxymethyl.

[0005] This invention also provides the application of evodiamine analogues in the preparation of anti-inflammatory drugs. At a concentration of 25 μM and an LPS concentration of 1 μg / mL, compounds 1c, 1t, 1u, and 1v showed superior NO-inhibiting abilities compared to the anti-inflammatory drug indomethacin, while 1a, 1b, and 1i were comparable to indomethacin. Compounds 1c, 1t, 1u, and 1v, which exhibited stronger NO-inhibiting abilities, showed weaker cytotoxic effects on RAW264.7 cells. The anti-inflammatory effects were significant, and the toxicity was very low, demonstrating high medical value and broad market prospects.

[0006] The advantages of this invention are:

[0007] 1. Under mild conditions, compound I undergoes condensation and oxidation reactions with 1H-indole-2-carboxaldehyde and its derivatives to generate 4(3H)-quinazolinone derivative (II) in high yield.

[0008] 2. Using inexpensive phthalocyanine iron as a catalyst, the target compound (III) was generated in a high yield.

[0009] 3. The only byproduct of this reaction is water, and the synthesis method is green and environmentally friendly.

[0010] 4. The erythromycin analogue synthesized in this scheme has significant anti-inflammatory effects and low toxicity, and can be used to prepare anti-inflammatory drugs in various dosage forms. Attached Figure Description

[0011] Figure 1 This invention provides a synthetic route for preparing eugenol analogues. Detailed Implementation

[0012] The present invention will be described below with reference to specific embodiments. It should be noted that the following embodiments are for illustrative purposes only and are not intended to limit the invention. Various other combinations and modifications within the scope of the present invention can be made without departing from its spirit or scope.

[0013] In the following embodiments, 1 The internal standard for H NMR testing was tetramethylsilane (TMS).

[0014] Example 1:

[0015] The reaction steps are as follows:

[0016] 1. Synthesis of compound 1a

[0017]

[0018] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, indomethacin (1 mmol, 163.1 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =50:1) gave 162 mg of white solid compound 3a (yield 90%).

[0019] Under electromagnetic stirring, compound 3a (0.5 mmol, 90 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 0.6 mmol, 136 mg) was added under an ice-water bath. The reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 100: 3) gave 131.2 mg of yellow solid compound 4a (yield 86%).

[0020] Compound 4a (0.1 mmol, 30.6 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 26.4 mg of yellow solid compound 1a (yield 90%). 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.0 Hz, 1H), 7.78–7.70 (m, 3H), 7.59 (s, 1H), 7.46–7.43 (m, 1H), 7.39–7.34 (m, 2H), 7.20 (t, J= 7.3 Hz, 1H), 4.67 (t, J = 5.8 Hz, 2H), 4.44 (t, J = 5.8 Hz, 2H).

[0021] 2. Synthesis of Compound 1b

[0022]

[0023] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 5-methoxyindosanhydride (1 mmol, 193 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 :V 甲醇 = 50: 1) yielded 168 mg of white solid compound 3b (yield 80%).

[0024] Under electromagnetic stirring, compound 3b (0.5 mmol, 105 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) yielded 129 mg of yellow solid compound 4b (yield 77%).

[0025] Compound 4b (0.1 mmol, 33.5 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) yielded 20.6 mg of yellow solid compound 1b (yield 65%). 1 H NMR (500 MHz, DMSO) δ 7.83 (s, 1H), 7.71–7.66 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.37 (s,1H), 7.31 (t, J = 8.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 4.56 (s, 2H), 3.90 (s, 3H), 3.33 (s, 2H).

[0026] 3. Synthesis of Compound 1c

[0027]

[0028] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 5-bromoindocyanine anhydride (1 mmol, 240.9 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 :V 甲醇 = 50: 1) yielded 196 mg of white solid compound 3c (yield 76%).

[0029] Under electromagnetic stirring, compound 3c (0.5 mmol, 129 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) yielded 152 mg of white solid compound 4c (yield 79%).

[0030] Compound 4c (0.1 mmol, 38.3 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3:1) gave 28.4 mg of white solid compound 1c (78% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.38 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.53 (s, 1H), 7.35 (s, 2H), 7.20 (s, 1H), 4.64 (s, 2H), 4.42 (s, 2H).

[0031] 4. Synthesis of compound 1d

[0032]

[0033] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 5-fluoroindosanhydride (1 mmol, 181 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 50: 1) yielded 156.5 mg of white solid compound 3d (yield 79%).

[0034] Under electromagnetic stirring, compound 3d (0.5 mmol, 99 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) gave 117.9 mg of a yellow solid compound 4d (yield 73%).

[0035] Compound 4d (0.1 mmol, 32.3 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚= 3:1) gave 25.9 mg of a yellow solid compound 1d (yield 85%). ¹H NMR (500 MHz, DMSO) δ 8.26–8.18 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.50–7.44 (m, 1H), 7.44 (s, 1H), 7.37–7.32 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 4.55 (s, 4H).

[0036] 5. Synthesis of compound 1e

[0037]

[0038] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 5-chloroindocyanine anhydride (1 mmol, 197 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 50: 1) yielded 188 mg of white solid compound 3e (yield 88%).

[0039] Under electromagnetic stirring, compound 3e (0.5 mmol, 107 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) yielded 149 mg of yellow solid compound 4e (yield 88%).

[0040] Compound 4e (0.1 mmol, 33.9 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 26.3 mg of yellow solid compound 1e (yield 82%). 1 H NMR (500 MHz, DMSO) δ 8.04 (s, 1H), 7.81 (d, J = 8.5Hz, 1H), 7.69 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 4.54 (s, 4H).

[0041] 6. Synthesis of compound 1f

[0042]

[0043] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 5-methylindocyanine anhydride (1 mmol, 177 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 :V 甲醇 = 50: 1) yielded 145.6 mg of white solid compound 3f (yield 75%).

[0044] Under electromagnetic stirring, compound 3f (0.5 mmol, 97 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) yielded 138.8 mg of white solid compound 4f (yield 87%).

[0045] Compound 4f (0.1 mmol, 31.9 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) yielded 22.3 mg of white solid compound 1f (yield 74%). 1 H NMR (500 MHz, DMSO) δ 7.95 (s, 1H), 7.70 (d, J = 8.0Hz, 1H), 7.64 – 7.58 (m, 3H), 7.38 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.14(t, J = 7.5 Hz, 1H), 4.54 (s, 4H), 2.45 (s, 3H).

[0046] Synthesis of 1g of compound 7

[0047]

[0048] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 4,5-dimethoxyindosanhydride (1 mmol, 223 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 50: 1) yielded 3g of a white solid compound of 187.3 mg (yield 78%).

[0049] Under electromagnetic stirring, 3 g (0.5 mmol, 120 mg) of the compound, tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) yielded 4 g of a yellow solid compound of 158.8 mg (yield 87%).

[0050] In a dry reaction tube equipped with a magnetic stir bar, 4 g of compound (0.1 mmol, 36.5 mg), iron phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) yielded 1 g of a yellow solid compound of 19.1 mg (yield 55%). 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.40–7.33 (m, 2H), 7.22–7.19 (m, 1H), 7.18 (d, J = 5.0Hz, 1H), 4.67 (t, J = 6.0 Hz, 2H), 4.49–4.42 (m, 2H), 4.03 (s, 3H), 4.02 (s,3H).

[0051] Synthesis of Compound 8 (1h)

[0052]

[0053] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 4-bromoindocyanine anhydride (1 mmol, 240.9 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 :V 甲醇 = 50: 1) yielded 190.9 mg of a white solid compound over 3 hours (yield 74%).

[0054] Under electromagnetic stirring, compound 3h (0.5 mmol, 129 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) gave 153.2 mg of a yellow solid compound over 4 hours (yield 80%).

[0055] Compound 4h (0.1 mmol, 38.3 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 21.9 mg of a yellow solid compound 1h (yield 60%). 1 H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 5.0 Hz, 1H), 7.91 (s, 1H), 7.74 (d, J = 6.5 Hz, 1H), 7.57–7.49 (m, 2H), 7.36 (s, 2H), 7.20 (s,1H), 4.64 (s, 2H), 4.43 (s, 2H).

[0056] 9. Synthesis of Compound 1i

[0057]

[0058] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 4-fluoroindosanhydride (1 mmol, 181 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 50: 1) yielded 164.4 mg of white solid compound 3i (yield 83%).

[0059] Under electromagnetic stirring, compound 3i (0.5 mmol, 99 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) gave 150 mg of white solid compound 4i (yield 93%).

[0060] Compound 4i (0.1 mmol, 32.3 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) yielded 22 mg of white solid compound 1i (yield 72%). 1 H NMR (500 MHz, DMSO) δ 8.21 (t, J = 7.8 Hz, 1H), 7.72 (d,J = 8.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 10.5 Hz, 1H), 7.43(s, 1H), 7.34 (d, J = 6.5 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), 4.55 (s, 4H).

[0061] Synthesis of Compound 1j

[0062]

[0063] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 4-chloroindocyanine anhydride (1 mmol, 197 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 50: 1) yielded 177.6 mg of white solid compound 3j (yield 83%).

[0064] Under electromagnetic stirring, compound 3j (0.5 mmol, 107 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100: 3) yielded 135.6 mg of white solid compound 4j (yield 80%).

[0065] Compound 4j (0.1 mmol, 33.9 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) yielded 22.5 mg of white solid compound 1j (yield 70%). 1H NMR (500 MHz, DMSO) δ 8.13 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 10.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 7.16 (d, J = 7.0Hz, 1H), 4.54 (s, 4H).

[0066] Synthesis of compound 1k

[0067]

[0068] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 3-methylindocyanine anhydride (1 mmol, 177 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 :V 甲醇 = 50: 1) yielded 149.5 mg of white solid compound 3k (yield 77%).

[0069] Under electromagnetic stirring, compound 3k (0.5 mmol, 97 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) yielded 118 mg of yellow solid compound 4k (yield 74%).

[0070] Compound 4K (0.1 mmol, 31.9 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 18.7 mg of yellow solid compound 1k (yield 62%). 1 H NMR (500 MHz, DMSO) δ 8.00 (d, J = 8.0 Hz, 1H), 7.73(d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.45(s, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5Hz, 1H), 4.54 (s, 4H), 2.62 (s, 3H).

[0071] Synthesis of Compound 12

[0072]

[0073] Under electromagnetic stirring, acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 3-methoxyindosanhydride (1 mmol, 193 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 :V 甲醇 = 50: 1) yielded 159.6 mg of white solid compound 3l (yield 76%).

[0074] Under electromagnetic stirring, compound 3L (0.5 mmol, 105 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =100:3) gave 134 mg of yellow solid compound 4l (yield 80%).

[0075] Compound 4L (0.1 mmol, 33.5 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 21.6 mg of yellow solid compound 1 l (yield 68%). 1 H NMR (500 MHz, DMSO) δ 7.73 (t, J = 7.0 Hz, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.44 – 7.36 (m, 3H), 7.32 (t, J = 7.8 Hz, 1H), 7.15 (t,J = 7.8 Hz, 1H), 4.55 (s, 4H), 3.97 (s, 3H).

[0076] Synthesis of compound 1m (13)

[0077]

[0078] Under electromagnetic stirring, compound 3a (0.5 mmol, 90 mg), tetrahydrofuran (30 mL), 6-chloro-1H-indole-2-carboxaldehyde (0.75 mmol, 134.2 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath. The reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 100: 3) gave 142.4 mg of yellow solid compound 4m (yield 84%).

[0079] Compound 4m (0.1 mmol, 33.9 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 27 mg of yellow solid compound 1m (yield 84%). 1 H NMR (500 MHz, DMSO) δ 8.15 (d, J = 8.0 Hz, 1H), 7.82 (t,J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.70 (t, J = 9.0 Hz, 2H), 7.49 (t, J = 7.5Hz,1H), 7.43 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 4.55 (s, 4H).

[0080] 14 Synthesis of Compound 1n

[0081]

[0082] Under electromagnetic stirring, compound 3a (0.5 mmol, 90 mg), tetrahydrofuran (30 mL), 5-chloro-1H-indole-2-carboxaldehyde (0.75 mmol, 134.2 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 100: 3) yielded 135.6 mg of yellow solid compound 4n (yield 80%).

[0083] Compound 4n (0.1 mmol, 33.9 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 22.8 mg of yellow solid compound 1n (yield 74%). 1 H NMR (500 MHz, DMSO) δ 8.16 (t, J = 8.5 Hz, 1H), 7.85–7.77(m, 2H), 7.74–7.69 (m, 1H), 7.68–7.61 (m, 1H), 7.5–7.47 (m, 1H), 7.40 (t, J =8.0 Hz, 1H), 7.31 (t, J = 8.8 Hz, 1H), 4.55 (d, J = 8.5 Hz, 4H).

[0084] Synthesis of Compound 10 (15)

[0085]

[0086] Under electromagnetic stirring, compound 3a (0.5 mmol, 90 mg), tetrahydrofuran (30 mL), 6-bromo-1H-indole-2-carboxaldehyde (0.75 mmol, 167.2 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 100: 3) gave 141.7 mg of yellow solid compound 4o (yield 74%).

[0087] Compound 4O (0.1 mmol, 38.3 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 25.2 mg of white solid compound 1o (yield 69%). 1 H NMR (500 MHz, DMSO) δ 8.15 (d, J = 8.0Hz, 1H), 7.92(s, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.5Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.27–7.25 (m, 1H), 4.55 (s, 4H).

[0088] Synthesis of compound 1p (16)

[0089]

[0090] Under electromagnetic stirring, compound 3a (0.5 mmol, 90 mg), tetrahydrofuran (30 mL), 5-chloro-1H-indole-2-carboxaldehyde (0.75 mmol, 119.3 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath. The reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 100: 3) gave 132.4 mg of yellow solid compound 4p (yield 83%).

[0091] Compound 4p (0.1 mmol, 31.9 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stirrer. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) yielded 21.1 mg of white solid compound 1p (yield 70%). 1 H NMR (500 MHz, DMSO) δ 8.17 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.50 (s, 3H), 7.34 (s, 1H),7.16 (d, J = 8.5 Hz, 1H), 4.53 (d, J = 14.5 Hz, 4H), 2.41 (s, 3H).

[0092] 17 Synthesis of compound 1q

[0093]

[0094] Under electromagnetic stirring, compound 3a (0.5 mmol, 90 mg), tetrahydrofuran (30 mL), 4-methoxy-1H-indole-2-carboxaldehyde (0.75 mmol, 131.3 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 100: 3) gave 137.4 mg of yellow solid compound 4q (yield 82%).

[0095] Compound 4q (0.1 mmol, 33.5 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 19.6 mg of yellow solid compound 1q (yield 62%). 1 H NMR (500 MHz, DMSO) 8.16 (d, J = 8.0 Hz, 1H), 7.82 (t,J = 7.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.36 (s,1H), 7.25 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 7.5 Hz, 1H), 4.57– 4.48 (m, 4H), 3.93 (s, 3H).

[0096] Synthesis of Compound 1r (18)

[0097]

[0098] Under electromagnetic stirring, compound 3a (0.5 mmol, 90 mg), tetrahydrofuran (30 mL), 5-methoxy-1H-indole-2-carboxaldehyde (0.75 mmol, 131.3 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 100: 3) yielded 117 mg of yellow solid compound 4r (yield 70%).

[0099] Compound 4r (0.1 mmol, 33.5 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) yielded 21.6 mg of yellow solid compound 1r (yield 68%). 1 H NMR (500 MHz, DMSO) δ 8.16 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.53–7.46 (m, 2H), 7.33 (s,1H), 7.18 (d, J = 2.5 Hz, 1H), 6.98–6.96 (m, 1H), 4.57–4.52 (m, 2H), 4.51–4.48 (m, 2H), 3.80 (s, 3H).

[0100] Synthesis of Compound 1s (19)

[0101]

[0102] Under electromagnetic stirring, compound 3d (0.5 mmol, 99 mg), tetrahydrofuran (30 mL), 5-methoxy-1H-indole-2-carboxaldehyde (0.75 mmol, 131.3 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 100: 3) gave 130.7 mg of yellow solid compound 4s (yield 74%).

[0103] Compound 4S (0.1 mmol, 35.3 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 石油醚 = 3: 1) gave 24.1 mg of yellow solid compound 1s (yield 72%). 1 H NMR (500 MHz, CDCl3) δ 7.92 (dd, J = 8.5, 3.0 Hz, 1H),7.74 (q, J = 4.5 Hz, 1H), 7.49 –7.45 (m, 1H), 7.44 (s, 1H), 7.28 (s, 1H),7.12 (d, J = 2.5 Hz, 1H), 7.03 – 7.01 (m, 1H), 4.65 (t, J = 5.8 Hz, 2H), 4.40 (t, J = 5.8 Hz, 2H), 3.88 (s, 3H).

[0104] Synthesis of Compound 1t

[0105]

[0106] Under electromagnetic stirring, acetonitrile (30 mL) and 2-amino-1,3-propanediol (1.5 mmol, 136.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, indocyanine anhydride (1 mmol, 163 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 40: 1) yielded 172.2 mg of white solid compound 3t (yield 82%).

[0107] Under electromagnetic stirring, compound 3t (0.5 mmol, 105 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =50:1) gave 142.4 mg of yellow solid compound 4t (yield 85%).

[0108] Compound 4t (0.1 mmol, 33.5 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 24 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 200: 1) yielded 26 mg of yellow solid compound 1t (yield 82%). 1H NMR (500 MHz, DMSO) δ 8.19 (d, J = 8.0 Hz, 1H), 7.85 (d,J = 7.5 Hz, 1H), 7.76–7.70 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.52 (t, J =7.5 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz,1H), 5.44–5.34 (m, 2H), 4.99–4.96 (m, 2H), 4.38–4.35 (m, 2H), 3.48 (d, J =9.5 Hz, 1H), 3.25 (d, J = 8.5 Hz, 1H).

[0109] Synthesis of Compound 1u (21)

[0110]

[0111] Under electromagnetic stirring, acetonitrile (30 mL) and 2-amino-1,3-propanediol (1.5 mmol, 136.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 5-fluoroindosanhydride (1 mmol, 181 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 40: 1) gave 150.5 mg of white solid compound 3u (yield 66%).

[0112] Under electromagnetic stirring, compound 3t (0.5 mmol, 114 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =50:1) gave 130.6 mg of yellow solid compound 4u (yield 74%).

[0113] Compound 4u (0.1 mmol, 35.3 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 24 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 200: 1) yielded 23.9 mg of a yellow solid compound 1u (yield 68%). 1 H NMR (500 MHz, DMSO) δ 7.88–7.86 (m, 1H), 7.81–7.79 (m,1H), 7.77–7.72 (m, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.34 (t, J =7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 5.37 (t, J = 6.0 Hz, 2H), 4.97 (d, J =6.5 Hz, 1H), 4.37–4.34 (m, 1H), 3.50–3.46 (m, 1H), 3.28–3.22 (m, 1H).

[0114] Synthesis of Compound 1v

[0115]

[0116] Under electromagnetic stirring, acetonitrile (30 mL) and 2-amino-1,3-propanediol (1.5 mmol, 136.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 5-bromoindocyanine anhydride (1 mmol, 241 mg) was added under ice-water bath conditions. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 40: 1) yielded 178.6 mg of white solid compound 3v (yield 62%).

[0117] Under electromagnetic stirring, compound 3v (0.5 mmol, 144 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =50:1) yielded 185.9 mg of green solid compound 4v (yield 90%).

[0118] Compound 4V (0.1 mmol, 41.3 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 24 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 200: 1) yielded 32.8 mg of green solid compound 1v (yield 83%). 1 H NMR (500 MHz, DMSO) δ 8.25 (s, 1H), 7.98 (d, J = 9.0Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.67–7.62 (m, 2H), 7.43 (s, 1H), 7.34 (t,J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 5.36 (d, J = 6.0 Hz, 2H), 4.96 (d,J = 6.5 Hz, 1H), 4.37–4.33 (m, 1H), 3.50–3.46 (m, 1H), 3.28–3.18 (m, 1H).

[0119] Synthesis of compound 1w (23)

[0120]

[0121] Under electromagnetic stirring, acetonitrile (30 mL) and 2-amino-1,3-propanediol (1.5 mmol, 136.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 5-methoxyindosanhydride (1 mmol, 193 mg) was added under ice-water bath conditions. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 40: 1) yielded 136.86 mg of white solid compound 3w (yield 57%).

[0122] Under electromagnetic stirring, compound 3w (0.5 mmol, 120 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =50:1) gave 142.4 mg of yellow solid compound 4w (yield 78%).

[0123] Compound 4w (0.1 mmol, 36.5 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 24 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 200: 1) yielded 24.3 mg of yellow solid compound 1w (yield 70%). 1H NMR (500 MHz, DMSO) δ 7.73–7.66 (m, 2H), 7.62 (d, J =8.5 Hz, 1H), 7.59–7.55 (m, 1H), 7.45 –7.48 (m, 1H), 7.37–7.28 (m, 2H), 7.15(t, J = 7.5 Hz, 1H), 5.35–5.40 (m, 2H), 4.96 (d, J = 13.0 Hz, 1H), 4.33–4.36(m, 1H), 3.90 (s, 3H), 3.45–3.49 (m, 1H), 3.20–3.26 (m, 1H).

[0124] 24 Synthesis of Compound 1x

[0125]

[0126] Under electromagnetic stirring, acetonitrile (30 mL) and 2-amino-1,3-propanediol (1.5 mmol, 136.6 mg) were added sequentially to a 100 mL round-bottom flask. Then, 3-methylindocyanine anhydride (1 mmol, 177 mg) was added under an ice-water bath. The reaction was carried out at 0 °C for 30 min, followed by a further reaction at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 40: 1) yielded 121 mg of white solid compound 3x (yield 54%).

[0127] Under electromagnetic stirring, compound 3x (0.5 mmol, 112 mg), tetrahydrofuran (30 mL), 1H-indole-2-carboxaldehyde (0.75 mmol, 109 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 =50:1) gave 153.6 mg of yellow solid compound 4x (yield 88%).

[0128] Compound 4x (0.1 mmol, 34.9 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 24 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 200: 1) yielded 16.6 mg of a yellow solid compound 1x (yield 50%). 1 H NMR (500 MHz, DMSO) δ 8.03 (d, J = 8.0 Hz, 1H), 7.75(d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.45(s, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5Hz, 1H), 5.37 (t, J = 5.5 Hz, 2H), 4.97 (d, J = 6.5 Hz, 1H), 4.37–4.34 (m,1H), 3.50–3.46 (m, 1H), 3.26–3.13 (m, 1H), 2.64 (s, 3H).

[0129] Synthesis of compound 1y (25)

[0130]

[0131] Under electromagnetic stirring, compound 3t (0.5 mmol, 105 mg), tetrahydrofuran (30 mL), 6-bromo-1H-indole-2-carboxaldehyde (0.75 mmol, 167.2 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath, and the reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇= 50: 1) yielded 165.2 mg of yellow solid compound 4y (yield 80%).

[0132] Compound 4y (0.1 mmol, 41.3 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 24 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 200: 1) yielded 28.4 mg of yellow solid compound 1y (yield 72%). 1 H NMR (500 MHz, DMSO) δ 8.18 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.72–7.66 (m, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 5.35 (s, 2H), 5.00 (t, J = 14.8Hz, 1H), 4.39–4.28 (m, 1H), 3.49–4.45 (m, 1H), 3.33– 3.22 (m, 1H).

[0133] Synthesis of Compound 1z (26)

[0134]

[0135] Under electromagnetic stirring, compound 3t (0.5 mmol, 105 mg), tetrahydrofuran (30 mL), 6-chloro-1H-indole-2-carboxaldehyde (0.75 mmol, 134.5 mg), anhydrous magnesium sulfate (1.65 mmol, 198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol, 47.5 mg) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature under a nitrogen atmosphere for 4 h. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 mmol, 136 mg) was added under an ice-water bath. The reaction was continued at room temperature for 4 h after 30 min. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇= 50: 1) gave 156.8 mg of yellow solid compound 4z (yield 85%).

[0136] Compound 4z (0.1 mmol, 36.9 mg), ferric phthalocyanine (0.01 mmol, 5.7 mg), tripotassium phosphate (0.15 mmol, 31.8 mg), and N,N-dimethylformamide (1 mL) were added sequentially to a dry reaction tube equipped with a magnetic stir bar. The reaction was carried out at 150 °C for 24 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and dichloromethane, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). 二氯甲烷 V 甲醇 = 200: 1) yielded 26.3 mg of yellow solid compound 1z (yield 75%). 1 H NMR (500 MHz, DMSO) δ 8.19 (d, J = 8.0 Hz, 1H), 7.87–7.81 (m, 2H), 7.73 (t, J = 8.5 Hz, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.43 (s,1H), 7.18–7.16 (m, 1H), 5.35 (t, J = 6.0 Hz, 2H), 5.00 (d, J = 6.5 Hz, 1H), 4.37–4.33 (m, 1H), 3.50–3.46 (m, 1H), 3.29–3.14 (m, 1H).

[0137] The anti-inflammatory activity of the above-mentioned target products was initially screened. The anti-inflammatory activity was evaluated using the Griess method, which determined the inhibitory effect of the compounds on lipopolysaccharide (LPS)-induced NO release from RAW264.7 mouse macrophages. The results of the inhibitory effects of some target compounds on LPS-induced NO release from RAW264.7 mouse macrophages are shown in Table 1. The effect of the target compounds at a concentration of 25 μM on RAW264.7 cell viability is shown in Table 2.

[0138] Table 1

[0139] compound Concentration of NO released (μmol / L) LPS 20.68±0.34 1a 14.32±0.47 1b 15.01±0.27 1c 11.36±0.16 1i 14.77±0.31 1t 8.41±0.52 1u 6.13±0.28 1v 8.07±0.19 Indomethacin 13.18±0.23

[0140] Table 2

[0141] compound Cell viability (%) 1a 88.37±2.58 1b 98.26±1.34 1c 103.48±1.76 1i 118.60±0.63 1t 122.09±4.29 1u 111.62±1.12 1v 97.67±2.46 Indomethacin 111.04±3.31

[0142] The test results above show that when the concentration is 25 μM and the LPS concentration is 1 μg / mL, compounds 1c, 1t, 1u, and 1v have better ability to inhibit NO release than the anti-inflammatory drug indomethacin, while 1a, 1b, and 1i are comparable to indomethacin. Compounds 1c, 1t, 1u, and 1v, which have stronger ability to inhibit NO release, have weaker cytotoxic effects on RAW264.7 cells. They have significant anti-inflammatory effects and low toxicity.

[0143] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A seco- evodiamine analogue, characterized in that, The structural general formula is: wherein R 1 and R 2 are H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, amino, fluorine, chlorine, bromine, trifluoromethyl; R 3 is H, methyl, hydroxymethyl, methoxymethyl.

2. The evodiamine analog of claim 1, wherein R 1 and R 2 is H, methoxy, ethoxy, methyl, nitro, fluorine, chlorine, bromine, trifluoromethyl; R 3 is H, methyl, hydroxymethyl, methoxymethyl.

3. The evodiamine analog of claim 1, wherein R 1 is H, methoxy, methyl, fluoro, chloro, bromo; R 2 is H, methoxy, methyl, chloro, bromo; R 3 is H, hydroxymethyl.

4. The method of claim 1-3, wherein the method is characterized by The specific steps are: (1) with isatin anhydride or its derivatives as raw material, acylation reaction with ethanolamine or its derivatives to generate benzamide derivatives, its molecular structure formula is as follows: , wherein, R 1 is H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl; R 3 is H, methyl, hydroxymethyl, methoxymethyl; (2) condensation and oxidation reaction of the benzamide derivative prepared in step (1) with 1H-indole-2-carboxaldehyde or its derivative under acidic conditions to generate a 4(3H)-quinazolinone derivative, the molecular structural formula of which is as follows: wherein, R 1 and R 2 are H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl; R 3 is H, methyl, hydroxymethyl, methoxymethyl; (3) The 4(3H)-quinazolinone derivative prepared in step (2) is subjected to intramolecular hydrogen transfer reaction with phthalocyanine iron as a catalyst to generate evodiamine analogues, and the molecular structural formula is as follows: wherein, R 1 and R 2 are H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl; R 3 is H, methyl, hydroxymethyl, methoxymethyl.

5. Use of a pseudo-wonjuja alkaloid analog according to any one of claims 1-3 in the preparation of an anti-inflammatory drug.

Images