Synthetic method of indole derivative

Abstract

The invention provides a synthetic method of an indole derivative. An aniline derivative and aryl or heteroaryl olefin are subjected to a heating reaction under an anaerobic condition under the action of a palladium catalyst to obtain a compound, and the compound is reduced to obtain the indole derivative. The method disclosed by the invention is simple and safe in process operation, the used raw materials are economical and practical, the route is reasonable, the modifiable range is wide, the method is environment-friendly, the synthesis efficiency is improved, and the synthesis cost is reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing indole derivatives. Background Art

[0002] Indole is a planar heterocyclic molecule composed of a six-membered benzene ring and a five-membered nitrogen-containing pyrrole ring, also known as benzopyrrole. Indole and its derivatives are important fine chemical raw materials and chemical products, and have a wide range of important uses in the fields of industry, agriculture, and medicine. As an important class of heterocyclic compounds, indole compounds have biological activity and are widely present in the animal, plant, and microbial kingdoms. They have the characteristics of low toxicity and good biocompatibility, and play an important role in the field of anti-cancer drug innovation.

[0003] Taking indole as the lead compound, the indole derivatives obtained by structurally modifying different positions of the indole group using molecular hybridization strategies, the principle of splicing in drug design, and chemical synthesis can have a significant inhibitory effect on different cancer cells and malignant tumors. Patents (CN101516366) and (CN102307868A) report that a variety of indole derivatives show excellent in vitro activity and excellent in vivo anti-tumor effects. Due to its significant biopharmacological activity and unique plastic structure, the synthesis of indole derivatives has always been widely concerned by chemists. At present, there are many methods that can be used for the preparation of indole derivatives (Tetrahedron Letters, 2011, vol.52, #22, p.2837-2839; Organic Letters, 2003, vol.5, #18, p.3213-3216; WO2019 / 200232). However, these methods have limitations such as limited raw material sources, relatively low yields, and high difficulty in separation and purification. Therefore, it is of great significance to study and develop a novel, efficient, low-energy, environmentally friendly and easy-to-operate synthesis method of indole derivatives. Summary of the invention

[0004] In view of the defects of the prior art, the first purpose of the present invention is to provide a method for synthesizing indole derivatives. Compared with the existing prior art, this method has a reasonable route, simple operation, easier synthesis difficulty, a wide range of modifiability, and is environmentally friendly, thereby improving synthesis efficiency and reducing synthesis costs.

[0005] The purpose of the present invention is achieved through the following technical solutions: A method for synthesizing an indole derivative, using compound 1 and compound 2 as raw materials, obtaining compound 3 by palladium catalysis, and then reducing to obtain indole derivative 4: ; Among them, R1-R5 are one of H, halogen, cyano, nitro, aryl, heteroaryl, substituted heteroaryl or substituted aryl; Ar is one of aryl, heteroaryl, substituted heteroaryl or substituted aryl.

[0006] Furthermore, the synthesis method comprises: Step 1: Compound 1 and compound 2 are subjected to heating reaction under the action of a palladium catalyst in an oxygen-free condition to obtain compound 3; Step 2: Using a reducing agent to reduce the compound 3 obtained in step 1 to obtain an indole derivative 4.

[0007] Furthermore, the Lewis base in the heating reaction in step 1 is one or more of potassium iodide and sodium iodide.

[0008] Furthermore, the solvent used in step 1 is one or more solvents selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, tetrahydrofuran, benzene, xylene, 1,4-dioxane, ethylene glycol dimethyl ether, ethanol, and water.

[0009] Furthermore, the temperature of the heating reaction in step 1 is 60-120°C, preferably 80-100°C.

[0010] Furthermore, the palladium catalyst in step 1 is one or more of PdCl2, Pd(OAc)2, Pd(PPh3)Cl2, Pd(dppf)Cl2, preferably PdCl2.

[0011] Furthermore, the heating reaction in step 1 is carried out under nitrogen protection.

[0012] Furthermore, the reduction reaction of compound 3 and the reducing agent in step 2 is carried out under the protection of hydrogen.

[0013] Furthermore, in the step 2, the reduction reaction temperature of compound 3 and the reducing agent is 40-100°C with stirring for 5.0 hours, and the reduction reaction temperature is preferably 50-80°C.

[0014] Furthermore, the reducing agent used in step 2 includes one or more of Pd / C, Pd(OH)2 / C, PtO2, Fe powder, Zn powder, Raney Ni, and hydrosulfite.

[0015] Beneficial effects of the present invention: The method of the invention has simple and safe process operation, uses economical raw materials, has a reasonable route, has a wide modifiability range, is environmentally friendly, improves synthesis efficiency, and greatly reduces synthesis cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is the 1H NMR spectrum of 4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole in step (1) of Example 1; Figure 2 1H NMR chart of 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-imidazole in step (2) of Example 1; Figure 3 This is the 1H NMR chart of 5,7-difluoro-2-(4-fluorophenyl)-3-(1-(5-methyl-1H-imidazol-4-yl)ethyl)-1H-indole in step (5) of Example 1. DETAILED DESCRIPTION

[0017] To make the purpose, technical scheme and advantages of the present invention clearer, each embodiment of the present invention will be described in detail below. However, it will be appreciated by those skilled in the art that in each embodiment of the present invention, many technical details are proposed in order to enable the reader to better understand the present invention. However, even without these technical details and various changes and modifications based on the following embodiments, the technical scheme claimed in each claim of the present invention can also be implemented. The raw materials used in the following embodiments of the present invention are conventionally commercially available unless otherwise specified, and the experimental operations used are conventional operations in the art unless otherwise specified.

[0018] Unless otherwise specified, the raw materials used in the following examples are all commercially available in the art. Example 1

[0019] This embodiment provides a synthetic method for preparing an indole derivative, which comprises the following steps:

[0020] (1) To a solution of 4-iodo-5-methyl-1H-imidazole (3.0 g, 14.4 mmol) in tetrahydrofuran (30 mL) was added NaH (864 mg, 21.6 mmol) at 0°C and stirred at 0°C for 20 minutes. SEMCl (2.3 g, 21.6 mmol) was added to the mixture. The reaction mixture was stirred at 0°C for 2.0 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated to obtain 4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (4.0 g, yield: 83.3%) as a yellow oil.

[0021] 1H NMR (400 MHz, Chloroform-d) δ 7.73 (s, 1H), 5.21 (d, J = 1.8 Hz,2H), 3.53 – 3.47 (m, 2H), 2.24 (s, 3H), 0.94 – 0.89 (m, 3H), -0.01 (s, 9H).

[0022] (2) Pd(dppf)Cl2 (21 mg, 29.4 umol) and K2CO3 (121 mg, 882 umol) were added to a solution of 4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (100 mg, 294 umol) and potassium salt of vinyl trifluoroborate (28 mg, 294 umol) in 1,4-dioxane (2.0 mL) and water (0.2 mL). The reaction mixture was stirred at 100°C overnight under nitrogen protection. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined, washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative TLC (DCM / MeOH = 15:1) to give 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-imidazole (50 mg, yield: 71.4%) as a yellow solid.

[0023] LCMS: M+H=239.10, 1H NMR (400 MHz, Chloroform-d) δ 7.59 (m, 1H), 6.67– 6.55 (m, 1H), 5.53 (d, J = 17.8 Hz, 1H), 5.41 – 5.30 (m, 1H), 5.22 (m, 2H), 3.53 – 3.44 (m, 2H), 2.29 (m, 3H), 0.90 (m, 2H), -0.01 (d, J = 2.6 Hz, 9H). (3) To a solution of 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-imidazole (240 mg, 965 umol) and 2,4-difluoro-6-((4-fluorophenyl)ethynyl)aniline (300 mg, 1.25 mmol) in DMF (5 mL) were added KI (208 mg, 1.25 mmol) and PdCl2 (17 mg, 96.5 umol). The reaction mixture was stirred at 100°C overnight under nitrogen protection. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined, washed with water (20 mL) and brine (20 ml), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by preparative TLC (Pet. Ether / EtOAc=3:1) to give 5,7-difluoro-2-(4-fluorophenyl)-3-(1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)vinyl)-1H-indole (60 mg, 13% yield).

[0024] LCMS: [M+H]+=484.10; (4) Pd / C (10 mg) was added to a solution of 5,7-difluoro-2-(4-fluorophenyl)-3-(1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethenyl)-1H-indole (50 mg, 130 umol) in tetrahydrofuran (4 mL) and methanol (4 mL). The mixture was stirred at 50°C for 5.0 hours under the protection of hydrogen. The mixture was filtered and concentrated in vacuo to give 5,7-difluoro-2-(4-fluorophenyl)-3-(1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)-1H-indole (30 mg, yield: 60%) as a yellow oil.

[0025] LCMS: [M+H]+=486.15.

[0026] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-3-(1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)-1H-indole (30 mg, 61.7 umol) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2.0 hours. The mixture was concentrated in vacuo and purified by preparative HPLC to give 5,7-difluoro-2-(4-fluorophenyl)-3-(1-(5-methyl-1H-imidazol-4-yl)ethyl)-1H-indole (9.5 mg, yield: 43.1%) as a white solid.

[0027] LCMS: [M+H]+=356.05, 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.94 (s, 1H), 7.60 (dd, J= 8.4, 5.4 Hz, 2H), 7.38 (t, J = 8.6 Hz, 2H), 7.27 (d, J = 10.0 Hz, 1H), 6.92(s, 1H), 4.35 (d, J = 7.4 Hz, 1H), 1.71 (d, J = 7.2 Hz, 3H), 1.67 (s, 3H). Example 2

[0028] This embodiment provides a synthetic method for preparing an indole derivative, which comprises the following steps:

[0029] (1) KI (429.4 mg, 2.59 mmol) and PdCl2 (35 mg, 199 umol) were added to a solution of methyl 4-amino-3-phenylethynylbenzoate (500 mg, 1.99 mmol) and styrene (249 mg, 2.39 mmol) in DMF (8 mL). The reaction mixture was stirred at 100 °C overnight under nitrogen protection. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were combined, washed with water (30 mL) and brine (30 ml), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by preparative TLC (Pet.Ether / EtOAc=5:1) to give methyl 2-phenyl-3-(1-phenylvinyl)-1H-indole-5-carboxylate (200 mg, yield 28%).

[0030] Int2-1: LCMS: [M+H]+ = 354.2 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1 H), 7.81 – 7.78 (m, 1 H), 7.50 (d, J = 7.2 Hz, 1 H), 7.46 – 7.35 (m, 10 H), 5.91 – 5.72 (m, 2 H), 3.96 (s, 3H) (2) Pd(OH)2 / C (40 mg) was added to a solution of methyl 2-phenyl-3-(1-phenylvinyl)-1H-indole-5-carboxylate (200 mg, 0.56 mmol) in dichloromethane (4 mL) and methanol (4 mL). The mixture was stirred at 50°C for 5.0 hours under hydrogen protection. The mixture was filtered and concentrated in vacuo to obtain methyl 2-phenyl-3-(1-phenylethyl)-1H-indole-5-carboxylate (150 mg, yield: 74%) as a pale yellow solid.

[0031] TM: LCMS: [M+H]+ = 356.2 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.71 (s, 1H), 7.81 – 7.78 (m, 1 H), 7.670 (d, J = 8.4 Hz, 1 H), 7.43 – 7.39 (m, 5 H), 7.35 – 7.29 (m, 4H), 7.22-7.19 (m, 1H), 4.50- 4.48 (m,1H), 3.96 (s, 3H), 1.46 (d, J=7.2Hz, 3H). Example 3

[0032] This embodiment provides a synthetic method for preparing an indole derivative, which comprises the following steps: To a solution of 3-amino-4-(pyridin-2-ylethynyl)benzonitrile (300 mg, 1.37 mmol) and styrene (171 mg, 1.64 mmol) in DMF (5 mL) were added KI (295.3 mg, 1.78 mmol) and PdCl2 (24.3 mg, 137umol). The reaction mixture was stirred at 100 °C overnight under nitrogen protection. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined, washed with water (20 mL) and brine (20 ml), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by preparative TLC (Pet.Ether / EtOAc=4:1) to give 3-(1-phenylvinyl)-2-(pyridin-2-yl)-1H-indole-6-carbonitrile (70 mg, yield 16%).

[0033] Int3-1: LCMS: [M+H]+ = 322.1 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.74 – 8.73 (m, 1 H), 8.04– 8.00 (m, 1 H), 7.87 – 7.85(m, 1 H), 7.65 – 7.35 (m, 9 H), 5.91 – 5.70 (m, 2H) (2) Pd(OH)2 / C (10 mg) and Pd / C (10 mg) were added to a solution of 3-(1-phenylethenyl)-2-(pyridin-2-yl)-1H-indole-6-carbonitrile (70 mg, 0.22 mmol) in dichloromethane (4 mL) and methanol (4 mL). The mixture was stirred at 50°C overnight under the protection of hydrogen. The mixture was filtered and concentrated in vacuo to obtain (3-(1-phenylethyl)-2-(pyridin-2-yl)-1H-indol-6-yl)methanamine (30 mg, yield: 42%) as a brown solid.

[0034] TM: LCMS: [M+H]+ = 328.2 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H),8.74 – 8.72 (m, 1H), 8.04 –7.98 (m, 2 H), 7.64 – 7.62 (m, 1 H), 7.53 – 7.59 (m, 1 H), 7.33 – 7.27 (m, 5H), 7.24 - 7.15 (m, 2 H), 4.50- 4.47 (m, 4H), 4.03-4.00 (m, 2 H), 1.46 (d, J=7.2 Hz, 3H).

[0035] Finally, it should be noted that those skilled in the art can understand that the above-mentioned embodiments are specific examples for realizing the present invention, and in actual applications, various changes can be made in form and details without departing from the spirit and scope of the present invention.

Claims

1. A method for synthesizing an indole derivative, characterized in that: Compound 1 and compound 2 are used as raw materials, and compound 3 is obtained by palladium catalysis, and then reduced to obtain indole derivative 4: ； Among them, R1-R5 are one of H, halogen, cyano, nitro, aryl, heteroaryl, substituted heteroaryl or substituted aryl; Ar is one of aryl, heteroaryl, substituted heteroaryl or substituted aryl.

2. The synthesis method according to claim 1, characterized in that The synthesis method comprises: Step 1: Compound 1 and compound 2 are subjected to heating reaction under the action of a palladium catalyst in an oxygen-free condition to obtain compound 3; Step 2: Using a reducing agent to reduce the compound 3 obtained in step 1 to obtain an indole derivative 4.

3. The synthesis method according to claim 2, characterized in that The Lewis base in the heating reaction in step 1 is one or more of potassium iodide and sodium iodide.

4. The synthesis method according to claim 2, characterized in that The solvent used in the step 1 is one or more solvents including N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, tetrahydrofuran, benzene, xylene, 1,4-dioxane, ethylene glycol dimethyl ether, ethanol and water.

5. The synthesis method according to claim 2, characterized in that The temperature of the heating reaction in step 1 is 60-120°C, preferably 80-100°C.

6. The synthesis method according to claim 2, characterized in that The palladium catalyst in step 1 is one or more of PdCl2, Pd(OAc)2, Pd(PPh3)Cl2, Pd(dppf)Cl2, preferably PdCl2.

7. The synthesis method according to claim 2, characterized in that The heating reaction in step 1 is carried out under nitrogen protection.

8. The synthesis method according to claim 2, characterized in that The reduction reaction between compound 3 and the reducing agent in step 2 is carried out under the protection of hydrogen.

9. The synthesis method according to claim 2, characterized in that: In the step 2, the reduction reaction temperature of compound 3 and the reducing agent is 40-100°C with stirring for 5.0 hours, and the reduction reaction temperature is preferably 50-80°C.

10. The synthesis method according to claim 2, characterized in that: The reducing agent used in the step 2 includes one or more of Pd / C, Pd(OH)2 / C, PtO2, Fe powder, Zn powder, Raney Ni, and hydrosulfite.

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