A method for the synthesis of indole derivatives

Abstract

The present application provides a kind of synthesis method of indole derivative.The derivative of aniline and aryl or heteroaryl olefin are heated under the action of palladium catalyst and oxygen-free condition to obtain a compound, which is reduced to obtain indole derivative.The method of the present application is simple and safe in process operation, the raw materials used are economical and practical, the route is reasonable, the range of modification is wide, it is friendly to environment, the synthesis efficiency is improved, and the synthesis cost is reduced.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of an indole derivative. BACKGROUND

[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 very wide and important uses in the fields of industry, agriculture and medicine. As an important class of heterocyclic compounds, indole compounds have biological activity, widely exist in the animal, plant and microbial kingdoms, have low toxicity and good biocompatibility, and play an important role in the field of anticancer drug innovation.

[0003] Indole derivatives obtained by modifying the structures of different positions of indole as a lead compound using molecular hybridization strategies, splicing principles in drug design and chemical synthesis can have significant inhibitory effects on different cancer cells and malignant tumors. Patents (CN101516366) and (CN102307868A) report that various indole derivatives show excellent in vitro activity and excellent in vivo antitumor effects. Due to their significant biological and pharmacological activities and unique plasticity structures, the synthesis of indole derivatives has attracted widespread attention from chemists. At present, there are various 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 source of raw materials, relatively low yield, and high difficulty in separation and purification. Therefore, it is of great significance to develop a novel, efficient, low-energy, environmentally friendly and easy-to-operate synthesis method of indole derivatives. SUMMARY

[0004] In view of the defects of the prior art, the first object of the present application is to provide a synthesis method of an indole derivative. Compared with the prior art, the method has reasonable route, simple operation, relatively easy synthesis difficulty, wide range of modifiability, environmental friendliness, improved synthesis efficiency and reduced synthesis cost.

[0005] The object of the present application is achieved by the following technical solutions.

[0006] A synthesis method of an indole derivative, which uses compound 1 and compound 2 as raw materials, obtains compound 3 through palladium catalysis, and then reduces to obtain indole derivative 4:

[0007] ;

[0008] wherein R1-R5 are one of H, halogen, cyano, nitro, aryl, heteroaryl, substituted heteroaryl or substituted aryl; and Ar is one of aryl, heteroaryl, substituted heteroaryl or substituted aryl.

[0009] Further, the synthetic method comprises:

[0010] Step one: compound 1 and compound 2 are heated under the action of a palladium catalyst in an oxygen-free condition to obtain compound 3;

[0011] Step two: compound 3 obtained in step one is reduced using a reducing agent to obtain indole derivative 4.

[0012] Further, the Lewis base in the heating reaction in step one is one or more of potassium iodide and sodium iodide.

[0013] Further, the solvent used in step one is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, tetrahydrofuran, benzene, xylene, 1,4-dioxane, ethylene glycol dimethyl ether, ethanol and water.

[0014] Further, the temperature of the heating reaction in step one is 60-120°C, preferably 80-100°C.

[0015] Further, the palladium catalyst in step one is one or more of PdCl2, Pd(OAc)2, Pd(PPh3)Cl2 and Pd(dppf)Cl2, preferably PdCl2.

[0016] Further, the heating reaction in step one is carried out under nitrogen protection.

[0017] Further, the reduction reaction of compound 3 and the reducing agent in step two is carried out under hydrogen protection.

[0018] Further, the reduction reaction temperature of compound 3 and the reducing agent in step two is 40-100°C stirring for 5.0 hours, and the reduction reaction temperature is preferably 50-80°C.

[0019] Further, the reducing agent used in step two includes one or more of Pd / C, Pd(OH)2 / C, PtO2, Fe powder, Zn powder, Raney Ni and safety powder.

[0020] Advantages of the present application:

[0021] The method has simple and safe process operation, uses economical and practical raw materials, has reasonable route, wide modification range, is environment-friendly, improves synthesis efficiency and greatly reduces synthesis cost. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 1H NMR chart of 4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole in step (1) of Example 1;

[0023] Figure 2 1H NMR chart of 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-imidazole in step (2) of Example 1;

[0024] Figure 3 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

[0025] In order to make the objectives, technical solutions and advantages of the present application clearer, the embodiments of the present application will be described in detail below. However, those skilled in the art can understand that, in the embodiments of the present application, many technical details are presented in order to make the readers better understand the present application. However, the technical solutions claimed in each claim of the present application can be realized even without these technical details and based on various changes and modifications of the following embodiments. The raw materials used in the following embodiments of the present application are commercially available if not otherwise specified, and the experimental operations used are conventional operations in the art if not otherwise specified.

[0026] The raw materials used in the following embodiments are commercially available if not otherwise specified. Example 1

[0027] The present embodiment provides a synthetic method for preparing an indole derivative, which comprises the following steps:

[0028]

[0029] (1) To a solution of 4-iodo-5-methyl-lH-imidazole (3.0 g, 14.4 mmol) in tetrahydrofuran (30 mL) was added NaH (864 mg, 21.6 mmol) at 0 °C and stirred for 20 min at 0 °C. To the mixture was added SEMCl (2.3 g, 21.6 mmol). The reaction mixture was stirred for 2.0 h at 0 °C. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed with water (20 mL), brine (20 mL), dried over Na2S04, filtered and concentrated to give 4-iodo-5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (4.0 g, yield: 83.3%) as yellow oil.

[0030] 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).

[0031] (2) To a solution of 4-iodo-5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazole (100 mg, 294 umol) and potassium vinyltrifluoroborate (28 mg, 294 umol) in 1,4-dioxane (2.0 mL) and water (0.2 mL) was added Pd(dppf)Cl2(21 mg, 29.4 umol) and K2C03(121 mg, 882 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 x 20 mL). The organic layers were combined, washed with water (20 mL) and brine (20 mL), dried over Na2S04, filtered and concentrated to dryness. The residue was purified by preparative TLC (DCM / MeOH = 15: 1) to give 5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-lH-imidazole (50 mg, yield: 71.4%) as yellow solid.

[0032] 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).

[0033] (3) To a solution of 5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-lH- imidazole (240 mg, 965 umol) and 2,4-difluoro-6-((4-fluorophenyl)ethynyl)aniline (300 mg, 1.25 mmol) in DMF (5 mL) was added KI (208 mg, 1.25 mmol) and PdCl2(17 mg, 96.5 umol). The reaction mixture was stirred at 100 °C under nitrogen overnight. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, washed with water (20 mL) and brine (20 mL), dried over Na2S04, 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-(l-(5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)vinyl)-lH-indole (60 mg, yield 13%).

[0034] LCMS: [M+H]+=484.10;

[0035] (4) To a solution of 5,7-difluoro-2-(4-fluorophenyl)-3-(l-(5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)vinyl)-lH-indole (50 mg, 130 umol) in tetrahydrofuran (4 mL) and methanol (4 mL) was added Pd / C (10 mg). The mixture was stirred at 50 °C under hydrogen for 5.0 h. The mixture was filtered and concentrated in vacuo to give 5,7-difluoro-2-(4-fluorophenyl)-3-(l-(5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)ethyl)-lH-indole (30 mg, yield: 60%) as a yellow oil.

[0036] LCMS: [M+H]+=486.15.

[0037] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-3-(l-(5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)ethyl)-lH-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-(l-(5-methyl-lH-imidazol-4- yl)ethyl)-lH-indole as a white solid (9.5 mg, yield: 43.1%).

[0038] LCMS: [M+H]+=356.05,

[0039] 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

[0040] This example provides a synthetic method for preparing an indole derivative, which comprises the following steps:

[0041]

[0042] (1) To a solution of 4-amino-3-phenylethynylbenzoic acid methyl ester (500 mg, 1.99 mmol) and styrene (249 mg, 2.39 mmol) in DMF (8 mL) was added KI (429.4 mg, 2.59 mmol) and PdCl2(35 mg, 199 umol). The reaction mixture was stirred at 100 °C under nitrogen overnight. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, washed with water (30 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated to dryness. The crude product was purified by preparative TLC (Pet. Ether / EtOAc = 5: 1) to give 2-phenyl-3-(l-phenylvinyl)-lH-indole-5-carboxylic acid methyl ester (200 mg, yield 28%).

[0043] Int2-1:

[0044] LCMS: [M+H]+ = 354.2

[0045] 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)

[0046] (2) 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) was added Pd(OH)2 / C (40 mg). The mixture was stirred at 50 °C for 5.0 hours under hydrogen protection. The mixture was filtered and concentrated in vacuo to give methyl 2-phenyl-3-(1-phenylethyl)-1H-indole-5-carboxylate (150 mg, yield: 74%) as a light yellow solid.

[0047] TM:

[0048] LCMS: [M+H]+ = 356.2

[0049] 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, 1 H), 4.50- 4.48 (m,1H), 3.96 (s, 3 H), 1.46 (d, J=7.2Hz,3H)。 Example 3

[0050] This example provides a synthetic method for preparing an indole derivative, which comprises the following steps:

[0051] 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) was added KI (295.3 mg, 1.78 mmol) and PdCl2(24.3 mg, 137 umol). The reaction mixture was stirred at 100 °C under nitrogen overnight. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, washed with water (20 mL) and brine (20 ml), dried over Na2S04, filtered and concentrated to dryness. The crude product was purified by preparative TLC (Pet. Ether / EtOAc = 4: 1) to give 3-(l-phenylethenyl)-2-(pyridin-2-yl)-lH-indole-6-carbonitrile (70 mg, yield 16%).

[0052] Int3-1:

[0053] LCMS: [M+H]+ = 322.1

[0054] 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)

[0055] (2) To a solution of 3-(l-phenylethenyl)-2-(pyridin-2-yl)-lH-indole-6-carbonitrile (70 mg, 0.22 mmol) in dichloromethane (4 mL) and methanol (4 mL) was added Pd(OH)2 / C (10 mg) and Pd / C (10 mg). The mixture was stirred at 50 °C under hydrogen overnight. The mixture was filtered and concentrated in vacuo to give (3-(l-phenylethyl)-2-(pyridin-2-yl)-lH-indol-6-yl)methanamine (30 mg, yield: 42%) as a brown solid.

[0056] TM:

[0057] LCMS: [M+H]+ = 328.2

[0058] 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).

[0059] Finally, it should be noted that the ordinary skilled person in the art can understand that the above-mentioned embodiments are specific examples for implementing the present application, and in actual applications, various changes can be made in form and details without departing from the spirit and scope of the present application.

Claims

1. A method for the synthesis of an indole derivative, characterized in that, The compound 3 is obtained by using compound 1 and compound 2 as raw materials and through palladium catalysis, and then the indole derivative 4 is obtained by reduction: Wherein, R1 is one of aryl or heteroaryl, and Ar is one of aryl or heteroaryl; in addition, R2-R5 are one of H, halogen, cyano, nitro, aryl or heteroaryl; The synthesis method comprises: Step one: compound 1 and compound 2 are heated to react under the action of a palladium catalyst in an oxygen-free condition to obtain compound 3; Step two: a reducing agent is used to reduce the compound 3 obtained in the step one to obtain the indole derivative 4; The Lewis base in the heating reaction in the step one is one or more of potassium iodide and sodium iodide; The palladium catalyst in the step one is PdCl2.

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

3. The method of synthesis of claim 1, wherein, The temperature of the heating reaction in the step one is 80-100 DEG C.

4. The method of synthesis of claim 1, wherein, The heating reaction in the step one is carried out under nitrogen protection.

5. The method of synthesis of claim 1, wherein, The reduction reaction of compound 3 and the reducing agent in the step two is carried out under hydrogen protection.

6. The method of synthesis of claim 1, wherein, The reduction reaction temperature of compound 3 and the reducing agent in the step two is 40-100 DEG C under stirring for 5.0 hours, and the reduction reaction temperature is 50-80 DEG C.

7. The method of synthesis of claim 1, wherein, The reducing agent used in the step two comprises one or more of Pd / C, Pd(OH)2 / C, PtO2, Fe powder, Zn powder, Raney Ni and safety powder.

Images