A process for the preparation of N-(2-acetylamino phenyl)-7-azaindole
By using the [Ru(p-cymene)Cl2]2 catalyst system under mild conditions, the efficient preparation of N-(2-acetamidophenyl)-7-azaindole was achieved, solving the problem of high temperature and high pressure in the existing technology, reducing costs and increasing yield.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- QINGDAO UNIV OF SCI & TECH
- Filing Date
- 2023-12-18
- Publication Date
- 2026-06-23
AI Technical Summary
Existing technologies for preparing N-(2-acylaminophenyl)-7-azaindole require complex process routes and high-temperature, high-pressure conditions, resulting in high costs, low efficiency, and unsuitability for industrial production.
The reaction was carried out in one step under mild conditions using [Ru(p-cymene)Cl2]2 as the main catalyst, AgNTf2 as the co-catalyst, and alkali metal acetic acid salt as the reaction promoter. 1,2-Dichloroethane or dichloromethane was used as the solvent, the reaction temperature was 50-80℃, and the reaction time was 8-24 hours. The subsequent separation was carried out by silica gel column chromatography.
It significantly shortens the process flow, reduces preparation costs, improves production safety and efficiency, and achieves high yield of the target product, making it suitable for industrial production.
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Figure CN117736204B_ABST
Abstract
Description
Technical Field
[0001] This application pertains to the synthesis technology of organic material compound intermediates, specifically relating to a method for preparing N-(2-acetamidophenyl)-7-azaindole. Background Technology
[0002] Benzo[4,5]imidazol[1,2-a]indole and quinoxaline[1,2-a]indole are important heterocyclic structural units widely used in materials chemistry. For example, US2019 / 0252623A1 discloses benzo[4,5]imidazol[1,2-a]indole compounds as barrier layer materials for organic layers in OLED devices. The patent describes a general method for preparing this type of compound: As can be seen from the above synthetic routes, N-(2-acylaminophenyl)indole is the key component in the synthesis of this type of fused nitrogen heterocyclic structure - benzo[4,5]imidazol[1,2-a]indole (J. Org. Chem., 2017, 82, 10158-10166; Org. Bio. Chem., 2016, 14, 2297–2305). However, when the above synthetic methods are used for different nitrogen heterocyclic skeletons, such as 7-azaindole, the corresponding formula A starting material is not readily available, requiring the design of complex process routes to pre-prepare the corresponding formula A starting material compound, which will obviously further increase the preparation cost and add steps. In addition, it is known in the art that N-(2-acylaminophenyl)-7-azaindole can be conveniently used to obtain quinoxaloline[1,2-a]indole under phosphorus oxychloride / reflux conditions (J. Org. Chem., 2018, 83, 10555-10563):
[0003] Therefore, it is worthwhile to study how to shorten the process and directly prepare N-(2-acylaminophenyl)-7-azaindole compounds with readily available raw materials in high yield. Dong Lin et al. disclosed that N-phenyl-7-azaindole can be prepared in one step by reacting 3-methyl-1,4,2-dioxazol-5-one with N-acetamidophenyl)-7-azaindole in the presence of [Cp*CoCl2]2 / AgNTf2. However, this method uses the low-boiling-point solvent dichloromethane and requires a reaction at a high temperature (100℃) for 36 hours, which is inefficient, energy-intensive, and makes it difficult to ensure production safety, making it unsuitable for industrial production (J.Org.Chem.,2018,83,10555-10563). The inventors accidentally discovered during their research that by improving the reaction conditions of N-phenyl-7-azaindole and 3-methyl-1,4,2-dioxazol-5-one, N-(2-acetamidophenyl)-7-azaindole could be prepared under milder conditions with high efficiency and high yield, thus leading to the present invention. Summary of the Invention
[0004] The purpose of this invention is to overcome the deficiencies of the prior art and provide a method for preparing N-(2-acetamidophenyl)-7-azaindole efficiently and in high yield by reacting N-phenyl-7-azaindole with 3-methyl-1,4,2-dioxazol-5-one under mild conditions in a single step with [Ru(p-cymene)Cl2]2 as the main catalyst, AgNTf2 as the co-catalyst, and an alkali metal salt of acetate as the reaction promoter.
[0005] A method for preparing N-(2-acetamidophenyl)-7-azaindole according to the present invention is characterized by comprising the following steps:
[0006] N-phenyl-7-azaindole, 3-methyl-1,4,2-dioxazol-5-one, [Ru(p-cymene)Cl2]2, AgNTf2, and reaction promoters were added to a reactor, followed by the addition of an organic solvent. The atmosphere inside the reactor was then replaced with an inert atmosphere, and the reaction was stirred at 50–80 °C for 8–24 hours. After complete reaction and purification, N-(2-acetamidophenyl)-7-azaindole was obtained. The reaction formula is as follows:
[0007]
[0008] According to the aforementioned preparation method of the present invention, the reaction aid is an alkali metal acetate, specifically any one of sodium acetate and potassium acetate, preferably sodium acetate.
[0009] According to the aforementioned preparation method of the present invention, the organic solvent is selected from any one or more of 1,2-dichloroethane (DCE) and dichloromethane (DCM), preferably 1,2-dichloroethane (DCE). The amount of solvent used is such that the concentration of N-phenyl-7-azaindole in the reaction system is 0.01 to 1 mol / L, preferably 0.1 mol / L.
[0010] According to the aforementioned preparation method of the present invention, the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably a nitrogen atmosphere.
[0011] According to the aforementioned preparation method of the present invention, the molar ratio of N-phenyl-7-azaindole, 3-methyl-1,4,2-dioxazol-5-one, [Ru(p-cymene)Cl2]2, AgNTf2 and the reaction aid is 1:(1-5):(0.01-0.1):(0.05-0.5):(0.05-1.0); preferably 1:2.5:0.05:0.2:0.5.
[0012] According to the aforementioned preparation method of the present invention, the reaction temperature is preferably 60-70°C, more preferably 60°C; the reaction time is preferably 8-12 hours, more preferably 12 hours.
[0013] According to the aforementioned preparation method of the present invention, the purification process is as follows: the reaction solution is concentrated to dryness and separated by silica gel column chromatography to obtain N-(2-acetamidophenyl)-7-azaindole.
[0014] This invention has the following significant technical advantages:
[0015] 1) Compared with US2019 / 0252623A1, the method of the present invention can obtain the intermediate N-(2-acetamidophenyl)-7-azaindole from readily available raw materials in one step, which significantly shortens the process flow and reduces the preparation steps and costs of organic materials.
[0016] 2) Compared to the method described in J. Org. Chem., 2018, 83, 10555-10563, the method of this invention uses [Ru(p-cymene)Cl2]2 as the main catalyst, further reducing the activation energy required for the reaction and avoiding the high temperature and high pressure conditions required for operation at high temperature (100°C) using the low-boiling-point solvent DCM. The reaction conditions are mild and simple, significantly improving production safety. Under the optimized catalytic system of this invention, the reaction can be completed in 12 hours at 60-70°C and normal pressure, greatly improving production efficiency. Furthermore, the method of this invention exhibits a high yield for the target product N-(2-acetamidophenyl)-7-azaindole. Attached Figure Description
[0017] Figure 1 N-(2-acetamidophenyl)-7-azaindole prepared by the method of Example 1 1 H NMR spectrum
[0018] Figure 2 N-(2-acetamidophenyl)-7-azaindole prepared by the method of Example 1 13 C NMR spectrum Detailed Implementation
[0019] The present invention will be further described in detail below with reference to specific embodiments. Unless otherwise specified, all reagents used herein were obtained through conventional commercial channels and were not further purified or dehydrated.
[0020] Example 1
[0021] In a 25 mL Schlenk sealed reactor equipped with a magnetic stirrer, N-phenyl-7-azaindole (38.8 mg, 0.2 mmol), 3-methyl-1,4,2-dioxazol-5-one (50.5 mg, 2.5 eq, 0.5 mmol), [Ru(p-cymene)Cl2]2 (5 mol%, 3 mg, approx. 0.01 mmol), AgNTf2 (20 mol%, 15.5 mg, approx. 0.04 mmol), and NaOAc (0.5 eq, 8.2 mg, 0.1 mmol) were added sequentially. Subsequently, 1,2-dichloroethane (0.1 M, based on N-phenyl-7-azaindole) was added as an organic solvent. The atmosphere in the reactor was purged three times with argon. The reactor was then placed at 60 °C and stirred for 12 hours. TLC / GC-MS analysis confirmed complete consumption of the starting N-phenyl-7-azaindole, at which point the reaction was terminated. The reaction solution was concentrated to dryness under reduced pressure and separated by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 20:1) to obtain 45.7 mg of the target product N-(2-acetamidophenyl)-7-azaindole, with a yield of 91%. The structural characterization data of the product are as follows: 1 H NMR (500MHz, CDCl3) δ9.24 (s, 1H), 8.35 (d, J = 4.7Hz, 1H), 8.05-8.02 (m, 2H), 7.43 (t, J = 7.3Hz, 1H), 7.3 8(d,J=3.5Hz,1H),7.30-7.26(m,2H),7.19(dd,J=7.7,4.8Hz,1H),6.71(d,J=3.5Hz,1H),1.93(s,3H). 13C NMR (126MHz, CDCl3) δ168.74,147.82,143.22,132.94,131.10,130.39,130.15,128.27,127.19,126.26,125.82,121.86,116.92,103.02,24.39.
[0022] Example 2
[0023] In a 25 mL Schlenk sealed reactor equipped with a magnetic stirrer, N-phenyl-7-azaindole (38.8 mg, 0.2 mmol), 3-methyl-1,4,2-dioxazol-5-one (50.5 mg, 2.5 eq, 0.5 mmol), [Ru(p-cymene)Cl2]2 (5 mol%, 3 mg, approx. 0.01 mmol), AgNTf2 (20 mol%, 15.5 mg, approx. 0.04 mmol), and NaOAc (0.5 eq, 8.2 mg, 0.1 mmol) were added sequentially. The organic solvent dichloromethane (0.1 M, based on N-phenyl-7-azaindole) was then added, and the atmosphere in the reactor was purged with argon three times. The reactor was then placed at 60 °C and stirred for 12 hours. The reaction was terminated after TLC / GC-MS showed that the starting material N-phenyl-7-azaindole was completely consumed. The reaction solution was concentrated to dryness under reduced pressure and separated by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 20:1) to obtain 41.7 mg of the target product N-(2-acetamidophenyl)-7-azaindole, with a yield of 83%.
[0024] Example 3
[0025] In a 25 mL Schlenk sealed reactor equipped with a magnetic stirrer, N-phenyl-7-azaindole (38.8 mg, 0.2 mmol), 3-methyl-1,4,2-dioxazol-5-one (50.5 mg, 2.5 eq, 0.5 mmol), [Ru(p-cymene)Cl2]2 (5 mol%, 3 mg, approx. 0.01 mmol), AgNTf2 (20 mol%, 15.5 mg, approx. 0.04 mmol), and NaOAc (0.5 eq, 8.2 mg, 0.1 mmol) were added sequentially. The organic solvent 1,2-dichloroethane (0.1 M, based on N-phenyl-7-azaindole) was then added, and the atmosphere in the reactor was purged with argon three times. The reactor was then placed at 70 °C and stirred for 12 hours. The reaction was terminated after TLC / GC-MS confirmed that the starting material N-phenyl-7-azaindole was completely consumed. The reaction solution was concentrated to dryness under reduced pressure and separated by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 20:1) to obtain 44.7 mg of the target product N-(2-acetamidophenyl)-7-azaindole, with a yield of 89%.
[0026] Example 4
[0027] In a 25 mL Schlenk sealed reactor equipped with a magnetic stirrer, N-phenyl-7-azaindole (38.8 mg, 0.2 mmol), 3-methyl-1,4,2-dioxazol-5-one (50.5 mg, 2.5 eq, 0.5 mmol), [Ru(p-cymene)Cl2]2 (5 mol%, 3 mg, approx. 0.01 mmol), AgNTf2 (20 mol%, 15.5 mg, approx. 0.04 mmol), and KOAc (0.5 eq, 9.8 mg, 0.1 mmol) were added sequentially. The organic solvent 1,2-dichloroethane (0.1 M, based on N-phenyl-7-azaindole) was then added, and the atmosphere in the reactor was purged three times with argon. The reactor was then stirred at 70°C for 12 hours. After TLC / GC-MS analysis confirmed complete consumption of the starting material N-phenyl-7-azaindole, the reaction was terminated. The reaction solution was concentrated to dryness under reduced pressure and separated by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate = 20:1) to obtain 40.2 mg of the target product N-(2-acetamidophenyl)-7-azaindole, with a yield of 80%.
[0028] Comparative Example 1
[0029] The main catalyst [Ru(p-cymene)Cl2]2 was replaced with [Cp*CoCl2]2, and the rest was the same as in Example 1. The yield of the target product N-(2-acetamidophenyl)-7-azaindole was 26%.
[0030] Comparative Example 2
[0031] Without the addition of the auxiliary agent NaOAc, the rest was the same as in Example 1, and the yield of the target product N-(2-acetamidophenyl)-7-azaindole was 37%.
[0032] The embodiments described above are merely preferred embodiments of the present invention and are not exhaustive examples of all possible implementations of the present invention. For those skilled in the art, any obvious modifications made without departing from the principles and spirit of the present invention should be considered to be included within the scope of protection of the claims of the present invention.
Claims
1. A method for preparing N-(2-acetamidophenyl)-7-azaindole, characterized in that, Includes the following steps: N-phenyl-7-azaindole, 3-methyl-1,4,2-dioxazol-5-one, [Ru(p-cymene)Cl2]2, AgNTf2, and reaction promoters were added to a reactor, followed by the addition of an organic solvent. The atmosphere inside the reactor was then replaced with an inert atmosphere, and the reaction was stirred at 60-70°C for 8-12 hours. After complete reaction and purification, N-(2-acetamidophenyl)-7-azaindole was obtained. The reaction formula is as follows: ； The reaction aid is an alkali metal acetate; the organic solvent is selected from either 1,2-dichloroethane (DCE) or dichloromethane (DCM). The alkali metal acetate is either sodium acetate or potassium acetate.
2. The preparation method according to claim 1, characterized in that, The organic solvent is selected from 1,2-dichloroethane (DCE).
3. The preparation method according to claim 1, characterized in that, The inert atmosphere is either a nitrogen atmosphere or an argon atmosphere.
4. The preparation method according to claim 1, characterized in that, The molar ratio of N-phenyl-7-azaindole, 3-methyl-1,4,2-dioxazol-5-one, [Ru(p-cymene)Cl2]2, AgNTf2 and reaction aids is 1: (1-5): (0.01-0.1): (0.05-0.5): (0.05-1.0).
5. The preparation method according to claim 4, characterized in that, The molar ratio of N-phenyl-7-azaindole, 3-methyl-1,4,2-dioxazol-5-one, [Ru(p-cymene)Cl2]2, AgNTf2 and reaction aids is 1:2.5:0.05:0.2:0.
5.
6. The preparation method according to claim 1, characterized in that, The reaction temperature was 60℃; the reaction time was 12 hours.
7. The preparation method according to claim 1, characterized in that, The purification process is as follows: the reaction solution is concentrated to dryness and separated by silica gel column chromatography to obtain N-(2-acetamidophenyl)-7-azaindole.