Continuous flow synthesis method of indole compound containing acyl at 3-site

Abstract

The invention relates to the technical field of chemical engineering, in particular to a continuous flow synthesis method of 3-site acyl-containing indole compounds, which specifically comprises the following steps: simultaneously pumping an indole compound solution and a diethyl aluminum chloride solution into a first group of micro-channel continuous flow reactors for mixed reaction; simultaneously introducing a material flowing out of the first group of microchannel continuous flow reactors and an acylation reagent solution into a second group of microchannel continuous flow reactors for reaction; and collecting the reaction liquid in the second group of microchannel continuous flow reactors, cooling, adding an acid solution, carrying out a quenching reaction, separating out a solid, filtering to obtain a crude product, and recrystallizing to obtain the 3-site acyl-containing indole compound. The method has the advantages of mild reaction conditions, simple raw materials, high yield, good purity, less three wastes, easy post-treatment, suitableness for industrial large-scale production, and environmental protection; the product yield can reach 80% or above, and the product purity can reach 99% or above.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical engineering, and particularly relates to a continuous flow synthesis method of 3-acyl indole compounds. Background Art

[0002] Indole compounds are an important fine chemical raw material, widely existing in nature. Due to their unique chemical structure and biological activity, they are widely used in industries such as pesticides, pharmaceuticals, spices, dyes, feeds, foods, and additives. Introducing an alkanoyl group at the C3 position of indole compounds to synthesize 3-acyl indole compounds has important application value and has been widely concerned and studied. For example: 3-acetylindole and 3-trifluoroacetylindole are important synthetic raw materials and intermediates, which are not only used in the synthesis of new compounds but also in the synthesis of drugs, such as the synthesis of Alzheimer's drugs and anti-AIDS drugs.

[0003] Currently, the introduction of an alkanoyl group at the C3 position of indole is mainly achieved by carrying out Friedel-crafts acylation reaction using different Lewis acids and acylating reagents. However, due to the characteristics of the indole system, it usually leads to competition between 1-acylation and 1,3-diacylation, and side reactions such as self-polymerization of indole and the formation of other by-products of diindolylmethane are often observed under acidic conditions. Acylating N-protected indole is usually a good choice, which can avoid the formation of 1-acyl derivatives, but the protection and deprotection therein will increase the difficulty of the reaction.

[0004] Existing reaction conditions are relatively harsh, or the steps are cumbersome, and the production cost is high; or both the reaction raw materials and products need pretreatment or post-treatment, which requires high equipment requirements, causes large environmental pollution, and has a low yield. Therefore, it is difficult to carry out large-scale production. In addition, most of the commercially available 3-acyl indoles currently have insufficient purity. For example, the currently commercially available products of 3-acetylindole are all with a purity of 98% or 97%, and the appearance color is red, which is difficult to meet the biomedical use standards. Summary of the Invention

[0005] In order to improve the purity of 3-acyl indole compounds and solve the technical problem that the production process is difficult to scale up, a continuous flow synthesis method of 3-acyl indole compounds is provided. Through the continuous flow process of the present invention, the operation is simple, the raw materials are simple, the yield of 3-acyl indole compounds is increased, and the product purity is high, up to 99%.

[0006] To achieve the above object, the present invention is realized through the following technical solutions:

[0007] A continuous flow synthesis method of 3-acyl indole compounds, comprising the following steps:

[0008]

[0009] S1. Simultaneously pump the indole compound solution and the diethylaluminum chloride solution into the first group of microchannel continuous flow reactors for mixing and reaction;

[0010] S2. Simultaneously introduce the material flowing out from the first group of microchannel continuous flow reactors and the acylating reagent solution into the second group of microchannel continuous flow reactors for reaction;

[0011] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors. After cooling, add an acid solution to carry out a quenching reaction while precipitating a solid. Filter to obtain a crude product, and recrystallize to obtain an indole compound containing an acyl group at the 3-position;

[0012] Among them, the indole compound has the chemical structure of formula I; the indole compound containing an acyl group at the 3-position has the chemical structure of formula II;

[0013] R1 is selected from one of a hydrogen atom, a normal alkyl or isoalkyl with 1-5 carbon atoms, a normal alkoxy or isoalkoxy with 1-5 carbon atoms, and a halogen;

[0014] R2 is selected from one of a hydrogen atom, a normal alkyl or isoalkyl with 1-5 carbon atoms;

[0015] R3 is selected from one of a normal alkyl or isoalkyl with 1-5 carbon atoms, a phenyl group, a trifluoroalkyl group, an alkoxyphenyl group, and a trialkoxyphenyl group.

[0016] Further, R1 is selected from one of a hydrogen atom, a methoxy group, a chlorine atom, a bromine atom, a methyl group, and an ethyl group; R2 is selected from a hydrogen atom or a methyl group; R3 is selected from one of a methyl group, an ethyl group, a tert-butyl group, a trifluoromethyl group, a phenyl group, a methoxyphenyl group, and a trimethoxyphenyl group.

[0017] Further, the acylating reagent is selected from one or more of acyl halides, acid anhydrides, and cyanide compounds, such as acetyl chloride, propionyl chloride, pivaloyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoyl chloride, 4-methoxybenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, etc.

[0018] Further, the molar ratio of the indole compound, diethylaluminum chloride, and the acylating reagent is 1: 1-1.5: 1.5-3.

[0019] Further, the temperature of the first group of microchannel continuous flow reactors is set below 10°C; the temperature of the second group of microchannel continuous flow reactors is set below 10°C; preferably, the temperatures of the two groups of reactors are 0-10°C respectively; more preferably, the temperatures of the two groups of reactors are 5-10°C respectively.

[0020] Furthermore, the residence time of the material in the first group of microchannel continuous flow reactors is 40 - 60 seconds; the residence time of the material in the second group of microchannel continuous flow reactors is in the range of 80 - 95 seconds.

[0021] Furthermore, the concentration of the indole compound solution is 0.5 - 3 mol / L; the concentration of the diethylaluminum chloride solution is 0.5 - 3 mol / L; the concentration of the acylating reagent solution is 1 - 5 mol / L.

[0022] Furthermore, the solvent in the indole compound solution is dichloromethane;

[0023] the solvent in the diethylaluminum chloride solution is n - hexane;

[0024] the solvent in the acylating reagent solution is dichloromethane.

[0025] Furthermore, the temperature is lowered to 0 - 5 °C and 0.5 - 3 mol / L aqueous hydrochloric acid solution is added for quenching reaction; recrystallization is carried out using ethanol and ethyl acetate.

[0026] Beneficial technical effects:

[0027] The present invention relates to a method for introducing an acyl group at the C3 position of indole compounds, and efficiently realizes the synthesis of indole compounds with an acyl group at C3 through a microchannel continuous flow technology. The yield and purity of the indole compounds with an acyl group at the 3 - position of the present invention are effectively improved; the reaction conditions of the present invention are relatively mild, the raw materials are simple, the yield is high, the purity is good, and the three wastes are less. The post - treatment is relatively easy and suitable for large - scale industrial production, which is green and environmentally friendly; the present invention is carried out in a microchannel continuous flow reactor, the intermediate products do not need to be separated, and after the reaction is completed, only simple quenching and cooling crystallization are required to obtain high - purity indole compounds with an acyl group at the 3 - position. Description of the Drawings

[0028] Figure 1 It is a process method for continuously synthesizing 3 - acetylindole in Examples 1 - 13; the marks ①②③ are all plunger pumps, ④ is the first group of microchannel continuous flow reactors, and ⑤ is the second group of microchannel continuous flow reactors;

[0029] Figure 2 It is the liquid chromatography purity spectrum of the product 3 - acetylindole in Example 1. Specific Embodiments

[0030] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments and drawings of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and in no way limits the present invention and its application or use. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0031] Unless otherwise specifically stated, the numerical values set forth in these embodiments do not limit the scope of the present invention. Technologies and methods known to those of ordinary skill in the relevant art may not be discussed in detail, but where appropriate, such technologies and methods should be regarded as part of the specification. In all examples shown and discussed herein, any specific value should be construed as merely exemplary and not as a limitation. Therefore, other examples of the exemplary embodiments may have different values.

[0032] The experimental methods without specific conditions noted in the following embodiments are generally determined according to national standards; if there are no corresponding national standards, they are carried out according to general standard requirements or general methods.

[0033] The microchannel continuous flow reactor, the first group of microchannel continuous flow reactors ④ is composed of two glass chips, and the second group of microchannel continuous flow reactors ⑤ is composed of five glass chips. The liquid holding capacity of each glass chip is 20 mL. The tube diameter of the microchannel continuous flow reactor is 1 mm. The residence time refers to the time required for the material to pass through the microchannel continuous flow reactor. The specific calculation method is: residence time = liquid holding volume × (60 s / min) / total volume flow rate; the liquid holding volume is the capacity of the continuous flow reactor, and the fixed value of a single chip is 20 mL; the total volume flow rate is the sum of the flow rates of each injection pump.

[0034] Example 1

[0035] The microchannel continuous flow synthesis method of 3-acetylindole, the process flow is as Figure 1 shown, and includes the following steps:

[0036] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make up to 200 mL, and stir until the indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0037] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (28 mL, 0.4 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make up to 200 mL, and stir until the acetyl chloride is completely dissolved to obtain a 2 mol / L acetyl chloride dichloromethane solution.

[0038] S1. Feed the diethylaluminum chloride n-hexane solution (250 mL, 1 mol / L) at a flow rate of 25 mL / min and the indole dichloromethane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min into the first group of microchannel continuous flow reactors set at a temperature of 10°C using a plunger pump. The residence time of the mixed reaction of the materials in the first group of microchannel continuous flow reactors is 53 s;

[0039] S2. Feed the material flowing out of the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 2 mol / L) with a set flow rate of 25 mL / min into the second group of microchannel continuous flow reactors set at a temperature of 10°C simultaneously. The residence time of the reaction of the materials in the second group of microchannel continuous flow reactors is 86 s;

[0040] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0°C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The appearance of the product is white crystals, and the yield is 92 wt%.

[0041] Perform 1H NMR and 13C NMR tests on 3-acetylindole, and the results are as follows:

[0042] 1 H NMR (400 MHz, DMSO-d6): δ = 11.91 (s, 1H), 8.30 (d, J = 2.9 Hz, 1H), 8.19 (d, J = 7.3 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.19 (p, J = 6.4, 6.0 Hz, 2H), 2.45 (s, 3H);

[0043] 13 C NMR (100 MHz, DMSO): δ = 192.67, 136.63, 134.32, 125.26, 122.69, 121.63, 121.30, 116.77, 112.04, 27.20.

[0044] Detect the purity of 3-acetylindole in this case according to the enterprise standard Q / CYDZ 3862 - 2025. The liquid chromatogram is as Figure 2 shown, and it can be seen that the purity of the product is as high as 99.4 wt%.

[0045] Example 2

[0046] The microchannel continuous flow synthesis method of 3-acetylindole includes the following steps:

[0047] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) into a 500 mL three-necked flask. Under nitrogen protection, add anhydrous dichloromethane to make the volume up to 200 mL. Stir until indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0048] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (28 mL, 0.4 mol) into a 500 mL three-necked flask. Under nitrogen protection, add anhydrous dichloromethane to make the volume up to 200 mL. Stir until acetyl chloride is completely dissolved to obtain a 2 mol / L acetyl chloride dichloromethane solution.

[0049] S1. Feed the diethylaluminum chloride n-hexane solution (250 mL, 1 mol / L) into the first group of microchannel continuous flow reactors set at 5°C at a flow rate of 25 mL / min, and feed the indole dichloromethane solution (200 mL, 1 mol / L) into the first group of microchannel continuous flow reactors set at 5°C at a flow rate of 20 mL / min. The residence time of the mixing reaction of the materials in the first group of microchannel continuous flow reactors is 53 s;

[0050] S2. Feed the material flowing out of the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 2 mol / L) with a set flow rate of 25 mL / min into the second group of microchannel continuous flow reactors set at 5°C at the same time. The residence time of the reaction of the materials in the second group of microchannel continuous flow reactors is 86 s;

[0051] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0°C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The product appearance is white crystals, and the yield is 93 wt% (purity 99%).

[0052] Example 3

[0053] A microchannel continuous flow synthesis method of 3-acetylindole, comprising the following steps:

[0054] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) into a 500 mL three-necked flask. Under nitrogen protection, add anhydrous dichloromethane to make the volume up to 200 mL. Stir until indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0055] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (28 mL, 0.4 mol) into a 500 mL three-necked flask. Under nitrogen protection, add anhydrous dichloromethane to make the volume up to 200 mL. Stir until acetyl chloride is completely dissolved to obtain a 2 mol / L acetyl chloride dichloromethane solution.

[0056] S1. Feed the diethylaluminum chloride n - hexane solution (250 mL, 1 mol / L) at a flow rate of 25 mL / min and the indole dichloromethane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min into the first - group microchannel continuous - flow reactor set at 0 °C using a plunger pump. The residence time for the mixed reaction of the materials in the first - group microchannel continuous - flow reactor is 53 s;

[0057] S2. Feed the material flowing out of the first - group microchannel continuous - flow reactor and the acetyl chloride dichloromethane solution (200 mL, 2 mol / L) with a set flow rate of 25 mL / min into the second - group microchannel continuous - flow reactor set at 0 °C simultaneously. The residence time for the reaction of the materials in the second - group microchannel continuous - flow reactor is 86 s;

[0058] S3. Collect the reaction solution in the second - group microchannel continuous - flow reactor, cool the reaction solution to 0 °C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3 - acetylindole. The product appearance is white crystals, and the yield is 85 wt% (purity 98.5%).

[0059] Example 4

[0060] A microchannel continuous - flow synthesis method of 3 - acetylindole, comprising the following steps:

[0061] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) to a 500 - mL three - necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until the indole is completely dissolved to obtain a 1 - mol / L indole dichloromethane solution;

[0062] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (28 mL, 0.4 mol) to a 500 - mL three - necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until the acetyl chloride is completely dissolved to obtain a 2 - mol / L acetyl chloride dichloromethane solution.

[0063] S1. Feed the diethylaluminum chloride n - hexane solution (250 mL, 1 mol / L) at a flow rate of 25 mL / min and the indole dichloromethane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min into the first - group microchannel continuous - flow reactor set at 20 °C using a plunger pump. The residence time for the mixed reaction of the materials in the first - group microchannel continuous - flow reactor is 53 s;

[0064] S2. Feed the material flowing out from the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 2 mol / L) with a flow rate set at 25 mL / min into the second group of microchannel continuous flow reactors with the temperature set at 20 °C simultaneously. The residence time of the material in the second group of microchannel continuous flow reactors for the reaction is 86 s;

[0065] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0 °C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The product appearance is white crystals, and the yield is 76 wt% (purity 98.3%).

[0066] Example 5

[0067] A microchannel continuous flow synthesis method of 3-acetylindole, comprising the following steps:

[0068] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0069] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (28 mL, 0.4 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until acetyl chloride is completely dissolved to obtain a 2 mol / L acetyl chloride dichloromethane solution.

[0070] S1. Feed the diethylaluminum chloride n-hexane solution (250 mL, 1 mol / L) at a flow rate of 25 mL / min and the indole dichloromethane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min into the first group of microchannel continuous flow reactors with the temperature set at 40 °C by using a plunger pump. The residence time of the material in the first group of microchannel continuous flow reactors for the mixing reaction is 53 s;

[0071] S2. Feed the material flowing out from the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 2 mol / L) with a flow rate set at 25 mL / min into the second group of microchannel continuous flow reactors with the temperature set at 40 °C simultaneously. The residence time of the material in the second group of microchannel continuous flow reactors for the reaction is 86 s;

[0072] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0 °C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until the pH is 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The product is white crystals in appearance, with a yield of 36 wt% (purity 98%).

[0073] Example 6

[0074] The microchannel continuous flow synthesis method of 3-acetylindole includes the following steps:

[0075] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0076] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (28 mL, 0.4 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until acetyl chloride is completely dissolved to obtain a 2 mol / L acetyl chloride dichloromethane solution.

[0077] S1. Feed the diethylaluminum chloride n-hexane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min and the indole dichloromethane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min into the first group of microchannel continuous flow reactors set at a temperature of 10 °C by using a plunger pump. The residence time for the mixed reaction of the materials in the first group of microchannel continuous flow reactors is 60 s;

[0078] S2. Feed the material flowing out of the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 2 mol / L) with a set flow rate of 25 mL / min into the second group of microchannel continuous flow reactors set at a temperature of 10 °C at the same time. The residence time for the reaction of the materials in the second group of microchannel continuous flow reactors is 92 s;

[0079] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0 °C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until the pH is 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The product is white crystals in appearance, with a yield of 88 wt% (purity 99%).

[0080] Example 7

[0081] The microchannel continuous flow synthesis method of 3-acetylindole includes the following steps:

[0082] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) to a 500 mL three-necked flask. Under nitrogen protection, add anhydrous dichloromethane to make the volume up to 200 mL. Stir until indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0083] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (28 mL, 0.4 mol) to a 500 mL three-necked flask. Under nitrogen protection, add anhydrous dichloromethane to make the volume up to 200 mL. Stir until acetyl chloride is completely dissolved to obtain a 2 mol / L acetyl chloride dichloromethane solution.

[0084] S1. Feed the diethylaluminum chloride n-hexane solution (300 mL, 1 mol / L) into the first group of microchannel continuous flow reactors set at 10 °C at a flow rate of 30 mL / min, and feed the indole dichloromethane solution (200 mL, 1 mol / L) into the first group of microchannel continuous flow reactors set at 10 °C at a flow rate of 20 mL / min. The retention time of the mixed reaction of the materials in the first group of microchannel continuous flow reactors is 48 s;

[0085] S2. Feed the material flowing out of the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 2 mol / L) with a set flow rate of 25 mL / min into the second group of microchannel continuous flow reactors set at 10 °C at the same time. The retention time of the reaction of the materials in the second group of microchannel continuous flow reactors is 80 s;

[0086] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors. Cool the reaction solution to 0 °C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The appearance of the product is white crystals, and the yield is 90 wt% (purity 98%).

[0087] Example 8

[0088] A microchannel continuous flow synthesis method of 3-acetylindole, comprising the following steps:

[0089] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) to a 500 mL three-necked flask. Under nitrogen protection, add anhydrous dichloromethane to make the volume up to 200 mL. Stir until indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0090] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (28 mL, 0.4 mol) to a 500 mL three-necked flask. Under nitrogen protection, add anhydrous dichloromethane to make the volume up to 200 mL. Stir until acetyl chloride is completely dissolved to obtain a 2 mol / L acetyl chloride dichloromethane solution.

[0091] S1. Feed the diethylaluminum chloride n - hexane solution (400 mL, 1 mol / L) at a flow rate of 40 mL / min and the indole dichloromethane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min into the first - stage microchannel continuous - flow reactor with a set temperature of 10 °C using a plunger pump. The residence time of the mixed reaction of the materials in the first - stage microchannel continuous - flow reactor is 40 s;

[0092] S2. Feed the material flowing out of the first - stage microchannel continuous - flow reactor and the acetyl chloride dichloromethane solution (200 mL, 2 mol / L) with a set flow rate of 20 mL / min into the second - stage microchannel continuous - flow reactor with a set temperature of 10 °C simultaneously. The residence time of the reaction of the materials in the second - stage microchannel continuous - flow reactor is 75 s;

[0093] S3. Collect the reaction solution in the second - stage microchannel continuous - flow reactor, cool the reaction solution to 0 °C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3 - acetylindole. The appearance of the product is white crystals, and the yield is 63 wt% (purity 98%).

[0094] Example 9

[0095] A microchannel continuous - flow synthesis method of 3 - acetylindole, comprising the following steps:

[0096] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) to a 500 - mL three - necked flask, add anhydrous dichloromethane to make up to 200 mL under nitrogen protection, and stir until the indole is completely dissolved to obtain a 1 - mol / L indole dichloromethane solution;

[0097] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (14 mL, 0.2 mol) to a 500 - mL three - necked flask, add anhydrous dichloromethane to make up to 200 mL under nitrogen protection, and stir until the acetyl chloride is completely dissolved to obtain a 1 - mol / L acetyl chloride dichloromethane solution.

[0098] S1. Feed the diethylaluminum chloride n - hexane solution (250 mL, 1 mol / L) at a flow rate of 25 mL / min and the indole dichloromethane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min into the first - stage microchannel continuous - flow reactor with a set temperature of 10 °C using a plunger pump. The residence time of the mixed reaction of the materials in the first - stage microchannel continuous - flow reactor is 53 s;

[0099] S2. Feed the material flowing out from the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 1 mol / L) with a flow rate set at 25 mL / min into the second group of microchannel continuous flow reactors with the temperature set at 10°C simultaneously. The residence time of the material in the second group of microchannel continuous flow reactors for the reaction is 86 s;

[0100] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0°C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The appearance of the product is white crystals, and the yield is 78 wt% (purity 98.2%).

[0101] Example 10

[0102] A microchannel continuous flow synthesis method of 3-acetylindole, comprising the following steps:

[0103] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to a constant volume of 200 mL, and stir until indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0104] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (21 mL, 0.3 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to a constant volume of 200 mL, and stir until acetyl chloride is completely dissolved to obtain a 1.5 mol / L acetyl chloride dichloromethane solution.

[0105] S1. Feed the diethylaluminum chloride n-hexane solution (250 mL, 1 mol / L) at a flow rate of 25 mL / min and the indole dichloromethane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min into the first group of microchannel continuous flow reactors with the temperature set at 10°C by using a plunger pump. The residence time of the material in the first group of microchannel continuous flow reactors for the mixing reaction is 53 s;

[0106] S2. Feed the material flowing out from the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 1.5 mol / L) with a flow rate set at 25 mL / min into the second group of microchannel continuous flow reactors with the temperature set at 10°C simultaneously. The residence time of the material in the second group of microchannel continuous flow reactors for the reaction is 86 s;

[0107] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0 °C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The product appears as white crystals, and the yield is 97 wt% (purity 99.4%).

[0108] Example 11

[0109] The microchannel continuous flow synthesis method of 3-acetylindole includes the following steps:

[0110] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to a constant volume of 200 mL, and stir until indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0111] Preparation of acetyl chloride dichloromethane solution: Add acetyl chloride (42 mL, 0.6 mol) to a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to a constant volume of 200 mL, and stir until acetyl chloride is completely dissolved to obtain a 3 mol / L acetyl chloride dichloromethane solution.

[0112] S1. Feed the diethylaluminum chloride n-hexane solution (250 mL, 1 mol / L) at a flow rate of 25 mL / min and the indole dichloromethane solution (200 mL, 1 mol / L) at a flow rate of 20 mL / min into the first group of microchannel continuous flow reactors set at a temperature of 10 °C by using a plunger pump. The residence time of the materials in the first group of microchannel continuous flow reactors for the mixed reaction is 53 s;

[0113] S2. Feed the material flowing out of the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 3 mol / L) with a set flow rate of 25 mL / min into the second group of microchannel continuous flow reactors set at a temperature of 10 °C at the same time. The residence time of the materials in the second group of microchannel continuous flow reactors for the reaction is 86 s;

[0114] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0 °C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The product appears as white crystals, and the yield is 90 wt% (purity 98.5%).

[0115] Example 12

[0116] The microchannel continuous flow synthesis method of 3-acetylindole includes the following steps:

[0117] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) into a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until the indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0118] Preparation of acetyl chloride dichloromethane solution: Add acetic anhydride (28 mL, 0.3 mol) into a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until the acetic anhydride is completely dissolved to obtain a 1.5 mol / L acetic anhydride dichloromethane solution.

[0119] S1. Feed the diethylaluminum chloride n-hexane solution (250 mL, 1 mol / L) into the first group of microchannel continuous flow reactors set at 10 °C at a flow rate of 25 mL / min, and feed the indole dichloromethane solution (200 mL, 1 mol / L) into the first group of microchannel continuous flow reactors at a flow rate of 20 mL / min. The retention time of the mixed reaction of the materials in the first group of microchannel continuous flow reactors is 53 s;

[0120] S2. Feed the material flowing out from the first group of microchannel continuous flow reactors and the acetyl chloride dichloromethane solution (200 mL, 1.5 mol / L) with a set flow rate of 25 mL / min into the second group of microchannel continuous flow reactors set at 10 °C at the same time. The retention time of the reaction of the materials in the second group of microchannel continuous flow reactors is 86 s;

[0121] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0 °C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole. The appearance of the product is white crystals, and the yield is 80 wt% (purity 98.5%).

[0122] Example 13

[0123] A microchannel continuous flow synthesis method of 3-acetylindole, comprising the following steps:

[0124] Preparation of indole dichloromethane solution: Add indole (23.4 g, 0.2 mol) into a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until the indole is completely dissolved to obtain a 1 mol / L indole dichloromethane solution;

[0125] Preparation of acetyl chloride dichloromethane solution: Add acetonitrile (16 mL, 0.3 mol) into a 500 mL three-necked flask, add anhydrous dichloromethane under nitrogen protection to make the volume up to 200 mL, and stir until the acetonitrile is completely dissolved to obtain a 1.5 mol / L acetonitrile dichloromethane solution.

[0126] S1. Feed the diethylaluminum chloride n-hexane solution (250 mL, 1 mol / L) into the first group of microchannel continuous flow reactors set at 10°C at a flow rate of 25 mL / min, and feed the indole dichloromethane solution (200 mL, 1 mol / L) into the first group of microchannel continuous flow reactors at a flow rate of 20 mL / min. The residence time of the mixed reaction of the materials in the first group of microchannel continuous flow reactors is 53 s;

[0127] S2. Feed the material flowing out of the first group of microchannel continuous flow reactors and the acetonitrile dichloromethane solution (200 mL, 1.5 mol / L) with a set flow rate of 25 mL / min into the second group of microchannel continuous flow reactors set at 10°C at the same time. The residence time of the reaction of the materials in the second group of microchannel continuous flow reactors is 86 s;

[0128] S3. Collect the reaction solution in the second group of microchannel continuous flow reactors, cool the reaction solution to 0°C, slowly add 1 mol / L hydrochloric acid aqueous solution to quench the reaction until pH = 7 - 8, precipitate solids, filter to obtain the crude product, and recrystallize with ethanol and ethyl acetate to obtain 3-acetylindole with a yield of 33 wt% (purity 98%).

[0129] The process parameters of Examples 1 to 13 above are shown in Table 1 below.

[0130] Table 1 Microchannel continuous flow reaction process parameters of 3-acetylindole

[0131]

[0132]

[0133] As can be seen from Table 1, when the temperatures of the two groups of microchannels are 0 - 10°C, the residence time in the first group of microchannel reactors is 40 - 60 s, and the residence time in the second group of microchannel reactors is 82 - 95 s, the yield of 3-acetylindole obtained is as high as over 80%;

[0134] Preferably, when the temperatures of the two groups of microchannels are 5 - 10°C, the residence time in the first group of microchannel reactors is 40 - 55 s, and the residence time in the second group of microchannel reactors is 80 - 88 s, the yield of 3-acetylindole obtained is as high as over 90%, and the appearance of the product is white crystals.

[0135] Example 14

[0136] This example is a microchannel continuous flow synthesis method of 3-benzoylindole. The preparation process is the same as that in Example 10, with the difference that the acylating reagent is benzoyl chloride (34.8 mL, 0.3 mol) to prepare a 200 mL, 1.5 mol / L benzoyl chloride dichloromethane solution; the product is 3-benzoylindole, and the yield is 87 wt% (purity 99%).

[0137] The 1H NMR and 13C NMR tests of 3-benzoylindole were carried out, and the results are as follows:

[0138] 1 H NMR(400MHz,DMSO-d6):δ=12.12(s,1H),8.30(d,J=8.0Hz,1H),7.97(s,1H),7.82(d,J=7.2Hz,2H),7.63-7.58(m,1H),7.56-7.51(m,3H),7.29-7.22(m,2H);

[0139] 13 C NMR(100MHz,DMSO-d6):δ=190.44,140.99,137.17,136.17,131.47,128.75,126.71,123.59,122.29,121.86,115.45,112.60。

[0140] Example 15

[0141] This example is a microchannel continuous flow synthesis method of 4-methoxy-3-benzoylindole. The preparation process is the same as that in Example 10, with the difference that 4-methoxyindole (29.4 g, 0.2 mol) is used to prepare a 200 mL, 1 mol / L 4-methoxyindole dichloromethane solution, and benzoyl chloride (34.8 mL, 0.3 mol) is used to prepare a 200 mL, 1.5 mol / L benzoyl chloride dichloromethane solution; the product is 4-methoxy-3-benzoylindole, and the yield is 88 wt% (purity 99%).

[0142] The 1H NMR and 13C NMR tests of 4-methoxy-3-benzoylindole were carried out, and the results are as follows:

[0143] 1 H NMR(400MHz,DMSO-d6):δ=11.90(s,1H),7.74-7.71(m,3H),7.61-7.57(m,1H),7.50-7.46(m,2H),7.24-7.07(m,2H),6.62(d,J=7.2Hz,1H),3.55(s,3H);

[0144] 1313C NMR (100 MHz, DMSO-d6): δ = 190.50, 153.92, 140.88, 138.65, 132.12, 132.02, 129.49, 128.38, 124.22, 116.78, 116.12, 105.73, 102.46, 55.34。

[0145] Example 16

[0146] This example is a microchannel continuous flow synthesis method of 5-chloro-3-benzoylindole. The preparation process is the same as that of Example 10, with the difference that: 5-chloroindole (30.3 g, 0.2 mol) is made into a 200 mL, 1 mol / L 5-chloroindole dichloromethane solution, and benzoyl chloride (34.8 mL, 0.3 mol) is made into a 200 mL, 1.5 mol / L benzoyl chloride dichloromethane solution; the product is 5-chloro-3-benzoylindole, and the yield is 86 wt% (purity 99%).

[0147] 1H NMR and 13C NMR tests were performed on 5-chloro-3-benzoylindole, and the results are as follows:

[0148] 1 1H NMR (400 MHz, DMSO-d6): δ = 12.27 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.05 (s, 2H), 7.80 (d, J = 7.2 Hz, 2H), 7.65 - 7.46 (m, 4H), 7.29 (dd, J = 8.4, 2.0 Hz, 2H);

[0149] 13 13C NMR (100 MHz, DMSO-d6): δ = 190.31, 140.53, 137.61, 135.70, 131.81, 128.98, 128.91, 127.92, 127.13, 123.69, 121.05, 114.97, 114.43。

[0150] Example 17

[0151] This example is a microchannel continuous flow synthesis method of 6-methyl-3-benzoylindole. The preparation process is the same as that of Example 10, with the difference that: 6-methylindole (26.2 g, 0.2 mol) is made into a 200 mL, 1 mol / L 6-methylindole dichloromethane solution, and benzoyl chloride (34.8 mL, 0.3 mol) is made into a 200 mL, 1.5 mol / L benzoyl chloride dichloromethane solution; the product is 6-methyl-3-benzoylindole, and the yield is 90 wt% (purity 99%).

[0152] The nuclear magnetic resonance hydrogen spectrum and carbon spectrum of 6-methyl-3-benzoylindole were tested, and the results are as follows:

[0153] 1 H NMR(400MHz,DMSO-d6):δ=11.92(s,1H),7.58-7.45(m,5H),7.36(d,J=7.9Hz,1H),7.30(d,J=7.8Hz,1H),7.11-7.07(m,1H),7.00-6.96(m,1H),2.35(s,3H);

[0154] 13 C NMR(100MHz,DMSO-d6):δ=192.33,145.00,142.12,135.45,131.55,128.87,128.49,127.75,122.36,121.47,120.48,112.96,111.76,14.67。

[0155] Example 18

[0156] This example is a microchannel continuous flow synthesis method of 5-bromo-3-acetylindole. The preparation process is the same as that of Example 10, with the difference that: 5-bromoindole (39.2 g, 0.2 mol) was made into a 200 mL, 1 mol / L 5-bromoindole dichloromethane solution; the product is 5-bromo-3-acetylindole, and the yield is 86 wt% (purity 99%).

[0157] The nuclear magnetic resonance hydrogen spectrum and carbon spectrum of 5-bromo-3-acetylindole were tested, and the results are as follows:

[0158] 1 H NMR(400MHz,DMSO-d6):δ=12.13(s,1H),8.37(s,1H),8.32(s,1H),7.47(d,J=8.8Hz,1H),7.36(d,J=8.8Hz,1H),2.47(s,3H);

[0159] 13 C NMR(100MHz,DMSO-d6):δ=193.19,136.06,135.88,127.52,125.79,123.89,116.71,114.92,114.68,27.66。

[0160] Example 19

[0161] This example is a microchannel continuous flow synthesis method of 5-bromo-2-methyl-3-(4-methoxybenzoyl)indole. The preparation process is the same as that in Example 10, with the difference that: 5-bromo-2-methylindole (42 g, 0.2 mol) is made into a 200 mL, 1 mol / L 5-bromo-2-methylindole dichloromethane solution, and 4-methoxybenzoyl chloride (40.6 mL, 0.3 mol) is made into a 200 mL, 1.5 mol / L 4-methoxybenzoyl chloride dichloromethane solution; the product is 5-bromo-2-methyl-3-(4-methoxybenzoyl)indole, and the yield is 82 wt% (purity 99%).

[0162] The nuclear magnetic resonance hydrogen spectrum and carbon spectrum of 5-bromo-2-methyl-3-(4-methoxybenzoyl)indole were tested, and the results are as follows:

[0163] 1 H NMR(400MHz,DMSO-d6)δ=11.88(s,1H),7.67-7.64(m,2H),7.40(d,J=8.0Hz,1H),7.36(d,J=7.9Hz,1H),7.15-7.00(m,4H),3.87(s,3H),2.44(s,3H);

[0164] 13 C NMR(100MHz,DMSO-d6)δ=191.00,162.35,143.81,135.40,134.12,131.21,127.80,122.08,121.15,120.40,114.02,113.15,111.67,55.87,14.52。

[0165] Example 20

[0166] This example is a microchannel continuous flow synthesis method of 6-methoxy-3-(3,4,5-trimethoxybenzoyl)indole. The preparation process is the same as that in Example 10, with the difference that: 6-methoxyindole (29.4 g, 0.2 mol) is made into a 200 mL, 1 mol / L 6-methoxyindole dichloromethane solution, and 3,4,5-trimethoxybenzoyl chloride (56.4 mL, 0.3 mol) is made into a 200 mL, 1.5 mol / L 3,4,5-trimethoxybenzoyl chloride dichloromethane solution; the product is 6-methoxy-3-(3,4,5-trimethoxybenzoyl)indole, and the yield is 84 wt% (purity 99%).

[0167] The nuclear magnetic resonance hydrogen spectrum and carbon spectrum of 6-methoxy-3-(3,4,5-trimethoxybenzoyl)indole were tested, and the results are as follows:

[0168] 11H NMR (400 MHz, DMSO-d6): δ = 11.84 (s, 1H), 8.12 (s, 1H), 7.97 - 7.96 (m, 1H), 7.10 - 7.09 (s, 2H), 7.01 (s, 1H), 6.90 (d, J = 8.7 Hz, 1H), 3.87 (s, 6H), 3.82 (s, 3H), 3.77 (s, 3H);

[0169] 13 13C NMR (100 MHz, DMSO-d6): δ = 189.29, 157.01, 153.07, 140.46, 138.09, 136.26, 135.14, 122.59, 120.84, 115.40, 112.10, 106.47, 95.63, 60.59, 56.45, 55.73.

[0170] Example 21

[0171] This example is a microchannel continuous flow synthesis method of 5-methyl-3-propionylindole. The preparation process is the same as that of Example 10, with the difference being that 5-methylindole (26.2 g, 0.2 mol) is made into a 200 mL, 1 mol / L 5-methylindole dichloromethane solution, and propionyl chloride (26.1 mL, 0.3 mol) is made into a 200 mL, 1.5 mol / L propionyl chloride dichloromethane solution; the product is 5-methyl-3-propionylindole, and the yield is 87 wt% (purity 99%).

[0172] 1H NMR and 13C NMR tests were carried out on 5-methyl-3-propionylindole, and the results are as follows:

[0173] 1 1H NMR (300 MHz, DMSO-d6): δ = 11.75 (s, 1H), 8.23 (s, 1H), 8.041 (m, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.02 (m, 1H), 2.84 (q, J = 7.4 Hz, 2H), 2.38 (s, 3H), 1.10 (t, J = 7.4 Hz, 3H);

[0174] 13 13C NMR (75 MHz, DMSO-d6): δ = 195.7, 134.9, 133.4, 130.2, 125.7, 124.1, 121.1, 115.6, 111.6, 31.7, 21.3, 9.2.

[0175] Example 22

[0176] This example is a microchannel continuous flow synthesis method of 5-bromo-3-pivaloylindole. The preparation process is the same as that of Example 10, with the difference being that 5-bromoindole (39.2 g, 0.2 mol) is made into a 200 mL, 1 mol / L 5-bromoindole dichloromethane solution, and pivaloyl chloride (36.7 mL, 0.3 mol) is made into a 200 mL, 1.5 mol / L pivaloyl chloride dichloromethane solution; the product is 5-bromo-3-pivaloylindole, and the yield is 87 wt% (purity 99%).

[0177] 1H NMR and 13C NMR tests were performed on 5-bromo-3-pivaloylindole, and the results are as follows:

[0178] 1 H NMR(300MHz,DMSO-d6):δ=12.04(s,1H),8.42(m,1H),8.40(s,1H),7.41(dd,J=8.6,0.5Hz,1H),7.30(m,1H),1.31(s,9H);

[0179] 13 C NMR(75MHz,DMSO-d6):δ=201.1,134.3,133.5,128.9,125.0,124.1,114.2,113.7,111.6,43.3,28.3。

[0180] Example 23

[0181] This example is a microchannel continuous flow synthesis method of 3-trifluoroacetylindole. The preparation process is the same as that of Example 10, with the difference being that trifluoroacetic anhydride (42.3 mL, 0.3 mol) is made into a 200 mL, 1.5 mol / L trifluoroacetic anhydride dichloromethane solution; the product is 3-trifluoroacetylindole, and the yield is 65 wt% (purity 99%).

[0182] 1H NMR and 13C NMR tests were performed on 3-trifluoroacetylindole, and the results are as follows:

[0183] 1 H NMR(400MHz,DMSO-d6):δ=12.76(s,1H),8.53(s,1H),8.22(d,J=4.8Hz,1H),7.63(d,J=5.6Hz,1H),7.38(s,2H);

[0184] 13 C NMR(100MHz,DMSO-d6):δ=174.3.4(q,J C-F =32Hz),138.1(q,J C-F= 4 Hz), 137.1, 126.2, 124.8, 123.9, 121.5, 117.4 (q, J C-F = 290 Hz), 113.5, 109.3; 19 19F NMR (376 MHz, DMSO): δ = -71.28.

[0185] The corresponding products of the raw materials in Examples 14 to 23 above are shown in Table 2.

[0186] Table 2 Products Corresponding to the Raw Materials Used in the Reactions of Examples 14 to 23

[0187]

[0188] As described above, the above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and all should be covered by the protection scope of the present invention.

Claims

1. A continuous flow synthesis method of a 3 - position acyl - containing indole compound, characterized in that, It includes the following steps: S1. Simultaneously pump an indole compound solution and a diethylaluminum chloride solution into a first group of microchannel continuous flow reactors for mixing and reaction; S2. Simultaneously introduce the material flowing out from the first group of microchannel continuous flow reactors and an acylating reagent solution into a second group of microchannel continuous flow reactors for reaction; S3. Collect the reaction solution in the second group of microchannel continuous flow reactors. After cooling, add an acid solution to carry out a quenching reaction while precipitating a solid. Filter to obtain a crude product, and recrystallize to obtain an indole compound containing an acyl group at the 3-position; wherein the indole compound has a chemical structure of Formula I; the indole compound containing an acyl group at the 3-position has a chemical structure of Formula II; R1 is selected from one of a hydrogen atom, a normal alkyl or isoalkyl with 1-5 carbon atoms, a normal alkoxy or isoalkyloxy with 1-5 carbon atoms, and a halogen; R2 is selected from one of a hydrogen atom, a normal alkyl or isoalkyl with 1-5 carbon atoms; R3 is selected from one of a normal alkyl or isoalkyl with 1-5 carbon atoms, a phenyl group, a trifluoroalkyl group, an alkoxyphenyl group, and a trialkoxyphenyl group.

2. The continuous flow synthesis method of a 3-position acyl-containing indole compound according to claim 1, wherein R1 is selected from one of a hydrogen atom, a methoxy group, a chlorine atom, a bromine atom, a methyl group, and an ethyl group; R2 is selected from a hydrogen atom or a methyl group; R3 is selected from a methyl group, an ethyl group, a tert-butyl group, a trifluoromethyl group, a phenyl group, a methoxyphenyl group, and a trimethoxyphenyl group.

3. The continuous flow synthesis method of a 3 - position acyl - containing indole compound according to claim 2, wherein, The acylating reagent is selected from one or more of acyl halides, acid anhydrides, and cyano compounds.

4. A continuous flow synthesis method of a 3 - position acyl - containing indole compound according to claim 3, characterized in that, The acylating reagent is selected from one or more of acetyl chloride, propionyl chloride, pivaloyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoyl chloride, 4-methoxybenzoyl chloride, and 3,4,5-trimethoxybenzoyl chloride.

5. A continuous flow synthesis method of a 3 - position acyl - containing indole compound according to claim 4, characterized in that, The molar ratio of the indole compound, diethylaluminum chloride, and the acylating reagent is 1:1-1.5:1.5-3.

6. The continuous flow synthesis method of a 3-position acyl-containing indole compound according to claim 5, characterized in that, The temperature of the first group of microchannel continuous flow reactors is set below 10°C; the temperature of the second group of microchannel continuous flow reactors is set below 10°C.

7. A continuous flow synthesis method of a 3 - acyl indole compound according to claim 5, characterized in that, The residence time of the material in the first group of microchannel continuous flow reactors is 40-60 seconds; the residence time of the material in the second group of microchannel continuous flow reactors is in the range of 80-95 seconds.

8. A continuous flow synthesis method of a 3 - acyl indole compound according to claim 5, characterized in that The concentration of the indole compound solution is 0.5-3 mol / L; the concentration of the diethylaluminum chloride solution is 0.5-3 mol / L; the concentration of the acylating reagent solution is 1-5 mol / L; The solvent in the indole compound solution is dichloromethane; The solvent in the diethylaluminum chloride solution is n-hexane; The solvent in the acylating reagent solution is dichloromethane.

9. The continuous flow synthesis method of a 3 - acyl indole compound according to claim 5, characterized in that, Cool to 0-5°C and add a 0.5-3 mol / L hydrochloric acid aqueous solution to carry out a quenching reaction; recrystallize using ethanol and ethyl acetate.

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