A method for synthesizing indole-3-carbaldehyde compounds in a microchannel

Abstract

The present invention relates to a method for synthesizing indole-3-carbaldehyde compounds in a microchannel. Using indole compounds as substrate raw materials, phosphorus oxychloride as a catalyst, and DMF as an aldehyde group source and solvent, a formylation reaction is carried out through a microchannel reactor to obtain the target product indole-3-carbaldehyde compounds. Compared with the prior art, the process route of the present invention is simple, efficient, and low-cost. The reaction is carried out at room temperature, shortening the reaction time, increasing the reaction yield, greatly reducing the reaction energy consumption, and facilitating continuous production on a kilogram scale.

Description

Technical Field

[0001] The invention belongs to the technical field of fine synthesis and relates to a method for synthesizing indole-3-carboxaldehyde compounds through a microchannel. Background Art

[0002] Indole derivatives have a wide range of applications in materials, agriculture, pharmacy and other fields. The synthesis of indole derivatives is an important research topic in heterocyclic chemistry. Indole-3-carboxaldehyde compounds are important intermediates in organic synthesis and drug synthesis and are widely used. For example, they can be used to synthesize biologically active tryptamine compounds and their derivatives, plant growth regulators, and can also be used in the total synthesis of natural products, such as toad venom tryptamine and psilocybin. Therefore, how to efficiently synthesize indole-3-carboxaldehyde compounds has always been a topic of interest.

[0003] At present, the synthesis of indole-3-carboxaldehyde compounds at home and abroad mainly uses indole as the raw material, usually using traditional phosphorus oxychloride (POCl 3 ) and N,N-dimethylformamide (DMF) as reaction reagents through Vilsmeier-Hacck reaction. Due to the potential safety hazards of the experiment, long reaction time and high temperature control requirements, it is difficult to carry out continuous and batch production; other synthesis methods such as Reimer-Tiemann reaction, reaction of indole salt with acyl chloride, Duff reaction, Rieche reaction, Friedel-Crafts acylations reaction and other traditional processes often have poor reaction selectivity and are therefore difficult to industrialize. Summary of the invention

[0004] The purpose of the present invention is to provide a method for synthesizing indole-3-carboxaldehyde compounds through a microchannel.

[0005] The purpose of the present invention can be achieved by the following technical solutions:

[0006] A method for synthesizing indole-3-carboxaldehyde compounds through a microchannel, wherein the synthesis process route is as follows:

[0007]

[0008] The specific process is: using indole compounds as substrate raw materials, phosphorus oxychloride as catalyst, DMF as aldehyde source and solvent, a formylation reaction is carried out through a microchannel reactor to obtain the target product indole-3-carboxaldehyde compounds;

[0009] The chemical structural formula of the indole compound is:

[0010]

[0011] Wherein, R is H, C3-C30 alkyl, amino, halogen, aryl, or alkoxy.

[0012] Further, R is selected from methyl, ethyl, propyl, isopropyl, butyl, halogen, amino, substituted amino, aryl, alkoxy (such as methoxy).

[0013] Furthermore, during the formylation reaction, the residence time of each substance molecule participating in the reaction in the microchannel reactor is 40s to 130s, preferably 90s.

[0014] Furthermore, the temperature of the formylation reaction is 0-65°C.

[0015] Furthermore, the preferred temperature for the formylation reaction is room temperature.

[0016] Furthermore, during the formylation reaction, the equivalent ratio of the indole compound, phosphorus oxychloride and DMF in the microchannel reactor is 1:(1.1-1.4):(5-15), and the optional ratio is 1:1.1:10.

[0017] Furthermore, during the formylation reaction, the indole compound is mixed with part of DMF to form a reaction solution and connected to the microchannel reactor through an independent sample pump, and phosphorus oxychloride is also mixed with part of DMF to form a reaction solution and connected to the microchannel reactor through an independent sample pump.

[0018] Furthermore, the total flow rate of the microchannel reactor is greater than or equal to 30 mL / min, and the flow rate of each sample pump is maintained at 15 mL / min to 50 mL / min.

[0019] Furthermore, during the formylation reaction, the indole compound and DMF are prepared into a reaction solution with a concentration of 1.0 to 2.0 mol / L, and phosphorus oxychloride and DMF are prepared into a reaction solution with a concentration of 0.8 to 2.5 mol / L. Preferably, the concentration of indole and DMF is 1.8 mol / L, and the concentration of phosphorus oxychloride and DMF is 1.5 mol / L.

[0020] Furthermore, the obtained indole-3-carboxaldehyde compound is selected from but not limited to any one of the following compounds:

[0021]

[0022]

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] (I) The process for continuously synthesizing indole-3-carboxaldehyde compounds of the present invention adopts a microchannel reaction system, which can achieve precise control of the reaction process, ultimately produce high-purity compounds, and greatly improve the yield.

[0025] (II) In the process of the present invention for continuously synthesizing indole-3-carboxaldehyde compounds, the average reaction time of a single micro-unit is only tens of seconds, which greatly improves the reaction efficiency and reduces energy consumption compared to tens of minutes in a batch process.

[0026] (V) The continuous synthesis microchannel reaction system of the present invention divides the original large-dose reaction into multiple micro-unit reactions, thereby realizing a small-dose reaction. The entire reaction process is continuous, avoiding the risk of temperature runaway due to local overheating, and the reaction is carried out at room temperature with high yield, thereby improving the safety of the reaction.

[0027] Microchannel reactor technology has gradually become a research hotspot in the field of international fine chemical technology. Microchannel reactor is a three-dimensional structural element that can be used for chemical reactions and is manufactured with a fixed matrix using special micromachining technology. Microchannel reactors usually contain very small channel sizes (equivalent diameter less than 500um) and channel diversity, and fluids flow, mix, and react in these channels. Therefore, this micro-structured chemical equipment has a very large specific surface area (surface area / volume). The advantage brought about by this is the great mass transfer and heat transfer efficiency, that is, it can achieve accurate control of the reaction temperature and instantaneous mixing of the reaction materials with precise proportions, thereby improving yield selectivity, safety, and product quality. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solution and advantages of the present invention more clear, the present invention is described in detail below in conjunction with specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0029] The synthesis process adopted in the present invention is first described below:

[0030] The present invention provides a method for synthesizing indole-3-carboxaldehyde compounds based on a microchannel reactor, and the synthesis process route thereof is as follows:

[0031] The synthetic process route is as follows:

[0032]

[0033] The specific process is: using indole compounds as substrate raw materials, phosphorus oxychloride as catalyst, DMF as aldehyde source and solvent, a formylation reaction is carried out through a microchannel reactor to obtain the target product indole-3-carboxaldehyde compounds;

[0034] The chemical structural formula of the indole compound is:

[0035]

[0036] Wherein, R is H, C3-C30 alkyl, amino, halogen, aryl, or alkoxy.

[0037] In some specific embodiments, R is selected from methyl, ethyl, propyl, isopropyl, butyl, halogen, amino, substituted amino, aryl, and methoxy.

[0038] In some specific embodiments, during the formylation reaction, the residence time of each substance molecule participating in the reaction in the microchannel reactor is 40s to 100s, preferably 90s.

[0039] In some specific embodiments, the temperature of the formylation reaction is 0-65°C.

[0040] In some specific embodiments, the temperature of the formylation reaction is room temperature.

[0041] In some specific embodiments, during the formylation reaction, the equivalent ratio of the indole compound, phosphorus oxychloride and DMF in the microchannel reactor is 1:(1.1-1.4):(5-15), and the optional ratio is 1:1.1:10.

[0042] In some specific embodiments, during the formylation reaction, the indole compound is mixed with part of DMF to form a reaction liquid and connected to the microchannel reactor through an independent sample pump, and phosphorus oxychloride is also mixed with part of DMF to form a reaction liquid and connected to the microchannel reactor through an independent sample pump.

[0043] In a more specific embodiment, the total flow rate of the microchannel reactor is greater than or equal to 30 mL / min, and the flow rate of each sample pump is maintained at 15 mL / min-50 mL / min.

[0044] In a more specific embodiment, during the formylation reaction, the indole compound and DMF are prepared into a reaction solution with a concentration of 1.0 to 2.0 mol / L, and phosphorus oxychloride and DMF are prepared into a reaction solution with a concentration of 0.8 to 2.5 mol / L. Preferably, the concentration of indole and DMF is 1.8 mol / L, and the concentration of phosphorus oxychloride and DMF is 1.50 mol / L.

[0045] The above process is described below in conjunction with more detailed embodiments.

[0046] Example 1

[0047] Synthesis of compound C1

[0048]

[0049] First, nitrogen was introduced into the microchannel to fill the system with nitrogen, and the temperature was set to the room temperature of the day. Then, indole (1125mmol) and DMF 600mL were added to a 1000mL flask filled with nitrogen. After fully dissolving, a pump with a flow rate of 15mL / min was connected in sequence. 580mL DMF was first added to another 1000mL flask filled with nitrogen, and phosphorus oxychloride (120mL) was added under stirring, and a 15mL / min pump was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. First, the material was introduced for 3 minutes to fill the microchannel, and then the material was received. The material stayed in the microchannel reactor for 96s. The reacted material was added to 500mL ice water and stirred for 15 minutes to quench the reaction. After boiling, cooling and crystallization were precipitated, and suction filtration was performed, washing, drying and weighing were performed to obtain a red needle-shaped crystalline solid with a yield of 91%. The mother liquor was distilled and DMF was recovered.

[0050] 1 H NMR (400MHz, DMSO): δ12.15(s,1H),9.95(s,1H),8.29(d,J=3.1Hz,1H),8.11(d,J=7.5Hz,1H),7.52(d,J=7.9Hz,1H),7.31–7.17(m,2H).

[0051] Example 2

[0052] Comparative Example 1 Conventional Synthesis of C1

[0053] The materials and proportions were synthesized under the same conditions as in Example 1. A 2.0 L flask equipped with a mechanical stirrer, a jacketed circulating heat exchanger, a condenser reflux device, and a constant pressure hopper was heated to room temperature and heated with N 2 After purging, indole (1125mmol, 132g) and DMF 600mL were added, stirred and fully dissolved, phosphorus oxychloride (120mL, dissolved in 580mL DMF) solution was slowly added dropwise within 1.0 hour, stirred and reacted after completion of the addition, thin layer chromatography (TLC) was used to detect the degree of completion of the reaction, and it took 4.0 hours for indole to be consumed, and it was considered that the reaction was complete, and ice water 500mL was slowly added, and the reaction was stirred for 0.5 hour to quench the active substance, and the mixture was boiled for 0.5 hour, and was placed in a 5.0L stainless steel barrel while hot and cooled, and crystals were precipitated, filtered under reduced pressure, and the filter cake was washed and dried, and weighed, and the yield was 85%. The mother liquor was distilled and DMF was recovered.

[0054] Example 3

[0055] Comparative Example 2 Conventional Synthesis of C1

[0056] Except that the reaction temperature was 50° C., other conditions were the same as those in Comparative Example 1, the indole was completely consumed in 2.0 hours, and the product yield was 80%. The mother liquor was distilled to recover DMF.

[0057] Example 4

[0058] Comparative Example 3

[0059] Except that the reaction temperature was 70° C., other conditions were the same as those in Comparative Example 1, the indole was completely consumed in 1.0 hour, and the product yield was 71%. The mother liquor was distilled to recover DMF.

[0060] Example 5

[0061] Synthesis of compound C2

[0062]

[0063] First, nitrogen was introduced into the microchannel to fill the system with nitrogen, and the temperature was set at 45°C. Then, 5-methyl-1-indole (800mmol) and DMF 500mL were added to a 1000mL flask filled with nitrogen. After fully dissolving, a pump with a flow rate of 20mL / min was connected in sequence. 400mL DMF was first added to another 1000mL flask filled with nitrogen, and phosphorus oxychloride (104mL) was added under stirring, and a 30mL / min pump head was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel with the material. After 7 minutes, the material was received. The material stayed in the microchannel reactor for 58s. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, the crystals were cooled and filtered, washed, dried and weighed to obtain a crystalline solid with a yield of 75%. The mother liquor was distilled to recover DMF.

[0064] 1 H NMR (300 MHz, CDCl 3 )δ10.04(s,1H),8.71(br,1H),8.13(d,J=0.6Hz,1H),7.81(d,J=3Hz,1H),7.33(d,J=8.4Hz,1H),7.15(dd,J1=8.4Hz,J2=1.5Hz,1H),2.49(s,3H).

[0065] Example 6

[0066] Comparative Example 4C2 Conventional Synthesis

[0067] The reaction device and the treatment process are the same as those in comparative example 1. The material amounts and proportions are the same as those in example 5, the reaction temperature is set at 45°C, and according to TLC detection, it takes 4 hours for the substrate to be completely consumed, and the reaction yield is 55%. The mother liquor is distilled to recover DMF.

[0068] Example 7

[0069] Synthesis of compound C3

[0070]

[0071] First, nitrogen was introduced into the microchannel to fill the system with nitrogen, and the temperature was set to 55°C. Then, 4-bromoindole (1.0 mol) and DMF 550 mL were added to a 1000 mL flask filled with nitrogen. After fully dissolving, a pump with a flow rate of 40 mL / min was connected. 660 mL of DMF was first added to another 1000 mL flask filled with nitrogen. Phosphorus oxychloride (102 mL) was added under stirring and connected to a 50 mL / min pump head. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel. After 5 minutes, the material was received. The material stayed in the microchannel reactor for 32 seconds. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, it was cooled, and after crystallization, it was filtered, washed, dried and weighed to obtain a crystalline solid with a yield of 79%. The mother liquor was distilled to recover DMF.

[0072] 1 H NMR (DMSO-d6, 300MHz): δ7.18 (t, 1H, J = 8.0Hz), 7.48 (d, 1H, J = 8.0Hz), 7.57 (d, 1H, J = 8.0Hz), 8.32 (s, 1H), 9.87 (s, 1H), 10.68 (brs, 1H).

[0073] Example 8

[0074] Comparative Example 5 Conventional Synthesis of C3

[0075] The reaction device and the treatment process are the same as those in comparative example 1. The material amounts and proportions are the same as those in example 7, the reaction temperature is 55° C., and according to TLC detection, the reaction takes 6.5 hours to complete, and the reaction yield is 60%. The mother liquor is distilled to recover DMF.

[0076] Example 9

[0077] Synthesis of compound C4

[0078]

[0079] First, nitrogen was introduced into the microchannel to fill the system with nitrogen, and the temperature was set at 65°C. Then, 5-bromoindole (1.0 mol) and DMF 500 mL were added to a 1000 mL flask filled with nitrogen. After sufficient dissolution, a pump with a flow rate of 20 mL / min was connected. 740 mL of DMF was first added to another 1000 mL flask filled with nitrogen, and phosphorus oxychloride (120 mL) was added under stirring. A 32 mL / min pump head was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel. After 5 minutes, the material was received. The material stayed in the microchannel reactor for 55 s. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, it was cooled. After crystallization, it was filtered, washed, dried and weighed to obtain a crystalline solid with a yield of 95%. The mother liquor was distilled to recover DMF.

[0080] 1 H NMR (MeOD-d4, 400MHz): δ7.37(m,2H,), 8.12(s,1H), 8.29(s,1H), 9.87(s,1H), 10.20(s,1H).

[0081] Example 10

[0082] Comparative Example 6 Conventional Synthesis of C4

[0083] The reaction device and the treatment process are the same as those in comparative example 1. The material amounts and proportions are the same as those in example 9, the reaction temperature is 65° C., and according to TLC detection, the reaction takes 5.0 hours to complete, and the reaction yield is 80%. The mother liquor is distilled to recover DMF.

[0084] Embodiment 11

[0085] Synthesis of compound C7

[0086]

[0087] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. The temperature was set at 5°C. Then, 5-ethylindole (1.0 mol) and DMF 1000 mL were added to a 1000 mL flask filled with nitrogen. After fully dissolved, a pump with a flow rate of 15 mL / min was connected. 600 mL of DMF was first added to another 650 mL flask filled with nitrogen. Phosphorus oxychloride (100 mL) was added under stirring. A 15 mL / min pump head was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was introduced for 3 minutes to fill the microchannel. After 10 minutes, the material was received. The material stayed in the microchannel reactor for 100 s. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, it was cooled. After crystallization, it was filtered, washed, dried and weighed to obtain a crystalline solid with a yield of 66%. The mother liquor was distilled to recover DMF.

[0088] 1 H NMR (400 MHz, CDCl 3 ): δ12.07(s,1H),10.20(s,1H),8.02(d,J=8.6Hz,1H),7.25(dd,J=8.6,1.7Hz,1H),2.77(q,J=7.6Hz,2H),2.70(s,2H),1.29(t,J=7.6Hz,3H).

[0089] Example 12

[0090] Comparative Example 7C7 Conventional Synthesis

[0091] The reaction device and the treatment process are the same as those in comparative example 1. The material amounts and proportions are the same as those in example 11, the reaction temperature is 5° C., and according to TLC detection, the reaction takes 7.0 hours to complete, and the reaction yield is 50%. The mother liquor is distilled to recover DMF.

[0092] Example 13

[0093] Synthesis of compound C8

[0094]

[0095] First, nitrogen was introduced into the microchannel to fill the system with nitrogen, and the temperature was set to 0°C. Then, 4-methylindole (1.0 mol) and DMF 950 mL were added to a 1000 mL flask filled with nitrogen. After fully dissolving, a pump with a flow rate of 20 mL / min was connected. 630 mL of DMF was first added to another 1000 mL flask filled with nitrogen. Phosphorus oxychloride (100 mL) was added under stirring and a 15 mL / min pump head was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel. The material was received after 5 minutes. The material stayed in the microchannel reactor for 83 s. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, it was cooled, and after crystallization, it was filtered, washed, dried and weighed to obtain a crystalline solid with a yield of 80%. The mother liquor was distilled to recover DMF.

[0096] 1 H NMR (400 MHz, CDCl 3 ): δ10.17(1H,s),9.17(1H,s)7.94(1H,d,J=3.2Hz),7.27(1H,d,J=8.0Hz),7.20(1H,t,J=7.3Hz),7.08(1H,d,J=7.1Hz),2.85(3H,s).

[0097] Embodiment 14

[0098] Comparative Example 8C8 Conventional Synthesis

[0099] The reaction device and the treatment process are the same as those in Comparative Example 1. The material amounts and proportions are the same as those above, the reaction temperature is 0°C, and according to TLC detection, the reaction takes 6.5 hours to complete, and the reaction yield is 50%. The mother liquor is distilled to recover DMF.

[0100] Embodiment 15

[0101] Synthesis of compound C6

[0102]

[0103] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. The temperature was set to room temperature. Then, 5-benzylindole (1.0 mol) and DMF 900 mL were added to a 1000 mL flask filled with nitrogen. After fully dissolving, a pump with a flow rate of 20 mL / min was connected. 680 mL of DMF was first added to another 1000 mL flask filled with nitrogen. Phosphorus oxychloride (110 mL) was added under stirring. A 16 mL / min pump was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel. The material was received after 5 minutes. The material stayed in the microchannel reactor for 80 s. The received material was added to ice water and stirred for 15 minutes to quench the reaction. The reaction was cooled after boiling. After crystallization, suction filtration was performed, washing, drying and weighing were performed to obtain a crystalline solid with a yield of 75%. The mother liquor was distilled to recover DMF.

[0104] 1 H NMR (DMSO): 7.58 (t, 2H, 3J = 7.6Hz), 7.63–7.78 (m, 5H), 8.49 (d, 2H, 3J = 7.6Hz), 9.98 (s, 1H), 12.50ppm (brs, 1H).

[0105] Example 16

[0106] Comparative Example 9C6 Conventional Synthesis

[0107] The reaction device and the treatment process are the same as those in Comparative Example 1. The material amounts and proportions are the same as those in Example 16. The reaction temperature is room temperature. According to TLC detection, the reaction takes 7.0 hours to complete, and the reaction yield is 55%. The mother liquor is distilled to recover DMF.

[0108] Embodiment 17

[0109] Synthesis of compound 17

[0110]

[0111] First, nitrogen was introduced into the microchannel to fill the system with nitrogen, and the temperature was set at 35°C. Then, 5-chloroindole (1.0 mol) and DMF 950 mL were added to a 1000 mL flask filled with nitrogen. After fully dissolving, a pump with a flow rate of 20 mL / min was connected. 750 mL of DMF was first added to another 1000 mL flask filled with nitrogen, and phosphorus oxychloride (120 mL) was added under stirring and then connected to a 17 mL / min pump. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel. After 8 minutes, the material was received. The material stayed in the microchannel reactor for 78 seconds. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, it was cooled, and after crystallization, it was filtered, washed, dried and weighed to obtain a crystalline solid with a yield of 88%. The mother liquor was distilled to recover DMF.

[0112] 1 H NMR (500MHz, Acetone-d6): δ11.33(s,1H)10.03(s,1H)8.29(s,1H)8.23(d,J=1.96Hz,1H)7.58(d,J=8.56Hz,1H)7.28(dd,J=8.68,2.08Hz,1H).

[0113] Embodiment 18

[0114] Comparative Example 10 Conventional Synthesis of C17

[0115] The reaction device and the treatment process are the same as those in Comparative Example 1. The material amounts and proportions are the same as those in Example 18, the reaction temperature is 35° C., and according to TLC detection, the reaction takes 6.0 hours to complete, and the reaction yield is 75%. The mother liquor is distilled to recover DMF.

[0116] Embodiment 19

[0117] Synthesis of compound C9

[0118]

[0119] First, nitrogen was introduced into the microchannel to fill the system with nitrogen at room temperature. Then, 7-chloroindole (1.0 mol) and DMF 850 ​​mL were added to a 1000 mL flask filled with nitrogen. After fully dissolving, a pump with a flow rate of 20 mL / min was connected. 630 mL of DMF was first added to another 1000 mL flask filled with nitrogen. Phosphorus oxychloride (102 mL) was added under stirring and a 16 mL / min pump was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel. The material was received after 7 minutes. The material stayed in the microchannel reactor for 80 s. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, it was cooled. After crystallization, suction filtration was performed, washing, drying and weighing were performed to obtain a crystalline solid with a yield of 78%. The mother liquor was distilled to recover DMF.

[0120] 1 H NMR (500MHz, DMSO-d6) δ12.22(1H,br s),9.93(1H,s),8.34(1H,s),8.07(1H,d,J=9.0Hz),7.57(1H,d,J=1.5),7.25(1H,dd,J=1.8,7.8Hz).

[0121] Embodiment 20

[0122] Comparative Example 11C9 Conventional Synthesis

[0123] The reaction device and the treatment process are the same as those in Comparative Example 1. The material amounts and proportions are the same as those in Example 20. The reaction temperature is room temperature. According to TLC detection, the reaction takes 5.5 hours to complete, and the reaction yield is 55%. The mother liquor is distilled to recover DMF.

[0124] Embodiment 21

[0125] Synthesis of compound C10

[0126]

[0127] First, nitrogen was introduced into the microchannel to fill the system with nitrogen, and the temperature was set at 35°C. Then, 6-methylindole (1.0 mol) and DMF 850 ​​mL were added to a 1000 mL flask filled with nitrogen. After sufficient dissolution, a pump with a flow rate of 20 mL / min was connected. 780 mL of DMF was first added to another 1000 mL flask filled with nitrogen, and phosphorus oxychloride (120 mL) was added under stirring. A 20 mL / min pump head was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel. The material was received after 5 minutes. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, it was cooled, and after crystallization, it was filtered, washed, dried and weighed to obtain a crystalline solid with a yield of 84%. The mother liquor was distilled to recover DMF.

[0128] 1 H NMR (500MHz, Acetone-d6) δ11.33(s,1H)10.03(s,1H)8.29(s,1H)8.23(d,J=1.96Hz,1H)7.58(d,J=8.56Hz,1H)7.28(dd,J=8.68,2.08Hz,1H).

[0129] Embodiment 22

[0130] Comparative Example 12C10 Conventional Synthesis

[0131] The reaction device and the treatment process are the same as those in comparative example 1. The material amounts and proportions are the same as those in example 22, the reaction temperature is 35° C., and according to TLC detection, the reaction takes 5.0 hours to complete, and the reaction yield is 65%. The mother liquor is distilled to recover DMF.

[0132] Embodiment 23

[0133] Synthesis of compound C18

[0134]

[0135] First, nitrogen was introduced into the microchannel to fill the system with nitrogen at room temperature. Then, 6-iodoindole (500mmol) and DMF 450mL were added to a 1000mL flask filled with nitrogen. After fully dissolving, a pump with a flow rate of 15mL / min was connected in sequence. 450mL DMF was first added to another 1000mL flask filled with nitrogen. Phosphorus oxychloride (50mL) was added under stirring and a 15mL / min pump head was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel. The material was received after 5 minutes. The material stayed in the microchannel reactor for 96s. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, it was cooled and crystallized. After crystallization, suction filtration was performed, washing, drying and weighing were performed to obtain a crystalline solid with a yield of 87%. The mother liquor was distilled to recover DMF.

[0136] 1 H NMR(400MHz,DMSO-d6):12.19(1H,s),9.92(1H,s),8.30(1H,d,J=2.0),8.08(1H,d d, J1=9.0, J2=2.5), 7.32 (1H, dd, J1=9.0, J2=2.5), 7.08 (1H, td, J1=9.0, J2=2.5).

[0137] Embodiment 24

[0138] Comparative Example 13C18 Conventional Synthesis

[0139] The reaction device and the treatment process are the same as those in comparative example 1. The material amounts and proportions are the same as those in example 24. The reaction temperature is room temperature. According to TLC detection, the reaction takes 4.0 hours to complete, and the reaction yield is 67%. The mother liquor is distilled to recover DMF.

[0140] Embodiment 25

[0141] Synthesis of compound C19

[0142]

[0143] First, nitrogen was introduced into the microchannel to fill the system with nitrogen at room temperature. Then, 6-methoxyindole (1.0 mol) and DMF 850 ​​mL were added to a 1000 mL flask filled with nitrogen. After fully dissolving, a pump with a flow rate of 20 mL / min was connected. 780 mL of DMF was first added to another 1000 mL flask filled with nitrogen. Phosphorus oxychloride (120 mL) was added under stirring and a 20 mL / min pump was connected. After the preparation work was completed, the switches of the two pumps were started at the same time to allow the material to flow into the microchannel. The material was first introduced for 3 minutes to fill the microchannel. The material was received after 5 minutes. The material stayed in the microchannel reactor for 72 seconds. The received material was added to ice water and stirred for 15 minutes to quench the reaction. After boiling, it was cooled. After crystallization, suction filtration was performed, washing, drying and weighing were performed to obtain a crystalline solid with a yield of 77%. The mother liquor was distilled to recover DMF.

[0144] 1 H NMR (300MHz): δ3.82 (s, 3H), 6.85 (dd, J = 8.6Hz, J = 2.2Hz, 1H), 6.99 (d, J = 2.2Hz, 1H), 7.98 (d, J = 8.6Hz, 1H), 8.05 (s, 1H), 9.89 (s, 1H), 12.08 (s, 1H).

[0145] Embodiment 26

[0146] Comparative Example 14C19 Conventional Synthesis

[0147] The reaction device and the treatment process are the same as those in comparative example 1. The material amounts and proportions are the same as those in example 24. The reaction temperature is room temperature. According to TLC detection, the reaction takes 6.0 hours to complete, and the reaction yield is 52%. The mother liquor is distilled to recover DMF.

[0148] Embodiment 27

[0149] Synthesis and properties of compound C20

[0150]

[0151] First, nitrogen gas was introduced into the microchannel to fill the system with nitrogen gas at room temperature. Then, 7-methylindole (1.0 mol) and 850 mL of DMF were added to a 1000 mL flask filled with nitrogen gas. After complete dissolution, a pump with a flow rate of 20 mL / min was connected. First, 780 mL of DMF was added to another 1000 mL flask filled with nitrogen gas, and phosphorus oxychloride (120 mL) was added under stirring. A 20 mL / min pump was connected. After the preparation work was completed, the switches of both pumps were started simultaneously to allow the materials to flow into the microchannel. It was introduced for 3 minutes to fill the microchannel with the materials. After 7 minutes, the materials began to be received. The materials stayed in the microchannel reactor for 72 s. The received materials were added to ice water and stirred for 15 minutes to quench the reaction. After boiling and cooling, when crystals precipitated, filtration, washing, drying, and weighing were carried out to obtain crystalline solids with a yield of 82%. The mother liquor was distilled to recover DMF.

[0152] 1 1H NMR (400 MHz, DMSO-d6): 12.19 (1H, s), 9.94 (s, 1H), 8.30 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.05–7.15 (m, 2H), 2.50 (s, 3H). The mother liquor was distilled to recover DMF.

[0153] Example 28

[0154] Synthesis of Compound C15

[0155]

[0156] First, nitrogen gas was introduced into the microchannel to fill the system with nitrogen gas at 35 °C. Then, 7-bromoindole (1.0 mol) and 850 mL of DMF were added to a 1000 mL flask filled with nitrogen gas. After complete dissolution, a pump with a flow rate of 20 mL / min was connected. First, 790 mL of DMF was added to another 1000 mL flask filled with nitrogen gas, and phosphorus oxychloride (110 mL) was added under stirring. A 20 mL / min pump was connected. After the preparation work was completed, the switches of both pumps were started simultaneously to allow the materials to flow into the microchannel. It was introduced for 3 minutes to fill the microchannel with the materials. After 5 minutes, the materials began to be received. The materials stayed in the microchannel for 72 s. The received materials were added to ice water and stirred for 15 minutes to quench the reaction. After boiling and cooling, when crystals precipitated, filtration, washing, drying, and weighing were carried out to obtain crystalline solids with a yield of 85%. The mother liquor was distilled to recover DMF.

[0157] 1H NMR (300MHz; Acetone-d6)11.37(1H,brs),10.08(1H,s),8.31(1H,s),8.24(1H,dd,J=0.8and 7.9),7.51(1H,dd,J=0.8and 7.7),7.21(1H,t,J=7.7)

[0158] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for synthesizing indole-3-carbaldehyde compounds in a microchannel, characterized in that, using indole compounds as substrates, phosphorus oxychloride as a catalyst, and DMF as an aldehyde group source and solvent, a formylation reaction is carried out through a microchannel reactor to obtain the target product indole-3-carbaldehyde compounds; The chemical structural formula of the indole compound is: wherein, R is selected from methyl, ethyl, propyl, isopropyl, butyl, halogen, amino, substituted amino, aryl, alkoxy; During the formylation reaction, the residence time of each substance molecule participating in the reaction in the microchannel reactor is 40 s to 100 s; The temperature of the formylation reaction is 0 to 65 °C; During the formylation reaction, the equivalent ratio of indole compounds, phosphorus oxychloride and DMF in the microchannel reactor is 1:(1.1 - 1.4):(5 - 15); During the formylation reaction, the indole compound and a part of DMF are made into a reaction solution and introduced into the microchannel reactor through an independent sample pump, and phosphorus oxychloride and a part of DMF are made into a reaction solution and introduced into the microchannel reactor through an independent sample pump.

2. The method for synthesizing indole-3-carbaldehyde compounds in a microchannel according to claim 1, characterized in that, The total flow rate of the microchannel reactor is greater than or equal to 30 mL / min.

3. The method for synthesizing indole-3-carbaldehyde compounds in a microchannel according to claim 1 or 2, characterized in that, The flow rate of the sample pump is maintained at 15 mL / min to 50 mL / min.

4. The method for synthesizing indole-3-carbaldehyde compounds in a microchannel according to claim 1, characterized in that, During the formylation reaction, the indole compound and DMF are made into a reaction solution with a concentration of 1.0 - 2.0 mol / L, and phosphorus oxychloride and DMF are made into a reaction solution with a concentration of 0.8 - 2.5 mol / L.

5. The method for synthesizing indole-3-carbaldehyde compounds in a microchannel according to claim 1, characterized in that, The obtained indole-3-carbaldehyde compounds are selected from any one of the following compounds:

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