A method for synthesizing indole-5-carboxaldehyde compounds based on microchannel reactor

Abstract

The present invention relates to a method for synthesizing indole-5-formaldehyde compounds based on a microchannel reactor, comprising the following steps: (1) adding halogenated indole compounds and tetrahydrofuran to a flask filled with nitrogen, fully dissolving, and then adding mixed alkyl lithium and lithium grab agent for stirring; (2) adding a tetrahydrofuran solution of formate to another flask filled with nitrogen; (3) pumping the materials obtained from step (1) and step (2) into a microchannel reactor filled with nitrogen for formylation reaction, quenching, extracting, and concentrating and crystallizing the materials obtained after the reaction, and obtaining the target product indole-5-formaldehyde compounds. Compared with the prior art, the synthetic route of the present invention is simple, efficient, low-cost, can be reacted continuously, and the reaction time is greatly shortened using a microchannel reactor, saving energy.

Description

Technical Field

[0001] The invention belongs to the technical field of fine synthesis and relates to a method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor. Background Art

[0002] 5-Indolecarboxaldehyde compounds are important biochemical reagents and pharmaceutical raw materials. Since 5-Indolecarboxaldehyde contains highly active aldehyde groups, it can be easily connected or converted into other functional groups, making it an important raw material for synthesizing many indole drugs. In clinical medicine, derivatives based on 5-Indolecarboxaldehyde are widely used to treat various diseases and have achieved excellent therapeutic effects. For example, the drug naratriptan for treating migraine (Alexander WO, Darko B, Martin R O. Indole derivative [P]. GB2208646, 1989.).

[0003] At present, the traditional process for the synthesis of 5-indolecarboxaldehyde is to use the relatively cheap 3-methyl-4-nitro-benzoic acid as the raw material, and then undergo esterification (Hidenori N, Xingguo L, Hiroyuki A. Effect of the ortho Modification of Azobenzene on the Photoregulatory Efficiency of DNA Hybridization and the Thermal Stability of its cis Form[J]. Chem. Eur. J.. 2010, 16: 2054-2062.), amination (Showalter HD, Li S. Concise Syntheses of the Novel 1H-Pyrrolo[3,2-g]quinazoline Ring System and its[2,3-f]Angular Isomer[J]. J. Org. Chem.. 1996, 61: 1155-1158.), dehydration (Krishnappa M, Mohamed AP. Rapid Method of Converting Primary Amides to Nitriles and Nitriles to Primary Amides by ZnCl2 using Microwavesunder Different Reaction Conditions[J].Synthetic Communications..2007,37:1545-1550.), then synthesize the indole ring by LB method (Batcho AD,Leimgruber W.Intermediates for Indoles[P],US3976639,1976.), and finally reduce the cyano group to obtain 5-indole formaldehyde (Hojatollah M,AbbasS.Synthesis of carbon-14analogue of 1,5diaryl-5-[14C]-1,2,3-triazoles[J].Applied Radiation and Isotopes..2004,60:665-668.). This method has low raw material cost and simple purification, but has more reaction steps and more waste, resulting in high total cost.In addition, 5-bromoindole is directly lithiated with a lithium reagent and then reacted with DMF (Mikel PM, John FS, Henry R. Metal-halogen exchange of bromoindoles. A route to substituted indoles [J]. J. Org. Chem.. 1986, 51 (26): 5106-10.). The advantage of this method is that the synthesis route is short and the final product can be synthesized in one step. However, the disadvantages are also obvious. First, the KH and t-BuLi used are relatively active, and industrial mass production is relatively dangerous. Secondly, the reaction is carried out at a low temperature of -78°C. Although this temperature can be achieved in industry with a liquid nitrogen bath, it is costly and relatively dangerous. There is also a Pd-catalyzed cyanation reaction, which reduces the cyano group to generate an aldehyde group (Fujikawa Y, Urano Y, Komatsu T. Design and Synthesis of Highly Sensitive Fluorogenic Substrates for Glutathione S-Transferase and Application for Activity Imaging in Living Cells [J]. Journal of the American Chemical Society.. 2008, 130 (44): 14533-14543.). The reaction uses 5-bromoindole as the raw material, which is cyanated to form 5-cyanoindole, and then the cyano group is reduced to an aldehyde group. The reaction requires the use of highly toxic drugs. Summary of the invention

[0004] The purpose of the present invention is to provide a method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor.

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

[0006] A method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor, characterized in that it comprises the following steps:

[0007] (1) Add a halogenated indole compound and tetrahydrofuran to a flask filled with nitrogen, fully dissolve them, then add the mixed alkyl lithium and lithium grabber and stir evenly;

[0008] (2) Add a tetrahydrofuran solution of formate into another flask filled with nitrogen;

[0009] (3) pumping the materials obtained in step (1) and step (2) into a microchannel reactor filled with nitrogen to carry out a formylation reaction, and quenching, extracting, concentrating and crystallizing the materials after the reaction to obtain the target product indole-5-carboxaldehyde compound;

[0010] The chemical structural formula of the halogenated indole compound is:

[0011]

[0012] Wherein, R is H, C1-C10 alkyl, halogen, alkoxy or amino;

[0013] X is selected from Cl, Br, I, sulfonate, and when X is sulfonate, R is halogen.

[0014] Further, the synthesis process route of the present invention is as follows:

[0015]

[0016] Furthermore, R is methyl, ethyl, propyl, isopropyl, tert-butyl, halogen, amino, or alkoxy.

[0017] Furthermore, X may be Br.

[0018] Furthermore, the alkyl lithium is one or a combination of methyl lithium, butyl lithium, sec-butyl lithium, and tert-butyl lithium.

[0019] Furthermore, the lithium-grabbing agent is selected from nitrogen-containing, oxygen-containing, multidentate organic compounds that can coordinate with Li ions, which are selected from at least one of ethylene glycol dimethyl ether, tetramethylethylenediamine, and 12-crown-4 ether, and can be 12-crown-4 ether.

[0020] Furthermore, the formate is selected from methyl formate, ethyl formate, propyl formate, butyl formate, and phenyl formate, and butyl formate can be selected.

[0021] Furthermore, the temperature during the formylation reaction is -60°C to 90°C, optionally -20°C to 50°C, and the residence time of the reaction materials in the microchannel reactor is 40 to 120s, optionally 90s.

[0022] Furthermore, the ratio of the halogenated indole compound, alkyl lithium, lithium grabber and formate substance is 1:(1.5-3.0):(1.5-3.0):(2.0-4.0), which can be optionally 1:2.0:2.0:1.5.

[0023] Furthermore, the total flow rate of the microchannel reactor is greater than or equal to 30 mL / min, and the flow rates of the materials obtained in step (1) and step (2) are maintained at 15 mL / min to 40 mL / min.

[0024] Furthermore, in the material obtained in step (1), the concentration of the halogenated indole compound is 0.5-2.0 mol / L, and can be 1.0 mol / L, and the concentrations of the alkyl lithium and the lithium grabbing agent are 1.0-2.0 mol / L, and can be 1.5 mol / L;

[0025] In the material obtained in step (2), the concentration of formate is 1.0-2.0 mol / L, and can be optionally 1.5 mol / L.

[0026] Further, the obtained indole-5-carboxaldehyde compound is selected from any one of the following compounds:

[0027]

[0028]

[0029] One of the innovations of the present invention is to use a lithium grabbing agent to treat alkyl lithium, and to use the powerful coordination ability of the lithium grabbing agent to complex with metal lithium ions, break or weaken the electrostatic binding between lithium ions and alkyl groups, release more alkyl anions, and capture the halogen or sulfonate group on the indole ring to form an indole anion intermediate, which is further subjected to a nucleophilic addition-elimination reaction with formate to obtain indole formaldehyde. The addition of the lithium grabbing agent effectively improves the reaction activity, accelerates the completion of the nucleophilic substitution reaction of the halogenated indole ring, and improves the reaction activity. The second innovation of the present invention is to use a microchannel reactor to synthesize indole formaldehyde, which has a short material contact time, uniform mixing, is conducive to the reaction, is easy to control the reaction heat exchange, and the reaction can be carried out continuously.

[0030] Compared with the prior art, the present invention has the following advantages:

[0031] (I) The synthetic route for synthesizing indole-5-carboxaldehyde compounds of the present invention is simple and can be produced continuously by adopting a continuous one-pot synthesis process.

[0032] (II) The use of a microchannel reactor can achieve precise control of the reaction process, ultimately producing high-purity compounds and significantly improving the yield.

[0033] (II) In the process of the present invention for continuously synthesizing indole-5-carboxaldehyde compounds, the average reaction time of a single micro-unit is only tens of seconds, which greatly improves the reaction efficiency compared to tens of minutes in a batch process.

[0034] (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 poor local heat conduction. The reaction can be carried out in the range of -60°C to 90°C, thereby improving the safety of the reaction.

[0035] Microchannel reactor technology has gradually become a research hotspot in the field of international fine chemical technology. A 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 500 μm) 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 resulting advantage is a great mass transfer and heat transfer efficiency, that is, it can achieve precise control of the reaction temperature and instantaneous mixing of the reaction materials in precise proportions, improve yield selectivity, safety, and product quality, and at the same time, the equipment is small in size and low in energy consumption. DETAILED DESCRIPTION

[0036] 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, etc. 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.

[0037] The synthesis process adopted in the present invention is first described below:

[0038] The present invention provides a method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor, and the synthesis process route thereof is as follows:

[0039]

[0040] The specific steps may include:

[0041] (1) Add a halogenated indole compound and tetrahydrofuran to a flask filled with nitrogen, fully dissolve them, then add the mixed alkyl lithium and lithium grabber and stir evenly;

[0042] (2) Add a tetrahydrofuran solution of formate into another flask filled with nitrogen;

[0043] (3) pumping the materials obtained in step (1) and step (2) into a microchannel reactor filled with nitrogen to carry out a formylation reaction, and quenching, extracting, concentrating and crystallizing the materials after the reaction to obtain the target product indole-5-carboxaldehyde compound;

[0044] The chemical structural formula of the halogenated indole compound is:

[0045]

[0046] Wherein, R is H, C1-C10 alkyl, halogen, alkoxy or amino;

[0047] X is selected from Cl, Br, I, sulfonate, and when X is sulfonate, R is halogen.

[0048] In some specific embodiments, R is methyl, ethyl, propyl, isopropyl, tert-butyl, halogen, amino, or alkoxy.

[0049] In some specific embodiments, X can be optionally Br.

[0050] In some specific embodiments, the alkyl lithium is one or a combination of methyl lithium, butyl lithium, sec-butyl lithium, tert-butyl lithium.

[0051] In some specific embodiments, the lithium-grabbing agent is selected from nitrogen-containing, oxygen-containing, multidentate organic compounds that can coordinate with Li ions, which are selected from at least one of ethylene glycol dimethyl ether, tetramethylethylenediamine, and 12-crown-4 ether, and can be 12-crown-4 ether.

[0052] In some specific embodiments, the formate is selected from methyl formate, ethyl formate, propyl formate, butyl formate, and phenyl formate, and ethyl formate can be selected.

[0053] In some specific embodiments, the temperature during the formylation reaction is -60 to 90°C, optionally -20 to 25°C, and the residence time of the reaction materials in the microchannel reactor is 40 to 120s, optionally 90s.

[0054] In some specific embodiments, the ratio of the halogenated indole compound, alkyl lithium, lithium grabber, and formate substance is 1:(1.5-3.0):(1.5-3.0):(2.0-4.0), and can be optionally 1:2.0:2.0:2.0.

[0055] In some specific embodiments, the total flow rate of the microchannel reactor is greater than or equal to 30 mL / min, and the flow rates of the materials obtained in step (1) and step (2) are maintained at 15 mL / min to 50 mL / min.

[0056] In some specific embodiments, in the material obtained in step (1), the concentration of the halogenated indole compound is 0.5-2.0 mol / L, and can be 1.0 mol / L, and the concentrations of the alkyl lithium and the lithium grabbing agent are 0.8-2.0 mol / L, and can be 1.5 mol / L;

[0057] In the material obtained in step (2), the concentration of formate is 1.0-2.0 mol / L, and can be optionally 1.5 mol / L.

[0058] In some specific embodiments, the obtained indole-5-carboxaldehyde compound is selected from any one of the following compounds:

[0059]

[0060]

[0061] The above process is described below in conjunction with more specific embodiments.

[0062] Example 1

[0063] Synthesis of compound C1

[0064] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. Then, 0.1 mol of 5-bromoindole and 100 mL of tetrahydrofuran were added to the flask filled with nitrogen to fully dissolve them. 0.3 mol of n-butyl lithium (2.0 M, 150 mL) and 0.3 mol of 12-crown-4 ether were mixed, stirred, and added to the 5-bromoindole substrate. A sampling pump with a flow rate of (20 ml / min) was connected. 0.3 mol of ethyl formate and 200 mL of tetrahydrofuran were added to another flask filled with nitrogen to prepare a solution. The flow rate was connected to the pump. The reaction temperature is 0°C, and the material flows into the microchannel reactor. The material stays in the microchannel reactor for 72 seconds. The ratio of substrate: alkyl lithium: lithium grabber: formate is 1:3:3:3. The reaction continues for 5 minutes to allow the material to fill the microchannel. After 7 minutes, the material is received and added into 100 g of ice water for quenching. After rotary evaporation to recover tetrahydrofuran, petroleum ether is added for extraction. The product is crystallized after concentration with a yield of 90%.

[0065] 1 H NMR (DMSO-d6): 11.66 (br, 1H), 10.00 (s, 1H), 8.22 (s, 1H), 7.67 (d, 1H,, J = 7.9), 7.60 (br, 1H), 7.57 (d, 1H, J = 7.6), 6.70 (br, 1H).

[0066] Example 2

[0067] The operation was the same as in Example 1. Only the ratio of the reaction materials was adjusted to 1:2:2:2:1 for the substrate: alkyl lithium: lithium chelating agent: formate, and the reaction yield was 82%.

[0068] Example 3C1 Conventional Synthesis

[0069] The type and proportion of the reactants are the same as in Example 1. Dry N2 was blown into a 1.0L round-bottom flask equipped with mechanical stirring, inert gas protection, constant temperature oil bath, constant pressure feeding funnel, and sampling port. Under the protection of N2, a THF solution of 5-bromoindole was added, stirred, and a THF solution of butyl lithium and 12-crown-4 ether was added dropwise. The temperature in the bottle was maintained at 0°C. After stirring for 30 minutes, a THF solution of formate was slowly added dropwise. Samples were taken from the sampling port every 0.5 hours for TLC analysis. The reaction was considered to be complete when the 5-bromoindole point disappeared. The reaction was completed after 5.0 hours of reaction. 100g of ice water was slowly added to quench the reaction. After stirring for 15 minutes, THF was recovered by rotary evaporation. The liquid in the remaining material was extracted with petroleum ether. The solid matter in the remaining material was combined with the extracted organic phase, and the product was obtained by recrystallization with a yield of 80%.

[0070] Example 4

[0071] Synthesis of compound C2

[0072] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. Then, 0.1 mol of 7-fluoro-5-iodoindole and 100 mL of tetrahydrofuran were added to the flask filled with nitrogen and fully dissolved. 0.25 mol of methyl lithium (2.0 M, 125 mL) and 0.2 mol of ethylene glycol dimethyl ether (DME) were mixed and stirred and added to the substrate solution. A sampling pump with a flow rate of (20 ml / min) was connected. To another flask filled with nitrogen, 0.3 mol of butyl formate (dissolved in 200 mL of tetrahydrofuran) was added. ) solution, connected to the injection pump with a flow rate of (20ml / min), after the preparation work is completed, start the switches of the two pumps at the same time, the reaction temperature is 40℃, the material is pumped into the microchannel, the residence time is 72s, wherein the ratio of substrate: alkyl lithium: lithium grabber: formate is 1:2.5:2:3, continue for 5 minutes to allow the material to fill the microchannel, and start receiving the material after 7 minutes. The material that has completed the reaction is added into 100g of ice water for quenching, tetrahydrofuran is recovered by rotary evaporation, and then petroleum ether is added for extraction. The product is crystallized after concentration, and the yield is 78%.

[0073] 1 H NMR (CDCl3): 10.0 (s, 1H), 8.76 (br, 1H), 7.97 (s, 1H), 7.47 (dd, J = 11.0, 1H), 7.35 (m, 1H), 6.76 (m, 1H).

[0074] Example 5

[0075] The operation was the same as in Example 4, except that the reaction temperature was adjusted to 60°C, and the reaction yield was 67%.

[0076] Example 6 Conventional Synthesis of C2

[0077] The synthesis apparatus and operation were the same as those in Example 3. The reaction substrates and proportions were the same as those in Example 4. The reaction took 5.0 h and the yield was 61%.

[0078] Example 7

[0079] Synthesis of compound C3

[0080] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. Then, 0.1 mol of 3-chloro-5-sulfonate indole and 80 mL of tetrahydrofuran were added to the flask filled with nitrogen and fully dissolved. 0.15 mol of tert-butyl lithium (1.0 M, 150 mL) and 0.15 mol of tetramethylethylenediamine (TMEDA) were mixed and stirred and then added to the substrate. A sampling pump with a flow rate of (25 ml / min) was connected. Methyl formate (0.3 mol dissolved in 200 mL of tetrahydrofuran) was first added to another flask filled with nitrogen. The solution was connected to a sampling pump with a flow rate of (25 ml / min). After the preparation work was completed, the two pumps were switched on at the same time. The reaction temperature was -15°C, and the material was pumped into the microchannel reactor with a residence time of 58 seconds. The ratio of substrate: alkyl lithium: lithium grabber: formate was 1:1.5:1.5:3. The reaction continued for 5 minutes to allow the material to fill the microchannel. After 7 minutes, the material was received and the material that had completed the reaction was added to 100 g of ice water for quenching. THF was recovered by rotary evaporation, and petroleum ether was added for extraction. The product was crystallized after concentration with a yield of 90%.

[0081] 1 H NMR (CDCl3): δ = 10.08 (s, 1H), 8.66 (bs, 1H), 8.18 (s, 1H), 7.83 (dd, J1 = 8.6Hz, J2 = 1.4Hz, 1H), 7.47 (d, J = 8.6Hz, 1H), 7.31 (d, J = 2.5Hz, 1H).

[0082] Example 8

[0083] Same as Example 7. Only the reaction temperature was adjusted to 0°C, and the reaction yield was 81%.

[0084] Example 9

[0085] Same as Example 7. Only the reaction temperature was adjusted to room temperature, and the reaction yield was 71%.

[0086] Example 10

[0087] Same as Example 7. Only the reaction temperature was adjusted to 40°C, and the reaction yield was 60%.

[0088] Embodiment 11

[0089] Synthesis of compound C4

[0090] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. Then, 0.1 mol of 7-dimethylamino-5-bromoindole and 150 mL of tetrahydrofuran were added to the flask filled with nitrogen and fully dissolved. 0.25 mol of n-butyl lithium (2.0 M, 125 mL) and TMEDA were added. 0.1mol was mixed and stirred and then added to the substrate, and an injection pump with a flow rate of (15ml / min) was connected. Propyl formate (0.4mol, 250mL tetrahydrofuran) solution was first added to another flask filled with nitrogen, and an injection pump with a flow rate of (15ml / min) was connected. After the preparation work was completed, the switches of the two pumps were started at the same time. The reaction temperature was room temperature, and the materials flowed into the microchannel with a residence time of 100s. The ratio of substrate: alkyl lithium: lithium grabber: formate was 1:2.5:1:4. The microchannel was filled with materials for 5 minutes. After 7 minutes, the materials were received, and the materials that had completed the reaction were added to 100g ice water for quenching. THF was recovered by rotary evaporation, and then petroleum ether was added for extraction. The product was crystallized after concentration with a yield of 77%.

[0091] 1 H NMR (400MHz, CDCl3): δ9.9 (s, 1H), 9.88 (s, 1H), 8.19 (s, 1H), 7.14 (d, J = 8.2Hz, 1H), 6.96 (s, 1H), 6.56 (d, J = 8.2Hz, 1H), 3.01 (s, 6H).

[0092] Example 12

[0093] Synthesis of compound C5

[0094] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. Then, 0.1 mol of 7-methoxy-5-chloroindole and 200 mL of tetrahydrofuran were added to the flask filled with nitrogen and fully dissolved. 0.25 mol (1.0 M, 250 mL) of tert-butyl lithium and DME were added. 0.15mol was mixed and stirred and then added to the substrate, and an injection pump with a flow rate of (30ml / min) was connected. To another flask filled with nitrogen, a solution of butyl formate (0.2mol and 200mL tetrahydrofuran) was first added, and an injection pump with a flow rate of (15ml / min) was connected. After the preparation work was completed, the switches of the two pumps were started at the same time. The reaction temperature was -20°C, and the materials were pumped into the microchannel with a residence time of 64s. The ratio of substrate: alkyl lithium: lithium grabber: formate was 1:2.5:1.5:2.0. The microchannel was filled with the materials for 5 minutes. After 7 minutes, the materials were received, and the materials that had completed the reaction were added to 100g ice water for quenching. THF was recovered by rotary evaporation, and then petroleum ether was added for extraction. The product was crystallized after concentration with a yield of 87%.

[0095] 1H NMR (400MHz, CDCl3): δ = 10.2 (s, 1H), 9.87 (s, 1H), 8.56 (s, 1H), 7.29 (s, 1H), 7.16 (d, J = 7.5Hz, 1H), 6.55 (d, J = 7.4Hz, 1H), 3.97 (s, 3H).

[0096] Embodiment 13

[0097] The operation was the same as in Example 12, except that the reaction temperature was adjusted to 5°C, and the reaction yield was 80%.

[0098] Embodiment 14

[0099] The operation was the same as in Example 13, except that the lithium-separating agent was changed to 12-crown-4, and the reaction yield was 88%.

[0100] Example 15 Conventional Synthesis of C5

[0101] The device and reaction process were the same as those in Example 3. The material feeding, proportioning and reaction temperature were the same as those in Example 12. It took 7.5 hours for TLC to detect that the substrate was completely consumed, and the product yield was 62%.

[0102] Example 16

[0103] Synthesis of compound C6

[0104] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. Then, 0.1 mol of 7-benzyl-5-iodoindole and 75 mL of tetrahydrofuran were added to the flask filled with nitrogen to fully dissolve. 0.3 mol of tert-butyl lithium (1.0 M, 300 mL) and 0.3 mol of 12-crown-4-ether were mixed and stirred and then added to the substrate. A sampling pump with a flow rate of (15 ml / min) was connected. Phenyl formate (0.3 mol and 350 mL of tetrahydrofuran) was first added to another flask filled with nitrogen. The solution was connected to a sampling pump with a flow rate of (15 ml / min). After the preparation work was completed, the two pumps were switched on at the same time. The reaction temperature was room temperature, and the material was pumped into the microchannel with a residence time of 100 s. The ratio of substrate: alkyl lithium: lithium grabber: formate was 1:3:3:3. The reaction continued for 5 minutes to allow the material to fill the microchannel. After 5 minutes, the material was received and the material that had completed the reaction was added to ice water for quenching. THF was recovered by rotary evaporation and then petroleum ether was added for extraction. The product was crystallized after concentration with a yield of 78%.

[0105] 1 H NMR (400MHz, CDCl3): δ = 10.3 (s, 1H), 9.87 (s, 1H), 8.74 (s, 1H), 7.58 (s, 1H), 7.26 (m, 6H), 6.51 (d, J = 8.2Hz, 1H), 4.01 (s, 2H).

[0106] Embodiment 17

[0107] The operation was the same as in Example 16, except that the reaction temperature was changed to -15°C, and the reaction yield was 85%.

[0108] Example 18 Conventional Synthesis of C6

[0109] The device and reaction process were the same as those in Example 3. The material feeding, proportioning and reaction temperature were the same as those in Example 16. It took 6.0 hours for TLC to detect that the substrate was completely consumed, and the product yield was 60%.

[0110] Embodiment 19

[0111] Synthesis and characterization of compound C7

[0112] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. Then, 0.1 mol of 3-tert-butyl-5-bromoindole and 150 mL of tetrahydrofuran were added to the flask filled with nitrogen to fully dissolve. 0.15 mol (2.0 M, 75 mL) of methyl lithium and 0.2 mol of DME were mixed and stirred and then added to the substrate. The sample injection pump with a flow rate of (20 ml / min) was pumped into another flask filled with nitrogen. 0.2 mol of butyl formate and 220 mL of tetrahydrofuran were first added to the solution. The liquid is pumped into the sampling pump with a flow rate of (20ml / min). After the preparation work is completed, the switches of the two pumps are started at the same time. The reaction temperature is room temperature, and the material flows into the microchannel reactor with a residence time of 75s. The ratio of substrate: alkyl lithium: lithium grabber: formate is 1:1.5:2:3. It continues for 5 minutes to allow the material to fill the microchannel. After 7 minutes, the material is received, and the material that has completed the reaction is added to 100g of ice water for quenching, and then petroleum ether is added for extraction. The product is crystallized after concentration, and the yield is 80%.

[0113] 1 H NMR (400MHz, CDCl3): δ = 10.8 (s, 1H), 9.82 (s, 1H), 7.76 (d, J = 7.4Hz, 2H), 7.74 (d, J = 7.5Hz, 1H), 7.20 (s, 1H), 1.37 (s, 9H).

[0114] Embodiment 20

[0115] The operation was the same as in Example 19, except that the lithium-separating agent was changed to TMEDA. The reaction yield was 88%.

[0116] Example 21 Conventional Synthesis of C7

[0117] The device and reaction process were the same as those in Example 3. The material feeding, proportioning and reaction temperature were the same as those in Example 19. It took 5.0 hours for TLC to detect that the substrate was completely consumed, and the product yield was 71%.

[0118] Embodiment 22

[0119] Synthesis of compound C8

[0120] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. Then, 0.1 mol of 7-chloro-5-sulfonate indole and 80 mL of tetrahydrofuran were added to the flask filled with nitrogen to fully dissolve them. 0.15 mol of tert-butyl lithium (1.0 M, 150 mL) and TMEDA were added. 0.2mol was mixed and stirred and then added to the substrate, and an injection pump with a flow rate of (15ml / min) was connected. In another flask filled with nitrogen, a solution of 0.2mol of ethyl formate and 250mL of tetrahydrofuran was first added, and an injection pump with a flow rate of (15ml / min) was connected. After the preparation work was completed, the switches of the two pumps were started at the same time. The reaction temperature was -10°C, and the materials were pumped into the microchannel reactor with a residence time of 100s. The ratio of substrate: alkyl lithium: lithium grabber: formate was 1:1.5:2:3. The microchannel was filled with the materials for 5 minutes. After 7 minutes, the materials were received, and the materials that had completed the reaction were added to 100g of ice water for quenching, and then petroleum ether was added for extraction. The product was crystallized after concentration with a yield of 72%.

[0121] 1 H NMR (CDCl3): δ=10.00(s,1H),8.60(br,1H),8.08(s,1H),7.79(d,J)1.3Hz,1H),7.37(dd,J)3.2,2.4Hz,1H),6.77(dd,J)3.3,2.3Hz,1H).

[0122] Embodiment 23

[0123] The operation was the same as in Example 22, except that the reaction temperature was changed to 0°C. The reaction yield was 82%.

[0124] Example 24C8 Conventional Synthesis

[0125] The device and reaction process are the same as those in Example 3. The material feeding, proportioning and reaction temperature are the same as those in Example 22. It takes 6.0 h for TLC detection to show that the substrate is completely consumed, and the product yield is 63%.

[0126] Embodiment 25

[0127] Synthesis of compound C12

[0128] First, nitrogen was introduced into the microchannel to fill the system with nitrogen. Then, 0.1 mol of 4-chloro-5-sulfonate indole and 150 mL of tetrahydrofuran were added to the flask filled with nitrogen to fully dissolve them. 0.15 mol of n-butyl lithium (2.0 M, 75 mL) and DME were added. 0.2mol was mixed and stirred and then added to the substrate, and an injection pump with a flow rate of (20ml / min) was pumped in. To another flask filled with nitrogen, 0.3mol of ethyl formate and 220mL of tetrahydrofuran solution were first added, and an injection pump with a flow rate of (20ml / min) was connected. After the preparation work was completed, the switches of the two pumps were started at the same time. The reaction temperature was 10°C, and the materials flowed into the microchannel with a residence time of 72s. The ratio of substrate: alkyl lithium: lithium grabber: formate was 1:1.5:2:3. The microchannel was filled with materials for 5 minutes. After 7 minutes, the materials were received, and the materials that had completed the reaction were added to 100g of ice water for quenching, and then petroleum ether was added for extraction. The product was crystallized after concentration with a yield of 75%.

[0129] 1 H NMR (DMSO-d6) δ10..50(s,1H),10.2(s,1H),8.03(m,1H),7.65(d,J=8.6Hz,1H), 7.20(d,J=7.7Hz,1H), 6.83(d,J=8.0Hz,1H).

[0130] Embodiment 26

[0131] The operation was the same as in Example 25, except that the lithium-separating agent was changed to TMEDA. The reaction yield was 84%.

[0132] Example 27C12 Conventional Synthesis

[0133] The device and reaction process were the same as those in Example 3. The material feeding, proportioning and reaction temperature were the same as those in Example 22. It took 5.5 hours for TLC to detect that the substrate was completely consumed, and the product yield was 61%.

[0134] Embodiment 28

[0135] The operation was the same as in Example 1, except that the lithium ionizing agent was not added. TLC was performed every 2 minutes, and it was found that no product was generated. The obtained material was pumped into the microchannel reactor again, and there was still no target product in the effluent.

[0136] Embodiment 29

[0137] The operation was the same as in Example 3, except that the lithium reagent was not added. TLC was performed every 15 minutes after the addition of the formate, and no product was found to be generated. After stirring for 5.0 hours, no target product was found to be generated.

[0138] 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-5-carboxaldehyde compounds based on a microchannel reactor, characterized in that: The following steps are involved: (1) Add a halogenated indole compound and tetrahydrofuran to a flask filled with nitrogen, fully dissolve them, and then add the mixed alkyl lithium and lithium grabber and stir; (2) Add a tetrahydrofuran solution of formate into another flask filled with nitrogen; (3) pumping the materials obtained in step (1) and step (2) into a microchannel reactor filled with nitrogen to carry out a formylation reaction, and quenching, extracting, concentrating and crystallizing the materials after the reaction to obtain the target product indole-5-carboxaldehyde compound; The chemical structural formula of the halogenated indole compound is: Wherein, R is H, C1-C10 alkyl, halogen, alkoxy or amino; X is selected from Cl, Br, I, sulfonate, and when X is sulfonate, R is halogen; The lithium-grabbing agent is selected from at least one of ethylene glycol dimethyl ether, tetramethylethylenediamine, and 12-crown-4 ether; The formate ester is selected from methyl formate, ethyl formate, propyl formate, butyl formate, and phenyl formate; The chemical structural formula of the indole-5-carboxaldehyde compound is:

2. The method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor according to claim 1, characterized in that: R is methyl, ethyl, propyl, isopropyl, tert-butyl, halogen, amino, or alkoxy.

3. The method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor according to claim 1, characterized in that: The alkyl lithium is one or a combination of methyl lithium, butyl lithium, sec-butyl lithium and tert-butyl lithium.

4. The method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor according to claim 1, characterized in that: The temperature during the formylation reaction is -60°C to 90°C, and the residence time of the reaction materials in the microchannel reactor is 40 to 120 seconds.

5. The method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor according to claim 1, characterized in that: The ratio of the halogenated indole compound, alkyl lithium, lithium-separating agent and formate substance is 1:(1.5-3.0):(1.5-3.0):(2.0-4.0).

6. The method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor according to claim 1, characterized in that: The total flow rate of the microchannel reactor is greater than or equal to 30 mL / min, and the flow rates of the materials obtained in step (1) and step (2) are maintained at 15 mL / min-50 mL / min.

7. The method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor according to claim 1, characterized in that: In the material obtained in step (1), the concentration of the halogenated indole compound is 0.5-2.0 mol / L, and the concentrations of the alkyl lithium and the lithium grabbing agent are 0.8-2.0 mol / L respectively; In the material obtained in step (2), the concentration of formate is 1.0-2.0 mol / L.

8. The method for synthesizing indole-5-carboxaldehyde compounds based on a microchannel reactor according to claim 1, characterized in that: The obtained indole-5-carboxaldehyde compound is selected from any one of the following compounds:

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