KR102143528B1 - Continuous Microfluidic Reactor for High-Temperature Reaction and Preparation Method for Indole Derivatives Using the Reactor - Google Patents

Abstract

The present invention relates to a continuous microfluidic reactor for a high-temperature reaction which can perform a reaction under a stable condition even in the case of a reaction under heating, and a method for preparing an indole derivative using the same. Particularly, the continuous microfluidic reactor for a high-temperature reaction includes: an inlet through which a sample is introduced by a pump; a flow path for a reaction, one end of which is linked to the inlet; a back pressure controller linked to the other end of the flow path for a reaction; and an outlet through which the sample passing through the back pressure controller is discharged. The continuous microfluidic reactor for a high-temperature reaction causes no formation of microbubbles in the flow path for a reaction even in the case of a reaction under heating, and can perform a reaction even at a temperature equal to or higher than the boiling point of a solvent.

Description

Continuous Microfluidic Reactor for High-Temperature Reaction and Preparation Method for Indole Derivatives Using the Reactor}

The present invention relates to a continuous microfluidic reactor for a high-temperature reaction capable of reacting under stable conditions even during a heating reaction, and a method for producing an indole derivative using the same.

Indole residues are widely present in a number of natural and synthetic molecules with important biological activities, and are used in a variety of fields such as pharmaceuticals, dyes, fungicides, health supplements and perfumes.

Among them, indole-3-carboxaldehyde, which has an aldehyde group substituted at the 3 position, is not only a useful component that exhibits physiological efficacy by itself, but also attracts a lot of attention as a useful precursor for pharmaceuticals and electrical materials. . Indole-3-carboxaldehyde is a substance produced by the conversion of tryptophan, an essential amino acid contained in a large amount of green vegetables, by intestinal microbes in vivo.It is reported that it has the effect of promoting mucosal healing and regulating toxin production in pathogenic E. coli. Has been. Indole-3-carboxaldehyde is also used as an anticancer drug indole-3-carbinol and 3,3'-diindolylmethane (DIM) or trisindolyl used as an antibiotic. It is usefully used as a precursor for the synthesis of physiologically active indole derivatives including methane (Trisindolylmethane). In addition, it is also used as a monomer that forms a thin film on the surface of glassy carbon, which is an oxidation region of an electrode.

Indole-3-carboxaldehyde is formed by formylation of the 3-position of indole, but the carbonyl group involves various side reactions such as CC, CN coupling reaction, and oxidation reaction, so many steps must be taken. . Traditional indole-3-carboxaldehyde production methods, including the Vilsmeier-Haack reaction (J. Org. Chem. 10(3) (1945) 255-258), use toxic POCl ₃ in stoichiometric amounts or in excess. A strong acid or strong base of is used and the reaction proceeds at high temperature. Therefore, in addition to the environmental problems caused by the generation of wastewater, when indole is substituted with an acid, a base, or a weak functional group in temperature, there is a problem that it is difficult to apply and the selectivity is low.

Su et al. (J. Am. Chem. Soc. 133(31) (2011) 11924-7) disclosed a method of formylating the 3-position of indole under mild conditions using a Ru catalyst and N-methyl aniline. The main strategy of this method is to break the N-bond of N-methyl aniline through the formation of an iminium ion intermediate. After the publication of Su et al., methods for formylating the 3-position of indole using various different catalysts and amines have been developed, but all of them must use an excess of pivalic acid as an additive. Therefore, if there is a weak functional group in the acid, it is difficult to apply, so its use is limited. Since then, many researchers have initiated the preparation of indole-3-carboxaldehyde, but it can be applied only to specific functional groups, requires a long reaction time at high temperature, the process is too complex and uses toxic substances, etc. Problems remain.

Recently, Wang et al (Tetrahedron Letters 58(30) (2017) 2877-2880) used I ₂ as a catalyst for formylation, hexamethylenetetraamine (HMTA) as a carbon source, and oxygen or air as a solvent as an oxidizing agent. A method for producing indole-3-carboxaldehyde by a batch reaction of the reaction scheme described in was disclosed. Wang et al. did not use a metal catalyst by the above method, and indole-3-carboxaldehyde in a high yield in a short time (for example, in the case of unsubstituted indole, a yield of 97% when reacted at 120°C for 0.8 hours). It claimed to be possible to manufacture. However, as described in the following comparative example, the present inventors performed numerous repeated experiments with different conditions to actually prepare indole-3-carboxaldehyde by Wang et al.'s method, but the results of Wang et al. could not be reproduced. By optimizing your own reaction conditions, for a 1 mmol scale reaction When reacting for 6 hours, only a yield of less than 70% could be obtained. This suggests that essential components not described in Wang et al.'s thesis are necessary for 3-formylation of indole, or that the experimental conditions must be controlled very precisely. Even if the reaction time and reaction yield can be applied by the method suggested by Wang et al., the reaction time becomes longer as the size of the batch reactor increases because oxygen or air acts as an oxidizing agent during the reaction and activated carbon is used as an additive. There is a problem in applying it to mass production due to the high yield and the complex treatment process after the reaction.

On the other hand, the reaction using a continuous flow reactor by microchemical reaction technology shows innovative advantages over conventional batch reactions, and dangerous and unstable chemicals can also be applied to various reactions. In the microfluidic system, various experimental conditions can be controlled, and the use of microreactive elements connected in parallel opens the possibility of using them for mass production. The present inventors applied for a continuous flow reactor suitable for individual chemical reactions using a microfluidic system, and registered patent No. 10-1662516 (continuous reactor for gas-liquid photoreaction and photoreaction method using the same), registered patent No. It has been registered as No. 10-1721216 (Continuous microfluidic reaction system for immiscible liquid-liquid reaction and reaction method using the same).

In the case of a continuous microfluidic reactor, when the reaction temperature is high, microbubbles are generated in the fluid, thereby interfering with the flow of the fluid, so there is a problem in controlling the reaction time or temperature. In particular, when the reaction temperature is higher than the boiling point of the solvent, there is a limitation that a continuous microfluidic reactor cannot be used. In addition, since the microfluidic reactor has a narrow flow path, all reactants are not dissolved, but if a solid substance is included, the flow of the fluid in the microfluidic reactor is uneven, and the flow path may be blocked by the solid substance. There is a difficulty in proceeding the reaction in a fluid reactor.

Registered Patent No. 10-1662516 Registered Patent No. 10-1721216

J. Org. Chem. 10(3) (1945) 255-258 J. Am. Chem. Soc. 133(31) (2011) 11924-7 Tetrahedron Letters 58(30) (2017) 2877-2880

An object of the present invention is to provide a continuous microfluidic reactor that does not affect the flow of fluid because microbubbles are not generated in the reaction flow path even during a heating reaction, and can be applied even when the reaction temperature is higher than the boiling point of the solvent. do.

Another object of the present invention is to provide a method for effectively 3-formylating an indole derivative using the continuous microfluidic reactor.

The present invention for achieving the above object is an injection port through which a sample is injected by a pump; A reaction flow path having one end connected to the injection port; A back pressure regulator connected to the other end of the reaction flow path; And it relates to a continuous microfluidic reactor, characterized in that the reaction is possible at a temperature above the boiling point of the solvent, without forming microbubbles in the reaction flow path during the heating reaction including; .

A back pressure regulator is a type of safety device that opens the valve only when the pressure regulator is below a predetermined pressure, whereas the back pressure regulator allows the valve to open only when the pressure is above a predetermined pressure. In the continuous microfluidic reactor of the present invention, since the evaporation of the solvent is suppressed by increasing the pressure in the reaction flow path by the back pressure regulator, microbubbles are not formed. Micro-bubbles formed by evaporation of the solvent interfere with mixing of the reaction liquid or even heat transfer in the reaction flow path, and when micro-bubbles fuse to form large air bubbles, in severe cases, the flow of the fluid is affected. This problem is more serious as the reaction temperature approaches the boiling point of the solvent, and if the reaction temperature exceeds the boiling point of the solvent, the reaction by a conventional continuous microfluidic reactor becomes impossible. In the present invention, by using a back pressure regulator to maintain the pressure in the reaction flow path higher than atmospheric pressure, generation of microbubbles is suppressed, and reaction is possible at a temperature equal to or higher than the boiling point of the solvent. It is natural that the critical pressure of the back pressure regulator can be appropriately selected and used according to the desired reaction conditions.

In the continuous microfluidic reactor of the present invention, a plurality of injection ports may be formed so that each reaction solution is separately injected. When there are a plurality of injection ports, a mixing channel may be separately provided at the tip of the reaction channel so that the reaction liquid injected through each injection port can be mixed.

In the continuous microfluidic reactor of the present invention, the pump must be operable at a pressure higher than the critical pressure of the back pressure regulator. In addition, accessories included in the continuous microfluidic reactor, including the reaction flow path, such as unions and joints, must also be usable at the critical pressure of the back pressure regulator.

It is preferable that the width of the reaction flow path is 0.1 to 5.0 mm. The narrower the width of the reaction flow path, the smaller the temperature deviation in the flow path, and thus, there is no side reaction or decrease in the reaction rate in a high-temperature reaction, which is advantageous for a stable reaction, but the reaction capacity decreases, so productivity may be lowered. On the other hand, if the width of the reaction flow path is too wide, the effective reaction volume increases, but the reaction efficiency decreases because even heat transfer in the flow path is disturbed.

The present invention also relates to a chemical reaction using the continuous microfluidic reactor. In the case of using the continuous microfluidic reactor of the present invention, the present inventors were able to carry out the 3-formylation reaction of indole with a fast reaction rate and high yield without using solid additives such as activated carbon. On the other hand, in the case of a batch reaction, unlike Wang et al.'s report, even if a solid additive such as activated carbon is used, the reaction rate or reaction yield is not significantly improved, so an essential composition not disclosed in the method suggested by Wang et al. It was suggested that conditions were required, or precise control of reaction conditions was required.

In the present invention, the 3-formylation reaction of indole uses hexamethylenetetraamine (HMTA) as a carbon source and iodine as a catalyst, and does not require additives such as activated carbon.

The reaction solvent is preferably N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), or a mixture of the solvent and water, but the use of other solvents is not excluded. When using a mixed solvent with water, it will be easy for those skilled in the art to properly adjust the ratio in consideration of the solubility of the indole derivative.

In the present invention, the 3-formylation reaction of indole was preferably carried out at 120 to 160°C. As the reaction temperature increases, the reaction rate increases. Therefore, if the reaction temperature is too low, the reaction rate becomes too low, and there is little difference in the reaction rate when the reaction temperature is about 150 to 160°C.

The equivalent weight of the reaction reagent used also affects the reaction rate. The iodine equivalent was preferably 0.2 to 1.0 equivalent, and the reaction rate also increased as the iodine equivalent increased in the above range. The HMTA equivalent was preferably 1.0 to 3.0 equivalent, and the reaction rate increased as the HMTA equivalent increased in the above range. Accordingly, in consideration of the economic performance according to the reaction rate, the amount of iodine and/or HMTA used, and the cost of the process required for the post-treatment process, an appropriate amount may be used within the above range.

According to the method of the present invention, the indole derivative was capable of 3-formylation in both the electron donor substituent and the electron acceptor substituent.

As described above, according to the continuous microfluidic reactor of the present invention, even during the heating reaction, microbubbles are not generated in the reaction flow path, so it is possible to prevent the flow of fluid due to bubbles from being disturbed, so that the reaction time can be constantly adjusted, and the reaction conditions It is easy to control, so more effective reaction is possible.

In addition, when the continuous microfluidic reactor of the present invention is used, the reaction is possible at a temperature higher than the boiling point of the solvent, and thus it can be usefully used in a wider range of reactions.

In addition, when the continuous microfluidic reactor of the present invention is used, the 3-formylation reaction of the indole derivative can be carried out in high yield, so that it can be easily applied to mass production.

1 is a reaction scheme of 3-formylation of indole according to the prior art.
Figure 2 is a graph showing the effect of solvent on 3-formylation of indole in a batch reactor.
3 is a graph showing the effect of additives on 3-formylation of indole in a batch reactor (100° C. reaction).
4 is a graph showing the effect of additives on 3-formylation of indole in a batch reactor (120° C. reaction).
5 is a schematic diagram of a continuous microfluidic reactor according to an embodiment of the present invention.
6 is a graph showing the effect of I ₂ equivalents on 3-formylation of indole in a continuous microfluidic reactor.
7 is a graph showing the yield according to reaction time for each I ₂ equivalent for 3-formylation of indole in a continuous microfluidic reactor.
8 is a graph showing the effect of temperature on 3-formylation of indole in a continuous microfluidic reactor.

Hereinafter, the present invention will be described in more detail with reference to the attached examples. However, these embodiments are merely examples for easily explaining the content and scope of the technical idea of the present invention, and thus the technical scope of the present invention is not limited or changed. It will be obvious to those skilled in the art that various modifications and changes are possible within the scope of the technical idea of the present invention based on these examples.

[Example]

Comparative Example: Preparation of indole using batch reaction

1) The result of Wang et al.

First, the experimental results reported by Wang et al. are summarized in Table 1 below. According to Wang et al., oxygen in the air acts as an oxidizing agent. Wang et al. reacted significantly with activated carbon, so when no activated carbon was added, 0.1 g of activity was carried out compared to 51% reaction in 10 hours at 100°C when an equivalent amount of I ₂ was used. When carbon was added, it was reported that 3-formylation of indole proceeds in a yield of 97% in 6 hours at 100°C and 97% in 0.8 hours at 120°C. At 130° C., the yield decreased to 94%. In addition, even if the equivalent of iodine was reduced to 0.2 equivalent, the yield or reaction time was not affected.

2) 3-formylation reaction of indole using Wang et al.'s method

By applying the method of Wang et al., indole (1 mmol), HMTA (2 mmol), I ₂ , and DMF were added to a round flask and heated to react. Samples were collected over time, and the progress of the reaction was analyzed using GC/MS (Agilent Technologies 2890 GC system/5975C VL MSD with Triple-Axis Detector) and shown in Table 2.

Comparing Entry 1 and 2 in Table 2, the yield when reacting at 95°C for 8 hours without adding activated carbon is 52%, the yield when reacting at 120°C for 7 hours is 67%, and the yield when reacting for 10 hours Increasing the reaction temperature to 65% and 68% respectively increased the reaction rate, but did not affect the final reaction yield. This was somewhat higher than the reaction yield in Wang et al's experiment (entry 1 in Table 1). When the reaction temperature was increased to 140°C, the initial reaction rate was fast, but the yield was greatly reduced, which is believed to be because the reactant, intermediate product, or final product is not stable at a temperature of 140°C (Entry 5).

Reducing the equivalent of iodine to 0.2 equivalent (Entry 2 vs 4) slightly decreased the reaction rate, but did not significantly affect the reaction yield. This is somewhat consistent with the results of Wang et al.

It was confirmed that the reaction rate decreased when the volume of the solvent was increased (Entry 3 vs 4). However, only the initial reaction rate was accelerated, but it had little effect on the final yield.

Overall, in the absence of activated carbon, the 3-formylation reaction of indole was somewhat faster than that reported by Wang et al. and showed a high yield.

However, the effect of the addition of activated carbon was completely different from that reported by Wang et al. Even when the amount of solvent used was the same as the conditions of Wang, etc. (entry 6 in Table 1), the reaction time and reaction yield were almost the same as that of Entry 3 in which no activated carbon was added, so it was confirmed that there was little effect from activated carbon. there was.

Accordingly, the effect of additional variables on the reaction in the batch reaction was evaluated below.

3) Evaluation of the influence of the solvent on the 3-formylation reaction of indole

Indole (1 mmol), HMTA (2 mmol), I ₂ (0.2 mmol), and 10 ml of a solvent were added to a 25 ml round flask and reacted at 120°C. As a solvent, DMF, DMF/water 1:1 (v/v) mixture, MIBK, or toluene/water 1:1 (v/v) mixture was used. Samples were collected over time, and the progress of the reaction was analyzed using GC/MS (Agilent Technologies 2890 GC system/5975C VL MSD with Triple-Axis Detector).

2 is a graph showing the results, when using a mixture of water and DMF than the DMF alone solvent used by Wang et al., the reaction rate and yield were highest. After that, even if the reaction time increased, the yield did not increase further. The increase in the yield by the addition of water appears to be due to the increase in the solubility of HMTA, which was not dissolved in DMF, by water. The reaction hardly proceeded with toluene or other solvents.

4) Evaluation of the effect of additives on the 3-formylation reaction of indole

In order to reconfirm the effect of the activated carbon used in Wang et al.'s reaction and to confirm its substitute, indole-3-formylation reaction was performed by adding activated carbon or graphene oxide to the reaction conditions optimized in 2).

3 and 4 are graphs evaluating the effect of activated carbon or graphene oxide on the reaction at 100° C. and 120° C. using the reaction sample of the amount described in 2), respectively.

However, as can be seen in FIGS. 3 and 4, unlike Wang et al.'s report, the addition of activated carbon or graphene oxide hardly affected the reaction rate or final yield, and the reaction proceeded somewhat slowly at 100°C, but at 120°C. The yield after 20 hours was almost the same as in.

Example 1: Fabrication of a continuous microfluidic reactor

Polytetrafluoroethylene (PTFE) tube (OD: 1.6 mm, ID: 1 mm, length: 16 m; Bohlender, Germany) and polyether ether ketone (PEEK) material for OD 1.6 mm Union (Upchurch Scientific, USA), ethylene tetrafluoroethylene (ETFE) screw and parol (Upchurch Scientific, USA), back pressure regulator (40, 75, 100, 250 psi; Upchurch Scientific, USA) And a dual pump (KP-22-13, SS, FLOM, Japan) or a syringe pump (Legato 210, KD Scientific, USA) to fabricate a continuous flow reactor using the microfluidic system of the structure shown in FIG. 5.

The components used in the microfluidic system are all materials that can be used at high temperatures (~260°C) and high pressures (~500 psi).

Example 2: 3-formylation reaction of indole in a continuous microfluidic reactor

1) Evaluation of the effect of solvents on the 3-formylation reaction of indole

Using the continuous microfluidic reactor prepared in Example 1, 3-formylation of indole was performed using the volumes of DMF and water shown in Table 3 below as solvents. The total volume of solvent was 40 ml.

Specifically, indole (4 mmol) and I ₂ (4 mmol) were dissolved in DMF, and HMTA (8 mmol) was dissolved in water or a mixture of water and MIBK, respectively, and then combined at room temperature until a clear solution was obtained. Stirred. The reaction mixture was introduced into the continuous microfluidic reactor prepared in Example 1 using a dual pump. The continuous microfluidic reactor used a 75 psi back pressure regulator. The temperature of the oil bath was set to 140°C, and since the volume of the reaction flow path in which the reaction occurred in the reactor was 12.6 ml (0.1 × 0.1 × 3.14 × 1600), the flow rate was adjusted to 1.26 ml/min so that the reaction time was 10 minutes.

The reaction solution discharged through the back pressure regulator was analyzed by GC/MS, and the yield is shown in Table 1. As a result, it was confirmed that the reaction proceeds fastest in a mixture of 1:1 (v/v) DMF/water. DMSO also showed a similar yield to DMF, but DMF was more advantageous in consideration of economic performance and subsequent processing.

2) Evaluation of the effect of the reactor on the 3-formylation reaction of indole

The 3-formylation reaction of indole was carried out in the same manner as in Entry 2 of 1), except that the inner diameter and length of the tube used in the reactor and the flow rate were changed accordingly. The effect of the reactor was evaluated and the results are shown in Table 4.

As can be seen in Table 4, the length seems to have a greater influence than the inner diameter of the tube. As the length of the tube increases, the flow rate increases for the same reaction time, so it seems that the reaction material is effectively mixed in the tube, and the reaction is active. It is thought that the decrease in the inner diameter also decreases the yield due to the slow flow rate.

3) I for the 3-formylation reaction of indole ₂ Evaluate the impact of equivalents

In the same manner as in Entry 2 of 1), except that only the equivalent of I ₂ is changed, the equivalent of I ₂ is The effect of indole on the 3-formylation reaction was evaluated, and the results are shown in FIG. 6. As can be seen from FIG. 6, as the equivalent of I ₂ increased, the reaction yield increased after the same reaction time, indicating the highest yield at 1.0 equivalent, and the yield decreased as the equivalent of I ₂ increased further.

7 shows the reaction times were adjusted to 5, 10, 15, and 30 minutes by adjusting the flow rates to 2.52, 1.26, 0.84 and 0.42 ml/min, respectively. When the reaction time was increased up to 1 equivalent of I _{2, the} yield increased. When the reaction time was further increased to 1.5 equivalents, the yield decreased as the reaction time was longer than 10 minutes. According to the result of additional analysis of the reaction solution by NMR, when the I ₂ equivalent was higher than 1 equivalent, a by-product was produced. When KI was used instead of I ₂ , the reaction hardly proceeded.

4) Evaluation of the effect of HMTA equivalent on the 3-formylation reaction of indole

The HMTA equivalent is the same as in Entry 2 of 1), except that only the equivalent of I ₂ is changed. The effect of indole on the 3-formylation reaction was evaluated, and the results are shown in Table 5.

Table 5 shows that as the equivalent of HMTA increases, the yield of 3-formylation of indole gradually increases when reacting for 10 minutes.

5) Evaluation of the effect of reaction concentration on the 3-formylation reaction of indole

The reaction concentration is the same as in Entry 2 of 1), except that only the concentration of the sample, that is, the amount of total solvent is changed. The effect of indole on the 3-formylation reaction was evaluated, and the results are shown in Table 6. In Table 6, the concentration was described as the concentration in the reaction mixture based on indole. As can be seen from Table 6, the reaction yield gradually decreased as the concentration of the reaction solution increased.

6) Evaluation of the effect of reaction temperature on the 3-formylation reaction of indole

Except for changing the reaction temperature, the reaction temperature is reduced by the same method as in Entry 2 of 1) The effect of indole on the 3-formylation reaction was evaluated, and the results are shown in Table 7. The pressure of the back pressure regulator used in the continuous microfluidic reactor is shown in FIG. 8.

From FIG. 8, as the reaction temperature increased, the yield during the 10 minute reaction gradually increased, and the increase in the reaction yield was gentle after 130°C. The yield at 140° C. was 76%, and the yield at 150 and 160° C. was 80%, and even if the temperature was higher than 150° C., the yield did not increase further.

In contrast, Wang et al. reported that the yield decreased when the temperature was reacted at 130°C than at 120°C during the batch reaction.

Table 7 shows the yield of the reaction solution after changing the reaction time to 5 minutes, 8 minutes, 10 minutes and 15 minutes by changing the flow rate to 2.52, 2.58, 1.26 and 0.84 ml/min at each temperature.

The higher the reaction temperature, the faster the reaction rate, but after reaching a yield of 80%, the increase in the yield was very gentle, and the yield after 15 minutes was almost the same at 140-160°C. The time required to complete the reaction of 1 mmol at 140°C is 15 minutes + 10 (ml)/1.26 (ml/min) = 23 minutes, compared to the batch reaction time required to obtain a yield of about 70%, compared to 10 hours. Even if only the required time was considered, the efficiency was more than 26 times higher.

7) 3-formylation reaction of indole derivatives

Except for changing the indole derivative, the 3-formylation reaction of indole proceeded by the method 1), and the yield after 10 minutes is shown in Table 8. However, in Table 8, DMF:water was used in a total of 10 ml in a ratio of 6:4 (v/v), and 8 and 9 used DMF:water in 8: A total of 12 ml was used at a ratio of 4 (v/v), the reaction temperature was carried out at 150° C., and a back pressure regulator of 100 psi was used.

As can be seen in Table 8 below, it can be confirmed that 3-formylation of indole proceeds at a high yield for 10 minutes regardless of the position of the substituent or the type of the substituent, except for Entry 4 and 5 where the substituents are alkylamines. there was.

Claims (6)

An injection port through which the sample is injected by the pump;
A reaction flow path having one end connected to the injection port;
A back pressure regulator connected to the other end of the reaction flow path; And
An outlet through which the sample passing through the back pressure regulator is discharged;
Including, during the heating reaction, microbubbles are not formed in the reaction flow path, and a mixed solution of indole, hexamethylenetetraamine, and iodine solution is reacted in a continuous microfluidic reactor capable of reaction at a temperature above the boiling point of the solvent. 3-formylation method of indole derivatives.
The method of claim 1,
The method of 3-formylation of an indole derivative, wherein the pump is operable at a pressure higher than the critical pressure of the back pressure regulator.
The method of claim 1 or 2,
3-formylation method of an indole derivative, characterized in that the width of the reaction channel is 0.1 ~ 5.0 mm.
delete The method of claim 1 or 2,
The solvent in the reaction is N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), or 3-formylation method of an indole derivative, characterized in that it contains a mixture of the solvent and water.
The method of claim 5,
The reaction temperature is a 3-formylation method of an indole derivative, characterized in that 120 ~ 160 ℃.

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