Method for synthesizing 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde

Abstract

The invention discloses a preparation method for synthesizing 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde, which comprises the following steps: carrying out continuous flow bromination reaction on a compound o-fluoroacetophenone in a formula I to obtain a compound bromide in a formula II, and reacting the compound in the formula II with malononitrile to obtain a compound dinitrile in a formula III, and then carrying out hydrogenation reaction to obtain a compound 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde as shown in a formula IV. The continuous flow process for synthesizing the 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde has the advantages of short reaction period, high safety controllability, high production efficiency, simplicity and convenience in operation, environmental friendliness and suitability for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde. Background Art

[0002] 5-(2-Fluorophenyl)-1H-pyrrole-3-carboxaldehyde is an important raw material for the preparation of vonaprazan fumarate. Vonaprazan fumarate is suitable for patients with peptic esophagitis, Helicobacter pylori infection, duodenal ulcer, esophagitis, gastric ulcer, gastroesophageal reflux disease and peptic ulcer. This drug is a new type of acid-suppressing drug created and developed by Takeda Pharmaceutical Company of Japan. It is a potassium ion competitive acid blocker (P-CAB) that competitively and reversibly inhibits K + Binds to the proton pump and blocks the K + With H + Exchange, stop the secretion of gastric acid, and thus achieve the effect of acid suppression. The good acid suppression effect and safety of vonoprazan fumarate can shorten the course of treatment and greatly improve the patient's compliance and cure rate.

[0003] 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde is one of the most critical intermediates for preparing vonoprazan fumarate. The synthesis method reported in patents US9266831 and CN201080018114 uses o-fluoroacetophenone as a starting material and is prepared through five steps of bromination, condensation, cyclization, dechlorination, and hydrogenation. The reaction steps are long, the overall reaction yield is not high, and the Pd / C catalyst used is expensive, which increases the cost of the product.

[0004]

[0005] Therefore, there are still certain deficiencies in the preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, and developing a new preparation method thereof has important practical significance. Summary of the invention

[0006] In view of the deficiencies in the prior art, the purpose of the present invention is to provide a method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, aiming to improve production efficiency and process controllability and reduce process risks. The method is simple to operate, has a short reaction route and is environmentally friendly, and is suitable for industrial production.

[0007] The present invention provides the following technical solutions:

[0008] A method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde comprises:

[0009] (1) The compound of formula I is subjected to bromination reaction with a bromination reagent to obtain a compound of formula II:

[0010]

[0011] (2) The compound of formula II reacts with malononitrile to obtain a compound of formula III:

[0012]

[0013] (3) The compound of formula III is subjected to hydrogenation reaction to obtain the compound of formula IV:

[0014]

[0015] Furthermore, the specific steps involved are as follows:

[0016] (1) o-Fluoroacetophenone, solvent and initiator are mixed in a certain proportion to obtain feed liquid A. Bromination reagent or bromination reagent mixed with solvent is feed liquid B. Feed liquid A and feed liquid B are introduced into a mixer at a certain flow rate and then directly enter into a microreactor for reaction to obtain a reaction liquid of compound of formula II. The reaction liquid is directly subjected to the next step of reaction after quenching, washing and separation to obtain feed liquid C.

[0017] (2) Malononitrile is mixed with the above feed liquid C to obtain feed liquid D. Alkali is mixed with dichloromethane to obtain feed liquid E. Feed liquid D and feed liquid E are introduced into a mixer at a certain flow rate and then directly enter a microreactor for reaction to obtain a reaction liquid of compound III. The reaction liquid is quenched, pH is adjusted, liquids are separated, and vacuum concentrated. After crystallization and suction filtration, solid compound III is obtained.

[0018] (3) Compound III, additives, acid and solvent are mixed in a certain proportion, and compound IV is obtained by one-step hydrogenation in the presence of a catalyst. The reaction solution is quenched, pH adjusted, separated, concentrated under reduced pressure, and crystallized and filtered to obtain the finished product 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde.

[0019] The inventors have found that the compound of formula I, o-fluoroacetophenone, is used as a starting material to react with a bromination reagent to obtain a compound of formula II, which is then simply quenched, separated and dried, and then directly subjected to the next step of reaction. The compound of formula II reacts with malononitrile to obtain a compound of formula III, and the yield of the two-step reaction is as high as over 90%. The compound of formula III is subjected to continuous hydrogenation to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (compound of formula IV), and after recrystallization, a product with a liquid chromatography purity of over 99% is obtained, and the yield is over 70%.

[0020] As a preferred embodiment, in the present invention, in step (1), the solvent is dichloromethane, the initiator is azobisisobutyronitrile, the mass fraction of o-fluoroacetophenone in the feed liquid A is 15-40%, and the mass fraction of azobisisobutyronitrile is 0.8-2.0%.

[0021] As a preferred embodiment, in the present invention, in step (1), the bromination reagent is bromine water, the solvent used is dichloromethane, and the mass fraction of bromine water in feed liquid B is 20-50%.

[0022] The molar ratio of o-fluoroacetophenone, azobisisobutyronitrile and bromine water contained in the feed liquid A and the feed liquid B in the step (1) introduced into the device is 1: 0.01-0.3: 0.5-2.0, and the preferred molar ratio is 1: 0.02-0.1: 0.85-1.2.

[0023] In step (1), the mixer is a microchannel reactor, a membrane dispersion reactor or a micro-sieve reactor. The mixing temperature in the mixer is -10 to 60° C. and the mixing time is 0.1 to 1 second.

[0024] The reaction temperature of the microchannel reactor in step (2) is -10 to 60° C., preferably 5 to 50° C. The residence time of the reaction liquid in the reactor is 5 to 45 minutes, preferably 15 to 30 minutes.

[0025] As a preferred embodiment, in the present invention, in step (2), the mass fraction of malononitrile in the feed liquid D is 5-10%.

[0026] As a preferred embodiment, in the present invention, in step (2), the base used is DIPEA or Et2N, preferably DIPEA. The mass fraction of DIPEA in the feed solution E is 50-100%.

[0027] The molar ratio of the feed liquid D in step (2) introduced into the device, malononitrile, DIPEA and o-fluoroacetophenone (the first step reaction is directly fed to the next step reaction without purification, and the molar ratio of the second step reaction is calculated based on o-fluoroacetophenone) contained in the feed liquid E is 0.85-2.0:0.9-2.5:1, and the preferred molar ratio is 0.9-1.5:1.0-1.6:1.

[0028] In step (2), the mixer is a microchannel reactor, a membrane dispersion reactor or a micro-sieve reactor. The mixing temperature in the mixer is -10 to 60°C and the mixing time is 0.1 to 1 second.

[0029] The reaction temperature of the microchannel reactor in step (2) is -10 to 60° C., preferably 5 to 30° C. The residence time of the reaction liquid in the reactor is 1 to 25 minutes, preferably 2 to 25 minutes.

[0030] As a preferred embodiment, in the present invention, in step (3), the catalyst is Raney cobalt or Raney nickel, preferably Raney cobalt. The mass ratio of the catalyst to the compound of formula III is 0.01:1 to 0.5:1, and the more preferred mass ratio of the catalyst to the compound of formula III is 0.03:1 to 0.3:1.

[0031] As a preferred embodiment, in the present invention, in step (3), 1,4-diazabicyclo[2.2.2]octane needs to be added, and the equivalent ratio of 1,4-diazabicyclo[2.2.2]octane to the compound of formula III is 0.05:1 to 6:1, and the preferred molar ratio is 0.1:1.0 to 2.0:1.

[0032] As a preferred embodiment, in the present invention, in the step (3): it is necessary to carry out under acidic conditions, and the acid is one of formic acid, acetic acid, propionic acid, trifluoroacetic acid, hydrochloric acid, and sulfuric acid, preferably acetic acid.

[0033] As a preferred embodiment, in the present invention, in step (3): it is necessary to carry out under hydrogen and pressurized conditions, the pressure is 0.01-1 MPa, and the preferred pressure is 0.1-0.8 MPa. The reaction solvent is one of methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water or a mixed solvent thereof, preferably a mixed solvent of tetrahydrofuran and water. The reaction temperature is -5-50°C, and the reaction time is 2-20 hours.

[0034] As a preferred embodiment, in the present invention, in the step (3), the post-treatment includes: quenching with water, adjusting pH, liquid separation, concentrating under reduced pressure, and purifying by crystallization.

[0035] Compared with the existing technology for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, the beneficial effects of the present invention are as follows:

[0036] (1) The process is short and the product can be prepared in three steps.

[0037] (2) In the first step, due to the continuous flow reaction technology, the product residence time is short, so the dibrominated product is low. In addition, the first step is not purified and is directly used as the second step continuous flow reaction, which greatly improves the efficiency.

[0038] (3) In the third step, the product can be prepared by one-step hydrogenation.

[0039] (4) High product purity: The purity of the 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde obtained by the present invention is as high as 99% or more after liquid chromatography detection.

[0040] (5) Easy to industrialize: The reagents used in each step of the present invention are all commonly used reagents, with low toxicity and environmental friendliness; the process flow is simple, continuous operation, short reaction cycle, high safety and controllability, high production efficiency, and the first two steps effectively solve the problems in the existing autoclave intermittent process production. The conditions used are all commonly used conditions for industrial production, and each step is simple to operate, which is suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1The process flow chart of the present invention for synthesizing the intermediate bromide of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde;

[0042] Figure 2 The present invention is a process flow chart of the process equipment for synthesizing the dicyano product of the intermediate of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde. DETAILED DESCRIPTION

[0043] The following examples will help to further understand the present invention, but are not intended to limit the present invention.

[0044] The raw material o-fluoroacetophenone and other reagents and solvents used in the examples were purchased commercially. The instruments used for testing and analysis in the examples were: AV-500 NMR (Bruker, Germany); MS instrument was Thermo LcqFleet 2 (Thermo Fisher Scientific, USA). Liquid chromatograph was 1260 (Agilent Technologies, USA).

[0045] Example 1

[0046]

[0047] Add 20g o-fluoroacetophenone, 35g dichloromethane, 0.71g AIBN to the reaction bottle, protect with nitrogen, and start stirring. Cool down to 0-5°C, add 25.5g bromine solution (diluted with 48g DCM), heat up to 20-30°C, react for 6-7 hours, and detect by TLC. After the reaction is complete, add 100g water, separate the layers, collect the organic phase, wash the organic phase once with saturated sodium carbonate, and take the lower organic phase. The obtained bromide solution is directly used for the next step reaction. (HPLC detection, raw material 2%, product 87%, dibromide 11%).)

[0048] The bromide solution obtained above was cooled to -10-0°C, 9.6g of malononitrile was added, and stirring was started. 20.5g of DIPEA was added dropwise, and the temperature was controlled below 0°C. After the addition was completed, the mixture was stirred for 2-3 hours under the heat preservation condition. After TLC detection, hydrochloric acid was added dropwise to adjust the pH to 6-7. After the addition was completed, the mixture was heated to 20-30°C, stirred for half an hour, concentrated under reduced pressure to remove the organic solvent, and filtered to collect the filter cake. The filter cake was crystallized with isopropanol and dried to obtain 22.8g of dicyano product with a yield of 77.9% (total yield of two steps).

[0049] 1H NMR (500MHz,CDCl3):δ8.01(td,J=7.7,1.8Hz,1H),7.69-7.63(m,1H),7.38-7.28(m,1H),7.25-7.17(m,1H),4.38(t,J=6.6Hz,1H),3.76(dd,J=6.6,3.3Hz,2H).MS:202-203(MH).HPLC:XDB-C18 4.6*250,acetonitrile / water 60:40,235nm,35min.

[0050] Example 2

[0051]

[0052] Add 20g o-fluoroacetophenone, 35g dichloromethane, 0.71g AIBN to the reaction bottle, protect with nitrogen, and start stirring. Cool down to 0-5°C, add 23.1g bromine solution (diluted with 45g DCM), heat up to 20-30°C, react for 6-7 hours, and detect by TLC. After the reaction is complete, add 100g water, separate the layers, collect the organic phase, wash the organic phase once with saturated sodium carbonate, and take the lower organic phase. The obtained bromide solution is directly used for the next step reaction. (HPLC detection, raw material 7%, product 86%, dibromide 8%).

[0053] The bromide solution obtained above was cooled to -10-0°C, 9.6g of malononitrile was added, and stirring was started. 20.5g of DIPEA was added dropwise, and the temperature was controlled below 0°C. After the addition was completed, the mixture was stirred for 2-3 hours under the temperature preservation condition. After TLC detection, hydrochloric acid was added dropwise to adjust the pH to 6-7. After the addition was completed, the mixture was heated to 20-30°C, stirred for half an hour, concentrated under reduced pressure to remove the organic solvent, and filtered to collect the filter cake. The filter cake was crystallized with isopropanol and dried to obtain 22.4g of dicyano product with a yield of 76.5% (total yield of two steps).

[0054] Example 3

[0055]

[0056] Add 20g o-fluoroacetophenone, 35g dichloromethane, 0.71g AIBN to the reaction bottle, protect with nitrogen, and start stirring. Cool down to 0-5°C, add 25.5g bromine solution (diluted with 48g DCM), heat up to 20-30°C, react for 6-7 hours, and detect by TLC. After the reaction is complete, add 100g water, separate the layers, collect the organic phase, wash the organic phase once with saturated sodium carbonate, and take the lower organic phase. The obtained bromide solution is directly used for the next step reaction. (HPLC detection, raw material 2%, product 87%, dibromide 11%).)

[0057] The bromide solution obtained above was cooled to -10-0°C, 9.6g of malononitrile was added, and stirring was started. 16g of Et3N was added dropwise, and the temperature was controlled below 0°C. After the addition was completed, the mixture was stirred for 2-3 hours under the heat preservation condition. After TLC detection, hydrochloric acid was added dropwise to adjust the pH to 6-7. After the addition was completed, the mixture was heated to 20-30°C, stirred for half an hour, concentrated under reduced pressure to remove the organic solvent, and filtered to collect the filter cake. The filter cake was crystallized with isopropanol and dried to obtain 20.2g of dicyano product with a yield of 69.0% (total yield of two steps).

[0058] Example 4

[0059]

[0060] Weigh 50g of o-fluoroacetophenone, 88g of dichloromethane, and 1.9g of AIBN, stir evenly, and adjust the volume to obtain feed liquid A. Use 110g of DCM solution to adjust the volume to obtain feed liquid B. Use horizontal flow pumps to transport feed liquid A and feed liquid B to No. 1 T-type microchannel mixer (5 cm), the mixer temperature is 55°C, the feed liquid A flow rate is 8ml / min, and the feed liquid B flow rate is 7.4ml / min. The mixer is connected to a 5ml*5 plate microreactor, the plate microreactor temperature is 30°C, the residence time is 15min, collect the solution containing the brominated product at the outlet of the plate microreactor, wash it once with saturated sodium carbonate, and take the lower organic phase to obtain feed liquid C. (HPLC detection, raw material 1%, product 96%, dibrominated 3%).

[0061] Add 24g of malononitrile to the above-obtained bromine solution, stir and dissolve, and adjust the volume to obtain liquid D, and control the temperature to 10-15°C. Add 51.5g of DIPEA, control the temperature to 10-15°C, and adjust the volume to obtain liquid E. Liquid D and liquid E are respectively transported to No. 2 T-type microchannel mixer (5 cm) using a horizontal flow pump. The mixer temperature is 10°C, the flow rate of liquid A is 9.5ml / min, and the flow rate of liquid B is 3.1ml / min. The mixer is connected to a 5ml*4 plate microreactor, the temperature of the plate microreactor is 15°C, the residence time is 5min, and the outlet of the plate microreactor is collected to obtain a solution containing a dicyano product, and hydrochloric acid is added dropwise to adjust the pH to 6-7. After the addition is completed, the temperature is raised to 20-30°C, stirred for half an hour, concentrated under reduced pressure to remove the organic solvent, filtered, and the filter cake is collected. The filter cake was crystallized with isopropanol and dried to obtain 65.9 g of dicyano product with a yield of 90.0% (total yield of two steps).

[0062] Example 5

[0063]

[0064] Weigh 40g of o-fluoroacetophenone, 71g of dichloromethane, and 1.5g of AIBN, stir evenly, and adjust the volume to obtain feed liquid A. Use 88g of DCM solution to adjust the volume to obtain feed liquid B. Use horizontal flow pumps to transport feed liquid A and feed liquid B to T-type microchannel mixer No. 1 respectively. The mixer temperature is 55°C, the feed liquid A flow rate is 8ml / min, and the feed liquid B flow rate is 7.4ml / min. The mixer is connected to a 5ml*5 plate microreactor. The temperature of the plate microreactor is 30°C, and the residence time is 14min. Collect the outlet of the plate microreactor to obtain a solution containing the brominated product, wash it once with saturated sodium carbonate, and take the lower organic phase to obtain feed liquid C. (HPLC detection, raw material 1%, product 96%, dibrominated 3%).

[0065] Add 19.2g of malononitrile to the bromide solution obtained above, stir and dissolve, and adjust the volume to obtain liquid D, which is controlled to 10-15°C. Dissolve 41g of DIPEA in 41g of DCM, control the temperature to 10-15°C, and adjust the volume to obtain liquid E. Use a horizontal flow pump to transport liquid D and liquid E to the No. 2 T-type microchannel mixer, the mixer temperature is 10°C, the liquid A flow rate is 9.5ml / min, and the liquid B flow rate is 3.7ml / min. The mixer is connected to a 5ml*4 plate microreactor, the plate microreactor temperature is 15°C, the residence time is 5min, collect the plate microreactor outlet to obtain a solution containing dicyano products, and add hydrochloric acid to adjust the pH to 6-7. After the addition is completed, heat to 20-30°C, stir for half an hour, concentrate under reduced pressure to remove the organic solvent, filter, and collect the filter cake. The filter cake was crystallized with isopropanol and dried to obtain 53 g of dicyano product with a yield of 90.5% (total yield of two steps).

[0066] Example 6

[0067]

[0068] Weigh 30g of raw material dinitrile compound, 17.5g of 1,4-diazabicyclo[2.2.2]octane, 2.8g of Raney cobalt (cobalt>45%), 70ml of THF, 50ml of acetic acid, and 15ml of water, and add them to the autoclave. Turn on the stirring, pass hydrogen to 0.6-0.8MPa, raise the temperature to 10-15°C, and keep the reaction for 17-19 hours. After TLC detection, filter and remove the catalyst after the reaction is complete. Add 110ml of ethyl acetate, adjust the pH to 7-8 with 6N sodium hydroxide, stir for 30 minutes, separate the liquids, and collect the organic phase. Adjust the pH of the organic phase to 5-6 with 4N hydrochloric acid and stir for one hour. Separate the liquids, wash the organic phase once with saturated brine, collect the organic phase, dry, and concentrate under reduced pressure to remove the organic solvent. The residue is recrystallized with 30ml of ethyl acetate and 65ml of n-hexane, and dried to obtain 19.9g of the final product, with a liquid chromatography purity of 99.3% and a yield of 70.9%.

[0069] 1 H NMR (500 MHz, CDCl3): δ 12.19 (brs, 1H), 9.78 (s, 1H), 7.82-7.76 (m, 2H), 7.31-7.22 (m, 3H), 6.93 (d, J = 1.6 Hz, 1H). MS: 189-190 (MH). HPLC: XDB-C18 4.6*250, acetonitrile / water 60:40, 235 nm, 35 min.

[0070] Example 7

[0071]

[0072] Weigh 50g of raw material dinitrile compound, 29.2g of 1,4-diazabicyclo[2.2.2]octane, 4.7g of Raney cobalt (cobalt>45%), 120ml of THF, 80ml of acetic acid, and 25ml of water, and add them to the autoclave. Turn on the stirring, pass hydrogen to 0.6-0.8MPa, raise the temperature to 10-15°C, and keep the reaction for 17-19 hours. After TLC detection, filter and remove the catalyst after the reaction is complete. Add 110ml of ethyl acetate, adjust the pH to 7-8 with 6N sodium hydroxide, stir for 30 minutes, separate the liquids, and collect the organic phase. Adjust the pH of the organic phase to 5-6 with 4N hydrochloric acid and stir for one hour. Separate the liquids, wash the organic phase once with saturated brine, collect the organic phase, dry, and concentrate under reduced pressure to remove the organic solvent. The residue is recrystallized with 50ml of ethyl acetate and 110ml of n-hexane, and dried to obtain 33.5g of the final product, with a liquid chromatography purity of 99.2% and a yield of 71.6%.

[0073] Example 8

[0074]

[0075] Weigh 20g of raw material dinitrile compound, 1.9g of Raney cobalt (cobalt>45%), 50ml THF, 33ml acetic acid, 10ml water, and add them to the autoclave. Turn on the stirring, pass hydrogen to 0.6-0.8MPa, heat to 10-15°C, and keep warm for 17-19 hours. TLC detection, after the reaction is complete, filter to remove the catalyst. 75ml ethyl acetate is added, and the pH is adjusted to 7-8 with 6N sodium hydroxide. After stirring for 30 minutes, separate the liquids and collect the organic phase. The organic phase is adjusted to pH 5-6 with 4N hydrochloric acid and stirred for one hour. Separate the liquids, wash the organic phase once with saturated brine, collect the organic phase, dry, and concentrate under reduced pressure to remove the organic solvent. The residue is recrystallized with 12ml ethyl acetate and 30ml n-hexane, and dried to obtain 8.1g of the final product, with a liquid chromatography purity of 99% and a yield of 43.3%.

[0076] Example 9

[0077]

[0078] Weigh 30g of raw material dinitrile compound, 17.5g of 1,4-diazabicyclo[2.2.2]octane, 2.8g of Raney nickel, 70ml of THF, 50ml of acetic acid, and 15ml of water, and add them to the autoclave. Turn on the stirring, pass hydrogen to 0.6-0.8MPa, heat to 10-15°C, and keep warm for 17-19 hours. After TLC detection, filter and remove the catalyst after the reaction is complete. Add 110ml of ethyl acetate, adjust the pH to 7-8 with 6N sodium hydroxide, stir for 30 minutes, separate the liquids, and collect the organic phase. Adjust the pH of the organic phase to 5-6 with 4N hydrochloric acid and stir for one hour. Separate the liquids, wash the organic phase once with saturated brine, collect the organic phase, dry, and concentrate under reduced pressure to remove the organic solvent. The residue is recrystallized with 22ml of ethyl acetate and 48ml of n-hexane, and dried to obtain 14.6g of the final product, with a liquid chromatography purity of 99.2% and a yield of 52%.

Claims

1. A method for synthesizing 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, wherein the structure of the 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde is as follows: It is characterized in that include: (1) The compound of formula I is subjected to bromination reaction with a bromination reagent to obtain a compound of formula II: (2) The compound of formula II is subjected to condensation reaction with malononitrile to obtain a compound of formula III: (3) The compound of formula III is subjected to hydrogenation reaction to obtain the compound of formula IV:

2. The method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde according to claim 1, characterized in that: In step (1), the brominating agent is liquid bromine or NBS, and the molar ratio of the compound of formula I to the brominating agent is 1:0.3 to 1:2.0; During the reaction, an initiator and a solvent are added, wherein the initiator is azobisisobutyronitrile and the solvent is dichloromethane.

3. The method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde according to claim 2, characterized in that: In step (1), the bromination reaction is carried out in a microreactor; During the reaction, the compound of formula (I) and the initiator are first dissolved in a solvent to form a feed liquid A, and at the same time, the bromination reagent is dissolved in a solvent to form a feed liquid B, and then the feed liquid A and the feed liquid B are respectively transported to a mixer for mixing, and then introduced into a plate-type microreactor for reaction to obtain a solution containing a brominated product; The mixer is a microchannel reactor, a membrane dispersion reactor or a micro-sieve reactor; The solution containing the brominated product is directly introduced into step (2) after washing.

4. The method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde according to claim 3, characterized in that: In step (1), the temperature in the plate-type microreactor is 25 to 35° C., and the residence time is 10 to 30 minutes.

5. The method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde according to claim 1, characterized in that: In step (2), the condensation reaction is carried out under the action of an organic base and a solvent; The organic base is DIPEA or Et3N, and the solvent is dichloromethane.

6. The method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde according to claim 5, characterized in that: In step (2), malononitrile is first added to the solution of the compound of formula II to obtain a feed liquid D after dissolution, and an organic base or a solution of an organic base is directly used as a feed liquid E. Then, the feed liquid D and the feed liquid E are respectively transported to a mixer for mixing, and then introduced into a plate microreactor for reaction to obtain a solution containing a dicyano product, and then the dicyano product is obtained through post-treatment; The mixer is a microchannel reactor, a membrane dispersion reactor or a micro-sieve reactor.

7. The method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde according to claim 6, characterized in that: In step (2), the temperature in the plate microreactor is 10-20° C., and the residence time is 3-10 min; In step (2), the post-treatment includes: quenching, adjusting pH, liquid separation, concentration under reduced pressure, crystallization and suction filtration, and drying to obtain the dicyano product.

8. The method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde according to claim 1, characterized in that: In step (3), the hydrogenation reaction is carried out under the action of a catalyst and an additive; The catalyst is Raney cobalt or Raney nickel, and the mass ratio of the catalyst to the compound of formula III is 0.01:1 to 0.5:1; The additive is 1,4-diazabicyclo[2.2.2]octane, and the molar ratio of the additive to the compound of formula III is 0.05:1 to 6:1; The hydrogenation reaction is carried out under hydrogen and pressure conditions, and the pressure is 0.01-1 MPa.

9. The method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde according to claim 1, characterized in that: In step (3), the hydrogenation reaction is carried out under acidic conditions, and the acid used is one of formic acid, acetic acid, propionic acid, trifluoroacetic acid, hydrochloric acid, and sulfuric acid; The solvent for the hydrogenation reaction is one of methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water or a mixed solvent thereof.

10. The method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde according to claim 1, characterized in that: In step (3), the reaction temperature is -5 to 50°C and the reaction time is 2 to 20 hours; After the reaction is completed, post-treatment includes: quenching the reaction solution, adjusting the pH, separating the liquid, concentrating under reduced pressure, filtering the crystals, and drying to obtain the product.

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