A method for intensifying the passerini reaction based on thin liquid film microreactor

Abstract

The application discloses a method for intensifying a Passerini reaction based on a thin liquid film microreactor, and belongs to the technical field of process intensification of the Passerini reaction. In the method, a gas pipeline at an inlet section of the microreactor is extended into a pipeline of the microreactor, so that a uniform ultra-thin liquid film is formed on the inner wall of the pipeline, and alpha-acyloxyformamide can be synthesized efficiently and rapidly, and a pure product can be obtained by rotary evaporation. The method combines the advantages of the past methods, meets the requirements of high efficiency, rapidness, low cost and green chemistry, and can synthesize the product very simply and rapidly, thereby providing good experimental conditions for development of new molecules. Meanwhile, a continuous flow chemistry platform is built, thereby laying a foundation for subsequent industrial application.

Description

Technical Field

[0001] This invention belongs to the field of Passerini reaction process enhancement technology, and particularly relates to a method for enhancing the Passerini reaction based on a thin liquid film microreactor. Background Technology

[0002] The Passerini reaction, a three-component condensation reaction proposed in 1921 by the Italian chemist Mario Passerini, involves the condensation of an isonitrile compound, a carbonyl compound (aldehyde or ketone), and a carboxylic acid compound to produce an α-acyloxyformamide or an α-alkoxyamide. It is now often referred to as the Passerini multicomponent reaction (PMR) (Gazz. Chim. Ital. 1921). The Passerini reaction not only boasts high atom utilization but also produces important organic molecules, which can be used to synthesize many important natural products, complex molecules, and pharmaceutical molecules, demonstrating significant practical value and application prospects (Chem. Sci., 2021, 12, 15445-15472). Furthermore, since 2011, this reaction has been developed into a multicomponent polymerization reaction, which can be used to control the polymer backbone structure and synthesize renewable monomer polymers. Therefore, developing new PMR reactions and enhancing reaction rates and selectivity have been key areas of focus.

[0003] Past research has focused on improving reaction rates, reducing costs, shortening reaction times, and employing greener synthesis methods, achieving significant results. For example, using water instead of organic solvents not only increases the reaction rate by more than 300 times compared to organic solvents (J. Am. Chem. Soc. 2004, 126, 2, 444–445), but also meets the requirements of "green chemistry" (ACS Appl. Polym. Mater. 2025, 7, 18, 12812–12820). Other strategies for improving the rate of the Passerini reaction include solvent-free methods, microwave methods, grinding with specialized equipment, microwave microchannels, and microdroplets. Therefore, under mild reaction conditions, simple, rapid, efficient, green, and continuous synthetic methods remain the preferred approach for constructing α-acyloxyformamides.

[0004] However, these methods still have some problems, such as the need to construct special experimental apparatus, excessively long reaction times, low reaction yields, and the use of special catalysts, making them unsuitable for large-scale production in engineering. Therefore, it is necessary to provide a method for enhancing the Passerini reaction that can synthesize high-purity products in a shorter time, and that is simple to operate and easy to scale up. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention proposes a method for enhancing the Passerini reaction based on a thin-film microreactor. This invention uses a simple reaction method, which greatly shortens the reaction time and improves the reaction efficiency.

[0006] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a method for enhancing the Passerini reaction based on a thin-film microreactor, comprising the following steps: The reactants are mixed using a micro mixer and then introduced into a microreactor. The reactants are a carboxylic acid compound solution, a carbonyl compound solution, and an isonitrile compound solution. The gas phase pipeline, liquid phase pipeline and microreactor pipeline are connected by a T-junction, and the reaction temperature is controlled by a water bath. The gas flow rate is controlled by a gas mass flow meter, thereby adjusting the thickness of the liquid film inside the reactor. The thickness of the liquid film inside the microreactor does not exceed 25 μm; The gas pipe at the inlet section of the microreactor extends into the microreactor pipe, thereby forming a uniform liquid film on the inner wall of the pipe.

[0007] The principle of this invention: The thin-film microreactor of this invention enables the formation of an ultrathin liquid film within a pipe. The uniform spreading of the liquid on the pipe wall increases the interfacial range of the solvent, while allowing for rapid solvent evaporation. This creates a gas-phase-like limiting condition within the microreactor's pipes, enhancing the desolvation effect, increasing reagent reactivity, and strengthening the enthalpy and entropy effects of the reaction. This thermodynamically regulates the reaction kinetics and improves the reaction yield. Simultaneously, the increased specific surface area of ​​the thin-film liquid film within the pipe shortens the transfer distance and enhances the heat and mass transfer rate, freeing the reaction from the constraints of heat and mass transfer. Therefore, the thin-film method for synthesizing α-acyloxyformamides effectively meets the requirements. Furthermore, compared to thin films formed on paper or platforms, the thin-film microreactor, with its easier product collection, cleaner reaction process, less pollution, and ability to achieve continuous reactions, provides a more efficient and sustainable approach. Based on the thin-film microreactor, a continuous flow chemistry platform has also been built, laying the industrial foundation for subsequent pilot-scale and scale-up operations.

[0008] Furthermore, the microreactor is selected from serpentine pipes or straight pipes.

[0009] Furthermore, the molar ratio of the carboxylic acid compound, carbonyl compound, and isonitrile compound is 1:2:2.

[0010] Furthermore, the carboxylic acid compound is selected from one of benzoic acid, o-fluorobenzoic acid, m-fluorobenzoic acid, and o-nitrobenzoic acid; The carbonyl compound is selected from phenylacetaldehyde or 2-nitrobenzaldehyde; The isonitrile compound is benzyl isonitrile.

[0011] Furthermore, the reaction temperature is controlled to not exceed 81°C by using a water bath.

[0012] Furthermore, during the process of mixing the reactants in the reactor using the micro mixer, the liquid phase flow rate is regulated by a pump, and the gas-liquid phase flow rate ratio is not less than 1000.

[0013] Furthermore, the liquid phase flow rate is 1 mL / min, and the gas phase flow rate is not less than 1000 mL / min, preferably 3000-6000 mL / min.

[0014] Furthermore, the microreactor is connected to a high-pressure constant flow pump via a pipeline for pumping in methanol to quench the reaction.

[0015] Furthermore, the methanol flow rate is 5-15 mL / min.

[0016] Furthermore, the residence time is 6.4-40 s before the methanol is pumped in to quench the reaction.

[0017] Compared with the prior art, the present invention has the following advantages and technical effects: This invention discloses a method for enhancing the Passerini reaction using a thin-film microreactor, which forms a thin film by adjusting the gas-liquid ratio. In this invention, when the liquid phase flow rate is 1 mL / min and the nitrogen gas flow rate is 6000 mL / min (i.e., a gas-liquid ratio of 1:6000), a ring flow is formed within the reactor pipe, resulting in an average liquid film thickness of 10.2 μm, thus constructing a thin-film microreactor. Using benzoic acid, phenylacetaldehyde, and benzyl isonitrile as raw materials and acetonitrile as solvent, α-acyloxyformamide can be synthesized efficiently and rapidly within 30 s at 30°C with a conversion rate of 99.61% and a yield of 98.33%. The pure product can then be obtained simply by rotary evaporation. This method meets the requirements of high efficiency, speed, low cost, and green chemistry, enabling very simple and rapid synthesis of the product and providing excellent experimental conditions for the development of new molecules. Simultaneously, a continuous flow chemistry platform is established, laying the foundation for subsequent industrial applications. Attached Figure Description

[0018] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 This is a flowchart of the method for enhancing the Passerini reaction based on a thin-film microreactor according to Embodiment 1 of the present invention; Figure 2 This is a graph showing the trend of liquid film thickness inside the tube as a function of gas-liquid velocity ratio at 30℃. Figure 3 The graph shows the trend of benzoic acid conversion rate and α-acyloxyformamide yield as a function of liquid film thickness. Detailed Implementation

[0019] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0020] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0021] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0022] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0023] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0024] Embodiments of the present invention provide a method for enhancing the Passerini reaction based on a thin-film microreactor, comprising the following steps: The reactants are mixed using a micro mixer and then introduced into a microreactor. The reactants are a carboxylic acid compound solution, a carbonyl compound solution, and an isonitrile compound solution. The gas phase pipeline, liquid phase pipeline and microreactor pipeline are connected by a T-junction, and the reaction temperature is controlled by a water bath. The gas flow rate is controlled by a gas mass flow meter, thereby adjusting the thickness of the liquid film inside the reactor. The thickness of the liquid film inside the microreactor does not exceed 25 μm; The gas pipe at the inlet of the microreactor extends into the microreactor pipe, thereby forming a uniform liquid film on the inner wall of the pipe. After the reaction is completed, the gas-liquid mixture flows through a gas-liquid separator; the gas is separated from the upper outlet, and the liquid is collected from the lower outlet to prepare the sample for testing.

[0025] This invention uses reversed-phase high-performance liquid chromatography (RP-HPLC) to separate and analyze the products, and uses liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) to determine the product molecules. The quenched reaction solution is filtered through a 0.22 μm filter. 100 μL of the solution is taken and diluted to 1 mL with a 1:1 (volume ratio) mixture of methanol and water. The sample preparation is now complete.

[0026] In a preferred embodiment of the invention, two micromixers are used to mix the reactants in the microreactor, ensuring that the reactants are mixed to the greatest extent possible at the inlet of the microreactor.

[0027] In a preferred embodiment of the present invention, the thickness of the liquid film inside the microreactor is 10-25 μm.

[0028] In a preferred embodiment of the present invention, the microreactor is selected from a serpentine pipe or a straight pipe.

[0029] In a preferred embodiment of the present invention, the microreactor material includes, but is not limited to, glass, copper, and stainless steel.

[0030] For example, the microreactor used in the following embodiments of the present invention is a glass serpentine tube.

[0031] In a preferred embodiment of the present invention, the solvents in the carboxylic acid compound solution, the carbonyl compound solution, and the isonitrile compound solution are all acetonitrile. The preparation method is as follows: the carboxylic acid compound, the carbonyl compound, and the isonitrile compound are added to acetonitrile respectively and stirred evenly to obtain carboxylic acid compound solution, carbonyl compound solution, and isonitrile compound solution of corresponding concentrations.

[0032] In a preferred embodiment of the present invention, the molar ratio of the carboxylic acid compound, the carbonyl compound, and the isonitrile compound is 1:2:2.

[0033] In a preferred embodiment of the present invention, the carboxylic acid compound is selected from one of benzoic acid, o-fluorobenzoic acid, m-fluorobenzoic acid and o-nitrobenzoic acid; The carbonyl compound is selected from phenylacetaldehyde or 2-nitrobenzaldehyde; The isonitrile compound is benzyl isonitrile.

[0034] In a preferred embodiment of the invention, the reaction temperature is controlled to not exceed 81°C using a water bath. For example, the reaction temperature is controlled to be 30°C using a water bath.

[0035] In a preferred embodiment of the present invention, the thickness of the liquid film within the microreactor is controlled by the gas-liquid phase flow rate ratio. The gas-liquid phase flow rate ratio in the microreactor is controlled to be no less than 1000, preferably with a liquid phase flow rate of 1 mL / min and a gas phase flow rate of no less than 1000 mL / min, preferably with a gas phase flow rate of 3000-6000 mL / min. For example, the liquid phase flow rate is 1 mL / min and the gas phase flow rate is 6000 mL / min; the liquid phase flow rate is 1 mL / min and the gas phase flow rate is 5000 mL / min; the liquid phase flow rate is 1 mL / min and the gas phase flow rate is 4000 mL / min; the liquid phase flow rate is 1 mL / min and the gas phase flow rate is 3000 mL / min.

[0036] In a preferred embodiment of the present invention, an inert gas is used as a carrier gas and does not participate in the reaction.

[0037] In a preferred embodiment of the invention, the microreactor is connected to a high-pressure constant flow pump via a pipeline for pumping in methanol to quench the reaction.

[0038] In a preferred embodiment of the invention, the methanol flow rate is 5-15 mL / min. For example, the methanol flow rate is 8 mL / min.

[0039] In a preferred embodiment of the present invention, the residence time before pumping in methanol to quench the reaction is 6.4-40 s, preferably 32 s.

[0040] The method of this invention can be used to prepare α-acyloxyformamides having the following structural formula: In this group, R1 is a carboxylic acid compound group, R2 is a carbonyl compound group, and R3 is an isonitrile compound group.

[0041] In a preferred embodiment of the present invention, α-acyloxyformamide is synthesized efficiently and rapidly within 30 seconds at 30°C using benzoic acid, phenylacetaldehyde, and benzyl isonitrile as raw materials and acetonitrile as solvent, with a conversion rate of 99.61% and a yield of 98.33%. The product has high purity, and subsequent pure product can be obtained simply by rotary evaporation. For example, the solution after the reaction is completed is collected and concentrated and purified by rotary evaporation (50°C, 100 rpm, 200 mbar vacuum) to obtain a pale yellow solid, which is then analyzed by NMR to confirm the synthesis of the product molecule.

[0042] This invention utilizes gas shearing to form a thin liquid film within the pipes of a microreactor, thus constructing a thin liquid film microreactor. The thickness of the liquid film is reduced by adjusting the gas-liquid phase flow rate ratio, thereby accelerating the reaction process. This invention is the first to use a thin-film method for the Passerini reaction within the pipes of a microreactor. In the thin liquid film microreactor, the liquid spreads uniformly within the pipe walls to form an ultrathin liquid film, greatly increasing the solvent interface area and thus reducing the reaction entropy and enthalpy. Furthermore, the rapid evaporation of the solvent creates gas-phase-like limiting conditions within the pipes, enhancing the desolvation effect and further increasing the reactivity of the reagent. Compared to traditional reactions, the thin-film method overcomes the problems of poor reactivity and numerous byproducts. Simultaneously, the products of the thin liquid film microreactor are easy to collect, the reaction process is clean with minimal pollution, and continuous reactions can be achieved. α-Acyloxyformamide can be synthesized efficiently and rapidly with a conversion rate of 99.61% and a yield of 98.33% within 32 s and 30 °C.

[0043] This invention forms a thin film by adjusting the gas-liquid phase flow rate ratio. In this invention, when the liquid phase flow rate is 1 mL / min and the nitrogen gas flow rate is 6000 mL / min (i.e., the gas-liquid ratio is 1:6000), a ring flow is formed within the reactor pipe, resulting in an average liquid film thickness of 10.8 μm, thus constructing a thin-film microreactor. Using benzoic acid, phenylacetaldehyde, and benzyl isonitrile as raw materials and acetonitrile as solvent, α-acyloxyformamide can be synthesized efficiently and rapidly within 30 s at 30°C with a conversion rate of 99.61% and a yield of 98.33%. The pure product can then be obtained simply by rotary evaporation. This invention combines the advantages of previous methods while meeting the requirements of high efficiency, speed, low cost, and green chemistry. It enables very simple and rapid synthesis of products, providing excellent experimental conditions for the development of new molecules. Furthermore, it establishes a continuous flow chemistry platform, laying the foundation for subsequent industrial applications.

[0044] Unless otherwise specified, the room temperature in this invention is 25±2℃.

[0045] All raw materials used in the embodiments of the present invention were obtained through commercial purchase.

[0046] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0047] The technical solution of the present invention will be further illustrated by the following embodiments.

[0048] Example 1 A method for enhancing the Passerini reaction based on a thin-film microreactor is shown in the flowchart below. Figure 1As shown, the specific steps are as follows: weigh benzoic acid (164.9 mg, 150 mM), phenylacetaldehyde (317.7 μL, 300 mM), and benzyl isonitrile (328.5 μL, 300 mM) and dissolve them in 9 mL of acetonitrile. After complete dissolution, draw the solutions into 10 mL syringes and attach them to syringe pumps. The benzoic acid solution in syringe pump 1 and the phenylacetaldehyde solution in syringe pump 2 are mixed by micromixer 1 and then by micromixer 2 with the benzyl isonitrile solution in syringe pump 3. To avoid the influence of residual liquid in the connecting pipeline, adjust the single-head pump parameters to a flow rate of 0.35 mL / min and a flow rate of 0.7 mL to ensure that the liquid phase flow rate in the pipeline is 1 mL / min. The water bath temperature was 30 ℃. The gas (nitrogen, the same below) flow rate was controlled at 6000 mL / min (i.e., gas phase flow rate of 6000 mL / min) using a gas flow controller. To begin the experiment: the syringe was turned on, valve 1 was opened, and valve 2 remained closed. Benzoic acid and phenylacetaldehyde were premixed in micromixer 1, then mixed with the benzyl isonitrile solution in micromixer 2. The mixed solution flowed through a three-way valve into the serpentine glass tube (i.e., the microreactor is a serpentine glass tube). The gas pipe should extend into the microreactor pipe to ensure uniform liquid film spreading. The entire microreactor should be placed in the water bath to ensure internal temperature regulation. After the experiment, wait 30 seconds until no liquid flow remained in the pipe. Then, valve 1 was closed, valve 2 was opened, and a high-pressure constant flow pump was turned on to pump methanol at a flow rate of 8 mL / min to quench the reaction and collect the solution. The collected solution was filtered using a 0.22 μm filter. 100 μL of the filtrate was diluted to 1 mL with a 1:1 (volume ratio) mixture of methanol and water. After sample preparation, high-performance liquid chromatography (HPLC) was used for testing. The conversion and yield of the reaction were determined using the external standard method. At 30 °C, with a liquid flow rate of 1 mL / min, a gas flow rate of 6000 mL / min, a liquid film thickness of 10.2 μm, and a residence time of 32 s (due to increased gas-liquid shear in the pipe, residence time refers to the time from the liquid phase entering the microreactor to its exit), the benzoic acid conversion was 99.61%, and the α-acyloxyformamide yield was 98.33%. Its structural formula is... The NMR data for α-acyloxyformamide are as follows: 1H NMR (600 MHz, CD3OD) δ 8.02(d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.29– 7.24 (m, 6H), 7.22 – 7.19 (m, 2H), 7.16 (d, J = 7.3 Hz, 2H), 5.43 (t, J =6.6 Hz, 1H), 4.36 (s, 2H), 3.24 (d, J = 6.7 Hz, 2H). Example 2 A method for enhancing the Passerini reaction based on a thin-film microreactor comprises the following steps: Benzoic acid (164.9 mg, 150 mM), phenylacetaldehyde (317.7 μL, 300 mM), and benzyl isonitrile (328.5 μL, 300 mM) are weighed and dissolved in 9 mL of acetonitrile. After complete dissolution, the solutions are drawn into 10 mL syringes, which are then attached to syringe pumps. The benzoic acid solution in syringe pump 1 and the phenylacetaldehyde solution in syringe pump 2 are mixed by micromixer 1 and then by micromixer 2 with the benzyl isonitrile solution in syringe pump 3. To avoid the influence of residual liquid in the connecting pipeline, the single-head pump parameters are adjusted to a flow rate of 0.35 mL / min and a flow rate of 0.7 mL to ensure that the liquid phase flow rate in the pipeline is 1 mL / min. The water bath temperature was 30 ℃, and the gas flow rate was 5000 mL / min. To begin the experiment: the syringe was turned on, valve 1 was opened, and valve 2 remained closed. Benzoic acid and phenylacetaldehyde were premixed in micromixer 1, then mixed with the benzyl isonitrile solution in micromixer 2. The mixed solution flowed through a three-way valve into the serpentine glass tube (i.e., the microreactor is a serpentine glass tube). The gas pipe should extend into the microreactor pipe to ensure uniform liquid film spreading. The entire microreactor was placed in a water bath to ensure internal temperature regulation. After the experiment, wait 32 s until no liquid flow remained in the pipe. Then, valve 1 was closed, valve 2 was opened, and a high-pressure constant flow pump was turned on to pump methanol at a flow rate of 8 mL / min to quench the reaction and collect the solution. The collected solution was filtered using a 0.22 μm filter. 100 μL of the filtrate was diluted to 1 mL with a 1:1 mixture of methanol and water. The sample preparation was complete, and high-performance liquid chromatography (HPLC) was used for testing. The conversion rate and yield of the reaction were determined using the external standard method. At 30 °C, with a liquid flow rate of 1 mL / min, a gas flow rate of 5000 mL / min, a liquid film thickness of 11.2 μm, and a residence time of 32 s, the benzoic acid conversion rate was 95.66%, and the α-acyloxyformamide yield was 94.68%.

[0049] Example 3 A method for enhancing the Passerini reaction based on a thin-film microreactor comprises the following steps: Benzoic acid (164.9 mg, 150 mM), phenylacetaldehyde (317.7 μL, 300 mM), and benzyl isonitrile (328.5 μL, 300 mM) are weighed and dissolved in 9 mL of acetonitrile. After complete dissolution, the solutions are drawn into 10 mL syringes, which are then attached to syringe pumps. The benzoic acid solution in syringe pump 1 and the phenylacetaldehyde solution in syringe pump 2 are mixed by micromixer 1 and then by micromixer 2 with the benzyl isonitrile solution in syringe pump 3. To avoid the influence of residual liquid in the connecting pipeline, the single-head pump parameters are adjusted to a flow rate of 0.35 mL / min and a flow rate of 0.7 mL to ensure that the liquid phase flow rate in the pipeline is 1 mL / min. The water bath temperature was 30 ℃, and the gas flow rate was 4000 mL / min. To begin the experiment: the syringe was turned on, valve 1 was opened, and valve 2 remained closed. Benzoic acid and phenylacetaldehyde were premixed in micromixer 1, then mixed with the benzyl isonitrile solution in micromixer 2. The mixed solution flowed through a three-way valve into the serpentine glass tube (i.e., the microreactor is a serpentine glass tube). The gas pipe should extend into the microreactor pipe to ensure uniform liquid film spreading. The entire microreactor should be placed in a water bath to ensure internal temperature regulation. After the experiment, wait 30 seconds until no liquid flow remained in the pipe. Then, valve 1 was closed, valve 2 was opened, and a high-pressure constant flow pump was turned on to pump methanol at a flow rate of 8 mL / min to quench the reaction and collect the solution. The collected solution was filtered using a 0.22 μm filter. 100 μL of the filtrate was diluted to 1 mL with a 1:1 mixture of methanol and water. The sample preparation was completed, and high-performance liquid chromatography (HPLC) was used for testing. The conversion rate and yield of the reaction were determined using the external standard method. At 30 °C, with a liquid flow rate of 1 mL / min, a gas flow rate of 4000 mL / min, a liquid film thickness of 12.5 μm, and a residence time of 32 s, the benzoic acid conversion rate was 90.49%, and the α-acyloxyformamide yield was 87.43%.

[0050] Example 4 A method for enhancing the Passerini reaction based on a thin-film microreactor comprises the following steps: Benzoic acid (164.9 mg, 150 mM), phenylacetaldehyde (317.7 μL, 300 mM), and benzyl isonitrile (328.5 μL, 300 mM) are weighed and dissolved in 9 mL of acetonitrile. After complete dissolution, the solutions are drawn into 10 mL syringes, which are then attached to syringe pumps. The benzoic acid solution in syringe pump 1 and the phenylacetaldehyde solution in syringe pump 2 are mixed by micromixer 1 and then by micromixer 2 with the benzyl isonitrile solution in syringe pump 3. To avoid the influence of residual liquid in the connecting pipeline, the single-head pump parameters are adjusted to a flow rate of 0.35 mL / min and a flow rate of 0.7 mL to ensure that the liquid phase flow rate in the pipeline is 1 mL / min. The water bath temperature was 30 ℃, and the gas flow rate was 3000 mL / min. To begin the experiment: the syringe was turned on, valve 1 was opened, and valve 2 remained closed. Benzoic acid and phenylacetaldehyde were premixed in micromixer 1, then mixed with the benzyl isonitrile solution in micromixer 2. The mixed solution flowed through a three-way valve into the serpentine glass tube. The gas pipe should extend into the microreactor pipe to ensure uniform liquid film spreading. The entire microreactor was placed in a water bath to ensure temperature regulation within the microreactor. After the experiment, wait 30 seconds until no liquid flow remained in the pipe. Then, valve 1 was closed, valve 2 was opened, and a high-pressure constant flow pump was turned on to pump methanol at a flow rate of 8 mL / min to quench the reaction and collect the solution. The collected solution was filtered using a 0.22 μm filter. 100 μL of the filtrate was diluted to 1 mL with a 1:1 mixture of methanol and water. The sample preparation was complete, and high-performance liquid chromatography (HPLC) was used for testing. The conversion rate and yield of the reaction were determined using the external standard method. At 30 °C, with a liquid flow rate of 1 mL / min, a gas flow rate of 3000 mL / min, a liquid film thickness of 15.4 μm, and a residence time of 32 s, the benzoic acid conversion rate was 85.99%, and the α-acyloxyformamide yield was 61.99%.

[0051] Example 5 A method for enhancing the Passerini reaction based on a thin-film microreactor comprises the following steps: Benzoic acid (164.9 mg, 150 mM), phenylacetaldehyde (317.7 μL, 300 mM), and benzyl isonitrile (328.5 μL, 300 mM) are weighed and dissolved in 9 mL of acetonitrile. After complete dissolution, the solutions are drawn into 10 mL syringes, which are then attached to syringe pumps. The benzoic acid solution in syringe pump 1 and the phenylacetaldehyde solution in syringe pump 2 are mixed by micromixer 1 and then by micromixer 2 with the benzyl isonitrile solution in syringe pump 3. To avoid the influence of residual liquid in the connecting pipeline, the single-head pump parameters are adjusted to a flow rate of 0.35 mL / min and a flow rate of 0.7 mL to ensure that the liquid phase flow rate in the pipeline is 1 mL / min. The water bath temperature was 30 ℃, and the gas flow rate was 6000 mL / min. To begin the experiment: the syringe was turned on, valve 1 was opened, and valve 2 remained closed. Benzoic acid and phenylacetaldehyde were premixed in micromixer 1, then mixed with the benzyl isonitrile solution in micromixer 2. The mixed solution flowed through a three-way valve into the serpentine glass tube. The gas pipe should extend into the microreactor pipe to ensure uniform liquid film spreading. The entire microreactor was placed in a water bath to ensure temperature regulation within the microreactor. After the experiment, wait 30 seconds until no liquid flow remained in the pipe. Then, valve 1 was closed, valve 2 was opened, and a high-pressure constant flow pump was turned on to pump methanol at a flow rate of 8 mL / min to quench the reaction and collect the solution. The collected solution was filtered using a 0.22 μm filter. 100 μL of the filtrate was diluted to 1 mL with a 1:1 mixture of methanol and water. The sample preparation was completed, and high-performance liquid chromatography (HPLC) was used for testing. The conversion rate and yield of the reaction were determined using the external standard method. At 30 °C, with a liquid flow rate of 1 mL / min, a gas flow rate of 6000 mL / min, a liquid film thickness of 10.2 μm, and a residence time of 25.6 s, the benzoic acid conversion rate was 91.67%, and the α-acyloxyformamide yield was 88.97%.

[0052] Example 6 A method for enhancing the Passerini reaction based on a thin-film microreactor comprises the following steps: Benzoic acid (164.9 mg, 150 mM), phenylacetaldehyde (317.7 μL, 300 mM), and benzyl isonitrile (328.5 μL, 300 mM) are weighed and dissolved in 9 mL of acetonitrile. After complete dissolution, the solutions are drawn into 10 mL syringes, which are then attached to syringe pumps. The benzoic acid solution in syringe pump 1 and the phenylacetaldehyde solution in syringe pump 2 are mixed by micromixer 1 and then by micromixer 2 with the benzyl isonitrile solution in syringe pump 3. To avoid the influence of residual liquid in the connecting pipeline, the single-head pump parameters are adjusted to a flow rate of 0.35 mL / min and a flow rate of 0.7 mL to ensure that the liquid phase flow rate in the pipeline is 1 mL / min. The water bath temperature was 30 ℃, and the gas flow rate was 6000 mL / min. To begin the experiment: the syringe was turned on, valve 1 was opened, and valve 2 remained closed. Benzoic acid and phenylacetaldehyde were premixed in micromixer 1, then mixed with the benzyl isonitrile solution in micromixer 2. The mixed solution flowed through a three-way valve into the serpentine glass tube. The gas pipe should extend into the microreactor pipe to ensure uniform liquid film spreading. The entire microreactor was placed in a water bath to ensure temperature regulation within the microreactor. After the experiment, wait 30 seconds until no liquid flow remained in the pipe. Then, valve 1 was closed, valve 2 was opened, and a high-pressure constant flow pump was turned on to pump methanol at a flow rate of 8 mL / min to quench the reaction and collect the solution. The collected solution was filtered using a 0.22 μm filter. 100 μL of the filtrate was diluted to 1 mL with a 1:1 mixture of methanol and water. The sample preparation was completed, and high-performance liquid chromatography (HPLC) was used for testing. The conversion rate and yield of the reaction were determined using the external standard method. At 30 °C, with a liquid flow rate of 1 mL / min, a gas flow rate of 6000 mL / min, a liquid film thickness of 10.2 μm, and a residence time of 19.2 s, the benzoic acid conversion rate was 88.33%, and the α-acyloxyformamide yield was 82.98%.

[0053] Example 7 A method for enhancing the Passerini reaction based on a thin-film microreactor comprises the following steps: Benzoic acid (164.9 mg, 150 mM), phenylacetaldehyde (317.7 μL, 300 mM), and benzyl isonitrile (328.5 μL, 300 mM) are weighed and dissolved in 9 mL of acetonitrile. After complete dissolution, the solutions are drawn into 10 mL syringes, which are then attached to syringe pumps. The benzoic acid solution in syringe pump 1 and the phenylacetaldehyde solution in syringe pump 2 are mixed by micromixer 1 and then by micromixer 2 with the benzyl isonitrile solution in syringe pump 3. To avoid the influence of residual liquid in the connecting pipeline, the single-head pump parameters are adjusted to a flow rate of 0.35 mL / min and a flow rate of 0.7 mL to ensure that the liquid phase flow rate in the pipeline is 1 mL / min. The water bath temperature was 30 ℃, and the gas flow rate was 6000 mL / min. To begin the experiment: the syringe was turned on, valve 1 was opened, and valve 2 remained closed. Benzoic acid and phenylacetaldehyde were premixed in micromixer 1, then mixed with the benzyl isonitrile solution in micromixer 2. The mixed solution flowed through a three-way valve into the serpentine glass tube. The gas pipe should extend into the microreactor pipe to ensure uniform liquid film spreading. The entire microreactor was placed in a water bath to ensure temperature regulation within the microreactor. After the experiment, wait 30 seconds until no liquid flow remained in the pipe. Then, valve 1 was closed, valve 2 was opened, and a high-pressure constant flow pump was turned on to pump methanol at a flow rate of 8 mL / min to quench the reaction and collect the solution. The collected solution was filtered using a 0.22 μm filter. 100 μL of the filtrate was diluted to 1 mL with a 1:1 mixture of methanol and water. The sample preparation was completed, and high-performance liquid chromatography (HPLC) was used for testing. The conversion rate and yield of the reaction were determined using the external standard method. At 30 °C, with a liquid flow rate of 1 mL / min, a gas flow rate of 6000 mL / min, a liquid film thickness of 10.2 μm, and a residence time of 12.8 s, the benzoic acid conversion rate was 80.42%, and the α-acyloxyformamide yield was 71.68%.

[0054] Example 8 A method for enhancing the Passerini reaction based on a thin-film microreactor comprises the following steps: Benzoic acid (164.9 mg, 150 mM), phenylacetaldehyde (317.7 μL, 300 mM), and benzyl isonitrile (328.5 μL, 300 mM) are weighed and dissolved in 9 mL of acetonitrile. After complete dissolution, the solutions are drawn into 10 mL syringes, which are then attached to syringe pumps. The benzoic acid solution in syringe pump 1 and the phenylacetaldehyde solution in syringe pump 2 are mixed by micromixer 1 and then by micromixer 2 with the benzyl isonitrile solution in syringe pump 3. To avoid the influence of residual liquid in the connecting pipeline, the single-head pump parameters are adjusted to a flow rate of 0.35 mL / min and a flow rate of 0.7 mL to ensure that the liquid phase flow rate in the pipeline is 1 mL / min. The water bath temperature was 30 ℃, and the gas flow rate was 6000 mL / min. To begin the experiment: the syringe was turned on, valve 1 was opened, and valve 2 remained closed. Benzoic acid and phenylacetaldehyde were premixed in micromixer 1, then mixed with the benzyl isonitrile solution in micromixer 2. The mixed solution flowed through a three-way valve into the serpentine glass tube. The gas pipe should extend into the microreactor pipe to ensure uniform liquid film spreading. The entire microreactor was placed in a water bath to ensure temperature regulation within the microreactor. After the experiment, wait 30 seconds until no liquid flow remained in the pipe. Then, valve 1 was closed, valve 2 was opened, and a high-pressure constant flow pump was turned on to pump methanol at a flow rate of 8 mL / min to quench the reaction and collect the solution. The collected solution was filtered using a 0.22 μm filter. 100 μL of the filtrate was diluted to 1 mL with a 1:1 mixture of methanol and water. The sample preparation was completed, and high-performance liquid chromatography (HPLC) was used for testing. The conversion rate and yield of the reaction were determined using the external standard method. At 30 °C, with a liquid flow rate of 1 mL / min, a gas flow rate of 6000 mL / min, a liquid film thickness of 10.2 μm, and a residence time of 6.4 s, the benzoic acid conversion rate was 79.96%, and the α-acyloxyformamide yield was 73.33%.

[0055] Comparative Example 1 A method for enhancing the Passerini reaction based on a thin-film microreactor comprises the following steps: Benzoic acid (164.9 mg, 150 mM), phenylacetaldehyde (317.7 μL, 300 mM), and benzyl isonitrile (328.5 μL, 300 mM) are weighed and dissolved in 9 mL of acetonitrile. After complete dissolution, the solutions are drawn into 10 mL syringes, which are then attached to syringe pumps. The benzoic acid solution in syringe pump 1 and the phenylacetaldehyde solution in syringe pump 2 are mixed by micromixer 1 and then by micromixer 2 with the benzyl isonitrile solution in syringe pump 3. To avoid the influence of residual liquid in the connecting pipeline, the single-head pump parameters are adjusted to a flow rate of 0.35 mL / min and a flow rate of 0.7 mL to ensure that the liquid phase flow rate in the pipeline is 1 mL / min. The water bath temperature was 30 ℃, and the gas flow rate was 2000 mL / min. To begin the experiment: the syringe was turned on, valve 1 was opened, and valve 2 remained closed. Benzoic acid and phenylacetaldehyde were premixed in micromixer 1, then mixed with the benzyl isonitrile solution in micromixer 2. The mixed solution flowed through a three-way valve into the serpentine glass tube. The gas pipe should extend into the microreactor pipe to ensure uniform liquid film spreading. The entire microreactor should be placed in a water bath to ensure internal temperature regulation. After the experiment, wait 30 seconds until no liquid flow remained in the pipe. Then, valve 1 was closed, valve 2 was opened, and a high-pressure constant flow pump was turned on to pump methanol at a flow rate of 8 mL / min to quench the reaction and collect the solution. The collected solution was filtered using a 0.22 μm filter. 100 μL of the filtrate was diluted to 1 mL with a 1:1 mixture of methanol and water. The sample preparation was complete, and high-performance liquid chromatography (HPLC) was used for testing. The conversion rate and yield of the reaction were determined using the external standard method. At 30 °C, with a liquid flow rate of 1 mL / min, a gas flow rate of 2000 mL / min, a liquid film thickness of 27.9 μm, and a residence time of 32 s, the benzoic acid conversion rate was 72.90%, and the α-acyloxyformamide yield was 42.87%.

[0056] The graph shows the trend of benzoic acid conversion and α-acyloxyformamide yield as a function of liquid film thickness. Figure 3As shown, when the gas-liquid phase velocity ratio is high, the liquid film thickness is extremely thin, forming an extremely confined space. The system is dominated by interfacial thermodynamics and non-equilibrium kinetics, enhancing the interfacial effect and lowering the reaction energy barrier. Simultaneously, the extreme diffusion path ensures that both reactant encounter time and product escape time are on the order of milliseconds, allowing products to rapidly leave the reaction interface once formed. However, as the gas-liquid phase velocity ratio decreases, the liquid film thickness increases, the bulk effect gradually strengthens, and the interfacial effect correspondingly decreases. Many intermediates cannot overcome the energy barrier to transform into the target product. At this point, for reaction intermediates, only some molecules can access the low activation energy pathway created by the film; most intermediate molecules cannot reach the interface and return to the high activation energy reaction pathway. Therefore, the conversion rate and yield differ significantly and decrease rapidly.

[0057] Table 1 shows a comparison of reactor performance.

[0058] Table 1 Note: In Table 1, "Bulk" refers to the bulk reaction test. The three reactants (benzoic acid, phenylacetaldehyde, and benzoic acid) were prepared into solutions, mixed in a beaker, and a strong magnetic stirrer was added. The reaction was carried out at room temperature using a magnetic stirrer at 400 rpm for 2 h. Specifically, 183.2 mg of benzoic acid was dissolved in 10 mL of acetonitrile solution (150 mM), 353.4 μL of phenylacetaldehyde was dissolved in 10 mL of acetonitrile solution (300 mM), and 365.3 μL of benzoic acid was dissolved in 10 mL of acetonitrile solution (150 mM). The three solutions were mixed in a beaker, and a strong magnetic stirrer was added. The reaction was carried out at room temperature using a magnetic stirrer at 400 rpm for 2 h.

[0059] As shown in Table 1, the method of the present invention can significantly shorten the residence time while increasing the yield of α-acyloxyformamide.

[0060] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for enhancing the Passerini reaction based on a thin-film microreactor, characterized in that, Includes the following steps: The reactants are mixed using a micro mixer and then introduced into a microreactor. The reactants are a carboxylic acid compound solution, a carbonyl compound solution, and an isonitrile compound solution. The gas phase pipeline, liquid phase pipeline and microreactor pipeline are connected by a T-junction, and the reaction temperature is controlled by a water bath. Gas flow rate is controlled by a gas mass flow meter; The thickness of the liquid film inside the microreactor does not exceed 25 μm; The gas pipe at the inlet section of the microreactor extends into the microreactor pipe.

2. The method for enhancing the Passellini reaction based on a thin-film microreactor according to claim 1, characterized in that, The microreactor is selected from serpentine pipes or straight pipes.

3. The method for enhancing the Passellini reaction based on a thin-film microreactor according to claim 1, characterized in that, The molar ratio of carboxylic acid compound, carbonyl compound and isonitrile compound is 1:2:

2.

4. The method for enhancing the Passellini reaction based on a thin-film microreactor according to claim 3, characterized in that, The carboxylic acid compound is selected from one of benzoic acid, o-fluorobenzoic acid, m-fluorobenzoic acid, and o-nitrobenzoic acid; The carbonyl compound is selected from phenylacetaldehyde or 2-nitrobenzaldehyde; The isonitrile compound is benzyl isonitrile.

5. The method for enhancing the Passellini reaction based on a thin-film microreactor according to claim 1, characterized in that, The reaction temperature is controlled to not exceed 81℃ by using a water bath.

6. The method for enhancing the Passellini reaction based on a thin-film microreactor according to claim 1, characterized in that, The thickness of the liquid film in the microreactor is controlled by the gas-liquid phase flow rate ratio, which is kept at no less than 1000.

7. The method for enhancing the Passellini reaction based on a thin-film microreactor according to claim 6, characterized in that, The liquid phase flow rate is 1 mL / min, and the gas phase flow rate is not less than 1000 mL / min.

8. The method for enhancing the Passellini reaction based on a thin-film microreactor according to claim 1, characterized in that, The microreactor is connected to a high-pressure constant flow pump via a pipeline, which is used to pump in methanol to quench the reaction.

9. The method for enhancing the Passellini reaction based on a thin-film microreactor according to claim 8, characterized in that, The methanol flow rate is 5-15 mL / min.

10. The method for enhancing the Passellini reaction based on a thin-film microreactor according to claim 8, characterized in that, The residence time is 6.4-40 s before the methanol is pumped in to quench the reaction.

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