A method for continuously preparing 4-AA by using a high-stability solid-supported ruthenium catalyst

Abstract

This invention relates to the field of pharmaceutical intermediate synthesis technology, and discloses a method for the continuous preparation of 4-AA using a highly stable supported ruthenium catalyst. The method involves preparing a substrate solution by combining a 4-AA precursor cyclizer, acetate, and an acetonitrile-acetic acid mixed solvent. The resulting liquid peracetic acid is directly used as the oxidant solution. After pre-cooling, the solution is continuously fed into a fixed-bed reactor packed with the supported ruthenium catalyst for oxidative acetylation. The oxidant is added in stages along the material flow direction. The reaction solution undergoes reducing quenching, extraction, washing, concentration, and crystallization to obtain 4-AA. This invention reduces ruthenium component migration and loss, shortens the residence time of liquid peracetic acid before the reaction, reduces its decomposition risk, improves reaction heat transfer and oxidant concentration distribution, and enhances continuous operation stability and reaction safety.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a method for the continuous preparation of 4-AA using a highly stable supported ruthenium catalyst. Background Technology

[0002] 4-AA, or (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]azacyclobutane-2-one, is an important chiral intermediate in the synthesis of carbapenem antibiotics. Current processes typically use (3S)-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]azacyclobutane-2-one as a starting material, and oxidize and acetoxylate the carbon-hydrogen bonds on the azacyclobutane ring using peracetic acid, acetate, and ruthenium catalysts to obtain 4-AA. Publicly available techniques utilize RuCl3 or Ru / C catalyzed reactions for this process.

[0003] The ruthenium trioxide used in current industrial production can form soluble ruthenium compounds with high-valence ruthenium active species in the reaction system. Although this can achieve the oxidative transformation of cyclic compounds, the ruthenium catalytic component easily enters the liquid phase, requiring adsorption, filtration, or precipitation to remove ruthenium impurities after the reaction. Since ruthenium is a precious metal, the loss of catalyst with the mother liquor and wastewater not only increases production costs but also makes it more difficult to control metal residues in the product and treat ruthenium-containing wastewater.

[0004] Loading the ruthenium active component onto a solid support facilitates direct separation and recycling of the catalyst from the reaction solution. However, when using conventional impregnated ruthenium-supported catalysts in strongly oxidizing acidic systems containing both peracetic acid and acetic acid, problems such as migration, aggregation, or desorption of the ruthenium active component from the support surface may still occur. Some supports may also experience pore blockage, mechanical pulverization, or byproduct coverage of active sites during continuous operation, leading to a decrease in catalyst activity and making it difficult to meet the requirements of long-term continuous production.

[0005] Furthermore, traditional 4-AA preparation processes typically employ batch reactors. Peracetic acid requires slow, dropwise addition at low temperatures, which can lead to localized high oxidant concentrations, uneven temperature distribution, and concentrated heat release within the reactor. As production scales up, the heat and mass transfer efficiency of batch reactions decreases, increasing the likelihood of side reactions, greater batch-to-batch product variability, and limiting equipment production efficiency.

[0006] Therefore, it is necessary to provide a method for the continuous preparation of 4-AA using a highly stable supported ruthenium catalyst. By confining the ruthenium active component in pores and coating it with an outer layer, the migration and loss of the ruthenium component can be reduced. Furthermore, the reaction temperature can be controlled by continuous fixed-bed reaction, staged addition of oxidant, and heat exchange between beds. This will improve the recovery rate of the precious metal ruthenium, reduce catalyst consumption and post-processing costs, and improve the continuity, stability, and safety of the 4-AA production process. Summary of the Invention

[0007] To overcome the shortcomings of the prior art, the present invention aims to provide a method for the continuous preparation of 4-AA using a highly stable supported ruthenium catalyst. This method involves constructing ruthenium oxide supported on zirconia-modified mesoporous silica and forming a porous silica confinement layer on its outer surface. Simultaneously, it combines fixed-bed continuous reaction, staged addition of oxidant, and interbed heat exchange to reduce ruthenium component migration and loss, improve reaction temperature and oxidant concentration distribution, and enhance the reaction stability and safety of the 4-AA preparation process.

[0008] To achieve the above objectives, the present invention provides the following technical solution: a method for the continuous preparation of 4-AA using a highly stable supported ruthenium catalyst, comprising the following steps:

[0009] S1. Mix the 4-AA precursor cyclizer, acetate, and the first organic solvent to obtain a substrate solution;

[0010] S2. The prepared liquid peracetic acid is used directly as an oxidant solution and then used in subsequent continuous reactions.

[0011] S3. After pre-cooling the substrate solution and oxidant solution respectively, they are continuously fed into a fixed-bed reactor filled with a supported ruthenium catalyst, so that the 4-AA precursor cyclizer undergoes an oxidative acetoxylation reaction under the action of the supported ruthenium catalyst, and a reaction solution containing 4-AA is continuously obtained.

[0012] The supported ruthenium catalyst includes a zirconia-modified mesoporous silica support, a ruthenium oxide active component loaded in the pores of the zirconia-modified mesoporous silica support, and a porous silica confinement layer covering the outer surface of the zirconia-modified mesoporous silica support.

[0013] S4. The reaction solution containing 4-AA is continuously introduced into the quenching unit and mixed with a reducing quenching solution to decompose the residual peracetic acid. Then, after extraction, washing, concentration and crystallization, 4-AA is obtained.

[0014] Wherein, the 4-AA precursor cyclizer is (3S)-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]azacyclobutane-2-one, and the 4-AA is (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]azacyclobutane-2-one;

[0015] The oxidant solution is added in stages along the material flow direction within the fixed-bed reactor.

[0016] Further, in step S1, the first organic solvent includes acetonitrile and acetic acid, wherein the volume ratio of acetonitrile to acetic acid is 1:0.1 to 0.8;

[0017] The acetate is one of anhydrous sodium acetate and anhydrous potassium acetate;

[0018] The molar ratio of the acetate to the 4-AA precursor cyclizer is 0.8 to 1.3:1.

[0019] Further, in step S2, the mass fraction of peracetic acid in the liquid peracetic acid is 20-40%, and the liquid peracetic acid is pre-cooled and continuously transported after preparation; the molar ratio of peracetic acid to 4-AA precursor cyclizer is 2.0-4.0:1.

[0020] Furthermore, in step S3, based on the mass of the zirconia-modified mesoporous silica carrier, the mass content of the zirconia is 5-25%;

[0021] Based on the total mass of the supported ruthenium catalyst, the mass content of ruthenium is 0.2% to 2.5%.

[0022] The thickness of the porous silica confinement layer is 3–30 nm;

[0023] The active component of ruthenium oxide is ruthenium oxide nanoparticles.

[0024] Further, the supported ruthenium catalyst is prepared according to the following steps:

[0025] A1. The mesoporous silica support is dispersed in a first alcohol-water mixed solvent, a zirconium precursor is added, the pH of the system is adjusted to 8.0-10.0, and the system is stirred and hydrolyzed at 40-70℃ for 2-6 hours. After solid-liquid separation, washing and drying, the system is calcined at 400-600℃ for 2-5 hours in air atmosphere to obtain a zirconium oxide modified mesoporous silica support.

[0026] A2. Dissolve the ruthenium precursor in a second alcohol-water mixed solvent to prepare a ruthenium-containing impregnation solution with a ruthenium ion concentration of 0.01–0.10 mol / L. Add the ruthenium-containing impregnation solution to the zirconia-modified mesoporous silica support at a volume 0.8–1.2 times the pore volume of the zirconia-modified mesoporous silica support for equal-volume impregnation. After aging for 6–18 h, dry at 80–120 °C for 4–12 h, and calcine at 250–400 °C for 2–5 h in an oxygen-containing atmosphere to convert the ruthenium precursor into an active ruthenium oxide component dispersed within the pores of the support, thus obtaining a composite support loaded with ruthenium oxide.

[0027] A3. The composite support for ruthenium oxide is dispersed in a third alcohol-water mixed solvent, and ammonia and a silicon source are added. The mass ratio of the silicon source to the composite support for ruthenium oxide is 0.05 to 0.30:1. The mixture is subjected to a hydrolysis-condensation reaction at 20 to 40°C for 4 to 12 hours. After solid-liquid separation, washing, and drying at 80 to 120°C, the mixture is heat-treated at 150 to 300°C for 2 to 5 hours to form a porous silica confinement layer on the outer surface of the zirconia-modified mesoporous silica support, thereby obtaining the supported ruthenium catalyst.

[0028] Furthermore, the zirconium precursor is at least one of zirconium n-propoxide, zirconium isopropoxide, zirconium oxychloride, and zirconium nitrate;

[0029] The ruthenium precursor is one of ruthenium trichloride and ruthenium nitrite;

[0030] The silicon source is one of tetraethyl orthosilicate and methyl orthosilicate;

[0031] The first alcohol-water mixed solvent, the second alcohol-water mixed solvent, and the third alcohol-water mixed solvent are each obtained independently by mixing ethanol and water.

[0032] Furthermore, in step S3, the substrate solution and the oxidant solution are pre-cooled to 0-10°C respectively;

[0033] The reaction temperature in the fixed-bed reactor is 5–15°C, and the reaction pressure is 0.5–1.0 MPa.

[0034] The total residence time of the substrate solution and oxidant solution in the fixed-bed reactor is 30–60 min.

[0035] Furthermore, in step S3, the fixed-bed reactor includes 2 to 4 catalyst beds arranged in series along the material flow direction, and an oxidant replenishment port and a heat exchange section are provided between two adjacent catalyst beds;

[0036] The oxidant solution is added in 2 to 4 stages through the fixed-bed reactor inlet and the oxidant replenishment port, wherein the oxidant solution added through the fixed-bed reactor inlet accounts for 40 to 50% of the total oxidant solution added;

[0037] In step S4, the reducing quenching solution is one of sodium sulfite aqueous solution and sodium bisulfite aqueous solution.

[0038] Compared with the prior art, the present invention has the following beneficial technical effects:

[0039] This invention uses zirconia-modified mesoporous silica as a support, loads the ruthenium oxide active component into the pores of the support, and forms a porous silica confinement layer on the outer surface of the support. Through the synergistic effect of pore confinement, support enhancement and outer layer coating, the migration, aggregation and desorption of ruthenium oxide nanoparticles can be inhibited, the loss of ruthenium components in strongly oxidizing acidic reaction systems can be reduced, and the structural stability and service life of the catalyst can be improved.

[0040] Zirconia-modified components can improve the surface stability of mesoporous silica supports and the bonding strength between ruthenium active components and supports. The porous silica confinement layer allows for mass transfer between reactants and products while physically confining the ruthenium active components, which helps maintain the high dispersion of the active components and improves catalytic activity and reusability.

[0041] This invention employs a fixed-bed reactor for continuous reaction, achieving direct separation of the catalyst and the reaction liquid. This avoids soluble ruthenium catalyst entering the post-processing steps with the reaction liquid, reducing ruthenium residue in the product, lowering the consumption of precious metal catalysts, and reducing the difficulty and production cost of treating ruthenium-containing waste liquid.

[0042] This invention adds the oxidant in stages along the material flow direction and sets up a heat exchange section between adjacent catalyst beds. This can avoid excessively high local concentrations of peracetic acid at the reactor inlet, disperse the heat of oxidation reaction, improve the temperature distribution and material mass transfer conditions in the reactor, reduce over-oxidation and other side reactions, and improve the safety and controllability of the reaction process.

[0043] After liquid peracetic acid is prepared, it is pre-cooled and continuously fed into a fixed-bed reactor, which can shorten its residence time before the reaction and reduce the risk of decomposition due to temperature rise or long-term storage. At the same time, by controlling the reaction temperature, reaction pressure and residence time, the oxidative acetoxylation reaction is carried out under stable conditions, which is beneficial to improving the conversion stability of the 4-AA precursor cyclizer, the selectivity of the target product and the quality consistency of different batches of products.

[0044] The continuous introduction of the reaction solution into the quenching unit and the timely decomposition of residual peracetic acid can terminate the subsequent oxidation reaction, reduce the adverse effects of residual oxidant on 4-AA products and post-processing equipment, and further improve the safety of the post-processing process and the stability of the products.

[0045] This invention combines catalyst immobilization, staged addition of oxidant, interbed heat exchange, and continuous quenching, making it suitable for long-term continuous operation. It can improve equipment utilization and production capacity per unit time, reduce downtime, cleaning, and repeated feeding operations in intermittent production, and has good prospects for industrial application. Attached Figure Description

[0046] Figure 1 This is a low-magnification TEM image of the supported ruthenium catalyst prepared in Example 1.

[0047] Figure 2 This is a high-magnification TEM image of the ruthenium-supported catalyst in Example 1. Detailed Implementation

[0048] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0049] The mesoporous silica carrier is SBA-15 type mesoporous silica, product number 900780, manufactured by Sigma-Aldrich; the product numbers for zirconium oxychloride octahydrate, zirconium isopropoxide, zirconium oxynitrate hydrate, ruthenium trichloride hydrate, ruthenium nitrite hydrate, nitrosyl ruthenium nitrate solution, nitrosyl ruthenium nitrate solution, tetraethyl orthosilicate, methyl orthosilicate, and methyl orthosilicate are 218472.

[0050] In the following examples, the 4-AA precursor cyclizer is (3S)-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]azacyclobutane-2-one, and the mesoporous silica support has an average pore size of 6-10 nm and a specific surface area of ​​500-800 m². 2 / g, pore volume is 1.2~1.5mL / g.

[0051] The 4-AA is (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]azacyclobutane-2-one.

[0052] Example 1

[0053] Preparation of supported ruthenium catalysts

[0054] A1. 50 parts of mesoporous silica support were added to 500 parts of a first alcohol-water mixed solvent composed of ethanol and water in a volume ratio of 4:1. The mixture was stirred and dispersed for 30 min. 2.63 parts of zirconium oxychloride aqueous solution (calculated as zirconium oxide) were added. The pH of the system was adjusted to 8.0 using 10% ammonia water. The mixture was stirred and hydrolyzed at 40 °C for 2 h. After solid-liquid separation and washing with deionized water and ethanol in sequence, the mixture was dried at 100 °C for 8 h and then calcined at 400 °C for 2 h in air atmosphere to obtain a zirconium oxide modified mesoporous silica support with a zirconium oxide content of 5%.

[0055] A2. Ruthenium trichloride was dissolved in a second alcohol-water mixed solvent with a volume ratio of 1:1 to prepare a ruthenium-containing impregnation solution with a ruthenium ion concentration of 0.035 mol / L. The volume of the ruthenium-containing impregnation solution was 0.8 times the pore volume of the zirconia-modified mesoporous silica support. After aging for 6 hours, it was dried at 80°C for 4 hours and then calcined at 250°C for 2 hours in air atmosphere to obtain a composite support loaded with ruthenium oxide, wherein the mass content of ruthenium element was controlled to be 0.4%.

[0056] A3. 50 parts of the composite support for ruthenium oxide were added to 500 parts of a third alcohol-water mixed solvent consisting of ethanol and water in a volume ratio of 4:1. 20 parts of ammonia water with a mass fraction of 25% and 2.5 parts of tetraethyl orthosilicate were added. The mixture was stirred at 20°C for 4 hours to carry out a hydrolysis-condensation reaction. After solid-liquid separation, washing with ethanol, and drying at 80°C, the mixture was heat-treated at 150°C for 2 hours to obtain a solid-supported ruthenium catalyst with a porous silica confinement layer with a thickness of 3-5 nm on the outer surface.

[0057] Continuous preparation of 4-AA

[0058] S1. Mix 0.10 mol of 4-AA precursor cyclizer, 0.08 mol of anhydrous sodium acetate, 200 mL of acetonitrile and 20 mL of acetic acid, and stir until homogeneous to obtain the substrate solution.

[0059] S2. Take liquid peracetic acid containing 0.20 mol of peracetic acid and a peracetic acid mass fraction of 20% and use it directly as an oxidant solution. After preparation, it enters the pre-cooling and continuous conveying process.

[0060] S3. Two catalyst beds are set up in the fixed bed reactor with an inner diameter of 20 mm along the material flow direction. A total of 40 g of the supported ruthenium catalyst is loaded into the two catalyst beds, and an oxidant replenishment port and a heat exchange section are set between the two catalyst beds.

[0061] S4. Pre-cool the substrate solution and oxidant solution to 0°C respectively. Continuously feed the substrate solution to the inlet of the fixed-bed reactor. At the same time, add the oxidant solution in two stages: 50% of the oxidant solution is added through the inlet of the fixed-bed reactor, and the other 50% is added through the oxidant replenishment port between the two catalyst beds.

[0062] S5. Control the reaction temperature in the fixed bed reactor to 5℃ and the reaction pressure to 0.5MPa. By adjusting the flow rates of the substrate solution and the oxidant solution, the total residence time of the material in the fixed bed reactor is made to 30min, so as to continuously obtain a reaction solution containing 4-AA.

[0063] S6. Continuously introduce the reaction solution containing 4-AA into the quenching unit, add a 10% sodium sulfite aqueous solution, until the starch-potassium iodide test paper no longer turns blue, in order to decompose the residual peracetic acid.

[0064] S7. The quenched reaction solution was extracted three times with ethyl acetate, each time using 0.5 times the volume of the reaction solution. After combining the organic phases, the solution was washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, filtration and vacuum concentration, the solution was crystallized with a mixed solvent of isopropanol and n-hexane in a volume ratio of 1:3 to obtain 4-AA crystals.

[0065] like Figure 1 As shown, Figure 1 The image shows a low-magnification transmission electron microscope (TEM) image of the ruthenium-supported catalyst prepared in Example 1. As can be seen from the image, the catalyst particles have a relatively intact overall morphology, with a relatively obvious porous structure inside the particles and a continuous and uniform coating layer formed on the outer edge, indicating that a porous silica confinement layer has been formed on the surface of the ruthenium oxide-modified mesoporous silica support.

[0066] Figure 2 This is a high-magnification transmission electron microscope image of the ruthenium oxide catalyst in Example 1. As can be seen from the image, the dark nanoparticles are relatively uniformly dispersed within the mesoporous support, and no obvious large-size agglomeration was observed, indicating that the ruthenium oxide active component can be well loaded and dispersed within the support pores. Simultaneously, the porous coating structure at the outer edge of the catalyst is clearly defined, effectively confining the ruthenium oxide active component while maintaining the mass transfer channels.

[0067] Example 2

[0068] Preparation of supported ruthenium catalysts

[0069] A1. 50 parts of mesoporous silica support were added to 500 parts of a first alcohol-water mixed solvent composed of ethanol and water in a volume ratio of 3:1. 8.82 parts of zirconium isopropoxide were added. The pH of the system was adjusted to 9.0 using 10% ammonia water. The mixture was stirred and hydrolyzed at 55°C for 4 hours. After solid-liquid separation, washing, and drying at 100°C for 8 hours, the mixture was calcined at 500°C for 3.5 hours in air to obtain a zirconium-modified mesoporous silica support with a zirconium content of 15%.

[0070] A2. Ruthenium nitrite was dissolved in a second alcohol-water mixed solvent with a volume ratio of 1:1 (ethanol and water) to prepare a ruthenium-containing impregnation solution with a ruthenium ion concentration of 0.070 mol / L. The ruthenium-containing impregnation solution was impregnated in an equal volume ratio to the pore volume of the zirconium oxide modified mesoporous silica support. After aging for 12 h, it was dried at 100 °C for 8 h and then calcined at 325 °C for 3.5 h in air atmosphere to obtain a ruthenium oxide composite support with a ruthenium element mass content of 1.0%.

[0071] A3. 50 parts of the composite support for ruthenium oxide were added to 500 parts of a third alcohol-water mixed solvent consisting of ethanol and water in a volume ratio of 3:1. 25 parts of ammonia water with a mass fraction of 25% and 9 parts of tetraethyl orthosilicate were added. The mixture was stirred at 30°C for 8 hours to carry out a hydrolysis-condensation reaction. After solid-liquid separation, washing with ethanol, and drying at 100°C, the mixture was heat-treated at 225°C for 3.5 hours to obtain a solid-supported ruthenium catalyst with a porous silica confinement layer with a thickness of 14-18 nm on the outer surface.

[0072] Continuous preparation of 4-AA

[0073] S1. Mix 0.10 mol of 4-AA precursor cyclizer, 0.10 mol of anhydrous sodium acetate, 200 mL of acetonitrile and 80 mL of acetic acid, and stir until homogeneous to obtain the substrate solution.

[0074] S2. Take liquid peracetic acid containing 0.30 mol of peracetic acid and a peracetic acid mass fraction of 30% and use it directly as an oxidant solution. After preparation, it enters the pre-cooling and continuous conveying process.

[0075] S3. Three catalyst beds are connected in series in the fixed-bed reactor along the material flow direction. Each catalyst bed is filled with 15g of the supported ruthenium catalyst. Oxidant replenishment port and heat exchange section are respectively provided between adjacent catalyst beds.

[0076] S4. Pre-cool the substrate solution and oxidant solution to 5°C respectively. Continuously feed the substrate solution to the inlet of the fixed-bed reactor and add the oxidant solution in three stages: 45% of the oxidant solution is added through the inlet of the fixed-bed reactor, 30% of the oxidant solution is added through the first oxidant replenishment port, and the remaining 25% of the oxidant solution is added through the second oxidant replenishment port.

[0077] S5. Control the reaction temperature in the fixed bed reactor to 10℃ and the reaction pressure to 0.75MPa, and adjust the flow rates of the substrate solution and oxidant solution to ensure that the total residence time of the material in the fixed bed reactor is 45min, so as to continuously obtain a reaction solution containing 4-AA.

[0078] S6. Continuously introduce the reaction solution containing 4-AA into the quenching unit, add a 10% sodium bisulfite aqueous solution, until the starch-potassium iodide test paper no longer turns blue.

[0079] S7. The quenched reaction solution was extracted three times with ethyl acetate, each time using 0.5 times the volume of the reaction solution. The organic phases were combined and washed sequentially with sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then, crystallization was carried out using a mixed solvent of isopropanol and n-hexane in a volume ratio of 1:3 to obtain 4-AA crystals.

[0080] Example 3

[0081] Preparation of supported ruthenium catalysts

[0082] A1. 50 parts of mesoporous silica support were added to 500 parts of a first alcohol-water mixed solvent composed of ethanol and water in a volume ratio of 2:1. 16.67 parts of zirconium nitrate (calculated as zirconium oxide) were added. The pH of the system was adjusted to 10.0 using 10% ammonia water. The mixture was stirred and hydrolyzed at 70°C for 6 hours. After solid-liquid separation, washing, and drying at 110°C for 10 hours, the mixture was calcined at 600°C for 5 hours in air to obtain a zirconium-modified mesoporous silica support with a zirconium oxide content of 25%.

[0083] A2. Ruthenium trichloride was dissolved in a second alcohol-water mixed solvent with a volume ratio of 1:1 to prepare a ruthenium-containing impregnation solution with a ruthenium ion concentration of 0.10 mol / L. The volume of the ruthenium-containing impregnation solution was 1.2 times the pore volume of the zirconia-modified mesoporous silica support. After aging for 18 h, it was dried at 120 °C for 12 h, and then calcined at 400 °C for 5 h in an oxygen-containing atmosphere to obtain a ruthenium oxide-supported composite support with a ruthenium element mass content of 1.5-2.0%.

[0084] A3. 50 parts of the composite support for ruthenium oxide were added to 500 parts of a third alcohol-water mixed solvent consisting of ethanol and water in a volume ratio of 2:1. 30 parts of ammonia water with a mass fraction of 25% and 15 parts of methyl orthosilicate were added. The mixture was stirred at 40°C for 12 hours to carry out a hydrolysis-condensation reaction. After solid-liquid separation, washing with ethanol, and drying at 120°C, the mixture was heat-treated at 300°C for 5 hours to obtain a solid-supported ruthenium catalyst with a porous silica confinement layer with a thickness of 25-30 nm on the outer surface.

[0085] Continuous preparation of 4-AA

[0086] S1. Mix 0.10 mol of 4-AA precursor cyclizer, 0.13 mol of anhydrous potassium acetate, 200 mL of acetonitrile and 160 mL of acetic acid, and stir until homogeneous to obtain the substrate solution.

[0087] S2. Take liquid peracetic acid containing 0.40 mol of peracetic acid and a peracetic acid mass fraction of 40% and use it directly as an oxidant solution. After preparation, it enters the pre-cooling and continuous conveying process.

[0088] S3. Four catalyst beds are connected in series in the fixed-bed reactor along the material flow direction. Each catalyst bed is filled with 12g of the supported ruthenium catalyst. Oxidant replenishment port and heat exchange section are respectively provided between adjacent catalyst beds.

[0089] S4. Pre-cool the substrate solution and oxidant solution to 10°C respectively. Continuously feed the substrate solution to the inlet of the fixed-bed reactor and add the oxidant solution in four stages. 40% of the oxidant solution is added from the inlet of the fixed-bed reactor, and the other three stages of oxidant solution are added from three oxidant replenishment ports at proportions of 25%, 20%, and 15%, respectively.

[0090] S5. Control the reaction temperature in the fixed-bed reactor to 15℃ and the reaction pressure to 1.0MPa, and adjust the flow rates of the substrate solution and oxidant solution to ensure that the total residence time of the material in the fixed-bed reactor is 60min, so as to continuously obtain a reaction solution containing 4-AA.

[0091] S6. Continuously introduce the reaction solution containing 4-AA into the quenching unit, add a 15% sodium bisulfite aqueous solution, until the starch-potassium iodide test paper no longer turns blue.

[0092] S7. The quenched reaction solution was extracted three times with ethyl acetate, each time using 0.5 times the volume of the reaction solution. The organic phases were combined and then washed, dried, filtered and concentrated under reduced pressure. Crystallization was then carried out using a mixed solvent of isopropanol and n-hexane in a volume ratio of 1:3 to obtain 4-AA crystals.

[0093] Comparative Example 1

[0094] The difference between this comparative example and Example 2 is that the supported ruthenium catalyst used did not modify the mesoporous silica support with zirconium oxide.

[0095] Specifically, a ruthenium trichloride solution is directly impregnated in a mesoporous silica support in an equal volume. After aging, drying and calcination, a porous silica confinement layer is formed on its outer surface to obtain a RuO2 / SiO2@SiO2 catalyst.

[0096] Except for the differences mentioned above, the substrate solution composition, peracetic acid dosage, reaction temperature, reaction pressure, residence time, oxidant addition method in stages, and post-treatment method are all the same as in Example 2.

[0097] This comparative example is used to investigate the effects of zirconia modification on the acid resistance of the support, the binding stability of the ruthenium active component, and the continuous operation performance of the catalyst.

[0098] Comparative Example 2

[0099] The difference between this comparative example and Example 2 is that the catalyst used does not have a porous silica confinement layer.

[0100] Specifically, a zirconia-modified mesoporous silica-supported ruthenium oxide catalyst was prepared according to steps A1 and A2 in Example 2. After the ruthenium precursor was impregnated, dried and calcined, it was used directly as a fixed-bed catalyst without the silicon source hydrolysis and condensation treatment in step A3.

[0101] Except for the differences mentioned above, the composition of the substrate solution, the composition of the oxidant solution, the method of adding the oxidant in stages, the reaction temperature, the reaction pressure, the residence time, and the post-treatment method are all the same as in Example 2.

[0102] This comparative example was used to investigate the inhibitory effect of porous silica confinement layers on the migration, aggregation, and loss of ruthenium components in ruthenium oxide nanoparticles.

[0103] Comparative Example 3

[0104] The difference between this comparative example and Example 2 is that the oxidant solution is not added in stages along the material flow direction in the fixed bed reactor, but is added continuously all at once from the inlet of the fixed bed reactor.

[0105] Specifically, after pre-cooling all the oxidant solution and substrate solution in Example 2 to 5°C, they are continuously fed into the fixed-bed reactor through the inlet, without adding oxidant through the oxidant replenishment port between the catalyst beds.

[0106] Except for the differences mentioned above, the supported ruthenium catalyst, substrate solution composition, total amount of peracetic acid, reaction temperature, reaction pressure, total residence time, and post-treatment method used are all the same as in Example 2.

[0107] This comparative example is used to investigate the effects of staged oxidant addition on local oxidant concentration, reaction temperature rise, target product selectivity, and the degree of side reactions in a fixed-bed reactor.

[0108] Comparative Example 4

[0109] The difference between this comparative example and Example 2 is that a ruthenium oxide catalyst supported on ordinary silica is used, and the catalyst does not contain zirconium oxide modified components or a porous silica confinement layer.

[0110] Specifically, ruthenium trichloride is impregnated in an unmodified mesoporous silica support, and after aging, drying and calcination, a common RuO2 / SiO2 catalyst is obtained.

[0111] Except for the differences mentioned above, the other reaction conditions and post-processing methods are the same as in Example 2.

[0112] This comparative example is used to investigate the synergistic effect of zirconia modification and porous silica confinement layer.

[0113] Comparative Example 5

[0114] The difference between this comparative example and Example 2 is that a batch reactor is used instead of a fixed-bed continuous reactor.

[0115] Specifically, the substrate solution of Example 2 was added to a reaction vessel with a stirring and cooling jacket. The oxidant solution was added dropwise over 45 minutes at 10°C. After the addition was completed, the reaction was continued at this temperature for another 45 minutes. After the reaction was completed, the reaction was quenched, extracted, washed, concentrated, and crystallized according to the method of Example 2.

[0116] The type of supported ruthenium catalyst, the molar ratio of substrate to oxidant, and the post-treatment method used in this comparative example are the same as in Example 2.

[0117] This comparative example is used to compare the differences between fixed-bed continuous reactors and traditional batch reactors in terms of heat transfer efficiency, local oxidant concentration, production continuity, and product quality consistency.

[0118] Performance testing

[0119] I. Testing Standards and Methods

[0120] Unless otherwise stated, each experiment was performed in triplicate, and the results were taken as the arithmetic mean. The examples and comparative examples used the same batch of 4-AA precursor cyclizer, peracetic acid, acetate, and analytical reagents to minimize the impact of batch variations on the test results.

[0121] 1.4-AA precursor cyclization conversion, 4-AA selectivity, and 4-AA content in the reaction solution

[0122] The determination was performed using high performance liquid chromatography.

[0123] The conversion rate of the 4-AA precursor cyclizer is calculated according to the following formula:

[0124] Conversion rate X = (n0 - n1) / n0 × 100%.

[0125] In the formula, n0 is the molar amount of 4-AA precursor cyclizer entering the reactor, and n1 is the molar amount of 4-AA precursor cyclizer remaining after the reaction.

[0126] 4-AA selectivity is calculated according to the following formula:

[0127] Selectivity S = n2 / (n0-n1) × 100%.

[0128] In the formula, n2 is the molar amount of 4-AA generated in the reaction solution.

[0129] 2.4-AA separation yield

[0130] The 4-AA obtained from crystallization was dried at 40°C and under a vacuum of no more than -0.085 MPa until the difference between two consecutive weighings did not exceed 0.2%, and the quality of the dried product was recorded.

[0131] The 4-AA separation yield is calculated according to the following formula:

[0132] Separation yield Y = m / (n0 × M) × 100%.

[0133] In the formula, m is the mass of the dried 4-AA product, n0 is the molar amount of the 4-AA precursor cyclizer added, and M is the molar mass of 4-AA.

[0134] Each experiment was conducted independently three times, and the separation yield was the average of the three experimental results.

[0135] 3. Ruthenium residue in the product

[0136] The residual amount of ruthenium in the product was determined by inductively coupled plasma mass spectrometry.

[0137] The residual amount of ruthenium in the product is calculated according to the following formula:

[0138] C = (c - c0) × V / m.

[0139] In the formula, C represents the residual ruthenium content in the product, in mg / kg; c represents the ruthenium concentration in the test solution; c0 represents the ruthenium concentration in the blank solution; V represents the final volume; and m represents the mass of the test sample.

[0140] 4. Amount of ruthenium leached from the reaction effluent

[0141] The effluent from the reaction was collected at 12h, 24h, 48h, 72h, 96h and 120h of continuous operation of the fixed-bed reactor.

[0142] Accurately measure 1.00 mL of the reaction effluent into a 50 mL volumetric flask, add 2 mL of nitric acid and 1 mL of hydrochloric acid, digest under sealed conditions, and dilute to the mark with a mixed solution of 2% hydrochloric acid and 1% nitric acid. Determine the ruthenium concentration according to the ICP-MS conditions described above.

[0143] The arithmetic mean of ruthenium concentration at each time point was used as the average ruthenium leaching amount in the reaction effluent.

[0144] 5. Catalyst stability during continuous operation

[0145] The catalysts used in each embodiment and comparative example were loaded into fixed-bed reactors of the same specifications and run continuously for 120 hours according to the corresponding process conditions.

[0146] The reaction effluent was collected every 12 hours during operation, and the conversion rate of the 4-AA precursor cyclizer was determined according to the above-mentioned high performance liquid chromatography method.

[0147] The initial conversion rate was the average of three sampling results within the first 4 hours of continuous operation, and the conversion rate after 120 hours of operation was the average of the sampling results at the 116th, 118th, and 120th hours.

[0148] The catalytic activity retention rate is calculated according to the following formula:

[0149] Activity retention rate R = X 120 / X initial × 100%.

[0150] In the formula, X 120 X represents the average conversion rate after 120 hours of continuous operation, with X initially representing the average conversion rate within the first 4 hours of operation.

[0151] The relative standard deviation of the continuous operation conversion rate is calculated based on the test data of all sampling points. The smaller the relative standard deviation, the better the stability of continuous operation.

[0152] For Comparative Example 5, which uses a batch reactor reaction, 10 batches of the same catalyst were continuously reacted, and the ratio of the conversion rate of the 10th batch to the conversion rate of the 1st batch was used as the activity retention rate.

[0153] 6. Reaction temperature stability

[0154] Platinum resistance temperature sensors with an accuracy of ±0.1℃ are installed at the inlet of the fixed bed reactor, the middle of each catalyst bed, the outlet of each catalyst bed, and the total outlet of the reactor.

[0155] During continuous operation, the temperature is recorded once per minute, and the difference between the highest measured temperature at each temperature measuring point and the set reaction temperature is calculated. The maximum value of this difference is taken as the maximum bed temperature rise.

[0156] The maximum bed temperature rise is calculated using the following formula:

[0157] ΔTmax = Tmax - T setting.

[0158] In the formula, Tmax is the highest temperature recorded at all temperature measurement points during continuous operation, and T is the reaction temperature set in the corresponding embodiment or comparative example.

[0159] In Comparative Example 5, temperature sensors were installed at the center of the reactor, near the reactor wall, and near the oxidant droplet inlet. The difference between the highest temperature recorded at all temperature measurement points and the set temperature was taken as the maximum reaction temperature rise.

[0160] Table 1: Reaction Performance and Product Quality Testing

[0161] Experimental group Precursor conversion rate / % 4-AA selectivity / % 4-AA separation yield / % HPLC purity / % Ruthenium residue in the product (mg / kg) Example 1 97.8±0.3 95.6±0.4 92.1±0.4 99.12±0.05 0.35±0.04 Example 2 98.5±0.2 96.3±0.3 93.0±0.3 99.24±0.04 0.32±0.03 Example 3 98.1±0.3 95.9±0.3 92.5±0.4 99.18±0.05 0.34±0.03 Comparative Example 1 94.2±0.5 91.7±0.6 84.9±0.7 98.45±0.09 2.86±0.18 Comparative Example 2 95.0±0.5 92.6±0.5 86.6±0.6 98.62±0.08 4.35±0.27 Comparative Example 3 97.1±0.4 88.8±0.7 84.7±0.8 97.93±0.12 0.39±0.04 Comparative Example 4 91.6±0.7 89.4±0.8 79.8±0.9 97.42±0.15 6.82±0.41 Comparative Example 5 96.8±0.6 92.1±0.7 87.6±0.7 98.37±0.11 0.48±0.05

[0162] Table 2: Test results of catalyst stability and continuous operation performance

[0163] Experimental group Average ruthenium leaching amount in effluent (mg / L) Activity retention rate / % Running conversion rate RSD / % Maximum bed / reaction temperature rise / °C Example 1 0.052 96.8 0.78 1.3 Example 2 0.046 97.6 0.78 1.1 Example 3 0.049 97.1 0.76 1.4 Comparative Example 1 0.410 82.4 4.63 1.2 Comparative Example 2 0.680 78.9 5.27 1.2 Comparative Example 3 0.050 96.1 1.18 5.6 Comparative Example 4 1.050 68.7 8.16 1.5 Comparative Example 5 0.067 <![CDATA[90.8 1 ]]> <![CDATA[3.12 2 ]]> 4.7

[0164] As shown in Tables 1 and 2, the conversion rates of the 4-AA precursor cyclizers in Examples 1-3 all exceeded 97.8%, the 4-AA selectivity exceeded 95.6%, the separation yield exceeded 92.1%, the HPLC purity of the products was not less than 99.12%, and the ruthenium residue in the products was not higher than 0.35 mg / kg. This indicates that the supported ruthenium catalyst used in this invention has high catalytic activity, target product selectivity, and metal support stability in continuous oxidative acetoxylation reactions. Among them, Example 2 showed the best overall performance, with precursor conversion, 4-AA selectivity, and separation yield reaching 98.5%, 96.3%, and 93.0%, respectively. The activity retention rate after 120 hours of continuous operation reached 97.6%, and the RSD of the operating conversion was only 0.78%.

[0165] Comparative Example 1, without zirconia modification of the mesoporous silica support, showed a significant increase in ruthenium leaching from the effluent and residual ruthenium in the product, indicating that zirconia modification can improve the stability of the support in a strongly acidic oxidizing system and enhance the binding between the active ruthenium oxide component and the support. Comparative Example 2, without a porous silica confinement layer, showed a further increase in ruthenium leaching and a significant decrease in activity retention, indicating that the porous silica confinement layer can inhibit the migration, aggregation, and desorption of ruthenium oxide nanoparticles. Comparative Example 3, with all the oxidant added through the reactor inlet, maintained a high precursor conversion rate, but the selectivity and separation yield of 4-AA decreased significantly, and the maximum temperature rise increased to 5.6℃, indicating that staged addition of the oxidant can reduce the local oxidant concentration, disperse the heat of reaction, and inhibit excessive oxidation side reactions. Comparative Example 4, using a conventional RuO2 / SiO2 catalyst, exhibited the highest ruthenium leaching rate, highest residual ruthenium content in the product, and lowest operational volatility, further demonstrating a synergistic stabilizing effect between the zirconia-modified support and the porous silica confinement layer. Comparative Example 5, employing a batch reactor reaction, showed higher maximum temperature rise and batch-to-batch volatility compared to the fixed-bed continuous reaction, indicating that the continuous reaction method of this invention is beneficial for improving heat and mass transfer conditions, enhancing reaction stability, and increasing product quality consistency.

[0166] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Unless otherwise specified, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0167] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

[0168] Those skilled in the art should understand that the above descriptions are merely several specific embodiments of the present invention, and not all embodiments.

Claims

1. A method for the continuous preparation of 4-AA using a highly stable supported ruthenium catalyst, characterized in that, Includes the following steps: S1. Mix the 4-AA precursor cyclizer, acetate, and the first organic solvent to obtain a substrate solution; S2. The prepared liquid peracetic acid is used directly as an oxidant solution and then used in subsequent continuous reactions. S3. After pre-cooling the substrate solution and oxidant solution respectively, they are continuously fed into a fixed-bed reactor filled with a supported ruthenium catalyst, so that the 4-AA precursor cyclizer undergoes an oxidative acetoxylation reaction under the action of the supported ruthenium catalyst, and a reaction solution containing 4-AA is continuously obtained. The supported ruthenium catalyst includes a zirconia-modified mesoporous silica support, a ruthenium oxide active component loaded in the pores of the zirconia-modified mesoporous silica support, and a porous silica confinement layer covering the outer surface of the zirconia-modified mesoporous silica support. S4. The reaction solution containing 4-AA is continuously introduced into the quenching unit and mixed with a reducing quenching solution to decompose the residual peracetic acid. Then, after extraction, washing, concentration and crystallization, 4-AA is obtained. Wherein, the 4-AA precursor cyclizer is (3S)-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]azacyclobutane-2-one, and the 4-AA is (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]azacyclobutane-2-one; The oxidant solution is added in stages along the material flow direction within the fixed-bed reactor.

2. The method for continuous preparation of 4-AA using a highly stable supported ruthenium catalyst according to claim 1, characterized in that, In step S1, the first organic solvent includes acetonitrile and acetic acid, and the volume ratio of acetonitrile to acetic acid is 1:0.1 to 0.

8. The acetate is one of anhydrous sodium acetate and anhydrous potassium acetate; The molar ratio of the acetate to the 4-AA precursor cyclizer is 0.8 to 1.3:

1.

3. The method for continuous preparation of 4-AA using a highly stable supported ruthenium catalyst according to claim 1, characterized in that, In step S2, the mass fraction of peracetic acid in the liquid peracetic acid is 20-40%, and the molar ratio of peracetic acid to the 4-AA precursor cyclizer is 2.0-4.0:

1.

4. The method for continuous preparation of 4-AA using a highly stable supported ruthenium catalyst according to claim 1, characterized in that, In step S3, based on the mass of the zirconia-modified mesoporous silica carrier, the mass content of the zirconia is 5-25%. Based on the total mass of the supported ruthenium catalyst, the mass content of ruthenium is 0.2% to 2.5%. The thickness of the porous silica confinement layer is 3–30 nm; The active component of ruthenium oxide is ruthenium oxide nanoparticles.

5. The method for continuous preparation of 4-AA using a highly stable supported ruthenium catalyst according to claim 1, characterized in that, The supported ruthenium catalyst is prepared according to the following steps: A1. The mesoporous silica support is dispersed in a first alcohol-water mixed solvent, a zirconium precursor is added, the pH of the system is adjusted to 8.0-10.0, and the system is stirred and hydrolyzed at 40-70℃ for 2-6 hours. After solid-liquid separation, washing and drying, the system is calcined at 400-600℃ for 2-5 hours in air atmosphere to obtain a zirconium oxide modified mesoporous silica support. A2. Dissolve the ruthenium precursor in a second alcohol-water mixed solvent to prepare a ruthenium-containing impregnation solution with a ruthenium ion concentration of 0.01–0.10 mol / L. Add the ruthenium-containing impregnation solution to the zirconia-modified mesoporous silica support at a volume 0.8–1.2 times the pore volume of the zirconia-modified mesoporous silica support for equal-volume impregnation. After aging for 6–18 h, dry at 80–120 °C for 4–12 h, and calcine at 250–400 °C for 2–5 h in an oxygen-containing atmosphere to convert the ruthenium precursor into an active ruthenium oxide component dispersed within the pores of the support, thus obtaining a composite support loaded with ruthenium oxide. A3. The composite support for ruthenium oxide is dispersed in a third alcohol-water mixed solvent, and ammonia and a silicon source are added. The mass ratio of the silicon source to the composite support for ruthenium oxide is 0.05 to 0.30:

1. The mixture is subjected to a hydrolysis-condensation reaction at 20 to 40°C for 4 to 12 hours. After solid-liquid separation, washing, and drying at 80 to 120°C, the mixture is heat-treated at 150 to 300°C for 2 to 5 hours to form a porous silica confinement layer on the outer surface of the zirconia-modified mesoporous silica support, thereby obtaining the supported ruthenium catalyst.

6. The method for continuous preparation of 4-AA using a highly stable supported ruthenium catalyst according to claim 5, characterized in that, The zirconium precursor is at least one of zirconium n-propoxide, zirconium isopropoxide, zirconium oxychloride, and zirconium nitrate. The ruthenium precursor is one of ruthenium trichloride and ruthenium nitrite; The silicon source is one of tetraethyl orthosilicate and methyl orthosilicate; The first alcohol-water mixed solvent, the second alcohol-water mixed solvent, and the third alcohol-water mixed solvent are each obtained independently by mixing ethanol and water.

7. The method for continuous preparation of 4-AA using a highly stable supported ruthenium catalyst according to claim 1, characterized in that, In step S3, the substrate solution and the oxidant solution are pre-cooled to 0-10°C respectively; The reaction temperature in the fixed-bed reactor is 5–15°C, and the reaction pressure is 0.5–1.0 MPa. The total residence time of the substrate solution and oxidant solution in the fixed-bed reactor is 30–60 min.

8. The method for continuous preparation of 4-AA using a highly stable supported ruthenium catalyst according to claim 1, characterized in that, In step S3, the fixed-bed reactor includes 2 to 4 catalyst beds arranged in series along the material flow direction, and an oxidant replenishment port and a heat exchange section are provided between two adjacent catalyst beds. The oxidant solution is added in 2 to 4 stages through the fixed-bed reactor inlet and the oxidant replenishment port, wherein the oxidant solution added through the fixed-bed reactor inlet accounts for 40 to 50% of the total oxidant solution added. In step S4, the reducing quenching solution is one of sodium sulfite aqueous solution and sodium bisulfite aqueous solution.

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