High-selectivity catalyst for synthesizing procaterol and preparation method thereof

Abstract

The invention belongs to the technical field of catalysts for drug synthesis, and particularly relates to a high-selectivity catalyst for synthesizing procaterol and a preparation method of the high-selectivity catalyst. The invention provides a high-selectivity catalyst for synthesizing procaterol. The high-selectivity catalyst comprises a La-doped ammonia modified mesoporous SiO2 carrier, and Pd particles and Cu particles are loaded on the La-doped ammonia modified mesoporous SiO2 carrier; wherein the loading capacity of the Pd is 0.5 wt%-1.0 wt%, and the loading capacity of the Cu is 1.5 wt%-2.0 wt%. The catalyst provided by the invention has the advantages of high selectivity, mild reaction conditions, strong stability and controllable cost, can significantly improve the reaction selectivity in the procaterol synthesis process, reduces the generation of byproducts, reduces the difficulty of separation and purification, and has a key support effect on promoting the industrial efficient production of procaterol.

Description

Technical Field

[0001] This invention belongs to the field of catalyst technology for drug synthesis, specifically relating to a highly selective catalyst for the synthesis of procaterol and its preparation method. Background Technology

[0002] Procaterol, a highly effective β2 receptor agonist, is widely used in the clinical treatment of respiratory diseases such as bronchial asthma, wheezing bronchitis, and chronic obstructive pulmonary disease. The global market demand has maintained an average annual growth rate of 8%-12%. The synthesis of procaterol involves multiple key reactions. Among them, the Fries rearrangement reaction (achieving acyl migration of quinolone intermediates) and the hydrogenation reduction reaction (constructing chiral amino structures) are the core steps determining product purity, yield, and production cost. The efficiency and selectivity of these two reactions are entirely dependent on the catalyst performance.

[0003] Currently, the catalysts used in the industrial synthesis of propatectrolinol mainly suffer from the following problems: (1) Low selectivity: In the synthesis of procaterol, the traditional Fries rearrangement reaction often uses Lewis acids such as AlCl3 and FeCl3 as catalysts. However, these catalysts have poor selectivity for acyl migration sites, and the proportion of by-products (such as para-substituted isomers, polyacylated products, etc.) is as high as 15%-22%, resulting in a yield of less than 70% of the target intermediate.

[0004] (2) Harsh reaction conditions: In the current hydrogenation reduction step of procaterol synthesis, the catalysts used (such as Pd / C) need to react under high temperature (120-150℃) and high pressure (3-5MPa) conditions, which not only consumes a lot of energy, but also easily leads to excessive hydrogenation of raw materials to generate impurities, increasing the cost of subsequent purification.

[0005] (3) Poor stability: Traditional catalysts can only be recycled 3-5 times, and are prone to metal ion dissolution (such as Al³⁺). + Pd² + This leads to an increased risk of heavy metal residues in the product, failing to meet the quality standards for pharmaceutical raw materials.

[0006] (4) High preparation cost: Some highly selective catalysts (such as chiral Rh complexes) rely on precious metals and have complex synthesis steps, resulting in high cost per ton of catalyst, which makes it difficult to meet the needs of large-scale industrial applications. Summary of the Invention

[0007] In view of this, the present invention provides a highly selective catalyst for the synthesis of procaterol and a method for preparing the same. The catalyst has the advantages of high selectivity, mild reaction conditions, strong stability and controllable cost, which is beneficial to the large-scale production of procaterol.

[0008] To solve the above technical problems, the present invention provides a highly selective catalyst for the synthesis of procaterol, comprising a La-doped ammonia-modified mesoporous SiO2 support, wherein Pd particles and Cu particles are loaded on the La-doped ammonia-modified mesoporous SiO2 support; wherein the loading amount of Pd is 0.5wt%-1.0wt% and the loading amount of Cu is 1.5wt%-2.0wt%.

[0009] This invention modifies mesoporous SiO2 with ammonia and does not involve La. First, it creates abundant active sites and a suitable electronic environment on the surface or pore surface of the support, enhancing the interaction between the support and the active components. Simultaneously, it optimizes the pore structure of the support, increasing the pore size. Then, a certain proportion of Pd and Cu are loaded onto the La-doped ammonia-modified mesoporous SiO2. Utilizing the synergistic catalytic effect between Pd and Cu, the properties of the active centers in the catalytic reaction are controlled, thereby significantly improving catalytic selectivity and activity. The highly selective catalyst obtained by this invention for the synthesis of procaterol can significantly improve the reaction selectivity in the procaterol synthesis process, reduce by-product formation, and lower the difficulty of separation and purification. It plays a crucial supporting role in promoting the efficient industrial production of procaterol.

[0010] In conjunction with the first aspect, the specific surface area of ​​the catalyst is 700-900 m². 2 / g, the average pore size of the La-doped ammonia-modified mesoporous SiO2 support is 8-15nm, and the size of the Pd particles and Cu particles is 12-20nm.

[0011] The high specific surface area of ​​700-900 m² / g allows Pd / Cu particles to form high-density active sites on the support surface and within the pores, avoiding the decrease in activity caused by particle agglomeration. Simultaneously, the high specific surface area enhances the adsorption capacity of the support for the reaction substrate, increasing the reaction rate and enabling Fries rearrangement and hydrogenation reactions to proceed efficiently under mild conditions (Fries rearrangement: 80-100℃, hydrogenation reaction: 0.5-1.0 MPa). The pore size of the La-doped ammonia-modified mesoporous SiO2 support, at 8-15 nm, is well-suited to the sizes of quinolone intermediates (molecular size approximately 5-8 nm) and chiral amino products (molecular size approximately 6-10 nm), achieving a "molecular sieving effect." This allows the target substrate to rapidly diffuse to the active centers within the pores while inhibiting the formation of large molecular byproducts (such as polyacylated products, molecular size >15 nm). Furthermore, the moderate pore size (8-15 nm) of the support reduces side reactions such as excessive hydrogenation and ecto-acylation. The 12-20 nm particle size of Pd and Cu particles provides ample catalytic active centers and allows them to be firmly anchored by electronic interactions between amino functional groups on the support surface and La doping, preventing aggregation during recycling.

[0012] Preferably, the catalyst has a specific surface area of ​​800-900 m². 2 / g, the average pore size of the La-doped ammonia-modified mesoporous SiO2 support is 9-12nm, and the size of the Pd particles and Cu particles is 12-18nm.

[0013] A second aspect of the present invention provides a method for preparing the above-mentioned highly selective catalyst for procaterol, comprising the steps of: Preparation of La-doped ammonia-modified mesoporous SiO2 support: Mesoporous SiO2 was uniformly dispersed in anhydrous ethanol, and aminosilane coupling agent and lanthanum salt were added sequentially to react. After solid-liquid separation, the obtained solid precursor was calcined, cooled, and ground to obtain the La-doped ammonia-modified mesoporous SiO2 support. Dual active component loading: The La-doped ammonia-modified mesoporous SiO2 support is dispersed in water to form a suspension. A mixed aqueous solution of palladium salt and copper salt is added and stirred to allow palladium ions and copper ions to be adsorbed onto the La-doped ammonia-modified mesoporous SiO2 support. Then, a reducing agent is added for reduction. After solid-liquid separation, the mixture is washed and dried to obtain the catalyst precursor. Activation treatment: The catalyst precursor is activated in a hydrogen atmosphere to obtain the highly selective catalyst for the synthesis of procaterol.

[0014] In conjunction with the second aspect, the aminosilane coupling agent is selected from at least one of 3-aminopropyltriethoxysilane, N-(n-butyl)-3-aminopropyltrimethoxysilane, bis(3-(triethoxysilyl)propyl)amine, and 3-aminopropyltrimethoxysilane; the lanthanum salt is selected from La(NO)3. 6H2O, La(NO3)3, LaCl3 6H2O, La(CH3COO)3 3H2O and La2(C2O4)3 At least one of 10H2O.

[0015] Modifying mesoporous SiO2 with aminosilane coupling agents can introduce amino functional groups onto the support surface, enhancing the support's adsorption capacity and binding strength for metal ions. Further incorporation of La can further regulate the surface electronic properties and pore structure of the support, improving its stability and dispersion performance, and providing a good foundation for subsequent loading of active components and catalytic reactions.

[0016] In conjunction with the second aspect, the palladium salt is selected from PdCl2, PdCl2 2H2O, Pd(NO3)2 At least one of 2H₂O and Pd(OAc)₂; the copper salt is selected from Cu(NO₃)₂ and CuCl₂. 2H₂O, Cu(OAc)₂ H2O and CuSO4 At least one of 5H2O; the reducing agent is selected from NaBH4 and N2H4. At least one of H2O, HCHO, (ascorbic acid) C6H8O6 and H2.

[0017] In conjunction with the second aspect, in the preparation step of the La-doped ammonia-modified mesoporous SiO2 support, the ratio of the amount of mesoporous SiO2 to the aminosilane coupling agent is 1 g : 0.25-0.3 mL, and the ratio of the amount of mesoporous SiO2 to the amount of lanthanum atoms in the lanthanum salt is 1 g : 28-45 μmol.

[0018] In conjunction with the second aspect, in the dual-active component loading step, the ratio of the La-doped ammonia-modified mesoporous SiO2 support to palladium atoms in the palladium salt is 1 g : 47-94 μmol, and the ratio to copper atoms in the copper salt is 1 g : 230-320 μmol; the ratio of the sum of the molar numbers of palladium atoms and copper atoms to the molar number of the reducing agent is 1 : 2.5-3.5.

[0019] In conjunction with the second aspect, in the preparation step of the La-doped ammonia-modified mesoporous SiO2 support: the reaction conditions of the mesoporous SiO2 with the aminosilane coupling agent are: 35-45℃ for 3.5-4.5h, and the reaction conditions with the lanthanum salt are: 55-65℃ for 1.5-2.5h. The roasting temperature is 480-520℃, and the roasting time is 2.5-3.5h.

[0020] In conjunction with the second aspect, in the dual-active component loading step, the pH of the suspension is adjusted to 5.0-5.5 before palladium salt aqueous solution and copper salt aqueous solution are added; the stirring adsorption temperature is 28-32℃ and the stirring adsorption time is 1.5-2.5h.

[0021] In conjunction with the second aspect, the activation specifically involves activating the catalyst precursor in an atmosphere with a hydrogen flow rate of 40-60 mL / min at 180-220 °C for 1.5-2.5 h.

[0022] The highly selective catalyst for the synthesis of procaterol provided by this invention has the following beneficial effects: 1. High selectivity: In the propatecorro Fries rearrangement reaction, the catalyst has a selectivity of ≥92% for the target ortho-acylated product and a byproduct ratio of ≤5%; in the subsequent hydrogenation reduction reaction, the selective hydrogenation rate for the amino site is ≥95%, avoiding the occurrence of excessive hydrogenation side reactions.

[0023] 2. Mild reaction conditions: When using the catalyst of this invention to synthesize procaterol, the Fries rearrangement reaction can be carried out at 80-100°C and atmospheric pressure, and the hydrogenation reaction temperature is reduced to 60-80°C and the pressure is reduced to 0.5-1.0 MPa, reducing energy consumption by more than 40% compared with the traditional process.

[0024] 3. Excellent stability: After 15 cycles, the catalyst of this invention retains an activity rate of ≥85%, and the metal ion dissolution is far lower than the pharmaceutical industry standard (Pd≤0.005ppm, Cu≤0.01ppm), providing a favorable guarantee for product quality.

[0025] 4. Low cost and controllable: By reducing the loading of the precious metal Pd (the Pd loading is only 1 / 3 of that of traditional Pd / C catalysts) and using readily available industrial raw materials, this invention greatly reduces the preparation cost per ton of catalyst and has the potential for large-scale application. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0027] It will be understood by those skilled in the art that, unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It should also be understood that terms such as those defined in general dictionaries should be understood to have the meaning consistent with their meaning in the context of the prior art, and should not be interpreted in an idealized or overly formal sense unless specifically defined.

[0028] Unless otherwise specified, the raw materials, reagents and equipment used in this invention are all conventional commercially available reagents and equipment.

[0029] Currently, the catalysts used in the industrial synthesis of procaterol mainly suffer from problems such as low selectivity, harsh reaction conditions, poor catalyst stability, easy dissolution of metal ions, and high preparation costs. These problems result in high production costs for procaterol, and the yield needs to be further improved. In addition, they also increase the cost of separation and purification, making it difficult to achieve large-scale production.

[0030] In view of this, the present invention provides a highly selective catalyst that exhibits high selectivity in both the Fries rearrangement and hydrogenation reduction reactions, significantly reducing the occurrence of side reactions. Moreover, the catalyst can make the reaction conditions of the Fries rearrangement and hydrogenation reactions milder, reducing production energy consumption. At the same time, the catalyst also has excellent stability, with metal ion dissolution rates far below pharmaceutical industry standards, and has broad application prospects.

[0031] The following detailed embodiments illustrate the highly selective catalyst for the synthesis of procaterol and its preparation method provided by the present invention.

[0032] Example 1 This embodiment provides a highly selective catalyst for the synthesis of procaterol, and its preparation method is as follows: Preparation of La-doped ammonia-modified mesoporous SiO2 support: 10 g of mesoporous SiO2 (specific surface area ≥800 m² / g, pore size 6-10 nm) was added to 50 mL of anhydrous ethanol and ultrasonically dispersed for 30 min to form a uniform suspension. Under nitrogen protection and stirring at 40 °C, 2.5 mL of 3-aminopropyltriethoxysilane was slowly added dropwise, and the reaction was continued with stirring for 4 h. 0.18 g of La(NO3)3 was then added to the reaction system. 6H2O (416 μmol) was heated to 60 °C and reacted for 2 h. Then, ethanol was removed by vacuum distillation to obtain a solid precursor. The solid precursor was placed in a muffle furnace and calcined at 500 °C for 3 h under a nitrogen atmosphere at a heating rate of 5 °C / min. After cooling to room temperature, it was ground through a 100-mesh sieve to obtain a La-doped ammonia-modified mesoporous SiO2 support, denoted as La-SiO2-NH2.

[0033] Dual active component loading: Weigh 5g of La-SiO2-NH2 support, add 40mL of deionized water, stir to form a support suspension, and adjust the pH to 5.2 with 0.1mol / L HCl; prepare 20mL of 0.02mol / L PdCl2 solution (containing Pd²⁺). + 30 mL of 0.4 mmol) and 0.05 mol / L Cu(NO3)2 solution (containing Cu²⁺) + 1.5 mmol), after thoroughly mixing the two solutions, slowly add them dropwise to the carrier suspension, and stir for adsorption at 30°C for 2 h; while stirring, add 57 mL of 0.1 mol / L NaBH4 solution (NaBH4 and Pd²) dropwise. + and Cu² +The total molar ratio is 3:1), and the reaction is carried out at room temperature with stirring for 1 hour to achieve the formation of metal ions Pd². + and Cu² + The reduction was carried out; after the reaction was complete, the solid was separated by centrifugation and washed with deionized water until no Cl- was found in the filtrate. - (AgNO3 detection), then wash three times with anhydrous ethanol to remove residual impurities on the surface, and dry in a vacuum drying oven at 60°C for 8 hours to obtain the catalyst precursor.

[0034] Activation treatment: The catalyst precursor was added to a fixed bed reactor and activated for 2 hours at a heating rate of 3℃ / min to 200℃ under a hydrogen atmosphere (flow rate of 50 mL / min). After cooling, a highly selective catalyst (denoted as Pd-Cu / La-SiO2-NH2) was obtained.

[0035] Tests showed that the loading of Pd was 0.8 wt% and the loading of Cu was 1.8 wt%.

[0036] Example 2 This embodiment provides a highly selective catalyst for the synthesis of procaterol, and its preparation method is as follows: Preparation of La-doped ammonia-modified mesoporous SiO2 support: 10 g of mesoporous SiO2 (specific surface area ≥800 m² / g, pore size 6-10 nm) was added to 50 mL of anhydrous ethanol and ultrasonically dispersed for 30 min to form a uniform suspension. Under nitrogen protection and stirring at 35 °C, 3 mL of 3-aminopropyltrimethoxysilane was slowly added dropwise, and the reaction was continued with stirring for 4.5 h. 0.123 g of LaCl3 was then added to the reaction system. 6H2O (containing La) 3+ 348 μmol) was heated to 58 °C and reacted for 2.5 h. Then, the ethanol was removed by vacuum distillation to obtain a solid precursor. The solid precursor was placed in a muffle furnace and calcined at 480 °C for 3.5 h under a nitrogen atmosphere at a heating rate of 5 °C / min. After cooling to room temperature, it was ground through a 100-mesh sieve to obtain a La-doped ammonia-modified mesoporous SiO2 support, denoted as La-SiO2-NH2.

[0037] Dual active component loading: Weigh 5g of La-SiO2-NH2 support, add 40mL of deionized water, stir to form a support suspension, and adjust the pH to 5.0 with 0.1mol / L HCl; prepare 0.02mol / L Pd(NO3)2 solutions separately. 11.75 mL of 2H₂O solution (containing Pd²⁺) +0.235 mmol) and 0.05 mol / L CuSO4 23 mL of 5H₂O solution (containing Cu²⁺) + 1.15 mmol), after thoroughly mixing the two solutions, slowly added dropwise to the carrier suspension, and stirred at 28 °C for 2.5 h for adsorption; while stirring, 34.62 mL of 0.1 mol / L NaBH4 solution (NaBH4 and Pd²) was added dropwise. + and Cu² + The total molar ratio was 2.5:1), and the reaction was stirred at room temperature for 1 hour to achieve the desired Pd² metal ion concentration. + and Cu² + The reduction was carried out; after the reaction was complete, the solid was separated by centrifugation and washed with deionized water until no Cl- was found in the filtrate. - (AgNO3 detection), then wash three times with anhydrous ethanol to remove residual impurities on the surface, and dry in a vacuum drying oven at 60°C for 8 hours to obtain the catalyst precursor.

[0038] Activation treatment: The catalyst precursor was added to a fixed bed reactor and activated for 2.5 h at a heating rate of 3 °C / min to 180 °C under a hydrogen atmosphere (flow rate of 50 mL / min). After cooling, a highly selective catalyst (denoted as Pd-Cu / La-SiO2-NH2) was obtained.

[0039] Tests showed that the loading of Pd was 0.6 wt% and the loading of Cu was 1.6 wt%.

[0040] Example 3 This embodiment provides a highly selective catalyst for the synthesis of procaterol, and its preparation method is as follows: Preparation of La-doped ammonia-modified mesoporous SiO2 support: 10 g of mesoporous SiO2 (specific surface area ≥800 m² / g, pore size 6-10 nm) was added to 50 mL of anhydrous ethanol and ultrasonically dispersed for 30 min to form a uniform suspension. Under nitrogen protection and stirring at 45 °C, 2.8 mL of N-(n-butyl)-3-aminopropyltrimethoxysilane was slowly added dropwise, and the reaction was continued with stirring for 3.5 h. 0.166 g of La(CH3COO)3 was then added to the reaction system. 3H2O (containing La) 3+448 μmol) was heated to 60 °C and reacted for 2 h, followed by vacuum distillation to remove ethanol, yielding a solid precursor; the solid precursor was placed in a muffle furnace and calcined at 520 °C for 2.5 h under a nitrogen atmosphere at a heating rate of 5 °C / min, and then cooled to room temperature and ground through a 100-mesh sieve to obtain a La-doped ammonia-modified mesoporous SiO2 support, denoted as La-SiO2-NH2.

[0041] Dual active component loading: Weigh 5g of La-SiO2-NH2 support, add 40mL of deionized water, stir to form a support suspension, and adjust the pH to 5.4 with 0.1mol / L HCl; prepare 23.5mL of 0.02mol / L Pd(OAc)2 solution (containing Pd²⁺). + 0.47 mmol) and 28 mL of 0.05 mol / L Cu(NO3)2 solution (containing Cu²⁺) + 1.4 mmol), after thoroughly mixing the two solutions, slowly add them dropwise to the carrier suspension, and stir at 30 °C for 2 h for adsorption; while stirring, add 46.75 mL of 0.1 mol / L NaBH4 solution (NaBH4 and Pd²) dropwise. + and Cu² + The total molar ratio was 2.5:1), and the reaction was stirred at room temperature for 1 hour to achieve the desired Pd² metal ion concentration. + and Cu² + The reduction was carried out; after the reaction was complete, the solid was separated by centrifugation and washed with deionized water until no Cl- was found in the filtrate. - (AgNO3 detection), then wash three times with anhydrous ethanol to remove residual impurities on the surface, and dry in a vacuum drying oven at 60°C for 8 hours to obtain the catalyst precursor.

[0042] Activation treatment: The catalyst precursor was added to a fixed bed reactor and activated at 220°C for 1.5 h under a hydrogen atmosphere (flow rate of 50 mL / min) at a heating rate of 3°C / min. After cooling, a highly selective catalyst (denoted as Pd-Cu / La-SiO2-NH2) was obtained.

[0043] Tests showed that the loading of Pd was 0.9 wt% and the loading of Cu was 2.0 wt%.

[0044] Comparative Example 1 This comparative example provides a catalyst for the synthesis of procaterol, and its preparation method is as follows: Preparation of ammonia-modified mesoporous SiO2 support: 10 g of mesoporous SiO2 (specific surface area ≥800 m² / g, pore size 6-10 nm) was added to 50 mL of anhydrous ethanol and ultrasonically dispersed for 30 min to form a uniform suspension. Under nitrogen protection and stirring at 40 °C, 2.5 mL of 3-aminopropyltriethoxysilane was slowly added dropwise, and the reaction was continued with stirring for 4 h. The ethanol was removed by vacuum distillation to obtain a solid precursor. The solid precursor was placed in a muffle furnace and calcined at 500 °C for 3 h under a nitrogen atmosphere at a heating rate of 5 °C / min. After cooling to room temperature, it was ground through a 100-mesh sieve to obtain an ammonia-modified mesoporous SiO2 support, denoted as SiO2-NH2.

[0045] Dual active component loading: The specific steps are the same as those in Example 1, and will not be repeated here.

[0046] Activation treatment: The specific steps are the same as those in Example 1, and will not be repeated here.

[0047] Comparative Example 2 This comparative example provides a catalyst for the synthesis of procaterol, and its preparation method is as follows: Preparation of Zr-doped ammonia-modified mesoporous SiO2 support: 10 g of mesoporous SiO2 (specific surface area ≥800 m² / g, pore size 6-10 nm) was added to 50 mL of anhydrous ethanol and ultrasonically dispersed for 30 min to form a uniform suspension. Under nitrogen protection and stirring at 40 °C, 2.5 mL of 3-aminopropyltriethoxysilane was slowly added dropwise, and the reaction was continued with stirring for 4 h. 0.15 g of Zr(NO3)4 was then added to the reaction system. 5H2O (349.3 μmol) was heated to 60 °C and reacted for 2 h. Then, ethanol was removed by vacuum distillation to obtain a solid precursor. The solid precursor was placed in a muffle furnace and calcined at 500 °C for 3 h under a nitrogen atmosphere at a heating rate of 5 °C / min. After cooling to room temperature, it was ground through a 100-mesh sieve to obtain a La-doped ammonia-modified mesoporous SiO2 support, denoted as Zr-SiO2-NH2.

[0048] Dual active component loading: The specific steps are the same as those in Example 1, and will not be repeated here.

[0049] Activation treatment: The specific steps are the same as those in Example 1, and will not be repeated here.

[0050] Comparative Example 3 This comparative example provides a catalyst for the synthesis of procaterol, and its preparation method is as follows: Preparation of La-doped ammonia-modified mesoporous SiO2 support: The specific steps are the same as those in Example 1, and will not be repeated here.

[0051] Single active component loading: Weigh 5g of La-SiO2-NH2 support, add 40mL of deionized water, stir to form a support suspension, and adjust the pH to 5.2 with 0.1mol / L HCl; prepare 20mL of 0.02mol / L PdCl2 solution (containing Pd²⁺). + 0.4 mmol (Pd loading was the same as in Example 1, 0.8 wt%) was slowly added dropwise to the carrier suspension, and the mixture was stirred and adsorbed at 30 °C for 2 h. While stirring, 12 mL of 0.1 mol / L NaBH4 solution (NaBH4 and Pd²) was added dropwise. + The molar ratio is 3:1), and the reaction is carried out at room temperature with stirring for 1 hour to achieve the formation of metal ions Pd². + The reduction was carried out; after the reaction was complete, the solid was separated by centrifugation and washed with deionized water until no Cl- was found in the filtrate. - (AgNO3 detection), then wash three times with anhydrous ethanol to remove residual impurities on the surface, and dry in a vacuum drying oven at 60°C for 8 hours to obtain the catalyst precursor.

[0052] Activation treatment: The specific steps are the same as those in Example 1, and will not be repeated here.

[0053] Comparative Example 4 This comparative example provides a catalyst for the synthesis of procaterol, and its preparation method is as follows: Preparation of La-doped ammonia-modified mesoporous SiO2 support: The specific steps are the same as those in Example 1, and will not be repeated here.

[0054] Dual active component loading: Weigh 5g of La-SiO2-NH2 support, add 40mL of deionized water, stir to form a support suspension, and adjust the pH to 5.2 with 0.1mol / L HCl; prepare 20mL of 0.02mol / L PdCl2 solution (containing Pd²⁺). + 30 mL of 0.4 mmol) and 0.05 mol / L Ni(NO3)2 solution (containing Ni²⁺) + 1.5 mmol of Ni was added, with the same Ni loading as in Example 1 (1.8 wt%). The two solutions were thoroughly mixed and then slowly added dropwise to the carrier suspension. The mixture was stirred and adsorbed at 30°C for 2 hours. While stirring, 57 mL of a 0.1 mol / L NaBH4 solution (NaBH4 and Pd²⁺) was added dropwise. + and Ni²+ The total molar ratio is 3:1), and the reaction is carried out at room temperature with stirring for 1 hour to achieve the formation of metal ions Pd². + and Ni² + The reduction was carried out; after the reaction was complete, the solid was separated by centrifugation and washed with deionized water until no Cl- was found in the filtrate. - (AgNO3 detection), then wash three times with anhydrous ethanol to remove residual impurities on the surface, and dry in a vacuum drying oven at 60°C for 8 hours to obtain the catalyst precursor.

[0055] Activation treatment: The specific steps are the same as those in Example 1, and will not be repeated here.

[0056] Test Example 1 The catalytic performance of the catalysts obtained in Examples 1-3 and Comparative Examples 1-4 was tested, and the results are shown in Table 1.

[0057] Table 1

[0058] As can be seen from Table 1, compared with the catalysts obtained in Comparative Examples 1-4, the catalysts provided in Examples 1-3 of the present invention have a larger specific surface area, the La-doped ammonia-modified mesoporous SiO2 support has a more suitable pore structure, the metal particle size distribution is more uniform and smaller, which is more conducive to improving catalytic activity, and the activity retention rate after 15 cycles is significantly higher, demonstrating superior structural characteristics and stability.

[0059] Test Example 2 The catalyst obtained in Example 1 was used to synthesize procaterol according to the following steps: Step 1: Add 2.65g of 8-butyryloxyquinolone and 26.5mL of dichloroethane to the reaction vessel, stir to dissolve, add 0.5g of the catalyst obtained in Example 1, replace the air in the reaction vessel with nitrogen three times (each replacement pressure 0.3MPa, pressure held for 5min); heat to 90℃, stir and react for 3h, after the reaction is completed, cool to room temperature, filter and collect the filtrate.

[0060] Step 2: Transfer the filtrate obtained in Step 1 into a high-pressure reactor, add 0.3g of the catalyst obtained in Example 1, and supplement with ethanol as a solvent (to make the solid-liquid ratio of the system 1:15 (mass-volume ratio)); replace the gas in the reactor with hydrogen three times (each replacement pressure 0.5MPa, pressure maintained for 5min), then introduce hydrogen to a pressure of 0.8MPa, raise the temperature to 70℃, and stir the reaction for 2h; after the reaction is completed, cool to room temperature, slowly release hydrogen to atmospheric pressure, filter to recover the catalyst, and collect the filtrate.

[0061] Step 3: Transfer the filtrate obtained in Step 2 into the reaction vessel, and slowly add 15g of ammonia water dropwise while stirring. During the dropwise addition process, control the temperature to ≤30℃. After the dropwise addition is completed, raise the temperature to 50℃ and stir the reaction for 1.5h. After the reaction is completed, remove part of the solvent by vacuum distillation and concentrate the system to 1 / 3 of the original volume to obtain the concentrated solution.

[0062] Step 4: Cool the concentrated solution obtained in Step 3 to 10-15℃, and slowly add hydrochloric acid dropwise while stirring to adjust the pH to 2.0-2.5. Control the temperature ≤20℃ during the dropwise addition process. After the addition is complete, continue stirring for 30 minutes, then raise the temperature to 30℃ and maintain this temperature with stirring for 1 hour. Then slowly cool to 0-5℃ and allow to stand for crystallization for 4 hours. Centrifuge to obtain crude procaterol hydrochloride. Wash the crude product twice with an appropriate amount of icy ethanol to remove surface impurities. Transfer the washed crude product to a vacuum drying oven and dry at 60℃ for 6 hours to obtain purified procaterol hydrochloride. The final total yield of procaterol product is 82%, with a purity of 99.5%.

[0063] The catalysts obtained in Examples 2-3 and Comparative Examples 1-4 were used to synthesize procaterol according to the above synthesis method. The yield and purity of the procaterol are shown in Table 2.

[0064] Table 2

[0065] As shown in Table 2, the catalyst provided by this invention can carry out the Fries rearrangement reaction at a lower temperature, and can also achieve the hydrogenation reaction at a lower temperature and pressure. In contrast, the catalysts obtained in Comparative Examples 1-4 exhibit poor catalytic activity, and the yield and purity of the procaterol obtained are inferior to those of Examples 1-3 of this invention. Furthermore, the catalysts provided in Examples 1-3 of this invention show a selectivity of ≥92% for the target ortho-acylated product in the Fries rearrangement reaction, with a byproduct ratio of ≤5%. In the hydrogenation reduction reaction, the selective hydrogenation rate at the amino site is ≥95%, avoiding the occurrence of excessive hydrogenation side reactions. In contrast, the catalysts in Comparative Examples 1-4 show poor selectivity for the target ortho-acylated product in the Fries rearrangement reaction, with a maximum selectivity of only 88%, a higher incidence of side reactions, and lower selective hydrogenation rates at the amino site compared to this invention. Moreover, the amount of metal ions dissolved in the drug prepared using the catalyst provided by this invention is far lower than the pharmaceutical industry standard, providing a favorable guarantee for product quality.

[0066] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A highly selective catalyst for the synthesis of procaterol, characterized in that, The invention includes a La-doped ammonia-modified mesoporous SiO2 support on which Pd particles and Cu particles are loaded; wherein the loading amount of Pd is 0.5wt%-1.0wt% and the loading amount of Cu is 1.5wt%-2.0wt%.

2. The highly selective catalyst for the synthesis of procaterol as described in claim 1, characterized in that, The catalyst has a specific surface area of ​​700-900 m². 2 / g, the average pore size of the La-doped ammonia-modified mesoporous SiO2 support is 8-15nm, and the size of the Pd particles and Cu particles is 12-20nm.

3. The method for preparing a highly selective catalyst for the synthesis of procaterol according to any one of claims 1-2, characterized in that the step... include: Preparation of La-doped ammonia-modified mesoporous SiO2 support: Mesoporous SiO2 was uniformly dispersed in anhydrous ethanol, and aminosilane coupling agent and lanthanum salt were added sequentially to react. After solid-liquid separation, the obtained solid precursor was calcined, cooled, and ground to obtain the La-doped ammonia-modified mesoporous SiO2 support. Dual active component loading: The La-doped ammonia-modified mesoporous SiO2 support is dispersed in water to form a suspension. A mixed aqueous solution of palladium salt and copper salt is added and stirred to allow palladium ions and copper ions to be adsorbed onto the La-doped ammonia-modified mesoporous SiO2 support. Then, a reducing agent is added for reduction. After solid-liquid separation, the mixture is washed and dried to obtain the catalyst precursor. Activation treatment: The catalyst precursor is activated in a hydrogen atmosphere to obtain the highly selective catalyst for the synthesis of procaterol.

4. The method for preparing the highly selective catalyst for the synthesis of procaterol as described in claim 3, characterized in that, The aminosilane coupling agent is selected from at least one of 3-aminopropyltriethoxysilane, N-(n-butyl)-3-aminopropyltrimethoxysilane, bis(3-(triethoxysilyl)propyl)amine, and 3-aminopropyltrimethoxysilane; the lanthanum salt is selected from La(NO)3. 6H2O, La(NO3)3, LaCl3 6H2O, La(CH3COO)3 3H2O and La2(C2O4)3 At least one of 10H2O.

5. The method for preparing the highly selective catalyst for the synthesis of procaterol as described in claim 3, characterized in that, The palladium salt is selected from PdCl2, PdCl2 2H2O, Pd(NO3)2 At least one of 2H2O and Pd(OAc)2; the copper salt is selected from Cu(NO3)2 and CuCl2. 2H₂O, Cu(OAc)₂ H2O and CuSO4 At least one of 5H2O; the reducing agent is selected from NaBH4 and N2H4. At least one of H2O, HCHO, C6H8O6 and H2.

6. The method for preparing the highly selective catalyst for the synthesis of procaterol as described in claim 3, characterized in that, In the preparation step of the La-doped ammonia-modified mesoporous SiO2 support, the ratio of mesoporous SiO2 to aminosilane coupling agent is 1 g : 0.25-0.3 mL, and the ratio of mesoporous SiO2 to lanthanum atoms in the lanthanum salt is 1 g : 28-45 μmol.

7. The method for preparing the highly selective catalyst for the synthesis of procaterol as described in claim 3, characterized in that, In the dual-active component loading step, the ratio of the La-doped ammonia-modified mesoporous SiO2 support to palladium atoms in the palladium salt is 1 g : 47-94 μmol, and the ratio of the La-doped ammonia-modified mesoporous SiO2 support to copper atoms in the copper salt is 1 g : 230-320 μmol; the ratio of the sum of the molar numbers of palladium atoms and copper atoms to the molar number of the reducing agent is 1 : 2.5-3.

5.

8. The method for preparing a highly selective catalyst for the synthesis of procaterol as described in claim 3 or 6, characterized in that, In the preparation step of the La-doped ammonia-modified mesoporous SiO2 support: the reaction conditions of the mesoporous SiO2 with the aminosilane coupling agent are: 35-45℃ for 3.5-4.5h, and the reaction conditions of the mesoporous SiO2 with the lanthanum salt are: 55-65℃ for 1.5-2.5h. The roasting temperature is 480-520℃, and the roasting time is 2.5-3.5h.

9. The method for preparing a highly selective catalyst for the synthesis of procaterol as described in claim 3 or 7, characterized in that, In the dual-active component loading step, the pH of the suspension is adjusted to 5.0-5.5 before palladium salt aqueous solution and copper salt aqueous solution are added; the stirring adsorption temperature is 28-32℃ and the stirring adsorption time is 1.5-2.5h.

10. The method for preparing the highly selective catalyst for the synthesis of procaterol as described in claim 3, characterized in that, The activation specifically involves activating the catalyst precursor in an atmosphere with a hydrogen flow rate of 40-60 mL / min at 180-220 °C for 1.5-2.5 h.

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