Preparation method of molecular sieve carrier for drug synthesis

Abstract

The application relates to the technical field of molecular sieve preparation, and specifically discloses a preparation method of a molecular sieve carrier for drug synthesis. The preparation method comprises the following steps: S1: uniformly mixing a mesopore template agent, water and a skeleton supporting agent, then sequentially adding an aluminum source, a micropore template agent and a silicon source, and performing a hydrolysis reaction to obtain a pre-gel; S2: placing the pre-gel under a unidirectional temperature gradient, performing directional freezing to obtain a solid columnar object; S3: performing vacuum freeze drying on the solid ice column to obtain a porous dry gel skeleton; S4: suspending the porous dry gel skeleton in a reaction kettle, performing in-situ crystallization treatment on the porous dry gel skeleton under heating by using a gas phase source to obtain a crystallization product; and S5: placing the precursor in a sintering equipment, performing step-by-step temperature rising roasting, and cooling to obtain the molecular sieve carrier. The molecular sieve carrier prepared by the application has a multi-level pore structure, can provide an efficient mass transfer channel for drug macromolecules, can significantly improve the accessibility of active sites, and can prolong the service life of a catalyst.

Description

Technical Field

[0001] This invention relates to the technical field of molecular sieve preparation, and specifically to a method for preparing a molecular sieve carrier for drug synthesis. Background Technology

[0002] In modern fine chemical and pharmaceutical synthesis industries, such as the synthesis of ibuprofen, naproxen, and various chiral drug intermediates, aluminosilicate molecular sieves are widely used as catalysts or active substance supports due to their unique solid acidity and shape-selective catalytic ability. With the development of targeted drugs and complex macromolecular drugs, the molecular size of drug intermediates has significantly increased. Traditional molecular sieve supports with only microporous structures (such as ZSM-5 and Beta-type) expose serious mass transfer bottlenecks when facing drug molecules with high steric hindrance. This is because the kinetic diameter of the drug molecule is larger than the pore size of the molecular sieve, preventing reactants from entering the abundant acidic sites inside the molecular sieve. The catalytic or supported reaction almost entirely occurs on the outer surface of the molecular sieve particles, resulting in wasted internal active sites. Furthermore, the high concentration of reactants on the outer surface easily triggers deep polymerization and cracking side reactions, and the generated carbon deposits rapidly block the micropore openings, causing catalyst deactivation. In industrial practice, this manifests as short continuous operating cycles, a precipitous drop in target product conversion rate, rapid blackening of the catalyst surface, and frequent shutdowns for regeneration, leading to huge energy consumption and economic losses when catalyzing large-volume aromatic drug intermediates.

[0003] The patent application with publication number CN118125464A discloses a method for preparing a hierarchical porous HZSM-5 molecular sieve, including the following steps: (1) mixing and grinding boron source, silicon source, aluminum source and template agent to obtain a uniform gel, and pouring the gel into an open polytetrafluoroethylene liner. The molar ratio of the gel is: B2O3:Al2O3:SiO2:template agent = 0.5~10:1:20~150:1~8; (2) pouring the gel into the open polytetrafluoroethylene liner from step (1). The polytetrafluoroethylene liner is placed vertically into the polytetrafluoroethylene liner containing the amine solution. The height of the liner containing the gel is lower than the height of the amine solution. The mass ratio of liquid to gel is amine solution: gel = 0~2:1. The liner is placed in the reaction vessel for static crystallization, washed and dried. (3) The sample obtained in step (2) is placed in a hydrothermal steam device for high-temperature treatment. The conditions are 100% steam at 600~800℃ for 1~6h to obtain multi-level porous HZSM-5 molecular sieve.

[0004] In this technical solution, the mesopores generated by boron source regulation and high-temperature steam treatment mainly rely on lattice defects and dealumination to form mesopores. The pore distribution is highly random. For large-volume drug molecules, the random pore network is difficult to provide a fast and smooth diffusion path. The migration path of molecules in the pores is tortuous, and the mass transfer resistance is large, which limits the accessibility of active sites. Summary of the Invention

[0005] To overcome the technical problems of random pore distribution and lack of ordered orientation structure in existing molecular sieve carriers, which leads to high mass transfer resistance and low accessibility of active sites for large-volume drug molecules, this invention provides a method for preparing molecular sieve carriers for drug synthesis.

[0006] A method for preparing a molecular sieve support for drug synthesis includes the following steps:

[0007] S1: After mixing the mesoporous template agent, water and framework support agent evenly, aluminum source, microporous template agent and silicon source are added in sequence, and a pregel is obtained after hydrolysis reaction;

[0008] S2: The pregel is placed under a unidirectional temperature gradient and then directionally frozen to obtain a solid columnar material;

[0009] S3: Vacuum freeze-drying of solid ice columns to obtain a porous dry gel skeleton;

[0010] S4: The porous dry gel framework is suspended in the reactor and subjected to in-situ crystallization treatment using a gas source under heating conditions to obtain the crystallized product.

[0011] S5: The precursor is placed in a sintering device and subjected to step-by-step heating and calcination. After cooling, the molecular sieve carrier is obtained.

[0012] The gaseous source is derived from an aqueous solution of organic amines.

[0013] In this technical solution, a framework support agent is introduced into the molecular sieve precursor to form a hybrid gel with a template agent and a silicon-aluminum source. An oriented macroporous framework is constructed by directional freezing, and after freeze-drying, micropores are formed by in-situ crystallization using a gas-phase transport process. Then, through stepwise calcination, a three-dimensional hierarchical porous molecular sieve support with macropores, mesopores, and micropores is obtained. This structure provides efficient mass transfer channels for drug macromolecules, improves the accessibility of active sites, inhibits side reactions, and significantly extends the catalyst lifetime.

[0014] Preferably, the mass ratio of the mesoporous template agent, the skeleton support agent, the aluminum source, the microporous template agent and the silicon source is (4~6):(1~2):(0.3~1.0):(10~12):(42~45).

[0015] In this technical solution, the ratio range enables the components to work synergistically, ensuring the stability and processability of the hybrid gel while regulating the silicon-to-aluminum ratio and acid center distribution of the molecular sieve, ultimately obtaining a carrier material with regular pores and suitable acidity.

[0016] Preferably, the skeletal support agent is nanocrystalline cellulose.

[0017] In this technical solution, nanocrystalline cellulose, with its nanofiber morphology and surface hydroxyl groups, can form stable hydrogen bonds with the precursor, playing a role in structural support and shaping the pore framework, effectively ensuring the integrity of the multi-level pore structure in subsequent processes.

[0018] Preferably, the mesoporous template agent is an amphiphilic polyether.

[0019] Preferably, the amphiphilic polyether is polyether P123 or polyether F127.

[0020] In this technical solution, both are typical amphiphilic triblock copolymers with a suitable ratio of hydrophilic and hydrophobic segments. They can self-assemble in the pregel system to form an ordered mesoporous micelle template, precisely control the pore size and channel regularity of the carrier, and meet the mass transfer requirements of drug macromolecules.

[0021] Preferably, the microporous template agent is a quaternary ammonium base.

[0022] More preferably, the quaternary ammonium base is tetrapropylammonium hydroxide.

[0023] In this technical solution, tetrapropylammonium hydroxide can effectively induce the directional crystallization of silicon-aluminum precursors, generating regular micropores with uniform pore size.

[0024] Preferably, the aluminum source is aluminum isopropoxide or sodium aluminate.

[0025] Preferably, the silicon source is tetraethyl orthosilicate.

[0026] Preferably, the organic amine aqueous solution is an ethylenediamine aqueous solution.

[0027] Preferably, in the organic amine aqueous solution, the volume ratio of organic amine to water is (15~20):(20~30).

[0028] In this technical solution, ethylenediamine has moderate volatility and can release a uniform alkaline gaseous atmosphere at high temperatures, providing a relatively stable alkaline environment for the in-situ crystallization of porous dry gel framework, driving the directional crystallization of silicon-aluminum precursor to generate regular micropores.

[0029] Preferably, in step S4, under the heating conditions, in-situ crystallization is performed using a gas source, specifically at 150~170℃ for a crystallization time of not less than 36 hours.

[0030] More preferably, the crystallization treatment time is 36~48h.

[0031] Preferably, in step S5, the stepped heating and roasting specifically includes: first heating to 250~300℃, holding for 100~120min, then heating to 350~400℃, holding for 100~120min, then heating to 550~600℃, and holding for 5~6h.

[0032] In summary, this application has the following beneficial effects:

[0033] This application achieves the controllable construction of hierarchical porous molecular sieves by introducing nanocrystalline cellulose and amphiphilic polyether, and through directional freezing, in-situ vapor-phase crystallization, and step-by-step calcination processes. Nanocrystalline cellulose serves as the framework support agent, and amphiphilic polyether as the mesoporous template agent. Together with a silica-alumina source and a microporous template agent, they form a stable hybrid gel. A macroporous framework is then constructed through directional freezing, followed by freeze-drying for shaping. Regular micropores are generated through in-situ crystallization using a vapor-phase transport process. Finally, step-by-step calcination removes the template and solidifies the framework, resulting in a three-dimensional hierarchical porous molecular sieve carrier with macropores, mesopores, and micropores. This provides efficient mass transfer channels for drug macromolecules, improves the accessibility of active sites, inhibits side reactions, and significantly extends catalyst lifetime. Detailed Implementation

[0034] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.

[0035] In the following examples, the test conditions for the molecular sieve support were as follows: the ketal protection reaction of 2-(4-isobutylphenyl)propanal, a precursor of ibuprofen synthesis, with ethylene glycol was used as a probe. 0.1 mol of 2-(4-isobutylphenyl)propanal, 0.15 mol of ethylene glycol, and 50 mL of toluene (a dehydrating agent) were added to a 100 mL three-necked flask. 0.5 g of the molecular sieve support prepared in the examples was added as a solid acid catalyst support. The reaction was refluxed at 110 °C for 2 h. The initial conversion rate, selectivity, and surface carbon deposition of the target ketal product were measured.

[0036] Example 1

[0037] The method for preparing the molecular sieve support for drug synthesis in this embodiment includes the following steps:

[0038] S1: Dissolve 4.0g F127 in 60.0mL deionized water and magnetically stir at 400rpm at 25℃ until the solution is completely clear, about 120min. Add 20.0g of aqueous suspension of nanocrystalline cellulose with a solid content of 5.0wt% and a length in the range of 100~200nm. Then, use an ultrasonic cell disruptor at 300W power to intermittently disperse the mixture for 30min to obtain a mixed solution.

[0039] 0.82 g of aluminum isopropoxide was added to 40.8 g of a 25 wt% tetrapropylammonium hydroxide aqueous solution. This mixture was then slowly added dropwise at a rate of 2.0 mL / min. 41.6 g of tetraethyl orthosilicate was then added dropwise with stirring at a rate of 2 mL / min using a precision peristaltic pump. The system was kept in a closed state and continuously stirred and hydrolyzed in a 40°C water bath for 600 min to obtain a pre-gel.

[0040] S2: Transfer the pregel obtained in step S1 into a cylindrical polytetrafluoroethylene mold with an inner diameter of 30 mm and a height of 50 mm. Place the bottom of the mold tightly on a copper cold source plate that is in direct contact with liquid nitrogen (corresponding temperature of -196℃). The side walls of the mold are wrapped with polyurethane insulation cotton to ensure that a strict longitudinal temperature gradient is formed inside the mold. Under these conditions, the freezing process lasts for 45 minutes until the gel is completely solidified from bottom to top into a white columnar substance, thus obtaining a solid columnar substance.

[0041] S3: The solid columnar material obtained in step S2 is quickly transferred to a vacuum freeze dryer; under the conditions of cold trap temperature set to -80℃ and vacuum degree of about 5Pa, it is maintained for sublimation drying for 72h to obtain a sponge-like porous dry gel skeleton.

[0042] S4: At the bottom of a stainless steel high-pressure reactor lined with polytetrafluoroethylene, a mixture of 20.0 mL deionized water and 15.0 mL ethylenediamine was added as a gas source; a porous polytetrafluoroethylene partition was placed in the middle of the reactor, and the porous dry gel skeleton prepared in step S3 was placed on the partition to prevent the dry gel skeleton from making physical contact with the bottom liquid. Then the reactor was sealed and placed in a homogeneous constant temperature drying oven, heated to 150°C at a heating rate of 2°C / min and kept at the temperature for crystallization for 48 hours. After the reaction was completed, it was naturally cooled to room temperature to obtain the crystallized product.

[0043] S5: The crystallized product obtained in step S4 is placed in a tube furnace and heated in stages at an air flow rate of 100 mL / min: first, the temperature is increased to 250℃ at a rate of 1℃ / min and held for 120 min, then the temperature is increased to 350℃ at a rate of 2℃ / min and held for 120 min, then the temperature is increased to 550℃ at a rate of 2℃ / min and held for 6 h; the furnace is then cooled to room temperature to obtain the molecular sieve support.

[0044] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this embodiment is 685 m². 2 / g; Total pore volume is 0.82cm³ 3 / g; BJH model test showed that the mesopore size was concentrated at 6.5nm; In the probe reaction, the initial conversion rate of the target ketal product was 98.5%, and the selectivity was 99.2%. After filtering and washing the catalyst, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 150 hours of continuous operation, the surface carbon content was 1.2wt%.

[0045] Example 2

[0046] The method for preparing the molecular sieve support for drug synthesis in this embodiment differs from that in Example 1 in that:

[0047] S1: Dissolve 4.0g F127 in 40.0mL deionized water and magnetically stir at 400rpm at 25℃ until the solution is completely clear, about 120min. Add 40.0g of aqueous suspension of nanocrystalline cellulose with a solid content of 5.0wt% and a length in the range of 100~200nm. Then, use an ultrasonic cell disruptor at 300W power to intermittently ultrasonically disperse the mixture for 30min to obtain a mixed solution.

[0048] 0.82 g of aluminum isopropoxide was added to 40.8 g of a 25 wt% tetrapropylammonium hydroxide aqueous solution. This mixture was then slowly added dropwise at a rate of 2.0 mL / min. 41.6 g of tetraethyl orthosilicate was then added dropwise with stirring at a rate of 2 mL / min using a precision peristaltic pump. The system was kept in a closed state and continuously stirred and hydrolyzed in a 40°C water bath for 600 min to obtain a pre-gel.

[0049] The rest is the same as in Example 1.

[0050] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this embodiment is 610 m². 2 / g; Total pore volume is 0.74cm³ 3 / g; BJH model test showed that the mesopore size was concentrated at 6.2nm; In the probe reaction, the conversion rate of the target ketal product was 95.0% and the selectivity was 98.8%. After filtering and washing the catalyst, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 180 hours of continuous operation, the surface carbon content was 1.0wt%.

[0051] Example 3

[0052] The method for preparing the molecular sieve support for drug synthesis in this embodiment differs from that in Example 1 in that:

[0053] S1: Dissolve 4.0g F127 in 60.0mL deionized water and magnetically stir at 400rpm at 25℃ until the solution is completely clear, about 120min. Add 20.0g of aqueous suspension of nanocrystalline cellulose with a solid content of 5.0wt% and a length in the range of 100~200nm. Then, use an ultrasonic cell disruptor at 300W power to intermittently disperse the mixture for 30min to obtain a mixed solution.

[0054] 0.33 g of sodium aluminate was added to 40.8 g of a 25 wt% tetrapropylammonium hydroxide aqueous solution. This mixture was then slowly added dropwise at a rate of 2.0 mL / min. 41.6 g of tetraethyl orthosilicate was then added dropwise with stirring using a precision peristaltic pump at a rate of 2 mL / min. The pH of the system was adjusted to 10.5 ± 0.2 using 0.1 mol / L nitric acid solution. The system was kept in a closed state and continuously stirred and hydrolyzed in a 40°C water bath for 600 min to obtain a pre-gel.

[0055] The rest is the same as in Example 1.

[0056] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this embodiment is 642 m². 2 / g; Total pore volume is 0.78cm³ 3 / g; BJH model test showed that the mesopore size was concentrated at 6.5nm; In the probe reaction, the initial conversion rate of the target ketal product was 99.1%, and the selectivity was 85.4%. After filtering and washing the catalyst, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 110 hours of continuous operation, the surface carbon content was 3.8wt%.

[0057] Example 4

[0058] The method for preparing the molecular sieve support for drug synthesis in this embodiment differs from that in Example 1 in that:

[0059] S1: Dissolve 4.0g P123 in 60.0mL deionized water and magnetically stir at 400rpm at 25℃ until the solution is completely clear, about 120min. Add 20.0g of nanocrystalline cellulose aqueous suspension with a solid content of 5.0wt% and a length in the range of 100~200nm. Then, use an ultrasonic cell disruptor at 300W power to intermittently ultrasonically disperse the mixture for 30min to obtain a mixed solution.

[0060] 0.82 g of aluminum isopropoxide was added to 40.8 g of a 25 wt% tetrapropylammonium hydroxide aqueous solution. This mixture was then slowly added dropwise at a rate of 2.0 mL / min. 41.6 g of tetraethyl orthosilicate was then added dropwise with stirring at a rate of 2 mL / min using a precision peristaltic pump. The system was kept in a closed state and continuously stirred and hydrolyzed in a 40°C water bath for 600 min to obtain a pre-gel.

[0061] S4: At the bottom of a stainless steel high-pressure reactor lined with polytetrafluoroethylene, a mixture of 20.0 mL deionized water and 15.0 mL ethylenediamine was added as a gas source; a porous polytetrafluoroethylene partition was placed in the middle of the reactor, and the porous dry gel skeleton prepared in step S3 was placed on the partition to prevent the dry gel skeleton from making physical contact with the bottom liquid. The reactor was then sealed and placed in a homogeneous constant temperature drying oven, heated to 170°C at a heating rate of 2°C / min and kept at that temperature for 36 hours for crystallization. After the reaction was completed, the product was naturally cooled to room temperature to obtain the crystallized product.

[0062] The rest is the same as in Example 1.

[0063] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this embodiment is 660 m². 2 / g; Total pore volume is 0.85cm³ 3 / g; BJH model test showed that the mesopore size was concentrated at 9.5nm; In the probe reaction, the initial conversion rate of the target ketal product was 97.5%, and the selectivity was 98.6%. After filtering and washing the catalyst, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 165 hours of continuous operation, the surface carbon content was 1.3wt%.

[0064] Example 5

[0065] The method for preparing the molecular sieve support for drug synthesis in this embodiment includes the following steps:

[0066] S1: Dissolve 6.0g F127 in 60.0mL deionized water and magnetically stir at 400rpm at 25℃ until the solution is completely clear, about 120min. Add 30.0g of aqueous suspension of nanocrystalline cellulose with a solid content of 5.0wt% and a length in the range of 100~200nm. Then, use an ultrasonic cell disruptor at 300W power to intermittently ultrasonically disperse the mixture for 30min to obtain a mixed solution.

[0067] 1.0 g of aluminum isopropoxide was added to 49.0 g of a 25 wt% tetrapropylammonium hydroxide aqueous solution. This mixture was then slowly added dropwise at a rate of 2.0 mL / min. 45 g of tetraethyl orthosilicate was then added dropwise with stirring using a precision peristaltic pump at a rate of 2 mL / min. The system was kept in a closed state and continuously stirred and hydrolyzed in a 40°C water bath for 600 min to obtain a pre-gel.

[0068] S2: Transfer the pregel obtained in step S1 into a cylindrical polytetrafluoroethylene mold with an inner diameter of 30 mm and a height of 50 mm. Place the bottom of the mold tightly on a copper cold source plate that is in direct contact with liquid nitrogen (corresponding temperature of -196℃). The side walls of the mold are wrapped with polyurethane insulation cotton to ensure that a strict longitudinal temperature gradient is formed inside the mold. Under these conditions, the freezing process lasts for 45 minutes until the gel is completely solidified from bottom to top into a white columnar substance, thus obtaining a solid columnar substance.

[0069] S3: The solid columnar material obtained in step S2 is quickly transferred to a vacuum freeze dryer; under the conditions of cold trap temperature set to -80℃ and vacuum degree of about 5Pa, it is maintained for sublimation drying for 72h to obtain a sponge-like porous dry gel skeleton.

[0070] S4: At the bottom of a stainless steel high-pressure reactor lined with polytetrafluoroethylene, a mixture of 30.0 mL deionized water and 20.0 mL ethylenediamine was added as a gas source; a porous polytetrafluoroethylene partition was placed in the middle of the reactor, and the porous dry gel skeleton prepared in step S3 was placed on the partition to prevent the dry gel skeleton from making physical contact with the liquid at the bottom. The reactor was then sealed and placed in a homogeneous constant temperature drying oven, heated to 150°C at a heating rate of 2°C / min and kept at the temperature for crystallization for 48 hours. After the reaction was completed, the product was naturally cooled to room temperature to obtain the crystallized product.

[0071] S5: Place the crystallized product obtained in step S4 in a tube furnace and perform step heating at an air flow rate of 100 mL / min: first heat to 300℃ at a rate of 1℃ / min and hold for 100 min, then heat to 400℃ at a rate of 2℃ / min and hold for 100 min, then heat to 600℃ at a rate of 2℃ / min and hold for 5 h; cool to room temperature with the furnace to obtain the molecular sieve support.

[0072] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this embodiment is 692 m². 2 / g; Total pore volume is 0.84cm³ 3 / g; BJH model test showed that the mesopore size was concentrated at 6.8nm; In the probe reaction, the initial conversion rate of the target ketal product was 98.2%, and the selectivity was 99.0%. After filtering and washing the catalyst, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 150h of continuous operation, the surface carbon content was 1.1wt%.

[0073] Comparative Example 1

[0074] The preparation method of the molecular sieve support for drug synthesis in this comparative example differs from that in Example 1 in that:

[0075] S2: Transfer the pregel obtained in step S1 into a cylindrical polytetrafluoroethylene mold with an inner diameter of 30 mm and a height of 50 mm. Place the bottom of the mold tightly on a copper cold source plate that is in direct contact with a dry ice-acetone bath (corresponding temperature of -78℃). The side walls of the mold are wrapped with polyurethane insulation cotton to ensure that a strict longitudinal temperature gradient is formed inside the mold. Under these conditions, the freezing process lasts for 150 minutes until the gel is completely solidified from bottom to top into a white columnar substance, thus obtaining a solid columnar substance.

[0076] The rest is the same as in Example 1.

[0077] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this comparative example was 590 m². 2 / g; Total pore volume is 0.65cm³ 3 / g; BJH model test showed that the mesopore size was concentrated at 8.0nm; In the probe reaction, the initial conversion rate of the target ketal product was 91.2%, and the selectivity was 97.5%. After filtering and washing the catalyst, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 85 hours of continuous operation, the surface carbon content was 4.5wt%.

[0078] Comparative Example 2

[0079] The preparation method of the molecular sieve support for drug synthesis in this comparative example differs from that in Example 1 in that:

[0080] S4: At the bottom of a stainless steel high-pressure reactor lined with polytetrafluoroethylene, a mixture of 20.0 mL deionized water and 15.0 mL ethylenediamine was added as a gas source; a porous polytetrafluoroethylene partition was placed in the middle of the reactor, and the porous dry gel skeleton prepared in step S3 was placed on the partition to prevent the dry gel skeleton from making physical contact with the liquid at the bottom. Then the reactor was sealed and placed in a homogeneous constant temperature drying oven, heated to 150°C at a heating rate of 2°C / min and kept at the temperature for crystallization for 24 hours. After the reaction was completed, it was naturally cooled to room temperature to obtain the crystallized product.

[0081] The rest is the same as in Example 1.

[0082] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this comparative example was 510 m². 2 / g; Total pore volume is 0.58cm³ 3 / g; BJH model test showed that the mesopore size was concentrated at 6.5nm; In the probe reaction, the conversion rate of the target ketal product was 82.1%. After filtering and washing the catalyst, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 60 hours of continuous operation, the carbon deposition was 6.2wt%.

[0083] Comparative Example 3

[0084] The preparation method of the molecular sieve support for drug synthesis in this comparative example differs from that in Example 1 in that:

[0085] In step S1, an equal volume of deionized water is used to replace the nanocrystalline cellulose suspension.

[0086] The rest is the same as in Example 1.

[0087] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this comparative example was 290 m². 2 / g; Total pore volume is 0.32cm³ 3 / g; irregular mesoporous; in the probe reaction, the initial conversion rate of the target ketal product was 75.4%, and the selectivity was 94.2%. After the catalyst was filtered and simply washed, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 40 hours of continuous operation, the surface carbon content was 15.2wt%.

[0088] Comparative Example 4

[0089] The preparation method of the molecular sieve support for drug synthesis in this comparative example differs from that in Example 1 in that:

[0090] F127 was not added in step S1;

[0091] The rest is the same as in Example 1.

[0092] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this embodiment is 385 m². 2 / g; Total pore volume is 0.41cm³ 3 / g; no mesoporous structure; in the probe reaction, the initial conversion rate of the target ketal product was 45.3%, and the selectivity was 92.6%. After the catalyst was filtered and simply washed, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 25 hours of continuous operation, the surface carbon content was 11.7wt%.

[0093] Comparative Example 5

[0094] The preparation method of the molecular sieve support for drug synthesis in this comparative example differs from that in Example 1 in that:

[0095] S4: In a stainless steel high-pressure reactor lined with polytetrafluoroethylene, add an alkaline aqueous solution (a mixture of ethylenediamine and deionized water in a volume ratio of 2:1.5) sufficient to completely submerge the dry gel matrix. Heat to 150°C at a heating rate of 2°C / min and crystallize at a constant temperature for 48 hours. After the reaction is completed, cool naturally to room temperature to obtain the crystallized product.

[0096] The rest is the same as in Example 1.

[0097] Testing revealed that the BET specific surface area of ​​the molecular sieve support prepared in this comparative example is 320 m². 2 / g; Total pore volume is 0.35cm³ 3 / g; non-directional mesoporous / macroporous structure; in the probe reaction, the initial conversion rate of the target ketal product was 62.8%, and the selectivity was 91.5%. After the catalyst was filtered and simply washed, it was repeatedly fed and continuously operated (simulating industrial continuous operation). After 35 hours of continuous operation, the surface carbon content was 9.8wt%.

[0098] It should be noted that although tetraethyl orthosilicate is used as the soluble silicon source in the above embodiments, methyl orthosilicate or high-purity silica sol can be used as equivalent substitutes in other embodiments. Meanwhile, the dropping rate of the tetraethyl orthosilicate is preferably set to the parameters described above. In actual operation, this dropping rate can be adjusted within the range of 1.0~5.0 mL / min depending on the ambient temperature. Specifically, if localized rapid hydrolysis and agglomeration are observed during the addition of the silicon source, the system temperature can be lowered to approximately 5°C beforehand, or the silicon source can be diluted with an equal volume of anhydrous ethanol before addition to slow down the hydrolysis kinetics.

[0099] The test results of Example 1 and Comparative Examples 3-4 show that in Example 1, the simultaneous introduction of nanocrystalline cellulose and mesoporous template agent resulted in higher BET specific surface area and total pore volume. In Comparative Example 3, the absence of nanocrystalline cellulose caused the gel skeleton to lose support and collapse violently during calcination, severely damaging the pore structure. In Comparative Example 4, the absence of mesoporous template agent preserved the macroporous skeleton but lacked the connecting effect of the mesoporous network, preventing the microporous active sites from being effectively accessed by macromolecules.

[0100] The test results from Example 1 and Comparative Example 1 show that Example 1, using liquid nitrogen deep freezing, allows ice crystals to grow directionally along a temperature gradient, forming regular and ordered oriented macropores after freeze-drying. Comparative Example 1, using dry ice-acetone bath freezing, suffers from reduced supercooling, leading to a decreased ice crystal nucleation rate and slower growth rate. The resulting ice crystals are large and poorly oriented, resulting in a chaotic and disordered pore structure. This difference in pore orientation directly leads to significant differences in mass transfer efficiency: ordered macropores provide rapid diffusion channels for drug macromolecules, while a chaotic pore network makes molecular migration paths tortuous and increases mass transfer resistance, thus affecting catalytic activity and resistance to carbon deposition.

[0101] The test results from Examples 1 and 4 show that precise control of mesoporous pore size can be achieved by selecting different types of mesoporous template agents. Example 1 used F127 as the mesoporous template agent, which has a suitable hydrophilic-hydrophobic segment ratio, resulting in stable micelle sizes and ultimately obtaining a mesoporous network with appropriate pore sizes. Example 4 used P123 instead of F127, which has longer hydrophobic segments and larger micelle cores. Under the synergistic effect of appropriately increasing the crystallization temperature, the mesoporous pore size was significantly expanded. This result indicates that the method of this application can achieve control of mesoporous size by selecting different block copolymers to meet the mass transfer requirements of drug molecules of different sizes, demonstrating good process adjustability and applicability.

[0102] As can be seen from the test results of Examples 1-3 and Comparative Examples 2 and 5, the gas phase transport process used in this application, combined with sufficient crystallization time, not only avoids the damage to the pore structure caused by the liquid environment, but also ensures the complete transformation of the amorphous pore walls into a highly crystalline microporous framework. It is a key process that balances the maintenance of macroscopic morphology and the integrity of microcrystalline structure.

Claims

1. A method for preparing a molecular sieve support for drug synthesis, characterized in that, Includes the following steps: S1: After mixing the mesoporous template agent, water and framework support agent evenly, aluminum source, microporous template agent and silicon source are added in sequence. After hydrolysis reaction, a pregel is obtained; the mesoporous template agent is amphiphilic polyether, the framework support agent is nanocrystalline cellulose, and the microporous template agent is quaternary ammonium base. S2: Transfer the pregel into the mold, and place the bottom of the mold tightly on a copper cold source plate that is in direct contact with liquid nitrogen at a temperature of -196℃; wrap the side wall of the mold with polyurethane insulation cotton to ensure that a strict longitudinal temperature gradient is formed inside the mold; the freezing process lasts for 45 minutes until the gel is completely solidified from bottom to top into a white columnar substance, thus obtaining a solid columnar substance. S3: Vacuum freeze-drying of solid ice columns to obtain a porous dry gel skeleton; S4: The porous dry gel framework is suspended in the reactor and subjected to in-situ crystallization treatment using a gas source under heating conditions to obtain the crystallized product. Under heating conditions, in-situ crystallization is carried out using a gas phase source, specifically at 150~170℃ for a crystallization time of not less than 36 hours. S5: The precursor is placed in a sintering device and subjected to step-by-step heating and calcination. After cooling, the molecular sieve carrier is obtained. The gaseous source is derived from an aqueous solution of organic amines.

2. The method for preparing a molecular sieve support for drug synthesis according to claim 1, characterized in that, The mass ratio of the mesoporous template agent, the skeleton support agent, the aluminum source, the microporous template agent and the silicon source is (4~6):(1~2):(0.3~1.0):(10~12):(42~45).

3. The method for preparing a molecular sieve support for drug synthesis according to claim 1, characterized in that, The amphiphilic polyether is polyether P123 or polyether F127.

4. The method for preparing a molecular sieve support for drug synthesis according to claim 1, characterized in that, The aluminum source is aluminum isopropoxide or sodium aluminate.

5. The method for preparing a molecular sieve support for drug synthesis according to claim 4, characterized in that, The silicon source is tetraethyl orthosilicate.

6. The method for preparing a molecular sieve support for drug synthesis according to claim 1, characterized in that, The organic amine aqueous solution is an ethylenediamine aqueous solution.