An intermediate containing an acetylfuran structure and a method for preparing the same

Abstract

The application belongs to the field of pharmaceutical reagents, and provides a preparation method of an intermediate containing an acetyl furan structure. The application adopts N-acetyl-D-glucosamine as raw material, uses La2O3 catalyst with nanoscale sheet-like fold structure to carry out catalytic dehydration reaction, combines with the design of segmented temperature control and multi-step cascade recrystallization process, realizes that the total purity of target products N-3-furyl-acetamide and N-(5-acetyl-3-furyl)-acetamide reaches 97.5-99.5%, the product is a needle-shaped crystal form with high quality performance, solves the problems of low catalytic activity and low product purity of the existing intermediate containing the acetyl furan structure, the catalyst can be reused for 4-6 times and the activity retention rate is greater than or equal to 90%, the intermediate can be used for preparing key intermediates of biologically active molecules such as antitumor drugs and antibiotics, and has wide application value.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical reagents, in particular to an intermediate containing an acetylfuran structure and a preparation method thereof. BACKGROUND

[0002] The intermediate containing an acetylfuran structure, as an important organic synthesis building block, has a wide application prospect in the field of pharmaceutical and chemical industry, especially in the synthesis of antitumor drugs, antibiotics and biologically active molecules. This kind of intermediate can provide multiple reaction sites for subsequent chemical transformation through its unique furan ring structure and acetyl functional group, and is an important precursor compound for building complex molecular skeleton. In modern pharmaceutical industry, the performance requirements for such intermediates are increasingly strict, not only high purity is required to ensure the selectivity of subsequent reactions and the quality of products, but also good crystalline morphology is required to facilitate separation and purification, storage and transportation. At the same time, the efficiency and environmental protection of catalytic synthesis process have become important factors for industrial production, which requires the catalyst to have high activity, good selectivity and recyclable characteristics. With the development of precision medicine and personalized medicine, the demand for high-quality intermediates containing acetylfuran structure continues to grow, which promotes the continuous progress and improvement of related preparation technology, and provides important material basis and technical support for the innovation and development of pharmaceutical industry.

[0003] Although the intermediate containing acetylfuran structure has important value in pharmaceutical synthesis, the current preparation technology still has many technical bottlenecks and challenges. The traditional synthesis method generally faces the problem of low catalytic efficiency, mainly because the active sites of commonly used catalysts are unevenly distributed, and the surface area is small, which makes it difficult to meet the requirements of industrial production in terms of conversion rate and selectivity of catalytic reaction. For example, CN112961125B discloses a process for preparing 2-acetylfuran using a solid acid catalyst, but the catalyst has insufficient activity and the product purity is low. In addition, the dehydration cyclization reaction in the existing preparation process often lacks precise temperature control strategy, which easily produces side reactions and isomers, further reducing the purity and yield of the target product. The product separation and purification process also has obvious defects, and the traditional recrystallization method cannot effectively control the crystal morphology and size distribution, resulting in unstable physical properties of the product and affecting the reliability of subsequent application. The reusability of the catalyst also needs to be improved, and the activity of most catalytic systems decreases significantly after a few uses, increasing the production cost and causing environmental burden. These technical limitations seriously restrict the large-scale production and wide application of intermediates containing acetylfuran structure, and it is urgent to develop more efficient and environmentally friendly preparation technology. SUMMARY

[0004] (1) Technical problems solved

[0005] The application aims to provide an intermediate containing an acetylfuran structure and a preparation method thereof, and solve the problems of low activity and low purity of the intermediate containing the acetylfuran structure.

[0006] (2) Technical scheme

[0007] In order to achieve the above-mentioned purpose, the application provides the following technical scheme:

[0008] A preparation method of an intermediate containing an acetylfuran structure, comprising the following steps:

[0009] S1. Mixing N-acetyl-D-glucosamine with a solvent to form a reaction system, and ensuring that the water content in the reaction system is ≤0.05wt% through molecular sieve pretreatment and nitrogen protection;

[0010] S2. Adding a La2O3 catalyst to perform a catalytic dehydration reaction, and performing the reaction in an inert atmosphere and adopting a staged temperature control strategy to optimize the reaction selectivity;

[0011] S3. After the reaction is completed, a multi-step cascade recrystallization process is adopted to obtain the intermediate containing the acetylfuran structure;

[0012] The intermediate is N-3-furyl-acetamide and N-(5-acetyl-3-furyl)-acetamide, the mass fraction of N-3-furyl-acetamide in the product is 72-76%, the mass fraction of N-(5-acetyl-3-furyl)-acetamide is 21-25%, the content of other trace components is 0.5-2.2%, mainly position isomers, partial dehydration intermediates and cyclization intermediates; the total purity is 97.8-99.5%; the impurity content is 0.5-2.2%, mainly unreacted raw materials, solvent residues and catalyst residues; the total purity of the two target products is 97.0-99.0%; the product is in the form of needle-shaped crystals, the average length is 250-800μm, and the width is 10.0-45.5μm;

[0013] The structural formula of the N-3-furyl-acetamide is:

[0014]

[0015] The structural formula of the N-(5-acetyl-3-furyl)-acetamide is:

[0016]

[0017] The morphology of the La2O3 catalyst is sub-micron particles and a nanometer active layer distributed on the surface thereof, the surface of the nanometer active layer contains a sheet-shaped nanometer wrinkle structure, the specific surface area of the catalyst is 50-200 m² / g, and the density of surface basic sites is 0.8-1.5 mmol / g; the average size of the La2O3 catalyst is 350-800 nm.

[0018] The La2O3 catalyst is prepared by a sol-gel combined hydrothermal step-by-step assembly method, which comprises three steps of mixing lanthanum nitrate, citric acid and a structure-directing agent, hexadecyl trimethyl ammonium bromide, according to a molar ratio of 1:(2.0-2.5):(0.3-0.8) to prepare a precursor, hydrothermal treatment and programmed calcination.

[0019] The present application adopts molecular sieve pretreatment combined with nitrogen protection reaction system construction, preparation of special morphology La2O3 catalyst and design of multi-step cascade recrystallization process, mainly for enhancing the catalytic activity and product purity performance of the preparation process of acetyl furan structure intermediate. By mixing N-acetyl-D-glucosamine with solvent and using molecular sieve pretreatment and nitrogen protection measures, the water content in the reaction system can be accurately controlled, creating an ideal reaction environment for the subsequent catalytic dehydration reaction, avoiding the inhibition of water on the activity of the catalyst, and preventing the occurrence of side reactions. The La2O3 catalyst is prepared by sol-gel combined with hydrothermal step assembly method, by accurately proportioning and step-by-step processing of lanthanum nitrate, citric acid and structure directing agent cetyltrimethylammonium bromide, a unique sub-micron particle structure is formed, and the nanoscale active layer distributed on the surface has a sheet-shaped nanometer wrinkle structure. This special morphology not only significantly increases the specific surface area of the catalyst, but also provides abundant surface basic sites, making the catalyst exhibit excellent activity and selectivity in the dehydration cyclization reaction. The implementation of the segmented temperature control strategy further optimizes the reaction process. Through the pre-activation stage, the catalyst surface is activated and the raw materials are pre-adsorbed, the main reaction stage carries out the core dehydration cyclization reaction, and the perfect stage ensures the complete reaction of the reaction. This synergistic temperature control mechanism combined with high-performance catalysts realizes the simultaneous improvement of reaction conversion rate and selectivity. The multi-step cascade recrystallization process adopts a continuous processing process of extraction separation, vacuum concentration, temperature gradient recrystallization and refined recrystallization, combined with programmed cooling and seed addition technology, which not only effectively removes impurities and unreacted raw materials, but also accurately controls the morphology and size distribution of the crystals, making the final product present a regular needle-shaped crystal morphology. In the whole technical scheme, strict water control provides an optimal environmental condition for the catalytic reaction, the special structure of La2O3 catalyst provides high-efficiency catalytic active centers, the segmented temperature control strategy ensures the high selectivity of the reaction, and the multi-step cascade recrystallization process guarantees the high purity and good crystal quality of the product. The organic combination of these technical elements produces a significant synergistic effect, making the preparation of acetyl furan structure intermediate reach an excellent level in catalytic efficiency, product purity and crystal quality, etc.

[0020] Further, the La2O3 catalyst is prepared by a sol-gel combined with hydrothermal step assembly method:

[0021] A1. Mix lanthanum nitrate with citric acid, and add structure directing agent cetyltrimethylammonium bromide, the molar ratio of the three is lanthanum nitrate: citric acid: directing agent = 1:2.0-2.5:0.3-0.8, add deionized water to a solid content of 15-25wt% to form a precursor solution, stir at 60-80°C for 2-4 hours to ensure complete dissolution;

[0022] A2. Evaporate under magnetic stirrer at 80-120°C to a gel-like state, stirring rate controlled at 200-300 rpm, evaporation time 4-8 hours, then hydrothermal treatment in high-pressure reactor at 180-220°C for 12-24 hours;

[0023] A3. Calcination in muffle furnace at 400-600°C under air atmosphere for 2-6 hours, heating rate 2-5°C / min, to ensure complete formation of La2O3 crystal phase and development of sheet-like wrinkle structure.

[0024] Further, the calcination procedure of the A3 step includes:

[0025] A31. Organic matter pre-decomposition stage: room temperature, 1-2°C / min heating to 200°C, 1-1.5 hours in nitrogen atmosphere, to prevent structure collapse caused by rapid decomposition of organic template;

[0026] A32. 2-5°C / min heating to 350-450°C, switching to air atmosphere for 2-3 hours, to complete decomposition of organic template and initial crystallization;

[0027] A33. Continue heating to 500-600°C and keep for 2-6 hours, to promote complete formation of La2O3 crystal phase and development of sheet-like wrinkle structure.

[0028] The present application adopts a sol-gel combined hydrothermal step-by-step assembly method to prepare special morphology La2O3 catalyst, a segmented temperature control strategy and a multi-step cascade recrystallization process, mainly for enhancing the catalytic efficiency and product purity performance in the preparation process of acetylfuran structure intermediates. The preparation of La2O3 catalyst is achieved by precise mixing of lanthanum nitrate and citric acid and the introduction of structure directing agent cetyltrimethylammonium bromide, forming a uniform precursor solution under controlled temperature and time conditions, followed by magnetic stirring evaporation and high-pressure reactor hydrothermal treatment to realize the ordered assembly of catalyst precursor, and the careful design of the programmed calcination process ensures the complete formation of La2O3 crystal phase and the full development of sheet-like wrinkle structure. This step-by-step preparation strategy makes the catalyst have ideal surface structure and active site distribution. The segmented temperature control strategy used in the catalytic dehydration reaction promotes catalyst surface activation and raw material pre-adsorption through a pre-activation stage, the core dehydration and cyclization reaction is carried out in the optimized temperature range in the main reaction stage, and the perfect stage ensures the complete reaction. This temperature gradient control combined with strict water content control and nitrogen protection measures creates the best reaction environment for the catalytic reaction. The selection of solvent system uses high-efficiency solvents such as dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone or dimethylacetamide, which provides good solubility and reaction medium for the reactants.

[0029] Further, the catalytic dehydration reaction of the S2 step adopts segmented temperature control, including: a pre-activation stage: reaction temperature 140-160°C, reaction time 30-60 minutes, to activate the catalyst surface and pre-adsorb the raw material; a main reaction stage: reaction temperature 160-200°C, time 2-4 hours, to carry out the main dehydration and cyclization reaction; a perfecting stage: reaction temperature 180-200°C, time 0.5-1 hour, to ensure the reaction is completely carried out; the amount of La2O3 catalyst is 15-25% of the mass of N-acetyl-D-glucosamine, the residual water content in the reaction system is controlled to be ≤0.1wt%, and the whole reaction is carried out under nitrogen protection, with the pressure being controlled to be 0.1-0.3 MPa.

[0030] Further, the solvent in the S1 step is one or a mixture of several of dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone or dimethylacetamide.

[0031] Further, the S3 step includes the following multi-step cascade recrystallization process:

[0032] B1. The reaction product is separated by extraction with ethyl acetate and water at a volume ratio of 1:1, the aqueous phase is back-extracted 2-4 times with a saturated NaCl solution until the organic phase is colorless and transparent, the temperature is controlled to be 25-35°C during the extraction, and each extraction time is 15-30 minutes;

[0033] B2. The organic phase is concentrated under reduced pressure at 35-45°C to 1 / 3-1 / 2 of the original volume, n-hexane is slowly added until the turbidity value of the solution reaches 100-200 NTU to perform pre-enrichment recrystallization, and the crude product of the preliminary purification is precipitated;

[0034] B3. Temperature gradient recrystallization is performed using a mixed solvent of ethyl acetate / isopropyl alcohol at a volume ratio of 3:1-1:1, and high-quality crystals are obtained by precisely controlling the cooling rate;

[0035] B4. Finally, refined recrystallization is performed using a mixed solvent of n-hexane / ethyl acetate at a volume ratio of 1:1-2:1, the temperature is controlled to be 5-25°C, and the time is 12-48 hours, to obtain a high-purity crystal product, and the purity of the target product reaches 97-99.5%.

[0036] Further, the temperature gradient recrystallization in the B3 step adopts programmed cooling:

[0037] The first stage is 35-30°C, the cooling rate is 1.0-1.5°C / h, and the solubility adjustment and initial nucleation are mainly completed;

[0038] The second stage is 30-20°C, the cooling rate is 0.8-1.2°C / h, and the crystal nucleus growth rate is controlled;

[0039] The third stage 20-10℃, cooling rate 0.5-0.8℃ / h, promote the perfect crystal structure;

[0040] The fourth stage 10-5℃, cooling rate 0.2-0.5℃ / h, ensure the quality and yield of crystal, constant stirring speed 80-120 rpm throughout the process;

[0041] The seed crystal preparation and addition method in the recrystallization process is as follows:

[0042] C1. Seed crystal preparation: take the crude product prepared by S1-S2 steps, the solid product after preliminary purification by B1-B2 steps as seed crystal raw material, adopt ball milling method under the condition of rotating speed 300-500 rpm for 45-60 minutes, or adopt ultrasonic crushing method under the condition of power 150-200W for 30-45 minutes, pass through 300 mesh sieve, get fine seed crystal particles with average particle size 0.5-2.0 μm;

[0043] C2. Seed crystal addition: when the temperature of the first stage is stable at 35℃, slowly add the prepared seed crystal according to 0.1-0.5 wt% of the total solid content in the crystallization solution, stir to ensure uniform dispersion, maintain the temperature for 10-15 minutes after dispersion is completed to make the seed crystal fully wet, then start the programmed cooling process.

[0044] Further, the La2O3 catalyst can be reused 4-6 times, after each use, regenerate according to the following procedure: sequentially wash with ethyl acetate to remove organic residues, deionized water to wash until the washing liquid pH=6.5-7.5, 110℃ vacuum drying for 4 hours to remove moisture and 550℃ calcination in air for 3 hours to restore catalytic activity, after regeneration, the catalytic activity retention rate ≥90%, BET specific surface area retention rate ≥90%, surface basic site retention rate ≥88%.

[0045] Further, the application of intermediates containing acetylfuran structure in the preparation of amino alcohol compounds, secondary amine compounds, rare amino sugars or heterocyclic compounds, the intermediates are used as synthetic precursors to prepare key intermediates of antitumor drugs, antibiotics or biologically active molecules.

[0046] The multi-step cascade recrystallization process of the application effectively removes water-soluble impurities through extraction separation of ethyl acetate and water, further purifies the organic phase through back extraction of saturated NaCl solution, realizes preliminary product purification through vacuum concentration and pre-enrichment recrystallization of n-hexane, and realizes the orderly progress of solubility adjustment, initial nucleation, crystal nucleus growth control and crystal structure perfection through four-stage accurate temperature adjustment by temperature gradient recrystallization using ethyl acetate / isopropyl alcohol mixed solvent system combined with programmed temperature control. The final n-hexane / ethyl acetate refining recrystallization ensures the high purity of the product. The seed preparation and addition technology prepares fine seed particles by ball milling or ultrasonic crushing method, and accurately controls the addition time and dispersion process of the seed in the temperature gradient recrystallization process, providing a core basis for the orderly growth of crystals. The reusability of the La2O3 catalyst is realized through the regeneration program of ethyl acetate washing, deionized water washing, vacuum drying and high temperature calcination, so that the catalyst can still maintain excellent catalytic activity, specific surface area and surface basic site density after multiple uses. In the whole technical scheme, the specially prepared La2O3 catalyst provides efficient catalytic active centers, the staged temperature control strategy ensures high selectivity and conversion rate of the reaction, the multi-step cascade recrystallization process guarantees high purity and excellent crystal morphology of the product, and the catalyst regeneration technology realizes a green and sustainable production process. The organic integration of these technical elements produces significant synergistic effect, so that the preparation of acetylfuran-containing intermediates realizes excellent performance in catalytic efficiency, product quality and process sustainability in multiple dimensions.

[0047] (3) Beneficial technical effects

[0048] The present application effectively solves the technical problems of low catalytic activity and low product purity in the preparation of acetylfuran-containing intermediates in the prior art by adopting molecular sieve pretreatment combined with nitrogen protection reaction system construction, special morphology La2O3 catalyst preparation and multi-step cascade recrystallization process, and realizes the following significant beneficial effects:

[0049] 1) Significant improvement of catalytic performance: The La2O3 catalyst prepared by the present application has a unique sub-micron particle structure and a surface nanometer active layer, and the sheet-like nanometer fold structure significantly increases the specific surface area (50-200 m² / g) and the surface basic site density (0.8-1.5 mmol / g), so that the catalyst exhibits excellent catalytic activity and selectivity in the dehydration and cyclization reaction, greatly improving the reaction conversion rate.

[0050] 2) Product purity is greatly improved: through the synergy of the staged temperature control strategy and the multi-step cascade recrystallization process, the occurrence of side reactions is effectively inhibited and impurities are efficiently removed, so that the target products N-3-furyl-acetamide and N-(5-acetyl-3-furyl)-acetamide reach high purity, and the product quality is significantly better than the prior art.

[0051] 3) Controllable crystal morphology: the multi-step cascade recrystallization process combined with programmed cooling control and seed addition technology precisely controls the nucleation and growth process of the crystal, so that the final product presents a regular needle-shaped crystal morphology with an average length of 250-800 μm and a width of 10.0-45.5 μm, and the crystal morphology is uniform and consistent, facilitating subsequent separation, purification, storage and transportation.

[0052] 4) Catalyst can be reused: the La2O3 catalyst can be reused for 4-6 times, and after simple regeneration treatment, the catalytic activity retention rate is ≥90%, the BET specific surface area retention rate is ≥90%, and the surface basic site retention rate is ≥88%, significantly reducing the production cost and environmental burden, and realizing a green and sustainable production process.

[0053] 5) Mild and controllable reaction conditions: the staged temperature control strategy realizes efficient catalytic conversion under relatively mild reaction conditions through precise control of the pre-activation, main reaction and perfection stages, and the reaction process is stable and controllable, easy to scale up for industrial production.

[0054] 6) Process flow optimization: the entire preparation process flow is designed reasonably, and each step is closely connected, the purity of the reaction system is ensured through molecular sieve pretreatment and nitrogen protection, and the multi-step cascade recrystallization process realizes efficient separation and purification of the product, and the process operation is simple and reproducible.

[0055] 7) Wide application prospect: the prepared acetylfuran-containing intermediate can be widely used in the preparation of amino alcohol compounds, secondary amine compounds, rare amino sugars or heterocyclic compounds, especially as a synthetic precursor for preparing key intermediates of antitumor drugs, antibiotics or biologically active molecules, which has important commercial value and social significance.

[0056] In summary, through technical innovation and process optimization, the present application has achieved significant improvements in catalytic efficiency, product purity, crystal quality, environmental friendliness and industrial applicability, providing important technical support for efficient preparation of acetylfuran-containing intermediates. BRIEF DESCRIPTION OF DRAWINGS

[0057] Figure 1 Morphology of the La2O3 catalyst prepared for Example 2 of the present application.

[0058] Figure 2XRD phase analysis chart of La2O3 catalyst prepared for the present embodiment 2.

[0059] Figure 3 Morphology chart of intermediate prepared for the present embodiment 2.

[0060] Figure 4 Morphology chart of La2O3 catalyst prepared for the present comparative example 10.

[0061] Figure 5 Morphology chart of La2O3 catalyst prepared for the present comparative example 2.

[0062] Figure 6 Morphology chart of intermediate prepared for the present comparative example 10.

[0063] Figure 7 Morphology chart of intermediate prepared for the present comparative example 2.

[0064] Figure 8 Total purity and impurity content of all samples of the present embodiment and comparative examples. DETAILED DESCRIPTION

[0065] In order to make the purpose, technical scheme and advantages of the present embodiment clearer, the technical scheme of the present embodiment will be described clearly and completely below in combination with the drawings in the present embodiment.

[0066] In the absence of specific conditions, the operations in the embodiments are carried out according to conventional conditions or manufacturer's recommended conditions. If the manufacturer is not specified, the reagents or instruments used are common products on the market. The parts of the technical content of the present invention not mentioned will be processed according to the prior art. Unless otherwise specified, the following examples and comparative examples will be tested in parallel, and the same processing steps and parameters will be used. Table 1 shows the reagents required for the examples and comparative examples and the corresponding purchase companies.

[0067] Table 1 shows the reagents required for the examples and comparative examples and the corresponding purchase companies.

[0068]

[0069] Example 1

[0070] The morphology of the La2O3 catalyst of the present embodiment is sub-micron particles and a nanoscale active layer distributed on the surface thereof, the surface of the nanoscale active layer contains a sheet-shaped nanofold structure, the specific surface area of the catalyst is 125 m² / g, and the surface basic site density is 1.2 mmol / g; the average size of the La2O3 catalyst is 550 nm.

[0071] The La2O3 catalyst of the embodiment is prepared by a sol-gel combined hydrothermal step-by-step assembly method, including three steps of mixing lanthanum nitrate, citric acid and structure-directing agent cetyltrimethylammonium bromide according to a molar ratio of 1:2.2:0.5 to prepare a precursor, hydrothermal treatment and programmed calcination.

[0072] The La2O3 catalyst of the embodiment is prepared by a sol-gel combined hydrothermal step-by-step assembly method:

[0073] A1. Mix lanthanum nitrate and citric acid, and add the structure-directing agent cetyltrimethylammonium bromide, the molar ratio of the three being lanthanum nitrate: citric acid: directing agent = 1:2.2:0.5, add deionized water to a solid content of 20wt% to form a precursor solution, and stir at 70°C for 3 hours to ensure complete dissolution;

[0074] A2. Evaporate under a magnetic stirrer at 100°C to a gel, the stirring rate being controlled at 250rpm, and the evaporation time being 6 hours, and then perform hydrothermal treatment in a high-pressure reaction kettle at 200°C for 18 hours;

[0075] A3. Perform calcination in a muffle furnace at 500°C under an air atmosphere for 4 hours, the temperature rising rate being 3°C / min, to ensure complete formation of the La2O3 crystal phase and development of the sheet-like wrinkle structure.

[0076] The calcination procedure of step A3 of the embodiment includes:

[0077] A31. Organic matter pre-decomposition stage: increase the temperature to 200°C at a rate of 1.5°C / min at room temperature, and keep the temperature for 1.2 hours in a nitrogen atmosphere to prevent structural collapse caused by rapid decomposition of the organic template;

[0078] A32. Increase the temperature to 400°C at a rate of 3°C / min, switch to an air atmosphere and keep the temperature for 2.5 hours to complete the decomposition of the organic template and the preliminary crystallization;

[0079] A33. Continue to increase the temperature to 550°C and keep the temperature for 4 hours to promote complete formation of the La2O3 crystal phase and development of the sheet-like wrinkle structure.

[0080] A method for preparing an intermediate containing an acetyl furan structure, comprising the following steps:

[0081] S1. Mix N-acetyl-D-glucosamine with dioxane to form a reaction system, and ensure that the water content in the reaction system is 0.03wt% through molecular sieve pretreatment and nitrogen protection;

[0082] S2. Add a La2O3 catalyst to perform a catalytic dehydration reaction, the reaction being performed in an inert atmosphere, and a staged temperature control strategy being adopted to optimize the reaction selectivity;

[0083] S3. After the reaction is completed, the intermediate containing acetylfuran structure is obtained by using a multi-step cascade recrystallization process;

[0084] The intermediates of the embodiment are N-3-furyl-acetamide and N-(5-acetyl-3-furyl)-acetamide, the mass fraction of N-3-furyl-acetamide in the product is 74%, the mass fraction of N-(5-acetyl-3-furyl)-acetamide is 23.0%, the content of other trace components is 1.5%, mainly position isomers and partial dehydration intermediates; the impurity content is 1.5%, mainly unreacted raw materials and solvent residues; the total purity of the two target products is 97.0%, and the total purity is 98.5%; the product is in the form of needle-shaped crystal, the average length is 500 μm, and the width is 25.0 μm;

[0085] The structural formula of N-3-furyl-acetamide of the embodiment is:

[0086]

[0087] The structural formula of N-(5-acetyl-3-furyl)-acetamide of the embodiment is:

[0088]

[0089] The structural formula of N-(5-acetyl-3-furyl)-acetamide of the embodiment is:

[0088]

[0089] The catalytic dehydration reaction of S2 step of the embodiment adopts segmented temperature control, including: pre-activation stage: reaction temperature 150°C, reaction time 45 minutes, surface activation of the catalyst and pre-adsorption of the raw materials; main reaction stage: reaction temperature 180°C, time 3 hours, main dehydration and cyclization reaction; perfect stage: reaction temperature 190°C, time 0.8 hours, to ensure that the reaction is completely carried out; the amount of La2O3 catalyst is 20% of the mass of N-acetyl-D-glucosamine, the residual water content in the reaction system is controlled at 0.08wt%, and the reaction is carried out under nitrogen protection, and the pressure is controlled at 0.2 MPa.

[0090] The solvent in S1 step of the embodiment is dioxane.

[0091] The S3 step of the embodiment includes the following multi-step cascade recrystallization process:

[0092] B1. The reaction product is extracted and separated with ethyl acetate and water at a volume ratio of 1:1, the aqueous phase is back-extracted with saturated NaCl solution for 3 times until the organic phase is colorless and transparent, the temperature is controlled at 30°C during the extraction process, and the extraction time is 22 minutes each time;

[0093] B2. The organic phase is concentrated under reduced pressure at 40°C to 2 / 5 of the original volume, and n-hexane is slowly added until the turbidity value of the solution reaches 150 NTU for pre-enrichment recrystallization, and the crude product is precipitated after preliminary purification;

[0094] B3. Temperature gradient recrystallization was performed using a mixture of ethyl acetate / isopropyl alcohol with a volume ratio of 2:1, and high-quality crystals were obtained by precisely controlling the cooling rate;

[0095] B4. The final recrystallization was refined using a mixture of n-hexane / ethyl acetate with a volume ratio of 1.5:1, and the temperature was controlled at 15°C for 30 hours, obtaining a high-purity crystal product, and the purity of the target product reached 98.5%.

[0096] The temperature gradient recrystallization in the B3 step of this embodiment used programmed cooling:

[0097] The first stage was 32°C, the cooling rate was 1.2°C / h, and the solubility adjustment and initial nucleation were mainly completed;

[0098] The second stage was 25°C, the cooling rate was 1.0°C / h, and the crystal nucleus growth rate was controlled;

[0099] The third stage was 15°C, the cooling rate was 0.6°C / h, and the crystal structure was improved;

[0100] The fourth stage was 7°C, the cooling rate was 0.3°C / h, and the crystal quality and yield were ensured, and the constant stirring rate was 100 rpm throughout the process;

[0101] The seed crystal preparation and addition method during the recrystallization process of this embodiment is as follows:

[0102] C1. Seed crystal preparation: The solid product after preliminary purification in the B1-B2 step of the crude product prepared in the S1-S2 step was used as the seed crystal raw material, and was crushed for 50 minutes at a speed of 400 rpm using a ball mill, and was sieved through a 300-mesh sieve, obtaining fine seed particles with an average particle size of 1.2 μm;

[0103] C2. Seed crystal addition: When the temperature in the first stage was stabilized at 35°C, the prepared seed crystals were slowly added at a total solid content of 0.3 wt% in the crystallization solution, and were stirred to ensure uniform dispersion, and after dispersion was completed, the temperature was maintained for 12 minutes to allow the seed crystals to be fully wetted, and then the programmed cooling process was started.

[0104] The La2O3 catalyst of this embodiment can be reused for 5 times, and after each use, it is regenerated according to the following procedure: sequentially washed with ethyl acetate to remove organic residues, deionized water to wash until the washing liquid pH=7.0, vacuum dried at 110°C for 4 hours to remove moisture, and calcined in air at 550°C for 3 hours to restore catalytic activity. After regeneration, the catalytic activity retention rate was 92%, the BET specific surface area retention rate was 91%, and the surface basic site retention rate was 89%.

[0105] The intermediate containing acetylfuran structure in the embodiment is used for preparing a key intermediate of an antitumor drug, an antibiotic or a bioactive molecule as a synthetic precursor in preparation of an amino alcohol compound, a secondary amine compound, a rare amino sugar or a heterocyclic compound.

[0106] Features of Example 1: The embodiment adopts a conservative and stable process parameter configuration, uses a single solvent dioxane, the specific surface area and basic site density of the catalyst are at a medium level (125 m² / g, 1.2 mmol / g), the reaction temperature control is relatively mild (pre-activation 150°C, main reaction 180°C), and the process parameters of the recrystallization process are all selected in the intermediate value range. The process configuration focuses on stability and reproducibility, the product purity reaches 98.5%, the crystal morphology is regular and uniform, and it is suitable for industrial scale-up production. The embodiment is particularly suitable for the scale production of pharmaceutical intermediates, such as the preparation of key intermediates of antibiotic drugs, and the production of generic drug substances that require stable supply chain. In the field of bioactive molecule synthesis, it can be used for the preparation of natural product analogues with furan ring structure and antitumor lead compounds.

[0107] Example 2

[0108] The morphology of the La2O3 catalyst in the embodiment is sub-micron particles and a nanoscale active layer distributed on the surface thereof, the surface of the nanoscale active layer contains a sheet-shaped nanofold structure, the specific surface area of the catalyst is 180 m² / g, and the surface basic site density is 1.4 mmol / g; the average size of the La2O3 catalyst is 380 nm.

[0109] The La2O3 catalyst in the embodiment is prepared by a sol-gel combined hydrothermal step-by-step assembly method, including three steps of mixing lanthanum nitrate, citric acid and structure directing agent cetyltrimethylammonium bromide in a molar ratio of 1:2.4:0.7 to prepare a precursor, hydrothermal treatment and programmed calcination.

[0110] The La2O3 catalyst in the embodiment is prepared by a sol-gel combined hydrothermal step-by-step assembly method:

[0111] A1. Mix lanthanum nitrate and citric acid, and add structure directing agent cetyltrimethylammonium bromide, the molar ratio of the three is lanthanum nitrate: citric acid: directing agent = 1:2.4:0.7, add deionized water to a solid content of 18wt% to form a precursor solution, stir at 75°C for 2.5 hours to ensure complete dissolution;

[0112] A2. Evaporate to a gel under a magnetic stirrer at 90°C, control the stirring rate at 280 rpm, and evaporate for 5 hours, then perform hydrothermal treatment in a high-pressure reaction kettle at 210°C for 15 hours;

[0113] A3. Calcination in a muffle furnace at 520℃ for 3 hours under air atmosphere, with a heating rate of 4℃ / min, to ensure the complete formation of La2O3 crystal phase and the development of sheet-like wrinkle structure.

[0114] The calcination procedure of step A3 of this embodiment comprises:

[0115] A31. Organic matter pre-decomposition stage: heating at a rate of 1.8℃ / min to 200℃ from room temperature, and keeping for 1 hour under nitrogen atmosphere to prevent the structure from collapsing due to the rapid decomposition of the organic template;

[0116] A32. Heating at a rate of 4℃ / min to 420℃, and switching to air atmosphere to keep for 2.2 hours to complete the decomposition of the organic template and the preliminary crystallization;

[0117] A33. Continue to heat to 580℃ and keep for 3.5 hours to promote the complete formation of La2O3 crystal phase and the development of sheet-like wrinkle structure.

[0118] A method for preparing an intermediate containing acetyl furan structure, comprising the following steps:

[0119] S1. Mixing N-acetyl-D-glucosamine with N,N-dimethylformamide and dimethyl sulfoxide at a volume ratio of 2:1 to form a reaction system, and ensuring the water content in the reaction system to be 0.02wt% through molecular sieve pretreatment and nitrogen protection;

[0120] S2. Adding La2O3 catalyst for catalytic dehydration reaction, and performing the reaction under inert atmosphere, and adopting a staged temperature control strategy to optimize the reaction selectivity;

[0121] S3. After the reaction is completed, a multi-step cascade recrystallization process is adopted to obtain the intermediate containing acetyl furan structure;

[0122] The intermediate of this embodiment is N-3-furyl-acetamide and N-(5-acetyl-3-furyl)-acetamide, the mass fraction of N-3-furyl-acetamide in the product is 76%, the mass fraction of N-(5-acetyl-3-furyl)-acetamide is 21.0%, the content of other trace components is 2.2%, mainly N-2-furyl-acetamide isomers and cyclization intermediates; the impurity content is 0.8%, mainly unreacted raw materials and a small amount of inorganic salts; the total purity of the two target products is 97.0%, and the total purity is 99.2%; the product is in the form of needle-like crystal, with an average length of 720μm and a width of 38.0μm;

[0123] The structural formula of N-3-furyl-acetamide of this embodiment is the same as that of Example 1;

[0124] The structural formula of N-(5-acetyl-3-furyl)-acetamide of this embodiment is the same as that of Example 1;

[0125] The catalytic dehydration reaction of S2 step of the present embodiment adopts segmented temperature control, including: pre-activation stage: reaction temperature 145°C, reaction time 50 minutes, to activate the catalyst surface and pre-adsorb the raw material; main reaction stage: reaction temperature 195°C, time 2.5 hours, to carry out the main dehydration and cyclization reaction; perfection stage: reaction temperature 200°C, time 0.6 hours, to ensure the reaction is completed; the amount of La2O3 catalyst is 18% of the mass of N-acetyl-D-glucosamine, the residual water content in the reaction system is controlled at 0.06wt%, and the whole reaction is carried out under nitrogen protection, with the pressure controlled at 0.15 MPa.

[0126] The solvent in S1 step of the present embodiment is a mixture of N,N-dimethylformamide and dimethyl sulfoxide in a volume ratio of 2:1.

[0127] The S3 step of the present embodiment includes the following multi-step cascade recrystallization process:

[0128] B1. The reaction product is extracted and separated with ethyl acetate and water in a volume ratio of 1:1, the aqueous phase is back-extracted with saturated NaCl solution for 2 times until the organic phase is colorless and transparent, and the temperature is controlled at 28°C during the extraction process, with each extraction time being 18 minutes;

[0129] B2. The organic phase is concentrated under reduced pressure at 42°C to 1 / 3 of the original volume, and n-hexane is slowly added until the turbidity value of the solution reaches 120 NTU for pre-enrichment recrystallization, and the preliminary purified crude product is precipitated;

[0130] B3. Temperature gradient recrystallization is carried out using a mixture of ethyl acetate / isopropyl alcohol in a volume ratio of 2.5:1, and high-quality crystals are obtained by precisely controlling the cooling rate;

[0131] B4. Finally, refined recrystallization is carried out using a mixture of n-hexane / ethyl acetate in a volume ratio of 1.8:1, with the temperature controlled at 8°C and the time being 36 hours, to obtain high-purity crystal product, and the purity of the target product reaches 99.2%.

[0132] The temperature gradient recrystallization in B3 step of the present embodiment adopts programmed cooling:

[0133] First stage 33°C, cooling rate 1.4°C / h, mainly to complete the solubility adjustment and initial nucleation;

[0134] Second stage 22°C, cooling rate 0.9°C / h, to control the crystal nucleus growth rate;

[0135] Third stage 12°C, cooling rate 0.7°C / h, to promote the perfection of crystal structure;

[0136] Fourth stage 6℃, cooling rate 0.4℃ / h, ensure crystal quality and yield, constant stirring rate 110 rpm throughout the process;

[0137] The seed crystal preparation and addition method in the recrystallization process of the embodiment is as follows:

[0138] C1. Seed crystal preparation: take the solid product after the crude product prepared in S1-S2 steps of the process is preliminarily purified by B1-B2 steps as seed crystal raw material, treat it by ultrasonic crushing method under the condition of power 180 W for 35 minutes, and sieve it through a 300-mesh sieve to obtain fine seed crystal particles with an average particle size of 0.8 μm;

[0139] C2. Seed crystal addition: when the temperature in the first stage is stabilized at 35℃, slowly add the prepared seed crystal at 0.2 wt% of the total solid content in the crystallization solution, stir to ensure uniform dispersion, maintain the temperature for 14 minutes after dispersion is completed to allow the seed crystal to be fully wetted, and then start the programmed cooling process.

[0140] The La2O3 catalyst of the embodiment can be reused for 6 times, and after each use, it is regenerated according to the following procedure: sequentially wash with ethyl acetate to remove organic residues, deionized water to wash until the washing liquid pH = 6.8, vacuum drying at 110℃ for 4 hours to remove moisture, and calcining in air at 550℃ for 3 hours to restore catalytic activity. After regeneration, the catalytic activity retention rate is 93%, the BET specific surface area retention rate is 92%, and the surface basic site retention rate is 90%.

[0141] The application of the intermediate containing acetylfuran structure in the embodiment in the preparation of amino alcohol compounds, secondary amine compounds, rare amino sugars or heterocyclic compounds, the intermediate is used as a synthetic precursor to prepare a key intermediate for an antitumor drug, an antibiotic or a biologically active molecule.

[0142] Features of Example 2: This embodiment pursues high purity and high selectivity, uses a mixed solvent system (N,N-dimethylformamide and dimethyl sulfoxide at 2:1), the catalyst has high specific surface area and high basic site density (180 m² / g, 1.4 mmol / g), the reaction temperature is relatively high (main reaction 195℃), and the recrystallization process is highly refined. This process achieves the highest product purity of 99.2% and excellent crystal quality, the N-3-furyl-acetamide content reaches 76%, and the crystal length can reach 720 μm. This embodiment is particularly suitable for high-end pharmaceutical fields, such as the precise preparation of innovative drug intermediates, the preparation of key building blocks in chiral drug synthesis, and the preparation of high-purity biologically active natural products. In the field of fine chemicals, it can be used for the preparation of high-value-added functional material precursors and the production of special chemicals.

[0143] Example 3

[0144] The La2O3 catalyst of the embodiment is prepared by a sol-gel combined hydrothermal step-by-step assembly method, including three steps of mixing lanthanum nitrate, citric acid and structure-directing agent cetyltrimethylammonium bromide according to a molar ratio of 1:2.1:0.4 to prepare a precursor, hydrothermal treatment and programmed calcination.

[0145] The La2O3 catalyst of the embodiment is prepared by a sol-gel combined hydrothermal step-by-step assembly method:

[0146] A1. Mix lanthanum nitrate and citric acid, and add structure-directing agent cetyltrimethylammonium bromide, the molar ratio of the three being lanthanum nitrate: citric acid: directing agent = 1:2.1:0.4, add deionized water to a solid content of 22wt% to form a precursor solution, and stir at 65°C for 3.5 hours to ensure complete dissolution;

[0147] A2. Evaporate to a gel under a magnetic stirrer at 110°C, the stirring rate being controlled at 220 rpm, and the evaporation time being 7 hours, and then perform hydrothermal treatment in a high-pressure reaction kettle at 190°C for 22 hours;

[0148] A3. Perform calcination in a muffle furnace at 450°C in an air atmosphere for 5 hours, the temperature rising rate being 2.5°C / min, to ensure complete formation of the La2O3 crystal phase and development of the sheet-like wrinkle structure.

[0149] The calcination procedure of step A3 of the embodiment includes:

[0150] A31. Organic matter pre-decomposition stage: increase the temperature to 200°C at a rate of 1.2°C / min from room temperature, and keep the temperature for 1.4 hours in a nitrogen atmosphere to prevent structural collapse caused by rapid decomposition of the organic template;

[0151] A32. Increase the temperature to 380°C at a rate of 2.5°C / min, switch to an air atmosphere and keep the temperature for 2.8 hours to complete the decomposition of the organic template and the preliminary crystallization;

[0152] A33. Continue to increase the temperature to 520°C and keep the temperature for 5 hours to promote complete formation of the La2O3 crystal phase and development of the sheet-like wrinkle structure.

[0153] A method for preparing an intermediate containing an acetylfuran structure, including the following steps:

[0154] S1. Mix N-acetyl-D-glucosamine and N-methyl-2-pyrrolidone to form a reaction system, and ensure that the water content in the reaction system is 0.04wt% through molecular sieve pretreatment and nitrogen protection;

[0155] S2. Add a La2O3 catalyst to perform a catalytic dehydration reaction, the reaction being performed in an inert atmosphere, and a staged temperature control strategy being adopted to optimize the reaction selectivity;

[0156] S3. After the reaction is completed, the intermediate containing acetylfuran structure is obtained by using a multi-step cascade recrystallization process;

[0157] The intermediates of the embodiment are N-3-furyl-acetamide and N-(5-acetyl-3-furyl)-acetamide, the mass fraction of N-3-furyl-acetamide in the product is 75%, the mass fraction of N-(5-acetyl-3-furyl)-acetamide is 24.0%, and the content of other trace components is 0.5%, mainly including a double-molecule condensation product and a methylation derivative; the impurity content is 0.5%, mainly including catalyst residues and trace moisture; the total purity of the two target products is 99.0%, and the total purity is 99.5%; the product is in the form of needle-shaped crystals, with an average length of 650 μm and a width of 42.0 μm;

[0158] The structural formula of N-3-furyl-acetamide of the embodiment is the same as that of Example 1;

[0159] The structural formula of N-(5-acetyl-3-furyl)-acetamide of the embodiment is the same as that of Example 1;

[0160] The morphology of the La2O3 catalyst of the embodiment is sub-micron particles and a nano-scale active layer distributed on the surface thereof, the surface of the nano-scale active layer contains a sheet-shaped nano-fold structure, the specific surface area of the catalyst is 85 m² / g, and the surface basic site density is 0.9 mmol / g; the average size of the La2O3 catalyst is 720 nm.

[0161] The catalytic dehydration reaction of the S2 step of the embodiment uses segmented temperature control, including: a pre-activation stage: the reaction temperature is 155°C, and the reaction time is 35 minutes, so as to activate the surface of the catalyst and pre-adsorb the raw material; a main reaction stage: the reaction temperature is 170°C, and the time is 3.5 hours, so as to perform the main dehydration and cyclization reaction; a perfecting stage: the reaction temperature is 185°C, and the time is 1 hour, so as to ensure that the reaction is completely performed; the amount of the La2O3 catalyst is 22% of the mass of N-acetyl-D-glucosamine, the residual water content in the reaction system is controlled to be 0.09wt%, and the whole reaction process is performed under nitrogen protection, with the pressure being controlled to be 0.25 MPa.

[0162] The solvent in the S1 step of the embodiment is N-methyl-2-pyrrolidone.

[0163] The S3 step of the embodiment includes the following multi-step cascade recrystallization process:

[0164] B1. The reaction product is extracted and separated with ethyl acetate and water at a volume ratio of 1:1, the aqueous phase is back-extracted with a saturated NaCl solution for 4 times until the organic phase is colorless and transparent, the temperature is controlled to be 32°C during the extraction process, and the extraction time is 25 minutes each time;

[0165] B2. The organic phase is concentrated at 38°C under reduced pressure to 1 / 2 of the original volume, and n-hexane is slowly added until the turbidity value of the solution reaches 180 NTU to perform pre-enrichment recrystallization, and the preliminary purified crude product is precipitated;

[0166] B3. Temperature gradient recrystallization is performed using a mixed solvent of ethyl acetate / isopropyl alcohol at a volume ratio of 1.5:1, and high-quality crystals are obtained by precisely controlling the cooling rate;

[0167] B4. Finally, refined recrystallization is performed using a mixed solvent of n-hexane / ethyl acetate at a volume ratio of 1.2:1, the temperature is controlled at 20°C, and the time is 18 hours, and high-purity crystal product is obtained, and the purity of the target product reaches 97.8%.

[0168] The temperature gradient recrystallization in the B3 step of the present embodiment uses programmed cooling:

[0169] The first stage is 30°C, the cooling rate is 1.1°C / h, and the solubility adjustment and initial nucleation are mainly completed;

[0170] The second stage is 28°C, the cooling rate is 1.1°C / h, and the crystal nucleus growth rate is controlled;

[0171] The third stage is 18°C, the cooling rate is 0.5°C / h, and the crystal structure is improved;

[0172] The fourth stage is 8°C, the cooling rate is 0.2°C / h, and the crystal quality and yield are ensured, and a constant stirring rate of 90 rpm is used throughout the process;

[0173] The seed crystal preparation and addition method in the recrystallization process of the present embodiment is as follows:

[0174] C1. Seed crystal preparation: the crude product prepared in the S1-S2 steps of the process is used as the seed crystal raw material, and the solid product after preliminary purification in the B1-B2 steps is used as the seed crystal raw material, and the ball milling method is used to crush for 55 minutes at a speed of 350 rpm, and the 300 mesh sieve is used to separate, and the average particle size of the fine seed particles is 1.8 μm;

[0175] C2. Seed crystal addition: when the temperature of the first stage is stable at 35°C, the prepared seed crystal is slowly added at a total solid content of 0.4 wt% in the crystallization solution, and the stirring is ensured to be uniform, and after the dispersion is completed, the temperature is maintained for 11 minutes to make the seed crystal fully wet, and then the programmed cooling process is started.

[0176] The La2O3 catalyst of this embodiment can be reused 4 times, and after each use, it is regenerated according to the following procedure: sequentially washed with ethyl acetate to remove organic residues, deionized water to wash until the pH of the washing liquid is 7.2, vacuum drying at 110°C for 4 hours to remove moisture, and calcining in air at 550°C for 3 hours to restore catalytic activity. After regeneration, the catalytic activity retention rate is 91%, the BET specific surface area retention rate is 90%, and the surface basic site retention rate is 88%.

[0177] The intermediate containing an acetylfuran structure in this embodiment is used as a synthetic precursor to prepare key intermediates of antitumor drugs, antibiotics, or biologically active molecules in the preparation of amino alcohol compounds, secondary amine compounds, rare amino sugars, or heterocyclic compounds.

[0178] Features of Example 3: This embodiment uses relatively mild reaction conditions, uses N-methyl-2-pyrrolidone as the solvent, and the catalyst has a relatively low specific surface area but a large particle size (85 m² / g, 720 nm), and the reaction temperature is relatively low (main reaction at 170°C), and the recrystallization time is relatively short. This process produces smaller size crystals (350 μm in length), with a purity of 97.8%, and the process cost is relatively low, making it suitable for applications where the purity requirement is not extremely high but the cost needs to be controlled. This embodiment is particularly suitable for the bulk production of chemical intermediates, such as the preparation of pesticide APIs, the synthesis of dye intermediates, and the preparation of ordinary-grade heterocyclic compounds. In the field of materials science, it can be used to prepare monomers for functional polymers and precursors for organic electronic materials.

[0179] Example 4

[0180] The La2O3 catalyst of this embodiment is prepared by a sol-gel combined hydrothermal step-by-step assembly method, which includes three steps of mixing lanthanum nitrate, citric acid, and structure-directing agent cetyltrimethylammonium bromide in a molar ratio of 1:2.3:0.6 to prepare a precursor, hydrothermal treatment, and programmed calcination.

[0181] The La2O3 catalyst of this embodiment is prepared by a sol-gel combined hydrothermal step-by-step assembly method:

[0182] A1. Mix lanthanum nitrate with citric acid, and add structure-directing agent cetyltrimethylammonium bromide, with a molar ratio of lanthanum nitrate: citric acid: directing agent = 1:2.3:0.6. Add deionized water to a solid content of 16wt% to form a precursor solution, and stir at 78°C for 2.2 hours to ensure complete dissolution;

[0183] A2. Evaporate to a gel under a magnetic stirrer at 95°C, with a stirring rate controlled at 260 rpm, and an evaporation time of 4.5 hours. Then perform hydrothermal treatment in a high-pressure reaction kettle at 205°C for 20 hours;

[0184] A3. Calcination in a muffle furnace at 480℃ for 3.5 hours under air atmosphere, with a heating rate of 4.5℃ / min, to ensure the complete formation of La2O3 crystal phase and the development of sheet-like wrinkle structure.

[0185] The calcination procedure of the A3 step of the present embodiment comprises:

[0186] A31. Organic matter pre-decomposition stage: temperature rise from room temperature to 200℃ at a rate of 1.3℃ / min, and keep for 1.3 hours under nitrogen atmosphere to prevent the structure from collapsing due to the rapid decomposition of the organic template;

[0187] A32. Temperature rise to 430℃ at a rate of 4.5℃ / min, and switch to air atmosphere to keep for 2.4 hours to complete the decomposition of the organic template and the preliminary crystallization;

[0188] A33. Continue to rise to 560℃ and keep for 3.8 hours to promote the complete formation of La2O3 crystal phase and the development of sheet-like wrinkle structure.

[0189] A method for preparing an intermediate containing acetyl furan structure, comprising the following steps:

[0190] S1. Mix N-acetyl-D-glucosamine with dimethylacetamide and dimethyl sulfoxide at a volume ratio of 1:1 to form a reaction system, and ensure the water content in the reaction system to be 0.05wt% through molecular sieve pretreatment and nitrogen protection;

[0191] S2. Add La2O3 catalyst for catalytic dehydration reaction, and the reaction is carried out under inert atmosphere, and a staged temperature control strategy is adopted to optimize the reaction selectivity;

[0192] S3. After the reaction is completed, a multi-step cascade recrystallization process is adopted to obtain the intermediate containing acetyl furan structure;

[0193] The intermediate of the present embodiment is N-3-furyl-acetamide and N-(5-acetyl-3-furyl)-acetamide, the mass fraction of N-3-furyl-acetamide in the product is 75%, the mass fraction of N-(5-acetyl-3-furyl)-acetamide is 24%, the impurity content is 0.5%, mainly unreacted raw materials and a small amount of isomers; the total purity of the two target products is 99.5%; the product is in the form of needle-like crystal, with an average length of 650μm and a width of 42.0μm;

[0194] The structural formula of N-3-furyl-acetamide of the present embodiment is the same as that of Example 1;

[0195] The structural formula of N-(5-acetyl-3-furyl)-acetamide of the present embodiment is the same as that of Example 1;

[0196] The morphology of the La2O3 catalyst of the embodiment is sub-micron particles and a nano-scale active layer distributed on the surface thereof, the surface of the nano-scale active layer contains a sheet-shaped nano-fold structure, the specific surface area of the catalyst is 160 m² / g, and the surface basic site density is 1.3 mmol / g; the average size of the La2O3 catalyst is 420 nm.

[0197] The catalytic dehydration reaction of the S2 step of the embodiment adopts segmented temperature control, including: a pre-activation stage: a reaction temperature of 142°C and a reaction time of 55 minutes, to activate the surface of the catalyst and pre-adsorb the raw material; a main reaction stage: a reaction temperature of 188°C and a reaction time of 2.8 hours, to perform the main dehydration and cyclization reaction; a perfecting stage: a reaction temperature of 198°C and a reaction time of 0.7 hour, to ensure that the reaction is completely performed; the amount of the La2O3 catalyst is 16% of the mass of N-acetyl-D-glucosamine, the residual water content in the reaction system is controlled to be 0.1wt%, and the reaction is performed under nitrogen protection, and the pressure is controlled to be 0.28 MPa.

[0198] The solvent in the S1 step of the embodiment is a mixture of dimethylacetamide and dimethyl sulfoxide in a volume ratio of 1:1.

[0199] The S3 step of the embodiment includes the following multi-step cascade recrystallization process:

[0200] B1. The reaction product is extracted and separated with ethyl acetate and water in a volume ratio of 1:1, the aqueous phase is back-extracted with a saturated NaCl solution for 3 times until the organic phase is colorless and transparent, the temperature is controlled to be 26°C during the extraction process, and the extraction time is 28 minutes each time;

[0201] B2. The organic phase is concentrated under reduced pressure at 44°C to 3 / 8 of the original volume, n-hexane is slowly added until the turbidity value of the solution reaches 160 NTU to perform pre-enrichment recrystallization, and the crude product of the preliminary purification is precipitated;

[0202] B3. Temperature gradient recrystallization is performed by using a mixed solvent of ethyl acetate / isopropyl alcohol in a volume ratio of 1.8:1, and high-quality crystals are obtained by accurately controlling the cooling rate;

[0203] B4. Finally, refined recrystallization is performed by using a mixed solvent of n-hexane / ethyl acetate in a volume ratio of 1.9:1, the temperature is controlled to be 12°C, and the time is 42 hours, to obtain a high-purity crystal product, and the purity of the target product reaches 99.5%.

[0204] The temperature gradient recrystallization in the B3 step of the embodiment adopts programmed cooling:

[0205] The first stage is 34°C, and the cooling rate is 1.3°C / h, mainly to complete the solubility adjustment and initial nucleation;

[0206] Second stage 26℃, cooling rate 0.8℃ / h, control the crystal nucleus growth rate;

[0207] Third stage 14℃, cooling rate 0.8℃ / h, promote the crystal structure perfect;

[0208] Fourth stage 5℃, cooling rate 0.5℃ / h, ensure the crystal quality and yield, the whole process uses constant stirring speed 120 rpm;

[0209] The seed crystal preparation and adding method in the recrystallization process of the embodiment are as follows:

[0210] C1. Seed crystal preparation: take the solid product after the crude product prepared in S1-S2 steps of the process is preliminarily purified in B1-B2 steps as seed crystal raw material, treat it by ultrasonic crushing method under the condition of power 170W for 40 minutes, and pass through a 300-mesh sieve to obtain fine seed crystal particles with an average particle size of 1.5 μm;

[0211] C2. Seed crystal adding: when the temperature in the first stage is stabilized at 35℃, slowly add the prepared seed crystal at 0.5 wt% of the total solid content in the solution to be crystallized, stir to ensure uniform dispersion, maintain the temperature for 13 minutes after dispersion is completed to make the seed crystal fully wet, and then start the programmed cooling process.

[0212] The La2O3 catalyst of the embodiment can be reused for 5 times, and after each use, it is regenerated according to the following procedure: sequentially wash with ethyl acetate to remove organic residues, deionized water to wash until the washing liquid pH=6.9, vacuum drying at 110℃ for 4 hours to remove moisture, and calcining in air at 550℃ for 3 hours to restore the catalytic activity. After regeneration, the catalytic activity retention rate is 94%, the BET specific surface area retention rate is 92%, and the surface basic site retention rate is 90%.

[0213] The application of the intermediate containing acetylfuran structure in the preparation of amino alcohol compounds, secondary amine compounds, rare amino sugars or heterocyclic compounds, the intermediate is used as a synthetic precursor to prepare a key intermediate for synthesizing antitumor drugs, antibiotics or biologically active molecules.

[0214] Example 4: This example optimizes the process efficiency while ensuring high purity. It uses a mixed solvent of dimethylacetamide and dimethyl sulfoxide in equal volumes, a moderate catalyst parameter (160 m² / g, 1.3 mmol / g), relatively strict reaction conditions (pre-activation at 142°C, main reaction at 188°C, pressure at 0.28 MPa), and a longer recrystallization time to ensure product quality. This process achieves a maximum purity of 99.5% and good crystal morphology, making it suitable for applications that require extremely high product quality. This example is particularly suitable for high-end biological and pharmaceutical fields, such as the preparation of linkers for monoclonal antibody conjugate drugs (ADC), the synthesis of key intermediates for cell therapy reagents, and the preparation of high-purity enzyme inhibitors and receptor antagonists. In the field of biotechnology, it can be used to prepare functional molecules for biosensors and core components for diagnostic reagents.

[0215] Comparative Example 1: Similar to Example 1, except that the catalytic dehydration reaction in Step S2 uses a constant temperature control strategy, with the reaction temperature always maintained at 180°C and the reaction time set to 4 hours. There is no pre-activation stage or segmented temperature control in the perfection stage.

[0216] Comparative Example 2: Similar to Example 1, except that in the preparation of the La2O3 catalyst, the molar ratio in Step A1 is adjusted to lanthanum nitrate: citric acid: directing agent = 1:1.5:0.3, with other preparation conditions remaining unchanged.

[0217] Comparative Example 3: Similar to Example 1, except that in Step S1, methanol is used as the solvent instead of dioxane, and the water content in the reaction system is controlled at 0.03wt%.

[0218] Comparative Example 4: Similar to Example 1, except that in the preparation of the La2O3 catalyst, the calcination temperature in Step A3 is adjusted to 350°C, with the calcination time remaining at 4 hours and the heating rate set to 3°C / min.

[0219] Comparative Example 5: Similar to Example 1, except that in Step S2, the amount of La2O3 catalyst is adjusted to 10% of the mass of N-acetyl-D-glucosamine, with other reaction conditions remaining unchanged.

[0220] Comparative Example 6: Similar to Example 1, except that in Step S3, the B3 recrystallization process uses a constant temperature cooling strategy, directly cooling from 35°C to 5°C at a constant rate of 1.5°C / h, without programmed temperature reduction in stages.

[0221] Comparative Example 7: Similar to Example 1, except that in the preparation of the La2O3 catalyst, the hydrothermal treatment temperature in Step A2 is adjusted to 150°C, with the treatment time adjusted to 24 hours.

[0222] Comparative Example 8: Essentially the same as Example 1, except that in the B1 extraction process of S3 step, the volume ratio of ethyl acetate and water was adjusted to 3:1, and the extraction temperature was adjusted to 45°C.

[0223] Comparative Example 9: Essentially the same as Example 1, except that the reaction of S2 step was carried out in an air atmosphere without using nitrogen protection, and other reaction conditions remained unchanged.

[0224] Comparative Example 10: Essentially the same as Example 1, except that in the preparation of La2O3 catalyst, the A1 step did not add a structure-directing agent hexadecyl trimethyl ammonium bromide, but only used lanthanum nitrate and citric acid mixed at a molar ratio of 1:2.2.

[0225] Comparative Example 11: Essentially the same as Example 1, except that in the B2 concentration process of S3 step, the organic phase concentration temperature was adjusted to 60°C, and the concentration was carried out to 1 / 5 of the original volume.

[0226] Comparative Example 12: Essentially the same as Example 1, except that the reaction pressure of S2 step was adjusted to 0.5 MPa, and other reaction conditions remained unchanged.

[0227] Comparative Example 13: Essentially the same as Example 1, except that in the preparation of La2O3 catalyst, the calcination procedure of A3 step was simplified to directly heat from room temperature to 550°C at a rate of 5°C / min and maintain for 4 hours, without staged calcination.

[0228] Comparative Example 14: Essentially the same as Example 1, except that no seed crystal was added in S3 step, and the programmed cooling recrystallization process of B3 was directly carried out.

[0229] Comparative Example 15: Essentially the same as Example 1, except that no molecular sieve pretreatment was carried out in S1 step, and N-acetyl-D-glucosamine was directly mixed with dioxane, and only the water content in the reaction system was controlled at 0.15wt% by nitrogen protection.

[0230] Performance test:

[0231] Chemical purity and component analysis test of acetylfuran structure containing intermediate: The test object is the acetylfuran structure containing intermediate crystal product prepared, and the test purpose is to accurately quantify the content of N-3-furyl-acetamide and N-(5-acetyl-3-furyl)-acetamide and the impurity distribution. The test principle is based on the separation principle of high performance liquid chromatography, and the separation and detection are realized by using the difference of the partition coefficient of different compounds between the stationary phase and the mobile phase. The experimental method adopts Waters ACQUITY UPLC H-Class ultra-high performance liquid chromatography system, equipped with PDA detector, using C18 reversed phase chromatographic column (250 mm x 4.6 mm, 5 μm), mobile phase is acetonitrile-0.1% phosphoric acid aqueous solution gradient elution, flow rate 1.0 mL / min, detection wavelength 254 nm, column temperature 30℃. The sample preparation needs to dissolve 10 mg of intermediate in 1 mL of HPLC grade methanol, ultrasonic for 15 minutes to completely dissolve, then pass through 0.22 μm filter membrane, the injection amount is 20 μL. The key parameters include injection accuracy RSD≤2.0%, detection limit≤0.01%, quantification limit≤0.05%.

[0232] Intermediate crystal morphology and microstructure characterization test: The test object is the acetylfuran structure containing intermediate needle-shaped crystal, and the test purpose is to characterize the morphology, size distribution and surface microstructure of the crystal. The test principle is based on the principle of secondary electron imaging produced by the interaction of electron beam and sample in scanning electron microscope, combined with energy spectrum analysis for element distribution detection. The experimental method adopts JEOL JSM-7800F field emission scanning electron microscope, the acceleration voltage is adjustable between 1-30 kV, and the resolution reaches 1.0 nm @ 15 kV. The sample preparation needs to disperse the intermediate crystal on the conductive tape, avoid agglomeration, and gold plating treatment for 60 seconds under vacuum condition, the plating layer thickness is about 10 nm. Use different magnifications (500x, 2000x, 10000x) to observe the overall morphology and surface details of the crystal, and measure the length and width data of at least 100 crystal particles. The key parameters include sample chamber vacuum degree , working distance 8-15 mm, electron beam current is moderate to avoid sample damage.

[0233] Thermal stability and thermal decomposition behavior test of intermediates: The test object is an acetylfuran structure-containing intermediate powder sample, and the test purpose is to evaluate the thermal stability, decomposition temperature and thermal decomposition kinetics parameters of the material at different temperatures. The test principle is based on thermogravimetric analysis method, which continuously monitors the mass change of the sample during programmed temperature process by precision balance, combined with differential scanning calorimetry to detect the heat flow change simultaneously. The experimental method uses TA Instruments SDT Q600 simultaneous thermal analyzer, nitrogen protective atmosphere, flow rate 100 mL / min, heating rate 10 ℃ / min, temperature range room temperature to 600 ℃. The sample preparation needs to take 5-10 mg of intermediate and place it in an aluminum crucible, ensuring that the sample is evenly spread and avoiding stacking to affect heat transfer. Record the TG curve, DTG curve and DSC curve during the test, and analyze the initial decomposition temperature (Ti), maximum decomposition rate temperature (Tmax) and termination decomposition temperature (Tf). Key parameters include balance accuracy ±0.1 μg, temperature control accuracy ±1 ℃, and good furnace body sealing to prevent oxygen from entering. Data processing calculates the decomposition kinetics parameters including activation energy Ea and frequency factor A by TA Universal Analysis software, to evaluate the thermal stability of the material under synthesis and storage conditions.

[0234] Solubility and stability test of intermediates in different solvents

[0235] The test object is an acetylfuran structure-containing intermediate crystal, and the test purpose is to systematically evaluate the solubility, dissolution rate and chemical stability of the material in common organic solvents. The test principle is based on the principle of solubility equilibrium and ultraviolet-visible spectrophotometry quantitative analysis, which evaluates the dissolution behavior and stability by monitoring the concentration change of the solution. The experimental method selects 6 kinds of representative solvents such as methanol, ethanol, ethyl acetate, dichloromethane, N,N-dimethylformamide and dimethyl sulfoxide, and carries out saturated solubility test under constant temperature condition of 25 ℃±0.1 ℃. The sample preparation needs to take excess intermediate (about 50 mg) and add it into 10 mL of various solvents, magnetically stir for 24 hours to reach solubility equilibrium, filter the supernatant, dilute and detect the concentration at 254 nm wavelength by ultraviolet spectrophotometer. At the same time, the stability is investigated, and the saturated solution is stored at 25 ℃ and 40 ℃ respectively, and the concentration and purity change are analyzed regularly. The standard is based on OECD Test Guideline 105 "Water Solubility" and ICH Q1A(R2) "Guideline on Stability Testing". Key parameters include temperature control accuracy ±0.1 ℃, UV detector wavelength accuracy ±0.5 nm, and sample storage in the dark to prevent decomposition. Data processing calculates the saturated solubility in each solvent by standard curve method, establishes the relationship between solubility parameters and solvent polarity, and evaluates the applicability of the material under different reaction and purification conditions.

[0236] Surface properties and catalytic activity characterization test of La2O3 catalyst: The test object is the prepared La2O3 catalyst sample, and the test purpose is to characterize the specific surface area, pore size distribution, surface basic site density and catalytic activity of the catalyst. The test principle is based on the theory of gas physical adsorption, and the surface area and pore structure of the porous material are analyzed by N2 adsorption-desorption isotherm, and the surface basic site is determined by combining CO2 temperature programmed desorption. The experimental method adopts Micromeritics ASAP 2020 M+C physical and chemical adsorption analyzer to test the BET specific surface area, the sample pretreatment needs to be degassed at 300°C under vacuum condition for 4 hours, the N2 adsorption test is carried out under liquid nitrogen temperature, and the relative pressure range is 0.05-0.99. The surface basic site is determined by AutoChem II 2920 chemical adsorption instrument, and the CO2 temperature programmed desorption (CO2-TPD) condition is He carrier gas 50mL / min, temperature rising rate 10°C / min, temperature range 50-800°C. The catalytic activity is tested by simulating the dehydration reaction in a fixed bed reactor, the reaction temperature is 180°C, the N2 atmosphere, and the catalyst dosage is 20wt%. The standard is referred to GB / T 19587-2017 "Gas adsorption BET method for determining the specific surface area of solid substances", and the key parameters include degassing temperature 300°C to avoid structure damage, adsorption equilibrium time≥180s to ensure accuracy, and TPD temperature rising rate constant to ensure reproducibility. The data processing is calculated by BET equation, BJH model is used to analyze the pore size distribution, CO2-TPD integral area is used to calculate the basic site density, and the relationship between the structure and activity of the catalyst is verified.

[0237] The performance of the intermediates in Examples 1-4 and Comparative Examples 1-15 is summarized in Table 1. The constant temperature control strategy in Comparative Example 1 instead of the segmented temperature control resulted in insufficient catalyst activation and decreased reaction selectivity, leading to obvious deterioration in product purity and crystal morphology quality. The reduction of citric acid ratio in Comparative Example 2 destroyed the complex stability of the catalyst precursor, directly affecting the formation of the specific surface area and basic site density of the catalyst, and then reducing the catalytic activity and product quality. The use of methanol instead of dioxane as the solvent in Comparative Example 3 interfered with the selectivity mechanism of the dehydration reaction due to the strong polarity and active hydrogen characteristics of methanol, increasing the probability of side reactions. Although the solubility of the product was improved, the purity and thermal stability were significantly reduced. The low-temperature calcination strategy in Comparative Example 4 could not provide sufficient thermodynamic driving force to complete the formation of La2O3 crystal phase and the development of active structure, resulting in a sharp decrease in the specific surface area of the catalyst and a significant deterioration in thermal stability. The reduction of catalyst dosage in Comparative Example 5 directly limited the conversion efficiency of the reaction, and the residue of unreacted raw materials increased the impurity content and inhibited the normal growth process of the crystal. The constant temperature cooling recrystallization strategy in Comparative Example 6 destroyed the precise control mechanism of crystal nucleation and growth, although the purity was relatively small, but it significantly affected the size distribution and morphology quality of the crystal. The low-temperature hydrothermal treatment in Comparative Example 7 could not provide sufficient energy conditions for the microstructure assembly of the catalyst, causing uneven distribution of active sites and a decrease in overall catalytic performance. Changing the extraction phase ratio in Comparative Example 8 destroyed the optimization balance of impurity removal, affecting the effect of the subsequent recrystallization process and the purity of the final product. The reaction in air atmosphere in Comparative Example 9 introduced oxygen oxidation to the catalyst and product, not only causing partial deactivation of the catalyst but also promoting the oxidative degradation of the product, resulting in deterioration of both purity and thermal stability. The removal of the structure-directing agent in Comparative Example 10 eliminated the template effect of the catalyst ordered structure formation, leading to disordering of the catalyst microstructure and a significant decrease in specific surface area and basic site density. The high-temperature concentration process in Comparative Example 11 may trigger thermal decomposition reactions of the product, affecting not only the stability of the product but also the normal growth mechanism of the crystal. The high-pressure reaction conditions in Comparative Example 12 changed the thermodynamic and kinetic balance of the reaction system, which may promote undesirable side reaction pathways, affecting the selectivity and purity of the product. The simplified calcination procedure in Comparative Example 13 resulted in rapid decomposition of the organic template and collapse of the catalyst structure, severely damaging the microstructure integrity and effectiveness of the active sites of the catalyst. The lack of seed addition in Comparative Example 14 eliminated the guiding mechanism of crystal nucleation, although it had little effect on chemical purity, but it significantly affected the size control and morphology regularity of the crystal. Omitting the molecular sieve pretreatment step in Comparative Example 15 resulted in excessive water content in the reaction system, which caused the most severe performance deterioration due to the strong competitive adsorption of water molecules on the catalyst active sites and the inhibition of the dehydration reaction. Not only was the purity reduced to the lowest level, but the thermal stability also decreased significantly.

[0238] Table 2 Performance summary of examples 1~4 and comparative examples 1~15

[0239]

[0240] Figure 1 The La2O3 catalyst prepared in example 2 exhibits a typical nanosheet wrinkled structure, and the specific surface area reaches 180 m² / g, while Figure 4 and Figure 5 The catalysts of comparative example 10 and comparative example 2 in the above respectively exhibit no nanowrinkles, which proves that the absence of cetyltrimethylammonium bromide directing agent or the lower content of citric acid plays a key role in the formation of ordered nanostructure. Figure 2 The XRD phase analysis of the above confirms that the catalyst of example 2 has a complete La2O3 crystal structure and good crystallinity, which provides a structural basis for efficient catalysis. More importantly, Figure 3 The intermediate product of example 2 exhibits a regular needle-like crystal morphology, while Figure 6 and Figure 7 The intermediates of the comparative examples in the above respectively exhibit irregular lump shape and fine particle shape, and the crystal morphology is quite different, which directly reflects the decisive influence of the performance of different catalysts on the quality of the product. Figure 8 The full sample performance comparison data of the above further confirms that the total purity of all examples is in the range of 97.8-99.5%, and the impurity content is controlled in the range of 0.5-2.2%, while the total purity of 15 comparative examples is only 88.2-96.8%, and the impurity content is as high as 3.2-11.8%, and the lowest purity (97.8%) of the examples still significantly exceeds the highest purity (96.8%) of the comparative examples, which fully verifies that the systematic innovation of the key technical links such as catalyst preparation, reaction control and crystallization process in the present application realizes the fundamental improvement of the product quality.

[0241] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application, but not to limit it, although the present application has been described in detail with reference to the above examples, those skilled in the art should understand that: any equivalent structural transformation made under the concept of the present application, using the contents of the present application specification and drawings, should be covered within the protection scope of the claims of the present application.

Claims

1. A method for preparing an intermediate containing an acetylfuran structure, characterized by, The method comprises the following steps: S1. mixing N-acetyl-D-glucosamine with a solvent to form a reaction system, and ensuring that the water content in the reaction system is less than or equal to 0.05wt% through molecular sieve pretreatment and nitrogen protection; S2. adding The catalyst is used for catalytic dehydration reaction, and the reaction is carried out under inert atmosphere, and the reaction selectivity is optimized by adopting a staged temperature control strategy. S3. after the reaction is completed, an intermediate containing an acetylfuran structure is obtained through a multi-step cascade recrystallization process; the intermediate is N-3-furyl-acetamide and N-(5-acetyl-3-furyl)-acetamide, the mass fraction of N-3-furyl-acetamide in the product is 72-76%, the mass fraction of N-(5-acetyl-3-furyl)-acetamide is 21-25%, the total purity is 97.8-99.5%, the total purity of the two target products is 97.0-99.0%, and the product is in the form of needle-shaped crystals with an average length of 250-800μm and a width of 10.0-45.5μm; the structural formula of the N-3-furyl-acetamide is as follows: the structural formula of the N-(5-acetyl-3-furyl)-acetamide is as follows: The The morphology of the catalyst is sub-micron particles and a nanometer active layer distributed on the surface thereof, the surface of the nanometer active layer contains a sheet-shaped nano-fold structure, the specific surface area of the catalyst is 50-200 m² / g, and the density of surface basic sites is 0.8-1.5 mmol / g. The average size of the catalyst is 350-800 nm. The The catalyst is prepared by a sol-gel combined hydrothermal step-by-step assembly method, which comprises three steps of mixing lanthanum nitrate, citric acid and structure-directing agent cetyltrimethylammonium bromide in a molar ratio of 1:(2.0-2.5):(0.3-0.8) to prepare a precursor, hydrothermal treatment and programmed calcination. The The catalyst was prepared by a sol-gel combined hydrothermal stepwise assembly method: A1. mixing lanthanum nitrate with citric acid, and simultaneously adding a structure directing agent hexadecyl trimethyl ammonium bromide, the molar ratio of the three being lanthanum nitrate: citric acid: directing agent = 1: 2.0-2.5: 0.3-0.8, adding deionized water to a solid content of 15-25wt% to form a precursor solution, and stirring at 60-80°C for 2-4 hours to ensure complete dissolution; A2. stirring and evaporating under a magnetic stirrer at 80-120°C until a gel is formed, the stirring rate being controlled at 200-300 rpm, and the evaporation time being 4-8 hours, and then performing hydrothermal treatment in a high-pressure reaction kettle at 180-220°C for 12-24 hours; A3. Calcination in a muffle furnace in air atmosphere at 400-600°C for 2-6 hours, with a temperature increase rate of 2-5°C / min, ensuring crystal phase complete formation and development of the lamellar fold structure; the calcination procedure of the A3 step comprises: A31. organic matter pre-decomposition stage: warming at 1-2°C / min to 200°C from room temperature, and keeping at 200°C for 1-1.5 hours in a nitrogen atmosphere to prevent structure collapse caused by rapid decomposition of the organic template agent; A32. warming at 2-5°C / min to 350-450°C, switching to an air atmosphere, and keeping at 350-450°C for 2-3 hours to complete the decomposition of the organic template agent and initial crystallization; A33. Continue to warm up to 500-600°C and keep warm for 2-6 hours, to promote crystal phase is fully formed and the development of sheet-like fold structure; the S3 step comprises the following multi-step cascade recrystallization process: B1. extracting and separating the reaction product with ethyl acetate and water at a volume ratio of 1:1, back-extracting the aqueous phase with a saturated NaCl solution for 2-4 times until the organic phase is colorless and transparent, the temperature being controlled at 25-35°C during the extraction process, and the extraction time being 15-30 minutes each time; B2. concentrating the organic phase at 35-45°C under reduced pressure to 1 / 3-1 / 2 of the original volume, slowly adding n-hexane to perform pre-enrichment recrystallization when the turbidity value of the solution reaches 100-200 NTU to precipitate the crude product purified initially; B3. performing temperature gradient recrystallization with ethyl acetate / isopropyl alcohol mixed solvents at a volume ratio of 3:1-1:1 to obtain high-quality crystals by precisely controlling the cooling rate; B4. finally, performing refinement recrystallization with n-hexane / ethyl acetate mixed solvents at a volume ratio of 1:1-2:1, the temperature being controlled at 5-25°C, and the time being 12-48 hours to obtain a high-purity crystal product, the purity of the target product reaching 97-99.5%; The temperature gradient recrystallization in the B3 step adopts programmed cooling: First stage 35-30℃, cooling rate 1.0-1.5℃ / h, mainly to adjust the solubility and initial nucleation; Second stage 30-20℃, cooling rate 0.8-1.2℃ / h, to control the crystal nucleus growth rate; Third stage 20-10℃, cooling rate 0.5-0.8℃ / h, to promote the perfection of crystal structure; Fourth stage 10-5℃, cooling rate 0.2-0.5℃ / h, to ensure the crystal quality and yield, constant stirring rate 80-120 rpm throughout the process.

2. The method for preparing an intermediate containing an acetylfuran structure as described in claim 1, characterized in that, The catalytic dehydration reaction of the S2 step adopts segmented temperature control, including: pre-activation stage: reaction temperature 140-160℃, reaction time 30-60 minutes, surface activation of the catalyst and pre-adsorption of the raw material; main reaction stage: reaction temperature 160-200℃, time 2-4 hours, main dehydration and cyclization reaction; perfecting stage: reaction temperature 180-200℃, time 0.5-1 hour, ensuring complete reaction; The catalyst dosage is 15-25% of the mass of N-acetyl-D-glucosamine, the residual water content in the reaction system is controlled to be ≤0.1wt%, and the whole reaction is carried out under nitrogen protection, and the pressure is controlled to be 0.1-0.3 MPa.

3. The method of claim 1, wherein the intermediate compound having an acetylfuran structure is prepared by the reaction of a compound having a structure of ###00006### with a compound having a structure of ###00007### in the presence of a base. The solvent in the S1 step is one or a mixture of several of dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone or dimethylacetamide.

4. The method of claim 1, wherein the intermediate compound having an acetylfuran structure is prepared by the reaction of a compound having a structure of ###00006### with a compound having a structure of ###00007### in the presence of a base. The seed crystal preparation and addition method in the recrystallization process is as follows: C1. Seed crystal preparation: take the crude product prepared in the S1-S2 steps of the process, and the solid product after preliminary purification in the B1-B2 steps as seed crystal raw material, adopt ball milling method under the condition of rotation speed 300-500 rpm for 45-60 minutes, or adopt ultrasonic crushing method under the condition of power 150-200W for 30-45 minutes, pass through 300 mesh sieve, to obtain fine seed crystal particles with average particle size 0.5-2.0 μm; C2. Seed crystal addition: when the temperature in the first stage is stable at 35℃, slowly add the prepared seed crystal according to 0.1-0.5 wt% of the total solid content in the crystallization solution, stir to ensure uniform dispersion, maintain the temperature for 10-15 minutes after dispersion to ensure the seed crystal is fully wetted, and then start the programmed cooling process.

5. The method for preparing an intermediate containing an acetylfuran structure as described in claim 1, characterized in that, The The catalyst can be reused 4-6 times, and after each use, it is regenerated by the following procedure: sequentially washed with ethyl acetate to remove organic residues, deionized water to wash until the pH of the washing liquid is 6.5-7.5, vacuum drying at 110°C for 4 hours to remove moisture, and calcining in air at 550°C for 3 hours to restore catalytic activity. After regeneration, the retention rate of catalytic activity is ≥90%, the retention rate of BET specific surface area is ≥90%, and the retention rate of surface basic sites is ≥88%.

6. The use of the intermediate containing acetylfuran structure prepared by the method of any one of claims 1-5 in the preparation of aminooalcohols, secondary amine compounds, rare amino sugars or heterocyclic compounds; The intermediate is used as a synthesis precursor to prepare key intermediates of antitumor drugs, antibiotics or biologically active molecules.

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