A method for preparing and purifying medical-grade piperitone
By using CuxBy/SiO2 catalyst to catalyze the dehydrogenation cyclization of diethylene glycol and combining it with cooling crystallization and melt crystallization techniques, the problems of catalyst stability and purification efficiency in the preparation of high-purity PDO were solved, and the preparation of high-purity PDO was achieved, which is suitable for medical-grade materials.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- BEIJING INSTITUTE OF PETROCHEMICAL TECHNOLOGY
- Filing Date
- 2026-02-10
- Publication Date
- 2026-06-05
AI Technical Summary
Existing technologies for preparing high-purity p-dioxanone (PDO) suffer from problems such as poor catalyst stability, numerous byproducts, low purification efficiency, and high solvent consumption, making it difficult to meet the quality requirements of medical-grade PDO.
The dehydrogenation cyclization reaction of diethylene glycol was catalyzed by CuxBy/SiO2 catalyst, and separation and purification were carried out by combining cooling crystallization and melt crystallization techniques to reduce the acidity of the catalyst surface, improve product selectivity, and improve purity through cyclic crystallization.
It has achieved the preparation of high-purity (above 99.99%) PDO, simplified the process, reduced solvent use, lowered energy consumption, has strong adaptability, and meets the requirements of medical-grade purity.
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Figure CN122145428A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of catalytic synthesis and separation and purification technology in organic chemical engineering, specifically to a method for obtaining high-purity p-dioxanone by using CuB / SiO2 to catalyze the dehydrogenation of diethylene glycol and then separating and purifying it. Background Technology
[0002] Poly(p-dioxanone) (PPDO) is a medical material with good biocompatibility, bioabsorbability, and biodegradability. Due to the unique ether bonds in its molecular chain, PPDO has excellent flexibility and tensile strength, making it an ideal material for manufacturing absorbable surgical sutures. It is widely used in biodegradable medical products such as vascular ligation clips, orthopedic repair materials, and human scaffolds.
[0003] High-purity p-dioxanone (PDO) is the monomer for synthesizing medical-grade PPDO, but its high production cost severely restricts the large-scale application of PPDO in the pharmaceutical and healthcare fields. Therefore, developing a low-cost preparation technology for medical-grade PDO has become an urgent problem to be solved. Among them, the copper-catalyzed dehydrogenation cyclization of diethylene glycol to prepare PDO is a promising technical route for industrial application.
[0004] Regarding the catalytic dehydrogenation of diethylene glycol to PDO, patent US5310945 discloses data on the catalytic dehydrogenation of diethylene glycol to PDO using Cu-Zn / Al2O3 at 350℃. However, the product contains a large amount of acid catalytic byproducts such as 1,4-dioxane, ethylene glycol, and acetic acid. Patent CN 1325162C proposes modifying the Cu-Zn / Al2O3 catalyst with alkali metals, alkaline earth metals, and rare earth oxides to reduce diethylene glycol hydrolysis and PDO polymerization initiated by acidic sites on the catalyst surface, achieving an initial PDO selectivity of over 99%. However, after long-term operation, the structural stability of the catalyst deteriorates, and the acid catalytic byproducts increase accordingly. Patent CN112473675A proposes using neutral SiO2 to replace the acidic Al2O3 support to prepare a Cu / SiO2 catalyst and introducing basic sodium oxide on its surface to reduce acid catalytic byproducts, achieving a PDO selectivity of 95%. However, under the reaction conditions, the loss of sodium and the accumulation of copper on the catalyst surface lead to low catalyst structural stability. Patent CN118904339B further employs alkoxysilane to hydrophobize the surface of Cu / SiO2 catalyst and improves PDO selectivity to 98%, but the catalyst modification process is cumbersome and uses a large amount of organic solvents, which is not conducive to industrial production.
[0005] Regarding the separation and purification of diethylene glycol dehydrogenation cyclization products to prepare high-purity PDO, patents KR100301218B1 and KR1020060031046A propose methods for separating PDO using isopropanol and mixed solvents of isopropanol and C5-C7 saturated alkanes, respectively. After purification, the PDO purity exceeds 99.9%, but multiple recrystallizations are required, resulting in high solvent consumption and low purification efficiency. Patent KR100761001B1 provides a method for purifying PDO using multi-level layer melt crystallization, which is simple and produces a product purity as high as 99.99%. However, it requires a PDO mass fraction of at least 90% in the raw material, high selectivity and yield requirements for diethylene glycol dehydrogenation cyclization products, and a narrow range of compatible catalytic reaction systems. Patent KR100675964B1 further combines solution crystallization-melt crystallization-vacuum distillation technology to obtain high-purity PDO, but this method has drawbacks such as introducing organic solvents, a long process flow, and high operational difficulty. Patent CN119707911A reports a method for purifying PDO by extraction-crystallization coupled with gas stripping, achieving a product purity of 99.9%. However, this method also requires the introduction of organic solvents and is cumbersome. Patents CN119841801A and CN119841802A disclose methods for purifying PDO by vacuum distillation coupled with solution crystallization and vacuum distillation coupled with melt crystallization, respectively. However, the azeotropic reaction between PDO and residual diethylene glycol results in low separation efficiency and high energy consumption during the distillation process, and solution crystallization requires the introduction of additional organic solvents.
[0006] To address the shortcomings of existing high-purity PDO preparation technologies, this invention aims to provide a novel method for PDO preparation and purification. This method features a stable reaction process, high product selectivity, simple product separation and purification, and high purity, meeting the quality requirements for medical-grade PDO. Summary of the Invention
[0007] To address the aforementioned problems, a first aspect of the present invention provides a method for producing medical-grade p-dioxanone, comprising using Cu x B y The SiO2 catalyst catalyzes the dehydrogenation cyclization reaction of diethylene glycol to produce a product containing p-dioxanone. The product is then separated and purified to obtain high-purity p-dioxanone. Here, x represents the mass fraction of Cu in the total mass of the catalyst, which is 10 wt%-40 wt%, and y represents the mass fraction of B in the total mass of the catalyst, which is 0.1 wt%-5 wt%. The separation and purification includes a cooling crystallization step and a melt crystallization step.
[0008] By using Cu x B yThe SiO2 catalyst catalyzes the dehydrogenation cyclization of diethylene glycol to produce p-dioxanone, exhibiting high product selectivity and resulting in a relatively high concentration of p-dioxanone in the product. Furthermore, compared to conventional solvent crystallization purification methods, which often require complex equipment such as distillation and rectification, involve multiple processes, and necessitate the use of additional solvents, and generate azeotropic products during purification, leading to significant material waste, this method offers a more robust separation and purification process. This method combines cooling crystallization and melt crystallization, making it highly adaptable to different raw materials. It requires only that the mass fraction of p-dioxanone in the diethylene glycol catalytic dehydrogenation cyclization product be no less than 60 wt%, and it can achieve a purity of over 99.99 wt%, meeting medical-grade purity requirements. The entire reaction and purification process is shown in the attached figure. Figure 1 As shown.
[0009] In some preferred embodiments, x is 20 wt%-30 wt%; y is 1 wt%-2 wt%.
[0010] In some embodiments, the diethylene glycol dehydrogenation cyclization reaction includes: mixing a diethylene glycol feedstock with a hydrogen-containing gas and passing it through a Cu-filled container. x B y The reaction is carried out in a fixed-bed reactor with SiO2 catalyst.
[0011] In some embodiments, the reaction temperature of the diethylene glycol dehydrogenation cyclization reaction is 200-350°C, and the liquid hourly space velocity of the diethylene glycol feedstock is 0.1-5 h⁻¹. -1 The hydrogen-containing gas is hydrogen or a mixture of hydrogen and an inert gas, wherein the partial pressure of hydrogen is 0.01-0.5 MPa.
[0012] In some preferred embodiments, the reaction temperature of the diethylene glycol dehydrogenation cyclization reaction is 240-260°C, and the liquid hourly space velocity of the diethylene glycol feedstock is 0.5-1 h⁻¹. -1 The partial pressure of hydrogen is 0.05-0.1 MPa.
[0013] In some embodiments, the product contains a mass fraction of p-dioxanone greater than 60 wt%.
[0014] In some embodiments, the product contains a mass fraction of p-dioxanone greater than 80 wt%.
[0015] In some embodiments, the cooling crystallization is performed by cooling and filtration, without the need to add a solvent.
[0016] In some embodiments, the cooling temperature for the cooling crystallization is -10°C to 20°C.
[0017] In some preferred embodiments, the cooling temperature for the cooling crystallization is 5°C to 15°C.
[0018] In some embodiments, the product obtained from the cooling crystallization step contains more than 90 wt% p-dioxanone.
[0019] In some preferred embodiments, the product obtained from the cooling crystallization step contains more than 95 wt% p-dioxanone.
[0020] In some embodiments, the melt crystallization step may be repeated 1-4 times.
[0021] In some preferred embodiments, the melt crystallization employs one or both of layer melt crystallization and suspension melt crystallization.
[0022] In some preferred embodiments, the melt crystallization is performed using layer melt crystallization.
[0023] In some embodiments, the melt crystallization includes the following steps: (1) Crystallization: Add p-dioxanone crystals as seed crystals to the crude p-dioxanone mother liquor, cool down to crystallize, and filter to obtain p-dioxanone crystal A; (2) Sweating: The p-dioxanone crystal A is heated to induce sweating, and the mixture after sweating is filtered again to obtain p-dioxanone crystal B. The p-dioxanone crystal B is heated to melt. (3) Cycle: Use the product obtained in step (2) as raw material and repeat the operations of step (1) and step (2).
[0024] The cycle can be repeated multiple times until the purity of p-dioxanone exceeds 99.99 wt%.
[0025] In some preferred embodiments, in step (1), the purity of the p-dioxanone crystals added as seed crystals is not less than 99.9%; the temperature of the mother liquor when the seed crystals are added is 15-35℃; the amount of seed crystals added is 0.01 wt%-1 wt% of the crude p-dioxanone mother liquor; the cooling rate of the crystallization process is 0.01-5℃ / min, and the target temperature is 0-20℃; In step (2), the heating rate of the sweating process is 0.01-5℃ / min, and the target temperature is 15-35℃; the heating rate of the melting process is 0.1-10℃ / min, and the target temperature is 35-45℃.
[0026] In some preferred embodiments, in step (1), the purity of the p-dioxanone crystals added as seed crystals is not less than 99.99%; the temperature of the mother liquor when the seed crystals are added is 20-25°C; the amount of seed crystals added is 0.05 wt%-0.1 wt% of the crude p-dioxanone mother liquor; the cooling rate of the crystallization process is 0.1-1°C / min, and the target temperature is 10-15°C; In step (2), the heating rate of the sweating process is 0.1-1℃ / min, and the target temperature is 20-30℃; the heating rate of the melting process is 0.5℃ / min, and the target temperature is 35-40℃.
[0027] This invention modifies a traditional Cu / SiO2 catalyst using B to reduce the acidity of the catalyst surface, promote the dispersion of active Cu species, and thus reduce Cu content. x B y The formation of acid-catalyzed byproducts in the SiO2-catalyzed diethylene glycol dehydrogenation cyclization reaction is reduced, improving the selectivity for dioxane and the structural stability and lifespan of the catalyst.
[0028] In this invention, a medium-to-high concentration of p-dioxanone is obtained by catalytic reaction using a suitable catalyst. The raw material is then separated and purified using coupled cooling crystallization and melt crystallization techniques. No additional processing or solvents are required, and the material exhibits high tolerance, yielding medical-grade p-dioxanone with a purity exceeding 99.99%. This method offers high product purity and yield, is simple in process, has low energy consumption, and requires no additional solvents, demonstrating promising prospects for industrialization.
[0029] By adapting the diethylene glycol dehydrogenation cyclization reaction system with medium to high product yields to the separation and purification method of this invention, the reaction products do not require additional processing, while the filtrate is recovered to improve the overall product yield. Attached Figure Description
[0030] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the following detailed description to explain the invention, but do not constitute a limitation thereof.
[0031] Figure 1 This is a schematic diagram of the separation and purification process of dioxane; Figure 2A This is a gas chromatogram of the product of diethylene glycol after catalytic dehydrogenation in Example 14; Figure 2B This is a gas chromatogram of the product of diethylene glycol after catalytic dehydrogenation in Example 14, after cooling and crystallization. Figure 2C-2EThe gas chromatograms of the product of diethylene glycol after catalytic dehydrogenation in Example 14, after cooling and crystallization, and then after one, two, or three melt crystallizations. Detailed Implementation
[0032] A first aspect of the present invention provides a method for producing medical-grade p-dioxanone, comprising using Cu x B y The SiO2 catalyst catalyzes the dehydrogenation cyclization reaction of diethylene glycol to produce a product containing p-dioxanone. The product is then separated and purified to obtain high-purity p-dioxanone. Here, x represents the mass fraction of Cu in the total mass of the catalyst, which is 10 wt%-40 wt%, and y represents the mass fraction of B in the total mass of the catalyst, which is 0.1 wt%-5 wt%. The separation and purification includes a cooling crystallization step and a melt crystallization step.
[0033] The traditional Cu / SiO2 catalyst used for the dehydrogenation cyclization reaction of diethylene glycol was modified by using B to reduce the acidity of the catalyst surface, promote the dispersion of active Cu species, thereby reducing the formation of acid catalytic byproducts in the CuB / SiO2 catalytic dehydrogenation cyclization reaction of diethylene glycol, improving the selectivity for dioxane, as well as the structural stability and service life of the catalyst.
[0034] Furthermore, compared to conventional solvent crystallization purification methods, which often require distillation and rectification equipment, are more complex, involve multiple processes, and require additional solvents, and generate azeotropic products during purification, resulting in significant material waste, simple melt crystallization requires high purity raw materials. The separation and purification process of this invention combines cooling crystallization and melt crystallization. This method is highly adaptable to different raw materials; it can be used as long as the mass fraction of p-dioxanone in the diethylene glycol catalytic dehydrogenation cyclization product raw material is not less than 60 wt%, and it can achieve a purity of over 99.99 wt% for p-dioxanone, meeting medical-grade purity requirements.
[0035] In some preferred embodiments, x is 20 wt%-30 wt%; y is 1 wt%-2 wt%.
[0036] Further control of the Cu and B content in the catalyst can better improve the catalyst's activity and selectivity for the product.
[0037] In some embodiments, the diethylene glycol dehydrogenation cyclization reaction includes: mixing a diethylene glycol feedstock with a hydrogen-containing gas and passing it through a Cu-filled container. x B y The reaction is carried out in a fixed-bed reactor with SiO2 catalyst.
[0038] Using a fixed-bed reaction process can promote thorough mixing of raw materials and sufficient contact between the catalyst and the reactants, while maintaining a certain contact time, which can ensure the conversion rate of the reaction.
[0039] In some embodiments, the reaction temperature of the diethylene glycol dehydrogenation cyclization reaction is 200-350°C, and the liquid hourly space velocity of the diethylene glycol feedstock is 0.1-5 h⁻¹. -1 The hydrogen-containing gas is hydrogen or a mixture of hydrogen and an inert gas, wherein the partial pressure of hydrogen is 0.01-0.5 MPa.
[0040] Suitable reaction conditions are beneficial for further controlling the kinetics of catalytic reactions and improving product selectivity.
[0041] In some preferred embodiments, the reaction temperature of the diethylene glycol dehydrogenation cyclization reaction is 240-260°C, and the liquid hourly space velocity of the diethylene glycol feedstock is 0.5-1 h⁻¹. -1 The partial pressure of hydrogen is 0.05-0.1 MPa.
[0042] Optimizing reaction conditions is beneficial for further controlling the kinetics of catalytic reactions and improving product selectivity.
[0043] In some embodiments, the product contains a mass fraction of p-dioxanone greater than 60 wt%.
[0044] In some embodiments, the product contains a mass fraction of p-dioxanone greater than 80 wt%.
[0045] Using the catalyst system of the present invention, the conversion rate of the diethylene glycol dehydrogenation cyclization reaction and the selectivity for dioxane are both high. Therefore, the mass fraction of dioxane in the product is high, which facilitates the subsequent separation and purification process.
[0046] In some embodiments, the cooling crystallization is performed by cooling and filtration, without the need to add a solvent.
[0047] The cooling crystallization process used in this invention differs from traditional solvent recrystallization processes. It requires no additional solvent, reducing waste solvent pollution and the formation of azeotropic products. Furthermore, it is simpler to operate, reducing process costs.
[0048] In some embodiments, the cooling temperature for the cooling crystallization is -10°C to 20°C.
[0049] The cooling crystallization process is carried out at a temperature significantly lower than the reaction temperature, and the process is conducted under conditions below room temperature, which can improve the crystallization efficiency.
[0050] In some preferred embodiments, the cooling temperature for the cooling crystallization is 5°C to 15°C.
[0051] In the dual-phase selection process balancing energy consumption and crystallization efficiency, the cooling temperature is chosen to be neither too low. This ensures high crystallization efficiency and high product purity.
[0052] In some embodiments, the product obtained from the cooling crystallization step contains more than 90 wt% p-dioxanone.
[0053] Cooling crystallization is a preliminary purification process that removes most impurities from the material. Through cooling crystallization, the content of p-dioxanone in raw materials exceeding 60 wt% can be roughly increased to greater than 90 wt%, meeting the requirements of the melt crystallization process. Figure 2A As shown, the raw material contains a relatively large number of impurities. After cooling and crystallization (such as...), Figure 2B As shown in the figure, the impurity content is significantly reduced.
[0054] In some preferred embodiments, the product obtained from the cooling crystallization step contains more than 95 wt% p-dioxanone.
[0055] With better control over the dioxane content and cooling conditions in the product material, the dioxane content in the material can be further increased.
[0056] The crude product is obtained through a cooling crystallization process, which removes most of the impurities. Further purification is then achieved through melt crystallization. Melt crystallization is a highly efficient and energy-saving separation and purification method with advantages such as high selectivity, mild operating conditions, environmental friendliness, and high safety. It is widely used for the separation and purification of heat-sensitive substances, substances with similar boiling points, and azeotropic mixtures.
[0057] In some preferred embodiments, the melt crystallization step can be repeated 1-4 times.
[0058] To improve the purification effect, the melt crystallization step can be repeated multiple times, ultimately achieving a purity of over 99.99 wt% for dioxane.
[0059] In some preferred embodiments, the melt crystallization employs one or both of layer melt crystallization and suspension melt crystallization.
[0060] Based on the distribution pattern between the crystals and the melt, melt crystallization can be divided into layer crystallization and suspension crystallization. In layer melt crystallization, the crystal layer grows from the wall towards the inside of the crystallizer, while in suspension melt crystallization, the crystals grow in three dimensions within the melt. Layer melt crystallization has advantages such as fast growth rate, simple equipment, no scaling, and easy solid-liquid separation, but it is an intermittent operation with low processing capacity. Suspension melt crystallization can be operated continuously, has good heat and mass transfer performance, large processing capacity, and high efficiency, but the equipment is complex, solid-liquid separation is difficult, and it is prone to scaling and clogging.
[0061] In some preferred embodiments, the melt crystallization is performed using layer melt crystallization.
[0062] Considering operational costs and production efficiency, layer melt crystallization is generally chosen for separation and purification. In some embodiments, the melt crystallization includes the following steps: (1) Crystallization: Add p-dioxanone crystals as seed crystals to the crude p-dioxanone mother liquor, cool down to crystallize, and filter to obtain p-dioxanone crystal A; (2) Sweating: The p-dioxanone crystal A is heated to induce sweating, and the mixture after sweating is filtered again to obtain p-dioxanone crystal B. The p-dioxanone crystal B is heated to melt. (3) Cycle: Use the product obtained in step (2) as raw material and repeat the operations of step (1) and step (2).
[0063] To further improve purification efficiency, the melt crystallization step can be repeated multiple times, ultimately achieving a purity of over 99.99 wt% for dioxanone. During this cycle, the filtrate generated during the sweating process is recycled back to the mother liquor for reuse, thereby reducing product waste and improving raw material utilization.
[0064] In some preferred embodiments, in step (1), the purity of the p-dioxanone crystals added as seed crystals is not less than 99.9%; the temperature of the mother liquor when the seed crystals are added is 15-35℃; the amount of seed crystals added is 0.01 wt%-1 wt% of the crude p-dioxanone mother liquor; the cooling rate of the crystallization process is 0.01-5℃ / min, and the target temperature is 0-20℃; In step (2), the heating rate of the sweating process is 0.01-5℃ / min, and the target temperature is 15-35℃; the heating rate of the melting process is 0.1-10℃ / min, and the target temperature is 35-45℃.
[0065] Performing the melt crystallization process within the above-mentioned conditions can result in higher purification efficiency and product purity for dioxane. The gas chromatogram of the product after one melt crystallization step is shown below. Figure 2C As shown, it can be seen that compared to Figure 2B The content of dioxanehexanone was significantly increased. Secondary melt crystallization, and even tertiary melt crystallization, can be performed as needed. The purified gas chromatographic results are as follows... Figure 2D and Figure 2E As shown in the figures, the material was further purified, and after three melt crystallizations, almost only dioxane was present.
[0066] In some preferred embodiments, in step (1), the purity of the p-dioxanone crystals added as seed crystals is not less than 99.99%; the temperature of the mother liquor when the seed crystals are added is 20-25°C; the amount of seed crystals added is 0.05 wt%-0.1 wt% of the crude p-dioxanone mother liquor; the cooling rate of the crystallization process is 0.1-1°C / min, and the target temperature is 10-15°C; In step (2), the heating rate of the sweating process is 0.1-1℃ / min, and the target temperature is 20-30℃; the heating rate of the melting process is 0.5℃ / min, and the target temperature is 35-40℃.
[0067] Further optimized melt crystallization operating conditions can better balance efficiency and the purity of p-dioxanone in the final product.
[0068] In some embodiments, melt crystallization further includes the following steps: when dioxane crude product is crystallized and sweated to obtain dioxane product, the filtrate can be recycled to mother liquor for reuse to reduce the waste of raw materials.
[0069] The separation and purification process of this invention is highly adaptable to raw materials. By coupling the reaction system of diethylene glycol catalytic dehydrogenation cyclization to generate p-dioxanone, no additional processing or solvent addition is required. It exhibits high material tolerance, achieving purification of the reaction product to obtain medical-grade p-dioxanone. The entire reaction and purification process is attached. Figure 1 As shown.
[0070] In some implementations, Cu x B y The preparation of the / SiO2 catalyst includes the following steps: (1) A copper-ammonia complex solution is formed by stirring a certain mass of copper compound, ammonia water and water at 30°C. The copper compound is at least one of copper nitrate, copper chloride, copper sulfate and copper acetate, preferably copper nitrate; the concentration of the ammonia water is 13-15 mol / L. (2) Add a certain mass of silica sol to the above complexing solution, age at 30°C, then raise the temperature to 80°C and continue stirring to evaporate ammonia until the solution... p The H value dropped to around 7; (3) Filter the solution obtained in step (2), wash the filter cake, and dry it at 120°C to obtain Cu / SiO2 catalyst precursor; (4) The Cu / SiO2 catalyst precursor was immersed in a boric acid aqueous solution and dried at 120°C to obtain Cu x B y / SiO2 catalyst precursor; (5) Cu x B y The SiO2 catalyst precursor was calcined at 400℃ to obtain Cu. x B y / SiO2 catalyst.
[0071] In some preferred embodiments, the Cu obtained after calcination x B y The SiO2 catalyst was pressed into tablets at 20 MPa, and then crushed and sieved to obtain 10-20 mesh catalyst particles.
[0072] In some preferred embodiments, the catalyst is pre-reduced using atmospheric pressure hydrogen at a pre-reduction temperature of 250-400°C, preferably 300-350°C.
[0073] In this invention, a coupled cooling crystallization and melt crystallization technique is used to separate and purify medium-to-high concentration p-dioxanone raw materials. No additional processing or solvents are required, and the material has a high tolerance, yielding medical-grade p-dioxanone with a purity exceeding 99.99%. This method achieves high product purity and yield, is simple in process, has low energy consumption, and requires no additional solvents, demonstrating promising prospects for industrialization.
[0074] The present invention will be described in detail below with reference to specific embodiments. However, the specific embodiments described herein are only for illustration and explanation of the present invention and do not constitute a limitation on the present invention, nor are the embodiments of the present invention limited thereto.
[0075] In addition, unless otherwise specified, all reagents and pharmaceuticals involved in this invention are commercially available products.
[0076] Unless otherwise specified, the reagents and chemicals of this invention are of analytical grade and can be used directly without further processing.
[0077] The reaction products were analyzed by gas chromatography, using a Shimadzu GC-2014 gas chromatograph.
[0078] Example Catalyst preparation: (1) Prepare an aqueous solution of soluble copper salt, and add ammonia water under stirring to form a copper-ammonia complex solution; (2) Add silica sol to the above complexing solution, maintain the temperature at 30°C and stir for 4 hours, then raise the temperature to 80°C and continue stirring until the solution reaches the required concentration. p The H value dropped to around 7; (3) The filter cake was filtered, washed, and dried at 120°C to obtain the Cu / SiO2 catalyst precursor; (4) The Cu / SiO2 catalyst precursor was impregnated with boric acid aqueous solution and dried at 120℃ to obtain Cu x B y / SiO2 catalyst precursor; (5) Cu x B y The SiO2 catalyst precursor was calcined in a tube furnace at 400°C for 4 hours to obtain Cu. x B y The SiO2 catalyst was pressed into tablets at 20 MPa, and then crushed and sieved to obtain 10-20 mesh catalyst particles.
[0079] Catalytic dehydrogenation and cyclization of diethylene glycol: Cu x B y The SiO2 catalyst is loaded into a fixed-bed reactor and pre-reduced. Diethylene glycol and hydrogen are then introduced to bring the diethylene glycol into contact with the catalyst. The reaction temperature is 200-350℃, the hydrogen pressure is 0.01-0.5 MPa, and the liquid hourly space velocity (LISH) of the diethylene glycol is 0.1-5 h⁻¹. -1 .
[0080] Example 1 Cu 30 Preparation of B1 / SiO2 catalyst 48.32 g of Cu(NO3)2·3H2O was dissolved in 300 mL of deionized water at room temperature. 136.24 g of 25% ammonia solution was added and stirred for 30 minutes to obtain a copper-ammonia complex solution. Then, 97.44 g of silica sol (30 wt%) was added dropwise to the above solution and stirred continuously at 30 °C for 4 hours. The temperature was then raised to 80 °C and stirred at a constant temperature until the pH of the solution dropped to approximately 7. The resulting filter cake was filtered, washed, and dried at 120 °C to obtain a Cu / SiO2 catalyst precursor with a Cu mass fraction of 30%. Finally, 20 g of the above Cu / SiO2 catalyst precursor was impregnated in an aqueous solution containing 1.14 g of boric acid, dried at 120 °C, and calcined at 400 °C to obtain a Cu catalyst containing 30 wt% copper and 1 wt% boron. 30 B1 / SiO2 catalyst.
[0081] Example 2 Cu 20 Preparation of B1 / SiO2 catalyst 28.99 g of Cu(NO3)2·3H2O was dissolved in 200 mL of deionized water at room temperature. 81.74 g of 25% ammonia solution was added and stirred for 30 minutes to obtain a copper-ammonia complex solution. Then, 101.52 g of silica sol (30 wt%) was added dropwise to the above solution and stirred continuously at 30 °C for 4 hours. The temperature was then raised to 80 °C and stirred at a constant temperature until the pH of the solution dropped to approximately 7. The resulting filter cake was filtered, washed, and dried at 120 °C to obtain a Cu / SiO2 catalyst precursor with a Cu mass fraction of 20%. Finally, 20 g of the above Cu / SiO2 catalyst precursor was impregnated in an aqueous solution containing 1.72 g of boric acid, dried at 120 °C, and calcined at 400 °C to obtain a Cu catalyst containing 20 wt% copper and 1 wt% boron. 20 B1 / SiO2 catalyst.
[0082] Example 3-10 Cu x B y / SiO2 catalyst preparation Using the same method as in Examples 1 and 2, but with varying amounts of Cu(NO3)2·3H2O, ammonia, silica sol, and boric acid, a series of Cu samples with Cu mass fractions between 10% and 40% and B mass fractions between 0.1% and 5% were prepared. x B y / SiO2 catalysts are listed in Table 1. Among them, x Represents the mass fraction of Cu. y This represents the mass fraction of B.
[0083] Example 11 Cu x B y / SiO2-catalyzed diethylene glycol dehydrogenation cyclization reaction The Cu obtained in Examples 1-10 x B y The SiO2 catalyst was pressed into tablets under 20 MPa pressure, crushed, and sieved to obtain 10-20 mesh catalyst particles. 10 grams of these catalyst particles were loaded into a fixed-bed reactor and reduced with hydrogen at 300°C for 1 hour. The hydrogen-pretreated catalyst was then subjected to a reaction at 250°C, a hydrogen pressure of 0.1 MPa, and a diethylene glycol space velocity of 1.0 h⁻¹. -1 The reaction was carried out under the specified conditions. The reaction results are shown in Table 1.
[0084] Table 1 Cu x B y / SiO2-catalyzed dehydrogenation cyclization of diethylene glycol to prepare p-dioxanone (PDO) Comparative Example 1: Preparation of Cu / SiO2 catalyst The Cu / SiO2 catalyst precursor was prepared using the same method as in Example 1, and the Cu / SiO2 catalyst was obtained after calcination at 400°C for 4 hours, wherein the mass fraction of Cu was 30 wt%.
[0085] Comparative Example 2: Cu / SiO2-catalyzed diethylene glycol dehydrogenation cyclization reaction The Cu / SiO2 catalyst obtained in Comparative Example 1 was evaluated using the same method as in Example 11 for the catalytic performance of Cu / SiO2 in the dehydrogenation and cyclization of diethylene glycol. The conversion of diethylene glycol was 88.1%, and the selectivity for dioxane was 76.6%.
[0086] As shown in Table 1 and Comparative Example 2, the addition of B to the Cu / SiO2 catalyst significantly improved both the conversion rate of diethylene glycol and the selectivity for dioxane (PDO). Furthermore, when the B content was greater than 1 wt%, the PDO product selectivity was greater than 90%, and the PDO concentration in the product was not less than 80 wt%.
[0087] Example 12: Separation and purification of p-dioxanone Collect 1000g of the product liquid obtained in Example 11 from the catalyst obtained in Example 1 (p-dioxanone mass fraction greater than 95 wt%), cool it to 10°C at a rate of 0.1°C / min for crystallization, and obtain crystals after filtration. The crystals were heated to 40°C at a rate of 0.5°C / min to obtain crude p-dioxanone. This crude product was then loaded into a jacketed column with an inner diameter of 5 cm and cooled to 25°C at a rate of 0.1°C / min. 0.1 wt% of p-dioxanone seed crystals (99.99% purity) were added, and the temperature was lowered to 15°C at a rate of 0.1°C / min for crystallization. The residue was filtered off to obtain p-dioxanone crystal A. P-dioxanone crystal A was heated to 20°C at a rate of 0.1°C / min for sweating, and filtered to obtain p-dioxanone crystal B. P-dioxanone crystal B was heated to 40°C at a rate of 0.5°C / min to obtain a primary melt-crystallized product. Using the primary melt-crystallized product as raw material, the same melt-crystallization and sweating operations were repeated to obtain a secondary melt-crystallized product. The purity and yield of the obtained p-dioxanone products are shown in Table 2. The single-pass yield of dioxane was 53.8%; the filtrate from each layer of melting and crystallization process was recycled to the mother liquor for reuse, resulting in an overall yield of 80.2% for dioxane.
[0088] Table 2 shows the results of the separation and purification of dioxane-1,5-dioxane products. Example 13: Separation and purification of p-dioxanone Collect 1000g of the product liquid obtained in Example 11 from the catalyst obtained in Example 1 (p-dioxanone mass fraction greater than 95 wt%), cool it to 10°C at a rate of 0.1°C / min for crystallization, and obtain crystals after filtration. The crystals were heated to 40°C at a rate of 0.5°C / min to obtain crude p-dioxanone. The crude product was placed in a 1-liter jacketed reactor and cooled to 25°C at a rate of 0.1°C / min under stirring at 200 r / min. 0.1 wt% of p-dioxanone seed crystals (99.99% purity) were added, and then the temperature was lowered to 15°C at a rate of 0.1°C / min for crystallization. The residual liquid was filtered off to obtain p-dioxanone crystal A. P-dioxanone crystal A was heated to 20°C at a rate of 0.1°C / min for sweating, and filtered to obtain p-dioxanone crystal B. P-dioxanone crystal B was heated to 40°C at a rate of 0.5°C / min to obtain a primary suspension melt crystallization product. Using the primary suspension melt crystallization product as raw material, the same method was used to repeat the melt crystallization and sweating operations to obtain a secondary suspension melt crystallization product. The purity and yield of the obtained dioxane product are shown in Table 3.
[0089] Table 3. Results of separation and purification of dioxane products. Example 14: Separation and purification of p-dioxanone Collect 1000g of the product liquid obtained in Example 11 from the catalyst obtained in Example 9 (p-dioxanone mass fraction greater than 80 wt%), cool it to 0°C at a rate of 0.1°C / min to crystallize, and obtain crystals after filtration. The crystals were heated to 40°C at a rate of 0.5°C / min to obtain crude p-dioxanone. The crude product was then placed in a jacketed column with an inner diameter of 5 cm and cooled to 25°C at a rate of 0.1°C / min. 0.1 wt% of p-dioxanone seed crystals (purity 99.99%) were added, and the temperature was lowered to 10°C at a rate of 0.1°C / min for crystallization. After filtering out the residual liquid, p-dioxanone crystal A was obtained. P-dioxanone crystal A was heated to 20°C at a rate of 0.1°C / min for sweating, and after filtration, p-dioxanone crystal B was obtained. P-dioxanone crystal B was heated to 40°C at a rate of 0.5°C / min to obtain a single-layer melt crystallization product. Using the product from the first-stage melt crystallization as raw material, secondary and tertiary melt crystallization and sweating operations were performed using the same method, with the crystallization temperature at 15℃, ultimately yielding a 99.99% p-dioxanone product, as shown in Table 4. Gas chromatograms of the p-dioxanone product at different operational stages are attached. Figures 2A-2E As shown.
[0090] Table 4. Results of separation and purification of dioxane products. The results above show that the method of the present invention was used to catalytically dehydrogenate diethylene glycol to generate p-dioxanone, and the product was separated and purified without the need for any additional solvent. The final p-dioxanone obtained had a purity of 99.99%, which meets the requirements for medical grade purity.
[0091] Comparative Examples 3-5 were purified by recrystallization to obtain p-dioxanone. 1000 g of the catalyst obtained in Example 1 was collected and used to produce a solution of dioxane (greater than 95 wt%) in Example 11. This solution was then added to equal masses of ethyl acetate, tetrahydrofuran, or isopropanol solvent. The mixture was stirred at 40°C for 30 minutes, then cooled to -5°C at a rate of 0.1°C / min and maintained at this temperature for 2 hours to allow crystallization. The resulting crystals were filtered and then subjected to secondary and tertiary crystallization in the same manner. The results are shown in Table 5.
[0092] Table 5. Solvent crystallization purification results of dioxane products As can be seen from the results in Table 5, the conventional solvent crystallization purification method not only requires the use of additional solvents, resulting in a large waste of materials, but also requires multiple crystallization processes, resulting in low overall yield and purity of dioxane.
[0093] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.
Claims
1. A method for producing medical-grade p-dioxanone, characterized in that, Using Cu x B y The dehydrogenation cyclization reaction of diethylene glycol is catalyzed by SiO2 catalyst to produce a product containing p-dioxanone. The product is then separated and purified to obtain high-purity p-dioxanone. Where x represents the mass fraction of Cu in the total mass of the catalyst, x is 10 wt%-40 wt%, and y represents the mass fraction of B in the total mass of the catalyst, y is 0.1 wt%-5 wt%. The separation and purification process includes a cooling crystallization step and a melting crystallization step.
2. The method according to claim 1, characterized in that, x is 20 wt%-30 wt%; y is 1 wt%-2 wt%.
3. The method according to claim 1, characterized in that, The diethylene glycol dehydrogenation cyclization reaction includes: mixing diethylene glycol feedstock with hydrogen-containing gas and passing it through a Cu-filled container. x B y The reaction is carried out in a fixed-bed reactor with SiO2 catalyst.
4. The method according to claim 3, characterized in that, The diethylene glycol dehydrogenation cyclization reaction is carried out at a temperature of 200-350°C, and the liquid hourly space velocity (LHSV) of the diethylene glycol feedstock is 0.1-5 h⁻¹. -1 The hydrogen-containing gas is hydrogen or a mixture of hydrogen and an inert gas, wherein the partial pressure of hydrogen is 0.01-0.5 MPa.
5. The method according to claim 4, characterized in that, The diethylene glycol dehydrogenation cyclization reaction is carried out at a temperature of 240-260°C, and the liquid hourly space velocity (LHSV) of the diethylene glycol feedstock is 0.5-1 h⁻¹. -1 The partial pressure of hydrogen is 0.05-0.1 MPa.
6. The method according to claim 1, characterized in that, The product contains a mass fraction of p-dioxanone greater than 60 wt%, preferably greater than 80 wt%.
7. The method according to any one of claims 1-6, characterized in that, The cooling crystallization process employs cooling and filtration methods, eliminating the need for solvent addition.
8. The method according to claim 7, characterized in that, The cooling temperature for the cooling crystallization is -10°C to 20°C, preferably 5°C to 15°C.
9. The method according to claim 7, characterized in that, The product obtained from the cooling crystallization step contains more than 90 wt% p-dioxanone, preferably more than 95 wt%.
10. The method according to any one of claims 1-6, characterized in that, The melting and crystallization step is repeated 1-4 times.
11. The method according to any one of claims 1-6, characterized in that, The melt crystallization is performed using one or both of layer melt crystallization and suspension melt crystallization.
12. The method according to any one of claims 1-6, characterized in that, The melt crystallization includes the following steps: (1) Crystallization: Add p-dioxanone crystals as seed crystals to the crude p-dioxanone mother liquor, cool down to crystallize, and filter to obtain p-dioxanone crystal A; (2) Sweating: The p-dioxanone crystal A is heated to induce sweating, and the solid-liquid mixture after sweating is filtered to obtain p-dioxanone crystal B. The p-dioxanone crystal B is heated to melt. (3) Cycle: Use the product obtained in step (2) as raw material and repeat the operations of step (1) and step (2).
13. The method according to claim 12, characterized in that, In step (1), the purity of the p-dioxanone crystals added as seed crystals is not less than 99.9%, preferably not less than 99.99%; the temperature of the mother liquor when the seed crystals are added is 15-35℃, preferably 20-25℃; the amount of seed crystals added is 0.01 wt%-1 wt% of the crude p-dioxanone mother liquor, preferably 0.05 wt%-0.1 wt%; the cooling rate of the crystallization process is 0.01-5℃ / min, preferably 0.1-1℃ / min, and the target temperature is 0-20℃, preferably 10-15℃. In step (2), the heating rate of the sweating process is 0.01-5℃ / min, preferably 0.1-1℃ / min, and the target temperature is 15-35℃, preferably 20-30℃; the heating rate of the melting process is 0.1-10℃ / min, and the target temperature is 35-45℃.