Preparation of ligand-modified palladium-carbon catalyst and its application in selective hydrogenation of mifepristone
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ZHEJIANG UNIV OF TECH
- Filing Date
- 2024-12-26
- Publication Date
- 2026-06-19
AI Technical Summary
The existing technology for the selective hydrogenation of mifepristone to angostone suffers from low catalyst activity, poor selectivity, and the preparation process is not green and environmentally friendly enough, making it difficult to carry out efficiently at room temperature and pressure.
A palladium-on-carbon catalyst modified with amino ligands was prepared by wet impregnation reduction, which uniformly supported Pd on activated carbon. The catalyst was then combined with sodium borohydride reduction to generate a catalyst in which zero-valent and divalent palladium coexisted, which was used for the selective hydrogenation of mifepristone.
A highly selective hydrogenation reaction of mifepristone was achieved at room temperature and low pressure, with a conversion rate of up to 96% and a selectivity of up to 99%. The catalytic activity and selectivity are superior to commercial catalysts, and the preparation process is green and environmentally friendly.
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Abstract
Description
Technical Field
[0001] This invention relates to the preparation of a ligand-modified palladium-on-carbon catalyst and its application in the selective hydrogenation reaction of the steroid hormone drug mifepristone. Background Technology
[0002] Aglepristone is synthesized by selectively hydrogenating the carbon-carbon triple bond in mifepristone. It is a steroid hormone-type enol drug, belonging to the class of competitive progesterone antagonists. It is used to treat various progesterone-dependent symptoms, insulin-resistant diabetes, and eosinophilic hyperplasia. It is approved for animal pregnancy termination, treatment of pyometra and induction of parturition, and treatment of progesterone-induced fibroadenoma of the mammary glands. It competitively binds to glucocorticoid receptors, thereby affecting glucocorticoid activity. Steroid drugs are a class of compounds with diverse pharmacological effects. In 2016, global sales of steroid hormone drugs exceeded US$100 billion, making it the second largest class of drugs after antibiotics. By modifying the structure of steroid drugs, their efficacy, bioavailability, and safety can be optimized, resulting in more efficient and safer drug treatment regimens.
[0003] Currently, there are no systematic reports in the literature on the selective hydrogenation of mifepristone to angostone; only a very limited number of publications mention this compound. In 1987, F. Zumstein et al. reported the preparation of gram-level angostone via column chromatography. In 2018, J. Garcia-Calvo et al. reported the synthesis at the milligram level using a self-made, expensive palladium catalyst. The two main problems are: ① the large molecular weight of the reactants leads to significant steric hindrance; ② the strong adsorption of the target product during the reaction easily leads to over-hydrogenation, resulting in poor efficiency of the half-hydrogenation reaction. Therefore, developing a highly active, highly selective, and environmentally friendly catalyst for the synthesis of angostone has significant scientific and practical implications.
[0004] Palladium-on-carbon (PAC) catalysts are catalysts in which palladium (Pd) is supported on carbon of different types (with varying pore structures, specific surface areas, and surface chemical properties). Pd, with its unique electronic configuration, is an important active component in petrochemicals and organic synthesis for selective hydrogenation, oxidation, and petroleum reforming. Activated carbon is a simple, common, and low-cost support. However, commonly used industrial PAC and Lindela catalysts often fail to simultaneously achieve excellent activity and selectivity in hydrogenation reactions. PAC catalysts are typically prepared using wet chemical impregnation and chemical reduction, requiring various reducing agents such as acetone, methanol, formaldehyde, and polyols. The excessive use of solvents and reducing agents not only wastes resources and pollutes the environment but also poses numerous safety risks. Hydrogen thermal reduction can also be used to reduce PAC catalysts, but this process operates within the 200-500°C range, resulting in high energy consumption and cost, limiting the realization of green chemistry and chemical engineering. Therefore, this invention provides a simple, safe, and environmentally friendly method for preparing PAC catalysts. Summary of the Invention
[0005] To address the aforementioned technical problems in the existing technology, the present invention aims to provide a ligand-modified palladium-on-carbon catalyst and its application in the selective hydrogenation reaction of the steroid hormone alkynyl alcohol drug mifepristone. The palladium-on-carbon catalyst is synthesized by a simple impregnation method. When the catalyst of the present invention is applied to the selective hydrogenation reaction of mifepristone, it can react rapidly at room temperature and pressure and exhibits high selectivity and hydrogenation activity.
[0006] This invention uses activated carbon and palladium nitrate as raw materials and generates a series of palladium-carbon catalysts modified with different ligand modifiers through wet impregnation and reduction at a suitable temperature. After palladium loading, a palladium-carbon catalyst with zero-valent palladium and divalent palladium coexisting can be obtained by reduction with sodium borohydride.
[0007] The technical solution adopted in this invention is as follows:
[0008] A ligand-modified palladium-on-carbon catalyst for the selective hydrogenation of mifepristone, wherein the catalyst support is amino-ligand-modified activated carbon, the active component is noble metal Pd, the noble metal Pd is uniformly supported on the support, the loading of Pd in the catalyst is 1-10%, and the content of positively valenced Pd in the catalyst accounts for 40-60% of the total noble metal Pd element.
[0009] Further, the amino ligand is at least one selected from ethylenediamine, n-butylamine, phenylethylamine, ethylenediaminetetraacetic acid, benzylamine, and triethylamine, preferably ethylenediamine, and the mass ratio of the amino ligand to activated carbon is 1.5-3:1, preferably 1.8-2:1.
[0010] Furthermore, the Pd loading in the catalyst is 3-5%, the content of positively valence Pd in the catalyst accounts for 50-60% of the total Pd content, and the particle size of the Pd particles is 1-5 nm.
[0011] This invention also discloses a method for preparing a ligand-modified palladium-on-carbon catalyst for the selective hydrogenation of mifepristone, comprising the following steps:
[0012] 1) Add activated carbon carrier and amino ligand to deionized water, heat to 45-55℃ and stir for 5-25 hours, then filter. Wash the solid product with deionized water, dry it, and grind it to obtain amino ligand modified activated carbon carrier.
[0013] 2) The support obtained in step 1) is immersed in an aqueous solution of Pd precursor. After stirring at a water bath temperature of 45-55℃ to allow the Pd precursor to be fully adsorbed onto the support, sodium borohydride solution is added dropwise. The reduction reaction is carried out by stirring at a water bath temperature of 45-55℃ for 1-5 hours. Then, the solution is filtered, washed, dried, and ground to obtain the final catalyst product.
[0014] Furthermore, in step 1), the water bath temperature is 50℃±2℃, and the stirring time is 10-15h.
[0015] Furthermore, in step 2), the Pd precursor is palladium nitrate, the amount of sodium borohydride is 1.6-2 times the molar amount of the Pd precursor, the temperature of the reduction reaction is 50℃±2℃, and the time of the reduction reaction is 1.5-2.5h.
[0016] The palladium-on-carbon catalyst is used in the selective hydrogenation reaction of mifepristone. The application method is as follows: mifepristone is dissolved in an organic solvent to prepare a solution. The organic solvent is one or more of ethanol, acetone, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and diethyl ether. The solution is added to a stainless steel high-pressure batch reactor, and then the palladium-on-carbon catalyst is added. The selective hydrogenation reaction is carried out under hydrogen gas conditions.
[0017] Furthermore, in the application method, the concentration of mifepristone in the solution is 20-50 mg / mL, and the mass ratio of catalyst to mifepristone is 0.02-0.1:1, preferably 0.04-0.05:1.
[0018] Furthermore, in the application method, the hydrogen pressure is from atmospheric pressure to gauge pressure of 1 MPa, preferably 0.1 MPa to 0.2 MPa, the reaction temperature is 15-100℃, preferably 30-50℃, and the reaction time is 20-80 min, preferably 30-60 min.
[0019] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:
[0020] 1. Activated carbon has a complex porous structure, and its surface contains functional groups such as hydroxyl groups. When the activated carbon support is modified with amino ligands, the trace hydroxyl groups on the support surface provide suitable sites for amino ligand grafting. Subsequently, amino protonation adsorbs metal ions through electrostatic interactions, improving metal dispersion and resulting in smaller and more uniformly distributed Pd nanoparticles loaded on the support. The catalyst preparation process in this invention is green, simple, time-consuming, energy-efficient, and has low production costs. Furthermore, the palladium-on-carbon catalyst exhibits good stability to air, water, and heat.
[0021] 2. When palladium-on-carbon catalysts, which are commonly used in the prior art, are applied to the selective hydrogenation of mifepristone, they exhibit low catalytic activity and poor selectivity, and are prone to over-hydrogenation. The specific reasons can be attributed to two points: (1) the substrate mifepristone has a large molecular weight and significant steric hindrance; (2) the target product is strongly adsorbed during the reaction, leading to over-hydrogenation. In contrast, the palladium-on-carbon catalysts modified with different ligand modifiers prepared in this invention can perform the semi-hydrogenation of mifepristone at room temperature and low pressure, with a hydrogenation selectivity as high as 96% and a hydrogenation activity greater than 99%. Both the catalytic activity and selectivity are superior to most commercial catalysts.
[0022] 3. The active site of the mifepristone hydrogenation catalyst of this invention is Pd. 0 With Pd 2+ Pd 0 Pd is responsible for activating hydrogen. 2+ Pd is responsible for increasing the hydrogen coverage on the catalyst surface. 0 With Pd 2+ The catalyst synergistically lowers the reaction energy barrier, promoting the selective hydrogenation of mifepristone. Compared to catalysts commonly used for alkyne hydrogenation, the catalyst of this invention contains Pd... 2+ The content is lower than that of Pd 0+ Higher concentrations of Pd lead to better adsorption and desorption of hydrogen and reactants on the catalyst surface. 2+ Catalysts with a content in the middle range of 40-60% exhibit good activity, while those with a content that is too low show poor catalyst activity. Attached Figure Description
[0023] Figure 1a The image shows a TEM image of the 5 wt% Pd / C catalyst from Example 7.
[0024] Figure 1b The image shows a TEM image of the 5 wt% Pd / CA-5h catalyst from Example 8.
[0025] Figure 1c The image shows a TEM image of the 5 wt% Pd / CA-12h catalyst from Example 8.
[0026] Figure 1d The image shows a TEM image of the 5 wt% Pd / CA-24h catalyst from Example 8.
[0027] Figure 2 The XRD characterization results are as follows: for the 5 wt% Pd / C catalyst of Example 7, and for the 5 wt% Pd / CA-5h, 5 wt% Pd / CA-12h, and 5 wt% Pd / CA-24h catalysts of Example 8.
[0028] Figure 3 The graph shows a comparison of the conversion rate of mifepristone and the selectivity of angostrol when the 5wt% Pd / CA-12h catalyst prepared in Example 8 was used in the catalytic hydrogenation of mifepristone. Detailed Implementation
[0029] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.
[0030] Example 1: Pd / C catalyst based on ethylenediamine ligand modification
[0031] Catalyst preparation includes the following steps:
[0032] 1) Using activated carbon and palladium nitrate as raw materials, 1g of activated carbon was first dispersed in 50ml of deionized water, and 2g (2.25ml) of ethylenediamine was added and sonicated for 30min. Then, the mixture was transferred to a 50℃ water bath and stirred for 5h for modification reaction. After filtration, deionized water was added during filtration to wash until the solution pH=7. The filtered solid was transferred to a 100℃ vacuum drying oven for drying. After 12h, it was taken out and cooled at room temperature to obtain the activated carbon carrier modified with ethylenediamine, which was then ground for use.
[0033] 2) 1g of the modified activated carbon support powder obtained in step 1) was added to 30ml of deionized water to obtain a support suspension. Palladium nitrate was then dissolved in deionized water to prepare a 20mg / mL metal salt solution. 5.40ml of the palladium nitrate aqueous solution was mixed with 30ml of the prepared support suspension, according to a Pd loading of 5wt% in the catalyst. The mixture was stirred in a 50℃ water bath for 2 hours. Then, 10ml of a 30mg / mL sodium borohydride aqueous solution was added and stirring continued for 2 hours. The mixture was then filtered, washed with water until neutral, and dried overnight in a 100℃ vacuum drying oven. After cooling to room temperature, it was finely ground to obtain the Pd / C catalyst modified with ethylenediamine ligands.
[0034] The Pd / C catalyst based on ethylenediamine ligand modification prepared in Example 1 was applied to the selective hydrogenation reaction of mifepristone to synthesize angostone, including the following steps:
[0035] S1: Dissolve 750mg mifepristone in 30ml tetrahydrofuran to prepare a reaction solution. Add the reaction solution to a 50mL stainless steel high-pressure batch reactor, then add 30mg catalyst. After tightening the reactor, introduce hydrogen gas. First, replace the air in the reactor with hydrogen gas 5 times to purge the air in the reactor, then fill with hydrogen gas until the gauge pressure is 0.1MPa.
[0036] S2: The reaction temperature was set at 30℃, and the magnetic stirring speed at 800 r / min. Samples were taken for analysis during the reaction to calculate the conversion rate of mifepristone and the selectivity of angostone. Following the above experimental procedure, the results were as follows: the conversion rate was 65.28% and the selectivity was 96.97% after 30 min of reaction; the conversion rate was 98.76% and the selectivity was 95.16% after 60 min of reaction.
[0037] In the embodiments of this invention, the conversion rate data refers to the conversion rate of mifepristone, and the selectivity data refers to the selectivity of angostazine.
[0038] Example 2: Pd / C catalyst modified with n-butylamine ligand
[0039] Example 2: The catalyst preparation steps were repeated in Example 1, except that in "step 1), 2g of ethylenediamine was replaced with 2g of n-butylamine". All other conditions remained the same, and a Pd / C catalyst based on n-butylamine ligand modification was finally obtained.
[0040] The catalyst of Example 2 was tested for selective hydrogenation of mifepristone according to the method of Example 1. The experimental results were as follows: the conversion rate was 46.13% and the selectivity was 97.05% after 30 min of reaction; the conversion rate was 82.25% and the selectivity was 96.07% after 60 min of reaction.
[0041] Example 3: Pd / C catalyst based on phenylethylamine modification
[0042] Example 3: The catalyst preparation steps were repeated in Example 1, except that 2g of ethylenediamine was replaced with 2g of phenylethylamine in "step 1"), and the other conditions remained unchanged, and a Pd / C catalyst based on phenylethylamine modification was finally obtained.
[0043] The catalyst of Example 3 was used to test the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were as follows: the conversion rate was 24.97% and the selectivity was 96.80% after 30 min of reaction; the conversion rate was 37.70% and the selectivity was 97.13% after 60 min of reaction.
[0044] Example 4: Pd / C catalyst based on ethylenediaminetetraacetic acid modification
[0045] Example 4: The catalyst preparation steps were repeated in Example 1, except that in "step 1), 2g of ethylenediamine was replaced with 2g of ethylenediaminetetraacetic acid (EDTA)," while the other conditions remained unchanged. Finally, a Pd / C catalyst based on EDTA modification was obtained.
[0046] The catalyst of Example 4 was tested for selective hydrogenation of mifepristone according to the method of Example 1. The experimental results were as follows: the conversion rate was 83.11% and the selectivity was 93.50% after 30 min of reaction; the conversion rate was 98.69% and the selectivity was 75.98% after 60 min of reaction.
[0047] Example 5: Pd / C catalyst based on benzylamine modification
[0048] Example 5: The catalyst preparation steps were repeated in Example 1, except that 2g of ethylenediamine was replaced with 2g of benzylamine in "step 1"), and the other conditions remained unchanged, and a Pd / C catalyst based on benzylamine modification was finally obtained.
[0049] The catalyst of Example 5 was tested for selective hydrogenation of mifepristone according to the method of Example 1. The experimental results were as follows: the conversion rate was 86.62% and the selectivity was 90.88% after 30 min of reaction; the conversion rate was 98.99% and the selectivity was 79.58% after 60 min of reaction.
[0050] Example 6: Triethylamine-Modified Pd / C Catalyst
[0051] Example 6: The catalyst preparation steps were repeated in Example 1, except that 2g of ethylenediamine was replaced with 2g of triethylamine in "step 1"), and the other conditions remained unchanged, and a Pd / C catalyst based on triethylamine modification was finally obtained.
[0052] The catalyst of Example 6 was tested for selective hydrogenation of mifepristone according to the method of Example 1. The experimental results were as follows: the conversion rate was 40.75% and the selectivity was 94.23% after 30 min of reaction; the conversion rate was 83.12% and the selectivity was 80.14% after 60 min of reaction.
[0053] Example 7: Pd / C catalyst supported on commercial activated carbon
[0054] Catalyst preparation: Using activated carbon and palladium nitrate as raw materials, palladium nitrate was dissolved in deionized water to prepare a 20 mg / mL metal salt solution. 5.40 mL of the palladium nitrate aqueous solution was mixed with 1 g of activated carbon dispersed in 30 mL of deionized water, according to a Pd loading of 5 wt%. The mixture was stirred in a 50 °C water bath for 2 h, then 10 mL of a prepared 30 mg / mL sodium borohydride solution was added and stirring continued for another 2 h. The mixture was then filtered, washed with water until neutral, and dried overnight in a 100 °C vacuum drying oven. After cooling to room temperature, it was finely ground to obtain a Pd / C catalyst based on commercially available activated carbon, named the 5 wt% Pd / C catalyst.
[0055] The catalyst of Example 7 was tested for selective hydrogenation of mifepristone according to the method of Example 1. The experimental results were as follows: the conversion rate was 70.70% and the selectivity was 89.43% after 30 min of reaction; the conversion rate was 98.97% and the selectivity was 82.47% after 60 min of reaction.
[0056] Example 8: Pd / C catalysts modified with ethylenediamine for different times
[0057] Example 8: The catalyst preparation steps were repeated in Example 1, except that the stirring and modification reaction time in "step 1) was replaced with 5h, 12h, and 24h respectively". Finally, Pd / C catalysts modified with ethylenediamine for 5h, 12h, and 24h were obtained and named 5wt%Pd / CA-5h catalyst, 5wt%Pd / CA-12h catalyst, and 5wt%Pd / CA-24h catalyst respectively.
[0058] The TEM characterization results of the 5 wt% Pd / C catalyst from Example 7 and the 5 wt% Pd / CA-5h, 5 wt% Pd / CA-12h, and 5 wt% Pd / CA-24h catalysts from Example 8 are summarized in Figure 1, corresponding to sub-plots a, b, c, and d in Figure 1, respectively. From the TEM results of sub-plots a, b, c, and d in Figure 1, it can be seen that the average particle sizes of the Pd particles supported on the catalysts are 3.47 nm, 2.23 nm, 1.86 nm, and 1.65 nm, respectively.
[0059] The XRD characterization results of the 5 wt% Pd / C catalyst in Example 7 and the 5 wt% Pd / CA-5h, 5 wt% Pd / CA-12h, and 5 wt% Pd / CA-24h catalysts in Example 8 are shown in [Figure Number]. Figure 2 .from Figure 2It can be seen that all four catalysts exhibit diffraction peaks at 2θ = 40°, which are attributed to the Pd(111) crystal plane. Furthermore, the peak intensity decreases with increasing modification time, indicating that the Pd particle size does indeed gradually decrease with prolonged modification time. Characterization confirms that modifying the support with ethylenediamine ligands followed by palladium loading does indeed result in smaller and more uniformly distributed Pd nanoparticles on the support.
[0060] Subsequent BET testing revealed that all four catalysts were mesoporous carbon materials with pore sizes ranging from 5 to 7 nm. The catalyst in Example 7, without modification, had a specific surface area of 986.3 cm². 2 / g, pore volume maintained at 0.8cm 3 / g. However, in Example 8, the specific surface area of the activated carbon support was significantly reduced after modification with ethylenediamine. The specific surface areas of the 5wt% Pd / CA-5h catalyst, 5wt% Pd / CA-12h catalyst, and 5wt% Pd / CA-24h catalyst in Example 8 were 95.5 cm², respectively. 2 / g, 296.6cm 2 / g, 278.9cm 2 / g, while the amino ligands block the macropores on the support, causing the catalyst's pore volume to increase from the unmodified 0.8 cm³ in Example 7. 3 / g decreased to 0.2-0.3cm 3 / g (the macropores become clogged upon attachment of the ligand, with pore volumes remaining between 0.2-0.3 regardless of modification time), but the specific surface area slightly increases to 296.6 cm² with increasing modification time. 2 The concentration of Pd / NP on the catalyst is approximately 1 g / g, further indicating that the modification time should not be too long. Although modification is advantageous for the dispersion of Pd / NP on the catalyst, prolonged modification will gradually clog the micropores, hindering reactant diffusion and mass transfer. In summary, the optimal catalyst is a Pd / C catalyst modified with ethylenediamine ligands for 12 hours. X-ray photoelectron spectroscopy (XPS) shows the optimal catalyst concentration of Pd / NP. 2+ It accounts for 55% of the total Pd content.
[0061] In Example 8, during the preparation of the Pd / C catalyst modified with ethylenediamine ligands for 12 hours, the molar amount of sodium borohydride was 1.68 times that of palladium nitrate, meaning that theoretically, 84% of the Pd / C catalyst could be modified with ethylenediamine ligands. 2+ Ions reduced to Pd 0 Elemental, but experimental results show that only about 45% of Pd is present. 2+ Ions reduced to Pd 0 The reason for this might be:
[0062] ①Although sodium borohydride is a strong reducing agent, if the palladium compound has a complex morphology, some palladium ions may be encapsulated inside some ligand structures, making it difficult for sodium borohydride to access these palladium ions and completely reduce them to zero-valent palladium, resulting in the continued presence of divalent palladium.
[0063] ② Secondly, from the perspective of chemical equilibrium, reduction is a reversible process. Under certain conditions, an equilibrium may be reached between zero-valent palladium and divalent palladium. Even with the addition of excess sodium borohydride, the reaction will not proceed entirely towards the formation of zero-valent palladium. For example, when certain substances that can stably coordinate with divalent palladium are present in the reaction system, the divalent palladium will be relatively stable and difficult to further reduce.
[0064] The 5wt% Pd / CA-5h catalyst of Example 8 was used to test the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were: 65.28% conversion and 96.97% selectivity after 30 min of reaction; and 99.97% conversion and 95.16% selectivity after 60 min of reaction.
[0065] The 5wt% Pd / CA-12h catalyst of Example 8 was used to test the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were: 96.89% conversion and 97.83% selectivity after 30 min of reaction; and 98.96% conversion and 97.64% selectivity after 60 min of reaction.
[0066] The 5 wt% Pd / CA-24h catalyst of Example 8 was used for the selective hydrogenation of mifepristone according to the method of Example 1. The experimental results were: 98.57% conversion and 95.18% selectivity after 30 min of reaction; and 97.92% conversion and 90.51% selectivity after 60 min of reaction.
[0067] This indicates that modification with ethylenediamine can improve the selectivity of the catalyst, and the catalyst prepared after 12 hours of modification has the best performance, achieving efficient and selective hydrogenation of mifepristone at room temperature and low pressure.
[0068] In addition, a reuse experiment was conducted on the 5wt% Pd / CA-12h catalyst from Example 8 for the selective hydrogenation of mifepristone. The experimental procedure for the catalytic reaction was the same as in Example 1. The reaction time for each batch of catalytic reaction was 30 min. After the reaction, the catalyst was separated from the reaction solution, washed with ethanol, and reused in the next batch of catalyst reuse reaction. Considering that a small amount of catalyst loss is inevitable during recovery, approximately 10%, about 3 mg of catalyst was added for each subsequent batch of catalyst reuse. The comparison of mifepristone conversion and angostone selectivity results when the catalyst was reused according to this experimental method is shown in the figure below. Figure 3 It can be seen that the catalyst has good stability, and its catalytic activity basically did not decrease after seven consecutive uses.
[0069] Example 9: Semi-hydrogenation activity of the catalyst prepared in Example 1 at different temperatures.
[0070] The 5wt% Pd / CA-12h catalyst from Example 8 was used to test the selective hydrogenation of mifepristone according to the method of Example 1. The experimental procedure was repeated in Example 1, except that the temperature of the catalytic reaction was changed, while the other conditions remained the same. The temperatures of the catalytic reaction were changed to 15℃, 20℃, 25℃, 30℃, 50℃, and 100℃, respectively. The hydrogen pressure of the reaction was set to 0.1 MPa (gauge pressure). The other conditions were the same as in Example 1. The experimental results after 30 min of catalytic reaction are shown in Table 1.
[0071] Table 1
[0072] Reaction temperature (°C) Conversion rate (%) Selectivity (%) 15 51.59 97.48 20 85.72 96.94 25 88.76 95.16 30 96.89 97.83 50 98.79 96.58 100 99.65 60.28
[0073] As shown in Table 1, excessively low temperatures lead to a decrease in conversion rate, while excessively high temperatures result in a significant decrease in hydrogenation selectivity. This is because hydrogen dissociation becomes slower at low temperatures, thus affecting the degree of hydrogenation. At high temperatures, the heat released by the hydrogenation reaction cannot be dissipated quickly enough, causing the catalytic system temperature to become too high, leading to increased catalyst carbon buildup and accelerated deactivation. Furthermore, excessively high temperatures increase over-hydrogenation products, thus reducing the selectivity of the catalytic reaction. Simultaneously, the catalyst's valence state is easily reduced by reactants and hydrogen at high temperatures, causing Pd in the catalyst to accumulate. 2+ The content decreased, while Pd 0 With Pd 2+ The ratio of [specific components] has a significant impact on catalytic activity. Therefore, controlling the temperature between 30-50℃ is considered the optimal reaction temperature.
[0074] Example 10: Semi-hydrogenation activity of the catalyst prepared in Example 1 under different pressures
[0075] The 5wt% Pd / CA-12h catalyst from Example 8 was used to test the selective hydrogenation reaction of mifepristone according to the method in Example 1, with the only difference being the change in hydrogen pressure during the catalytic reaction; all other conditions remained the same. The hydrogen pressures for the catalytic reaction were changed to atmospheric pressure (hydrogen balloon), gauge pressure 0.1 MPa, gauge pressure 0.2 MPa, gauge pressure 0.5 MPa, and gauge pressure 1 MPa, respectively. The reaction temperature was set at 25°C, and the other conditions were the same as in Example 1. The experimental results after 30 min of catalytic reaction are shown in Table 2.
[0076] Table 2
[0077] Reaction pressure Conversion rate (%) Selectivity (%) Atmospheric pressure (hydrogen balloon) 59.24 95.53 Gauge pressure 0.1 MPa 96.89 97.83 Gauge pressure 0.2 MPa 97.52 97.30 Gauge pressure 0.5 MPa 98.09 89.53 Gauge pressure 1.0 MPa 98.88 86.10
[0078] Table 2 shows that the comparative experimental results indicate that hydrogen pressure has a significant impact on the reaction outcome. Too low a pressure reduces the hydrogen partial pressure, preventing the hydrogenation reaction from proceeding fully and resulting in a lower conversion rate. Increasing the reaction pressure promotes the hydrogenation reaction, accelerates the reaction rate, improves selectivity, inhibits coking, reduces catalyst deactivation, and extends catalyst lifespan by minimizing carbon buildup. However, excessively high pressure leads to a high hydrogen concentration (Pd). 2+ The pole was completely reduced to Pd 0 On the contrary, it will reduce the catalytic ability.
[0079] Comparative Example 1: A commercial palladium-on-carbon catalyst without ligand modification was used for the selective hydrogenation of mifepristone. The catalyst was derived from a purchased 5 wt% commercial palladium-on-carbon catalyst.
[0080] The catalyst of Comparative Example 1 was used to test the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results showed that the conversion rate of 5 wt% commercial palladium on carbon catalyst for the selective hydrogenation of mifepristone to angostone was 78.48% and the selectivity was 84.89% after 30 min of reaction; and the conversion rate was 98.68% and the selectivity was 67.49% after 60 min of reaction.
[0081] Comparative Example 2: Pd / C catalyst based on ethylenediamine modified by hydrogen reduction method
[0082] Catalyst preparation includes the following steps:
[0083] 1) Using activated carbon and palladium nitrate as raw materials, 1g of activated carbon was first dispersed in 50ml of deionized water, and 2g (2.25ml) of ethylenediamine was added and sonicated for 30min. Then, the mixture was transferred to a 50℃ water bath and stirred for 12h for modification reaction. After filtration, deionized water was added during filtration to wash until the solution pH=7. The filtered solid was transferred to a 100℃ vacuum drying oven for drying. After 12h, it was taken out and cooled at room temperature to obtain the activated carbon carrier modified with ethylenediamine, which was then ground for use.
[0084] 2) 1g of the modified activated carbon support powder obtained in step 1) was added to 30ml of deionized water to obtain a support suspension. Palladium nitrate was then dissolved in deionized water to prepare a 20mg / mL metal salt solution. 5.40ml of the palladium nitrate aqueous solution was mixed with 30ml of the prepared support suspension, according to a Pd loading of 5wt% in the catalyst. The mixture was stirred in a 50℃ water bath for 2h, then the temperature was increased to 100℃ and the solution was stirred until dry. The resulting powder was then reduced in a tube furnace at 200℃ or 300℃ for 2h under a hydrogen atmosphere. The final catalysts were labeled as 5wt% Pd / CA-200℃ catalyst and...
[0085] 5wt% Pd / CA-300℃ catalyst.
[0086] The selective hydrogenation reaction of mifepristone was tested using the 5 wt% Pd / CA-200℃ catalyst of Comparative Example 2 according to the method of Example 1. The experimental results were: 55.71% conversion and 95.23% selectivity after 30 min of reaction; and 85.45% conversion and 81.78% selectivity after 60 min of reaction.
[0087] The selective hydrogenation reaction of mifepristone was tested using the 5 wt% Pd / CA-300℃ catalyst of Comparative Example 2 according to the method of Example 1. The experimental results were: 70.22% conversion and 95.11% selectivity after 30 min of reaction; and 90.98% conversion and 83.61% selectivity after 60 min of reaction.
[0088] Comparative Example 3: Pd / C catalyst based on ethylenediamine modified by formic acid reduction method
[0089] Catalyst preparation includes the following steps:
[0090] 1) Using activated carbon and palladium nitrate as raw materials, 1g of activated carbon was first dispersed in 50ml of deionized water, and 2g (2.25ml) of ethylenediamine was added and sonicated for 30min. Then, the mixture was transferred to a 50℃ water bath and stirred for 12h for modification reaction. After filtration, deionized water was added during filtration to wash until the solution pH=7. The filtered solid was transferred to a 100℃ vacuum drying oven for drying. After 12h, it was taken out and cooled at room temperature to obtain the activated carbon carrier modified with ethylenediamine, which was then ground for use.
[0091] 2) Next, disperse 1g of the ethylenediamine-modified activated carbon support from step 1) and 0.05g of NaCl in 30ml of deionized water, stir in a 50℃ water bath for 30min, then add 5.40ml of palladium nitrate aqueous solution to the mixture according to the Pd loading of 5wt% in the catalyst, continue stirring for 2h, adjust the pH of the mixture to 8-9 with 0.1mol / L NaOH solution, add 10ml of formic acid, stir at 50℃ for 2h, filter, wash with water until the solution is neutral, put it into a vacuum drying oven at 100℃ and dry overnight, take it out and cool it at room temperature, then grind it finely to obtain the Pd / C catalyst based on ethylenediamine modification prepared by formic acid reduction method.
[0092] The catalyst of Comparative Example 3 was used to test the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were: 36.33% conversion and 95.62% selectivity after 30 min of reaction; and 74.38% conversion and 86.22% selectivity after 60 min of reaction.
[0093] Comparative Example 4: Pd / C catalyst based on ethylenediamine modified by formaldehyde reduction method
[0094] Catalyst preparation includes the following steps:
[0095] 1) Using activated carbon and palladium nitrate as raw materials, 1g of activated carbon was first dispersed in 50ml of deionized water, and 2g (2.25ml) of ethylenediamine was added and sonicated for 30min. Then, the mixture was transferred to a 50℃ water bath and stirred for 12h for modification reaction. After filtration, deionized water was added during filtration to wash until the solution pH=7. The filtered solid was transferred to a 100℃ vacuum drying oven for drying. After 12h, it was taken out and cooled at room temperature to obtain the activated carbon carrier modified with ethylenediamine, which was then ground for use.
[0096] 2) Next, disperse 1g of the ethylenediamine-modified activated carbon support from step 1) and 0.05g of NaCl in 30ml of deionized water, stir in a 50℃ water bath for 30min, then add 5.40ml of palladium nitrate aqueous solution to the mixture according to the Pd loading of 5wt% in the catalyst, continue stirring for 2h, adjust the pH of the mixture to 8-9 with 0.1mol / L NaOH solution, then add 7.5ml of formaldehyde and stir at 50℃ for 2h, filter and wash with water until the solution is neutral, dry in a vacuum drying oven at 100℃ overnight, take it out and cool at room temperature, then grind it carefully to obtain the Pd / C catalyst based on ethylenediamine modification prepared by formaldehyde reduction method.
[0097] The catalyst of Comparative Example 4 was used to test the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were: 98.49% conversion and 92.96% selectivity after 20 min of reaction, and 99.65% conversion and 93.66% selectivity after 30 min of reaction.
[0098] As can be seen from the comparative examples, under the same reaction conditions, comparing the catalytic performance of a 5wt% commercial palladium-on-carbon catalyst for the semi-hydrogenation of mifepristone shows that its activity selectivity is far inferior to the heterogeneous catalyst of ethylenediamine-modified activated carbon supported Pd in this invention, further demonstrating the importance of amino ligand-modified carbon support in this invention.
[0099] Furthermore, by reducing the heterogeneous catalyst of Pd supported on ethylenediamine-modified activated carbon through different reduction methods, it was found that Pd was obtained by hydrogen reduction. 0+ Catalysts with a high proportion of active ingredients require a longer catalytic reaction time, failing to achieve the optimal catalytic activity and selectivity of this invention. Using formic acid and formaldehyde for reduction has two main drawbacks: firstly, it cannot achieve both high conversion and high selectivity; secondly, formic acid and formaldehyde are harmful to human health, and formaldehyde is highly volatile, easily exceeding safe limits, posing a threat to experimental results and participant safety. Experiments have shown that sodium borohydride reduction is the most effective, and the catalyst preparation process is green and pollution-free.
[0100] The above examples of mifepristone hydrogenation are exemplary. This invention is a novel supported hydrogenation catalyst with high activity and selectivity, capable of achieving near-100% conversion of mifepristone at room temperature and low pressure in a short time. Appropriate modifications to this invention by those skilled in the art, such as changing the hydrogenation substrate (small molecules or polymers containing carbon-carbon triple bonds), changing the ligand modifier, changing other oxide supports, and appropriately altering the reaction pressure, temperature, substrate concentration, etc., are all within the scope of this invention.
[0101] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.
Claims
1. Use of a palladium on carbon catalyst in the selective hydrogenation of mifepristone, characterized in that The catalyst support is amino ligand-modified activated carbon, and the active component is the noble metal Pd. The noble metal Pd is uniformly supported on the support, and the loading of Pd in the catalyst is 1-10 wt%. The content of positively valence Pd in the catalyst accounts for 40-60% of the total noble metal Pd element content. The amino ligand is ethylenediamine, and the mass ratio of the amino ligand to activated carbon is 1.5-3:
1.
2. The application as described in claim 1, characterized in that... The mass ratio of amino ligand to activated carbon is 1.8-2:
1.
3. The application as described in claim 1, characterized in that... The Pd loading in the catalyst is 3-5 wt%, the positive valence Pd content in the catalyst accounts for 50-60% of the total Pd content, and the Pd particle size is 1-5 nm.
4. The application as described in claim 1, characterized in that... The catalyst preparation method includes the following steps: 1) Add activated carbon carrier and amino ligand to deionized water, heat to 45-55℃ and stir for 5-25 hours, then filter. Wash the solid product with deionized water, dry it, and grind it to obtain amino ligand modified activated carbon carrier. 2) The support obtained in step 1) is immersed in an aqueous solution of Pd precursor. After stirring at a water bath temperature of 45-55℃ to allow the Pd precursor to be fully adsorbed onto the support, sodium borohydride solution is added dropwise. The reduction reaction is carried out by stirring at a water bath temperature of 45-55℃ for 1-5 hours. Then, the solution is filtered, washed, dried, and ground to obtain the final catalyst product.
5. The application as described in claim 4, characterized in that... In step 1), the water bath temperature is 50℃±2℃, and the stirring time is 10-15h.
6. The application as described in claim 4, characterized in that... In step 2), the Pd precursor is palladium nitrate, the amount of sodium borohydride is 1.6-2 times the molar amount of the Pd precursor, the temperature of the reduction reaction is 50℃±2℃, and the time of the reduction reaction is 1.5-2.5h.
7. The application as described in claim 1, characterized in that... Mifepristone is dissolved in an organic solvent to prepare a solution. The organic solvent is one or more of ethanol, acetone, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and diethyl ether. The solution is added to a stainless steel high-pressure batch reactor, and then the palladium catalyst on carbon is added. Selective hydrogenation reaction is carried out under hydrogen gas conditions.
8. The application as described in claim 7, characterized in that... The concentration of mifepristone in the solution is 20-50 mg / mL, and the mass ratio of catalyst to mifepristone is 0.02-0.1:
1.
9. The application as described in claim 8, characterized in that... The mass ratio of catalyst to mifepristone is 0.04-0.05:
1.
10. The application as described in claim 1, characterized in that... The hydrogen pressure ranges from atmospheric pressure to 1 MPa (gauge pressure), the reaction temperature is 15-100℃, and the reaction time is 20-80 min.
11. The application as described in claim 10, characterized in that... The hydrogen pressure is 0.1 MPa to 0.2 MPa (gauge pressure), the reaction temperature is 30-50℃, and the reaction time is 30-60 min.