Preparation of ligand-modified palladium carbon catalyst and application of ligand-modified palladium carbon catalyst in selective hydrogenation reaction of mifepristone

Abstract

The invention discloses preparation of a ligand-modified palladium-carbon catalyst and application of the ligand-modified palladium-carbon catalyst in selective hydrogenation reaction of mifepristone, a carrier of the catalyst is amino ligand-modified activated carbon, an active component is noble metal Pd, the noble metal Pd is uniformly loaded on the carrier, the loading amount of Pd in the catalyst is 1-10%, and the loading amount of Pd in the catalyst is 1-10%. And the content of the positive valence Pd in the catalyst accounts for 40-60% of the total amount of the noble metal Pd element. A series of palladium carbon catalysts modified by different ligands are generated through a dipping reduction method, hydroxyl on the surface of the modified carrier can provide appropriate sites for amino ligand grafting, then amino protonation adsorbs metal ions through electrostatic interaction, and the metal dispersity is improved; and the Pd nanoparticles loaded on the carrier are smaller in size and more uniform in distribution. When the catalyst disclosed by the invention is applied to the semi-hydrogenation reaction of the mifepristone to prepare the amcopristone, the selectivity of the amcopristone is up to 96%, and the conversion rate is greater than 99%.

Description

Technical Field

[0001] The invention relates to the preparation of a ligand-modified palladium-carbon catalyst and its application in the selective hydrogenation reaction of a steroid hormone drug, mifepristone. Background Art

[0002] Aglepristone is prepared by selective hydrogenation of the carbon-carbon triple bond in mifepristone. It is a steroid hormone enol drug and a competitive progesterone antagonist. It can be used to treat various progesterone-dependent symptoms, insulin-resistant diabetes, and eosinophilia. It is approved for animal pregnancy termination, treatment of uterine pyometra, induction of labor, and treatment of progesterone-induced fibroadenomatous breast hyperplasia. It can compete with glucocorticoid receptors to bind and affect glucocorticoids. 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 adjusting the structure of steroid drugs, their efficacy, bioavailability, and safety can be optimized to obtain more efficient and safe drug treatment plans.

[0003] At present, there is no literature systematically reporting the reaction of selective hydrogenation of mifepristone to angostrin, and only a few literatures mention this compound. In 1987, F. Zumstein et al. reported the preparation of gram-level angostrin by column chromatography. In 2018, J. Garcia-Calvo et al. reported the use of homemade expensive palladium catalysts to complete milligram-level synthesis. The two main problems are: ① The large molecular weight of the reactants has a large steric hindrance; ② Secondly, the strong adsorption of the target product during the reaction can easily lead to over-hydrogenation, making the efficiency of the semi-hydrogenation reaction poor. Therefore, it is of great scientific and practical significance to develop a highly active, highly selective and green catalyst for the synthesis of angostrin.

[0004] Palladium carbon catalyst is a catalyst with Pd as active component, which loads palladium on carbon of different types (pore structure, specific surface area and surface chemical properties), wherein Pd has a unique electronic configuration and is an important active component for selective hydrogenation, oxidation and oil reforming in petrochemical and organic synthesis; and activated carbon is a simple, common and low-cost carrier; and the palladium carbon catalyst and Lindela catalyst commonly used in industry are difficult to meet excellent activity and selectivity at the same time in hydrogenation reactions. Palladium carbon catalysts are usually prepared by wet chemical impregnation and chemical reduction, and various reducing agents such as acetone, methanol, formaldehyde, polyols, etc. are required, requiring the use of excessive solvents and reducing agents, which not only causes waste of resources and environmental pollution, but also has many safety risks. In addition, hydrogen thermal reduction can also be used to reduce palladium carbon catalysts, but the process operates within the range of 200-500°C, with high energy consumption and high cost, which limits the realization of green chemistry and chemical engineering. Therefore, the present invention provides a simple, safe and environmentally friendly preparation method of palladium carbon catalyst. Summary of the invention

[0005] In view of the above technical problems existing in the prior art, the purpose of the present invention is to provide a preparation of a ligand-modified palladium-carbon catalyst and its application in the selective hydrogenation reaction of the steroid hormone alkynol drug mifepristone. The palladium-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 show high selectivity and hydrogenation activity.

[0006] The present 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 reduction at a suitable temperature. After palladium loading, the palladium-carbon catalyst in which zero-valent palladium and divalent palladium coexist can be obtained through sodium borohydride reduction.

[0007] The technical solution adopted by the present invention is as follows:

[0008] A ligand-modified palladium-carbon catalyst for the selective hydrogenation of mifepristone. The carrier of the catalyst is activated carbon modified with amino ligands. The active component is noble metal Pd. The noble metal Pd is uniformly loaded on the carrier. The loading amount of Pd in ​​the catalyst is 1-10%, and the percentage of the positive-valence Pd content in the catalyst to the total amount of the noble metal Pd element is 40-60%.

[0009] Furthermore, the amino ligand is at least one of ethylenediamine, n-butylamine, phenylethylamine, ethylenediaminetetraacetic acid, benzylamine, and triethylamine, preferably ethylenediamine, and the mass ratio of the amino ligand to the 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 valenced Pd in ​​the catalyst accounts for 50-60% of the total amount of the precious metal Pd element, and the particle size of the precious metal Pd particles is 1-5 nm.

[0011] The present invention also discloses a method for preparing the ligand-modified palladium-carbon catalyst for selective hydrogenation of mifepristone, comprising the following steps:

[0012] 1) adding the activated carbon carrier and the amino ligand into deionized water, heating at 45-55° C. in a water bath, stirring for 5-25 hours, and then filtering with suction, washing the solid product with deionized water, drying, and grinding to obtain an activated carbon carrier modified with the amino ligand;

[0013] 2) Immerse the carrier obtained in step 1) in an aqueous solution of a Pd precursor, stir at a water bath temperature of 45-55°C to allow the Pd precursor to be fully adsorbed on the carrier, then drop a sodium borohydride solution into the carrier, continue stirring at a water bath temperature of 45-55°C for 1-5h to carry out a reduction reaction, then filter, wash, dry and grind to obtain the final catalyst product.

[0014] Furthermore, in step 1), the water bath temperature is 50°C±2°C, and the stirring time is 10-15h.

[0015] Furthermore, in step 2), the Pd precursor is palladium nitrate, the amount of sodium borohydride used is 1.6-2 times the molar amount of the Pd precursor, the temperature of the reduction reaction is 50°C±2°C, and the time of the reduction reaction is 1.5-2.5h.

[0016] The application of the palladium-carbon catalyst in the selective hydrogenation reaction of mifepristone is as follows: the mifepristone is dissolved in an organic solvent to prepare a solution, wherein the organic solvent is one or more of ethanol, acetone, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide and ether; the solution is added into a stainless steel high-pressure batch reactor; the palladium-carbon catalyst is then added; and a selective hydrogenation reaction is carried out under the condition of introducing hydrogen.

[0017] Furthermore, in the application method, the concentration of mifepristone in the solution is 20-50 mg / mL, and the mass ratio of the 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 normal pressure to 1 MPa gauge pressure, preferably 0.1 MPa gauge pressure to 0.2 MPa gauge pressure, the reaction temperature is 15-100°C, preferably 30-50°C, 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. The activated carbon has a complex pore structure inside, and its surface contains functional groups such as hydroxyl groups. When the activated carbon carrier is modified with an amino ligand, the trace hydroxyl groups on the carrier surface provide suitable sites for the amino ligand grafting. The amino groups are then protonated to adsorb metal ions through electrostatic action to improve the metal dispersion, making the Pd nanoparticles loaded on the carrier smaller in size and more evenly distributed. The catalyst preparation process of the present invention is green and simple, short in time and energy consumption, and low in production cost. At the same time, the palladium-carbon catalyst has good stability to air, water and heat.

[0021] 2. When the palladium-carbon catalyst commonly used in the prior art is used for the selective hydrogenation of mifepristone, the catalytic activity is low and the selectivity is poor, and over-hydrogenation reaction is very likely to occur. The specific reasons are attributed to two points: (1) the molecular weight of the reaction substrate mifepristone is large and has a large steric hindrance; (2) the adsorption of the target product during the reaction is strong, resulting in over-hydrogenation. In contrast, the palladium-carbon catalyst modified with different ligand modifiers prepared by the present invention can carry out the hydrogenation reaction of mifepristone at room temperature and low pressure, and its hydrogenation selectivity is as high as 96%, and the hydrogenation activity is greater than 99%. The catalytic activity and selectivity are better than most commercial catalysts.

[0022] 3. The active site of the mifepristone hydrogenation catalyst of the present invention is Pd 0 With Pd 2+ , where Pd 0 Responsible for activating hydrogen, Pd 2+ Responsible for increasing the hydrogen coverage on the catalyst surface, Pd 0 With Pd 2+ The catalyst of the present invention can reduce the reaction energy barrier and promote the selective hydrogenation of mifepristone. 2+ The content is higher than Pd 0+ High, more conducive to the adsorption and desorption of hydrogen and reactants on the catalyst surface, among which Pd 2+ The catalyst has better activity when the content is in the middle range of 40-60%, while the catalyst has poor activity when the content is too low. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1a This is the TEM image of the 5 wt % Pd / C catalyst of Example 7.

[0024] Figure 1b This is the TEM image of the 5wt% Pd / CA-5h catalyst of Example 8.

[0025] Figure 1c This is the TEM image of the 5wt% Pd / CA-12h catalyst of Example 8.

[0026] Figure 1d This is the TEM image of the 5wt% Pd / CA-24h catalyst of Example 8.

[0027] Figure 2 The XRD characterization results of the four catalysts are as follows: 5wt% Pd / C catalyst of Example 7 and 5wt% Pd / CA-5h catalyst, 5wt% Pd / CA-12h catalyst and 5wt% Pd / CA-24h catalyst of Example 8.

[0028] Figure 3 This is a comparison chart of the conversion rate of mifepristone and the selectivity of angostirone when the 5wt% Pd / CA-12h catalyst prepared in Example 8 is used in the catalytic hydrogenation reaction of mifepristone and the catalyst is reused. DETAILED DESCRIPTION

[0029] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0030] Example 1 Pd / C catalyst modified with ethylenediamine ligand

[0031] The catalyst preparation comprises the following steps:

[0032] 1) Using activated carbon and palladium nitrate as raw materials, first disperse 1g of activated carbon in 50ml of deionized water, add 2g (2.25ml) of ethylenediamine and ultrasonicate for 30min, then transfer the mixed solution to a 50°C water bath and stir for modification reaction for 5h before filtering. During the filtration process, add deionized water to wash until the solution pH = 7, transfer the filtered solid to a vacuum drying oven at 100°C and dry it. After 12h, take it out and cool it at room temperature to obtain an activated carbon carrier modified with ethylenediamine, which is ground for standby use.

[0033] 2) 1 g of the modified activated carbon carrier powder obtained in step 1) is added to 30 ml of deionized water to obtain a carrier suspension. Then palladium nitrate is dissolved in deionized water to prepare a 20 mg / mL metal salt solution, and 5.40 ml of palladium nitrate aqueous solution is mixed with 30 ml of the above-prepared carrier suspension according to the Pd loading amount in the catalyst of 5 wt%, stirred in a 50°C water bath for 2 hours, and then 10 ml of the prepared 30 mg / mL sodium borohydride aqueous solution is added and continued to stir for 2 hours, then filtered, washed with water until the solution is neutral, sent to a vacuum drying oven at 100°C and dried overnight, taken out and cooled at room temperature and then finely ground to obtain a Pd / C catalyst modified based on ethylenediamine ligands.

[0034] The Pd / C catalyst modified with ethylenediamine ligand prepared in Example 1 is applied to the selective hydrogenation reaction of mifepristone to synthesize angostirone, comprising the following steps:

[0035] S1: Dissolve 750 mg of mifepristone in 30 ml of tetrahydrofuran to prepare a reaction solution, add the reaction solution into a 50 mL stainless steel high-pressure batch reactor, add 30 mg of catalyst, tighten the reactor and introduce hydrogen, replace the air in the reactor with hydrogen 5 times, then evacuate the air in the reactor and fill it with hydrogen to a gauge pressure of 0.1 MPa.

[0036] S2: Set the reaction temperature to 30°C, the magnetic stirring rate to 800r / min, take samples during the reaction, and calculate the conversion rate of mifepristone and the selectivity of angostrin. According to the above experimental process, the experimental results are: the conversion rate of 30min reaction is 65.28%, and the selectivity is 96.97%; the conversion rate of 60min reaction is 98.76%, and the selectivity is 95.16%.

[0037] The conversion rate data in the examples of the present invention refer to the conversion rate of mifepristone, and the selectivity data refer to the selectivity of angostrin.

[0038] Example 2 Pd / C catalyst modified with n-butylamine ligand

[0039] Example 2 Catalyst preparation steps repeat Example 1, the only difference is "in step 1) 2g of ethylenediamine is replaced by 2g of n-butylamine", and other conditions remain unchanged, and finally a Pd / C catalyst modified based on n-butylamine ligand is obtained.

[0040] The catalyst of Example 2 was used for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were as follows: the conversion rate after 30 minutes of reaction was 46.13%, and the selectivity was 97.05%; the conversion rate after 60 minutes of reaction was 82.25%, and the selectivity was 96.07%.

[0041] Example 3 Pd / C catalyst modified with phenylethylamine

[0042] Example 3 Catalyst preparation steps repeat Example 1, the only difference is that "in step 1), 2 g of ethylenediamine is replaced by 2 g of phenylethylamine", and other conditions remain unchanged, and finally a Pd / C catalyst modified by phenylethylamine is obtained.

[0043] The catalyst of Example 3 was used for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were as follows: the conversion rate after 30 minutes of reaction was 24.97%, and the selectivity was 96.80%; the conversion rate after 60 minutes of reaction was 37.70%, and the selectivity was 97.13%.

[0044] Example 4 Pd / C catalyst modified with ethylenediaminetetraacetic acid

[0045] Example 4 Catalyst preparation steps repeat Example 1, the only difference is that "in step 1), 2g of ethylenediamine is replaced by 2g of ethylenediaminetetraacetic acid", and other conditions remain unchanged, and finally a Pd / C catalyst modified by ethylenediaminetetraacetic acid is obtained.

[0046] The catalyst of Example 4 was used for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results showed that the conversion rate after 30 minutes of reaction was 83.11% and the selectivity was 93.50%; the conversion rate after 60 minutes of reaction was 98.69% and the selectivity was 75.98%.

[0047] Example 5 Pd / C catalyst based on benzylamine modification

[0048] Example 5 Catalyst preparation steps repeat Example 1, the only difference is that "2 g of ethylenediamine is replaced by 2 g of benzylamine in step 1)", and the other conditions remain unchanged, and finally a Pd / C catalyst modified by benzylamine is obtained.

[0049] The catalyst of Example 5 was used for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results showed that the conversion rate after 30 minutes of reaction was 86.62% and the selectivity was 90.88%; the conversion rate after 60 minutes of reaction was 98.99% and the selectivity was 79.58%.

[0050] Example 6 Pd / C catalyst modified with triethylamine

[0051] The catalyst preparation steps of Example 6 are repeated in Example 1, with the only difference being that "in step 1), 2 g of ethylenediamine is replaced by 2 g of triethylamine", and the other conditions remain unchanged, and finally a Pd / C catalyst modified by triethylamine is obtained.

[0052] The catalyst of Example 6 was used for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results showed that the conversion rate after 30 minutes of reaction was 40.75% and the selectivity was 94.23%; the conversion rate after 60 minutes of reaction was 83.12% and the selectivity was 80.14%.

[0053] Example 7 Pd / C catalyst based on commercial activated carbon support

[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. According to the Pd loading in the catalyst of 5 wt%, 5.40 ml of the palladium nitrate aqueous solution was mixed with 1 g of activated carbon dispersed in 30 ml of deionized water, and stirred in a 50°C water bath for 2 h. Then 10 ml of the prepared 30 mg / mL sodium borohydride solution was added and continued to stir for 2 h. Then, it was filtered and washed with water until the solution was neutral. It was sent to a vacuum drying oven at 100°C and dried overnight. After being taken out and cooled at room temperature, it was finely ground to obtain a Pd / C catalyst based on commercial activated carbon loading, named 5wt% Pd / C catalyst.

[0055] The catalyst of Example 7 was used for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results showed that the conversion rate after 30 minutes of reaction was 70.70% and the selectivity was 89.43%; the conversion rate after 60 minutes of reaction was 98.97% and the selectivity was 82.47%.

[0056] Example 8 Pd / C catalyst modified with ethylenediamine for different times

[0057] The catalyst preparation steps of Example 8 are repeated as in Example 1, with the only difference being that "the stirring time for the modification reaction in step 1) is replaced with 5h, 12h, and 24h, respectively". Finally, Pd / C catalysts modified with ethylenediamine for 5h, 12h, and 24h were obtained, which were 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 5wt% Pd / C catalyst of Example 7 and the 5wt% Pd / CA-5h catalyst, 5wt% Pd / CA-12h catalyst, and 5wt% Pd / CA-24h catalyst of Example 8 are summarized in Figure 1, which correspond to the TEM results of sub-graphs a, b, c, and d in Figure 1. It can be seen from the TEM results of sub-graphs a, b, c, and d in Figure 1 that the average particle sizes of the Pd particles supported on the catalyst are 3.47nm, 2.23nm, 1.86nm, and 1.65nm, respectively.

[0059] The XRD characterization results of the 5wt% Pd / C catalyst of Example 7 and the 5wt% Pd / CA-5h catalyst, 5wt% Pd / CA-12h catalyst, and 5wt% Pd / CA-24h catalyst of Example 8 are shown in Figure 2 .from Figure 2It can be seen that all four catalysts have a diffraction peak at 2θ=40°, which is attributed to the Pd (111) crystal plane, and the peak intensity becomes weaker as the modification time increases, indicating that the particle size of Pd does gradually decrease as the modification time increases. Characterization proves that the Pd nanoparticles loaded on the carrier after the ethylenediamine ligand modification and then palladium loading do make the size of the Pd nanoparticles loaded on the carrier smaller and more evenly distributed.

[0060] Subsequently, the BET test revealed that the four catalysts were all mesoporous carbon materials with pore sizes ranging from 5 to 7 nm. The specific surface area of ​​the catalyst without modifier in Example 7 was 986.3 cm 2 / g, the pore volume is kept at 0.8cm 3 / g. In Example 8, the specific surface area of ​​the activated carbon carrier after modification with ethylenediamine is greatly reduced. 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 are 95.5 cm 2 / g, 296.6cm 2 / g, 278.9cm 2 / g, and the amino ligands will block the macropores on the support, so that the pore volume of the catalyst is reduced from 0.8 cm2 in Example 7 without modification. 3 / g is reduced to 0.2-0.3cm 3 / g (the macropores are blocked after the ligand is connected, and the pore volume is between 0.2-0.3 regardless of the modification time), but the specific surface area increases slightly to 296.6cm with the increase of modification time. 2 / g, further indicating that the modification time should not be too long. Although the modification is advantageous for the dispersion of PdNP on the catalyst, too long a modification will gradually block the micropores and be detrimental to the diffusion and mass transfer of the reactants. In summary, the best catalyst is the Pd / C catalyst modified with ethylenediamine ligand for 12h. X-ray photoelectron spectroscopy (XPS) shows that the Pd in ​​the best catalyst 2+ The content accounts for 55% of the total Pd element content.

[0061] Example 8 In the preparation of the Pd / C catalyst modified with ethylenediamine ligand for 12 hours, the molar amount of sodium borohydride is 1.68 times the molar amount of palladium nitrate, which means that theoretically 84% of Pd 2+ ion is reduced to Pd 0 The experimental results show that only about 45% of Pd 2+ ion is reduced to Pd 0 The reason may be:

[0062] ① Although sodium borohydride is a strong reducing agent, if the palladium compound exists in a complex form, some palladium ions may be wrapped inside some ligand structures, making it difficult for sodium borohydride to contact these palladium ions and unable to completely reduce them to zero-valent palladium, resulting in the existence of divalent palladium.

[0063] ② Secondly, consider it from the perspective of chemical equilibrium. The reduction reaction is a reversible process. Under certain conditions, a balance may be reached between zero-valent palladium and divalent palladium. Even if an excess of sodium borohydride is added, the reaction will not proceed completely in the direction of generating zero-valent palladium. For example, when there are certain substances in the reaction system that can stably coordinate with divalent palladium, the divalent palladium will be relatively stable and difficult to be further reduced.

[0064] The 5wt% Pd / CA-5h catalyst of Example 8 was tested for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were: the conversion rate after 30 minutes of reaction was 65.28%, and the selectivity was 96.97%; the conversion rate after 60 minutes of reaction was 99.97%, and the selectivity was 95.16%.

[0065] The 5wt% Pd / CA-12h catalyst of Example 8 was used for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were: the conversion rate after 30 minutes of reaction was 96.89%, and the selectivity was 97.83%; the conversion rate after 60 minutes of reaction was 98.96%, and the selectivity was 97.64%.

[0066] The 5wt% Pd / CA-24h catalyst of Example 8 was tested for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results were: the conversion rate after 30 minutes of reaction was 98.57%, and the selectivity was 95.18%; the conversion rate after 60 minutes of reaction was 97.92%, and the selectivity was 90.51%.

[0067] The results showed that modification with ethylenediamine could improve the selectivity of the catalyst, and the catalyst prepared after modification for 12 hours had the best performance, achieving efficient and selective hydrogenation of mifepristone at room temperature and low pressure.

[0068] In addition, the 5wt% Pd / CA-12h catalyst of Example 8 was subjected to a repeated application experiment for the selective hydrogenation reaction of mifepristone. The experimental steps of the catalytic reaction repeated those of Example 1. The reaction time of one batch of catalytic reactions was 30 minutes. After the reaction was completed, the catalyst was separated from the reaction solution. The separated and recovered catalyst was washed with ethanol and then applied to the next batch of catalyst application reactions. Considering that a small amount of loss is inevitable when the catalyst is recovered, the loss is about 10%, so about 3 mg of catalyst is added when the next batch of catalyst is applied. According to this experimental method, the conversion rate of mifepristone and the selectivity of angosturastone when the catalyst is reused are compared in the figure. Figure 3 It can be seen that the catalyst has good stability and the catalytic activity has basically not decreased after 7 consecutive uses.

[0069] Example 9 Semi-hydrogenation activity of the catalyst prepared based on Example 1 at different temperatures

[0070] The 5wt% Pd / CA-12h catalyst of Example 8 was tested for the selective hydrogenation of mifepristone according to the method of Example 1. The experimental steps were repeated in Example 1, except that the temperature of the catalytic reaction was changed, and the other conditions remained unchanged. The temperature of the catalytic reaction was changed to 15°C, 20°C, 25°C, 30°C, 50°C, and 100°C, respectively, and the hydrogen pressure of the reaction was set to a gauge pressure of 0.1 MPa. The other conditions were the same as in Example 1, and the experimental results of the catalytic reaction for 30 minutes are shown in Table 1.

[0071] Table 1

[0072] Reaction temperature (℃) 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 the data in Table 1, too low a temperature will lead to a decrease in conversion rate, while too high a temperature will significantly reduce the hydrogenation selectivity. This is because at low temperatures, the dissociation of hydrogen becomes slower, thus affecting the degree of hydrogenation. Under high temperature conditions, the heat released by the hydrogenation reaction cannot be taken away in time, which will cause the temperature of the catalytic system to be too high, increase the carbon deposition of the catalyst, and accelerate the deactivation rate; and too high a temperature will increase the over-hydrogenation products, thereby reducing the selectivity of the catalytic reaction; at the same time, the catalyst valence state is easily reduced by the reactants and hydrogen under high temperature conditions, causing the Pd in ​​the catalyst to 2+ The content decreased, while Pd 0 With Pd 2+ The ratio of has a great influence on the catalytic activity. Therefore, controlling the temperature at 30-50°C is the optimal reaction temperature.

[0074] Example 10 Semi-hydrogenation activity of the catalyst prepared in Example 1 at different pressures

[0075] The 5wt% Pd / CA-12h catalyst of Example 8 was tested for the selective hydrogenation of mifepristone according to the method of Example 1, except that the hydrogen pressure of the catalytic reaction was changed, and the other conditions remained unchanged. The hydrogen pressure of the catalytic reaction was changed to normal pressure (hydrogen balloon), gauge pressure 0.1MPa, gauge pressure 0.2MPa, gauge pressure 0.5MPa, gauge pressure 1MPa, respectively, the reaction temperature was set to 25°C, and the other conditions were the same as in Example 1. The experimental results of the catalytic reaction for 30min are shown in Table 2.

[0076] Table 2

[0077] Reaction pressure Conversion rate (%) Selectivity (%) Normal pressure (hydrogen balloon) 59.24 95.53 Gauge pressure 0.1MPa 96.89 97.83 Gauge pressure 0.2MPa 97.52 97.30 Gauge pressure 0.5MPa 98.09 89.53 Gauge pressure: 1.0MPa 98.88 86.10

[0078] The experimental results in Table 2 show that the hydrogen pressure has a great influence on the reaction results. If the pressure is too low, the hydrogen partial pressure will be reduced accordingly, so that the hydrogenation reaction cannot be fully carried out, resulting in a decrease in conversion rate. Increasing the reaction pressure is conducive to the hydrogenation reaction, speeding up the reaction rate, and also helping the selectivity of the hydrogenation reaction. It can also inhibit the coking reaction, reduce the deactivation rate of the catalyst, and reduce the carbon deposition on the catalyst, thereby extending the service life of the catalyst. However, when the pressure is too high, the hydrogen concentration is too high. 2+ The pole is completely reduced to Pd 0 On the contrary, it will reduce the catalytic ability.

[0079] Comparative Example 1: A commercial palladium-carbon catalyst without ligand modification was used for the selective hydrogenation of mifepristone. The catalyst was derived from a purchased 5 wt% commercial palladium-carbon catalyst.

[0080] The catalyst of Comparative Example 1 was tested for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results showed that 5 wt% of the commercial palladium-carbon catalyst was used for the selective hydrogenation of mifepristone to angostirone. The conversion rate after 30 min of reaction was 78.48%, and the selectivity was 84.89%; the conversion rate after 60 min of reaction was 98.68%, and the selectivity was 67.49%.

[0081] Comparative Example 2: Pd / C catalyst modified with ethylenediamine prepared by hydrogen reduction method

[0082] The catalyst preparation comprises the following steps:

[0083] 1) Using activated carbon and palladium nitrate as raw materials, first disperse 1g of activated carbon in 50ml of deionized water, add 2g (2.25ml) of ethylenediamine and ultrasonicate for 30min, then transfer the mixed solution to a 50°C water bath and stir for modification reaction for 12h and then filter. During the filtration process, add deionized water to wash until the solution pH = 7, transfer the filtered solid to a vacuum drying oven at 100°C and dry it. After 12h, take it out and cool it at room temperature to obtain an activated carbon carrier modified with ethylenediamine, which is ground for standby use.

[0084] 2) 1 g of the modified activated carbon carrier powder obtained in step 1) was added to 30 ml of deionized water to obtain a carrier suspension. Palladium nitrate was then dissolved in deionized water to prepare a 20 mg / mL metal salt solution. According to the Pd loading in the catalyst of 5 wt%, 5.40 ml of the palladium nitrate aqueous solution was mixed with 30 ml of the above-prepared carrier suspension, stirred in a 50°C water bath for 2 h, and then the temperature was raised to 100°C to dry the solution. The obtained powder was then reduced in a tubular furnace at 200°C or 300°C for 2 h under a hydrogen atmosphere. The catalysts finally prepared were marked as 5 wt% Pd / CA-200°C catalyst and

[0085] 5wt% Pd / CA-300°C catalyst.

[0086] The 5wt% Pd / CA-200°C catalyst of Comparative Example 2 was tested for the selective hydrogenation of mifepristone according to the method of Example 1. The experimental results showed that the conversion rate after 30 minutes of reaction was 55.71% and the selectivity was 95.23%; the conversion rate after 60 minutes of reaction was 85.45% and the selectivity was 81.78%.

[0087] The 5wt% Pd / CA-300℃ catalyst of Comparative Example 2 was tested for the selective hydrogenation of mifepristone according to the method of Example 1. The experimental results showed that the conversion rate after 30 minutes of reaction was 70.22% and the selectivity was 95.11%; the conversion rate after 60 minutes of reaction was 90.98% and the selectivity was 83.61%.

[0088] Comparative Example 3: Pd / C catalyst modified with ethylenediamine prepared by formic acid reduction method

[0089] The catalyst preparation comprises the following steps:

[0090] 1) Using activated carbon and palladium nitrate as raw materials, first disperse 1g of activated carbon in 50ml of deionized water, add 2g (2.25ml) of ethylenediamine and ultrasonicate for 30min, then transfer the mixed solution to a 50°C water bath and stir for modification reaction for 12h and then filter. During the filtration process, add deionized water to wash until the solution pH = 7, transfer the filtered solid to a vacuum drying oven at 100°C and dry it. After 12h, take it out and cool it at room temperature to obtain an activated carbon carrier modified with ethylenediamine, which is ground for standby use.

[0091] 2) Disperse 1 g of the activated carbon carrier modified with ethylenediamine in step 1) and 0.05 g of NaCl in 30 ml of deionized water, stir in a 50°C water bath for 30 min, then add 5.40 ml of an aqueous palladium nitrate solution to the mixture according to a Pd loading of 5 wt% in the catalyst, continue stirring for 2 h, adjust the pH of the mixture to 8-9 with a 0.1 mol / L NaOH solution, then add 10 ml of formic acid and stir at 50°C for 2 h, filter, wash with water until the solution is neutral, dry in a vacuum drying oven at 100°C overnight, take out, cool at room temperature, and grind carefully to obtain an ethylenediamine-modified Pd / C catalyst prepared by a formic acid reduction method.

[0092] The catalyst of Comparative Example 3 was used for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results showed that the conversion rate after 30 minutes of reaction was 36.33% and the selectivity was 95.62%; the conversion rate after 60 minutes of reaction was 74.38% and the selectivity was 86.22%.

[0093] Comparative Example 4: Pd / C catalyst modified with ethylenediamine prepared by formaldehyde reduction method

[0094] The catalyst preparation comprises the following steps:

[0095] 1) Using activated carbon and palladium nitrate as raw materials, first disperse 1g of activated carbon in 50ml of deionized water, add 2g (2.25ml) of ethylenediamine and ultrasonicate for 30min, then transfer the mixed solution to a 50°C water bath and stir for modification reaction for 12h and then filter. During the filtration process, add deionized water to wash until the solution pH = 7, transfer the filtered solid to a vacuum drying oven at 100°C and dry it. After 12h, take it out and cool it at room temperature to obtain an activated carbon carrier modified with ethylenediamine, which is ground for standby use.

[0096] 2) Disperse 1 g of the activated carbon carrier modified with ethylenediamine in step 1) and 0.05 g of NaCl in 30 ml of deionized water, stir in a 50°C water bath for 30 min, then add 5.40 ml of an aqueous palladium nitrate solution to the mixture according to a Pd loading of 5 wt% in the catalyst, continue stirring for 2 h, adjust the pH of the mixture to 8-9 with a 0.1 mol / L NaOH solution, then add 7.5 ml of formaldehyde and stir at 50°C for 2 h, filter and wash with water until the solution is neutral, dry in a vacuum drying oven at 100°C overnight, take out, cool at room temperature, and then grind carefully to obtain an ethylenediamine-modified Pd / C catalyst prepared by formaldehyde reduction.

[0097] The catalyst of Comparative Example 4 was used for the selective hydrogenation reaction of mifepristone according to the method of Example 1. The experimental results showed that the conversion rate after 20 minutes of reaction was 98.49% and the selectivity was 92.96%. The conversion rate after 30 minutes of reaction was 99.65% and the selectivity was 93.66%.

[0098] As can be seen from the comparative examples, by comparing the catalytic performance of 5 wt% commercial palladium-carbon catalyst for the semi-hydrogenation reaction of mifepristone under the same reaction conditions, it can be seen that its activity selectivity is far inferior to the heterogeneous catalyst of ethylenediamine-modified activated carbon loaded with Pd in ​​the present invention, further indicating the importance of amino ligand-modified carbon carrier in the present invention.

[0099] In addition, the heterogeneous catalyst of Pd supported on ethylenediamine-modified activated carbon was reduced by different reduction methods and it was found that Pd 0+ The catalysts that account for a large proportion of the total catalysts require a long time for the catalytic reaction, and cannot achieve the catalytic activity and selectivity of the best catalyst of the present invention. The use of formic acid and formaldehyde for reduction cannot achieve both high selectivity and high conversion rate, and secondly, formic acid and formaldehyde are harmful to the human body, and formaldehyde is highly volatile and easily exceeds the standard, posing a threat to the experimental results and the safety of the participants; the experiment found that the use of sodium borohydride for reduction has the best effect, and the process of preparing the catalyst is green and pollution-free.

[0100] The above examples of hydrogenation of mifepristone are all exemplary. The present invention is a novel supported hydrogenation catalyst with high activity and selectivity, which can achieve nearly 100% conversion of mifepristone in a short time at normal temperature and low pressure. It is within the scope of the present invention for those skilled in the art to make appropriate changes to the present invention, such as replacing the hydrogenation substrate (small molecule or polymer containing a carbon-carbon triple bond), replacing the ligand modifier, replacing other oxide carriers, and appropriately changing the reaction pressure, temperature, substrate concentration, etc.

[0101] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A ligand-modified palladium-carbon catalyst for the selective hydrogenation of mifepristone, characterized in that The carrier of the catalyst is amino ligand modified activated carbon, the active component is precious metal Pd, the precious metal Pd is uniformly loaded on the carrier, the loading amount of Pd in ​​the catalyst is 1-10%, and the percentage of positive valence Pd content in the catalyst accounts for 40-60% of the total amount of precious metal Pd element.

2. A ligand-modified palladium-carbon catalyst for the selective hydrogenation of mifepristone as claimed in claim 1, characterized in that The amino ligand is at least one of ethylenediamine, n-butylamine, phenylethylamine, ethylenediaminetetraacetic acid, benzylamine, and triethylamine, preferably ethylenediamine. The mass ratio of the amino ligand to the activated carbon is 1.5-3:1, preferably 1.8-2:

1.

3. A ligand-modified palladium-carbon catalyst for the selective hydrogenation of mifepristone as claimed in claim 1, characterized in that The Pd loading in the catalyst is 3-5%, the content of positively valenced Pd in ​​the catalyst accounts for 50-60% of the total amount of precious metal Pd element, and the particle size of the precious metal Pd particles is 1-5 nm.

4. A method for preparing a ligand-modified palladium-carbon catalyst for selective hydrogenation of mifepristone as claimed in claim 1, characterized in that The following steps are involved: 1) Add the activated carbon carrier and the amino ligand into deionized water, heat at 45-55°C in a water bath, stir for 5-25h, and then filter. Wash the solid product with deionized water, dry it, and grind it to obtain an activated carbon carrier modified with the amino ligand. 2) The carrier obtained in step 1) is immersed in an aqueous solution of a Pd precursor, stirred at a water bath temperature of 45-55°C to allow the Pd precursor to be fully adsorbed on the carrier, and then a sodium borohydride solution is added dropwise, and stirring is continued at a water bath temperature of 45-55°C for 1-5 hours to carry out a reduction reaction, followed by suction filtration, washing, drying, and grinding to obtain the final catalyst product.

5. A method for preparing a ligand-modified palladium-carbon catalyst for selective hydrogenation of mifepristone as claimed in claim 4, characterized in that In step 1), the water bath temperature is 50°C ± 2°C and the stirring time is 10-15h.

6. A method for preparing a ligand-modified palladium-carbon catalyst for selective hydrogenation of mifepristone as claimed in claim 4, characterized in that In step 2), the Pd precursor is palladium nitrate, the amount of sodium borohydride used is 1.6-2 times the molar amount of the Pd precursor, the temperature of the reduction reaction is 50°C ± 2°C, and the time of the reduction reaction is 1.5-2.5h.

7. Application of the palladium-carbon catalyst as claimed in claim 1 in the selective hydrogenation reaction of mifepristone.

8. The use according to claim 7, characterized in that Mifepristone is dissolved in an organic solvent to prepare a solution, wherein the organic solvent is one or more of ethanol, acetone, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide and ether, the solution is added into a stainless steel high-pressure batch reactor, and then the palladium-carbon catalyst is added, and a selective hydrogenation reaction is carried out under the condition of introducing hydrogen.

9. The use according to claim 7, characterized in that The concentration of mifepristone in the solution is 20-50 mg / mL, and the mass ratio of the catalyst to mifepristone is 0.02-0.1:1, preferably 0.04-0.05:

1.

10. The use according to claim 8, characterized in that The hydrogen pressure is from normal pressure to 1 MPa, preferably 0.1 MPa to 0.2 MPa. The reaction temperature is 15-100°C, preferably 30-50°C. The reaction time is 20-80 min, preferably 30-60 min.

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