A method for electrocatalytic oxidation of nickel molybdenum oxide to prepare 19-formyl-4-androstene-3,17-dione

Abstract

The present invention relates to a method for electrocatalytic oxidation of nickel molybdenum oxide to prepare 19-formyl-4-androstene-3,17-dione. This method uses a continuous flow electrolytic cell for the reaction. In the anodic chamber, a metal nickel molybdenum oxide catalyst is used as the working electrode, and 19-hydroxy-4-androstene-3,17-dione is used as the reaction substrate, which is dissolved in a mixed solution of an alkaline solution and an organic solvent as the anolyte. A nitroxide radical is added as a mediator, and an electrocatalytic oxidation reaction is carried out under a constant current. After the reaction is completed, 19-formyl-4-androstene-3,17-dione is obtained through post-treatment; in the cathodic chamber, nickel foam is used as a hydrogen evolution catalyst, and an alkaline solution is used as the catholyte for the hydrogen evolution reaction. The electrocatalytic oxidation reaction process of the present invention has mild conditions, is green and pollution-free, has a high raw material conversion rate, good selectivity for 19-formyl-4-androstene-3,17-dione, and a high yield. Moreover, compared with noble metal catalysts, the transition metal oxide catalyst used in the present invention has a low cost and avoids the consumption of rare noble metals.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a steroid hormone drug product, belonging to the technical field of fine chemical production, and particularly relates to a method for electrocatalytic oxidation of nickel molybdenum oxide to prepare 19-formyl-4-androstene-3,17-dione. Background Art

[0002] At present, steroid drugs are the second largest category of chemical drugs after antibiotics. Since the 1990s, the sales of steroid hormone drugs in the international market have been increasing at a rate of 10%-15% per year, and the global sales of steroid hormone drugs are expected to reach $150 billion in 2020. Steroid hormone drugs such as testosterone, nandrolone, tibolone, etc. are commonly used to treat diseases such as rheumatism, cardiovascular diseases, skin diseases, endocrine disorders, etc., and are widely used in the medical field. Steroid hormone drugs refer to hormone drugs containing a steroid structure in the molecule. Hormone drugs include prostaglandins, steroid hormones, and peptide hormones, among which steroid hormone drugs are the most important category of hormone drugs, are an indispensable and important drug in clinical practice, and are also an important part of steroid drugs. In the synthesis process of steroid hormone drugs, the conversion of alcohol to aldehyde or carbonyl is a very important oxidation reaction, such as the reaction of oxidizing 19-hydroxy-4-androstene-3,17-dione to 19-formyl-4-androstene-3,17-dione. 19-Formyl-4-androstene-3,17-dione is an important steroid drug intermediate, which can be used to prepare drugs such as tibolone, hydrocortisone, mifepristone, dienogest, norethisterone, etc. Mibolerone and tibolone products have both progestogenic, estrogenic, and androgenic activities, and have a significant effect on treating women's menopausal syndrome and preventing bone loss after menopause in women. The traditional method for producing 19-formyl-4-androstene-3,17-dione is to use chromium-based oxidants such as Collins reagent, pyridinium chlorochromate (PCC) reagent, and pyridinium dichromate (PDC) reagent. However, traditional chromium-based oxidants not only have certain toxicity and chromium metal waste residue pollutes the environment, but also have a long reaction time and low product selectivity.

[0003] Therefore, finding a greener production process with a more environmentally friendly environment has become the research focus of current fine chemical synthesis. Summary of the Invention

[0004] Aiming at the above problems existing in the prior art, the purpose of the present invention is to provide a method for electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione by nickel molybdenum oxide. The present invention uses metal nickel molybdenum oxide as a catalyst, and its preparation process is simple. As a catalyst for electrocatalytic oxidation to prepare 19-formyl-4-androstene-3,17-dione from 19-hydroxy-4-androstene-3,17-dione, its process is green and economical, the reaction process is simple and easy to operate, the catalyst cost is low and the reaction yield is high.

[0005] The method for electrocatalytic oxidation of nickel molybdenum oxide to prepare 19-formyl-4-androstene-3,17-dione controls the reaction current and voltage by a galvanostat, and uses a continuous flow electrolytic cell for the reaction. The cathode chamber and the anode chamber are separated by an ion exchange membrane. It is characterized in that in the anode chamber, metal nickel molybdenum oxide is used as a catalyst for the oxidation reaction and used as the working electrode. The reaction substrate 19-hydroxy-4-androstene-3,17-dione is dissolved in a mixed solvent as the anolyte, and a nitroxide radical is used as a mediator. The electrocatalytic oxidation reaction is carried out in a constant temperature water bath at a temperature of 30-50 °C, a current of 0.05-1.5 A, and an anode voltage of 0.5-1 V. After the reaction is completed, the reaction solution is cooled, an organic solvent is added for extraction, and the organic layer is taken and distilled under reduced pressure to obtain 19-formyl-4-androstene-3,17-dione. The metal nickel molybdenum oxide catalyst is composed of a three-dimensional porous material as a carrier, and the metal nickel molybdenum oxide is loaded on the three-dimensional porous material, and the ratio of nickel to molybdenum is 1:0-11; in the cathode chamber, nickel foam is used as a catalyst for the hydrogen evolution reaction and used as the counter electrode, and a weakly alkaline solution with a concentration of 0.1-1.0 mol / L is used as the catholyte for the hydrogen evolution reaction;

[0006] The reaction equation of the anodic reaction is as follows:

[0007]

[0008] Furthermore, the present invention also defines that the volumes of both the cathode chamber and the anode chamber are 200 mL; the concentration of the reactant 19-hydroxy-4-androstene-3,17-dione is 100 mmol / L.

[0009] Furthermore, the present invention also defines that the mixed solvent in the anode chamber is divided into a main solvent and a secondary solvent. The main solvent is an aqueous sodium carbonate solution with a concentration of 0.1-1.0 mol / L, preferably 1 mol / L; the secondary solvent is one of tetrahydrofuran, dichloromethane, acetonitrile or acetone, preferably acetonitrile; the volume ratio of the main solvent to the secondary solvent in the mixed solvent is 7:3-3:7.

[0010] Furthermore, the present invention also defines that the nitroxide radical is TEMPO, 4-amino-TEMPO, 4-acetylamino-TEMPO (ACT) or 4-hydroxy-TEMPO, and in the anodic mixed solution, the concentration of the nitroxide radical is 1-10 mmol / L.

[0011] Furthermore, the present invention also defines that in the cathode chamber, the weak alkaline solution is sodium carbonate solution, sodium bicarbonate solution, sodium phosphate solution or sodium hydrogen phosphate solution, preferably sodium carbonate solution, and its concentration is 1.0 mol / L.

[0012] Furthermore, the present invention also defines that the reaction time for the electrocatalytic oxidation reaction is 1000-5000 s, preferably 1300 s; the flow rate of continuously pumping the solution into the flow-through electrolytic cell by a peristaltic pump is 50-150 mL / min, preferably 120 mL / min.

[0013] Furthermore, the present invention also defines that the organic solvent for extraction is toluene, dichloromethane, chloroform, ethyl acetate or chloroform.

[0014] Furthermore, the present invention also defines that the three-dimensional porous material includes carbon felt or nickel foam. In the metal nickel molybdenum oxide, the feeding ratio of nickel to molybdenum is 1:0, 1:3, 1:5, 1:7, 1:9 or 1:11, and the loading amount of the metal oxide on the three-dimensional porous material carrier is 10 mg / cm 2 .

[0015] Furthermore, the present invention also defines that the preparation method of the metal nickel molybdenum oxide catalyst includes the following steps:

[0016] 1) According to the feeding ratio, dissolve the metal salt in 40 mL of deionized water, then add 40 mL of ethylene glycol thereto, and ultrasonically disperse the solution for 30 min to obtain solution A. The metals in the metal salt are nickel and molybdenum; the nickel salt is nickel nitrate, nickel chloride, nickel acetylacetonate, nickel bromide or nickel acetate; the molybdenum salt is ammonium molybdate, sodium molybdate, cobalt molybdate, calcium molybdate or manganese molybdate;

[0017] 2) Add the solution A in step 1) and the carrier into a hydrothermal autoclave, carry out hydrothermal reaction at 100-140 °C for 10-12 hours, cool to room temperature after the reaction, take out the carrier, then wash it three times with distilled water and ethanol, and then dry it in a vacuum drying oven at 60 °C to obtain the supported metal nickel molybdenum oxide catalyst.

[0018] Furthermore, the present invention also defines that the nickel salt in step 1) is nickel chloride and the molybdenum salt is calcium molybdate.

[0019] By adopting the above technologies, compared with the existing production process of 19-aldehyde-4-androstene-3,17-dione, the beneficial effects of the present invention are as follows:

[0020] 1) The oxidation reaction of the present invention uses electrons as the oxidant, completely avoiding the use of chemical oxidants, reducing costs while meeting the requirements of green environmental protection;

[0021] 2) The present invention synthesizes a nickel molybdenum oxide electrocatalyst by a method with low cost and short preparation process. By introducing metal molybdenum, the oxidation ability of nickel element is promoted, so that the nickel molybdenum oxide catalyst shows excellent catalytic activity and stability during the reaction process, and the selectivity and conversion rate of the product are high, providing basic application research for this type of material in the field of electrocatalysis and having broad application prospects;

[0022] 3) During the reaction process of the present invention, a peristaltic pump is used to continuously pump the solution into the reaction tank. Compared with the batch reactor (non-flowing), this flow mode effectively reduces the influence of concentration polarization during the reaction process, and the reaction performance is significantly improved;

[0023] 4) During the reaction process of the present invention, after combining the nickel molybdenum oxide catalyst with the medium ACT, etc., the oxidation current of the substrate 19-hydroxy-4-androstene-3,17-dione can reach 1.5 A, and the reaction time is shortened to within 1300 s. Compared with the batch reactor, the reaction time is greatly reduced, reducing costs and energy consumption. Description of the Drawings

[0024] Figure 1 SEM image of the NiMoO4 / GF catalyst of Example 1 at 1 μm;

[0025] Figure 2 SEM image of the NiMoO4 / GF catalyst of Example 1 at 100 nm;

[0026] Figure 3 Graph of the change of reactants over time for electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione in Example 1;

[0027] Figure 4 LSV comparison graph of the batch reactor of Example 9 and the flow reactor of Example 1. Detailed Description of the Invention

[0028] Now, the present invention will be further described in detail with reference to the embodiments. The application of the present invention is not limited to the following embodiments, and any formal modification made to the present invention will fall within the protection scope of the present invention.

[0029] Example 1: Synthesis of NiMoO4 / GF (Ni:Mo = 1:7) catalyst and its electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione

[0030] (1) According to the feeding ratio, 540 mg of nickel nitrate and 2.1 g of ammonium molybdate were dissolved in 40 mL of distilled water, and then 40 mL of ethylene glycol was added. The solution was ultrasonically dispersed for 30 minutes to obtain solution A;

[0031] (2) Solution A in step (1) and the three-dimensional porous material as the carrier were added into a hydrothermal reactor, and hydrothermal reaction was carried out at 120 °C for 10 hours. After the reaction, it was cooled, the carrier was taken out, and then washed three times with distilled water and ethanol, and then dried in a vacuum drying oven at 60 °C to obtain the supported nickel molybdenum oxide catalyst, marked as NiMoO4 / GF (Ni:Mo = 1:7). Its SEM scanning electron micrograph is as Figure 1 and 2 shown. It can be found from Figure 1 and Figure 2 that the NiMoO4 / GF catalyst has a nanoneedle morphology and is uniformly loaded.

[0032] The NiMoO4 / GF (Ni:Mo = 1:7) catalyst prepared in Example 1 was subjected to electrocatalytic oxidation at an electrolyte temperature of 30 °C to prepare 19-aldehyde-4-androstene-3,17-dione from 19-hydroxy-4-androstene-3,17-dione.

[0033] The oxidation of 19-hydroxy-4-androstene-3,17-dione was carried out by the constant current method. The current was controlled at 1.5 A by the constant current method in the electrochemical workstation. During the reaction, the reaction solution was continuously pumped into the flow-through electrolytic cell by a peristaltic pump, and the flow rate of the peristaltic pump was 120 mL / min. The anode chamber and the cathode chamber were separated by an ion exchange membrane. A mixed solution of 50 mL of 1.0 mol / L sodium carbonate aqueous solution and 50 mL of acetonitrile (the feeding volume ratio of the main solvent to the secondary solvent is 5:5) was used as the electrolytic solution in the anode chamber, and the temperature of the reaction solution was controlled at 30 °C. 100 mL of 1.0 mol / L sodium carbonate aqueous solution was used as the electrolytic solution in the cathode chamber; in the anode chamber of the electrolytic cell, the prepared NiMoO4 / GF (Ni:Mo = 1:7) catalyst was used as the working electrode and ACT was added as a medium for the oxidation reaction; in the cathode chamber of the electrolytic cell, nickel foam was used as the catalyst for the hydrogen evolution reaction for the hydrogen evolution reaction, specifically as follows:

[0034] S1: 3 g of 19-hydroxy-4-androstene-3,17-dione was taken as the reactant and added to the electrolytic solution in the anode chamber, and then 213 mg of ACT was added to the electrolytic solution in the anode chamber;

[0035] S2: Place the reaction solution in a constant temperature water bath to control the temperature of the reaction system at 30 °C, stir, and continuously pump the reaction solution into a flow reactor using a peristaltic pump. Control the current at 1.5 A and the anode voltage in the range of 0.5 - 1 V, and react for 1300 s.

[0036] S3: After cooling the electrolytic solution in the anode chamber in step S2 to room temperature, extract and layer it with dichloromethane, and evaporate and separate the dichloromethane phase to obtain the crude product of 19 - formyl - 4 - androstene - 3,17 - dione. Track by HPLC. According to Figure 3 It can be found that as the reaction time increases, the raw material 19 - hydroxy - 4 - androstene - 3,17 - dione gradually decreases, and the main product 19 - formyl - 4 - androstene - 3,17 - dione continuously increases. When the reaction reaches 1300 s, the conversion rate of the raw material is 98%, the selectivity of 19 - formyl - 4 - androstene - 3,17 - dione is 99%, and the yield is 97%.

[0037] Example 2: NiMoO4 / GF (Ni:Mo = 1:7) is used for electrocatalytic oxidation of 19 - hydroxy - 4 - androstene - 3,17 - dione to prepare 19 - formyl - 4 - androstene - 3,17 - dione

[0038] Perform electrocatalytic oxidation of 19 - hydroxy - 4 - androstene - 3,17 - dione to prepare 19 - formyl - 4 - androstene - 3,17 - dione using the NiMoO4 / GF (Ni:Mo = 1:7) catalyst prepared in Example 1 at an electrolytic solution temperature of 40 °C. The specific method is as follows:

[0039] S1: Take 3 g of 19 - hydroxy - 4 - androstene - 3,17 - dione as the reactant, add it to the electrolytic solution in the anode chamber, and then take 156 mg of TEMPO and add it to the electrolytic solution in the anode chamber.

[0040] S2: Place the reaction solution in a constant temperature water bath to control the temperature of the reaction system at 40 °C, stir, and continuously pump the reaction solution into a flow reactor using a peristaltic pump. The flow rate of the peristaltic pump is 100 mL / min, control the current at 1.5 A, and the anode voltage in the range of 0.5 - 1 V, and react for 1000 s.

[0041] S3: After cooling the electrolytic solution in the anode chamber in step S2 to room temperature, extract and layer it with dichloromethane, and evaporate and separate the dichloromethane phase to obtain the crude product of 19 - formyl - 4 - androstene - 3,17 - dione. Track by HPLC. When the reaction reaches 1300 s, the conversion rate of the raw material is 91%, the selectivity of 19 - formyl - 4 - androstene - 3,17 - dione is 99%, and the yield is 90%.

[0042] Example 3: NiMoO4 / GF (Ni:Mo = 1:7) is used for electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione

[0043] The NiMoO4 / GF (Ni:Mo = 1:7) catalyst prepared in Example 1 was used for electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione at an electrolyte temperature of 50 °C. The specific method is as follows:

[0044] S1: Take 3 g of 19-hydroxy-4-androstene-3,17-dione as the reactant and add it to the electrolytic solution in the anode chamber. Then take 171 mg of 4-amino-TEMPO and add it to the electrolytic solution in the anode chamber;

[0045] S2: Place the reaction solution in a constant temperature water bath to control the reaction system temperature at 50 °C, stir, and use a peristaltic pump to continuously pump the reaction solution into a flow-type reactor. The flow rate of the peristaltic pump is 75 mL / min, the current is controlled at 1.5 A, and the anode voltage control range is 0.5 - 1 V. React for 1300 s;

[0046] S3: After cooling the electrolytic solution in the anode chamber in step S2 to room temperature, extract and layer it with tetrahydrofuran. Evaporate and separate the tetrahydrofuran phase to obtain the crude product of 19-formyl-4-androstene-3,17-dione. By HPLC tracking, when the reaction reaches 1300 s, the raw material conversion rate is 96%, the selectivity of 19-formyl-4-androstene-3,17-dione is 99%, and the yield is 95%.

[0047] Example 4: Synthesis of NiMoO4 / GF (Ni:Mo = 1:3) catalyst and its electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione

[0048] (1) According to the feeding ratio, take 219.3 mg of nickel chloride and 1.23 g of sodium molybdate and dissolve them in 40 mL of distilled water. Then add 40 mL of ethylene glycol, and ultrasonically disperse the solution for 30 minutes to obtain solution A;

[0049] (2) Add solution A and the carrier in step (1) to a hydrothermal autoclave, carry out hydrothermal reaction at 100 °C for 12 hours. After the reaction, cool it, take out the carrier, then wash it three times with distilled water and ethanol, and then place it in a vacuum drying oven at 60 °C to dry to obtain the supported metal nickel molybdenum oxide catalyst, labeled as NiMoO4 / GF (Ni:Mo = 1:3);

[0050] The oxidation of 19-hydroxy-4-androstene-3,17-dione was carried out by the constant current method. The current was controlled at 1 A by the constant current method in the electrochemical workstation. During the reaction, the reaction solution was continuously pumped into the flow-through electrolytic cell using a peristaltic pump with a flow rate of 50 mL / min. The anode chamber and the cathode chamber were separated by an ion exchange membrane. A mixed solution of 30 mL of 1.0 mol / L sodium carbonate aqueous solution and 70 mL of acetone (the volume ratio of the main solvent to the secondary solvent was 3:7) was used as the electrolytic solution in the anode chamber, and the temperature of the reaction solution was controlled at 30 °C. 100 mL of 1.0 mol / L sodium carbonate aqueous solution was used as the electrolytic solution in the cathode chamber; in the anode chamber of the electrolytic cell, the prepared NiMoO4 / GF (Ni:Mo = 1:3) catalyst was used as the working electrode and 4-hydroxy-TEMPO was added as a mediator for the oxidation reaction; in the cathode chamber of the electrolytic cell, nickel foam was used as the catalyst for the hydrogen evolution reaction for the hydrogen evolution reaction.

[0051] The NiMoO4 / GF (Ni:Mo = 1:7) catalyst prepared in Example 4 was used for the electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione in the electrolyte to prepare 19-formyl-4-androstene-3,17-dione. The specific method is as follows:

[0052] S1: Take 3 g of 19-hydroxy-4-androstene-3,17-dione as the reactant and add it to the electrolytic solution in the anode chamber. Then take 172 mg of 4-hydroxy-TEMPO and add it to the electrolytic solution in the anode chamber.

[0053] S2: Place the reaction solution in a thermostatic water bath to control the temperature of the reaction system at 30 °C, stir, and use a peristaltic pump to continuously pump the reaction solution into the flow-through reactor with a flow rate of 50 mL / min. The current is controlled at 1 A, and the anode voltage control range is 0.5 - 1 V. React for 2000 s.

[0054] S3: After cooling the electrolytic solution in the anode chamber in step S2 to room temperature, extract and layer it with dichloromethane. Evaporate and separate the dichloromethane phase to obtain the crude product of 19-formyl-4-androstene-3,17-dione. By HPLC tracking, when the reaction reaches 2000 s, the raw material conversion rate is 100%, the selectivity of 19-formyl-4-androstene-3,17-dione is 87%, and the yield is 87%.

[0055] Example 5: Synthesis of NiMoO4 / GF (Ni:Mo = 1:5) catalyst and its electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione

[0056] (1) According to the feeding ratio, 219.3 mg of nickel acetylacetonate and 2.05 g of calcium molybdate were dissolved in 40 mL of distilled water, and then 40 mL of ethylene glycol was added. The solution was ultrasonically dispersed for 30 minutes to obtain solution A;

[0057] (2) Solution A in step (1) and the carrier were added into a hydrothermal reactor, and hydrothermal reaction was carried out at 120 °C for 10 hours. After the reaction, it was cooled. The carrier was taken, then washed three times with distilled water and ethanol, and then dried in a vacuum drying oven at 60 °C to obtain a supported metal nickel molybdenum oxide catalyst, marked as NiMoO4 / GF (Ni:Mo = 1:5);

[0058] The oxidation of 19-hydroxy-4-androstene-3,17-dione was carried out by the constant current method. The current was controlled at 1 A by the constant current method in the electrochemical workstation. During the reaction, the reaction solution was continuously pumped into the flow-through electrolytic cell by a peristaltic pump, and the flow rate of the peristaltic pump was 150 mL / min. The anode chamber and the cathode chamber were separated by an ion exchange membrane. A mixed solution of 50 mL of 1.0 mol / L sodium carbonate aqueous solution and 50 mL of tetrahydrofuran (the feeding volume ratio of the main solvent to the secondary solvent was 5:5) was used as the electrolytic solution in the anode chamber, and the temperature of the reaction solution was controlled at 30 °C. 100 mL of 1.0 mol / L sodium carbonate aqueous solution was used as the electrolytic solution in the cathode chamber; in the anode chamber of the electrolytic cell, the prepared NiMoO4 / GF (Ni:Mo = 1:5) catalyst was used as the working electrode and TEMPO was added as a mediator for the oxidation reaction; in the cathode chamber of the electrolytic cell, nickel foam was used as the catalyst for the hydrogen evolution reaction for the hydrogen evolution reaction.

[0059] The NiMoO4 / GF (Ni:Mo = 1:5) catalyst prepared in Example 5 was subjected to electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione in the electrolyte to prepare 19-formyl-4-androstene-3,17-dione. The current was controlled at 1 A by the constant current method in the electrochemical workstation. The specific method was as follows:

[0060] S1: 3 g of 19-hydroxy-4-androstene-3,17-dione was taken as the reactant and added to the electrolytic solution in the anode chamber, and then 156 mg of TEMPO was added to the electrolytic solution in the anode chamber;

[0061] S2: The reaction solution was placed in a constant temperature water bath to control the temperature of the reaction system at 30 °C, stirred, and the reaction solution was continuously pumped into the flow-through reactor by a peristaltic pump. The flow rate of the peristaltic pump was 150 mL / min, the current was controlled at 1 A, and the anode voltage control range was 0.5 - 1 V. The reaction was carried out for 2000 s;

[0062] S3: After cooling the electrolytic solution in the anode chamber in step S2 to room temperature, extract and layer it with dichloromethane, and evaporate and separate the dichloromethane phase to obtain the crude product of 19-aldehyde-4-androstene-3,17-dione. By tracking with HPLC, when the reaction reaches 2000 s, the conversion rate of the raw material is 78%, the selectivity of 19-aldehyde-4-androstene-3,17-dione is 89%, and the yield is 69%.

[0063] Example 6: Synthesis of NiMoO4 / GF (Ni:Mo = 1:9) catalyst and its electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-aldehyde-4-androstene-3,17-dione

[0064] (1) According to the feeding ratio, take 219.3 mg of nickel bromide and 3.7 g of manganese molybdate and dissolve them in 40 mL of distilled water, then add 40 mL of ethylene glycol, and ultrasonically disperse the solution for 30 minutes to obtain solution A;

[0065] (2) Add solution A and the carrier in step (1) into a hydrothermal reactor, carry out hydrothermal reaction at 140 °C for 12 hours, cool the reaction, take out the carrier, then wash it three times with distilled water and ethanol, and then dry it in a vacuum drying oven at 60 °C to obtain the supported metal nickel molybdenum oxide catalyst, labeled as NiMoO4 / GF (Ni:Mo = 1:9);

[0066] The oxidation of 19-hydroxy-4-androstene-3,17-dione is carried out by the constant current method. The current is controlled at 0.5 A by the constant current method in the electrochemical workstation. During the reaction, use a peristaltic pump to continuously pump the reaction solution into the flow-through electrolytic cell, and the flow rate of the peristaltic pump is 100 mL / min. The anode chamber and the cathode chamber are separated by an ion exchange membrane. A mixed solution of 50 mL of 1.0 mol / L sodium hydrogen phosphate aqueous solution and 50 mL of acetonitrile (the feeding volume ratio of the main solvent to the secondary solvent is 5:5) is used as the electrolytic solution in the anode chamber, and the temperature of the reaction solution is controlled at 30 °C. 100 mL of 1.0 mol / L sodium carbonate aqueous solution is used as the electrolytic solution in the cathode chamber; in the anode chamber of the electrolytic cell, the prepared NiMoO4 / GF (Ni:Mo = 1:9) catalyst is used as the working electrode and TEMPO is added as a medium for the oxidation reaction; in the cathode chamber of the electrolytic cell, nickel foam is used as the catalyst for the hydrogen evolution reaction for the hydrogen evolution reaction.

[0067] The NiMoO4 / GF (Ni:Mo = 1:9) catalyst prepared in Example 6 was subjected to electrocatalytic oxidation at an electrolyte temperature of 30 °C to produce 19 - formyl - 4 - androstene - 3,17 - dione from 19 - hydroxy - 4 - androstene - 3,17 - dione. The current was controlled at 0.5 A by the constant - current method in an electrochemical workstation. A mixed solution of 50 mL of 1.0 mol / L sodium hydrogen phosphate aqueous solution and 50 mL of acetonitrile (the feeding volume ratio of the main solvent to the secondary solvent is 5:5) was used as the electrolytic solution in the anodic chamber, and 100 mL of 1.0 mol / L sodium carbonate aqueous solution was used as the electrolytic solution in the cathodic chamber. The specific method is as follows:

[0068] S1: Take 3 g of 19 - hydroxy - 4 - androstene - 3,17 - dione as the reactant and add it to the electrolytic solution in the anodic chamber. Then take 312 mg of TEMPO and add it to the electrolytic solution in the anodic chamber;

[0069] S2: Place the reaction solution in a constant - temperature water bath to control the reaction system temperature at 60 °C, stir, and use a peristaltic pump to continuously pump the reaction solution into a flow - type reactor. The flow rate of the peristaltic pump is 100 mL / min, the current is controlled at 0.5 A, and the anodic voltage control range is 0.5 - 1 V. React for 4000 s;

[0070] S3: After cooling the electrolytic solution in the anodic chamber in step S2 to room temperature, extract and layer it with dichloromethane. Evaporate and separate the dichloromethane phase to obtain the crude product of 19 - formyl - 4 - androstene - 3,17 - dione. By HPLC tracking, when the reaction reaches 4000 s, the raw material conversion rate is 86%, the selectivity of 19 - formyl - 4 - androstene - 3,17 - dione is 92%, and the yield is 79%.

[0071] Example 7: Synthesis of NiMoO4 / GF (Ni:Mo = 1:11) catalyst and its electrocatalytic oxidation of 19 - hydroxy - 4 - androstene - 3,17 - dione to produce 19 - formyl - 4 - androstene - 3,17 - dione

[0072] (1) According to the feeding ratio, take 219.3 mg of nickel acetate and 4.5 g of cobalt molybdate and dissolve them in 40 mL of distilled water, then add 40 mL of ethylene glycol. The solution is ultrasonically dispersed for 30 minutes to obtain solution A;

[0073] (2) Add solution A in step (1) and the carrier to a hydrothermal autoclave, carry out hydrothermal reaction at 140 °C for 12 hours. After the reaction, cool it, take out the carrier, then wash it three times with distilled water and ethanol, and then place it in a vacuum drying oven at 60 °C to dry to obtain the supported metal nickel - molybdenum oxide catalyst, labeled as NiMoO4 / GF (Ni:Mo = 1:11);

[0074] The oxidation of 19-hydroxy-4-androstene-3,17-dione was carried out by the constant current method. The current was controlled at 0.5 A by the constant current method in the electrochemical workstation. During the reaction, the reaction solution was continuously pumped into the flow-through electrolytic cell using a peristaltic pump, and the flow rate of the peristaltic pump was 50 mL / min. The anode chamber and the cathode chamber were separated by an ion exchange membrane. A mixed solution of 40 mL of 1.0 mol / L sodium carbonate aqueous solution and 60 mL of acetonitrile (the feeding volume ratio of the main solvent to the secondary solvent was 4:6) was used as the electrolytic solution in the anode chamber, and the temperature of the reaction solution was controlled at 30 °C. 100 mL of 1.0 mol / L sodium carbonate aqueous solution was used as the electrolytic solution in the cathode chamber; in the anode chamber of the electrolytic cell, the prepared NiMoO4 / GF (Ni:Mo = 1:11) catalyst was used as the working electrode and ACT was added as a medium for the oxidation reaction; in the cathode chamber of the electrolytic cell, nickel foam was used as the catalyst for the hydrogen evolution reaction for the hydrogen evolution reaction.

[0075] The NiMoO4 / GF (Ni:Mo = 1:11) catalyst prepared in Example 7 was used for the electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione at an electrolyte temperature of 30 °C. The current was controlled at 0.5 A by the constant current method in the electrochemical workstation. During the reaction, a mixed solution of 40 mL of 1.0 mol / L sodium carbonate aqueous solution and 60 mL of acetonitrile (the feeding volume ratio of the main solvent to the secondary solvent was 4:6) was used as the electrolytic solution in the anode chamber, and 100 mL of 1.0 mol / L sodium carbonate aqueous solution was used as the electrolytic solution in the cathode chamber. The specific method was as follows:

[0076] S1: Take 3 g of 19-hydroxy-4-androstene-3,17-dione as the reactant and add it to the electrolytic solution in the anode chamber. Then take 213 mg of ACT and add it to the electrolytic solution in the anode chamber.

[0077] S2: Place the reaction solution in a constant temperature water bath to control the temperature of the reaction system at 30 °C, stir, and use a peristaltic pump to continuously pump the reaction solution into the flow-through reactor. The flow rate of the peristaltic pump is 120 mL / min, the current is controlled at 0.5 A, and the anode voltage control range is 0.5 - 1 V. React for 4000 s.

[0078] S3: After cooling the electrolytic solution in the anode chamber in step S2 to room temperature, extract and layer it with dichloromethane. Evaporate and separate the dichloromethane phase to obtain the crude product of 19-formyl-4-androstene-3,17-dione. By HPLC tracking, when the reaction reaches 4000 s, the raw material conversion rate is 94%, the selectivity of 19-formyl-4-androstene-3,17-dione is 93%, and the yield is 87%.

[0079] Example 8: Synthesis of Ni / GF Catalyst and Its Electrocatalytic Oxidation of 19-Hydroxy-4-androstene-3,17-dione to Prepare 19-Oxo-4-androstene-3,17-dione

[0080] (1) According to the feeding ratio, 219.3 mg of nickel nitrate was dissolved in 40 mL of distilled water, and then 40 mL of ethylene glycol was added. The solution was ultrasonically dispersed for 30 minutes to obtain solution A;

[0081] (2) Solution A in step (1) and the carrier were added to a hydrothermal autoclave, and hydrothermal reaction was carried out at 140 °C for 10 hours. After the reaction, it was cooled, the carrier was taken out, then washed three times with distilled water and ethanol, and then dried in a vacuum drying oven at 60 °C to obtain the supported metal nickel molybdenum oxide catalyst, labeled as Ni / GF;

[0082] The Ni / GF catalyst prepared in Example 8 was used for the electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-oxo-4-androstene-3,17-dione at an electrolyte temperature of 30 °C. The current was controlled at 0.5 A by the constant current method in an electrochemical workstation. A mixed solution of 70 mL of 1.0 mol / L sodium carbonate aqueous solution and 30 mL of acetonitrile (the feeding volume ratio of the main solvent to the secondary solvent was 7:3) was used as the electrolytic solution in the anodic chamber, and 100 mL of 1.0 mol / L sodium carbonate aqueous solution was used as the electrolytic solution in the cathodic chamber. The specific method was as follows:

[0083] S1: 3 g of 19-hydroxy-4-androstene-3,17-dione was taken as the reactant and added to the electrolytic solution in the anodic chamber, and 156 mg of TEMPO was added to the electrolytic solution in the anodic chamber;

[0084] S2: The reaction solution was placed in a constant temperature water bath to control the temperature of the reaction system at 30 °C, stirred, and the reaction solution was continuously pumped into a flow-type reactor using a peristaltic pump. The current was controlled at 0.5 A, and the anodic voltage control range was 0.5 - 1 V. The reaction was carried out for 5000 s;

[0085] S3: After the electrolytic solution in the anodic chamber in step S2 was cooled to room temperature, it was extracted and layered with dichloromethane. The dichloromethane phase was evaporated and separated to obtain the crude product of 19-oxo-4-androstene-3,17-dione. By HPLC tracking, when the reaction reached 5000 s, the raw material conversion rate was 86%, the selectivity of 19-oxo-4-androstene-3,17-dione was 93%, and the yield was 87%.

[0086] Comparative Example 9: Synthesis of NiMoO4 / GF (Ni:Mo = 1:7) Catalyst and Its Electrocatalytic Oxidation of 19-Hydroxy-4-androstene-3,17-dione to Prepare 19-oxo-4-androstene-3,17-dione

[0087] In a batch reactor, the NiMoO4 / GF (Ni:Mo = 1:7) catalyst prepared in Example 1 was used as the working electrode, and ACT was added as a mediator for the oxidation reaction. A platinum sheet was used as the counter electrode, and Ag / AgCl was used as the reference electrode. A mixed solution of 50 mL of 1.0 mol / L sodium carbonate aqueous solution and 50 mL of acetonitrile (the feeding volume ratio of the main solvent to the secondary solvent was 5:5) was used as the electrolytic solution. The temperature was controlled at 30 °C, and the constant current method was used to oxidize 19-hydroxy-4-androstene-3,17-dione. The current was controlled at 0.05 A by the constant current method in the electrochemical workstation. During the reaction, the reaction solution was directly in the electrolytic cell without the need for a peristaltic pump for circulation. The electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione was carried out as follows:

[0088] S1: Take 3 g of 19-hydroxy-4-androstene-3,17-dione as the reactant and add it to the electrolytic solution. Then take 213 mg of ACT and add it to the electrolytic solution;

[0089] S2: Place the reaction solution in a constant temperature water bath to control the reaction system temperature at 30 °C, stir, control the current at 0.05 A, and control the anode voltage range at 0.5 - 1 V, and react for 20000 s;

[0090] S3: After cooling the electrolytic solution in the anode chamber in step S2 to room temperature, extract and layer it with dichloromethane, and evaporate and separate the dichloromethane phase to obtain the crude product of 19-formyl-4-androstene-3,17-dione. By HPLC tracking, when the reaction reaches 20000 s, the raw material conversion rate is 40%, the selectivity of 19-formyl-4-androstene-3,17-dione is 60%, and the yield is 24%.

[0091] For the reaction of electrocatalytic oxidation of 19-hydroxy-4-androstene-3,17-dione to prepare 19-formyl-4-androstene-3,17-dione, comparing the six catalysts prepared above, the results are shown in Table 1.

[0092] Table 1 Catalytic effect table of catalysts in Examples 1 - 9

[0093]

[0094]

[0095] As can be seen from Table 1, compared with the catalyst containing only nickel, the raw material conversion rate, product selectivity and yield of the nickel molybdenum oxide catalyst are all improved. The NiMoO4 / GF (Ni:Mo = 1:7) catalyst in Example 1 of the present invention shows excellent catalytic effects. When the reaction reaches 1300 s, the raw material conversion rate is 98%, the selectivity of 19-aldehyde-4-androstene-3,17-dione is 99%, and the yield is 97%. The nickel molybdenum oxide catalyst has good electrocatalytic activity compared with other catalysts. The reason may be that Mo promotes the change of Ni to a higher valence state during the electrocatalytic oxidation process, accelerates electron transfer, increases the reaction rate, and promotes the oxidation of the substrate 19-aldehyde-4-androstene-3,17-dione. At the same time, compared with the batch reactor (Example 9), the reaction time using the flow reactor is greatly reduced, the cost is reduced, and the energy consumption is lowered. From Figure 4 the Lsv diagram, it can be seen that the current density of the continuous flow reaction is much greater than that of the batch reactor. This shows that the continuous flow reactor greatly improves the effect of the traditional batch reactor.

Claims

1. A method for electrocatalytic oxidation of nickel molybdenum oxide to prepare 19-aldehyde-4-androstene-3,17-dione, characterized in that It includes the following steps: 1) Preparation of NiMoO4 / GF catalyst, where Ni:Mo = 1:7: 1.1) According to the feeding ratio, take 540 mg of nickel nitrate and 2.1 g of ammonium molybdate and dissolve them in 40 mL of distilled water. Then add 40 mL of ethylene glycol, and ultrasonically disperse the solution for 30 minutes to obtain solution A; 1.2) Add solution A in step 1) and the three-dimensional porous material as the carrier into a hydrothermal autoclave, carry out hydrothermal reaction at 120 °C for 10 hours, cool after the reaction, take out the carrier, then wash it three times with distilled water and ethanol, and then place it in a vacuum drying oven at 60 °C for drying to obtain the supported metal nickel molybdenum oxide catalyst, labeled as NiMoO4 / GF, Ni:Mo = 1:7; 2) Preparation of 19-aldehyde-4-androstene-3,17-dione. The oxidation of 19-hydroxy-4-androstene-3,17-dione is carried out by the constant current method. The current is controlled at 1.5 A by the constant current method in the electrochemical workstation. During the reaction, use a peristaltic pump to continuously pump the reaction solution into a flow-through electrolytic cell, and the flow rate of the peristaltic pump is 120 mL / min; the anode chamber and the cathode chamber are separated by an ion exchange membrane. A mixed solution of 50 mL of 1.0 mol / L sodium carbonate aqueous solution and 50 mL of acetonitrile, with the feeding volume ratio of sodium carbonate aqueous solution to acetonitrile being 5:5, is used as the electrolytic solution in the anode chamber, and the temperature of the reaction solution is controlled at 30 °C. 100 mL of 1.0 mol / L sodium carbonate aqueous solution is used as the electrolytic solution in the cathode chamber; in the anode chamber of the electrolytic cell, the NiMoO4 / GF catalyst in step 1) is used as the working electrode and ACT is added as a medium for the oxidation reaction; in the cathode chamber of the electrolytic cell, nickel foam is used as the catalyst for the hydrogen evolution reaction for the hydrogen evolution reaction, specifically as follows: S1: Take 3 g of 19-hydroxy-4-androstene-3,17-dione as the reactant and add it to the electrolytic solution in the anode chamber. Then take 213 mg of ACT and add it to the electrolytic solution in the anode chamber; S2: Keep the reaction solution in a constant temperature water bath to control the temperature of the reaction system at 30 °C, stir, and use a peristaltic pump to continuously pump the reaction solution into a flow-through reactor. The current is controlled at 1.5 A, and the anode voltage control range is 0.5 - 1 V. React for 1300 s; S3: After cooling the electrolytic solution in the anode chamber in step S2 to room temperature, extract and layer it with dichloromethane, and evaporate and separate the dichloromethane phase to obtain the crude product of 19-aldehyde-4-androstene-3,17-dione.

2. A method for preparing 19-formyl-4-androstene-3,17-dione by electrocatalytic oxidation of nickel molybdenum oxide, which is characterized in that It includes the following steps: 1) Preparation of NiMoO4 / GF catalyst, where Ni:Mo = 1:7: 1.1) According to the feeding ratio, take 540 mg of nickel nitrate and 2.1 g of ammonium molybdate and dissolve them in 40 mL of distilled water. Then add 40 mL of ethylene glycol, and ultrasonically disperse the solution for 30 minutes to obtain solution A; 1.2) Add solution A and the three-dimensional porous material in step 1) as carriers into a hydrothermal reactor, carry out hydrothermal reaction at 120 °C for 10 hours, cool after the reaction, take out the carrier, then wash it three times with distilled water and ethanol, and then place it in a vacuum drying oven at 60 °C for drying to obtain a supported nickel molybdenum oxide catalyst, marked as NiMoO4 / GF, Ni:Mo = 1:7; 2) Preparation of 19-aldehyde-4-androstene-3,17-dione. The oxidation of 19-hydroxy-4-androstene-3,17-dione is carried out by the constant current method. The current is controlled at 1.5 A by the constant current method in the electrochemical workstation. During the reaction, the reaction solution is continuously pumped into the flow-through electrolytic cell using a peristaltic pump, and the flow rate of the peristaltic pump is 120 mL / min; the anode chamber and the cathode chamber are separated by an ion exchange membrane. A mixed solution of 50 mL of 1.0 mol / L sodium carbonate aqueous solution and 50 mL of acetonitrile, with the feeding volume ratio of sodium carbonate aqueous solution to acetonitrile being 5:5, is used as the electrolytic solution in the anode chamber, and the temperature of the reaction solution is controlled at 30 °C. 100 mL of 1.0 mol / L sodium carbonate aqueous solution is used as the electrolytic solution in the cathode chamber; in the anode chamber of the electrolytic cell, the NiMoO4 / GF catalyst in step 1) is used as the working electrode and ACT is added as a medium for the oxidation reaction; in the cathode chamber of the electrolytic cell, nickel foam is used as the catalyst for the hydrogen evolution reaction for the hydrogen evolution reaction, specifically as follows: S1: Take 3 g of 19-hydroxy-4-androstene-3,17-dione as the reactant and add it to the electrolytic solution in the anode chamber. Then take 171 mg of 4-amino-TEMPO and add it to the electrolytic solution in the anode chamber; S2: Place the reaction solution in a constant temperature water bath to control the temperature of the reaction system at 50 °C, stir, and use a peristaltic pump to continuously pump the reaction solution into the flow-through reactor. The flow rate of the peristaltic pump is 75 mL / min, the current is controlled at 1.5 A, and the anode voltage control range is 0.5 - 1 V. React for 1300 s; S3: After cooling the electrolytic solution in the anode chamber in step S2 to room temperature, extract and layer it with tetrahydrofuran, and evaporate and separate the tetrahydrofuran phase to obtain the crude product of 19-aldehyde-4-androstene-3,17-dione.

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