A method for the electro-synthesis of co2-based chiral pharmaceutical intermediates for space stations

Abstract

The present application belongs to the field of human-computer and environment engineering and catalytic chemical technology. In view of the urgent demand of on-demand manufacturing of first-aid drugs for future space stations and lunar bases, the present application proposes to use high-entropy ceramic microfluidic electrolytic cell, take CO2 as carbon source and water or nitrogen-containing waste as hydrogen / nitrogen source, and selectively synthesize a variety of small molecule drug intermediates including chiral alcohol, amine, ester, ether and the like by adjusting the voltage waveform applied on the chiral high-entropy catalyst. The present application utilizes the broad-spectrum catalytic activity provided by the "cocktail effect" of high-entropy materials, and combines the molecular sieving effect of chiral skeleton, to realize on-demand switch synthesis of a variety of chiral drug molecules in a single reaction, greatly reducing the load weight and expiration risk of drug reserves in space missions.

Description

Technical Field

[0001] This invention belongs to the fields of human-machine and environmental engineering and catalytic chemistry, and specifically relates to an electrosynthesis method for CO2-based chiral pharmaceutical intermediates for use in space stations. Background Technology

[0002] As human space exploration continues to advance, the routine operation of space stations and the construction of future lunar bases and other space facilities are gradually underway. During long space missions, ensuring the health of astronauts faces enormous challenges. Due to the unique characteristics of the space environment, such as cosmic radiation and microgravity, astronauts are more susceptible to illness, making the need for various emergency medications extremely urgent. However, spaceflight is extremely expensive, and carrying large quantities of medication would significantly increase the payload weight of spacecraft, thereby raising launch costs. Furthermore, medications have a limited shelf life, and their stability may be affected in the space environment. Expired medications not only become ineffective but also occupy valuable space. Therefore, how to achieve "on-demand manufacturing" of emergency medications in space has become a pressing issue. This requires both the creation of suitable space environment conditions for drug synthesis by the fields of human-machine interface and environmental engineering, and the development of efficient synthesis technologies by the field of catalytic chemistry.

[0003] In terms of research progress, electrosynthesis technology has achieved certain results in the field of organic synthesis in recent years. Traditional organic synthesis methods often require the use of large amounts of chemical reagents, generating a significant amount of waste and causing environmental pollution. Electrosynthesis technology, driven by electricity, has the advantages of being green and sustainable, and is gradually becoming a research hotspot. However, current electrosynthesis technology still has significant shortcomings in the synthesis of chiral compounds. Chiral compounds play a crucial role in the pharmaceutical field, as different chiral isomers may have different biological activities and pharmacological effects. Existing electrosynthesis methods are not effective in controlling the chiral selectivity of products; the synthesized products are usually racemic mixtures, requiring complex resolution processes to obtain a single chiral isomer. This not only increases production costs but also reduces synthesis efficiency.

[0004] In a closely related patent, patent CN119462574A proposes the preparation of 2-aryl-3-ketoimine tetrahydrofuran compounds from 4-aryl-3-butenol and diaryl ketone imine under organic electrochemical synthesis conditions in a single step. However, it lacks effective control over the chirality of the product and cannot meet the requirements for specific chiral pharmaceutical intermediates in aerospace environments. Patent CN116355752A achieves the directional conversion of CO2 and cellulose by constructing different microbial communities on the cathode and anode of an H-type electrolytic cell, enabling CO2 reduction at the cathode. However, this patent is essentially a biochemical reaction, which is easily deactivated by cosmic rays under the harsh conditions of aerospace. Patent CN111235598A discloses a method for obtaining spiro[4.5]trienone by using alkyne compounds and diselenyl ethers as reaction raw materials, continuously electrolyzing in a microchannel reaction device, and obtaining spiro[4.5]trienones through free radical cascade reaction and dearomatization. However, there is little research on the chiral control and selectivity of the product, making it difficult to achieve efficient synthesis of specific chiral pharmaceutical intermediates.

[0005] In summary, the current research and technical solutions still have significant shortcomings, as detailed below:

[0006] 1) Existing electrosynthesis technologies are difficult to achieve efficient and selective synthesis of specific chiral pharmaceutical intermediates, and cannot meet the "on-demand manufacturing" requirements for different chiral drugs in aerospace environments;

[0007] 2) The catalysts used in some methods are complex to prepare, costly, and have poor stability, making them unsuitable for long-term use in space missions;

[0008] 3) Some technologies have overly stringent requirements for reaction conditions, making it difficult to achieve stable control of reaction conditions in a space environment, resulting in low reliability and repeatability of the reaction. Summary of the Invention

[0009] This invention was made in view of the problems existing in the prior art. The innovation of this invention lies in the comprehensive application of electrocatalytic reaction kinetics, chiral chemistry theory, and surface science theory. The core of electrocatalytic reaction kinetics is the Butler-Volmer equation:

[0010] i=i0(exp(αnFη / RT)−exp(−(1−α)nFη / RT))

[0011] Where i is the current density, i0 is the exchange current density, α is the transfer coefficient, n is the number of electrons transferred in the reaction, F is the Faraday constant, η is the overpotential, R is the gas constant, and T is the temperature. This equation shows that the magnitude and variation of the overpotential η can be precisely controlled by changing the voltage waveform, amplitude, and duty cycle. Different voltage conditions cause the potential at the electrode surface to change differently over time, thus affecting the adsorption and desorption processes of reactant molecules on the electrode surface, as well as the activation energy of the reaction, ultimately altering the reaction rate and selectivity.

[0012] Chiral chemistry theory states that complexes formed by chiral ligands and metal centers possess unique spatial structures. These structures can selectively interact with reactant molecules, inducing reactions to proceed towards the formation of specific chiral isomers. In the chiral high-entropy catalyst of this invention, the synergistic effect of multiple transition metal elements produces a "cocktail effect," resulting in a rich variety of active sites on the catalyst surface. These active sites, in conjunction with the chiral ligands, provide reactants with more differentiated reaction pathways, thereby significantly improving the selectivity of chiral products.

[0013] Surface science theory posits that the adsorption state of reactant molecules on the catalyst surface plays a crucial role in the reaction process. Different voltage waveforms, amplitudes, and duty cycles alter the electron cloud density and electric field distribution on the catalyst surface, thereby affecting the adsorption mode and intensity of reactant molecules. For example, at high voltage amplitudes, reactant molecules may adsorb more tightly onto the catalyst surface, favoring certain specific reactions; while at low voltage amplitudes, the adsorption may be looser, driving the reaction in other directions.

[0014] From an energy perspective, according to the Arrhenius equation, the reaction system absorbs different amounts of energy under different voltage conditions, allowing the reaction to proceed along different reaction pathways and thus generate different products. For example, a trapezoidal voltage provides higher energy in a short period of time, which is beneficial for lowering the activation energy of certain reactions and promoting the rapid reaction towards the formation of chiral alcohols; while a sinusoidal voltage provides more stable and periodically changing energy, which may be more suitable for reactions that generate chiral amines.

[0015] To achieve the above objectives, the present invention provides an electrosynthesis method for CO2-based chiral pharmaceutical intermediates used in space stations, characterized by the following steps:

[0016] Step 1: Select silicon carbide ceramic powder with a purity of not less than 99.5% and a particle size range of 100~200 nm. Mix it with an additive at a mass ratio of 95:5. The additive is either alumina or titanium dioxide. Ball mill the mixture at 300 r / min for 12 h to ensure thorough and uniform mixing. Place the mixed material in a mold and cold press it under a pressure of 200 MPa to form a preliminary green body. Then, place the green body in a high-temperature sintering furnace and sinter it at a temperature of 1200℃ and a pressure of 10 MPa for 4 h to form a high-entropy ceramic substrate. Microchannel processing of the high-entropy ceramic substrate is performed using a combination of photolithography and plasma etching. First, a layer of photoresist is coated on the substrate surface. The pre-designed microchannel pattern is transferred onto the photoresist using photolithography. The microchannel configuration is a combination of serpentine and grid shapes to enhance the gas-liquid mixing effect. The width of the serpentine channel is 100~200 μm and the depth is 50~100 μm. The microchannels are spaced 200-300 μm apart, with grid cells of 150-250 μm side length. Then, a plasma etching machine is used to etch the areas not protected by photoresist, controlling the etching depth error to ±5 μm. After microchannel fabrication, the photoresist is removed. Anode and cathode substrates are prepared using physical vapor deposition (PVD). Platinum is used for the anode, and gold for the cathode, with an electrode thickness of 50-100 nm. The anode is positioned on one side of the microchannel, and the cathode on the other, with a distance of 300-500 μm between them to ensure uniform electric field distribution. A proton exchange membrane (PEM) with a thickness of 50-100 μm is used as a diaphragm between the anode and cathode chambers. The PEM is cut to a suitable size and placed over the microchannels between the anode and cathode, with the edges sealed with high-temperature sealant to ensure airtightness and prevent gas and liquid leakage.

[0017] Step 2: Select transition metal salts, including cobalt nitrate, nickel nitrate, ferric nitrate, manganese nitrate, and copper nitrate, and mix them in an equimolar ratio to form a metal salt aqueous solution with a total concentration of 0.1 mol / L. Thoroughly mix 0.1 mol / L chiral ligands (selected from chiral crown ethers and chiral porphyrins) with the metal salt aqueous solution. React for 24 h at 60℃, a stirring speed of 300 r / min, and a pH of 7.5–8.0. After the reaction, centrifuge the product, wash it three times alternately with deionized water and ethanol, then vacuum dry it at 100℃ for 12 h, calcine it in a tube furnace at 1100℃ for 6 h, anneal it naturally, and then grind it in a ball mill for 24 h to obtain chiral high-entropy catalyst powder. The chiral high-entropy catalyst is the core for achieving selective modulation of the product. Its multi-metal element composition produces a "cocktail effect," which, combined with the role of chiral ligands, provides possibilities for different reaction pathways.

[0018] Step 3: Connect the high-entropy ceramic microfluidic electrolyzer prepared in Step 1 to the power supply, gas supply system, and liquid supply system; the chiral high-entropy catalyst is coated using a drop-coating method combined with ultrasonic assistance; prepare a solution of chiral high-entropy catalyst with a concentration of 5-10 mg / mL, drop an appropriate amount of the solution onto the cathode surface, and then place the substrate in an ultrasonic cleaner and ultrasonically treat it at a frequency of 40 kHz for 15 min to ensure that the catalyst is uniformly coated on the cathode surface, with the coating area accounting for more than 80% of the cathode area; ensure that all systems are tightly and stably connected to provide a reliable operating basis for subsequent reactions;

[0019] Step 4: Using CO2 as the carbon source, CO2 gas is introduced into the electrolytic cell at a flow rate of 5-10 mL / min; using water or nitrogen-containing waste as the hydrogen / nitrogen source, water or nitrogen-containing waste solution is introduced into the electrolytic cell at a flow rate of 1-2 mL / min. Precise control of the flow rate can ensure that the reaction is carried out under appropriate material ratios.

[0020] Step 5: Adjust the voltage waveform applied to the chiral high-entropy catalyst according to the type of target chiral pharmaceutical intermediate. When using a trapezoidal voltage, the voltage amplitude is 1.5~2.5 V, the frequency is 20~60 Hz, and the duty cycle is 40%~60%. Under the "cocktail effect" of the high-entropy catalyst, the reaction is promoted towards the formation of chiral alcohols. When a sinusoidal voltage is selected, the voltage amplitude is 2~3 V, and the frequency is 40~80 Hz. By controlling the synergistic effect of multiple metal active sites in the chiral high-entropy catalyst, the formation of chiral amines is preferred. When a pulsed voltage is applied, the voltage amplitude is 1~3 V, the frequency is 10~100 Hz, and the duty cycle is 30%~70%. By adjusting the duty cycle, different intermediates can be controlled. A duty cycle of 30% is conducive to the formation of chiral ester intermediates with specific functional group substitutions. A duty cycle of 70% is conducive to the formation of chiral ether intermediates.

[0021] Step 6: Electrosynthesis reaction is carried out at a temperature of 25℃ and a pressure of 0.1 MPa for 2-6 hours. Suitable reaction temperature and pressure conditions can ensure the activity and stability of the chiral high-entropy catalyst and allow the reaction to proceed under mild conditions.

[0022] Step 7: After the reaction is complete, the reaction product is taken out of the electrolytic cell and separated and purified by extraction, distillation and other methods to obtain the target chiral pharmaceutical intermediate. The separation and purification process can remove impurities, improve the purity of the target product and meet the quality requirements of pharmaceutical intermediates.

[0023] Step 8: Perform performance testing on the prepared chiral pharmaceutical intermediate. Analyze its purity using high-performance liquid chromatography and test its optical rotation using a polarimeter. If the purity is below 95% or the optical rotation does not meet the requirements, adjust the parameters in the preparation process, such as voltage waveform parameters and reaction time, and re-prepare and test. Performance testing ensures that the product quality meets the standards, providing a guarantee for subsequent applications.

[0024] Specifically, in the high-entropy ceramic microfluidic electrolyzer described in step 1, the microchannel width is preferably 150 μm, the depth is preferably 80 μm, and the spacing is preferably 250 μm; the electrode thickness is preferably 80 nm.

[0025] The advantages of this invention are:

[0026] 1) By adjusting the voltage waveform, amplitude and duty cycle, combined with the effect of chiral high-entropy catalysts, a variety of chiral pharmaceutical intermediates can be synthesized efficiently.

[0027] 2) It enables the on-demand synthesis of multiple chiral drug molecules using a single reactor.

[0028] 3) It has good stability and adaptability. In special environments such as space stations, it can ensure that the reaction is carried out under stable conditions by real-time monitoring and automatic adjustment of reaction parameters. Attached Figure Description

[0029] Various other advantages and benefits will become apparent to those skilled in the art upon reading the following detailed description of preferred embodiments. The accompanying drawings are for illustrative purposes only and are not intended to limit the invention. In the drawings:

[0030] Figure 1 This is a schematic diagram of a high-entropy ceramic microfluidic electrolyzer. The diagram shows:

[0031] 1-Flow channel splitter; 2-Serpentine flow channel; 3-Flow channel pressure plate; 4-Grid flow channel; 5-Chiral high-entropy ceramic catalyst layer; 6-Gold deposition layer; 7-Proton exchange membrane; 8-Platinum deposition layer.

[0032] Figure 2 This is a schematic diagram of the microstructure of a chiral high-entropy catalyst.

[0033] Figure 3 Schematic diagrams of different voltage waveforms (trapezoidal wave, sine wave, pulse wave).

[0034] Figure 4 This is a flowchart of an electrosynthesis method for CO2-based chiral pharmaceutical intermediates used in space stations. Detailed Implementation

[0035] Exemplary embodiments of the invention will now be described in more detail with reference to the accompanying drawings. While exemplary embodiments of the invention are shown in the drawings, it should be understood that the invention may be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0036] As an embodiment of the present invention, an electrosynthesis method for CO2-based chiral pharmaceutical intermediates for space stations specifically includes the following steps: Step 1, selecting silicon carbide ceramic powder with a purity of not less than 99.5% and a particle size range of 100~200nm, mixing it with an additive at a mass ratio of 95:5, the additive being either alumina or titanium oxide, ball milling at 300r / min for 12 h to ensure thorough and uniform mixing, placing the mixed material in a mold, cold pressing it under a pressure of 200 MPa to form a preliminary green body, and then placing the green body in a high-temperature sintering furnace for sintering at a temperature of 1200℃ and a pressure of 10MPa for 4 hours. h, a high-entropy ceramic substrate was fabricated. Microchannel fabrication of the high-entropy ceramic substrate was performed using a combination of photolithography and plasma etching. First, a layer of photoresist was coated on the substrate surface. The pre-designed microchannel pattern was transferred onto the photoresist using photolithography. The microchannel configuration was designed as a combination of serpentine and grid shapes to enhance gas-liquid interaction. The serpentine channel portion had a width of 100–200 μm, a depth of 50–100 μm, and a spacing of 200–300 μm between adjacent channels. The grid cell side length of the grid-shaped channel portion was 150–250 μm. Then, a plasma etching machine was used to etch the areas not protected by the photoresist, with the etching depth error controlled within ±5 μm. After microchannel fabrication, the photoresist was removed. Anode and cathode substrates were prepared using physical vapor deposition (PVD). Platinum was used as the anode material, and gold as the cathode material. The electrode thickness was 50–100 μm. The anode is arranged on one side of the microchannel, and the cathode is arranged on the other side. The distance between the anode and cathode is 300~500 μm to ensure uniform electric field distribution. A proton exchange membrane with a thickness of 50~100 μm is used as a diaphragm between the anode and cathode chambers. The proton exchange membrane is cut to a suitable size and covered on the microchannel between the anode and cathode. The edges are sealed with high-temperature resistant sealant to ensure the airtightness between the anode and cathode chambers and prevent gas and liquid leakage. The microchannel width is preferably 150 μm, the depth is preferably 80 μm, and the spacing is preferably 250 μm. The electrode thickness is preferably 80 nm. Partial structure of the high-entropy ceramic microfluidic electrolyzer is shown in the attached figure. Figure 1 As shown;

[0037] Step 2: Select transition metal salts, including cobalt nitrate, nickel nitrate, ferric nitrate, manganese nitrate, and copper nitrate, and mix them in equimolar ratio to form a 0.1 mol / L aqueous solution of the metal salts. Thoroughly mix 0.1 mol / L chiral ligands (selected from chiral crown ethers and chiral porphyrins) with the aqueous solution of the metal salts. React for 24 h at 60℃, a stirring speed of 300 r / min, and a pH of 7.5–8.0. After the reaction, centrifuge the product, wash it three times alternately with deionized water and ethanol, then vacuum dry it at 100℃ for 12 h, calcine it in a tube furnace at 1100℃ for 6 h, anneal it naturally, and then grind it in a ball mill for 24 h to obtain chiral high-entropy catalyst powder. The chiral high-entropy catalyst is the core for achieving selective modulation of the product; its multi-metal element composition produces a "cocktail effect," which, combined with the role of chiral ligands, provides possibilities for different reaction pathways. Figure 2 This is a schematic diagram of the structure of a chiral high-entropy catalyst;

[0038] Step 3: Connect the high-entropy ceramic microfluidic electrolyzer prepared in Step 1 to the power supply, gas supply system, and liquid supply system; the chiral high-entropy catalyst is coated using a drop-coating method combined with ultrasonic assistance; prepare a solution of chiral high-entropy catalyst with a concentration of 5-10 mg / mL, drop an appropriate amount of the solution onto the cathode surface, and then place the substrate in an ultrasonic cleaner and ultrasonically treat it at a frequency of 40 kHz for 15 min to ensure that the catalyst is uniformly coated on the cathode surface, with the coating area accounting for more than 80% of the cathode area; ensure that all systems are tightly and stably connected to provide a reliable operating basis for subsequent reactions;

[0039] Step 4: Using CO2 as the carbon source, CO2 gas is introduced into the electrolytic cell at a flow rate of 5-10 mL / min; using water or nitrogen-containing waste as the hydrogen / nitrogen source, water or nitrogen-containing waste solution is introduced into the electrolytic cell at a flow rate of 1-2 mL / min. Precise control of the flow rate can ensure that the reaction is carried out under appropriate material ratios.

[0040] Step 5: Adjust the voltage waveform applied to the chiral high-entropy catalyst according to the type of the target chiral pharmaceutical intermediate; Appendix Figure 3Schematic diagrams of different voltage waveforms (trapezoidal wave, sine wave, pulse wave); When using a trapezoidal wave voltage, the voltage amplitude is 1.5~2.5 V, the frequency is 20~60 Hz, and the duty cycle is 40%~60%. Under this condition, the "cocktail effect" of the high-entropy catalyst promotes the reaction towards the formation of chiral alcohols; When a sine wave voltage is selected, the voltage amplitude is 2~3 V, the frequency is 40~80 Hz, and by controlling the synergistic effect of multiple metal active sites in the chiral high-entropy catalyst, it tends to generate chiral amines; When a pulse voltage is applied, the voltage amplitude is 1~3 V, the frequency is 10~100 Hz, and the duty cycle is 30%~70%. By adjusting the duty cycle, different intermediates can be controlled; When the duty cycle is 30%, it is favorable to generate chiral ester intermediates with specific functional group substitutions; When the duty cycle is 70%, it is easy to generate chiral ether intermediates;

[0041] Step 6: Electrosynthesis reaction is carried out at a temperature of 25℃ and a pressure of 0.1 MPa for 2-6 hours. Suitable reaction temperature and pressure conditions can ensure the activity and stability of the chiral high-entropy catalyst and allow the reaction to proceed under mild conditions.

[0042] Step 7: After the reaction is complete, the reaction product is taken out of the electrolytic cell and separated and purified by extraction, distillation and other methods to obtain the target chiral pharmaceutical intermediate. The separation and purification process can remove impurities, improve the purity of the target product and meet the quality requirements of pharmaceutical intermediates.

[0043] Step 8: Perform performance testing on the prepared chiral pharmaceutical intermediate. Analyze its purity using high-performance liquid chromatography and test its optical rotation using a polarimeter. If the purity is below 95% or the optical rotation does not meet the requirements, adjust the parameters in the preparation process, such as voltage waveform parameters and reaction time, and re-prepare and test. Performance testing ensures that the product quality meets the standards, providing a guarantee for subsequent applications.

[0044] Appendix Figure 4 Flowchart of the electrosynthesis method for CO2-based chiral pharmaceutical intermediates for use in space stations

[0045] The specific implementation method will be described in detail below with reference to the embodiments.

[0046] Example 1

[0047] A high-entropy ceramic microfluidic electrolyzer serves as the core reactor. The high-entropy ceramic substrate is made by mixing silicon carbide ceramic powder (99.5% purity, 150 nm particle size) with alumina at a mass ratio of 95:5, followed by sintering, microchannel fabrication, and electrode preparation. The microchannels combine serpentine and grid patterns. The serpentine channels are 150 μm wide and 75 μm deep, with an adjacent spacing of 250 μm. The grid cells have a side length of 200 μm, and the etching error is controlled within ±5 μm. The anode and cathode are platinum and gold electrodes, respectively, with a thickness of 75 nm and a spacing of 400 μm, separated by a 75 μm thick proton exchange membrane to ensure uniform electric field distribution and good sealing. The carbon source was CO2 gas with a purity of 99%; the hydrogen source was deionized water; the transition metal salts were cobalt nitrate, nickel nitrate, ferric nitrate, manganese nitrate, and copper nitrate, all of analytical grade, mixed in equimolar ratio to form a 0.1 mol / L aqueous solution; the chiral ligand was a chiral crown ether with a concentration of 0.1 mol / L. The aqueous solution of the metal salt and the chiral crown ether were reacted at 60℃, 300 r / min, and pH 7.8 for 24 h. The resulting chiral high-entropy catalyst was obtained by centrifugation, washing, drying, calcination, and ball milling. The catalyst was prepared into a 7 mg / mL solution, drop-coated onto the cathode, and ultrasonically treated. The CO2 flow rate was 7 mL / min, the water flow rate was 1.5 mL / min, a trapezoidal voltage was applied with an amplitude of 2.5 V, a frequency of 40 Hz, and a duty cycle of 50%, the reaction temperature was 25℃, the pressure was 0.1 MPa, and the current density was 30 mA / cm². 2 The reaction lasted for 5 hours. After the reaction, the product and unreacted starting material were initially separated by distillation, followed by analysis of the product using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Finally, the chiral isomers were separated using a chiral column. The purity of the final chiral alcohol product was determined to be 98%. The mass of chiral alcohol obtained after 5 hours of reaction was 180 mg, and the catalyst yield was 36 mg / (g). cat h), the selectivity of alcohols with specific chiral configurations is 78%.

[0048] Example 2

[0049] The high-entropy ceramic substrate of the high-entropy ceramic microfluidic electrolyzer is prepared by mixing silicon carbide ceramic powder with a purity of 99.6% and a particle size of 100 nm with titanium oxide at a mass ratio of 95:5. The microchannel is a serpentine flow channel with a width of 100 μm and a depth of 50 μm, an adjacent spacing of 200 μm, a grid cell side length of 150 μm, and an etching error of ±3 μm. The anode and cathode platinum and gold electrodes are 50 nm thick and spaced 300 μm apart, separated by a 50 μm thick proton exchange membrane. The carbon source is 99.5% pure CO2 gas, the hydrogen source is double-distilled deionized water, and the transition metal salt is an aqueous solution of analytical grade metal salt mixed in equimolar ratio to a total concentration of 0.1 mol / L. The chiral ligand is a chiral porphyrin with a concentration of 0.1 mol / L. The catalyst is prepared as a 5 mg / mL solution, drop-coated onto the cathode, and ultrasonically treated. The CO2 flow rate is 5 mL / min, and the saturated potassium nitrate solution flow rate is 1. A sinusoidal voltage was applied at a rate of mL / min, with the maximum amplitude slowly increasing from 2V to 3V and the frequency at 40 Hz. The reaction temperature was 25℃, the pressure was 0.1 MPa, and the current density was 20 mA / cm². 2 The reaction lasted for 2 hours; the remaining conditions were the same as in Example 1, and will not be repeated here.

[0050] After the reaction, the product and unreacted reactants were initially separated by extraction with dichloromethane as the extractant. The product was then analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS), and finally, the chiral isomers were separated using a chiral column. The final chiral amine product had a purity of 97%, and the catalyst yield was 20 mg / (g). cat h), the selectivity of specific chiral amine configurations is 72%.

[0051] Example 3

[0052] The high-entropy ceramic substrate was prepared by mixing silicon carbide ceramic powder with a purity of 99.7% and a particle size of 200 nm with alumina at a mass ratio of 95:5. The microchannel serpentine flow path was 200 μm wide and 100 μm deep, with an adjacent spacing of 300 μm and a grid cell side length of 250 μm. The anode and cathode platinum and gold electrodes were 100 nm thick and spaced 500 μm apart, separated by a 100 μm thick proton exchange membrane. The carbon source was 99.5% pure CO2 gas, and the hydrogen source was high-purity water prepared by an ultrapure water system. Transition metal salts were mixed in an equimolar ratio to form a metal salt aqueous solution with a total concentration of 0.1 mol / L. The chiral ligand was a chiral crown ether with a concentration of 0.1 mol / L. The catalyst was prepared as a 10 mg / mL solution, drop-coated onto the cathode, and ultrasonically treated. The CO2 flow rate was 10 mL / min, the water flow rate was 2 mL / min, a pulsed voltage was applied with an amplitude of 3 V, a frequency of 100 Hz, and a duty cycle of 30%, and the reaction temperature was 25℃ and the pressure was 0.1. MPa, current density 40 mA / cm² 2 The reaction lasted for 6 hours; the remaining conditions were the same as in Example 1, and will not be repeated here.

[0053] After the reaction, the product and unreacted starting material were initially separated by crystallization. The product was then analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS), and finally, the chiral isomers were separated using a chiral column. The purity of the chiral ester intermediate with specific functional group substitution was determined to be 96%, the mass of the chiral ester intermediate was 160 mg, and the catalyst yield was 40 mg / (g). cat h), the selectivity of chiral ester intermediates with specific chiral configurations is 75%.

[0054] Example 4

[0055] The high-entropy ceramic substrate was prepared by mixing silicon carbide ceramic powder with a purity of 99.5% and a particle size of 120 nm with titanium oxide at a mass ratio of 95:5. The microchannel serpentine flow channel was 120 μm wide and 60 μm deep with an adjacent spacing of 220 μm and a grid cell side length of 170 μm. The anode and cathode platinum and gold electrodes were 60 nm thick and spaced 350 μm apart, separated by a 60 μm thick proton exchange membrane. The carbon source was 99.5% pure CO2 gas, the hydrogen source was deionized water that had been filtered multiple times, and the chiral ligand was a chiral porphyrin with a concentration of 0.1 mol / L. The catalyst was prepared as a 6 mg / mL solution, dropped onto the cathode, and ultrasonically treated. The CO2 flow rate was 6 mL / min, the water flow rate was 1.2 mL / min, a trapezoidal voltage was applied with an amplitude of 1.5 V, a frequency of 35 Hz, and a duty cycle of 45%, and the reaction lasted for 5.5 h. The remaining conditions were the same as in Example 1 and will not be repeated.

[0056] After the reaction, the product and unreacted starting material were initially separated by a combination of distillation and extraction. The product was then analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS), and finally, the chiral isomers were separated using a chiral column. The final chiral alcohol product had a purity of 97.5%, yielded 150 mg of chiral alcohol after 5.5 h of reaction, and the catalyst yield was approximately 27.3 mg / (g). cat h), the selectivity of alcohols with specific chiral configurations is 74%.

[0057] Example 5

[0058] The high-entropy ceramic substrate was prepared by mixing silicon carbide ceramic powder with a purity of 99.8% and a particle size of 180 nm with alumina at a mass ratio of 95:5. The microchannel serpentine flow channel was 180 μm wide and 90 μm deep, with an adjacent spacing of 280 μm and a grid cell side length of 230 μm. The anode and cathode platinum and gold electrodes were 90 nm thick and spaced 450 μm apart, separated by a 90 μm thick proton exchange membrane. The carbon source was 99.5% pure CO2 gas, and the hydrogen source was deionized water treated with ion exchange resin. Transition metal salts were mixed in equimolar ratio to form a metal salt aqueous solution with a total concentration of 0.1 mol / L. The chiral ligand was a chiral crown ether with a concentration of 0.1 mol / L. The catalyst was prepared as an 8 mg / mL solution, drop-coated onto the cathode, and ultrasonically treated. The CO2 flow rate was 8 mL / min, the water flow rate was 1.6 mL / min, and a pulsed voltage was applied with an amplitude of 1 V, a frequency of 50 Hz, a duty cycle of 70%, and a current density of 35 mA / cm². 2 The reaction lasted for 4.5 h; the other conditions were the same as in Example 1, and will not be repeated here.

[0059] After the reaction, the product and unreacted starting material were initially separated by extraction. The product was then analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS), and finally, the chiral isomers were separated using a chiral column. The purity of the final chiral ether product was determined to be 96.8%. After 4.5 h of reaction, 140 mg of chiral ether was obtained, with a catalyst yield of approximately 31.1 mg / (g). cat h), the selectivity of chiral ethers with specific configurations is 76%.

[0060] The specific embodiments described above are only used to illustrate the spirit of the present invention. The scope of protection of the present invention is not limited thereto. For those skilled in the art, other embodiments can be easily made by means of changes, substitutions or modifications based on the technical content disclosed in this specification. All such other embodiments should be covered within the scope of protection of the present invention.

Claims

1. An electrosynthesis method for CO2-based chiral pharmaceutical intermediates for use in space stations, characterized in that... The method specifically includes the following steps: Step 1: Select silicon carbide ceramic powder with a purity of not less than 99.5% and a particle size range of 100~200 nm. Mix it with an additive at a mass ratio of 95:

5. The additive is either alumina or titanium dioxide. Ball mill the mixture at 300 r / min for 12 h to ensure thorough and uniform mixing. Place the mixed material in a mold and cold press it under a pressure of 200 MPa to form a preliminary green body. Then, place the green body in a high-temperature sintering furnace and sinter it at a temperature of 1200℃ and a pressure of 10 MPa for 4 h to form a high-entropy ceramic substrate. Microchannel processing of the high-entropy ceramic substrate is performed using a combination of photolithography and plasma etching. First, a layer of photoresist is coated on the substrate surface. The pre-designed microchannel pattern is transferred onto the photoresist using photolithography. The microchannel configuration is a combination of serpentine and grid shapes to enhance the gas-liquid mixing effect. The width of the serpentine channel is 100~200 μm and the depth is 50~100 μm. The microchannels are spaced 200-300 μm apart, with grid cells of 150-250 μm side length. Then, a plasma etching machine is used to etch the areas not protected by photoresist, controlling the etching depth error to ±5 μm. After microchannel fabrication, the photoresist is removed. Anode and cathode substrates are prepared using physical vapor deposition (PVD). Platinum is used for the anode, and gold for the cathode, with an electrode thickness of 50-100 nm. The anode is positioned on one side of the microchannel, and the cathode on the other, with a distance of 300-500 μm between them to ensure uniform electric field distribution. A proton exchange membrane (PEM) with a thickness of 50-100 μm is used as a diaphragm between the anode and cathode chambers. The PEM is cut to a suitable size and placed over the microchannels between the anode and cathode, with the edges sealed with high-temperature sealant to ensure airtightness and prevent gas and liquid leakage. Step 2: Select transition metal salts, including cobalt nitrate, nickel nitrate, ferric nitrate, manganese nitrate, and copper nitrate, and mix them in an equimolar ratio to form a metal salt aqueous solution with a total concentration of 0.1 mol / L. Thoroughly mix 0.1 mol / L chiral ligands (selected from chiral crown ethers and chiral porphyrins) with the metal salt aqueous solution. React for 24 h at 60℃, a stirring speed of 300 r / min, and a pH of 7.5–8.

0. After the reaction, centrifuge the product, wash it three times alternately with deionized water and ethanol, then vacuum dry it at 100℃ for 12 h, calcine it in a tube furnace at 1100℃ for 6 h, anneal it naturally, and then grind it in a ball mill for 24 h to obtain chiral high-entropy catalyst powder. The chiral high-entropy catalyst is the core for achieving selective modulation of the product. Its multi-metal element composition produces a "cocktail effect," which, combined with the role of chiral ligands, provides possibilities for different reaction pathways. Step 3: Connect the high-entropy ceramic microfluidic electrolyzer prepared in Step 1 to the power supply, gas supply system, and liquid supply system; the chiral high-entropy catalyst is coated using a drop-coating method combined with ultrasonic assistance; prepare a solution of chiral high-entropy catalyst with a concentration of 5~10 mg / mL, take an appropriate amount of solution and drop-coat it onto the cathode surface, then place the substrate in an ultrasonic cleaner and ultrasonically treat it at a frequency of 40kHz for 15 min to ensure that the catalyst is uniformly coated on the cathode surface, with the coating area accounting for more than 80% of the cathode area; ensure that the connection of each system is tight and stable to provide a reliable operating basis for subsequent reactions; Step 4: Using CO2 as the carbon source, CO2 gas is introduced into the electrolytic cell at a flow rate of 5-10 mL / min; using water or nitrogen-containing waste as the hydrogen / nitrogen source, water or nitrogen-containing waste solution is introduced into the electrolytic cell at a flow rate of 1-2 mL / min. Precise control of the flow rate can ensure that the reaction is carried out under appropriate material ratios. Step 5: Adjust the voltage waveform applied to the chiral high-entropy catalyst according to the type of the target chiral pharmaceutical intermediate. When using a trapezoidal voltage, the voltage amplitude is 1.5~2.5 V, the frequency is 20~60 Hz, and the duty cycle is 40%~60%. Under this condition, the "cocktail effect" of the high-entropy catalyst promotes the reaction towards the formation of chiral alcohols. When selecting a sinusoidal voltage, the voltage amplitude is 2~3 V, and the frequency is 40~80 Hz. By controlling the synergistic effect of multiple metal active sites in the chiral high-entropy catalyst, it tends to generate chiral amines. When applying a pulsed voltage, the voltage amplitude is 1~3 V, the frequency is 10~100 Hz, and the duty cycle is 30%~70%. By adjusting the duty cycle, different intermediates can be controlled. A duty cycle of 30% is conducive to the formation of chiral ester intermediates with specific functional group substitutions. A duty cycle of 70% is conducive to the formation of chiral ether intermediates. Step 6: Electrosynthesis reaction is carried out at a temperature of 25℃ and a pressure of 0.1 MPa for 2-6 h. Suitable reaction temperature and pressure conditions can ensure the activity and stability of the chiral high-entropy catalyst and allow the reaction to proceed under mild conditions. Step 7: After the reaction is complete, the reaction product is taken out of the electrolytic cell and separated and purified by extraction, distillation and other methods to obtain the target chiral pharmaceutical intermediate. The separation and purification process can remove impurities, improve the purity of the target product and meet the quality requirements of pharmaceutical intermediates. Step 8: Perform performance testing on the prepared chiral pharmaceutical intermediate. Analyze its purity using high-performance liquid chromatography and test its optical rotation using a polarimeter. If the purity is below 95% or the optical rotation does not meet the requirements, adjust the parameters in the preparation process, such as voltage waveform parameters and reaction time, and re-prepare and test. Performance testing ensures that the product quality meets the standards, providing a guarantee for subsequent applications.

2. The electrosynthesis method for CO2-based chiral pharmaceutical intermediates for space stations according to claim 1, characterized in that, The high-entropy ceramic microfluidic electrolyzer described in step 1 preferably has a microchannel width of 150 μm, a depth of 80 μm, and a spacing of 250 μm; the electrode thickness is preferably 80 nm.

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