A method for electro-catalytic oxidation preparation of levetiracetam pharmaceutical intermediate by using manganese-doped nickel selenide catalyst
Patent Information
- Application Number
- CN202410089013.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-01-23
- Publication Date
- 2026-10-20
- Estimated Expiration
- 2044-01-23
AI Technical Summary
[0005]针对现有技术存在的上述问题，本发明的目的是为了克服目前左乙拉西坦手性中间体电催化氧化的制备过程中消旋化和电流密度低的问题，本发明所制备的催化剂不采用贵金属成本低廉，并且采用电催化氧化法的反应条件温和并可通过调节电解条件来精确控制反应速度和进程，在电解过程中可达到较大的电流密度从而得到较高的时空产率
[0024]本发明使用多孔碳纤维作为催化剂载体，在反应中拥有较大的持液量，可使反应底物拥有足够停留时间发生反应。本发明使用多孔碳纤维作为催化剂载体并在其表面原位生长锰掺杂硒化镍纳米片，使催化剂具有较大的比表面积，可为底物的氧化提供大量反应场所和活性位点，此外锰的掺杂调节了反应中间体的吸附并促进了电荷转移，可在较大电流密度下保持长时间稳定性，与目前普遍采用的贵金属催化剂相比，本发明所采用的锰掺杂硒化镍基催化剂具有更低的成本。另外催化剂可以较好的固定在碳毡表面，因此可提高催化剂的稳定性。
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of electrocatalytic materials, specifically relating to a method for the electrocatalytic oxidation of levetiracetam drug intermediates using a manganese-doped nickel selenide catalyst. Background Technology
[0002] Levetiracetam ((S)-α-ethyl-2-oxo-1-pyrrolidineacetamide) rapidly gained FDA approval due to its superior pharmacokinetics and pharmacological activity. In clinical use, levetiracetam offers advantages such as low dosage, broad safety margin, no need for serum drug concentration monitoring, no interactions with other antiepileptic drugs, and relatively few side effects. Current synthetic methods present challenges including complex synthetic routes and multi-step chemical reactions. These routes involve multiple intermediates and intermediate products, and the preparation of some intermediates involves enantiomeric separation, increasing synthetic complexity. Furthermore, the synthesis of levetiracetam must consider sustainability and environmental friendliness, including the use of green solvents, catalysts, and more environmentally friendly reaction conditions to reduce waste and pollution. Therefore, finding an efficient and clean method to obtain levetiracetam intermediates with high chirality retention is of great significance.
[0003] In the synthetic route of levetiracetam, the preparation of the carboxylic acid intermediate (LEV-COOH) via the oxidation of the corresponding chiral primary alcohol precursor (LEV-CH2OH) is a particularly efficient route. However, the LEV-CH(OH)2 intermediate in this reaction is prone to isomerization during the reaction, reducing the chiral purity of the carboxylic acid product. LEV-CH(OH)2 is an aldehyde obtained after the oxidation of the alcohol LEV-CH2OH; further oxidation yields the acid LEV-COOH product. Therefore, a key challenge in this synthetic route is preserving the stereochemical configuration of the chiral primary alcohol precursor. In recent studies, electrochemical catalytic oxidation has attracted widespread attention due to its mild reaction conditions, ease of control, environmental friendliness, and economic feasibility.
[0004] There are currently no reports on manganese-doped nickel selenide alcohol oxidation electrocatalysts, their preparation, and their application in the preparation of chiral intermediates of levetiracetam. Summary of the Invention
[0005] To address the aforementioned problems in existing technologies, the purpose of this invention is to overcome the issues of racemization and low current density in the current preparation process of levetiracetam chiral intermediate electrocatalytic oxidation. The catalyst prepared by this invention does not use precious metals, resulting in low cost. Furthermore, the reaction conditions of the electrocatalytic oxidation method are mild, and the reaction rate and process can be precisely controlled by adjusting the electrolysis conditions. During the electrolysis process, a large current density can be achieved, thereby obtaining a high space-time yield.
[0006] The technical solution adopted in this invention is as follows:
[0007] A method for preparing levetiracetam drug intermediates via electrocatalytic oxidation using a manganese-doped nickel selenide catalyst is disclosed. The method employs a flow-through diaphragm electrolytic cell during constant current electrolysis, with the current controlled by an electrochemical workstation. The anode and cathode chambers of the flow-through diaphragm electrolytic cell are separated by an ion-exchange membrane. The manganese-doped nickel selenide catalyst electrode serves as the anode electrode. 1-[(2S)-1-hydroxybutane-2-yl]pyrrolidone-2-one LEV-CH2OH is dissolved in an alkaline solution with nitric oxide radical TEMPO as the anolyte. A cathode electrode is set in the cathode chamber, and an alkaline solution is used as the cathode solution for constant current electrolysis. The reaction time is 0.5-3 hours. After the reaction, the anolyte is post-treated to obtain the levetiracetam drug intermediate 2-pyrrolidone-n-butyric acid LEV-COOH. The reaction equation is as follows:
[0008]
[0009] Furthermore, the alkaline solution used for the anode and cathode is a potassium hydroxide solution, sodium hydroxide solution, sodium carbonate solution, or sodium bicarbonate solution, preferably a sodium bicarbonate solution, with a concentration of 0.1-1.0 mol / L.
[0010] Furthermore, the amount of TEMPO used is 5-12% of the molar amount of LEV-CH2OH, preferably 8-10%; the concentration of LEV-CH2OH in the anolyte is 10-200 mmol / L, preferably 50-100 mmol / L.
[0011] Furthermore, during constant current electrolysis, the current density is 50-200 mA / cm². 2 The cathode chamber electrode is made of nickel foam.
[0012] Furthermore, during the constant current electrolysis process, the pH of the anolyte reaction solution is stabilized at 8-12; the temperature of the constant temperature water bath during the reaction is 30-60℃; the voltage between the cathode and the anode is 1-10V; and the reaction time is 0.5-3 hours.
[0013] Furthermore, after the reaction is completed, the anolyte is post-treated as follows: the anolyte is extracted with an organic solvent to obtain an organic phase extract, and the organic layer is distilled under reduced pressure to obtain the target product; the organic solvent used for extraction is toluene, dichloromethane, chloroform or ethyl acetate.
[0014] Furthermore, the manganese-doped nickel selenide catalyst electrode is prepared by in-situ solvothermal growth of manganese-doped nickel selenide catalyst on the surface of porous carbon fiber as an electrode substrate. The loading of the manganese-doped nickel selenide catalyst on the porous carbon fiber is 5-10 mg / cm³.2 The porous carbon fiber is a carbon felt.
[0015] Furthermore, the preparation of the manganese-doped nickel selenide catalyst electrode includes the following process:
[0016] 1) After cleaning the surface impurities of the porous carbon fiber substrate with 2-4 mol / L hydrochloric acid and deionized water in sequence, it is placed in a muffle furnace for high-temperature activation hydrophilic treatment to obtain a pretreated porous carbon fiber substrate.
[0017] 2) Dissolve nickel salt, urea, ammonium fluoride, and manganese salt in deionized water to prepare a reaction solution;
[0018] 3) The porous carbon fiber substrate pretreated in step 1) is fully immersed in the reaction solution in step 2) and transferred to a reaction vessel with a polytetrafluoroethylene liner for solvothermal reaction at high temperature. After the reaction is completed, a manganese-doped Ni(OH)2 nanosheet precursor is obtained. It is then transferred into an oven for further drying to obtain a catalyst precursor.
[0019] 4) After the drying in step 3) is completed, the catalyst precursor is transferred to a tube furnace for heat treatment. The selenium source is placed at the top of the tube furnace, upstream of the catalyst precursor. Under the action of Ar gas, the manganese-doped Ni(OH)2 nanosheet precursor grown on the carbon felt surface is converted in situ into manganese-doped nickel selenide catalyst by chemical vapor deposition.
[0020] Furthermore, in step 1), the high-temperature activation in the muffle furnace is carried out at a temperature of 300-600℃ and the processing time is 0.5-2h; in step 2), the temperature of the solvothermal reaction is 90-150℃ and the solvothermal reaction time is 6-18h.
[0021] Further, in step 3), the selenium source is selenium powder, the molar ratio of selenium powder to nickel salt is 2.5-7.5:1, preferably 4.5-5:1, the Ar flow rate is 20-80 mL / min, the heat treatment temperature is 200-450℃, preferably 300-350℃, and the holding time is 1-5 h, preferably 2-3 h.
[0022] Further, in step 2), the molar ratio of nickel salt, urea, ammonium fluoride and manganese salt is 1:2-3:0.5-2:0.05-0.2, preferably 1:2.4-2.5:0.8-1.0:0.1-0.15.
[0023] By employing the above-described technology, the beneficial effects achieved by the present invention compared to the prior art are as follows:
[0024] This invention utilizes porous carbon fibers as a catalyst support, which possesses a large liquid holding capacity during the reaction, allowing the reaction substrate sufficient residence time to react. Furthermore, this invention employs porous carbon fibers as a catalyst support and grows manganese-doped nickel selenide nanosheets in situ on their surface, giving the catalyst a large specific surface area. This provides numerous reaction sites and active sites for substrate oxidation. In addition, manganese doping regulates the adsorption of reaction intermediates and promotes charge transfer, maintaining long-term stability at high current densities. Compared to currently used noble metal catalysts, the manganese-doped nickel selenide-based catalyst used in this invention has a lower cost. Moreover, the catalyst can be well immobilized on the carbon felt surface, thus improving catalyst stability.
[0025] This invention employs a green and mild electrochemical method, using an alkaline salt solution as a solvent during the reaction process, thus avoiding the large-scale use of organic solvents in chemical methods. Furthermore, it utilizes inexpensive and clean electrical energy as the driving force, making it environmentally friendly. In addition, the electrochemical synthesis method operates under mild conditions, and the reaction process is controllable.
[0026] This invention uses a membrane-type flow electrolyzer for the reaction, which can obtain a high space-time yield. LEV-COOH is directly obtained by electrocatalytic oxidation without the need for an additional chiral resolution step. The reaction steps are simple, and the catalyst does not use expensive precious metals, resulting in lower costs and significant economic value. Attached Figure Description
[0027] Figure 1a This is a SEM image of the Mn-NiSe / GF catalyst from Example 1 at 10 μm.
[0028] Figure 1b The image shows the Mn-NiSe / GF catalyst of Example 1 at 5 μm.
[0029] Figure 2 This is a schematic diagram of the electrolysis device.
[0030] Figure 3 The graph shows the changes of various components in the anolyte of the Mn-NiSe / GF catalyst in Example 1 over time during constant current electrolysis.
[0031] Figure 4 The conversion rate and ee value changes in the 6 cycles of reaction in Example 5.
[0032] Figure 5 This is a SEM image of the catalyst after the reaction in Example 5. Detailed Implementation
[0033] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.
[0034] Example 1: Preparation of manganese-doped nickel selenide catalyst and its electrocatalytic oxidation to produce LEV-COOH
[0035] The preparation of manganese-doped nickel selenide catalyst electrodes includes the following steps:
[0036] 1) Cut the carbon felt into 3×3cm pieces. 2 A rectangular piece of material was cleaned of surface impurities using 3 mol / L hydrochloric acid and deionized water, and then placed in a muffle furnace for high-temperature hydrophilic treatment at 500℃ for 1 hour to obtain hydrophilic carbon felt.
[0037] 2) Then weigh out 600mg nickel nitrate hexahydrate, 300mg urea, 70mg ammonium fluoride and 60mg manganese nitrate tetrahydrate respectively, mix them and dissolve them in 80mL deionized water, place them in an ultrasonic bath and sonicate and stir to make them fully dissolved.
[0038] 3) The hydrophilic carbon felt obtained in step 1) is fully immersed in the solution obtained in step 2) and transferred to a reaction vessel with a polytetrafluoroethylene liner. A solvothermal reaction is carried out at a high temperature of 120°C for 10 hours. After the reaction, a manganese-doped Ni(OH)₂ nanosheet precursor is obtained, which is then transferred to an oven for further drying to obtain a catalyst precursor.
[0039] 4) After drying, the catalyst precursor was transferred to a tube furnace for heat treatment. 800 mg of selenium powder was placed at the top of the tube furnace, upstream of the catalyst precursor. Under the protection of Ar gas at a flow rate of 50 mL / min, the temperature was increased to 350 °C at a rate of 2 °C / min and held at that temperature for 2 hours. After cooling to room temperature, the manganese-doped nickel selenide catalyst, labeled Mn-NiSe / GF, was obtained. Its scanning electron microscope image is shown below. Figure 1a and 1b As shown. From Figure 1a , Figure 1b It can be observed that the Mn-NiSe / GF catalyst grows uniformly on the surface of the carbon felt in the form of nanosheets, with a size of about 1 micrometer.
[0040] The catalytic performance of the Mn-NiSe / GF catalyst electrode prepared in Example 1 was tested using the following methods:
[0041] The Mn-NiSe / GF catalyst obtained above was directly used as the anode, and the current was controlled using an electrochemical workstation. The reaction was carried out in a flow-type diaphragm electrolyzer (see schematic diagram of the electrolysis unit). Figure 2The anode and cathode chambers of the flow-type diaphragm electrolyzer are separated by an ion-exchange membrane. 1.5 g of 1-[(2S)-1-hydroxybutane-2-yl]pyrrolidone-2-one (LEV-CH2OH) and 150 mg of TEMPO are dissolved in 100 mL of a 1 mol / L sodium bicarbonate aqueous solution and stirred until fully dissolved. The resulting solution is used as the anolyte. Nickel foam is used as the counter electrode in the cathode chamber, and a 1 mol / L sodium carbonate aqueous solution is used as the cathode solution. A pH meter is used to maintain the pH of the anolyte reaction solution at 8.5, the reaction system temperature at 30°C, and the current density at 150 mA / cm². 2 Constant current electrolysis for 45 minutes; as the reaction time progresses, the reaction results are tested as follows: Figure 3 As shown. Figure 3 The figure shows the time curve of LEV-CH2OH oxidation. It reveals that as the reaction time increases, the amount of the reactant LEV-CH2OH gradually decreases, while the amount of the main product LEV-COOH gradually increases. After the reaction, the product was extracted three times with 50 mL of dichloromethane. The organic phase was then subjected to vacuum distillation to obtain the levetiracetam pharmaceutical intermediate 2-pyrrolidone-n-butyric acid (LEV-COOH). The conversion rate was 98%, the selectivity was 99%, and the enantiomeric excess was 99%.
[0042] Example 2: Preparation of manganese-doped nickel selenide catalyst and its electrocatalytic oxidation to produce LEV-COOH
[0043] The preparation steps of the manganese-doped nickel selenide catalyst electrode in Example 2 differ from those in Example 1 only in that the time for the solvothermal reaction in "step 3" is extended to 15 hours, while other conditions remain unchanged.
[0044] The catalytic performance of the Mn-NiSe / GF catalyst prepared in Example 2 was tested using the following methods:
[0045] The Mn-NiSe / GF catalyst obtained above was directly used as the anode. The current was controlled using an electrochemical workstation, and the reaction was carried out in a flow-through membrane electrolyzer. The anode and cathode chambers of the flow-through membrane electrolyzer were separated by an ion-exchange membrane. 1.5 g of 1-[(2S)-1-hydroxybutane-2-yl]pyrrolidone-2-one (LEV-CH2OH) and 150 mg of TEMPO were dissolved in 100 mL of 1 mol / L sodium bicarbonate solution and stirred until fully dissolved. The resulting solution was used as the anolyte. Nickel foam was used as the counter electrode in the cathode chamber, and 1 mol / L sodium carbonate solution was used as the cathode solution. The pH of the anolyte reaction solution was maintained at 8.5 using a pH meter, the reaction system temperature was 30 °C, and the current density was 150 mA / cm². 2The reaction was electrolyzed under constant current for 45 minutes. After the reaction was completed, the product was extracted three times with 50 mL of dichloromethane. The organic phase was then subjected to vacuum distillation to obtain the levetiracetam drug intermediate 2-pyrrolidone-n-butyric acid (LEV-COOH) product. The conversion rate was 98%, the selectivity was 96%, and the enantiomeric excess was 91%.
[0046] Compared to Example 1, increasing the hydrothermal time for catalyst electrode preparation to 15 h results in larger Mn-Ni(OH)2 nanosheets, which is detrimental to the mass transfer process of the substrate on its surface, leading to a decrease in selectivity and a reduction in chiral purity.
[0047] Example 3: Preparation of manganese-doped nickel selenide catalyst and its electrocatalytic oxidation to produce LEV-COOH
[0048] The preparation steps of the manganese-doped nickel selenide catalyst electrode in Example 3 differ from those in Example 1 only in that the amount of manganese nitrate tetrahydrate in "step 2) is increased to 300 mg". In addition, the pH is 10.0 during electrolysis, while other conditions remain unchanged.
[0049] The catalytic performance of the Mn-NiSe / GF catalyst prepared in Example 3 was tested using the following method: The Mn-NiSe / GF catalyst obtained above was directly used as the anode. The current was controlled using an electrochemical workstation, and the reaction was carried out in a flow-through membrane electrolyzer. The anode and cathode chambers of the flow-through membrane electrolyzer were separated by an ion exchange membrane. 1.5 g of 1-[(2S)-1-hydroxybutane-2-yl]pyrrolidone-2-one (LEV-CH2OH) and 150 mg of TEMPO were weighed and dissolved in 100 mL of 1 mol / L sodium bicarbonate solution. The solution was stirred until fully dissolved, and the resulting solution was used as the anolyte. Nickel foam was used as the counter electrode in the cathode chamber, and 1 mol / L sodium carbonate solution was used as the cathode solution. The pH of the anolyte reaction solution was maintained at 10.0 using a pH meter, the reaction system temperature was 30 °C, and the current density was 150 mA / cm². 2 The reaction was electrolyzed under constant current for 45 minutes. After the reaction was completed, the product was extracted three times with 50 mL of dichloromethane. The organic phase was then subjected to vacuum distillation to obtain the levetiracetam drug intermediate 2-pyrrolidone-n-butyric acid (LEV-COOH) product. The conversion rate was 98%, the selectivity was 94%, and the enantiomeric excess was 90.2%.
[0050] Compared to Example 1, increasing the amount of manganese source added is not conducive to improving catalytic performance. In addition, in this example, the pH of the anolyte is 10.0, and the enol tautomerism problem of the chiral intermediate at high pH leads to a lower enantiomeric excess value.
[0051] Example 4: Preparation of manganese-doped nickel selenide catalyst and its electrocatalytic oxidation to produce LEV-COOH
[0052] The preparation steps of the manganese-doped nickel selenide catalyst electrode in Example 4 differ from those in Example 1 only in that "the isothermal holding time at 350°C in step 4) is reduced to 1 hour", while other conditions remain unchanged.
[0053] The catalytic performance of the Mn-NiSe / GF catalyst prepared in Example 4 was tested using the following method: The Mn-NiSe / GF catalyst obtained above was directly used as the anode. The current was controlled using an electrochemical workstation, and the reaction was carried out in a flow-through membrane electrolyzer. The anode and cathode chambers of the flow-through membrane electrolyzer were separated by an ion-exchange membrane. 1.5 g of 1-[(2S)-1-hydroxybutane-2-yl]pyrrolidone-2-one (LEV-CH2OH) and 150 mg of TEMPO were weighed and dissolved in 100 mL of 1 mol / L sodium bicarbonate solution. The solution was stirred until fully dissolved, and the resulting solution was used as the anolyte. Nickel foam was used as the counter electrode in the cathode chamber, and 1 mol / L sodium bicarbonate solution was used as the cathode solution. The pH of the anolyte reaction solution was maintained at 8.5 using a pH meter, the reaction system temperature was 30 °C, and the current density was 150 mA / cm². 2 The reaction was electrolyzed under constant current for 45 minutes. After the reaction was completed, the product was extracted three times with 50 mL of dichloromethane. The organic phase was then distilled under reduced pressure to obtain the levetiracetam drug intermediate 2-pyrrolidone-n-butyric acid (LEV-COOH) product. The conversion rate was 94%, the selectivity was 95%, and the enantiomeric excess was 98%.
[0054] Compared to Example 1, reducing the selenization time during the preparation of the manganese-doped nickel selenide catalyst in this example leads to a decrease in catalytic efficiency. This comparison demonstrates the importance of the selenization step for the LEV-CH2OH oxidation reaction.
[0055] Example 5: Preparation of manganese-doped nickel selenide catalyst and its electrocatalytic oxidation to produce LEV-COOH
[0056] The catalytic performance of the Mn-NiSe / GF catalyst prepared in Example 1 was tested after a 45-minute reaction. The specific method is as follows:
[0057] The reacted Mn-NiSe / GF catalyst was used directly as the anode. The current was controlled using an electrochemical workstation, and the reaction was carried out in a flow-through diaphragm electrolyzer. The anode and cathode chambers of the flow-through diaphragm electrolyzer were separated by an ion-exchange membrane. 1.5 g of 1-[(2S)-1-hydroxybutane-2-yl]pyrrolidone-2-one (LEV-CH2OH) and 150 mg of TEMPO were dissolved in 100 mL of 1 mol / L sodium bicarbonate solution and stirred until fully dissolved. The resulting solution was used as the anolyte. Nickel foam was used as the counter electrode in the cathode chamber, and 1 mol / L sodium carbonate solution was used as the cathode solution. The pH of the anolyte reaction solution was maintained at 8.5 using a pH meter, the reaction system temperature was 30 °C, and the current density was 150 mA / cm². 2 The reaction was electrolyzed under constant current for 45 minutes. After the reaction, the mixture was extracted three times with 50 mL of dichloromethane. The organic phase was then subjected to vacuum distillation to obtain the levetiracetam intermediate 2-pyrrolidone-n-butyric acid (LEV-COOH). The conversion rate of the reactants, the selectivity of the product, and the enantiomeric excess value (ee) were calculated. The Mn-NiSe / GF catalyst after the reaction was rinsed with water and dried. SEM images are shown below. Figure 5 .
[0058] In Example 5, the Mn-NiSe / GF catalyst was recycled according to the above electrolysis reaction process. The changes in conversion rate and ee value after 6 cycles are shown in [reference needed]. Figure 4 .
[0059] Example 5 is a cyclic reuse test of the manganese-doped nickel selenide catalyst. In the sixth reaction, the enantiomeric purity of the oxidation product 2-pyrrolidone-butyric acid (LEV-COOH) did not decrease significantly (starting material conversion rate was 96%, product selectivity was 95%, and enantiomeric excess was 95%), demonstrating the excellent stability of the catalyst.
[0060] Example 6: Preparation of manganese-doped nickel selenide catalyst and its electrocatalytic oxidation to produce LEV-COOH
[0061] The preparation steps of the manganese-doped nickel selenide catalyst electrode in Example 6 differ from those in Example 1 only in that manganese doping is not performed in step 2), and ammonium fluoride is not used as a mineralizing agent, while other conditions remain unchanged.
[0062] The catalytic performance of the NiSe / GF catalyst prepared in Example 6 was tested using the following methods:
[0063] The NiSe / GF catalyst obtained above was used directly as the anode. The current was controlled using an electrochemical workstation, and the reaction was carried out in a flow-through diaphragm electrolyzer. The anode and cathode chambers of the flow-through diaphragm electrolyzer were separated by an ion-exchange membrane. 1.5 g of 1-[(2S)-1-hydroxybutane-2-yl]pyrrolidone-2-one (LEV-CH2OH) and 150 mg of TEMPO were dissolved in 100 mL of 1 mol / L sodium bicarbonate solution and stirred until fully dissolved. The resulting solution was used as the anolyte. Nickel foam was used as the counter electrode in the cathode chamber, and 1 mol / L sodium carbonate solution was used as the cathode solution. The pH of the anolyte reaction solution was maintained at 8.5 using a pH meter, the reaction system temperature was 30 °C, and the current density was 150 mA / cm². 2 The reaction was electrolyzed under constant current for 45 minutes. After the reaction was completed, the product was extracted three times with 50 mL of dichloromethane. The organic phase was then distilled under reduced pressure to obtain the levetiracetam drug intermediate 2-pyrrolidone-n-butyric acid (LEV-COOH) product. The conversion rate was 82%, the selectivity was 70%, and the enantiomeric excess was 80%.
[0064] Compared to Example 1, the absence of manganese doping during catalyst electrode preparation reduced the catalytic effect of the catalyst, indicating that manganese doping has a significant impact on the catalyst. Furthermore, without the mineralizing agent ammonium fluoride, the nanosheets exhibited irregular morphology, affecting the transport process in the reaction.
[0065] Example 7: Preparation of manganese-doped nickel selenide catalyst and its electrocatalytic oxidation to produce LEV-COOH
[0066] The preparation steps of the manganese-doped nickel selenide catalyst electrode in Example 7 are the same as those in Example 1.
[0067] The catalytic performance of the Mn-NiSe / GF catalyst prepared in Example 7 was tested using the following methods:
[0068] The Mn-NiSe / GF catalyst obtained above was directly used as the anode. The current was controlled using an electrochemical workstation, and the reaction was carried out in a flow-through diaphragm electrolyzer. The anode and cathode chambers of the flow-through diaphragm electrolyzer were separated by an ion-exchange membrane. 1.5 g of 1-[(2S)-1-hydroxybutane-2-yl]pyrrolidone-2-one (LEV-CH2OH) and 150 mg of TEMPO were dissolved in 100 mL of 1 mol / L sodium bicarbonate solution and stirred until fully dissolved. The resulting solution was used as the anolyte. Nickel foam was used as the counter electrode in the cathode chamber, and 1 mol / L sodium bicarbonate solution was used as the cathode solution. The pH of the anolyte reaction solution was maintained at 8.5 using a pH meter, the reaction system temperature was 30 °C, and the current density was 100 mA / cm². 2The reaction was electrolyzed under constant current for 70 minutes. After the reaction was completed, the product was extracted three times with 50 mL of dichloromethane. The organic phase was then subjected to vacuum distillation to obtain the levetiracetam drug intermediate 2-pyrrolidone-n-butyric acid (LEV-COOH) product. The conversion rate was 98%, the selectivity was 91%, and the enantiomeric excess was 83%.
[0069] The difference between Example 7 and Example 1 is that the current density in the electrolysis experiment is reduced to 100 mA / cm². 2 The cathode electrolyte was 1 mol / L sodium bicarbonate. Compared to Example 1, Example 7 changed the cathode electrolyte to 1 mol / L sodium bicarbonate, resulting in a lower reaction current density. This led to a longer reaction time (the substrate required 70 min to react completely), which in turn resulted in a decrease in chiral purity.
[0070] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.
Claims
1. A method for the electrocatalytic oxidation of levetiracetam drug intermediates using a manganese-doped nickel selenide catalyst, characterized in that... A flow-through diaphragm electrolytic cell is used in the constant current electrolysis process. The current is controlled by an electrochemical workstation. The anode and cathode chambers of the flow-through diaphragm electrolytic cell are separated by an ion exchange membrane. A manganese-doped nickel selenide catalyst electrode is used as the anode electrode. 1-[(2S)-1-hydroxybutane-2-yl]pyrrolidone-2-one LEV-CH2OH is used as the reaction substrate and dissolved with nitric oxide radical TEMPO in an alkaline solution as the anolyte. A cathode electrode is set in the cathode chamber, and an alkaline solution is used as the cathode solution for constant current electrolysis. The reaction time is 0.5-3 hours. After the reaction, the anolyte is post-treated to obtain the levetiracetam drug intermediate 2-pyrrolidone-n-butyric acid LEV-COOH. The reaction equation is as follows: ； The manganese-doped nickel selenide catalyst electrode is prepared by in-situ growth of manganese-doped nickel selenide catalyst on the surface of porous carbon fiber as electrode substrate using a solvothermal method. The preparation process includes the following steps: 1) After cleaning the surface impurities of the porous carbon fiber substrate with 2-4 mol / L hydrochloric acid and deionized water in sequence, it is placed in a muffle furnace for high-temperature activation hydrophilic treatment to obtain a pretreated porous carbon fiber substrate. 2) Dissolve nickel salt, urea, ammonium fluoride, and manganese salt in deionized water to prepare a reaction solution; 3) The porous carbon fiber substrate pretreated in step 1) is fully immersed in the reaction solution in step 2) and transferred to a reaction vessel with a polytetrafluoroethylene liner for solvothermal reaction at 90~150℃ for 6-18h. After the reaction is completed, manganese-doped Ni(OH)2 nanosheet precursor is obtained, which is then transferred into an oven for drying to obtain catalyst precursor. 4) After the drying in step 3) is completed, the catalyst precursor is transferred to a tube furnace for heat treatment. The selenium source is placed at the top of the tube furnace and upstream of the catalyst precursor. Under the action of Ar gas, the manganese-doped Ni(OH)2 nanosheet precursor grown on the surface of porous carbon fiber is converted in situ into manganese-doped nickel selenide catalyst by chemical vapor deposition. In step 1), the high-temperature activation in the muffle furnace is carried out at a temperature of 300-600℃ for a processing time of 0.5-2 hours. In step 4), the selenium source is selenium powder, and the molar ratio of selenium powder to nickel salt is 2.5-7.5:
1. The heat treatment temperature is 300-350℃, and the holding time is 2-3h.
2. The method as described in claim 1, characterized in that... The alkaline solutions used for the anode and cathode are potassium hydroxide solution, sodium hydroxide solution, sodium carbonate solution, or sodium bicarbonate solution, with a concentration of 0.1-1.0 mol / L.
3. The method as described in claim 2, characterized in that... The alkaline solution used for the anode and cathode is a sodium bicarbonate solution.
4. The method as described in claim 1, characterized in that... The amount of TEMPO used is 5-12% of the molar amount of LEV-CH2OH; the concentration of LEV-CH2OH in the anolyte is 10-200 mmol / L.
5. The method as described in claim 4, characterized in that... The amount of TEMPO used is 8-10% of the molar amount of LEV-CH2OH; the concentration of LEV-CH2OH in the anolyte is 50-100 mmol / L.
6. The method as described in claim 1, characterized in that... During constant current electrolysis, the current density is 50-200 mA / cm². 2 The cathode chamber electrode is made of nickel foam.
7. The method as described in claim 1, characterized in that... During constant current electrolysis, the pH of the anolyte reaction solution is kept stable at 8-12; the temperature of the constant temperature water bath during the reaction is 30-60℃; the voltage between the cathode and the anode is 1-10 V; and the reaction time is 0.5-3 hours.
8. The method as described in claim 1, characterized in that... After the reaction is completed, the post-treatment process of the anolyte is as follows: the anolyte is extracted with an organic solvent to obtain an organic phase extract, and the organic layer is taken and distilled under reduced pressure to obtain the target product; the organic solvent used for extraction is toluene, dichloromethane, chloroform or ethyl acetate.
9. The method as described in claim 1, characterized in that... The manganese-doped nickel selenide catalyst electrode is prepared by in-situ growth of manganese-doped nickel selenide catalyst on the surface of porous carbon fiber as electrode substrate via a solvothermal method. The loading of the manganese-doped nickel selenide catalyst on the porous carbon fiber is 5-10 mg / cm³. 2 The porous carbon fiber is a carbon felt.
10. The method as described in claim 1, characterized in that... In step 4), the selenium source is selenium powder, and the molar ratio of selenium powder to nickel salt is 4.5-5:
1. The Ar flow rate is 20-80 mL / min.
11. The method as described in claim 1, characterized in that... In step 2), the molar ratio of nickel salt, urea, ammonium fluoride, and manganese salt is 1:2-3:0.5-2:0.05-0.
2.
12. The method as described in claim 11, characterized in that... In step 2), the molar ratio of nickel salt, urea, ammonium fluoride and manganese salt is 1:2.4-2.5:0.8-1.0:0.1-0.15.