A method for synthesizing nicotinic acid from pyridine by electrochemical carboxylation

Abstract

The application provides a method for synthesizing nicotinic acid from pyridine through electrochemical carboxylation, and belongs to the technical field of organic electrochemical synthesis. The method comprises the following steps: mixing pyridine, a supporting electrolyte and a solvent, stirring until complete dissolution, and obtaining a mixed electrolyte; placing the mixed electrolyte in an electrolytic cell, continuously introducing carbon dioxide into the electrolytic cell, and making the carbon dioxide fully dissolve in the electrolyte to obtain a carbon dioxide-saturated electrolyte; under a normal temperature and pressure environment, applying a constant current or a constant potential to the electrolytic cell to perform an electrochemical carboxylation reaction, and obtaining a reaction liquid containing nicotinic acid; after the electrochemical carboxylation reaction is completed, the reaction liquid is taken out, and after purification treatment, nicotinic acid is obtained. The application activates carbon dioxide in situ based on electrochemical action, simultaneously activates an inert C-H bond of pyridine in a directional manner, and completes a regioselective carboxylation reaction, so that nicotinic acid is synthesized from pyridine and carbon dioxide in one step under a normal temperature and pressure.

Description

Technical Field

[0001] This invention relates to the field of organic electrochemical synthesis technology, and in particular to a method for synthesizing nicotinic acid from pyridine via electrochemical carboxylation. Background Technology

[0002] Niacin (3-pyridinecarboxylic acid) is an essential B vitamin for the human body and an important intermediate in the pharmaceutical, fine chemical, and feed additive industries, with broad industrial application prospects. Currently, the mainstream process for industrial preparation of niacin is the chemical oxidation of 3-methylpyridine. Although this process is technically mature and suitable for large-scale continuous production, it requires the use of highly corrosive and oxidizing reagents such as nitric acid under high temperature and high pressure conditions, resulting in high equipment requirements, high investment and maintenance costs, and the generation of large amounts of nitrogen oxide-containing wastewater, making waste treatment difficult and environmental protection costs high, which is inconsistent with the development direction of green chemical industry.

[0003] Another commonly used industrial process is the hydrolysis of 3-cyanopyridine, which includes chemical hydrolysis and bio-enzymatic hydrolysis. This process offers relatively mild reaction conditions, good product selectivity, and high purity. However, the main raw material, 3-cyanopyridine, is highly toxic, posing significant safety risks during storage, transportation, and production, requiring extremely high levels of safety control. Furthermore, the process is time-consuming, inefficient, and difficult to dispose of the highly toxic raw materials and residual liquids, resulting in high safety and environmental costs, thus hindering its large-scale application.

[0004] Due to the strong inertness of the CH bond in pyridine molecules, regioselective carboxylation is difficult to achieve. Currently, there is no technical solution for the one-step electrochemical carboxylation of nicotinic acid using inexpensive raw material pyridine directly coupled with carbon dioxide. This technological gap has hindered the efficient, low-cost, and green industrial production of nicotinic acid for a long time.

[0005] Therefore, there is an urgent need to develop a method for synthesizing nicotinic acid in one step via electrochemical carboxylation using pyridine and carbon dioxide as raw materials at room temperature and pressure. Summary of the Invention

[0006] To overcome the shortcomings of existing technologies, the purpose of this invention is to provide a method for synthesizing nicotinic acid from pyridine via electrochemical carboxylation. Based on the electrochemical activation of carbon dioxide in situ, the method simultaneously and directionally activates the inert CH bond of pyridine and completes the regioselective carboxylation reaction. Using pyridine and carbon dioxide as raw materials, nicotinic acid is synthesized in one step at room temperature and pressure. This method effectively solves the problems of high raw material cost, complex reaction conditions, significant safety hazards, and serious pollution in existing nicotinic acid preparation methods. The overall method is simple, the raw materials are readily available, the atom utilization rate is high, it is green and environmentally friendly, and the product selectivity is good.

[0007] To achieve the above objectives, the present invention provides a method for synthesizing nicotinic acid from pyridine via electrochemical carboxylation, comprising the following steps: S1. Mix pyridine, supporting electrolyte and solvent, and stir until completely dissolved to obtain mixed electrolyte; S2. Place the mixed electrolyte in an electrolytic cell, and then continuously introduce carbon dioxide into the electrolytic cell to fully dissolve the carbon dioxide in the electrolyte to obtain a carbon dioxide saturated electrolyte. S3. Under normal temperature and pressure, a constant current or constant potential is applied to the electrolytic cell to carry out an electrochemical carboxylation reaction to obtain a reaction solution containing nicotinic acid. S4. After the electrochemical carboxylation reaction is completed, the reaction solution is taken out and purified to obtain nicotinic acid.

[0008] Preferably, in step S1, the supporting electrolyte is at least one of quaternary ammonium salt, alkali metal salt, and alkaline earth metal salt.

[0009] Preferably, the supporting electrolyte is at least one of tetrabutylammonium perchlorate, tetraethylammonium tetrafluoroborate, lithium perchlorate, and sodium perchlorate.

[0010] Preferably, in step S1, the solvent is acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ionic liquid, or a mixture of the above solvents and water.

[0011] Preferably, in step S2, the electrolytic cell is equipped with a working electrode and a counter electrode. The working electrode is any one of a glassy carbon electrode, a platinum electrode, a nickel electrode, and a copper electrode, and the counter electrode is a platinum sheet or a graphite rod.

[0012] Preferably, in step S3, the ambient temperature is 0℃~50℃, and the ambient pressure is 1 standard atmosphere.

[0013] Preferably, in step S3, the reaction time of the electrochemical carboxylation reaction is 2h to 24h.

[0014] Preferably, in step S3, when a constant current is applied to carry out the reaction, the current density of the constant current is 3 mA / cm². 2 ~8mA / cm 2 .

[0015] Preferably, in step S3, when a constant potential is applied to carry out the reaction, the potential range of the constant potential is -1.5V to -2.0V.

[0016] Preferably, in step S4, the purification process includes: acidifying the reaction solution to a pH value of 2-4, and then purifying the acidified reaction solution by at least one of extraction, concentration, recrystallization, and column chromatography separation.

[0017] Compared with the prior art, the present invention discloses at least the following technical effects: This invention utilizes electrochemical activation of carbon dioxide in situ and directionally activates the inert CH bonds of pyridine to achieve selective carboxylation, enabling the one-step synthesis of nicotinic acid under ambient temperature and pressure conditions. This solves the problems of high-cost pyridine derivatives, highly toxic cyano raw materials, and the use of high-temperature, high-pressure, and highly corrosive reagents that traditional processes rely on. It effectively simplifies the production process, reduces raw material and equipment costs, and avoids safety hazards and large amounts of pollutant emissions during production. It features a wide range of raw material sources, high atom utilization, strong reaction controllability, and good product selectivity, enabling the efficient, green, and safe industrial preparation of nicotinic acid. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 This is a flowchart of a method for synthesizing nicotinic acid from pyridine via electrochemical carboxylation according to the present invention. Detailed Implementation

[0020] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] like Figure 1 As shown, the present invention provides a method for synthesizing nicotinic acid from pyridine via electrochemical carboxylation, comprising the following steps: S1. Mix pyridine, supporting electrolyte and solvent, and stir until completely dissolved to obtain mixed electrolyte.

[0022] Specifically, the supporting electrolyte used in this step is at least one of quaternary ammonium salt, alkali metal salt, and alkaline earth metal salt; preferably, it is at least one of tetrabutylammonium perchlorate, tetraethylammonium tetrafluoroborate, lithium perchlorate, and sodium perchlorate. The solvent used is acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ionic liquid, or a mixture of any of the above solvents and water.

[0023] The supporting electrolyte effectively enhances the ion conductivity of the electrolyte, reduces system resistance, and ensures stable current transmission during the electrochemical carboxylation reaction, avoiding problems such as low reaction efficiency and uneven reaction due to insufficient conductivity. The selected electrolytes exhibit excellent solubility and electrochemical stability, preventing side reactions during electrolysis and effectively avoiding impurity formation. Furthermore, the specified organic solvents and aqueous mixed solvents possess good solubility for both pyridine raw materials and the supporting electrolyte, and have a wide electrochemical window, minimizing solvent decomposition during the electrolytic reaction. This ensures stable compatibility with the pyridine electrochemical carboxylation reaction system, providing a stable liquid-phase reaction environment for electron transfer, carbon dioxide activation, and pyridine carboxylation at the electrode surface. This significantly improves electrolyte stability and reaction uniformity, effectively enhancing the efficiency and product selectivity of the electrolysis reaction.

[0024] S2. Place the mixed electrolyte in an electrolytic cell, and then continuously introduce carbon dioxide into the electrolytic cell to fully dissolve the carbon dioxide in the electrolyte to obtain a carbon dioxide saturated electrolyte.

[0025] Specifically, the electrolytic cell used in this step is equipped with a working electrode and a counter electrode. The working electrode is any one of glassy carbon electrode, platinum electrode, nickel electrode, and copper electrode, and the counter electrode is a platinum sheet or graphite rod.

[0026] The aforementioned electrode materials all possess excellent conductivity, electrochemical stability, and catalytic activity. The working electrode stably provides an electron transfer interface, precisely activating the inert CH bonds of pyridine molecules and providing active sites for the carboxylation reaction. The counter electrode stably forms an electrolytic circuit, ensuring smooth circuit operation and eliminating side reaction interference. Simultaneously, the continuous introduction of carbon dioxide and saturated electrolyte ensures a sufficient carboxyl source in the reaction system, continuously supplying reactants for the electrochemical carboxylation reaction. This avoids incomplete reactions and low raw material conversion rates due to insufficient carbon dioxide concentration, guaranteeing the smooth progress of the pyridine-carbon dioxide carboxylation reaction and effectively improving raw material utilization.

[0027] S3. Under normal temperature and pressure, a constant current or constant potential is applied to the electrolytic cell to carry out an electrochemical carboxylation reaction, resulting in a reaction solution containing nicotinic acid.

[0028] Specifically, in this step, the temperature range is 0℃ to 50℃, and the atmospheric pressure is 1 standard atmosphere; the reaction time for the electrochemical carboxylation reaction is 2 hours to 24 hours. When using a constant current mode reaction, the current density is controlled at 3 mA / cm². 2 ~8mA / cm 2 When using a constant potential mode reaction, the potential range is controlled between -1.5V and -2.0V.

[0029] This invention utilizes ambient temperature and pressure reaction conditions, eliminating the need for high-temperature and high-pressure equipment, thus significantly reducing equipment investment and energy consumption. It also avoids problems such as excessive pyridine oxidation and increased byproducts caused by high temperatures. By controlling the provided current density and electrolysis potential, the electron transfer rate on the electrode surface can be adjusted, stably activating carbon dioxide to generate active carboxyl radicals, while simultaneously directionally activating pyridine molecules to achieve selective carboxylation of pyridine sites. Too low a current or potential parameter will result in insufficient electron supply, slow reaction rate, and low raw material conversion rate; too high a parameter will lead to solvent decomposition, electrode corrosion, and increased side reactions. Combined with a controllable reaction time of 2h to 24h, it ensures that pyridine fully participates in the carboxylation reaction, balancing reaction efficiency and product purity, and effectively harmonizing reaction rate, raw material conversion rate, and product selectivity.

[0030] S4. After the electrochemical carboxylation reaction is completed, the reaction solution is taken out and purified to obtain nicotinic acid.

[0031] Specifically, the purification process in this step is as follows: the reaction solution is acidified to a pH of 2-4, and then purified by at least one of the following methods: extraction, concentration, recrystallization, or column chromatography.

[0032] The system following the electrochemical reaction contains unreacted pyridine, electrolytes, and trace byproducts. Acidification to adjust the pH to 2-4 ensures the protonation of the nicotinic acid carboxyl groups, enhancing its stability and organic phase solubility, while simultaneously achieving preliminary separation of nicotinic acid from impurities. Combined with purification methods such as extraction, concentration, recrystallization, and column chromatography, residual raw materials, electrolytes, and byproducts can be removed step-by-step. This adapts to the post-processing requirements of different reaction systems, flexibly accommodating both industrial and laboratory preparation scenarios, ultimately yielding high-purity nicotinic acid and effectively improving product purity and yield.

[0033] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0034] Example 1 In an argon-filled glove box, a 50 mL electrolytic cell with a dual-chamber structure separated by a cation exchange membrane was selected. 0.79 g (10 mmol) of pyridine, 1.07 g (5 mmol) of tetrabutylammonium perchlorate (TBAP), and 20 mL of anhydrous acetonitrile were added to the anode chamber. The mixture was stirred until the solids were completely dissolved, preparing a homogeneous electrolyte. An equal volume of TBAP electrolyte was added to the cathode chamber. A glassy carbon electrode was then installed as the working electrode, and a platinum sheet electrode as the counter electrode, using an Ag / Ag... + A reference electrode is used to construct a complete electrolysis reaction system.

[0035] Dry carbon dioxide gas was continuously introduced into the electrolyte in the anode chamber at a flow rate of 10 mL / min for 30 min to completely remove air from the electrolyte and ensure full saturation of the electrolyte with carbon dioxide. Under ambient temperature (25℃) and normal pressure conditions, a constant current mode was used, with a current density set to 5 mA / cm². 2 The electrolysis reaction was carried out continuously for 12 hours, with carbon dioxide continuously introduced throughout the reaction.

[0036] After the electrolysis reaction was completed, all the reaction solution in the anode chamber was collected and transferred to a round-bottom flask. The reaction solution was acidified with 2M hydrochloric acid solution to adjust the pH of the system to 3.0. The acidified reaction solution was extracted three times with ethyl acetate. All organic phases were combined and dried with anhydrous sodium sulfate. After drying, the solution was concentrated under reduced pressure to obtain crude nicotinic acid. The crude product was purified by silica gel column chromatography, finally yielding 0.82 g of white solid nicotinic acid product, with a product yield of 66%. The purity of the product was greater than 98% as determined by high-performance liquid chromatography (HPLC).

[0037] Example 2 In an argon-filled glove box, a 50 mL electrolytic cell with a dual-chamber structure separated by a cation exchange membrane was selected. 0.79 g (10 mmol) of pyridine, 0.53 g (5 mmol) of lithium perchlorate (LiClO4), and 20 mL of N,N-dimethylformamide (DMF) were added to the anode chamber. The mixture was stirred until the solids were completely dissolved, resulting in a homogeneous electrolyte. An equal volume of lithium perchlorate electrolyte was added to the cathode chamber. A nickel mesh electrode was then installed as the working electrode, and a platinum sheet electrode as the counter electrode, along with an Ag / Ag... + A reference electrode is used to construct a complete electrolysis reaction system.

[0038] Dry carbon dioxide gas was continuously introduced into the electrolyte in the anode chamber at a flow rate of 10 mL / min for 30 min to completely remove air from the electrolyte and fully saturate it with carbon dioxide. The electrolysis reaction was carried out continuously for 8 h under the same constant current mode as in Example 1, at room temperature (25°C) and atmospheric pressure, with carbon dioxide continuously introduced throughout the reaction.

[0039] After the electrolysis reaction was completed, all the reaction solution in the anode chamber was collected and transferred to a round-bottom flask. The reaction solution was acidified with 2M hydrochloric acid solution to adjust the pH of the system to 2-4. The acidified reaction solution was directly cooled to 0°C for low-temperature crystallization. After the crystals were completely precipitated, the mixture was filtered, and the solid crystals were washed with cold water to thoroughly remove residual impurities on the surface. After drying at a constant temperature, nicotinic acid solid product was obtained with a product yield of 58%.

[0040] Example 3 In an argon-filled glove box, a 50 mL single-chamber electrolytic cell was selected. 0.79 g (10 mmol) of pyridine and 1.07 g (5 mmol) of tetrabutylammonium perchlorate (TBAP) were added, along with 20 mL of a mixed solvent of ionic liquid [BMIM][BF4] and water, with a volume ratio of ionic liquid to water of 9:1. The mixture was stirred until the solids were completely dissolved, resulting in a homogeneous electrolyte. A glassy carbon electrode was then installed as the working electrode, and a graphite rod as the counter electrode, along with an Ag / Ag... + A reference electrode is used to construct a complete electrolysis reaction system.

[0041] Dry carbon dioxide gas was continuously introduced into the electrolyte at a flow rate of 10 mL / min for 30 min to completely remove air from the electrolyte and ensure full saturation of the electrolyte with carbon dioxide. Under constant potential mode at room temperature (25℃) and normal pressure, the electrolysis potential was set to -1.8V (relative to Ag / Ag). + (Reference electrode), the electrolysis reaction was carried out continuously for 6 hours, with carbon dioxide continuously introduced throughout the reaction.

[0042] After the electrolysis reaction was completed, all the reaction solution in the electrolytic cell was collected and transferred to a round-bottom flask. Most of the mixed solvent in the system was removed by vacuum distillation, and the concentrated mother liquor was retained. An appropriate amount of deionized water was added to the concentrated mother liquor for crystallization treatment to promote the full precipitation of solid product. After solid-liquid separation and isothermal drying, high-purity nicotinic acid solid product was obtained with a product yield of 71%.

[0043] Therefore, the above-mentioned method for synthesizing nicotinic acid from pyridine via electrochemical carboxylation utilizes the in-situ activation of carbon dioxide through electrochemical action, while simultaneously directionally activating the inert CH bonds of pyridine and completing the regioselective carboxylation reaction. Using pyridine and carbon dioxide as raw materials, nicotinic acid is synthesized in one step at room temperature and pressure. This method effectively solves the problems of high raw material cost, complex reaction conditions, significant safety hazards, and severe pollution in existing nicotinic acid preparation methods. The overall method is simple, the raw materials are readily available, the atom utilization rate is high, it is green and environmentally friendly, and the product selectivity is good.

[0044] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0045] This document uses specific examples to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, those skilled in the art will recognize that, based on the ideas of the present invention, there will be changes in the specific implementation methods and application scope. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A method for synthesizing nicotinic acid from pyridine via electrochemical carboxylation, characterized in that, Includes the following steps: S1. Mix pyridine, supporting electrolyte and solvent, and stir until completely dissolved to obtain mixed electrolyte; S2. Place the mixed electrolyte in an electrolytic cell, and then continuously introduce carbon dioxide into the electrolytic cell to fully dissolve the carbon dioxide in the electrolyte to obtain a carbon dioxide saturated electrolyte. S3. Under normal temperature and pressure, a constant current or constant potential is applied to the electrolytic cell to carry out an electrochemical carboxylation reaction to obtain a reaction solution containing nicotinic acid. S4. After the electrochemical carboxylation reaction is completed, the reaction solution is taken out and purified to obtain nicotinic acid.

2. The method according to claim 1, characterized in that, In step S1, the supporting electrolyte is at least one of quaternary ammonium salt, alkali metal salt, and alkaline earth metal salt.

3. The method according to claim 2, characterized in that, The supporting electrolyte is at least one of tetrabutylammonium perchlorate, tetraethylammonium tetrafluoroborate, lithium perchlorate, and sodium perchlorate.

4. The method according to claim 1, characterized in that, In step S1, the solvent is acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ionic liquid, or a mixture of the above solvents and water.

5. The method according to claim 1, characterized in that, In step S2, the electrolytic cell is equipped with a working electrode and a counter electrode. The working electrode is any one of a glassy carbon electrode, a platinum electrode, a nickel electrode, and a copper electrode, and the counter electrode is a platinum sheet or a graphite rod.

6. The method according to claim 1, characterized in that, In step S3, the ambient temperature is 0℃~50℃, and the ambient pressure is 1 standard atmosphere.

7. The method according to claim 1, characterized in that, In step S3, the reaction time of the electrochemical carboxylation reaction is 2h to 24h.

8. The method according to claim 1, characterized in that, In step S3, when a constant current is applied to carry out the reaction, the current density of the constant current is 3 mA / cm². 2 ~8mA / cm 2 .

9. The method according to claim 1, characterized in that, In step S3, when a constant potential is applied to carry out the reaction, the potential range of the constant potential is -1.5V to -2.0V.

10. The method according to claim 1, characterized in that, In step S4, the purification process includes: acidifying the reaction solution to a pH value of 2-4, and then purifying the acidified reaction solution by at least one of extraction, concentration, recrystallization, and column chromatography separation.

Images