Method for electrochemical synthesis of histamine from histidine

Abstract

The invention relates to the technical field of organic electrochemical synthesis, and particularly discloses a method for generating histamine through decarboxylation hydrogenation by taking histidine as a raw material through an electrochemical decarboxylation coupling strategy. According to the method, amino-protected histidine is taken as a substrate, in an alkaline system in which electrolyte exists, a specific electrode material is selected and the current intensity is regulated and controlled, so that after directional removal of carboxyl in histidine molecules is realized, only simple protective group removal treatment is needed, and histamine can be efficiently generated. The method does not depend on biological enzyme catalysis, realizes chemical selective conversion through an electrochemical means, has the advantages of mild reaction conditions, simplicity and convenience in operation, environmental friendliness and the like, and has extremely high industrial production potential.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing histamine from histidine using an electrochemical approach. Background Technology

[0002] Histamine, as a key bioactive amine, is not only deeply involved in core physiological processes such as human immune regulation, nerve signal transduction, and digestive system function, but also an important intermediate in drug synthesis and biochemical research, playing an irreplaceable role in pharmaceutical development and life science exploration.

[0003] In the traditional preparation of histamine, the bio-enzymatic catalysis method was once the mainstream choice. For example, the technology disclosed in patent CN202411419770.X involves the decarboxylation of histidine by histidine decarboxylase to produce histamine. However, this method has significant limitations: histidine decarboxylase itself has poor stability and is easily deactivated by environmental factors such as temperature and pH; the reaction requires strict condition control, and the suitable environment for the enzymatic reaction needs to be precisely maintained; at the same time, the mixed system of enzyme and product makes the subsequent separation and purification process complex, which greatly limits its large-scale application.

[0004] In the field of chemical synthesis, the conversion of histidine to histamine hinges on two key reactions: the removal of the carboxyl group (-COOH) from the molecule and the hydrogenation reconstruction of the side chain. However, existing chemical synthesis methods also have significant drawbacks. For example, the technology employed in patent CN202011152910.3 requires a composite decarboxylation catalyst and high-temperature, high-pressure conditions to drive the reaction. Many conventional chemical methods commonly use strong oxidizing and reducing agents, which not only leads to low reaction selectivity and abundant byproducts, reducing the purity and yield of the target product, but also causes serious environmental pollution problems due to the difficulty in handling reagent residues and reaction waste, contradicting the concept of green synthesis. Therefore, this invention proposes a method for the electrochemical synthesis of histamine from histidine to at least partially solve the problems that may exist in the existing technology. Summary of the Invention

[0005] In view of the above problems, embodiments of the present invention are proposed to provide a new method for synthesizing histamine from histidine with mild reaction conditions, high conversion efficiency, and excellent selectivity, which overcomes or at least partially solves the above problems, thereby meeting the key need of breaking through the bottleneck of existing technology and promoting the upgrading of histamine industrial production.

[0006] Electrochemical synthesis technology offers an ideal solution to this need due to its unique advantages: it directly drives chemical reactions through electron transfer, eliminating the need for additional chemical oxidants or reducing agents, thus reducing side reactions and pollutants at the source; it also boasts advantages such as mild reaction conditions, high atom economy, and good environmental compatibility. This invention is based on this technological path, innovatively employing an electrochemical decarboxylation coupling strategy. By precisely controlling reaction parameters, it achieves the directional conversion of histidine to histamine, effectively overcoming the inherent defects of traditional bio-enzyme catalysis and chemical synthesis methods, and opening a new pathway for the efficient and green preparation of histamine.

[0007] To address the above problems, embodiments of the present invention disclose a method for the electrochemical synthesis of histamine from histidine, comprising:

[0008] S1. Constructing an electrolytic system: Using histidine containing an amino protecting group as a substrate, dissolve it in a solvent containing alkali and electrolyte at a predetermined molar ratio to form a reaction solution;

[0009] S2, Electrochemical decarboxylation coupling reaction: The reaction solution is placed in an electrolytic cell, and under preset electrolysis conditions, a constant current is passed through the reaction electrode to carry out the electrolysis reaction. After the reaction is completed, histamine containing an amino protecting group is obtained by separation and purification.

[0010] S3. Removal of amino protecting group: Add a protecting group removing agent to the reaction solution of histamine containing amino protecting group, stir the reaction, and obtain histamine by separation and purification.

[0011] Furthermore, the step of using histidine containing an amino protecting group as a substrate, dissolving it in a solvent containing alkali and electrolyte at a predetermined molar ratio to form a reaction solution includes:

[0012] The substrate (i.e., the above-mentioned histidine containing an amino protecting group) is dissolved in a solvent containing an alkali and a supporting electrolyte, with a molar ratio of base to histidine of 1.0 to 5.0:1 and a molar ratio of electrolyte to histidine of 0.05 to 0.5:1, to form a reaction solution with a histidine concentration of 0.05 to 1 mol / L.

[0013] Furthermore, the step of using histidine containing an amino protecting group as a substrate, dissolving it in a solvent containing alkali and electrolyte at a predetermined molar ratio to form a reaction solution includes:

[0014] Histidine containing any one of the amino protecting groups selected from benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), fluorenyloxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB), p-toluenesulfonyl (Tos), triphenylmethyl (Trt), and phthaloyl (Pht) is selected as the substrate.

[0015] The substrate is dissolved in a solvent containing an inorganic base and a supporting electrolyte or an organic base and a supporting electrolyte to form a reaction solution with a histidine concentration of 0.05–1 mol / L.

[0016] Further, the step of dissolving the substrate in a solvent containing an inorganic base and a supporting electrolyte, or a solvent containing an organic base and a supporting electrolyte, includes:

[0017] The substrate is dissolved in at least one inorganic base selected from sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, and in a protic or aprotic solvent containing at least one supporting electrolyte selected from tetrabutylammonium tetrafluoroborate, tetrabutylammonium bromide, tetrabutylammonium chloride, lithium perchlorate, and potassium hexafluorophosphate.

[0018] The substrate is dissolved in at least one organic base selected from triethylamine, pyridine, and N,N-diisopropylethylamine, and in a protic or aprotic solvent containing at least one supporting electrolyte selected from tetrabutylammonium tetrafluoroborate, tetrabutylammonium bromide, tetrabutylammonium chloride, lithium perchlorate, and potassium hexafluorophosphate.

[0019] Furthermore, the protic solvent includes at least one of water, methanol, and ethanol.

[0020] Furthermore, the aprotic solvent includes at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0021] Further, the reaction solution is placed in an electrolytic cell, and under preset electrolysis conditions, a constant current is passed through the reaction electrode to carry out the electrolysis reaction. After the reaction is completed, histamine containing an amino protecting group is obtained by separation and purification, comprising:

[0022] The reaction solution is placed in a single-chamber electrolytic cell or a double-chamber electrolytic cell with the anode and cathode separated by an ion exchange membrane, and an inert electrode is assembled as the anode and a metal electrode as the cathode.

[0023] Under preset electrolysis conditions, a constant current is passed through an inert electrode and a metal electrode to carry out an electrolysis reaction. After the reaction is completed, histamine containing an amino protecting group is obtained by separation and purification.

[0024] The process involves electrolyzing an inert electrode and a metal electrode under preset electrolysis conditions, followed by separation and purification to obtain histamine containing an amino protecting group.

[0025] Under the conditions of a constant current intensity of 5–50 mA, a current density of 10–4000 mA / cm², an electrolysis charge of 2–2.5 F / mol, and an electrolysis reaction temperature of room temperature (approximately 20–30 °C), a constant current is passed through an inert electrode and a metal electrode to carry out the electrolysis reaction. After the reaction is completed, histamine containing an amino protecting group is obtained by separation and purification.

[0026] Furthermore, the inert electrode includes: a platinum electrode, a graphite electrode, and a glassy carbon electrode;

[0027] The metal electrodes include copper electrodes, nickel electrodes, iron electrodes, stainless steel electrodes, and platinum electrodes.

[0028] Furthermore, the inert electrode also includes one of the following: carbon cloth, carbon felt, carbon rod, mesh porous glassy carbon, and nickel foam modified nanomaterials.

[0029] Further, the step of adding a protecting group removal agent to the reaction solution of histamine containing an amino protecting group, stirring the reaction, and obtaining histamine by separation and purification includes:

[0030] Add a protecting group remover to the reaction solution of histamine containing an amino protecting group, stir the reaction, and obtain histamine with the amino protecting group removed;

[0031] The reaction solution was adjusted to neutral, and histamine was obtained by extraction, concentration, and column chromatography.

[0032] Further, the step of adding a protecting group removing agent to the reaction solution of histamine containing an amino protecting group, stirring the reaction, and obtaining histamine with the amino protecting group removed includes:

[0033] Depending on the type of amino protecting group, an acid or base is selected as the protecting group removal agent and added to the reaction solution of histamine containing amino protecting groups. The reaction is stirred to obtain histamine with the amino protecting group removed.

[0034] Furthermore, the step of adjusting the reaction solution to neutral, and then obtaining pure histamine through extraction, concentration, and column chromatography includes:

[0035] Depending on the acidity or alkalinity of the protective group removal agent, a water-soluble inorganic base or inorganic acid is selected to adjust the reaction solution to neutral.

[0036] The inorganic acids or bases added for adjustment are removed by extraction, followed by concentration and column chromatography to obtain pure histamine.

[0037] Furthermore, the step of adjusting the reaction solution to neutral by selecting a water-soluble inorganic base or inorganic acid based on the acidity or alkalinity of the protecting group removal agent includes:

[0038] If the removing agent is acidic, a water-soluble inorganic base is selected to adjust the reaction solution to neutral. The water-soluble inorganic base includes one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide. If the removing agent is alkaline, a water-soluble inorganic acid is selected to adjust the reaction solution to neutral. The water-soluble inorganic acid includes hydrochloric acid, sulfuric acid, and ammonium chloride solution.

[0039] This invention has the following advantages:

[0040] This method utilizes histidine, containing an amino-protected group, as a substrate. It dissolves histidine in a solvent containing an alkali and an electrolyte at a predetermined molar ratio to form a reaction solution. The reaction solution is placed in an electrolytic cell, and under predetermined electrolytic conditions, a constant current is applied to the reaction electrodes for electrolysis. After the reaction, histamine containing an amino-protected group is obtained through separation and purification. A protecting group removal agent is added to the reaction solution containing the amino-protected histamine, and the reaction is stirred. Histamine is then obtained through separation and purification. This method achieves efficient conversion of histidine to histamine in an alkaline system through an electrochemical decarboxylation coupling reaction, overcoming the problems of existing methods that rely on enzyme catalysis or chemical reagents and have low selectivity. Using amino-protected histidine as a substrate, in an alkaline system with an electrolyte, by selecting specific electrode materials and controlling the current intensity, the carboxyl group in the histidine molecule is directionally removed, requiring only simple protecting group removal to efficiently generate histamine. This invention does not rely on biological enzyme catalysis, achieving chemoselective conversion through electrochemical means. It has advantages such as mild reaction conditions, simple operation, and environmental friendliness, and has extremely high potential for industrial production. Detailed Implementation

[0041] 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 specific embodiments.

[0042] It should be noted that in any embodiment of this application, the histidine of the amino protecting group is hereinafter referred to as histidine or substrate, and unless otherwise specified in this application, the histidine is histidine containing an amino protecting group.

[0043] A method for the electrochemical synthesis of histamine from histidine is disclosed. This method achieves efficient conversion of histidine to histamine in an alkaline system through an electrochemical decarboxylation coupling reaction, solving the problems of existing methods that rely on enzyme catalysis or chemical reagents and have low selectivity.

[0044] The principle of this invention is as follows:

[0045]

[0046] To achieve the above objectives, the present invention adopts the following technical solution:

[0047] An embodiment of the method for electrochemical synthesis of histamine from histidine provided by the present invention may specifically include:

[0048] S1. Constructing an electrolytic system: Using histidine containing an amino protecting group as a substrate, dissolve it in a solvent containing an alkali and an electrolyte at a predetermined molar ratio to form a reaction solution; specifically, the substrate (i.e., the above-mentioned histidine containing an amino protecting group) is dissolved in a solvent containing an alkali and a supporting electrolyte at a molar ratio of 1.0 to 5.0:1 and a molar ratio of electrolyte to histidine of 0.05 to 0.5:1 to form a reaction solution with a histidine concentration of 0.05 to 1 mol / L. The histidine containing any one of the following amino protecting groups is selected as the substrate: benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB), p-toluenesulfonyl (Tos), triphenylmethyl (Trt), and phthaloyl (Pht). The substrate is dissolved in a solvent containing an inorganic base and a supporting electrolyte or an organic base and a supporting electrolyte to form a reaction solution with a histidine concentration of 0.05–1 mol / L.

[0049] Further, the step of dissolving the substrate in a solvent containing an inorganic base and a supporting electrolyte, or a solvent containing an organic base and a supporting electrolyte, includes:

[0050] The substrate is dissolved in at least one inorganic base selected from sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, and in a protic or aprotic solvent containing at least one supporting electrolyte selected from tetrabutylammonium tetrafluoroborate, tetrabutylammonium bromide, tetrabutylammonium chloride, lithium perchlorate, and potassium hexafluorophosphate.

[0051] The substrate is dissolved in at least one organic base selected from triethylamine, pyridine, and N,N-diisopropylethylamine, and in a protic or aprotic solvent containing at least one supporting electrolyte selected from tetrabutylammonium tetrafluoroborate, tetrabutylammonium bromide, tetrabutylammonium chloride, lithium perchlorate, and potassium hexafluorophosphate.

[0052] The protic solvents mentioned above can be at least one of water, methanol, and ethanol. Aprotic solvents include at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0053] S2. Electrochemical decarboxylation coupling reaction: The reaction solution is placed in an electrolytic cell, and under preset electrolysis conditions, a constant current is passed through the reaction electrode to carry out the electrolysis reaction. After the reaction is completed, histamine containing an amino protecting group is obtained by separation and purification. Specifically, the reaction solution is placed in a single-chamber electrolytic cell or a double-chamber electrolytic cell with the anode and cathode separated by an ion exchange membrane, and an inert electrode is assembled as the anode and a metal electrode as the cathode. Under preset electrolysis conditions, a constant current is passed through the inert electrode and the metal electrode to carry out the electrolysis reaction. After the reaction is completed, histamine containing an amino protecting group is obtained by separation and purification.

[0054] Furthermore, the step of conducting an electrolytic reaction by passing a constant current through an inert electrode and a metal electrode under preset electrolysis conditions, and obtaining histamine containing an amino protecting group after separation and purification after the reaction, includes: conducting an electrolytic reaction by passing a constant current through an inert electrode and a metal electrode under the conditions of a constant current intensity of 5-50 mA, a current density of 10-4000 mA / cm2, an electrolysis charge of 2-2.5 F / mol, and an electrolysis reaction temperature of room temperature (approximately 20-30℃), and obtaining histamine containing an amino protecting group after separation and purification after the reaction.

[0055] Furthermore, the inert electrodes include: platinum electrodes, graphite electrodes, and glassy carbon electrodes; the metal electrodes include copper electrodes, nickel electrodes, iron electrodes, stainless steel electrodes, and platinum electrodes.

[0056] Furthermore, the inert electrode also includes one of the following: carbon cloth, carbon felt, carbon rod, mesh porous glassy carbon, and nickel foam modified nanomaterials.

[0057] S3. Removal of amino protecting group: Add a protecting group removing agent to the reaction solution of histamine containing amino protecting group, stir the reaction, and obtain histamine by separation and purification. This includes: adding a protecting group removing agent to the reaction solution of histamine containing amino protecting group, stirring the reaction; adjusting the reaction solution to neutral, and obtaining pure histamine by extraction, concentration, and column chromatography.

[0058] As an example, a method for the electrochemical synthesis of histamine from histidine includes the following steps:

[0059] The electrolysis system was constructed by dissolving histidine in a solvent, adding a base and an electrolyte, and stirring until completely dissolved to form a homogeneous reaction solution. Specifically:

[0060] The role of the base is to promote the dissociation of the carboxyl group of histidine and enhance its electrochemical activity. The preferred molar ratio is 1.0 to 5.0:1 (base: histidine). Too high or too low a base amount will lead to an increase in side reactions.

[0061] Electrolytes are supporting electrolytes used to improve the conductivity of the reaction solution. If the concentration is too high, it may cause adsorption on the electrode surface and reduce the reaction efficiency.

[0062] Preferably, the electrolyte is composed of tetraethylammonium bromide or tetraethylammonium iodide; wherein, the preferred molar ratio is 0.05 to 0.5:1 (electrolyte: histidine);

[0063] Organic solvents should be kept away from reacting chemically with reactants or catalysts to avoid interfering with the electrolysis process. Based on this principle, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethanol, methanol, acetonitrile, etc., are all suitable choices for this invention. Preferably, the organic solvent includes at least one of N,N-dimethylformamide, N-methylpyrrolidone, ethanol, methanol, and acetonitrile.

[0064] The histidine concentration was controlled at 0.05–1 mol / L to ensure uniform reaction.

[0065] The electrochemical decarboxylation coupling reaction involves transferring the reaction solution to an electrolytic cell, assembling an anode (inert electrode) and a cathode (metal electrode), connecting it to a DC power supply, and applying a constant current. During the reaction, histidine undergoes reductive decarboxylation at the cathode, where the carboxyl group is removed in the form of CO2, and the side chain is simultaneously hydrogenated and reconstituted to form the ethylamino group of histamine. Key parameters are controlled as follows:

[0066] The anode used in electrolysis can be selected from materials commonly used in the art that possess a three-dimensional porous structure and good electronic conductivity and stability, such as carbon cloth, carbon felt, carbon rods, porous glassy carbon, and nickel-modified nanomaterials. The cathode material can be selected from materials that also possess good conductivity, corrosion resistance, and a certain degree of mechanical strength, such as stainless steel, nickel, graphite carbon felt, platinum, and iron. Those skilled in the art can select a suitable combination based on the actual electrolysis conditions. Preferably, the anode material used in the electrolysis is selected from one of carbon cloth, carbon felt, carbon rods, porous glassy carbon, and nickel-modified nanomaterials; the cathode material is selected from one of stainless steel, nickel, graphite carbon felt, iron, and platinum.

[0067] This invention's electrolysis requires no specialized equipment; conventional electrolysis devices (such as universal integrated electrolytic cells) can be used, demonstrating good industrial applicability. During electrolysis, controlling the current density and charge is crucial for ensuring electrolysis efficiency, product quality, equipment safety, and economy. Excessive current density can lead to electrolyte overheating, electrode overload, or even damage, and may also increase side reactions, affecting the purity and yield of the target product. Furthermore, excessive current density can cause electrolyte decomposition, increasing energy consumption and potentially causing safety accidents. Therefore, the current density and charge in this invention are controlled within a suitable range. The preferred electrolysis current density is 10–400 A / cm², and the preferred electrolysis charge is 2–2.5 F / mol.

[0068] Reaction temperature: 20–60℃, preferably 25–40℃;

[0069] Because the amino group has a lower oxidation potential in electrochemical systems, the exposed histidine amino group is difficult to decarboxylate to generate histamine products during electrochemical processes. Therefore, the histidine required for the reaction needs to be protected. The histidine protecting group can be selected from benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB), p-toluenesulfonyl (Tos), triphenylmethyl (Trt), phthaloyl (Pht), etc., taking into account the ease of removal of the amino protecting group and its compatibility with the reaction. Therefore, the preferred histidine amino protecting group is tert-butyloxycarbonyl (Boc).

[0070] When using tert-butyloxycarbonyl (Boc) as the amino protecting group, after the electrolysis reaction is complete, hydrochloric acid or trifluoroacetic acid can be directly added to the system to remove the amino protecting group Boc. This reaction can be carried out in an electrolytic cell or transferred to a reaction vessel. The reaction process can be carried out at room temperature, and the reaction time should be 0.5–2 hours, depending on the degree of reaction. Preferably, hydrochloric acid is used as the removing agent in the experimental reaction to remove the Boc protecting group, and the amount of hydrochloric acid added is 20–30 times the amount of base added to the reaction system.

[0071] After the product separation and purification reaction was completed, the reaction solution was adjusted to pH 7-8, extracted with ethyl acetate 3-5 times, the organic phases were combined and concentrated, and histamine was obtained by silica gel column chromatography.

[0072] This invention employs an electrochemical method that eliminates the need for enzymes or chemical redox agents, achieving decarboxylation and hydrogenation through electron transfer. The reaction conditions are mild, energy consumption is low, and the process is environmentally friendly.

[0073] By controlling the type and amount of alkali, electrolyte concentration, electrode material and current intensity, highly selective and efficient conversion of histidine can be achieved.

[0074] The reaction system is simple, easy to operate, and easy to scale up, making it suitable for industrial production of histamine and its intermediates.

[0075] The following will further describe a method for the electrochemical synthesis of histamine from histidine in this exemplary embodiment.

[0076] Example 1:

[0077] Under ambient temperature and pressure, in an integrated reaction tank, N-Boc histidine (0.5 mmol), potassium hydroxide (1 mmol), tetrabutylammonium bromide (0.5 mmol), water (1 mL), and acetonitrile (9 mL) were mixed. A carbon sheet with a surface area of ​​2.25 cm² was used as the anode, and an iron sheet with a surface area of ​​2.25 cm² was used as the cathode. The mixture was stirred at room temperature until homogeneous. The power supply was turned on and adjusted to 10 mA for electrolysis for 1.5 hours. Then, hydrochloric acid (20 mmol) was added to the system, and the reaction was stirred at room temperature for 1 hour until the protecting groups were completely removed. The pH of the reaction solution was adjusted to 7–8 using a saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phase was concentrated and separated by silica gel column chromatography to obtain pure histamine in 78% yield.

[0078] Example 2:

[0079] Under ambient temperature and pressure, in an integrated reaction tank, N-Fmoc histidine (0.5 mmol), potassium hydroxide (1 mmol), tetrabutylammonium bromide (0.5 mmol), water (1 mL), and acetonitrile (9 mL) were mixed at room temperature with a 2.25 cm² carbon sheet as the anode and a 2.25 cm² iron sheet as the cathode. The mixture was stirred until homogeneous at room temperature. Power was applied and the voltage was adjusted to 10 mA for 1.5 hours. Then, dimethylamine (20 mmol) was added to the system and the mixture was stirred at room temperature for 1 hour until the protecting groups were completely removed. The pH of the reaction solution was adjusted to 7–8 using 1 mol / L dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. After concentration of the organic phase, it was separated by silica gel column chromatography to obtain pure histamine in 42% yield.

[0080] Example 3:

[0081] Under ambient temperature and pressure, in an integrated reaction tank, N-Boc histidine (0.5 mmol), potassium hydroxide (1 mmol), tetrabutylammonium tetrafluoroborate (0.5 mmol), water (1 mL), and acetonitrile (9 mL) were mixed. A carbon sheet with a surface area of ​​2.25 cm² was used as the anode, and an iron sheet with a surface area of ​​2.25 cm² was used as the cathode. The mixture was stirred at room temperature until homogeneous. The power supply was turned on and adjusted to 10 mA, and electrolysis was carried out for 1.5 hours. Then, hydrochloric acid (20 mmol) was added to the system, and the reaction was stirred at room temperature for 1 hour until the protecting groups were completely removed. The pH of the reaction solution was adjusted to 7-8 using a saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phase was concentrated and separated by silica gel column chromatography to obtain pure histamine with a yield of 62%.

[0082] Example 4:

[0083] Under ambient temperature and pressure, in an integrated reaction tank, N-Boc histidine (0.5 mmol), potassium hydroxide (1 mmol), tetrabutylammonium bromide (0.5 mmol), and acetonitrile (10 mL) were reacted. A carbon sheet with a surface area of ​​2.25 cm² was used as the anode, and an iron sheet with a surface area of ​​2.25 cm² was used as the cathode. The mixture was stirred evenly at room temperature. The power supply was turned on and adjusted to 10 mA, and electrolysis was carried out for 1.5 hours. Then, hydrochloric acid (20 mmol) was added to the system, and the reaction was stirred at room temperature for 1 hour until the protecting groups were completely removed. The pH of the reaction solution was adjusted to 7-8 using a saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phase was concentrated and separated by silica gel column chromatography to obtain pure histamine in 67% yield.

[0084] Example 5:

[0085] Under ambient temperature and pressure, in an integrated reaction tank, N-Boc histidine (0.5 mmol), sodium bicarbonate (1 mmol), tetrabutylammonium bromide (0.5 mmol), water (1 mL), and acetonitrile (9 mL) were mixed. A carbon sheet with a surface area of ​​2.25 cm² was used as the anode, and an iron sheet with a surface area of ​​2.25 cm² was used as the cathode. The mixture was stirred at room temperature until homogeneous. The power supply was turned on and adjusted to 10 mA, and electrolysis was carried out for 1.5 hours. Then, hydrochloric acid (20 mmol) was added to the system, and the reaction was stirred at room temperature for 1 hour until the protecting groups were completely removed. The pH of the reaction solution was adjusted to 7-8 using sodium bicarbonate, and the mixture was extracted three times with ethyl acetate. After concentration of the organic phase, it was separated by silica gel column chromatography to obtain pure histamine in a yield of 42%.

[0086] Example 6:

[0087] Under ambient temperature and pressure, in an integrated reaction tank, N-Boc histidine (0.5 mmol), sodium bicarbonate (1 mmol), tetrabutylammonium bromide (0.5 mmol), water (1 mL), and acetonitrile (9 mL) were mixed. A carbon sheet with a surface area of ​​2.25 cm² was used as the anode, and an iron sheet with a surface area of ​​2.25 cm² was used as the cathode. The mixture was stirred at room temperature until homogeneous. The power supply was turned on and adjusted to 10 mA, and electrolysis was carried out for 1.5 hours. Then, hydrochloric acid (20 mmol) was added to the system, and the reaction was stirred at room temperature for 1 hour until the protecting groups were completely removed. The pH of the reaction solution was adjusted to 7-8 using sodium bicarbonate, and the mixture was extracted three times with ethyl acetate. After concentration of the organic phase, it was separated by silica gel column chromatography to obtain pure histamine in a yield of 42%.

[0088] Example 7:

[0089] Under ambient temperature and pressure, in an integrated reaction tank, N-Boc histidine (5 mmol), potassium hydroxide (10 mmol), tetrabutylammonium bromide (5 mmol), water (10 mL), and acetonitrile (90 mL) were mixed at room temperature with a 22.5 cm² carbon sheet as the anode and a 22.5 cm² iron sheet as the cathode. The mixture was stirred until homogeneous at room temperature. Power was applied and the voltage was adjusted to 100 mA for 1.7 hours. Then, hydrochloric acid (300 mmol) was added to the system and the mixture was stirred at room temperature for 1 hour until the protecting groups were completely removed. The pH of the reaction solution was adjusted to 7–8 using a saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phase was concentrated and separated by silica gel column chromatography to obtain pure histamine in 75% yield.

[0090] Example 8:

[0091] Under ambient temperature and pressure, in an integrated flow reactor, N-Boc histidine (50 mmol), potassium hydroxide (100 mmol), tetrabutylammonium bromide (50 mmol), water (100 mL), and acetonitrile (900 mL) were mixed at room temperature. A carbon sheet with a surface area of ​​225 cm² was used as the anode, and an iron sheet with a surface area of ​​225 cm² was used as the cathode. The mixture was stirred until homogeneous at room temperature. The power supply was turned on and adjusted to 1 A, and electrolysis was performed for 2 hours. Then, hydrochloric acid (3 mol) was added to the system, and the reaction was stirred at room temperature for 1 hour until the protecting groups were completely removed. The pH of the reaction solution was adjusted to 7–8 using a saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phase was concentrated and separated by silica gel column chromatography to obtain pure histamine in 75% yield.

[0092] As an example, the protecting group remover added to the system needs to be quenched by adjusting the system to neutral. Commonly used methods for removing protecting groups include adding an acid / base. After the reaction, the acid / base needs to be quenched. Specifically, the process involves adding a protecting group remover to the reaction solution of histamine containing an amino protecting group, stirring the reaction, and obtaining histamine with the amino protecting group removed, including:

[0093] Depending on the type of amino protecting group, an acid or base is selected as the protecting group removal agent and added to the reaction solution of histamine containing amino protecting groups. The reaction is stirred to obtain histamine with the amino protecting group removed.

[0094] The process of adjusting the reaction solution to neutral, followed by extraction, concentration, and column chromatography to obtain pure histamine includes: adjusting the reaction solution to neutral by selecting a water-soluble inorganic base or inorganic acid based on the acidity or alkalinity of the protecting group removal agent; removing the inorganic acid or inorganic base added during adjustment by extraction; and then concentrating and separating by column chromatography to obtain pure histamine.

[0095] Furthermore, the step of adjusting the reaction solution to neutral by selecting a water-soluble inorganic base or inorganic acid based on the acidity or alkalinity of the protective group removal agent includes: if the removal agent is acidic, then a water-soluble inorganic base is selected to adjust the reaction solution to neutral, wherein the water-soluble inorganic base includes one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide; if the removal agent is alkaline, then a water-soluble inorganic acid is selected to adjust the reaction solution to neutral, wherein the water-soluble inorganic acid includes hydrochloric acid, sulfuric acid, and ammonium chloride solution.

[0096] It should be noted that, ideally, if the reaction solution is neutral after the reaction is complete, there is no need to adjust it to neutral.

[0097] Although preferred embodiments of the present invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of the embodiments of the present invention.

[0098] Finally, it should be noted that in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or terminal device that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or terminal device. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or terminal device that includes said element.

[0099] The above provides a detailed description of a method for the electrochemical synthesis of histamine from histidine. Specific examples have been used to illustrate the principles and implementation methods of the invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the invention. At the same time, those skilled in the art will recognize that there will be changes in the specific implementation methods and application scope based on the ideas of the invention. Therefore, the content of this specification should not be construed as a limitation of the invention.

Claims

1. A method for electrochemical synthesis of histamine from histidine, characterized in that, The application relates to a method for preparing histamine by electrochemical decarboxylation coupling reaction. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group.

2. The method of claim 1, wherein, The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group.

3. The method of claim 2, wherein, The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group.

4. The method of claim 3, wherein, The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group.

5. The method of claim 4, wherein, The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group.

6. The method of claim 4, wherein, The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group.

7. The method of claim 4, wherein, The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decarboxylation coupling reaction; and removing the amino protecting group. The method comprises the following steps: constructing an electrolysis system; performing electrochemical decar 8. The method of claim 7, wherein, The method comprises the following steps: under preset electrolysis conditions, constant current is supplied to inert electrodes and metal electrodes to carry out electrolysis reaction, and after the reaction is completed, histamine containing an amino protecting group is obtained through separation and purification. The constant current has an intensity of 5-50 mA, a current density of 10-4000 mA / cm 2 , an electrolysis electric quantity of 2-2.5 F / mol, and an electrolysis reaction temperature of room temperature. The inert electrode and the metal electrode are supplied with a constant current to perform an electrolysis reaction. After the reaction is completed, an amino-protected group-containing histamine is obtained through separation and purification.

9. The method according to claim 7 or 8, characterized in that, The inert electrodes comprise platinum electrodes, graphite electrodes and glassy carbon electrodes. The metal electrodes comprise copper electrodes, nickel electrodes, iron electrodes and stainless steel electrodes.

10. The method of claim 1, wherein, The method comprises the following steps: a protecting group removing agent is added to a reaction solution containing histamine with an amino protecting group, and the reaction is stirred to obtain histamine with the amino protecting group removed through separation and purification. The method comprises the following steps: a protecting group removing agent is added to a reaction solution containing histamine with an amino protecting group, and the reaction is stirred to obtain histamine with the amino protecting group removed through separation and purification. The reaction solution after the reaction is completed is adjusted to neutral, and histamine is obtained through extraction, concentration and column chromatography separation.

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