A method for preparing 2,3,5,6-pyridinetetramine by using a sodium amide / ammonia complex system

Abstract

The application discloses a method for preparing 2,3,5,6-pyridine tetramine by using a sodium amide / liquid ammonia composite system, and belongs to the field of organic chemical synthesis. The method uses 2,3,5,6-tetrachloropyridine as raw material, and under anhydrous and anaerobic conditions, sodium amide is dispersed in liquid ammonia to form a sodium amide / liquid ammonia composite reaction system, low-temperature pre-ammoniation treatment is carried out at 40 DEG C to 20 DEG C, and then through a segmented temperature rising mode, nucleophilic substitution reactions occur at four chloro sites in sequence to generate 2,3,5,6-pyridine tetramine. After the reaction is completed, the liquid ammonia is released, a quenching agent is added to terminate the reaction, and the target product is obtained by adjusting the pH or salt formation. The method does not depend on quaternary ammonium salt phase transfer catalysts and copper catalysts, the mass transfer of the reaction system is uniform, the side reactions are few, the product purification process is simple, and the method is suitable for industrial amplification production.

Description

Technical Field

[0001] This invention relates to a method for preparing 2,3,5,6-pyridinetetramine using a sodium amide / liquid ammonia composite system, belonging to the field of organic chemical synthesis. Background Technology

[0002] 2,3,5,6-Tetraaminopyridine (TAP) is a pyridine derivative with highly symmetrical and multifunctional amino substituents. This compound is not a typical chemical intermediate, but a crucial monomer indispensable for M5 fiber (PIPD fiber). PIPD fibers derived from TAP exhibit superior comprehensive properties compared to traditional aramid fibers (such as Kevlar®), including but not limited to: extremely high tensile strength and modulus, excellent compression resistance, outstanding heat resistance and flame retardancy, and low density. These properties give it irreplaceable strategic application value in defense and military industries (such as bulletproof armor and aerospace structural components), high-end industries (such as high-strength cables and abrasion-resistant materials), and special protective fabrics. Therefore, developing efficient, economical, and scalable TAP synthesis technology is a key link in promoting the progress of my country's high-performance materials industry.

[0003] Currently, the catalytic hydrogenation route centered on nitro reduction is the most mature and mainstream technical solution for synthesizing TAP. This route typically includes two key stages: the preparation of the precursor nitro compound and the catalytic reduction of the nitro group. Existing technologies generally use 2,6-diamino-3,5-dinitropyridine (DADNP) as the direct feedstock, and carry out catalytic hydrogenation in the presence of a catalyst to reduce two nitro groups (-NO2) to amino groups (-NH2) in one step, thereby obtaining TAP or its salts, for example, CN109761893A and CN103483249A. This process uses Pd / C as a catalyst and methanol as a solvent, and the reaction is carried out at a temperature of 20~45℃, successfully producing 2,3,5,6-pyridinetetraamine hydrochloride (TAP·3HCl).

[0004] Although the DADNP catalytic hydrogenation pathway has been extensively studied, from the perspective of industrial production and patent innovation, existing technologies still have the following technical shortcomings that urgently need to be addressed: 1. Catalyst cost and efficiency issues: Existing methods heavily rely on precious metal catalysts such as palladium (Pd). The scarcity and high price of precious metal resources not only directly increase production costs, but also restrict their large-scale economic application due to problems such as catalyst activity decay under harsh reaction conditions, metal dissolution, and difficulties in recovery and regeneration.

[0005] 2. Reaction conditions and safety hazards: Existing hydrogenation processes typically require a medium-pressure hydrogen environment (e.g., 0.5-2.0 MPa). The use of high-pressure hydrogen places extremely high demands on the safety, sealing, and operational procedures of reaction equipment, increasing equipment investment and the risks and costs of safe production, which is not conducive to its widespread application in ordinary chemical production environments.

[0006] 3. Complex post-processing and limited product form: The reaction primarily yields TAP hydrochloride (TAPH). To obtain free alkali or convert it into other salt forms (such as composite salts suitable for different polymerization systems), additional neutralization, ion exchange, or metathesis steps are required. This prolongs the process, increases waste generation, and may affect the purity of the final product.

[0007] 4. Limitations in Raw Material Sources and Synthetic Routes: The synthesis of DADNP typically requires nitration from 2,6-diaminopyridine. This nitration step may involve a highly corrosive mixed acid system, resulting in poor atom economy and environmental pressures. The entire technical route relies excessively on a single precursor, DADNP, lacking raw material diversity and route flexibility, thus exposing the entire industry chain to risks related to upstream raw material supply and pricing.

[0008] 5. Limitations of general methods for the synthesis of tetrasubstituted pyridines: Solid amination reagents are unevenly dispersed in conventional organic solvents, with high local alkali concentrations, which can easily lead to inconsistent step-substitution and the generation of mono-, di-, and tri-amino substituted intermediates; Although the simple liquid amination reagent system has advantages in cost and heat transfer, it usually requires the introduction of quaternary ammonium salts, copper catalysts, or specific high-pressure ammonolysis conditions to achieve tetrasubstituted pyridines, which increases the complexity of post-processing and the sources of impurities.

[0009] Therefore, there is an urgent need for a novel, efficient, economical and environmentally friendly method for preparing 2,3,5,6-pyridinetetramine to overcome the above-mentioned defects in the existing technology. Summary of the Invention

[0010] [Technical Issues] Existing methods for synthesizing 2,3,5,6-pyridinetetramine rely on noble metal catalysts, require high-pressure hydrogen, involve complex post-processing steps, and have limited substrate applicability.

[0011] [Technical Solution] To address the shortcomings of existing technologies, this invention aims to provide a novel method for synthesizing 2,3,5,6-pyridinetetramine or its salts. The primary objective of this invention is to reduce or avoid dependence on expensive noble metal catalysts; the second objective is to seek milder and safer reaction conditions, particularly reducing or avoiding the need for high-pressure hydrogen; the third objective is to simplify the process flow, solve the problems of uneven mass transfer of solid-state amination reagents and insufficient quadruple substitution of liquid-state amination reagents, and potentially directly obtain product forms more readily available for subsequent polymerization applications; the ultimate objective is to provide an alternative technological route that is readily available, lower in cost, greener, and suitable for industrial production, thereby enhancing my country's core technological competitiveness in the manufacturing of key monomers for high-performance polymers. The chemical formula of 2,3,5,6-pyridinetetramine is shown in Formula I:

[0012] Formula I The first objective of this invention is to provide a method for preparing 2,3,5,6-pyridinetetramine, comprising the following steps: (1) In a closed pressure-resistant reaction device, under anhydrous and oxygen-free conditions, at -40℃ to -20℃ and in an inert atmosphere, liquid ammonia was added, followed by sodium amino powder, and mixed to obtain a sodium amino / liquid ammonia system. (2) After mixing 2,3,5,6-tetrachloropyridine with liquid ammonia to form a slurry, the slurry is added to the sodium amino acid / liquid ammonia system described in step (1) at -40℃ to -20℃, and pre-ammoniated at -25℃ to -35℃ for 0.5 to 2 h, and pre-wetting and low-temperature pre-ammoniation are carried out first. (3) The pre-ammoniated system was subjected to a staged heating reaction, and the chlorination sites were gradually replaced by amino groups by a programmed heating to obtain 2,3,5,6-pyridinetetramine. (4) Cool the reaction system to below 20°C, depressurize to room temperature, terminate the reaction with a quencher and purify to obtain 2,3,5,6-pyridinetetramine.

[0013] In one embodiment of the present invention, the molar ratio of 2,3,5,6-tetrachloropyridine:sodium amino acid:liquid ammonia is approximately 1:(4~12):(120~200).

[0014] In one embodiment of the present invention, the specific procedure for the segmented heating reaction in step (3) is as follows: (a) In the first stage, the temperature is increased to 10℃~40℃ at a rate of 0.2~0.6℃ / min and held for 0.5~3 h; (b) Second stage: increase the temperature to 50℃~90℃ at a rate of 0.2~0.6℃ / min and hold for 2~10 h; (c) In the third stage, the temperature is increased to 90℃~130℃ at a rate of 0.2~0.6℃ / min and held for 2~12 h.

[0015] In one embodiment of the present invention, in step (1), liquid ammonia is added at a rate of 3 to 12 mL / min, and sodium amino powder is added at a rate of 0.5 to 3 g / min.

[0016] In one embodiment of the present invention, in step (2), 2,3,5,6-tetrachloropyridine is mixed with liquid ammonia at -60°C to -40°C to form a slurry.

[0017] In one embodiment of the present invention, in step (2), the slurry is added to the sodium amino acid / liquid ammonia system described in step (1) at a rate of 0.1~0.5 g / min.

[0018] In one embodiment of the present invention, in step (3), the reaction is carried out in a closed pressure-resistant reaction device under the self-generated pressure of the reaction system; preferably, the pressure of the reaction system is maintained at 0.25~0.45 MPa by adding inert gas.

[0019] In one embodiment of the present invention, in step (1), a co-solvent is added before adding sodium amino powder.

[0020] In one embodiment of the present invention, the co-solvent is selected from one or more of diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran; preferably diethylene glycol dimethyl ether.

[0021] In one embodiment of the present invention, the amount of co-solvent added does not exceed 20% of the volume of liquid ammonia.

[0022] In one embodiment of the present invention, in step (4), the quenching agent is selected from one or more of ammonium chloride alcohol solution, ammonium sulfate alcohol solution, alcohol-soluble hydrogen chloride, liquid ammonia saturated methanol or liquid ammonia saturated ethanol; preferably ammonium chloride alcohol solution or liquid ammonia saturated methanol.

[0023] In one embodiment of the present invention, the ammonium chloride alcohol solution is an ammonium chloride methanol solution with a concentration of 0.5~2 M; preferably 1 M; In one embodiment of the present invention, the dropping speed is controlled to be 0.8~1.5 mL / min, 70~150 rpm.

[0024] In one embodiment of the present invention, in step (4), purification is performed by recrystallization or washing.

[0025] The present invention also provides the application of the above method in the preparation of M5 fibers.

[0026] [Beneficial Effects] In the method provided by this invention, sodium amide is not used in the form of a simple solid powder in an organic solvent, but rather a highly dispersed composite system is pre-constructed in liquid ammonia. This reduces the probability of problems such as uneven reaction, localized exothermic reactions, and batch-to-batch instability in product yield and purity. Similarly, in the method provided by this invention, pre-ammoniation treatment is performed at -40℃ to -20℃ in the early stage of the reaction to reduce localized exothermic reactions and uneven substitution. Furthermore, the method provided by this invention effectively reduces residual chlorinated intermediates by implementing a staged heating strategy in the middle and later stages. The product yield reaches over 80%, and the purity reaches over 95%. In the post-processing, a stable amine salt is first formed, and then the free amine is released to facilitate product separation, drying, and storage. The reaction system of this invention does not rely on quaternary ammonium salts or copper-based catalysts, nor does it use high-boiling-point polar organic solvents as the main reaction medium. The reaction byproducts are mainly inorganic salts such as NaCl and NH4Cl, and there are no difficult-to-remove quaternary ammonium salts or metal catalyst residues, making it more suitable for continuous industrial production. Attached Figure Description

[0027] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0028] Figure 1 Compound of Example 1 1 HNMR spectrum; Figure 2 Compound of Example 1 13 CNMR plot; Figure 3 The image shows the infrared spectrum of the compound in Example 1. Detailed Implementation

[0029] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0030] The following embodiments are used to illustrate the present invention, but should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make various modifications or improvements without departing from the spirit of the present invention.

[0031] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0032] In this invention, liquid ammonia is preferably introduced into the reactor at a rate of 10-12 mL / min; sodium amide can be added in batches, with each batch adding 8%-15% of the total feed amount, and the preferred addition rate is 1.2-1.8 g / min; 2,3,5,6-tetrachloropyridine is preferably added in the form of liquid ammonia slurry, and the preferred addition rate is 0.25-0.40 g / min. During the heating stage, the temperature is preferably increased in stages at a rate of 0.4-0.6 °C / min. After the reaction is complete, the system is preferably cooled to below 20 °C and the pressure is slowly released, then the quencher is added dropwise at a rate of 1.0-1.5 mL / min, the preferred stirring rate is 80-120 rpm, and the preferred reaction termination time is 10-20 min.

[0033] The detection methods involved in the following embodiments: The products were measured using a 400MHz Bruker NMR instrument: the deuterated reagent was tetramethylsilane (TMS) as an internal standard, the concentration of which was approximately 8 mg / mL in the 1H NMR spectrum and approximately 20 mg / mL in the 1C NMR spectrum.

[0034] ATR-FTIR was tested using a Bruker Tensor II infrared spectrometer with 32 scans.

[0035] Product yield = Amount of raw materials used to produce the desired product ÷ Amount of raw materials fed into the plant × 100%.

[0036] The raw materials involved in the following embodiments: 2,3,5,6-Tetrachloropyridine: CAS#2402-79-1; 1 M ammonium chloride methanol solution: 53.5 g ammonium chloride (CAS#12125-02-9), dissolved in an appropriate amount of methanol and then diluted to 1 L.

[0037] Example 1: A method for preparing 2,3,5,6-pyridinetetramine using a sodium amide / liquid ammonia composite system. This embodiment provides a method for preparing 2,3,5,6-pyridinetetramine using a sodium amide / liquid ammonia composite system. Liquid ammonia, sodium amide, and 2,3,5,6-tetrachloropyridine are used as reactants. Liquid ammonia also acts as a solubilizer. The molar ratio of 2,3,5,6-tetrachloropyridine:sodium amide:liquid ammonia is approximately 1:6.7:148, as detailed below: (1) Reaction preparation: Vacuum and nitrogen gas are pumped into a dry 1 L pressure-resistant reactor and repeated twice to completely remove oxygen and moisture from the system; the jacket low temperature circulation is turned on to cool the reactor to -20℃; then 300 mL of liquid ammonia is slowly added at a rate of 10 mL / min.

[0038] (2) Formation of sodium amide / liquid ammonia composite system: Under conditions of -25℃ and 280 rpm, 24 g of sodium amide powder was added to the reactor in 8 batches, each batch being approximately 3.0 g, with the feeding rate controlled at 1.5 g / min; after each batch was added, there was a 4-min interval to avoid excessive local heat release. After all the powder was added, stirring was continued for 20 min to form a homogeneous sodium amide / liquid ammonia composite system.

[0039] (3) Low-temperature pre-ammoniation: The pressure-resistant reactor was further cooled to -30℃. Another dry flask was placed in a low-temperature bath (-40℃), and 20 g of 2,3,5,6-tetrachloropyridine was added, followed by 40 mL of liquid ammonia. The mixture was stirred and mixed to prepare a liquid ammonia slurry. The liquid ammonia slurry was added to the reactor through a constant-pressure dropping funnel or a low-temperature metering pump at -30℃ and 300 rpm, with the slurry addition rate controlled at 0.30 g / min. The mixture was pre-ammoniated at -30℃ and 300 rpm for 1 h.

[0040] (4) Segmented heating ammoniation reaction: Keep stirring at 300 rpm and heat according to the following procedure: In the first stage, the temperature was increased to 20℃ at a rate of 0.4℃ / min and held for 1 hour. In the second stage, the temperature was increased to 70℃ at a rate of 0.5℃ / min and held for 5 hours. In the third stage, the temperature was increased to 110℃ at a rate of 0.5℃ / min and held for 6 hours.

[0041] Throughout the process, the system maintains its own pressure, and if necessary, nitrogen is used to pressurize it to 0.25~0.45 MPa.

[0042] (5) Termination of reaction: After the reaction is completed, turn off the heating and use the jacketed circulating cooling water to reduce the temperature inside the vessel to below 10°C; then slowly depressurize to atmospheric pressure. After the pressure stabilizes, slowly add 30 mL of 1 M ammonium chloride methanol solution to the vessel, controlling the dropping rate to 1.2 mL / min, and stir at 100 rpm for 15 min to terminate the reaction.

[0043] (6) Purification: Filter to remove inorganic salts, concentrate the filtrate under reduced pressure to about 50 mL; then add 100 mL of deionized water, adjust the pH of the system to 8.5 with ammonia water, and precipitate solid; filter to collect solid, wash twice with water, 20 mL each time, and dry under vacuum at 60℃ and -0.098 MPa to obtain 2,3,5,6-pyridinetetramine.

[0044] The specific synthesis route is as follows:

[0045] The product yield was determined using a 400MHz Bruker nuclear magnetic resonance instrument, and the purity was 96.2% as determined by high-performance liquid chromatography (HPLC). Figures 1-3 ).

[0046] Table 1: 2,3,5,6-Pyridinium tetramine 1 HNMR and 13 CNMR data

[0047] Table 2: Infrared test data of 2,3,5,6-pyridinetetramine

[0048] Example 2: A method for preparing 2,3,5,6-pyridinetetramine using a sodium amide / liquid ammonia composite system. This embodiment is basically the same as Embodiment 1, except that a higher amount of liquid ammonia is used and a longer high-temperature holding period is adopted. The molar ratio of 2,3,5,6-tetrachloropyridine:sodium aminohydride:liquid ammonia is approximately 1:7.8:191, as detailed below: (1) Reaction preparation: Vacuum and nitrogen gas are pumped into a dry 1 L pressure-resistant reactor and repeated twice to completely remove oxygen and moisture from the system; the jacket low temperature circulation is turned on to cool the reactor to -20℃; then 400 mL of liquid ammonia is slowly added at a rate of 10 mL / min.

[0049] (2) Formation of sodium amide / liquid ammonia composite system: Under conditions of -20℃ and 280 rpm, 28 g of sodium amide powder was added to the reactor in 10 batches, with each batch containing approximately 2.8 g. The feeding rate was controlled at 1.5 g / min. After each batch was added, there was a 4-min interval to avoid excessive local heat release. After all the powder was added, stirring was continued for 25 min to form a homogeneous sodium amide / liquid ammonia composite system.

[0050] (3) Low-temperature pre-ammoniation: The pressure-resistant reactor was further cooled to -25℃. A separate dry flask was placed in a low-temperature bath (-40℃), and 20 g of 2,3,5,6-tetrachloropyridine was added, followed by 40 mL of liquid ammonia. The mixture was stirred and mixed to prepare a liquid ammonia slurry. At -25℃ and 300 rpm, the liquid ammonia slurry was added to the reactor through a constant-pressure dropping funnel or a low-temperature metering pump, with the slurry addition rate controlled at 0.35 g / min. After the addition was complete, the temperature was maintained and stirred for 2 h.

[0051] (4) Segmented heating ammoniation reaction: Keep stirring at 300 rpm and heat according to the following procedure: In the first stage, the temperature is increased to 30℃ at a rate of 0.5℃ / min and held for 1 hour. In the second stage, the temperature was increased to 80℃ at a rate of 0.5℃ / min and held for 6 hours. In the third stage, the temperature was increased to 120℃ at a rate of 0.4℃ / min and held for 8 hours.

[0052] Throughout the process, the system maintains its own pressure, and if necessary, nitrogen is used to pressurize it to 0.25~0.45 MPa.

[0053] (5) Termination of reaction: After the reaction is completed, turn off the heating and use the jacketed circulating cooling water to reduce the temperature inside the vessel to 20°C; then slowly depressurize to atmospheric pressure. After the pressure stabilizes, slowly add 30 mL of liquid ammonia saturated ethanol solution to the vessel, controlling the dropping rate to 1.0 mL / min, and stir at 100 rpm for 15 min to terminate the reaction.

[0054] (6) After filtration and desalting, the pH was adjusted to 2-3 with dilute hydrochloric acid to precipitate hydrochloride; then the pH was adjusted back to 8.0 with ammonia water to precipitate solid; filtered, washed twice with water, 20 mL each time, and dried under vacuum at 60℃ and -0.098 MPa to obtain 2,3,5,6-pyridinetetramine.

[0055] The product yield was determined to be approximately 85%, and the HPLC purity was approximately 97.0%.

[0056] Example 3: A method for preparing 2,3,5,6-pyridinetetramine using a sodium amide / liquid ammonia composite system. This embodiment is basically the same as Example 1, except that a small amount of co-solvent (diethylene glycol dimethyl ether) is added to improve the low-temperature suspension state of 2,3,5,6-tetrachloropyridine. The molar ratio of 2,3,5,6-tetrachloropyridine:sodium aminohydride:liquid ammonia is approximately 1:7:169, as detailed below: (1) Vacuum and nitrogen gas are pumped into a dry 1 L pressure-resistant reactor and repeated twice to completely remove oxygen and moisture from the system; the jacket low-temperature circulation is turned on to cool the reactor to -20℃; then 350 mL of liquid ammonia is slowly added at a rate of 10 mL / min, and 30 mL of diethylene glycol dimethyl ether is added as a co-solvent.

[0057] (2) Formation of sodium amide / liquid ammonia composite system: Under conditions of -20℃ and 300 rpm, 25 g of sodium amide powder was added to the reactor in 10 batches, each batch being approximately 2.5 g, with the addition rate controlled at 1.3 g / min; after each batch was added, there was a 4-min interval to avoid excessive local heat release. After all the powder was added, stirring was continued for 25 min to form a homogeneous sodium amide / liquid ammonia composite system.

[0058] (3) Low-temperature pre-ammoniation: The pressure-resistant reactor was further cooled to -20℃. A separate dry flask was placed in a low-temperature bath (-40℃), and 20 g of 2,3,5,6-tetrachloropyridine was added, followed by 40 mL of liquid ammonia. The mixture was stirred and mixed to prepare a liquid ammonia slurry. The liquid ammonia slurry was added to the reactor at -20℃ and 300 rpm using a constant-pressure dropping funnel or a low-temperature metering pump, with the addition rate controlled at 0.4 g / min. After the addition was complete, the temperature was maintained and the mixture was stirred for 1.5 h.

[0059] (4) Segmented heating ammoniation reaction: Keep stirring at 300 rpm and heat according to the following procedure: In the first stage, the temperature was increased to 40℃ at a rate of 0.5℃ / min and held for 1 hour. In the second stage, the temperature was increased to 80℃ at a rate of 0.6℃ / min and held for 8 hours. In the third stage, the temperature is increased to 100℃ at a rate of 0.5℃ / min and held for 4 hours.

[0060] Throughout the process, the system maintains its own pressure, and if necessary, nitrogen is used to pressurize it to 0.25~0.45 MPa.

[0061] (5) Termination of reaction: After the reaction is completed, turn off the heating and use the jacketed circulating cooling water to reduce the temperature inside the vessel to below 15°C; then slowly depressurize to atmospheric pressure. After the pressure stabilizes, slowly add 30 mL of ammonium chloride methanol solution to the vessel, controlling the dropping rate to 1.2 mL / min, and stir at 100 rpm for 15 min to terminate the reaction.

[0062] (6) Purification: Filter to remove inorganic salts, concentrate the filtrate under reduced pressure to about 50 mL; then add 100 mL of deionized water, adjust the pH of the system to 8.5 with ammonia water, and precipitate solid; filter, wash twice with water, 20 mL each time, and vacuum dry at 60℃ and -0.098 MPa to obtain 2,3,5,6-pyridinetetramine.

[0063] The product yield was determined to be approximately 80%, and the HPLC purity was approximately 95.4%.

[0064] Example 4: A method for preparing 2,3,5,6-pyridinetetramine using a sodium amide / liquid ammonia composite system This embodiment is basically the same as Embodiment 1, except that it examines a lower pre-ammoniation temperature and a higher final temperature. The molar ratio of 2,3,5,6-tetrachloropyridine:sodium aminoamide:liquid ammonia is approximately 1:7.2:156, as detailed below: (1) Reaction preparation: Vacuum and nitrogen gas are pumped into a dry 1 L pressure vessel and repeated twice to completely remove oxygen and moisture from the system; the jacket low temperature circulation is turned on to cool the vessel to -20℃; then 320 mL of liquid ammonia is slowly added at a rate of 10 mL / min.

[0065] (2) Formation of sodium amide / liquid ammonia composite system: Under conditions of -25℃ and 280 rpm, 26 g of sodium amide powder was added to the reactor in 10 batches, each batch being approximately 2.6 g, with the addition rate controlled at 1.2 g / min; after each batch was added, there was a 4-min interval to avoid excessive local heat release. After all the powder was added, stirring was continued for 25 min to form a homogeneous sodium amide / liquid ammonia composite system.

[0066] (3) Low-temperature pre-ammoniation: The pressure-resistant reactor was further cooled to -35℃. A separate dry flask was placed in a low-temperature bath (-40℃), and 20 g of 2,3,5,6-tetrachloropyridine was added, followed by 40 mL of liquid ammonia. The mixture was stirred and mixed to prepare a liquid ammonia slurry. The liquid ammonia slurry was added to the reactor at -35℃ and 300 rpm using a constant-pressure dropping funnel or a low-temperature metering pump, with the addition rate controlled at 0.25 g / min. After the addition was complete, the temperature was maintained and the mixture was stirred for 1 h.

[0067] (4) Segmented heating ammoniation reaction: Keep stirring at 300 rpm and heat according to the following procedure: In the first stage, the temperature was increased to 30℃ at a rate of 0.4℃ / min and held for 1 hour. In the second stage, the temperature was increased to 90℃ at a rate of 0.5℃ / min and held for 6 hours. In the third stage, the temperature was increased to 120℃ at a rate of 0.4℃ / min and held for 5 hours. Throughout the process, the system maintained autogenous pressure, and nitrogen was used to pressurize it to 0.25~0.45 MPa if necessary.

[0068] (5) Termination of reaction: After the reaction is completed, turn off the heating and use a jacketed cooling water system in conjunction with an external ice-salt bath to lower the system temperature to below 10°C. Then slowly depressurize to atmospheric pressure. After the pressure stabilizes, slowly add 25 mL of ammonium sulfate methanol solution to the reactor at a rate of 1.0 mL / min and stir at 100 rpm for 12 min to terminate the reaction.

[0069] (6) Purification: Filter to remove inorganic salts, concentrate the filtrate under reduced pressure to about 50 mL; then add 100 mL of deionized water, adjust the pH of the system to 9.0 with ammonia water, and precipitate solid; filter, wash twice with water, 20 mL each time, and vacuum dry at 60℃ and -0.098 MPa to obtain 2,3,5,6-pyridinetetramine.

[0070] The product yield was determined to be approximately 83%, and the HPLC purity was approximately 96.5%.

[0071] Example 5: A method for preparing 2,3,5,6-pyridinetetramine using a sodium amide / liquid ammonia composite system. This embodiment is basically the same as Example 1, except that this embodiment examines a different termination system (the quencher is a saturated liquid ammonia ethanol solution). The molar ratio of 2,3,5,6-tetrachloropyridine:sodium aminohydride:liquid ammonia is approximately 1:7.5:174, as detailed below: (1) Reaction preparation: Vacuum and nitrogen gas are pumped into a dry 1 L pressure-resistant reactor and repeated twice to completely remove oxygen and moisture from the system; the jacket low temperature circulation is turned on to cool the reactor to -20℃; then 360 mL of liquid ammonia is slowly added at a rate of 10 mL / min.

[0072] (2) Formation of sodium amide / liquid ammonia composite system: Under conditions of -20℃ and 300 rpm, 27 g of sodium amide powder was added to the reactor in 9 batches, each batch being approximately 3.0 g, with the addition rate controlled at 1.5 g / min; after each batch was added, there was a 4-min interval to avoid excessive local heat release. After all the powder was added, stirring was continued for 25 min to form a homogeneous sodium amide / liquid ammonia composite system.

[0073] (3) Low-temperature pre-ammoniation: The pressure-resistant reactor was further cooled to -30℃. A separate dry flask was placed in a low-temperature bath (-40℃), and 20 g of 2,3,5,6-tetrachloropyridine was added, followed by 40 mL of liquid ammonia. The mixture was stirred and mixed to prepare a liquid ammonia slurry. The liquid ammonia slurry was added to the reactor at -30℃ and 300 rpm using a constant-pressure dropping funnel or a low-temperature metering pump, with the slurry addition rate controlled at 0.30 g / min. After the addition was complete, the temperature was maintained and stirring was continued for 1 h.

[0074] (4) Segmented heating ammoniation reaction: Keep stirring at 300 rpm and heat according to the following procedure: In the first stage, the temperature was increased to 25℃ at a rate of 0.5℃ / min and held for 1 hour. In the second stage, the temperature was increased to 75℃ at a rate of 0.5℃ / min and held for 7 hours. In the third stage, the temperature was increased to 110℃ at a rate of 0.4℃ / min and held for 7 hours.

[0075] Throughout the process, the system maintains its own pressure, and if necessary, nitrogen is used to pressurize it to 0.25~0.45 MPa.

[0076] (5) Termination of reaction: After the reaction is completed, turn off the heating and use the jacketed circulating cooling water to reduce the temperature inside the vessel to 20°C; then slowly depressurize to atmospheric pressure. After the pressure stabilizes, slowly add 30 mL of liquid ammonia saturated ethanol solution to the vessel, controlling the dropping rate to 1.0 mL / min, and stir at 100 rpm for 15 min to terminate the reaction.

[0077] (6) Purification: Filter to remove inorganic salts, concentrate the filtrate under reduced pressure to about 50 mL; then add 100 mL of deionized water, adjust the pH of the system to 8.5 with ammonia water, and precipitate solid; filter, wash twice with water, 20 mL each time, and vacuum dry at 60℃ and -0.098 MPa to obtain 2,3,5,6-pyridinetetramine.

[0078] The product yield was determined to be approximately 84%, and the HPLC purity was approximately 96.8%.

[0079] Comparative Example 1 Same as Example 1, except that step (2) is omitted and sodium amino acid is not used: Experimental results show that a large number of triaminochloropyridine and diaminodichloropyridine intermediates can still be detected after the reaction, indicating insufficient complete tetrasubstituted products. The product yield is about 52% and the HPLC purity is about 82%.

[0080] Comparative Example 2 Similar to Example 1, the difference is that step (3) is adjusted. Instead of preparing liquid ammonia slurry in advance, 2,3,5,6-tetrachloropyridine powder is directly added to the pressure-resistant reactor: 20 g of 2,3,5,6-tetrachloropyridine is slowly added to the reactor at a feeding rate of 0.3 g / min under stirring (300 rpm), followed by a staged heating and ammoniation reaction. The results showed that the 2,3,5,6-tetrachloropyridine powder agglomerated, floated, and adhered to the reactor wall, resulting in decreased uniformity of the reaction system. Trichloro-1-aminopyridine, dichloro-2-aminopyridine, and 1-chloro-3-aminopyridine were detected in the product, and the product yield and purity were unstable in different batches.

[0081] Comparative Example 3 Similar to Example 1, except that step (3) is adjusted: after the addition of 2,3,5,6-tetrachloropyridine, the 1-hour pre-ammoniation is omitted, and the segmented heating ammoniation reaction is carried out directly. Experimental results show that omitting the low-temperature pre-ammoniation step results in insufficient initial substitution reaction in the reaction system, and a wider distribution of intermediates in the subsequent heating stage, leading to a decrease in both the yield and purity of the target product. The product yield is approximately 62%, and the HPLC purity is approximately 92%.

[0082] Comparative Example 4 Similar to Example 1, except that the segmented heating in step (4) is adjusted, and the temperature is directly increased to 120°C at a rate of 0.5°C / min, and held for 22 hours: Experimental results showed that the side reactions in the system increased significantly, the crude product became darker, the product yield was about 58%, and the HPLC purity was about 83%.

[0083] Comparative Example 5 Similar to Example 1, except that the amount of liquid ammonia added in step (1) is adjusted to 80 mL and 160 mL: Experimental results show that compared with the condition of 300 mL of liquid ammonia, when the amount of liquid ammonia is reduced to 80 mL and 160 mL, the suspension state and mass transfer efficiency of the reaction system change, thus affecting the formation of the target product. In particular, when the amount of liquid ammonia is lower, the system is more prone to sodium amide agglomeration and enhanced local exothermic reactions, resulting in a decrease in yield and purity.

[0084] When the amount of liquid ammonia added in step (1) was adjusted to 80 mL, the viscosity of the system increased significantly, the dispersibility of sodium amino was poor, and the local exothermic reaction was obvious after the addition of tetrachloropyridine slurry. After the reaction was completed, the yield of the target product was about 61%, and the HPLC purity was about 92.1%.

[0085] The amount of liquid ammonia added in step (1) was adjusted to 160 mL. During the experiment, the suspension state of the system was improved compared to the 80 mL condition, but there was still a local concentration that was too high. The product yield was about 71%, and the HPLC purity was about 93.7%.

[0086] Comparative Example 6 Similar to Example 1, except that steps (2) and (3) are adjusted, with low-temperature pre-ammoniation performed first, followed by the addition of sodium amide powder in batches: Experimental results show that under these conditions, the low-temperature pre-ammoniation process is difficult to carry out effectively due to the lack of a uniformly dispersed source of amino anions in the initial stage of the reaction system. Simultaneously, the subsequent addition of sodium amide tends to create a higher local alkali concentration, leading to enhanced local exothermic reactions and decreased homogeneity of the reaction system. The yield and purity of the final 2,3,5,6-pyridinetetramine obtained were both lower than in Example 1, with a product yield of only 70% and a purity of 94.6%. This indicates that it is preferable to first form a uniform and stable sodium amide / liquid ammonia composite system before adding the substrate for low-temperature pre-ammoniation, which is beneficial for improving reaction homogeneity and obtaining the target product with higher yield and purity.

[0087] Comparative Example 7 Similar to Example 1, except that the segmented heating amination reaction in step (4) is adjusted: (a) First stage: heat up to 50°C at 0.4°C / min and hold for 1 h; (b) Second stage: increase the temperature to 90°C at 0.5°C / min and hold for 12 h.

[0088] Experimental results show that side reactions were reduced, which is beneficial to improving purity, but the degree of raw material conversion was reduced to some extent, and the yield decreased.

[0089] Comparative Example 8 Similar to Example 1, except that the segmented heating amination reaction in step (4) is adjusted: (a) First stage: heat up to 20°C at a rate of 0.4°C / min and hold for 1 h; (b) Second stage: heat up to 70°C at a rate of 0.5°C / min and hold for 2 hours; (c) In the third stage, the temperature was increased to 110℃ at a rate of 0.5℃ / min and held for 10 h; Experimental results show that when measuring the final product, the side reactions of the system increased significantly due to the excessively long holding time at 110℃, resulting in problems such as darkening of the crude product color and an increase in impurities such as tar.

[0090] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Anyone skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the claims.

Claims

1. A method for preparing 2,3,5,6-pyridinetetramine, characterized in that, Includes the following steps: (1) In a closed pressure-resistant reaction device, under anhydrous and oxygen-free conditions, at -40℃ to -20℃ and in an inert atmosphere, liquid ammonia was added, followed by sodium amino powder, and mixed to obtain a sodium amino / liquid ammonia system. (2) After mixing 2,3,5,6-tetrachloropyridine with liquid ammonia to form a slurry, the slurry is added to the sodium amide / liquid ammonia system described in step (1) at -40℃ to -20℃ and pre-ammoniated at -40℃ to -20℃ for 0.5 to 2 h. (3) The pre-ammoniated system was subjected to a staged heating reaction to obtain 2,3,5,6-pyridinetetramine; (4) The reaction system was cooled to below 20°C, and after depressurization to room temperature, the reaction was terminated with a quencher and purified to obtain 2,3,5,6-pyridinetetramine; wherein, The molar ratio of 2,3,5,6-tetrachloropyridine:sodium aminoamide:liquid ammonia is approximately 1:(4~12):(120~200). The specific procedure for the segmented heating reaction is as follows: (a) In the first stage, the temperature is increased to 10℃~40℃ at a rate of 0.2~0.6℃ / min and held for 0.5~3 h; (b) Second stage: increase the temperature to 50℃~90℃ at a rate of 0.2~0.6℃ / min and hold for 2~10 h; (c) In the third stage, the temperature is increased to 90℃~130℃ at a rate of 0.2~0.6℃ / min and held for 2~12 h.

2. The method according to claim 1, characterized in that, In step (1), liquid ammonia is added at a rate of 3 to 12 mL / min, and sodium amino powder is added at a rate of 0.5 to 3 g / min.

3. The method according to claim 1, characterized in that, In step (2), the slurry is added to the sodium amino acid / liquid ammonia system described in step (1) at a rate of 0.1~0.5 g / min.

4. The method according to claim 1, characterized in that, In step (3), the reaction is carried out in a closed pressure-resistant reaction device under the self-generated pressure of the reaction system; preferably, the pressure of the reaction system is maintained at 0.25~0.45MPa by adding inert gas.

5. The method according to claim 1, characterized in that, In step (1), a co-solvent is added before adding sodium amino powder; Preferably, the co-solvent is selected from one or more of diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran; more preferably, it is diethylene glycol dimethyl ether.

6. The method according to claim 5, characterized in that, The amount of co-solvent added shall not exceed 20% of the volume of liquid ammonia.

7. The method according to claim 1, characterized in that, In step (4), the quenching agent is selected from one or more of the following: ammonium chloride alcohol solution, ammonium sulfate alcohol solution, alcohol-soluble hydrogen chloride, liquid ammonia saturated methanol or liquid ammonia saturated ethanol; preferably ammonium chloride alcohol solution or liquid ammonia saturated methanol.

8. The method according to claim 1 or 7, characterized in that, The ammonium chloride alcohol solution is a methanol solution of ammonium chloride with a concentration of 0.5~2 M; preferably 1 M; Preferably, the dropping speed is controlled at 0.8~1.5 mL / min, 70~150 rpm.

9. The method according to claim 1, characterized in that, In step (4), purification is carried out by recrystallization or washing.

10. The application of the method according to any one of claims 1 to 9 in the preparation of M5 fibers.

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