Process for the preparation of metamizole magnesium using 4-methylaminoantipyrine

Abstract

This invention belongs to the field of heterocyclic compound preparation technology, specifically relating to a method for preparing aminopyrine magnesium using 4-methylaminoantipyrine. The method includes the following steps: (1) mixing 4-methylaminoantipyrine, a main condensing agent, a stabilizing agent, a decolorizing agent, and an organic solvent, adding formaldehyde under controlled temperature to carry out a condensation reaction, adding a pH adjuster during the condensation reaction, and obtaining an aminopyrine reaction solution after the condensation reaction is completed; (2) adding a magnesium source and benzo[a]aza-15-crown-5 to the aminopyrine reaction solution for a heat preservation reaction; (3) after the heat preservation reaction, adding a coordination agent and an oligomeric ether agent, cooling down stepwise under stirring, and allowing it to stand for aging after cooling is completed; (4) filtering, washing, and vacuum drying the aged material to obtain aminopyrine magnesium. This method can obtain high-purity aminopyrine magnesium product while maintaining a high yield of aminopyrine magnesium.

Description

Technical Field

[0001] This invention belongs to the field of heterocyclic compound preparation technology, specifically relating to a method for preparing aminopyrine magnesium using 4-methylaminoantipyrine. Background Technology

[0002] 4-Methylaminoantipyrine, abbreviated as MAA, has CAS number 519-98-2, a molecular weight of 217.27, and its English name is 4-(Methylamino)-Antipyrine. 4-Methylaminoantipyrine is a key intermediate in the synthesis of metamizole. Metamizole magnesium has CAS number 63372-86-1, a molecular weight of 645.01, and its English name is Metamizole Magnesium.

[0003] Chinese patent CN110172038A discloses a one-pot process for preparing magnesium aminopyrine. The process involves dispersing 4-methylaminoantipyrine, formaldehyde, and one of magnesium salts, magnesium hydroxide, or magnesium oxide in a reaction medium, then introducing SO2 gas into the dispersion system to react and obtain magnesium aminopyrine. The magnesium salt is selected from magnesium carbonate or basic magnesium carbonate. The pressure introduced is controlled at 5~150 psi. The reaction medium is selected from methanol, ethanol, or isopropanol.

[0004] This patent describes a one-step method for directly synthesizing aminopyrine magnesium from 4-methylaminoantipyrine. This route eliminates the need for prior synthesis of aminopyrine sodium salt, resulting in a shorter process flow and eliminating the preparation and separation steps of aminopyrine sodium salt. However, the three-phase heterogeneous reaction system between the solid phase (magnesium salt, magnesium hydroxide, or magnesium oxide), liquid phase (reaction medium), and gas phase (SO2 gas) in this one-step method presents a natural bottleneck in mass transfer and control. Magnesium sources such as magnesium oxide, magnesium carbonate, and magnesium hydroxide have very low solubility in organic solvents such as methanol, ethanol, and isopropanol, and the reaction can only occur on the surface of solid particles. The reaction scale-up effect is significant, the mass transfer requirements are high, the reaction control is difficult, and it is difficult to scale up.

[0005] In addition, there is a two-step method to first synthesize sodium metamizole salt and then prepare magnesium metamizole salt. For example, in the first step, 4-methylaminoantipyrine is reacted with formaldehyde and sodium metabisulfite (or sodium bisulfite) in an ethanol medium to undergo Mannich condensation, introducing a sodium methanesulfonate group to the 4-methylamino group, thus generating sodium metamizole salt in one step. The essence of the reaction is the nucleophilic addition of 4-methylaminoantipyrine to the in-situ generated sodium hydroxymethylsulfonate (HO-CH2SO3Na). The second step uses a metathesis method, taking advantage of the fact that the solubility of magnesium metamizole salt in alcohol solvents is much lower than that of sodium metamizole salt. The sodium metamizole salt reacts with magnesium salts (magnesium chloride, magnesium sulfate, etc.) in an alcohol medium, causing magnesium metamizole salt to crystallize directly, thus obtaining the finished magnesium metamizole salt.

[0006] The two-step method is an improvement on the existing sodium analite process, requiring no major modifications to existing production equipment and processes, which is beneficial for industrial production. However, in the second step of the two-step method, the metathesis process and the lattice inclusion effect during crystal growth can trap sodium-containing metal salt and other impurity microcrystals inside the analgin magnesium crystal, making them difficult to remove. Even after multiple refining processes, sodium ion residue is difficult to reduce to below 0.05%, resulting in a naturally lower purity than the sodium-free one-step method. Summary of the Invention

[0007] The purpose of this invention is to provide a method for preparing aminopyrine magnesium using 4-methylaminoantipyrine, which can produce high-purity aminopyrine magnesium product while maintaining a high yield.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to the present invention includes the following steps: (1) Mix 4-methylaminoantipyrine, main condensing agent, stabilizer, decolorizing agent and organic solvent, add formaldehyde under controlled temperature to carry out condensation reaction, add pH adjuster during condensation reaction, and obtain aminopyrine reaction solution after condensation reaction. (2) Add magnesium source and benzo[a]-15-crown-5 to the aminopyrine reaction solution and carry out the reaction under heat preservation; (3) After the heat preservation reaction, add the coordination agent and oligoether agent, and cool down step by step under stirring. After the cooling is completed, let it stand and age. (4) The aged material is filtered, washed and vacuum dried to obtain aminopyrine magnesium.

[0009] in: In step (1), the main condensing agent is sodium metabisulfite, the stabilizing agent is sodium thiosulfate, the decolorizing agent is activated carbon, the organic solvent is ethanol, and the pH adjuster is sodium carbonate; by mass ratio, 4-methylaminoantipyrine:formaldehyde:main condensing agent:stabilizing agent:decolorizing agent:organic solvent =1:(0.18~0.25):(0.52~0.6):(0.10~0.18):(0.02~0.04):(1.7~2.2).

[0010] In step (1), the temperature is controlled at 30~40℃; the total condensation reaction time is 30~45min. When the condensation reaction has proceeded for 15~20min, a pH adjuster is added, and the addition of the pH adjuster is stopped when the pH of the condensation reaction system reaches 7.0~8.0.

[0011] In step (2), the magnesium source is prepared from magnesium chloride hexahydrate and anhydrous ethanol. According to the ratio of added amounts, the ratio of 4-methylaminoantipyrine: magnesium chloride hexahydrate: anhydrous ethanol in step (1) is 1:(0.5~0.58):(2500~3500). Both 4-methylaminoantipyrine and magnesium chloride hexahydrate are in kg, and anhydrous ethanol is in mL. The reaction temperature is 75~80℃ and the reaction time is 20~30min.

[0012] In step (3), by mass ratio, 4-methylaminoantipyrine in step (1): benzoza-15-crown-5 in step (2): coordination aid: oligoether aid = 1000:(0.9~1.5):(0.3~0.6):(5~10); the oligoether aid is tetraethylene glycol dimethyl ether, and the coordination aid is benzenesulfonyl chloride.

[0013] In step (3), the stirring rate is 70~100 rpm; the step-by-step cooling process is as follows: first, the temperature is lowered to 25~30℃ at a rate of 0.5~0.8℃ / min, and then lowered to 0~5℃ at a rate of 2~2.5℃ / min; the static aging temperature is 0~5℃, and the static aging time is 1~2h.

[0014] In step (4), the vacuum drying pressure is -0.09 to -0.07 MPa, the vacuum drying temperature is 60 to 80°C, and the vacuum drying time is 1 to 1.5 h.

[0015] The present invention uses benzoza-15-crown-5 instead of other single-crown ethers for the following reasons: Common single-crown ethers (such as 15-crown-5) are effective against Na + It has basic size recognition capabilities, but its flexible monocyclic structure requires conformational folding to complex metal ions, resulting in limited complexation selectivity and making it impossible to perfectly separate Na. + and Mg 2+ Benzaza-15-crown-5 stabilizes the spatial conformation of the crown ether unit via the benzene ring and secondary amine nitrogen, thus adapting it to sodium ions. Benzaza-15-crown-5 is compatible with Na+. + The complexation constant is higher than that of 15-crown ether-5.

[0016] Benzoaza-15-crown-5 has a large molecular size and interacts with benzenesulfonyl chloride, as well as with Na. + The resulting complex has high solubility in alcohol solvents, making it difficult to enter the lattice of magnesium aminopyrine or be encapsulated by crystals, and it remains completely in the liquid phase. Meanwhile, benzoza-15-crown-5 has a high boiling point and extremely low volatility, resulting in minimal loss during solvent recovery. It can be directly reused through simple filtrate recycling, with a recovery efficiency far higher than that of ordinary single-crown ethers.

[0017] The beneficial effects of this invention are as follows: (1) Benzoaza-15-crown-5 reacts with benzenesulfonyl chloride, and through the coordination of multiple electron donors such as nitrogen atom, oxygen atom and even sulfonyl group, it can selectively complex free Na in the aminopyrine reaction solution. + Significantly increases Na + The difference in partition coefficients between the crystallized crystalline phase and the liquid phase hinders Na + By embedding an anthracite magnesium lattice, the final product purity can reach over 99.93%, which is higher than the purity limit of conventional metathesis-recrystallization processes.

[0018] Conventional processes require multiple rounds of recrystallization to improve purity, with each round resulting in product dissolution and loss, often leading to a significant decrease in yield while purity increases. This invention simultaneously completes impurity removal and crystal form control during the crystallization process, eliminating the need for additional deep purification steps. It maintains a product yield of over 97.3% while achieving a purity of over 99.93%, thus achieving a balance between purity and yield and significantly improving raw material utilization.

[0019] (2) The complex formed by benzoza-15-crown-5 and benzenesulfonyl chloride, as well as tetraethylene glycol dimethyl ether, are readily soluble in organic solvents such as ethanol and isopropanol, while magnesium aminopyrine has extremely low solubility in alcohol solvents at low temperatures. After crystallization and pressure filtration, benzoza-15-crown-5, the coordination aid, and tetraethylene glycol dimethyl ether are completely retained in the filtrate, which can be recycled by direct reuse of the filtrate or simple solvent separation without the need for a complex regeneration process. This reduces the cost of adding additives (the amount of benzoza-15-crown-5, benzenesulfonyl chloride, and tetraethylene glycol dimethyl ether added is controllable and recyclable) and also reduces the discharge of waste, resulting in excellent process economy.

[0020] Furthermore, this additive requires only a low dosage to achieve significant effects and does not introduce a large amount of foreign impurities; its chemical properties are stable, requiring no complex operating conditions, and therefore it will not undergo side reactions with components such as aminopyrine magnesium. It is highly compatible with existing metathesis processes and does not require significant modifications to existing production equipment and processes.

[0021] (3) Benzoaza-15-crown-5 and the coordination aid act as lattice directing agents, which can selectively adsorb on specific crystal faces of aminopyrine magnesium crystals, regulate the crystal growth rate and growth direction, make the crystal morphology more regular and the crystal form more stable, reduce crystal defects and internal encapsulation space, and further reduce the probability of impurity inclusion; at the same time, regular crystals are easier to filter and wash, shortening the post-processing cycle.

[0022] This invention also incorporates oligoether additives, preferably tetraethylene glycol dimethyl ether. In an ethanol solvent system, multiple ether oxygen atoms of the linear polyether in tetraethylene glycol dimethyl ether can interact with the crown ether units in benzo[a]-15-crown-5, fully utilizing the solvation effect of tetraethylene glycol dimethyl ether, slowing down the crystal nucleation rate, avoiding disordered crystal development caused by explosive nucleation, slowing down the surface deposition rate of magnesium ions and aminopyrine anions, reducing impurity encapsulation caused by rapid crystal growth, and forming a functional complement to the selective adsorption of benzo[a]-15-crown-5 crystal faces. Detailed Implementation

[0023] The present invention will now be described and illustrated in detail with reference to the embodiments.

[0024] The raw materials used in the following examples and comparative examples are all commercially available products.

[0025] Example 1 Weigh out the raw materials required for the preparation of aminopyrine, including 1 kg of 4-methylaminoantipyrine, 0.20 kg of formaldehyde, 0.6 kg of sodium metabisulfite, 0.15 kg of sodium thiosulfate, 0.02 kg of activated carbon, 1.7 kg of ethanol and sufficient sodium carbonate.

[0026] Subsequently, 4-methylaminoantipyrine, sodium metabisulfite, sodium thiosulfate, activated carbon, and ethanol were added to a clean reaction vessel and stirred until the system formed a homogeneous suspension. The reaction vessel temperature was controlled at 30-35°C. Formaldehyde was slowly added, with the temperature controlled below 35°C during the dropwise addition process to avoid localized polymerization of formaldehyde or exacerbation of side reactions. After the formaldehyde addition was complete, steam heating was turned on, and the temperature was raised to a state of slight reflux of ethanol. The condensation reaction was carried out for a total of 45 minutes. When the reflux reached 20 minutes, sodium carbonate was slowly added to adjust the pH of the reaction solution to 7.7-8.0, and reflux was continued until the reaction endpoint. After the reaction was completed, the solution was filtered while hot and under pressure to remove insoluble impurities such as activated carbon, and the clear aminopyrine reaction solution was collected.

[0027] Weigh out the raw materials required for the preparation of magnesium aminopyrine, including 580g of magnesium chloride hexahydrate and 3500mL of anhydrous ethanol. Stir and dissolve the weighed magnesium chloride hexahydrate and anhydrous ethanol to obtain a magnesium chloride suspension; and 1500mg of benzoza-15-crown-5, 600mg of benzenesulfonyl chloride, and 5000mg of tetraethylene glycol dimethyl ether.

[0028] Subsequently, the prepared magnesium chloride suspension and benzo[a]aza-15-crown-5 were added to the aminopyrine reaction solution, heated to 75°C, stirred evenly, and reacted at 75°C for 30 min. After decolorization with activated carbon, the mixture was filtered while hot to obtain the filtrate. Benzenesulfonyl chloride and tetraethylene glycol dimethyl ether were added to the filtrate, and then the filtrate was cooled to 28°C at a rate of 0.6°C / min under low-speed stirring at 70 rpm, and then cooled to 5°C at a rate of 2°C / min. The mixture was allowed to stand and age for 2 h. After pressure filtration, the resulting filter cake was washed with anhydrous ethanol and dried under vacuum at -0.09 MPa and 80°C for 1 h to obtain 1453.2 g of aminopyrine magnesium salt, with a yield of 97.9% and a purity of 99.95%.

[0029] The filtrate contains complexes of benzo[a]aza-15-crown-5, benzenesulfonyl chloride, and sodium ions. These complexes are readily soluble in organic solvents such as ethanol and isopropanol. Tetraethylene glycol dimethyl ether is also miscible with various alcohol solvents. However, aminopyrine magnesium salt is insoluble in ethanol and isopropanol at low temperatures. Therefore, benzo[a]aza-15-crown-5, benzenesulfonyl chloride, and tetraethylene glycol dimethyl ether can be easily separated based on their different solubilities and recycled. The post-processing operation is simple.

[0030] Example 2 Weigh the raw materials required for the preparation of Analgin (sodium Analgin), including 1 kg of 4-methylaminoantipyrine, 0.18 kg of formaldehyde, 0.52 kg of sodium metabisulfite, 0.10 kg of sodium thiosulfate, 0.04 kg of activated carbon, 1.9 kg of ethanol and sufficient sodium carbonate.

[0031] Subsequently, 4-methylaminoantipyrine, sodium metabisulfite, sodium thiosulfate, activated carbon, and ethanol were added to a clean reaction vessel and stirred until the system formed a homogeneous suspension. The reaction vessel temperature was controlled at 32-37°C. Formaldehyde was slowly added, with the temperature controlled below 37°C during the dropwise addition process to avoid localized polymerization of formaldehyde or exacerbation of side reactions. After the formaldehyde addition was complete, steam heating was turned on, and the temperature was raised to a state of slight reflux of ethanol. The condensation reaction lasted for 38 minutes. When reflux reached 18 minutes, sodium carbonate was slowly added to adjust the pH of the reaction solution to 7.5-7.8, and reflux was continued until the reaction endpoint. After the reaction was completed, the solution was filtered while hot and under pressure to remove insoluble impurities such as activated carbon, and the clear aminopyrine reaction solution was collected.

[0032] Weigh out the raw materials required for the preparation of magnesium aminopyrine, including 500g of magnesium chloride hexahydrate and 2500mL of anhydrous ethanol. Stir and dissolve the weighed magnesium chloride hexahydrate and anhydrous ethanol to obtain a magnesium chloride suspension; and 1200mg of benzoza-15-crown-5, 300mg of benzenesulfonyl chloride, and 10000mg of tetraethylene glycol dimethyl ether.

[0033] Subsequently, the prepared magnesium chloride suspension and benzo[a]aza-15-crown-5 were added to the aminopyrine reaction solution, heated to 80°C, stirred evenly, and reacted at 80°C for 20 min. After decolorization with activated carbon, the mixture was filtered while hot to obtain the filtrate. Benzenesulfonyl chloride and tetraethylene glycol dimethyl ether were added to the filtrate, and then the filtrate was cooled to 30°C at a rate of 0.5°C / min under low-speed stirring at 90 rpm, and then cooled to 0°C at a rate of 2.5°C / min. The mixture was allowed to stand and age for 1.5 h. After pressure filtration, the resulting filter cake was washed with anhydrous ethanol and dried under vacuum at -0.07 MPa and 70°C for 1.2 h to obtain 1444.3 g of aminopyrine magnesium salt, with a yield of 97.3% and a purity of 99.94%.

[0034] The filtrate contains complexes of benzo[a]aza-15-crown-5, benzenesulfonyl chloride, and sodium ions. These complexes are readily soluble in organic solvents such as ethanol and isopropanol. Tetraethylene glycol dimethyl ether is also miscible with various alcohol solvents. However, aminopyrine magnesium salt is insoluble in ethanol and isopropanol at low temperatures. Therefore, benzo[a]aza-15-crown-5, benzenesulfonyl chloride, and tetraethylene glycol dimethyl ether can be easily separated based on their different solubilities and recycled. The post-processing operation is simple.

[0035] Example 3 Weigh the raw materials required for the preparation of Analgin (sodium Analgin), including 1 kg of 4-methylaminoantipyrine, 0.25 kg of formaldehyde, 0.55 kg of sodium metabisulfite, 0.18 kg of sodium thiosulfate, 0.03 kg of activated carbon, 2.2 kg of ethanol and sufficient sodium carbonate.

[0036] Subsequently, 4-methylaminoantipyrine, sodium metabisulfite, sodium thiosulfate, activated carbon, and ethanol were added to a clean reactor and stirred until the system formed a homogeneous suspension. The reactor temperature was controlled at 35-40°C. Formaldehyde was slowly added, with the temperature controlled below 40°C during the dropwise addition process to avoid localized polymerization of formaldehyde or exacerbation of side reactions. After the formaldehyde addition was complete, steam heating was turned on, and the temperature was raised to a state of slight reflux of ethanol. The condensation reaction was carried out for a total of 30 minutes. When the reflux reached 15 minutes, sodium carbonate was slowly added to adjust the pH of the reaction solution to 7.0-7.3, and reflux was continued until the reaction endpoint. After the reaction was completed, the solution was filtered while hot and under pressure to remove insoluble impurities such as activated carbon, and the clear aminopyrine reaction solution was collected.

[0037] Weigh out the raw materials required for the preparation of magnesium aminopyrine, including 550g of magnesium chloride hexahydrate, 3000mL of anhydrous ethanol, stir and dissolve the weighed magnesium chloride hexahydrate and anhydrous ethanol to obtain magnesium chloride suspension; and 900mg of benzoza-15-crown-5, 400mg of benzenesulfonyl chloride, and 7000mg of tetraethylene glycol dimethyl ether.

[0038] Subsequently, the prepared magnesium chloride suspension and benzo[a]aza-15-crown-5 were added to the aminopyrine reaction solution, heated to 78°C, stirred evenly, and reacted at 78°C for 25 min. After decolorization with activated carbon, the mixture was filtered while hot to obtain the filtrate. Benzenesulfonyl chloride and tetraethylene glycol dimethyl ether were added to the filtrate, and then the filtrate was cooled to 25°C at a rate of 0.8°C / min under low-speed stirring at 100 rpm, followed by a cooling to 3°C at a rate of 2.2°C / min, and allowed to stand for 1 h. The mixture was then filtered under pressure, and the resulting filter cake was washed with anhydrous ethanol and dried under vacuum at -0.08 MPa and 60°C for 1.5 h to obtain 1450.2 g of aminopyrine magnesium salt, with a yield of 97.7% and a purity of 99.93%.

[0039] The filtrate contains complexes of benzo[a]aza-15-crown-5, benzenesulfonyl chloride, and sodium ions. These complexes are readily soluble in organic solvents such as ethanol and isopropanol. Tetraethylene glycol dimethyl ether is also miscible with various alcohol solvents. However, aminopyrine magnesium salt is insoluble in ethanol and isopropanol at low temperatures. Therefore, benzo[a]aza-15-crown-5, benzenesulfonyl chloride, and tetraethylene glycol dimethyl ether can be easily separated based on their different solubilities and recycled. The post-processing operation is simple.

[0040] Comparative Example 1 Without adding benzenesulfonyl chloride, the remaining steps were the same as in Example 1, yielding 1367.1 g of aminopyrine magnesium salt with a yield of 92.1% and a purity of 92.35%.

[0041] Comparative Example 2 Without adding tetraethylene glycol dimethyl ether, the remaining steps were the same as in Example 1, and 1373.0 g of aminopyrine magnesium salt was obtained, with a yield of 92.5% and a purity of 93.48%.

[0042] Comparative Example 3 Without adding benzoza-15-crown-5, the remaining steps were the same as in Example 1, yielding 1361.1 g of aminopyrine magnesium salt, with a yield of 91.7% and a purity of 85.61%.

[0043] Comparative Example 4 By replacing benzoza-15-crown-5 with 15-crown ether-5 and following the same steps as in Example 1, 1364.1 g of aminopyrine magnesium salt was obtained, with a yield of 91.9% and a purity of 89.22%.

Claims

1. A method for preparing magnesium aminopyrine using 4-methylaminoantipyrine, characterized in that, Includes the following steps: (1) Mix 4-methylaminoantipyrine, main condensing agent, stabilizer, decolorizing agent and organic solvent, add formaldehyde under controlled temperature to carry out condensation reaction, add pH adjuster during condensation reaction, and obtain aminopyrine reaction solution after condensation reaction. (2) Add magnesium source and benzo[a]-15-crown-5 to the aminopyrine reaction solution and carry out the reaction under heat preservation; (3) After the heat preservation reaction, add the coordination agent and oligoether agent, and cool down step by step under stirring. After the cooling is completed, let it stand and age. (4) The aged material is filtered, washed and vacuum dried to obtain aminopyrine magnesium.

2. The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to claim 1, characterized in that, In step (1), the main condensing agent is sodium metabisulfite, the stabilizing agent is sodium thiosulfate, the decolorizing agent is activated carbon, the organic solvent is ethanol, and the pH adjuster is sodium carbonate.

3. The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to claim 1, characterized in that, In step (1), by mass ratio, 4-methylaminoantipyrine:formaldehyde:main condensing agent:stabilizing agent:decolorizing agent:organic solvent =1:(0.18~0.25):(0.52~0.6):(0.10~0.18):(0.02~0.04):(1.7~2.2).

4. The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to claim 1, characterized in that, In step (1), the temperature is controlled at 30~40℃; the total condensation reaction time is 30~45min.

5. The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to claim 4, characterized in that, In step (1), when the condensation reaction has proceeded for 15 to 20 minutes, a pH adjuster is added. When the pH of the condensation reaction system reaches 7.0 to 8.0, the addition of the pH adjuster is stopped.

6. The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to claim 1, characterized in that, In step (2), the magnesium source is prepared by magnesium chloride hexahydrate and anhydrous ethanol. According to the ratio of added amount, the ratio of 4-methylaminoantipyrine: magnesium chloride hexahydrate: anhydrous ethanol in step (1) is 1:(0.5~0.58):(2500~3500). Both 4-methylaminoantipyrine and magnesium chloride hexahydrate are in kg, and anhydrous ethanol is in mL.

7. The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to claim 1, characterized in that, In step (2), the heat preservation reaction temperature is 75~80℃ and the heat preservation reaction time is 20~30min.

8. The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to claim 1, characterized in that, In step (3), by mass ratio, 4-methylaminoantipyrine in step (1): benzoza-15-crown-5 in step (2): coordination aid: oligoether aid = 1000:(0.9~1.5):(0.3~0.6):(5~10); the oligoether aid is tetraethylene glycol dimethyl ether, and the coordination aid is benzenesulfonyl chloride.

9. The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to claim 1, characterized in that, In step (3), the stirring rate is 70~100 rpm; the step-by-step cooling process is as follows: first, the temperature is lowered to 25~30℃ at a rate of 0.5~0.8℃ / min, and then lowered to 0~5℃ at a rate of 2~2.5℃ / min; the static aging temperature is 0~5℃, and the static aging time is 1~2h.

10. The method for preparing magnesium aminopyrine using 4-methylaminoantipyrine according to claim 1, characterized in that, In step (4), the vacuum drying pressure is -0.09 to -0.07 MPa, the vacuum drying temperature is 60 to 80°C, and the vacuum drying time is 1 to 1.5 h.