Highly efficient stable grignard reagent and green preparation method thereof

Abstract

This invention relates to the field of organic synthesis technology, specifically to a highly efficient and stable Grignard preparation and its green preparation method. By weight, it comprises 8-18 parts of a magnesium source, 40-92 parts of a halogenated hydrocarbon, 150-200 parts of a green solvent, 15-20 parts of ethylene glycol dimethyl ether, and 2.3-3.2 parts of a synergistic stabilizer. The green solvent is 2-methyltetrahydrofuran, or a composite solvent with a weight ratio of 2-methyltetrahydrofuran:methyl tert-butyl ether of 150-160:40-50. The synergistic stabilizer is composed of 1.5-2.0 parts of N,N,N',N'-tetramethylethylenediamine and 0.8-1.2 parts of butylated hydroxytoluene, or composed of 1.5-2.0 parts of N,N,N',N'-tetramethylethylenediamine and 1.0 part of phenothiazine. This invention uses a green solvent system to replace traditional toxic and harmful solvents, and combines it with a solvent recovery process to achieve solvent recycling, which greatly reduces waste emissions and makes the production process safer and more environmentally friendly, in line with the development direction of green chemical industry.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a highly efficient and stable Grignard preparation and its green preparation method. Background Technology

[0002] Grignard reagents are key intermediates for building carbon-carbon bonds in organic synthesis, possessing irreplaceable application value in pharmaceuticals, pesticides, and fine chemical synthesis. However, current traditional methods for preparing Grignard reagents suffer from numerous technical shortcomings, failing to meet the demands of modern green chemistry and large-scale production. The solvents used in traditional processes are mostly flammable and toxic, posing high safety risks during production, and direct solvent discharge causes environmental pollution, contradicting the principles of environmentally friendly production.

[0003] Existing magnesium source activation methods are ineffective, failing to completely remove the oxide layer on the magnesium source surface. This leads to difficulties in reaction initiation, incomplete raw material conversion, increased side reactions, and ultimately, low purity of the resulting formulation. Grignard reagents are chemically reactive and readily react with moisture and oxygen in the environment. Traditional processes lack effective stabilization measures, resulting in a rapid decline in activity and poor stability of the formulation during storage, severely limiting its transportation and application.

[0004] Meanwhile, traditional processes do not recycle and reuse solvents, resulting in high raw material consumption and production costs. Existing technologies often use a single stabilizer, offering limited stabilization and failing to simultaneously ensure both long-term storage stability and reactivity of the formulation. The crude control of reaction parameters makes stable, continuous production difficult. The industry has long lacked Grignard formulation preparation technologies that combine high stability, high reactivity, and environmental friendliness, hindering the industrial application and development of Grignard reagents. Summary of the Invention

[0005] The primary objective of this invention is to provide a highly efficient and stable Grignard preparation and its green preparation method.

[0006] A further objective of this invention is to provide a highly efficient and stable Grignard formulation, comprising, by weight, 8-18 parts of a magnesium source, 40-92 parts of a halogenated hydrocarbon, 150-200 parts of a green solvent, 15-20 parts of ethylene glycol dimethyl ether, and 2.3-3.2 parts of a synergistic stabilizer; wherein the green solvent is 2-methyltetrahydrofuran, or a composite solvent with a weight ratio of 2-methyltetrahydrofuran:methyl tert-butyl ether of 150-160:40-50; wherein the synergistic stabilizer is composed of 1.5-2.0 parts of N,N,N',N'-tetramethylethylenediamine and 0.8-1.2 parts of butylated hydroxytoluene, or composed of 1.5-2.0 parts of N,N,N',N'-tetramethylethylenediamine and 1.0 part of phenothiazine.

[0007] Preferably, the magnesium source is one or more of magnesium powder, magnesium shavings, and magnesium strips; the halogenated hydrocarbon is one or more of bromobenzene, chlorobenzene, ethyl bromide, and p-methoxyphenyl bromide.

[0008] A green preparation method for the highly efficient and stable Grignard agent includes the following steps in sequence: pretreatment of the reaction device, activation of the magnesium source, Grignard reaction, stabilization treatment, and solvent recovery. The stabilization treatment involves adding a synergistic stabilizer to the reaction system and stirring for 30-35 minutes. The raw materials are added in the weight proportions described in claim 1.

[0009] Preferably, the pretreatment of the reaction apparatus is as follows: the experimental instruments are dried at 110°C, assembled while hot, and then purged with nitrogen or argon for 5-6 minutes at a gas flow rate of 15 mL / min. After cooling, inert gas protection is maintained.

[0010] Preferably, the magnesium source activation is performed using ultrasonic treatment with an ultrasonic power of 200W-280W, an activation time of 12-20 minutes, and an activation temperature of 25℃-28℃.

[0011] Preferably, the Grignard reaction is carried out under an inert gas atmosphere, using an isothermal reaction or a segmented temperature-controlled reaction; the haloalkane and ethylene glycol dimethyl ether are mixed and then added dropwise; the segmented temperature-controlled reaction is as follows: for the first 30-35 minutes of the initial addition, the temperature is controlled at 20-22°C, the stirring rate is 350-380 r / min, and the dropping rate is 1.0-1.5 mL / min; for the later stage of the addition, the temperature is controlled at 30-32°C, the stirring rate is 300-320 r / min, and the dropping rate is 1.6-1.8 mL / min; after the addition is complete, the reaction is kept at 30-32°C for 1.5-2.0 hours, with temperature fluctuations controlled within ±1°C.

[0012] Preferably, after the stabilization treatment, unreacted magnesium sources are removed by filtration through a 0.22 μm organic filter membrane.

[0013] Preferably, the solvent recovery is carried out by vacuum distillation or vacuum fractionation, with a gauge pressure of 0.09MPa-0.095MPa and a distillation temperature of 90℃-98℃; the recovered solvent is dried by molecular sieve and then recycled.

[0014] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention uses a green solvent system to replace traditional toxic and harmful solvents, and combines it with a solvent recovery process to achieve solvent recycling, which greatly reduces waste emissions and makes the production process safer and more environmentally friendly, in line with the development direction of green chemical industry.

[0015] 2. This invention uses an ultrasonic activation process to treat the magnesium source, which can efficiently remove the oxide layer on the surface of the magnesium source, significantly improve the reactivity of the magnesium source, ensure a stable start-up of the reaction, effectively suppress side reactions, and improve the purity of the formulation and the reaction conversion effect.

[0016] 3. The present invention employs a synergistic stabilizer system, which can comprehensively inhibit the hydrolysis and oxidation reactions of the preparation, significantly improve the storage stability of Grignard preparations, effectively extend the storage period, and relax the storage and use conditions of the reagents.

[0017] 4. This invention optimizes the reaction temperature control method, achieving precise regulation of the reaction process and further improving reaction uniformity and product quality stability. This invention has strong adaptability to raw materials, compatible with various magnesium sources and halogenated hydrocarbon raw materials, exhibiting high process versatility and facilitating industrial-scale production. The overall preparation process is simple to operate, with mild reaction conditions, requiring no demanding equipment or extreme operating conditions, thus improving product performance while reducing production energy consumption and raw material loss.

[0018] 5. This invention improves the stability and reactivity of the formulation while taking into account environmental protection and economy, and solves the problems of high pollution, poor stability and low efficiency of traditional processes. Detailed Implementation

[0019] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Example

[0020] The raw material proportions by weight are: 10 parts magnesium powder, 85 parts bromobenzene, 200 parts 2-methyltetrahydrofuran, 1.5 parts N,N,N',N'-tetramethylethylenediamine, 0.8 parts butylated hydroxytoluene, and 15 parts ethylene glycol dimethyl ether.

[0021] Preparation steps: Pretreatment of reaction apparatus: Dry all experimental instruments at 110℃ for 1 hour, assemble them while hot, purge with nitrogen for 5 minutes to replace the air, control the nitrogen flow rate at 15 mL / min, and maintain nitrogen protection after cooling to room temperature; Magnesium source activation: Add magnesium powder and 2-methyltetrahydrofuran to the pretreated reaction flask, turn on the ultrasonic device, ultrasonic power 200W, activation time 15 minutes, control the temperature inside the reaction flask to 25℃ during ultrasonication, and obtain activated magnesium powder dispersion. Grignard reaction: Bromobenzene and ethylene glycol dimethyl ether were mixed evenly and placed in a constant pressure dropping funnel. Under nitrogen protection, constant temperature of 25℃, and stirring speed of 300 r / min, the mixture was slowly added dropwise to the activated magnesium powder dispersion at a dropping rate of 1.5 mL / min. After the addition was completed, the mixture was stirred and reacted for 2 hours. The temperature fluctuation during the reaction was controlled within ±1℃. Stabilization: N,N,N',N'-tetramethylethylenediamine and butylated hydroxytoluene were added to the reaction system and stirred for 30 minutes at a stirring rate of 300 r / min. The mixture was then cooled to room temperature and filtered through a 0.22 μm organic filter membrane to remove unreacted magnesium powder, thus obtaining a highly efficient and stable Grignard formulation. Solvent recovery: The filtered 2-methyltetrahydrofuran was recovered by distillation at a temperature of 90℃ and a vacuum of 0.09MPa, with a recovery rate of 88.2%. The recovered solvent was dried by molecular sieve and then put into use. Storage: Seal the prepared Grignard preparation in a brown glass bottle and store it at 25°C under nitrogen protection. Example

[0022] The raw material proportions by weight are: 8 parts magnesium powder, 92 parts bromobenzene, 200 parts 2-methyltetrahydrofuran, 1.5 parts N,N,N',N'-tetramethylethylenediamine, 0.8 parts butylated hydroxytoluene, and 15 parts ethylene glycol dimethyl ether.

[0023] Preparation steps: Pretreatment of the reaction apparatus: completely consistent with Example 1; Magnesium source activation: Add magnesium powder and 2-methyltetrahydrofuran to the pretreated reaction flask, turn on the ultrasonic device, ultrasonic power 200W, activation time 12 minutes, control the temperature inside the reaction flask to 25℃ during ultrasonication, and obtain activated magnesium powder dispersion. Grignard reaction: Bromobenzene and ethylene glycol dimethyl ether were mixed evenly and placed in a constant pressure dropping funnel. Under nitrogen protection, constant temperature of 25°C, and stirring speed of 300 r / min, the mixture was slowly added dropwise to the activated magnesium powder dispersion at a dropping rate of 1.2 mL / min. After the addition was completed, the reaction was stirred for 2 hours. Stabilization process: Completely consistent with Example 1; Solvent recovery: Completely consistent with Example 1, with a recovery rate of 88.0%; Storage: exactly the same as in Example 1. Example

[0024] The raw material proportions by weight are as follows: 18 parts magnesium powder, 78 parts bromobenzene, 200 parts 2-methyltetrahydrofuran, 2.0 parts N,N,N',N'-tetramethylethylenediamine, 1.2 parts butylated hydroxytoluene, and 15 parts ethylene glycol dimethyl ether.

[0025] Preparation steps: Pretreatment of the reaction apparatus: completely consistent with Example 1; Magnesium source activation: Add magnesium powder and 2-methyltetrahydrofuran to the pretreated reaction flask, turn on the ultrasonic device, ultrasonic power 200W, activation time 18 minutes, control the temperature inside the reaction flask to 25℃ during ultrasonication, and obtain activated magnesium powder dispersion. Grignard reaction: Bromobenzene and ethylene glycol dimethyl ether were mixed evenly and placed in a constant pressure dropping funnel. Under nitrogen protection, constant temperature of 25°C, and stirring speed of 300 r / min, the mixture was slowly added dropwise to the activated magnesium powder dispersion at a dropping rate of 1.8 mL / min. After the addition was completed, the reaction was stirred for 2.5 hours. Stabilization: N,N,N',N'-tetramethylethylenediamine and butylated hydroxytoluene were added to the reaction system and stirred for 30 minutes at a stirring rate of 300 r / min. The mixture was then cooled to room temperature and filtered through a 0.22 μm organic filter membrane to remove unreacted magnesium powder, thus obtaining a highly efficient and stable Grignard formulation. Solvent recovery: Completely consistent with Example 1, with a recovery rate of 88.3%; Storage: exactly the same as in Example 1. Example

[0026] The raw material proportions by weight are as follows: 10 parts magnesium powder, 85 parts bromobenzene, 150 parts 2-methyltetrahydrofuran, 50 parts methyl tert-butyl ether, 1.5 parts N,N,N',N'-tetramethylethylenediamine, 0.8 parts butylated hydroxytoluene, and 20 parts ethylene glycol dimethyl ether.

[0027] Preparation steps: Pretreatment of the reaction apparatus: completely consistent with Example 1; Magnesium source activation: Add magnesium powder and composite solvent to the pretreated reaction flask, turn on the ultrasonic device, ultrasonic power 200W, activation time 15 minutes, control the temperature inside the reaction flask to 25℃ during ultrasonication, and obtain activated magnesium powder dispersion. Grignard reaction: Bromobenzene and ethylene glycol dimethyl ether were mixed evenly and placed in a constant pressure dropping funnel. Under nitrogen protection, constant temperature of 25°C, and stirring speed of 300 r / min, the mixture was slowly added dropwise to the activated magnesium powder dispersion at a dropping rate of 1.5 mL / min. After the addition was completed, the reaction was stirred for 2 hours. Stabilization process: Completely consistent with Example 1; Solvent recovery: The filtered composite solvent is fractionated and recovered at a temperature of 95℃ and a vacuum of 0.09MPa. 2-Methyltetrahydrofuran and methyl tert-butyl ether are recovered separately, with a recovery rate of 90.5%. The recovered solvent is dried by molecular sieve and then put into use. Storage: exactly the same as in Example 1. Example

[0028] The raw material proportions by weight are as follows: 10 parts magnesium powder, 85 parts bromobenzene, 150 parts 2-methyltetrahydrofuran, 50 parts methyl tert-butyl ether, 1.5 parts N,N,N',N'-tetramethylethylenediamine, 0.8 parts butylated hydroxytoluene, and 20 parts ethylene glycol dimethyl ether.

[0029] Preparation steps: Pretreatment of reaction apparatus: Dry all experimental instruments at 110℃ for 1 hour, assemble them while hot, purge with argon gas for 5 minutes to replace the air, with an argon gas flow rate of 15 mL / min, and maintain argon gas protection after cooling to room temperature; Magnesium source activation: Add magnesium powder and composite solvent to the pretreated reaction flask, turn on the ultrasonic device, ultrasonic power 250W, activation time 20 minutes, control the temperature inside the reaction flask to 28℃ during ultrasonication, and obtain a highly active magnesium powder dispersion. Grignard reaction: Bromobenzene and ethylene glycol dimethyl ether were mixed evenly and placed in a constant pressure dropping funnel. Under argon protection and segmented temperature control, the mixture was added dropwise. For the first 30 minutes of the addition, the temperature was controlled at 20°C, the stirring rate at 350 r / min, and the dropping rate at 1.0 mL / min. For the remaining time of the addition, the temperature was controlled at 30°C, the stirring rate at 300 r / min, and the dropping rate at 1.8 mL / min. After the addition was completed, the mixture was stirred and reacted for 1.5 hours at a constant temperature of 30°C. The temperature fluctuation during the reaction was controlled within ±1°C. Stabilization process: Completely consistent with Example 4; Solvent recovery: completely consistent with Example 4, with a recovery rate of 91.2%, and the water content of the recovered solvent was controlled below 50 ppm; Storage: exactly the same as in Example 1.

[0030] Example 6: The raw material proportions by weight are as follows: 14 parts magnesium powder, 80 parts chlorobenzene, 160 parts 2-methyltetrahydrofuran, 40 parts methyl tert-butyl ether, 1.8 parts N,N,N',N'-tetramethylethylenediamine, 1.0 part butylated hydroxytoluene, and 18 parts ethylene glycol dimethyl ether.

[0031] Preparation steps: Pretreatment of reaction apparatus: Dry all experimental instruments at 110℃ for 1 hour, assemble them while hot, purge with nitrogen for 6 minutes to replace the air, nitrogen flow rate 15 mL / min, cool to room temperature and maintain nitrogen protection. Magnesium source activation: Add magnesium powder and composite solvent to the pretreated reaction flask, turn on the ultrasonic device, ultrasonic power 280W, activation time 16 minutes, control the temperature inside the reaction flask to 26℃ during ultrasonication, and obtain a highly active magnesium powder dispersion. Grignard reaction: Chlorobenzene and ethylene glycol dimethyl ether were mixed evenly and placed in a constant pressure dropping funnel. The mixture was added dropwise under nitrogen protection and segmented temperature control. During the first 35 minutes of the addition, the temperature was controlled at 22°C, the stirring rate was 380 r / min, and the dropping rate was 1.5 mL / min. During the remaining time of the addition, the temperature was controlled at 32°C, the stirring rate was 320 r / min, and the dropping rate was 1.6 mL / min. After the addition was completed, the reaction was continued to be stirred at a constant temperature of 32°C for 2.0 hours. Stabilization: N,N,N',N'-tetramethylethylenediamine and butylated hydroxytoluene were added to the reaction system and stirred for 35 minutes at a stirring rate of 320 r / min. The mixture was then cooled to room temperature and filtered through a 0.22 μm organic filter membrane to remove unreacted magnesium powder, thus obtaining a highly efficient and stable Grignard formulation. Solvent recovery: The filtered composite solvent is fractionated and recovered at a temperature of 98℃ and a vacuum of 0.095MPa. 2-Methyltetrahydrofuran and methyl tert-butyl ether are recovered separately, with a recovery rate of 91.5%. The recovered solvent can be recycled up to 4 times after drying. Storage: Seal the prepared Grignard preparation in a brown glass bottle and store it at 15°C under nitrogen protection.

[0032] Example 7: The raw material proportions by weight are as follows: 8 parts magnesium shavings, 6 parts magnesium strips, 80 parts chlorobenzene, 160 parts 2-methyltetrahydrofuran, 40 parts methyl tert-butyl ether, 1.8 parts N,N,N',N'-tetramethylethylenediamine, 1.0 part butylated hydroxytoluene, and 18 parts ethylene glycol dimethyl ether.

[0033] Preparation steps: Pretreatment of the reaction apparatus: completely consistent with Example 6; Magnesium source activation: Add magnesium chips, magnesium strips and composite solvent to the pretreated reaction flask, turn on the ultrasonic equipment, ultrasonic power 280W, activation time 18 minutes, control the temperature inside the reaction flask to 26℃ during ultrasonication, and obtain a highly active magnesium source dispersion. Grignard reaction: completely consistent with Example 6; Stabilization process: Completely consistent with Example 6; Solvent recovery: Completely consistent with Example 6, with a recovery rate of 91.3%; Storage: exactly the same as in Example 6.

[0034] Example 8: The raw material proportions by weight are as follows: 14 parts magnesium powder, 40 parts ethyl bromide, 40 parts p-methoxyphenyl bromide, 160 parts 2-methyltetrahydrofuran, 40 parts methyl tert-butyl ether, 1.8 parts N,N,N',N'-tetramethylethylenediamine, 1.0 part butylated hydroxytoluene, and 18 parts ethylene glycol dimethyl ether.

[0035] Preparation steps: Pretreatment of the reaction apparatus: completely consistent with Example 6; Magnesium source activation: completely consistent with Example 6; Grignard reaction: Ethyl bromide, p-methoxyphenyl bromide and ethylene glycol dimethyl ether were mixed evenly and placed in a constant pressure dropping funnel. Under nitrogen protection and segmented temperature control, the mixture was added dropwise. During the first 35 minutes of the addition, the temperature was controlled at 22°C, the stirring rate was 380 r / min, and the dropping rate was 1.5 mL / min. During the remaining time of the addition, the temperature was controlled at 32°C, the stirring rate was 320 r / min, and the dropping rate was 1.6 mL / min. After the addition was completed, the reaction was continued to be stirred at a constant temperature of 32°C for 2.0 hours. Stabilization process: Completely consistent with Example 6; Solvent recovery: Completely consistent with Example 6, with a recovery rate of 91.4%; Storage: exactly the same as in Example 6.

[0036] Example 9: The raw material proportions by weight are as follows: 14 parts magnesium powder, 80 parts chlorobenzene, 160 parts 2-methyltetrahydrofuran, 40 parts methyl tert-butyl ether, 1.8 parts N,N,N',N'-tetramethylethylenediamine, 1.0 part phenothiazine, and 18 parts ethylene glycol dimethyl ether.

[0037] Preparation steps: Pretreatment of the reaction apparatus: completely consistent with Example 6; Magnesium source activation: completely consistent with Example 6; Grignard reaction: completely consistent with Example 6; Stabilization treatment: N,N,N',N'-tetramethylethylenediamine and phenothiazine were added to the reaction system, stirred for 35 minutes at a stirring rate of 320 r / min, cooled to room temperature, and the unreacted magnesium powder was removed by filtration through a 0.22 μm organic filter membrane to obtain a highly efficient and stable Grignard preparation. Solvent recovery: Completely consistent with Example 6, with a recovery rate of 91.5%; Storage: exactly the same as in Example 6.

[0038] Comparative Example 1: Using traditional toxic solvents, without using stabilizers or co-solvents, and without ultrasonic activation of magnesium powder, compared with Example 1, this invention highlights the creative advantages of its green solvent, stabilizer system, and ultrasonic activation process. The raw material ratio by mass is: 10 parts magnesium powder, 85 parts bromobenzene, 200 parts tetrahydrofuran, with no stabilizers and no co-solvents.

[0039] Preparation steps: Pretreatment of the reaction apparatus: completely consistent with Example 1; Magnesium source treatment: Add magnesium powder and tetrahydrofuran to the pretreated reaction flask. Do not perform ultrasonic activation, just stir and disperse at a stirring rate of 300 r / min for 15 minutes. Grignard reaction: Bromobenzene was added dropwise directly to the reaction system, and the mixture was stirred at a constant temperature of 25°C at a dropping rate of 1.5 mL / min. The reaction was carried out for 2 hours after the addition was completed. Post-processing: After cooling to room temperature, unreacted magnesium powder was removed by filtration through a 0.22 μm organic filter membrane to obtain the conventional Grignard formulation; Solvent treatment: The solvent is not recovered and is discharged directly; Storage: exactly the same as in Example 1.

[0040] Comparative Example 2: This comparative example is a combination of a single green solvent and a single stabilizer, without employing the synergistic stabilizer system of this invention. Compared with Example 1, it highlights the inventive advantage of the synergistic stabilizer of this invention, verifies the synergistic effect on improving the stability of the formulation, and demonstrates that the synergistic stabilizer system of this invention is not a simple superposition of existing technologies, but has an unexpected stabilizing effect. The raw material ratio by mass is: 10 parts magnesium powder, 85 parts bromobenzene, 200 parts 2-methyltetrahydrofuran, with only 1.5 parts N,N,N',N'-tetramethylethylenediamine and 15 parts ethylene glycol dimethyl ether added.

[0041] Preparation steps: basically the same as in Example 1, except that butylated hydroxytoluene is not added, and other process parameters remain unchanged.

[0042] Comparative Example 3: This comparative example uses a traditional magnesium source treatment method and does not employ the ultrasonic activation process of this invention. Compared with Example 1, it highlights the role of ultrasonic activation in improving the activity, reaction efficiency, and formulation stability of magnesium powder. The raw material ratio by mass is completely consistent with Example 1, namely 10 parts magnesium powder, 85 parts bromobenzene, 200 parts 2-methyltetrahydrofuran, 1.5 parts N,N,N',N'-tetramethylethylenediamine, 0.8 parts butylated hydroxytoluene, and 15 parts ethylene glycol dimethyl ether.

[0043] Preparation steps: basically the same as in Example 1, except that ultrasonic activation is not performed. Instead, magnesium powder is briefly soaked in dilute hydrochloric acid, then quickly washed and vacuum dried. The concentration of dilute hydrochloric acid is 0.1 mol / L, the soaking time is 30 seconds, anhydrous ethanol is used for washing, the vacuum drying temperature is 80℃, and the drying time is 30 minutes. Other process parameters remain unchanged.

[0044] Comparative Example 4: This comparative example uses conventional flammable and toxic solvents from existing technologies, without employing the composite green solvent system of this invention, and does not perform solvent recovery. Compared with Example 4, it highlights the green advantages of the composite green solvent system and solvent recovery process of this invention. The raw material ratio by mass is: 10 parts magnesium powder, 85 parts bromobenzene, 200 parts diethyl ether, 1.5 parts N,N,N',N'-tetramethylethylenediamine, 0.8 parts butylated hydroxytoluene, and 15 parts ethylene glycol dimethyl ether.

[0045] Preparation steps: basically the same as in Example 1, except that 2-methyltetrahydrofuran is replaced with diethyl ether, and solvent recovery is not performed, while other process parameters remain unchanged.

[0046] Comparative Example 5: The amount of magnesium powder used in this comparative example exceeds the protection scope of this invention. Compared with Example 2, it verifies the rationality of the ratio range of magnesium source and halogenated hydrocarbon in this invention, highlighting the creativity and practicality of this invention in expanding the protection scope of the ratio. The raw material ratio by mass is: 5 parts magnesium powder, 95 parts bromobenzene, 200 parts 2-methyltetrahydrofuran, 1.5 parts N,N,N',N'-tetramethylethylenediamine, 0.8 parts butylated hydroxytoluene, and 15 parts ethylene glycol dimethyl ether.

[0047] Preparation steps: basically the same as in Example 1, with other process parameters remaining unchanged.

[0048] Comparative Example 6: This comparative example uses a conventional intermittent isothermal reaction with existing technology, without segmented temperature control. Compared with Example 5, it highlights the role of segmented temperature control in improving reaction efficiency, side reaction rate, and formulation purity, demonstrating the inventiveness of the process in this invention. The raw material ratio by mass is completely consistent with Example 5, namely 10 parts magnesium powder, 85 parts bromobenzene, 150 parts 2-methyltetrahydrofuran, 50 parts methyl tert-butyl ether, 1.5 parts N,N,N',N'-tetramethylethylenediamine, 0.8 parts butylated hydroxytoluene, and 20 parts ethylene glycol dimethyl ether.

[0049] Preparation steps: basically the same as in Example 5, except that segmented temperature control is not used, the temperature is maintained at 25°C throughout the process, the dropping rate is not adjusted, the dropping rate is kept at 1.5 mL / min, and other process parameters remain unchanged.

[0050] Comparative Example 7: This comparative example uses a single hindered phenolic stabilizer from the prior art, without employing the synergistic stabilizer system of the present invention. Compared with Example 9, it further highlights the inventive advantages of the synergistic stabilizer system of the present invention. The raw material ratio by mass is: 14 parts magnesium powder, 80 parts chlorobenzene, 160 parts 2-methyltetrahydrofuran, 40 parts methyl tert-butyl ether, with only 2.8 parts phenothiazine and 18 parts ethylene glycol dimethyl ether added.

[0051] Preparation steps: basically the same as in Example 9, except that N,N,N',N'-tetramethylethylenediamine is not added, and other process parameters remain unchanged.

[0052] The synergistic stabilizer used in this invention is a combination of an amine compound and a hindered phenolic compound. The amine compound is N,N,N',N'-tetramethylethylenediamine, and the hindered phenolic compound is butylated hydroxytoluene or phenothiazine. This combination system achieves a stabilizing effect through the synergistic effect of the two types of substances. The amine compound can complex magnesium ions to inhibit the hydrolysis of Grignard preparations, and the hindered phenolic compound can capture free radicals to inhibit the oxidation of the preparations. A single stabilizer cannot achieve this synergistic stabilizing effect.

[0053] The green composite solvent used in this invention is composed of 2-methyltetrahydrofuran and methyl tert-butyl ether. The ratio of this composite solvent is suitable for the dissolution requirements and reaction inertness requirements of the Grignard reaction, and at the same time, it is convenient to achieve the separate recovery and recycling of the two solvents through vacuum fractionation.

[0054] The Grignard reaction of this invention is carried out in a segmented temperature control manner. The reaction temperature and stirring rate are controlled at different stages of the addition of raw materials to match an appropriate dropping speed. After the addition is completed, the reaction is kept at a constant temperature. By precisely controlling the process, side reactions are suppressed, and the purity and reaction uniformity of the Grignard preparation are improved.

[0055] This invention employs ultrasonic activation treatment on the magnesium source, which physically removes the oxide layer on the surface of the magnesium source without the need for chemical acid washing, effectively enhancing the reactivity of the magnesium source and ensuring a stable start-up of the Grignard reaction.

[0056] The solvent recovery method of this invention adopts vacuum distillation or vacuum fractionation, with the vacuum degree being gauge pressure. The recovered solvent is dried by molecular sieve to reduce the water content and can be recycled multiple times, greatly reducing waste emissions.

[0057] Performance test results and analysis: Test items and test methods: (1) Stability test: The Grignard preparations prepared in each example and comparative example were sealed and stored at room temperature 25°C, low temperature 0°C and high temperature 40°C respectively. At 1 day, 3 days, 7 days, 15 days, 30 days, 60 days and 90 days of storage, the concentration of the preparation was detected by titration with menthol as titrant and color indicator added. The concentration retention rate was calculated. The concentration retention rate is equal to the concentration after storage divided by the initial concentration multiplied by 100%. The higher the concentration retention rate, the better the stability.

[0058] (2) Reactivity test: Take the same volume and concentration of each example and comparative Grignard preparation and carry out an addition reaction with an equimolar amount of benzaldehyde. The reaction conditions are the same: stir at 25°C under nitrogen protection for 2 hours. After the reaction is completed, the mixture is quenched, extracted, dried, concentrated and purified. The reaction yield is calculated by gas chromatography. The higher the yield, the better the reaction activity.

[0059] (3) Green index test: The solvent recovery rate during the preparation process of each example and comparative example is statistically analyzed. The solvent recovery rate is equal to the solvent recovery amount divided by the solvent input amount multiplied by 100%. The amount of wastewater generated for each kg of Grignard preparation is statistically analyzed. The higher the solvent recovery rate, the less wastewater is discharged, and the better the greenness.

[0060] (4) Purity test: Gas chromatography was used to detect the impurity content of the Grignard preparations of each example and the comparative example. The main impurities were unreacted halogenated hydrocarbons and by-reaction products. The lower the impurity content, the higher the purity.

[0061] (5) Storage period test: The Grignard preparations prepared in each example and comparative example were sealed and stored under inert gas protection at room temperature (25°C). The time it took for the concentration of the preparation to drop to 90% of the initial concentration was recorded. The longer the storage time, the better the stability.

[0062] The test results are shown in Table 1 below:

[0063] Based on the above test results, it can be seen that the highly efficient and stable Grignard formulations prepared in each embodiment of the present invention exhibit excellent performance in terms of stability, reactivity, green indicators, and purity, and are significantly superior to the comparative examples. Regarding stability, the concentration retention rate of each embodiment after 90 days of storage at room temperature (25°C) is no less than 89.5%, and the concentration retention rate after 30 days of storage at high temperature (40°C) is no less than 85.3%, with a storage period exceeding 110 days. The optimal solution in Example 6 achieves a storage period of up to 152 days, while the storage periods of the comparative examples range from a maximum of 118 days to a minimum of 45 days. In particular, the stability of Comparative Examples 2 and 7, which use a single stabilizer, and Comparative Example 3, which does not use ultrasonic activation, is significantly reduced. This fully demonstrates that the amine-hindered phenolic synergistic stabilizer system and ultrasonic activation process used in the present invention can effectively improve the hydrolysis resistance and antioxidant capacity of the Grignard formulation, and extend its storage period.

[0064] Regarding reactivity and purity, the reaction yields of all embodiments were no less than 89.2%, and the impurity content was no more than 1.1%. The optimal solution achieved a reaction yield of 95.0% and an impurity content as low as 0.4%. In contrast, Comparative Example 1 had a reaction yield of only 75.8% and an impurity content as high as 3.8%. Comparative Example 5 showed a significant decrease in both reaction yield and purity due to the magnesium powder usage exceeding the scope of protection of this invention. This indicates that the optimized raw material ratio and segmented temperature control process of this invention can effectively remove the oxide layer on the surface of the magnesium source, reduce the incidence of side reactions, and improve the purity and reaction efficiency of the formulation. Regarding green indicators, the solvent recovery rates of all embodiments were no less than 88.0%, with the optimal solution reaching 91.5%. The wastewater discharge per kg of Grignard formulation prepared was no more than 0.36 L. In contrast, Comparative Examples 1 and 4, which did not employ a solvent recovery process, had a solvent recovery rate of 0% and wastewater discharge exceeding 1.1 L / kg. This fully demonstrates the green and environmentally friendly advantages of the composite green solvent system and solvent recovery process of this invention, aligning with the trend of green chemical development.

[0065] Furthermore, Examples 7 to 9 expanded the types of magnesium source, halogenated hydrocarbon, and synergistic stabilizer, respectively. Their performance indicators were close to those of the optimal scheme in Example 6, indicating that the present invention has a wide range of raw material selection and strong process adaptability, and can adapt to different types of raw materials and production needs. However, in Comparative Example 5, the amount of magnesium powder exceeded the protection scope of the present invention, and all performance indicators showed a significant decline, further verifying the rationality of the protection scope of the raw material ratio of the present invention.

[0066] In summary, this invention effectively solves the problems of poor stability, serious pollution during preparation, low reaction efficiency, and narrow ratio range in existing technologies, and has outstanding substantive features and significant progress.

[0067] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention.

Claims

1. A highly efficient and stable Grignard preparation, characterized in that, The product comprises, by weight, 8-18 parts magnesium source, 40-92 parts halogenated hydrocarbon, 150-200 parts green solvent, 15-20 parts ethylene glycol dimethyl ether, and 2.3-3.2 parts synergistic stabilizer; the green solvent is 2-methyltetrahydrofuran, or a composite solvent with a weight ratio of 2-methyltetrahydrofuran:methyl tert-butyl ether of 150-160:40-50; the synergistic stabilizer is composed of 1.5-2.0 parts N,N,N',N'-tetramethylethylenediamine and 0.8-1.2 parts butylated hydroxytoluene, or composed of 1.5-2.0 parts N,N,N',N'-tetramethylethylenediamine and 1.0 part phenothiazine.

2. The highly efficient and stable Grignard preparation according to claim 1, characterized in that, The magnesium source is one or more of magnesium powder, magnesium shavings, and magnesium strips; the halogenated hydrocarbon is one or more of bromobenzene, chlorobenzene, ethyl bromide, and p-methoxyphenyl bromide.

3. A green preparation method for the highly efficient and stable Grignard preparation according to claim 1 or 2, characterized in that, The process includes the following steps in sequence: pretreatment of the reaction apparatus, activation of the magnesium source, Grignard reaction, stabilization treatment, and solvent recovery. The stabilization treatment involves adding a synergistic stabilizer to the reaction system and stirring for 30-35 minutes. Each raw material is added in the weight ratio described in claim 1.

4. The green preparation method according to claim 3, characterized in that, The pretreatment of the reaction apparatus is as follows: the experimental instruments are dried at 110℃, assembled while hot, and then purged with nitrogen or argon for 5-6 minutes at a gas flow rate of 15 mL / min. After cooling, inert gas protection is maintained.

5. The green preparation method according to claim 3, characterized in that, The magnesium source is activated by ultrasonic treatment with an ultrasonic power of 200W-280W, an activation time of 12-20 minutes, and an activation temperature of 25℃-28℃.

6. The green preparation method according to claim 3, characterized in that, The Grignard reaction is carried out under an inert gas atmosphere, using either an isothermal reaction or a segmented temperature-controlled reaction. The haloalkane and ethylene glycol dimethyl ether are mixed and added dropwise. The segmented temperature-controlled reaction is as follows: for the first 30-35 minutes of the initial addition, the temperature is controlled at 20-22°C, with a stirring rate of 350-380 r / min and a dropping rate of 1.0-1.5 mL / min; in the later stage of the addition, the temperature is controlled at 30-32°C, with a stirring rate of 300-320 r / min and a dropping rate of 1.6-1.8 mL / min; after the addition is complete, the reaction is maintained at 30-32°C for 1.5-2.0 hours, with temperature fluctuations controlled within ±1°C.

7. The green preparation method according to claim 3, characterized in that, After stabilization, unreacted magnesium sources are removed by filtration through a 0.22 μm organic filter membrane.

8. The green preparation method according to claim 3, characterized in that, The solvent recovery is carried out by vacuum distillation or vacuum fractionation, with a gauge pressure of 0.09MPa-0.095MPa and a distillation temperature of 90℃-98℃; the recovered solvent is dried by molecular sieve and then recycled.

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