4-bma mother liquor membrane separation enrichment and low-temperature crystallization purification process

Abstract

This invention relates to the field of chemical separation and purification technology, and discloses a membrane separation, enrichment, and low-temperature crystallization purification process for 4-BMA mother liquor. The process includes mother liquor pretreatment and pH adjustment, primary nanofiltration membrane enrichment and isomer separation, secondary ultrafiltration membrane impurity removal, acid adjustment and conversion, gradient low-temperature crystallization, solid-liquid separation, and drying to obtain high-purity 4-BMA. By sequentially employing a combination separation process of ceramic microfiltration membrane, primary nanofiltration membrane, and secondary ultrafiltration membrane, impurities can be effectively removed, significantly improving the purity of 4-BMA. The use of a composite amine regulator successfully reduces isomer residue in the finished product. The use of a three-stage gradient programmed cooling to induce crystallization significantly reduces the encapsulation and residue of high-molecular impurities. This process solves the problems of low recovery rate of 4-BMA crystallization mother liquor and the difficulty in simultaneously removing isomers and high-molecular impurities.

Description

Technical Field

[0001] This invention relates to the field of chemical separation and purification technology, specifically a membrane separation, enrichment, and low-temperature crystallization purification process for 4-BMA mother liquor. Background Technology

[0002] Carbapenem antibiotics (i.e., penems) are a novel class of β-lactam antibiotics, known for their broad antibacterial spectrum and strong antibacterial activity. The key intermediate used in the synthesis of penem drugs is β-methylazazole-2-one (4-BMA). However, in the current industrial production and purification process of 4-BMA, conventional processes generally suffer from problems such as simple purification procedures, incomplete impurity removal, and low product recovery rates.

[0003] Traditional purification methods often employ simple filtration or crystallization, which are ineffective at separating structurally similar isomers, making it difficult to effectively separate them from the target product and resulting in high levels of isomer residues in the product. Furthermore, conventional crystallization methods involve rapid cooling, which can lead to problems such as explosive nucleation and crystal inclusion, trapping residual impurities from the mother liquor within the crystals and affecting the purity and appearance of the final product. In the conditioning and refining stages, traditional processes often use a single alkaline regulator, which has limited ability to adjust the system's pH and material state, failing to achieve precise separation of isomers from the target product. This results in some isomers precipitating along with the product, further reducing product purity and yield. In addition, existing processes have low recycling rates for the crystallization mother liquor, with most of it being directly discharged, causing raw material waste and increasing environmental pollution control pressures, which does not meet the current requirements for green, low-carbon, and efficient industrial production.

[0004] Therefore, in order to address the shortcomings of existing technologies, developing a purification process that offers good separation performance, high product purity, stable yield, and is environmentally friendly is of great significance for improving the quality and economic efficiency of 4-BMA products. Summary of the Invention

[0005] In order to overcome the shortcomings of the prior art, the present invention aims to provide a membrane separation enrichment and low-temperature crystallization purification process for 4-BMA mother liquor. This process can solve the problems of low recovery rate of 4-BMA crystallization mother liquor and difficulty in simultaneously removing isomers and high molecular weight impurities.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a process for membrane separation enrichment and low-temperature crystallization purification of 4-BMA mother liquor, comprising the following steps: S1. Pretreatment of mother liquor and pH adjustment: Take the 4-BMA crystallization mother liquor, remove mechanical impurities and colloidal particles through a 0.1~0.5μm ceramic microfiltration membrane, then add a compound amine regulator to the filtrate to adjust the pH of the system to 7.5~8.5, stir at 20~25℃ for 30~35min to selectively form ammonium salts from 4-BMA, and obtain the pretreated solution; S2. Enrichment and isomer separation by primary nanofiltration membrane: The pretreated solution is pumped into a primary nanofiltration membrane module with a molecular weight cutoff of 200~250 Da for cross-flow filtration. Small molecule solvents and unsalted free isomers permeate through the membrane, while 4-BMA ammonium salt is retained and concentrated to obtain primary concentrate. S3. Secondary ultrafiltration membrane impurity removal: The primary concentrate is pumped into a secondary ultrafiltration membrane module with a molecular weight cutoff of 800~1000 Da to remove high molecular weight polymer impurities. The permeate is a 4-BMA ammonium salt enriched solution. S4. Acidification and Conversion: Slowly add inorganic acid to the 4-BMA ammonium salt enrichment solution to adjust the pH to 2-3, and stir at 20-30℃ for 10-30 min to completely convert the 4-BMA ammonium salt into 4-BMA free acid to obtain the acidified solution. S5. Gradient low-temperature crystallization: A composite crystallization solvent is added to the acidification solution, and crystallization is induced by a three-stage gradient programmed cooling. The final crystallization temperature is controlled at -5℃ to -2℃ to obtain a crystal slurry. S6. Solid-liquid separation and drying: The crystal slurry is separated, washed, and vacuum dried to obtain a high-purity 4-BMA product; In step S1, the compound amine modifier is composed of triethylamine and diisopropylamine, with a mass ratio of 1:0.3 to 1:0.5. In step S5, the composite crystallization solvent is a mixture of purified water and isopropanol.

[0007] Further, in step S1, the 4-BMA crystallization mother liquor is the mother liquor produced after the industrial production of 4-BMA, and its conventional component range is: 10%~20% effective 4-BMA content, 3%~6% isomer content, 2%~5% high molecular weight polymer impurities, and the remainder is an organic solvent, which is one or a mixture of ethyl acetate, dichloromethane, and isopropanol.

[0008] Furthermore, in step S2, the primary nanofiltration membrane is a polyamide-polytetrafluoroethylene composite membrane with an operating pressure of 1.2~1.8MPa, an operating temperature of 22~28℃, and a crossflow velocity of 1.2~1.5m / s; the mass concentration of 4-BMA ammonium salt in the primary concentrate is controlled at 35%~42%.

[0009] Furthermore, in step S3, the operating pressure of the secondary ultrafiltration membrane is 0.6~1.0MPa, and the operating temperature is 30~35℃.

[0010] In the above steps, by appropriately increasing the system temperature to 30~35℃, the fluid viscosity of the primary concentrate can be effectively reduced, and the high concentration of 4-BMA ammonium salt can be prevented from undergoing concentration polarization inside the membrane module, causing premature precipitation and blockage of the membrane pores, thereby efficiently retaining polymer impurities.

[0011] Furthermore, in step S5, the volume ratio of purified water to isopropanol is 1:0.4 to 1:0.6.

[0012] Furthermore, in step S5, the three-stage gradient programmed cooling specifically includes: The first step involves cooling the temperature from 35℃ to 20℃ at a rate of 0.8~1.0℃ / h, while adding 0.2%~0.3% of pure 4-BMA as seed crystals during the cooling process. The second stage: the temperature drops from 20℃ to 8℃ at a rate of 0.3~0.5℃ / h; The third stage involves cooling the temperature from 8℃ to the final crystallization temperature of -5℃ to -2℃ at a rate of 0.1℃ to 0.2℃ / h, and then maintaining the temperature at the final crystallization temperature for 120 to 150 minutes to grow crystals.

[0013] Furthermore, in step S6, the washing process uses an isopropanol-water mixture pre-cooled to -5°C to 0°C, wherein the volume ratio of isopropanol to water is 1:1.

[0014] Furthermore, in step S6, the vacuum drying temperature is 35~40℃.

[0015] Compared with the prior art, the present invention has the following beneficial technical effects: This invention employs a combined separation process using ceramic microfiltration membranes, primary nanofiltration membranes, and secondary ultrafiltration membranes. This effectively removes mechanical impurities, colloidal particles, incompletely salted free isomers, and high-molecular-weight polymer impurities, significantly improving the purity of 4-BMA. In the pretreatment stage, a composite amine regulator is used, utilizing the alkalinity difference between triethylamine and diisopropylamine to construct a suitable pH buffer system. Simultaneously, the larger spatial configuration of diisopropylamine increases the solubility of the isomer ammonium salt in the solvent, overcoming the defect of single-amine regulation where rapid salt formation leads to the retention and precipitation of a large number of isomers along with 4-BMA by the membrane. This significantly reduces the isomer content of the final product. The process effectively eliminates residual polymer impurities. A three-stage gradient programmed cooling method is employed to induce crystallization, with seed crystals added during the cooling process. The cooling rate is gradually reduced to prevent explosive nucleation and crystal encapsulation, significantly decreasing the encapsulation and residue of polymeric impurities. Washing is performed using an isopropanol-water mixture pre-cooled to -5℃ to 0℃, balancing washing effectiveness with product dissolution loss and avoiding secondary dissolution due to improper washing solution ratios. The 4-BMA crystallization mother liquor, traditionally discarded in the process, is recycled, achieving a dual improvement in product recovery rate and purity. This significantly reduces raw material consumption and waste treatment costs, demonstrating significant economic and environmental benefits. Detailed Implementation

[0016] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some embodiments of the present invention, 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.

[0017] The reagents used in the following specific embodiments are of analytical grade. Additionally: The nanofiltration membrane used is a commercially available solvent-resistant polyamide-polytetrafluoroethylene composite membrane.

[0018] Example 1

[0019] A process for membrane separation enrichment and low-temperature crystallization purification of 4-BMA mother liquor, comprising the following steps: S1. Mother liquor pretreatment and pH adjustment: Take 100L of 4-BMA crystallization mother liquor (after sampling and weighing, the total mass of this batch of mother liquor is about 92.0kg, of which the effective content of 4-BMA is 12.5%, the content of isomers is 4.2%, and the content of high molecular weight polymer impurities is 2.8%), remove mechanical impurities and colloidal particles through a 0.1μm ceramic microfiltration membrane, and then add a compound amine regulator (the mass ratio of triethylamine to diisopropylamine is 1:0.3) to the filtrate to adjust the pH of the system to 7.5. Stir at 20℃ for 30min to selectively form ammonium salts from 4-BMA to obtain the pretreated solution; S2. Primary Nanofiltration Membrane Enrichment and Isomer Separation: The pretreated solution is pumped into a primary nanofiltration membrane module with a molecular weight cutoff of 200 Da. The nanofiltration membrane material used is a polyamide-polytetrafluoroethylene composite membrane. The operating pressure is controlled at 1.2 MPa, the operating temperature at 22℃, and the cross-flow velocity at 1.2 m / s for cross-flow filtration. Small molecule solvents and unsalted free isomers permeate through the membrane layer, while 4-BMA ammonium salt is retained and concentrated. During the filtration process, the volume of the permeate is collected and measured in real time for material balance calculation. When the predetermined target is reached, filtration is stopped to obtain a primary concentrate. The mass concentration of 4-BMA ammonium salt in the concentrate is controlled at 35%. S3. Secondary ultrafiltration membrane impurity removal: The primary concentrate is pumped into a secondary ultrafiltration membrane module with a molecular weight cutoff of 800 Da. The operating pressure is controlled at 0.6 MPa and the operating temperature at 30°C. High molecular weight polymer impurities are removed, and the permeate is collected, which is the 4-BMA ammonium salt enriched solution. S4. Acidification and Conversion: Slowly add hydrochloric acid with a molar concentration of 1 mol / L to the 4-BMA ammonium salt enrichment solution to adjust the pH to 2. Stir at 20℃ for 10 min to completely convert the 4-BMA ammonium salt into 4-BMA free acid and obtain the acidified solution. S5. Gradient Low-Temperature Crystallization: Add a composite crystallization solvent (purified water to isopropanol volume ratio of 1:0.4) to the acidified solution, mix thoroughly, and then start the three-stage gradient programmed cooling: The first step: the temperature was lowered from 35℃ to 20℃ at a rate of 0.8℃ / h, and pure 4-BMA, accounting for 0.2% of the mass of 4-BMA in the system, was added as seed crystals during the cooling process. The second phase: the temperature drops from 20℃ to 8℃ at a rate of 0.3℃ / h; The third step involves cooling the temperature from 8°C to -5°C at a rate of 0.1°C / h, and then maintaining the temperature at the final crystallization temperature for 120 minutes to obtain a crystal slurry. S6. Solid-liquid separation and drying: The crystal slurry is separated, and the crystal cake is washed twice with an isopropanol-water mixture pre-cooled to -5℃ (the volume ratio of isopropanol to water is 1:1). Finally, it is vacuum dried at 35℃ to obtain a high-purity 4-BMA product.

[0020] Example 2

[0021] A process for membrane separation enrichment and low-temperature crystallization purification of 4-BMA mother liquor, comprising the following steps: S1. Pretreatment of Mother Liquor and pH Adjustment: Take 100L of 4-BMA crystallization mother liquor (after sampling and weighing, the total mass of this batch of mother liquor is approximately 90.5kg, of which the effective content of 4-BMA is 10.8%, the content of isomers is 3.5%, and the content of high molecular weight polymer impurities is 2.2%), remove mechanical impurities and colloidal particles through a 0.5μm ceramic microfiltration membrane, and then add a compound amine regulator (the mass ratio of triethylamine to diisopropylamine is 1:0.5) to the filtrate to adjust the pH of the system to 8.5. Stir at 25℃ for 35min to selectively form ammonium salts from 4-BMA to obtain the pretreated solution; S2. Primary Nanofiltration Membrane Enrichment and Isomer Separation: The pretreated solution is pumped into a primary nanofiltration membrane module with a molecular weight cutoff of 250 Da. The nanofiltration membrane material used is a polyamide-polytetrafluoroethylene composite membrane. The operating pressure is controlled at 1.8 MPa, the operating temperature at 28 °C, and the cross-flow velocity at 1.5 m / s for cross-flow filtration. Small molecule solvents and unsalted free isomers permeate through the membrane layer, while 4-BMA ammonium salt is retained and concentrated. During the filtration process, the volume of the permeate is collected and measured in real time for material balance. When the predetermined target is reached, filtration is stopped to obtain a primary concentrate. The mass concentration of 4-BMA ammonium salt in the concentrate is controlled at 42%. S3. Secondary ultrafiltration membrane impurity removal: The primary concentrate is pumped into a secondary ultrafiltration membrane module with a molecular weight cutoff of 1000 Da. The operating pressure is controlled at 1.0 MPa and the operating temperature at 35°C. High molecular weight polymer impurities are removed, and the permeate is collected, which is the 4-BMA ammonium salt enriched solution. S4. Acidification and Conversion: Slowly add 1 mol / L hydrochloric acid to the 4-BMA ammonium salt enrichment solution to adjust the pH to 3. Stir at 30℃ for 30 min to completely convert the 4-BMA ammonium salt into 4-BMA free acid and obtain the acidified solution. S5. Gradient Low-Temperature Crystallization: Add a composite crystallization solvent (purified water to isopropanol volume ratio of 1:0.6) to the acidified solution, mix thoroughly, and then start the three-stage gradient programmed cooling: The first step: the temperature was lowered from 35℃ to 20℃ at a rate of 1.0℃ / h, and pure 4-BMA, accounting for 0.3% of the mass of 4-BMA in the system, was added as a seed crystal during the cooling process. The second phase: the temperature drops from 20℃ to 8℃ at a rate of 0.5℃ / h; The third step involves cooling the temperature from 8℃ to the final crystallization temperature of -2℃ at a rate of 0.2℃ / h, and then maintaining the temperature at the final crystallization temperature for 150 minutes to obtain a crystal slurry. S6. Solid-liquid separation and drying: The crystal slurry is separated, and the crystal cake is washed three times with an isopropanol-water mixture pre-cooled to 0°C (the volume ratio of isopropanol to water is 1:1). Finally, it is vacuum dried at 40°C to obtain a high-purity 4-BMA product.

[0022] Example 3

[0023] A process for membrane separation enrichment and low-temperature crystallization purification of 4-BMA mother liquor, comprising the following steps: S1. Mother liquor pretreatment and pH adjustment: Take 100L of 4-BMA crystallization mother liquor (after sampling and weighing, the total mass of this batch of mother liquor is about 94.0kg, of which the effective content of 4-BMA is 15.5%, the content of isomers is 5.2%, and the content of high molecular weight polymer impurities is 3.7%), remove mechanical impurities and colloidal particles through a 0.3μm ceramic microfiltration membrane, and then add a compound amine regulator (the mass ratio of triethylamine to diisopropylamine is 1:0.35) to the filtrate to adjust the pH of the system to 8.0. Stir at 21℃ for 34min to selectively form ammonium salts from 4-BMA to obtain the pretreated solution; S2. Primary Nanofiltration Membrane Enrichment and Isomer Separation: The pretreated solution is pumped into a primary nanofiltration membrane module with a molecular weight cutoff of 200 Da. The nanofiltration membrane material used is a polyamide-polytetrafluoroethylene composite membrane. The operating pressure is controlled at 1.5 MPa, the operating temperature at 25 °C, and the cross-flow velocity at 1.3 m / s for cross-flow filtration. Small molecule solvents and unsalted free isomers permeate through the membrane layer, while 4-BMA ammonium salt is retained and concentrated. During the filtration process, the volume of the permeate is collected and measured in real time for material balance calculation. When the predetermined target is reached, filtration is stopped to obtain a primary concentrate. The mass concentration of 4-BMA ammonium salt in the concentrate is controlled at 40%. S3. Secondary ultrafiltration membrane impurity removal: The primary concentrate is pumped into a secondary ultrafiltration membrane module with a molecular weight cutoff of 900 Da. The operating pressure is controlled at 0.8 MPa and the operating temperature at 32 °C. High molecular weight polymer impurities are removed, and the permeate is collected, which is the 4-BMA ammonium salt enriched solution. S4. Acidification and Conversion: Slowly add hydrochloric acid with a molar concentration of 1 mol / L to the 4-BMA ammonium salt enrichment solution to adjust the pH to 2. Stir at 25℃ for 20 min to completely convert the 4-BMA ammonium salt into 4-BMA free acid and obtain the acidified solution. S5. Gradient Low-Temperature Crystallization: Add a composite crystallization solvent (purified water to isopropanol volume ratio of 1:0.5) to the acidified solution, mix thoroughly, and then start the three-stage gradient programmed cooling: The first step: the temperature was lowered from 35℃ to 20℃ at a rate of 0.9℃ / h, and pure 4-BMA, accounting for 0.2% of the mass of 4-BMA in the system, was added as a seed crystal during the cooling process. The second phase: the temperature drops from 20℃ to 8℃ at a rate of 0.4℃ / h; The third step involves cooling the temperature from 8°C to the final crystallization temperature of -4°C at a rate of 0.1°C / h, and then maintaining the temperature at the final crystallization temperature for 130 minutes to obtain a crystal slurry. S6. Solid-liquid separation and drying: The crystal slurry is separated, and the crystal cake is washed three times with an isopropanol-water mixture pre-cooled to -2℃ (the volume ratio of isopropanol to water is 1:1). Finally, it is vacuum dried at 40℃ to obtain a high-purity 4-BMA product.

[0024] Comparative Example 1 The main difference between this comparative example and Example 3 is that in step S1, the combined amine regulator of triethylamine and diisopropylamine was not used. Instead, only triethylamine was added to adjust the pH of the system to 8.0. The remaining steps and parameters are consistent with those of Example 3.

[0025] Comparative Example 2 The main difference between this comparative example and Example 3 is that in step S2, the molecular weight cutoff of the primary nanofiltration membrane module is replaced by a conventional 300 Da instead of 200 Da. All other steps and parameters are the same as in Example 3.

[0026] Comparative Example 3 The main difference between this comparative example and Example 3 is that in step S4, the three-stage gradient programmed cooling to induce crystallization was not used. Instead, the uniformly mixed system was directly cooled from 35°C to the final crystallization temperature of -3°C at a relatively fast and constant cooling rate of 2.5°C / h and crystals were grown. The remaining steps and parameters were consistent with those of Example 3.

[0027] Comparative Example 4 The main difference between this comparative example and Example 3 is that in step S5, the volume ratio of isopropanol to water in the isopropanol-water mixture used for washing is changed from 1:1 to 2:1. All other steps and parameters are the same as in Example 3.

[0028] Performance testing The 4-BMA products obtained in Examples 1-3 and Comparative Examples 1-4 were analyzed for purity, isomers, and high molecular weight impurities using high-performance liquid chromatography (HPLC, external standard method). Specific chromatographic conditions were as follows: a column packed with octadecylsilane-bonded silica gel (250 mm length, 4.6 mm inner diameter, 5 μm particle size) was used; gradient elution was performed using 0.05 mol / L potassium dihydrogen phosphate buffer (adjusted to pH 3.0 with phosphoric acid) as mobile phase A and acetonitrile as mobile phase B; the detection wavelength was 220 nm; the flow rate was 1.0 mL / min; and the column temperature was 30 °C. Under these conditions, baseline separation of 4-BMA and its isomers was effectively achieved. Water content was determined using the Karl Fischer method, residual solvent was determined using gas chromatography, and other unknown impurities were calculated using the HPLC area normalization method. The total recovery rate of 4-BMA in a single-step crystallization process was then calculated based on the detection results. The test results are shown in Table 1.

[0029] Table 1: Performance Tests

[0030] As can be seen from Table 1, the purity of the 4-BMA products obtained in Examples 1-3 is all above 99.7%, the isomer residue is all below 0.2%, no polymeric impurities are detected, and the total recovery rate is consistently above 91%. This indicates that the process of the present invention has strong stability and excellent purification effect, and can meet the quality requirements of high-end pharmaceutical intermediates.

[0031] The comparison shows that in Comparative Example 1, only triethylamine was added in step S1 to adjust the pH of the system to 8.0. The system constructed using triethylamine alone had insufficient buffering capacity, which easily led to the co-precipitation of isomers. As a result, a large number of isomers were retained and precipitated along with 4-BMA by the membrane, and the residual isomers in the finished product were significantly increased. In Comparative Example 2, in step S2, the molecular weight cutoff of the primary nanofiltration membrane module was replaced from 200 Da to the conventional 300 Da. Due to the larger pore size, the 4-BMA ammonium salt retention rate decreased, product leakage was serious, and the total recovery rate was significantly reduced. In Comparative Example 3, in step S4, the three-stage gradient programmed cooling was not used to induce condensation. Instead of directly cooling the homogenized system to a rapid and constant cooling rate of 2.5℃ / h, from 35℃ to the final crystallization temperature of -3℃, the system was allowed to grow crystals. This rapid cooling caused explosive nucleation and crystal encapsulation, which not only significantly reduced the purity but also encapsulated a large number of high molecular weight impurities. In Comparative Example 4, in step S5, the volume ratio of isopropanol to water in the isopropanol-water mixture used for washing was changed from 1:1 to 2:1, increasing the proportion of isopropanol in the washing solution. Since free 4-BMA crystals have significant solubility in isopropanol, the high alcohol ratio caused severe secondary dissolution of the crystal cake during washing, resulting in a decrease in the overall recovery rate.

[0032] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0033] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

[0034] Those skilled in the art should understand that the above descriptions are merely several specific embodiments of the present invention, and not all embodiments.

Claims

1. A process for membrane separation, enrichment, and low-temperature crystallization purification of 4-BMA mother liquor, characterized in that, Includes the following steps: S1. Pretreatment of mother liquor and pH adjustment: Take the 4-BMA crystallization mother liquor, remove mechanical impurities and colloidal particles through a 0.1~0.5μm ceramic microfiltration membrane, then add a compound amine regulator to the filtrate to adjust the pH of the system to 7.5~8.5, stir at 20~25℃ for 30~35min to selectively form ammonium salts from 4-BMA, and obtain the pretreated solution; S2. Enrichment and isomer separation by primary nanofiltration membrane: The pretreated solution is pumped into a primary nanofiltration membrane module with a molecular weight cutoff of 200~250 Da for cross-flow filtration. Small molecule solvents and unsalted free isomers permeate through the membrane, while 4-BMA ammonium salt is retained and concentrated to obtain primary concentrate. S3. Secondary ultrafiltration membrane impurity removal: The primary concentrate is pumped into a secondary ultrafiltration membrane module with a molecular weight cutoff of 800~1000 Da to remove high molecular weight polymer impurities. The permeate is a 4-BMA ammonium salt enriched solution. S4. Acidification and Conversion: Slowly add inorganic acid to the 4-BMA ammonium salt enrichment solution to adjust the pH to 2-3, and stir at 20-30℃ for 10-30 min to completely convert the 4-BMA ammonium salt into 4-BMA free acid to obtain the acidified solution. S5. Gradient low-temperature crystallization: A composite crystallization solvent is added to the acidification solution, and crystallization is induced by a three-stage gradient programmed cooling. The final crystallization temperature is controlled at -5℃ to -2℃ to obtain a crystal slurry. S6. Solid-liquid separation and drying: The crystal slurry is separated, washed, and vacuum dried to obtain a high-purity 4-BMA product; In step S1, the compound amine modifier is composed of triethylamine and diisopropylamine, with a mass ratio of 1:0.3 to 1:0.

5. In step S5, the composite crystallization solvent is a mixture of purified water and isopropanol.

2. The 4-BMA mother liquor membrane separation enrichment and low-temperature crystallization purification process according to claim 1, characterized in that, In step S1, the 4-BMA crystallization mother liquor is the mother liquor produced after the industrial production of 4-BMA. Its conventional component range is: 10%~20% effective 4-BMA content, 3%~6% isomer content, 2%~5% high molecular weight polymer impurities, and the remainder is an organic solvent, which is one or a mixture of ethyl acetate, dichloromethane, and isopropanol.

3. The 4-BMA mother liquor membrane separation enrichment and low-temperature crystallization purification process according to claim 1, characterized in that, In step S2, the primary nanofiltration membrane is a polyamide-polytetrafluoroethylene composite membrane with an operating pressure of 1.2~1.8MPa, an operating temperature of 22~28℃, and a crossflow velocity of 1.2~1.5m / s; the mass concentration of 4-BMA ammonium salt in the primary concentrate is controlled at 35%~42%.

4. The 4-BMA mother liquor membrane separation enrichment and low-temperature crystallization purification process according to claim 1, characterized in that, In step S3, the operating pressure of the secondary ultrafiltration membrane is 0.6~1.0MPa, and the operating temperature is 30~35℃.

5. The 4-BMA mother liquor membrane separation enrichment and low-temperature crystallization purification process according to claim 1, characterized in that, In step S5, the volume ratio of purified water to isopropanol is 1:0.4 to 1:0.

6.

6. The 4-BMA mother liquor membrane separation enrichment and low-temperature crystallization purification process according to claim 1, characterized in that, In step S5, the three-stage gradient programmed cooling specifically includes: The first step involves cooling the temperature from 35℃ to 20℃ at a rate of 0.8~1.0℃ / h, while adding 0.2%~0.3% of pure 4-BMA as seed crystals during the cooling process. The second stage: the temperature drops from 20℃ to 8℃ at a rate of 0.3~0.5℃ / h; The third stage involves cooling the temperature from 8℃ to the final crystallization temperature of -5℃ to -2℃ at a rate of 0.1℃ to 0.2℃ / h, and then maintaining the temperature at the final crystallization temperature for 120 to 150 minutes to grow crystals.

7. The 4-BMA mother liquor membrane separation enrichment and low-temperature crystallization purification process according to claim 1, characterized in that, In step S6, the washing process uses an isopropanol-water mixture pre-cooled to -5℃~0℃, wherein the volume ratio of isopropanol to water is 1:

1.

8. The 4-BMA mother liquor membrane separation enrichment and low-temperature crystallization purification process according to claim 1, characterized in that, In step S6, the vacuum drying temperature is 35~40℃.

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